Abstract The expression patterns of microRNAs (small non-coding RNAs) are altered in many biological processes such as myogenesis. In this study, we aimed to investigate the impact of predicted miR-202, its target genes Akt2 and Rock-1 as a potential regulator of myoblast in the myocyte differentiation process using the C2C12 cell line. After confirmation of the differentiation process induced by 3% horse serum, the expression level of miRNA and its targets were evaluated. In the following, a luciferase assay was conducted to approve the effect of miRNA on its target. Our results indicated that miR-202 and Akt2 were significantly up-regulated during differentiation, while Rock-1 was downregulated. Co-transfection of miRNA with psiCHECK2-Rock-1 significantly presented that Rock-1 was directly targeted by miR-202. On the contrary, miR-202 has failed to enforce its inhibitory effect on Akt2 expression. In particular, miR-202 seems to be a regulator of muscle differentiation pathway thought targeting Rock-1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus, is responsible for coronavirus disease 2019 (COVID-19) pandemic of 2020. Experimental evidence suggests that microRNA can mediate an intracellular defence mechanism against some RNA viruses. The purpose of this study was to identify microRNA with predicted binding sites in the SARS-CoV-2 genome, compare these to their microRNA expression profiles in lung epithelial tissue and make inference towards possible roles for microRNA in mitigating coronavirus infection. We hypothesize that high expression of specific coronavirus-targeting microRNA in lung epithelia may protect against infection and viral propagation, conversely low expression may confer susceptibility to infection. We have identified 128 human microRNA with potential to target the SARS-CoV-2 genome, most of which have very low expression in lung epithelia. Six of these 128 microRNA are differentially expressed upon in vitro infection of SARS-CoV-2. Twenty-eight and 23 microRNA also target the SARS-CoV and MERS-CoV, respectively. In addition, 48 and 32 microRNA are commonly identified in two other studies. Further research into identifying bona fide coronavirus targeting microRNA will be useful in understanding the importance of microRNA as cellular defence mechanism against pathogenic coronavirus infections.

Sugarcane mosaic virus (SCMV) is a deleterious pathogen which causes widespread Sugarcane mosaic disease (SCMD) and is classified in the genus Potyvirus (Potyviridae), disseminated by the aphid vector. RNA interference (RNAi)-mediated antiviral innate immunity is a key biological process and antiviral defence system to interfere with viral genomes for controlling plant pathogens. The current study aims to analyze sugarcane (Saccharum officinarum L. and Saccharum spp.) locus-derived microRNAs (sof-miRNAs/ssp-miRNAs) with predicted potential for targeting the SCMV +ssRNA-encoded mRNAs, using ‘five algorithms’ approach. The ultimate goal in this research is to mobilize the in silico endogenous predicted sof-miRNAs/ssp-miRNAs to trigger RNAi catalytic pathway experimentally and generate sugarcane cultivars for evaluating potential antiviral resistance monitoring capability and capacity for SCMV. Experimentally validated mature sugarcane (S. officinarum, 2n = 8X = 80) and (S. spp., 2n = 100-120) sof-miRNAs/ssp-miRNAs (n = 28) were acquired for alignment with the SCMV genome. Of the 28 targeting mature locus-derived sof-miRNAs/ssp-miRNAs investigated, one sugarcane miRNA homolog, sof-miR159c, was concluded to localize potential binding site at genomic nucleotide site 3847 targeting CI ORF of SCMV. In order to validate target prediction accuracy, whether the sugarcane sof-miRNA/ssp-miRNA might bind predicted SCMV mRNA target(s), we created an integrated Circos plot. Genome-wide in-silico-predicted miRNA-mediated target gene regulatory network validated interactions that warrant in vivo analysis. The current work provides valuable evidence and biological material for generating SCMV-resistant sugarcane varieties.

MicroRNA (miRNA) is a typical class of small RNAs that could modulate gene expression in trans at the post-transcriptional level. miRNAs bind to the miRNA binding sites (MBSs) in target mRNAs by sequence complementarity. Alternative splicing (AS) is another commonly occurred process in pre-mRNAs that changes the isoforms of a gene. It is hypothesized that there should be an interaction for gene regulation that involves both AS and miRNA targeting. Studies have verified this hypothesis in the model organism Arabidopsis thaliana. High-throughput sequencing data suggested that in Arabidopsis a considerably large fraction of MBSs are affected by AS events. The overlapping between MBS and AS exceeds the randomly simulated number. Functional experiments have indicated that the AS events are required for the gene expression changes of miRNA targets. Therefore, AS and MBS are mutually favored. The observed expression changes caused by miRNAs could also be contributed by AS events. In the present perspective article, we propose that the AS analysis should be incorporated in the differential-expression analysis of miRNA studies. When defining a differentially-expressed gene, it should be clarified whether the change in gene expression is caused by AS events or solely by miRNA targeting.

Apple chlorotic leaf spot virus (ACLSV) is a widespread, deleterious and the most damaging pathogen of fruit tree plants including domesticated apple (Malus domestica) ―a great threat to apple production worldwide. The positive-sense single-stranded RNA genome of ACLSV (7.5 Kbp) encodes three proteins: RNA polymerase (Rep), movement protein (MP) and coat protein (CP). RNA interference (RNAi)-mediated antiviral innate immunity is a key sequence-specific biological phenomenon in eukaryotes to control plant viruses. The aim of this study was to analyze apple (M.domestica) locus-derived microRNAs (mdm-miRNAs) with predicted potential for targeting the ACLSV +ssRNA-encoded mRNAs, using ‘four algorithms’ approach. The ultimate goal in this research is to mobilize the in silico endogenous predicted mdm-miRNAs to trigger RNAi catalytic pathway experimentally and generate apple tree varieties for evaluating potential antiviral resistance monitoring capability and capacity for ACLSV. Experimentally validated mature apple (M.domestica, 2n = 2X = 34) mdm-miRNAs (n = 322) were acquired from miRBase database and tested for alignment with the ACLSV genome. Of the 322 targeting mature locus-derived mdm-miRNAs investigated, nine apple mdm-miRNA homologs (mdm-miR395k, mdm-miR5225c and mdm-miR7121 (a, b, c, d, e, f, g, h) were predicted by all ‘four algorithms’. Only fifty eight mdm-miRNAs were predicted consensus binding sites by union of consensus between two algorithms. The miRanda, RNA22, TAPIR algorithms predicted binding of mdm-miR395k at unique nucleotide position 4691, as the most effectively interacting mdm-miRNAs in targeting the ORF1 sequence. In order to validate target prediction accuracy, whether the apple mdm-miRNAs might bind predicted ACLSV mRNA target(s), we created an integrated Circos plot. Genome-wide in-silico-predicted miRNA-mediated target gene regulatory network validated interactions that warrant in vivo analysis. The current work provides valuable evidence and biological material for generating ACLSV-resistant apple varieties.

Cigarette smoke (CS) is a major driver of many respiratory diseases including chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC). Tobacco causes oxidative stress, impaired phagocytosis of alveolar macrophages (AMs), and alterations in gene expression in the lungs of smokers. MicroRNAs (miRNAs) are small non-coding RNAs that influence several bi-ological processes and interfere with several regulatory pathways. The purpose of this study was to assess the effect of active CS on miRNAs expression in AMs obtained from bronchoalveolar lavage (BAL) of ever- or never-smoker subjects and patients with COPD or NSCLC. BAL specimens were collected from 43 sex-matched subjects to determine the expression of has-miR-34a-5p, 17-5p, 16-5p, 106a-5p, 223-5p, and 20a-5p before and after in vitro CS exposure by RT-PCR. In addition, bioin-formatic analysis of miRNAs target genes linked to inflammation was performed. Distinct and common miRNA expression profiles were identified in response to CS, suggesting their possible role in smoking-related diseases. It is noteworthy that, following exposure to CS, the expression levels of hsa-miR-34a-5p and 17-5p in both ever- or never-smokers, 106a-5p in never-smokers and 20a-5p in ever-smokers, shifted towards those found in individuals with COPD, suggesting them like a risk factor in developing this lung condition. Moreover, we identified miRNA targets involved in the immune system or AMs property regulation using in silico analysis. In conclusion, our study iden-tified miRNA signatures in AMs exposed to CS, indicating that CS is an important driver of epige-netic changes that contribute to the onset of various lung diseases.

For the treatment of cancer and other diseases, therapeutic targeting of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) is an attractive approach. RNA-based therapeutics have been extensively researched over the past decade, with antisense oligonucleotides and small interfering RNAs being the most commonly used. Some of these have even gained FDA approval. However, the results of trials have been mixed, with some studies reporting strong effects while others have shown limited effectiveness or toxicity. Alternative treatments, such as antimiRNAs, are currently in clinical trials. There is growing interest in the use of lncRNA-based therapies. This Perspective discusses the main challenges of ncRNA therapeutics, including specificity, delivery and tolerability. It also highlights emerging approaches that aim to improve their success.

Age-related sarcopenia meaningfully increases the risks of functional limitations and mortality in the elderly. Although circulating microRNAs (c-miRNAs) are associated with aging-related cellular senescence and inflammation, the relationships between c-miRNAs and sarcopenia in the elderly remain unclear. This study investigates whether circulating myo-miRNAs and inflammation-related miRNAs are associated with sarcopenia in the elderly. This study recruited 77 eligible subjects (41 males and 36 females) from 597 community-dwelling older adults, and then divided into normal (n=24), dynapenic (loss of muscular function without mass, n=35), and sarcopenic groups (loss of muscular function with mass, n=18). Moreover, myo-miRNAs (c-miRNA-133a and c-miRNA-486), inflammation-related miRNAs (c-miRNA-21 and c-miRNA-146a), and inflammatory-related cytokine levels in plasma were determined using quantitative polymerase chain reaction and ELISA, respectively. The results demonstrated that sarcopenic group exhibited lesser skeletal muscle mass index (SMI), handgrip strength, and gait speed, as well as, lower c-miR-486 and c-miR-146a levels, compared to those of normal and dynapenic groups. Moreover, c-miR-486 level was positively related to SMI (r=0.334, P=0.003), whereas c-miR-146a level was positively associated with SMI (r=0.240, P=0.035) and handgrip strength (r=0.253, P=0.027). In the receiver operating characteristic analysis for predicting sarcopenia, the area under the curve in c-miR-486 was 0.708 (95% confidence interval: 0.561-0.855, P=0.008) and c-miR-146a was 0.676 (95% CI: 0.551-0.801, P=0.024). However, no significant relationships were observed between SMI/ handgrip strength/gait speed and plasma myeloperoxidase/interleukin-1?/interleukin-6 levels. In conclusion, myo-miRNA (c-miR-486) and inflammation-related miRNA (c-miR-146a) are superior to inflammatory peroxide/cytokines in plasma for serving as critical biomarkers of age-related sarcopenia.

Non-coding RNAs, specifically microRNAs (miRNAs), exhibit altered expression and contribute significantly to the pathological processes observed in numerous diseases, encompassing various types of human cancers. Recent discoveries regarding miRNAs underscore their crucial roles in tumor pathogenesis and their responses to diverse therapeutic interventions. miRNAs are a subset of non-coding RNAs that regulate the expression of a multitude of genes post-transcriptionally and thus are potential diagnostic, prognostic, and predictive biomarkers and have also emerged as potential therapeutics. Because miRNAs are involved in the post-transcriptional regulation of their target mRNAs via repressing gene expression, defects in the miRNA biogenesis pathway and miRNA expression perturb the expression of a multitude of oncogenic or tumor-suppressive target genes that are involved in the pathogenesis of various cancers. As such, numerous miRNAs have been identified to be downregulated or upregulated in many types of cancers functioning as either oncomiRs or oncosuppressor miRs. Moreover, dysregulation of miRNA biogenesis pathways can also change miRNA expression and function in cancer. Profiling deregulated miRNAs in many cancer types has been shown to correlate with disease diagnosis, indicate optimal treatment options, and predict response to a specific therapy. Specific miRNA signatures can track all stages of disease including many cancer types and hold potential as biomarkers and therapeutic targets as well as therapeutics as miRNA mimics and inhibitors (antagomirs). As such, identifying specific miRNAs and mRNAs they regulate in many types of cancer along with downstream pathways can be used as potential therapeutic targets. Because a single miRNA can regulate a pool of targets involved in similar cellular processes and pathways, thereby amplifying the cellular response, this potentially makes miRNAs powerful therapeutics to restore cell functions that are altered as part of a disease phenotype. However, because a single miRNA regulates multiple gene expressions their cellular effects are numerous leading to potential off-target effects. Besides their intended targeting issues, there is a need to reduce the immunogenic reactions and determine the minimal dosing to achieve the desired effect while minimizing side effects. As such, a careful risk evaluation of miRNA therapeutics is needed to minimize off-target effects and to avoid overdosing of miRNA drugs. Furthermore, a limited understanding and validation of the specific roles of miRNAs limits their clinical application. In addition, there are many challenges concerning the delivery, sensitivity, specificity, toxicity, and applicability of the potential utility of miRNAs as therapeutic targets or therapeutics. Thus, future work will warrant if miRNAs can be used as cancer biomarkers as well as therapeutics for clinical application.

This study aimed to investigate the diagnostic potential of circulating microRNAs (miRNAs) for detecting early myocardial fibrosis development in HFpEF patients. This observational study used a case-control research design. Peripheral blood samples were isolated from 25 HFpEF patients and 25 normal patients. They were measured for NTproBNP levels using ELISA, as well as MicroRNA-1, 21, and 29 levels using RT-PCR. All patients also underwent echocardiography for global longitudinal strain (GLS) to measure the myocardial fibrosis progression. Data were analyzed using SPSS 25.0. HFpEF patients had significantly higher GLS compared to the normal patients (-13±2.4% vs -19±3.2%; p < 0.05), suggesting HFpEF patients tended to have myocardial fibrosis. HFpEF patients also had significantly higher microRNA-1 and microRNA-21 compared to the normal patients (p < 0.05), but they had lower microRNA-1 (p < 0.05). There was a positive correlation between microRNA-1 (r = 0.753; p < 0.05) and microRNA-21 (r = 0.675; p < 0.05) and an inverse correlation with microRNA-29 (r = -0.653; p < 0.05) based on the GLS findings. By using a GLS cutoff of -15% for myocardial fibrosis, microRNA-1, microRNA-21, and microRNA-29 were found to be able to predict myocardial fibrosis based on GLS with a specificity of 78% and sensitivity of 75%. Increasing microRNA-1 and microRNA-21 followed by decreasing microRNA-29 in HFpEF patients suggest early myocardial fibrosis.

MicroRNAs are tissue-specifically expressed short RNAs that serve post-transcriptional gene reg-ulation. A specific microRNA can bind to mRNAs of different genes and thereby suppress their protein production. In the context of the complex phenotype of fibromyalgia, we used the Axiom miRNA Target Site Genotyping Array to search genome-wide for DNA variations in microRNA genes, their regulatory regions and in the 3'UTR of protein-coding genes. To identify dis-ease-relevant DNA polymorphisms, a cohort of 176 female fibromyalgia patients was studied in comparison to a cohort of 162 healthy women. The association between 48.329 markers and fibromyalgia was investigated using logistic regression adjusted for population stratification. 29 markers had p-values < 1 × 10-3 and the strongest asso-ciation was observed for rs758459 (p-value of 0.0001), located in the Neurogenin 1 gene, targeted by hsa-miR-130a-3p. Furthermore, we identified a gene locus (rs2295963) predicted to disrupt binding of hsa-miR-1-3p. Both microRNAs were previously reported to be differentially expressed in fi-bromyalgia patients. Despite its limited statistical power, this study reports two microRNA-related polymorphisms which may play a functional role in the pathogenesis of fibromyalgia. For a better understanding of the disease pattern, further functional analyses on the biological significance of microRNAs and microRNA-related polymorphisms are required.

Study of micro-RNA regulatory networks (known as miRNA’s or miR’s), during development and in known pathologies have been the basis of study over the past decades. Herein, we recapitulate these findings in order to highlight the best underlying mechanisms found to date. We also seek to elucidate how miRNA dysregulation can be associated with many cardiovascular diseases. Furthermore, we discuss miR regulation mechanism during in early development in vivo and invitro. Since many of the miR’s are precursors to transcriptional regulation, we relate back to their molecular control as we can then look together at the fundamental disease they might be exacerbating by this dysregulation.

Background. Transferrin receptor 1 (TfR1), glucose transporter 1 (GLUT1), and CD98hc are candidates for targeted therapy at the blood-brain barrier (BBB). Our objective was to challenge the expression of TfR1, GLUT1, and CD98hc in brain capillaries by the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Methods. Primary mouse brain capillary endothelial cells (BCECs) and brain capillaries isolated from mice injected intraperitoneally with VPA were examined using RT-qPCR and ELISA. Targeting to the BBB was performed by injecting monoclonal anti-TfR1 (Ri7217)-conjugated gold nanoparticles measured using ICP-MS. Results. In BCECs co-cultured with glial cells, Tfrc mRNA expression was significantly higher after 6 h VPA returning to baseline after 24 h. In vivo Glut1 mRNA expression was significantly higher in males, but not females', receiving VPA, whereas Cd98hc mRNA expression was unaffected by VPA. TfR1 increased significantly in vivo after VPA, whereas GLUT1 and CD98hc were unchanged. Uptake of anti-TfR1-conjugated nanoparticles was unaltered by VPA in spite upregulated TfR expression. Conclusions. VPA upregulates TfR1 in brain endothelium in vivo and in vitro. VPA does not increase GLUT1 and CD98hc proteins. The increase in TfR1 does not result in higher anti-TfR1 antibody targetability, suggesting targeting sufficiently occurs with available transferrin receptors without further contribution from accessory VPA-induced TfR1.

The blood that remains in the placenta and umbilical cord after the birth of the infant is referred to as umbilical cord blood (UCB), which has the advantages of convenient source and less ethical controversy. MicroRNA (miRNA) is a class of non-coding RNAs that can regulate gene expression after translation and transcription. Alterations in miRNA expression involve changes in a range of gene expression pathways. An increasing body of research indicates that miRNAs are implicated in many human disorders and are involved in almost all biological medium processes. Due to their high stability in UCB, circulating miRNAs are considered promising biomarkers for diagnosis and disease prognosis. Herein, we conduct a comprehensive review to summarize the roles of diverse UCB miRNAs from different perspectives, including UCB miRNA as biomarker for developmental projections and disease diagnosis, the relationship between maternal gestational status and neonatal UCB miRNA expression, the therapeutic function of exosomal UCB miRNA, miRNA expression profiles in UCB cell lineages. Taken together, miRNAs in UCB are very promising biomarkers for indicating physiological states, disease states, drug responses, development states, or health conditions, which can help in diagnosing, classifying, and predicting diseases, prognosis, or providing personalized treatment plans for patients.

Over recent years, nanocarriers have played an ever-increasing role in clinical and biomedical applications owing to their unique physicochemical properties and surface functionalities. Lately, much effort has been directed towards the development of smart, stimuli-responsive nanocarriers that are capable of releasing their cargos in response to specific stimulus. These intelligent-responsive nanocarriers can be further surface-functionalized so as to achieve active tumor targeting in a sequential manner, which can be simply modulated by the stimuli. By applying this methodological approach, these intelligent-responsive nanocarriers can be directed to different target-specific organs, tissues or cells, and exhibit on-demand controlled drug release that may enhance therapeutic effectiveness and reduce systemic toxicity. Light, an external stimulus, is one of the most promising triggers for use in nanomedicine to stimulate on-demand drug release from nanocarriers. Light-triggered drug release can be achieved by light irradiation at different wavelengths, either in UV, visible or even NIR region, depending on the photophysical properties of the photo-responsive molecule embedded in the nanocarrier system, the structural characteristics and material composition of the nanocarrier system. In this review, we highlighted the emerging functional role of light in nanocarriers, with emphasis on light-responsive liposomes and dual-targeted stimuli-responsive liposomes. Moreover, we provided the up-to-date phototriggered targeting strategies and mechanisms of light-triggered drug release from liposomes and NIR-responsive nanocarriers. Lastly, we addressed the current challenges, advances, and future perspectives for the deployment of light-responsive liposomes in targeted drug delivery and therapy.

Plant activators have emerged as promising alternatives to conventional pesticides for crop disease manage-ment due to their unique mode of action. By priming the plant's innate immune system, these compounds can induce systemic acquired resistance against a broad spectrum of pathogens without directly inhibiting their proliferation. Key advantages of plant activators include prolonged defense activity, lower effective dosages, and negligible risk of developing pathogen resistance. Among the various defensive pathways tar-geted, the salicylic acid (SA) signaling cascade has been extensively explored, leading to the successful devel-opment of commercial activators like benzothiadiazole for widespread application in crop protection. While the action sites of many SA-targeting activators have been preliminarily mapped to different steps along the pathway, a comprehensive understanding of their precise mechanisms remains elusive. This review provides a historical perspective on plant activator development and outlines diverse screening strategies employed across multiple levels, from whole-plant bioassays to molecular and transgenic approaches. We expound on the intricate components, biological relevance, and regulatory circuits governing the SA pathway, while criti-cally examining the structural features, bioactivities, and proposed modes of action of classical activators such as benzothiadiazole derivatives, salicylic acid analogs, and other small molecules. Insights from field trials as-sessing their practical applicability are also discussed. Furthermore, we highlight the current status, challenges, and future prospects in the realm of SA-targeting activator development globally, with a focus on recent en-deavors in China. Collectively, this comprehensive review aims to synthesize existing knowledge and provide a roadmap for future research toward developing more potent and mechanistically understood plant activa-tors that fortify crop immunity against disease.

The nuclear hormone family of receptors regulates gene expression. The androgen receptor (AR) shuttles upon ligand binding and homodimerization from the cytosol into the nucleus to activate gene expression. Thyroid hormone receptors(TR), retinoic acid receptors (RAR), and the vitamin D receptor (VDR) are present in the nucleus bound to chromatin as a heterodimer with the retinoid X receptors (RXR) and repress gene expression. Ligand binding leads to transcription activation. The hormonal ligands for these receptors play crucial roles to ensure the proper conduct of very many tissues and exert effects on prostate cancer (PCa) cells. Androgens support PCa proliferation and deprivation alone or with chemotherapy is the standard therapy for PCa. RAR activation and 3,5,3'-triiodo-L-thyronine (T3) stimulation of TR support the growth of PCa cells. Ligand stimulation of VDR drives growth arrest, differentiation, and apoptosis of PCa cells. Often these receptors are explored as separate avenues to find treatments for PCa and other cancers. However, there is accumulating evidence to support receptor interactions and crosstalk of regulatory events whereby a better understanding might lead to new combinatorial treatments.

MicroRNA (miRNA) is small non-coding RNAs that play vital roles in post-transcriptional gene regulation by inhibiting mRNA translation or promoting mRNA degradation. Dysregulation of miRNA has been implicated in numerous human diseases, including cancers. The family members of miR-34 (miR-34s), composed of miR-34a, miR-34b, and miR-34c, have emerged as the most extensively studied tumor-suppressive miRNAs. In this comprehensive review, we aim to provide an overview of the major signaling pathways and gene networks regulated by the miR-34s in various cancers and highlight the critical tumor suppressor role of miR-34s. Furthermore, we will discuss the potential of using miR-34 mimics as a novel therapeutic approach against cancer, while also addressing the challenges associated with their development and delivery. It is anticipated that gaining a deeper understanding of the functions and mechanisms of miR-34s in cancer will greatly contribute to the development of effective miR-34-based cancer therapeutics.

RNA editing involves the insertion, deletion or substitution of single nucleotides within a RNA molecule, without altering the DNA sequence. Adenosine to inosine (A-to-I) editing consists of an RNA modification where single adenosines along the RNA sequence are converted into inosines. Such a biochemical transformation is catalyzed by enzymes belonging to the family of adenosine deaminases acting on RNA (ADARs) and occurs either co- or post-transcriptionally. Initially, the A-to-I RNA editing phenomenon was discovered and studied in messenger RNAs (mRNAs), where it can influence RNA splicing and cause the recoding of codon sequences. The employment of more powerful, high-throughput detection methods has recently revealed that A-to-I editing widely occurs in non-coding RNAs, including microRNAs (miRNAs). MiRNAs are a class of small regulatory non-coding RNAs (ncRNAs) acting as translation inhibitors, known to exert relevant roles in controlling cell cycle, proliferation, and cancer development. Indeed, a growing number of recent researches have evidenced the importance of miRNA editing in cancer biology by exploiting various detection and validation methods. Herein, we briefly overview early and currently available A-to-I miRNA editing detection and validation methods and discuss the significance of A-to-I miRNA editing in human cancer.

Coronary artery disease (CAD) and hypertension significantly contribute to cardiovascular morbidity and mortality. MicroRNAs (miRNAs) have recently emerged as promising biomarkers and therapeutic targets for these conditions. This systematic review conducts a thorough analysis of the literature, with a specific focus on investigating miRNA expression patterns in patients with CAD and hypertension. The review encompasses an unspecified number of eligible studies that employed a variety of patient demographics and research methodologies, resulting in diverse miRNA expression profiles. This review highlights the complex involvement of miRNAs in CAD and hypertension and the potential for advances in diagnostic and therapeutic strategies. Future research endeavours are imperative to validate these findings and elucidate the precise roles of miRNAs in disease progression, offering promising avenues for innovative diagnostic tools and targeted interventions.

Lactococcus lactis is a potential bacterial cell factory to develop delivery systems for vaccines and therapeutic proteins. Large progress has been made in applications using engineered L. lactis against, e.g., inflammatory bowel disease and cervical cancer, but improvement of secretion and cell anchoring efficacy is still desirable. A double-labelling method based on biarsenical hairpin binding and nickel-polyhistidine affinity was used for visualization of protein trafficking and quantification of targeted proteins on the cell surface and in the cytoplasm. To investigate the importance of mature domain targeting signals (MTSs), we generated truncated constructs encoding 126, 66, and 26 amino acid residues from the N-terminus of the basic membrane protein A (BmpA) and fused those with the gene for the human papillomavirus serotype 16 (HPV16) E7 oncoprotein. Overexpression of fusion proteins was observed to come at a cost of cell proliferation. L. lactis cells produced and displayed the shortest fusion protein only with difficulty, suggesting that the entire absence of a homologous sequence containing MTSs significantly impedes export and surface anchoring of fusion proteins. With 40 amino acids following the signal peptide and containing one MTS, effective translocation was possible. Mutations of MTSs towards increased hydrophobicity resulted in an increase of secreted and surface-displayed fusion protein, suggesting the potential to design rationally improved constructs.

The hematopoietic transcription factor Ikaros (IKZF1) regulates normal B cell development and functions as a tumor suppressor in precursor B cell acute lymphoblastic leukemia (B-ALL). MicroRNAs (miRNAs) are small regulatory RNAs that through post-transcriptional gene regulation play critical roles in intracellular processes including cell growth in cancer. However, the role of Ikaros in the regulation of miRNA expression in developing B cells is unknown. In this study, we examined the Ikaros-regulated miRNA targets using patient-derived IKZF1-mutated B-ALL xenograft-derived cell lines. Inducible expression of wild-type Ikaros (the Ik1 isoform) caused B-ALL growth arrest and exit from the cell cycle. Global miRNA expression analysis revealed a total of 31 miRNAs regulated by IK1, and ChIP-seq analysis showed that Ikaros bound to several Ik1-responsive miRNA genes. Examination of the prognostic significance of miRNA expression in B-ALL indicate that the IK1-regulated miRNAs hsa-miR-26b, hsa-miR-130b and hsa-miR-4649 are significantly associated with outcome in B-ALL. Our findings establish a potential regulatory circuit between the tumor-suppressor Ikaros and the oncogenic miRNA networks in IKZF1-mutated B-ALL. These results indicate that Ikaros regulates the expression of a subset of miRNAs, of which several may contribute to B-ALL growth.

Tackling the intricacies of network dismantling in complex systems poses significant challenges. This task has relevance across various practical domains, yet traditional approaches focus primarily on singular metrics, such as the number of nodes in the Giant Connected Component (GCC) or average pairwise connectivity. In contrast, we propose a unique metric that concurrently targets nodes with the highest degree and reduces the GCC size. Given the NP-hard nature of optimizing this metric, we introduce MaxShot, an innovative end-to-end solution that leverages graph representation learning and reinforcement learning. Through comprehensive evaluations on both synthetic and real-world datasets, our method consistently outperforms leading benchmarks in accuracy and efficiency. These results highlight MaxShot’s potential as a superior approach to address the network dismantling problem effectively.

Sepsis is a life-threatening condition with high hospital mortality. Elevated mortality has also been observed in patients after hospital discharge due to post-sepsis syndrome (PSS). The etiology of PSS is still not entirely known, but it involves inflammation. Plasma extracellular vesicles (EVs) are recognized as a unique mechanism of intercellular communication in inflammatory processes. It has been reported that EV microRNA (miRNA) production during the acute sepsis phase may persist until after disease resolution and is associated with PSS. We employed mass spectrometry and qPCR analysis to determine the protein and miRNA composition of plasma-derived EVs of 36 patients during sepsis-related hospitalization, immediately after ICU discharge (post-sepsis), and three, six, twelve, and up to 36 months post-sepsis. We determined that patients’ immune system cells were the primary EV source. Fifteen differentially expressed EV miRNAs (DEmiRs) were identified in samples from septic patients compared to the control group. Predictive analyses revealed that these DEmiRs could influence inflammation by modulating pathways mediated by NF-κB, STAT3, and TLR4 signaling activation. Thirteen miRNAs (-15b-5p,-16-5p,-20a-5p,-25-3p,-27a-3p,-29a-3p,-30d-5p,-93-5p,-146a-5p,-148a-3p,-191-5p,-195-5p,-223-3p) were downregulated in the death group compared to the survivor group, making them candidate prognostic markers of ICU survival. One year after ICU discharge, the expression of miR-21-5p and miR-195-5p were decreased in the survivor group. The miRNAs identified in the present study represent potential biomarkers for the survival prognosis of post-sepsis patients.

The pig is an important source of meat production and provides a valuable model for certain human diseases. MicroRNA (miRNA), which is non-coding RNA and regulates gene expression at the posttranscriptional level, plays a critical role in various biological processes. Studies on identification and function of mature miRNAs in multiple pig tissues are increasing, yet the literature is limited. Therefore, we reviewed current research to determine the miRNAs expressed in specific pig tissues that are involved in carcass values (including muscle and adipocytes), reproduction (including pituitary, testis, and ovary), and development of some solid organs (e.g., brain, lung, kidney, and liver). We also discuss the possible regulating mechanisms of miRNA. Finally, as pig organs are suitable candidates for xenotransplantation, biomarkers of their miRNA in xenotransplantation were evaluated.

Metals play vital roles in biological systems, with iron/heme being essential for cellular and metabolic functions necessary for survival and/or virulence in many bacterial pathogens. Given the rise of bacterial resistance to current antibiotics, there is an urgent need for the development of non-toxic and novel antibiotics that do not contribute to resistance to other antibiotics. Gallium, which mimics iron, has emerged as a promising antimicrobial agent, offering a novel approach to combat bacterial infections. Gallium does not have any known functions in biological systems. Gallium exerts its effects primarily by replacing iron in redox enzymes, effectively inhibiting bacterial growth by targeting multiple iron/heme-dependent biological processes and suppressing the development of drug resistance. The aim of this review is to highlight recent findings on the mechanisms of action of gallium and provide further insights into the development of gallium-based compounds. Understanding the mechanisms underlying gallium’s biological activities will enhance its therapeutic application across various medical fields, offering promising avenues for the treatment of infectious diseases, cancer, and inflammatory conditions.

Iron (Fe) is co-factor for enzymes of the developing brain necessitating sufficient supply. We investigated the effects of administering ferric derisomaltose/Fe isomaltoside (FDI) subcutaneously to Fe deficient (ID) pregnant rats on cerebral and hepatic concentrations of essential metals and gene expression of ferroportin and hepcidin. Pregnant rats subjected to ID were injected with FDI on the day of mating (E0), 14 days into pregnancy (E14), or the day of birth (Postnatal (P0)). The efficacy was evaluated by determination of cerebral and hepatic Fe in pups on P0 and as adults on P70, and the concentration of copper (Cu) and zinc (Zn). Females fed an ID diet (5.2 mg/kg Fe) had offspring with significantly lower cerebral and hepatic Fe compared to female controls fed a standard diet (158 mg/kg Fe). Cerebral Cu increased irrespective of supplying a standard diet or administering FDI combined with the standard diet. Hepatic hepcidin was significantly lower following ID, whereas cerebral hepcidin was virtually undetectable in all experimental groups. In conclusion, administering FDI subcutaneously to ID pregnant rats on EO normalizes cerebral Fe in the fetus, but when applied at later gestational ages, additional Fe to the offspring is needed to normalize cerebral and hepatic Fe.

The emergence of the H3N2 influenza virus in 1968 marked a significant event as it crossed the species barrier. Since then, ongoing mutational dynamics have led to the formation of antigenic clusters, prompting the World Health Organization to advocate for regular updates to H3N2 vaccines. Research in the Western Pacific region underscores the necessity for heightened awareness and effective control strategies. Stemming from avian influenza A, the 1968 H3N2 influenza pandemic resulted in the deaths of one million people globally, with its seasonal variants primarily affecting older individuals and causing severe illness due to antigenic drift. To address the challenge of vaccine efficacy against H3N2 mutations, researchers are exploring innovative strategies such as precise antigenic material administration, controlled release patterns, understanding immune system mechanisms, and glycan engineering. This review comprehensively examines various aspects of the Influenza A (H3N2) virus, encompassing its virological characteristics, evolutionary trends, global epidemiology, vaccination strategies, antiviral interventions, and emerging diagnostic approaches. It underscores the impact of antigenic variation on vaccine design and effectiveness, seasonal outbreak patterns, pandemic potential, and the interplay between viral factors and host immune responses. Moreover, the review evaluates antiviral therapies and the issue of drug resistance, emphasising the necessity for multidisciplinary approaches involving researchers, healthcare professionals, and policymakers to comprehend H3N2 and enhance public health interventions.

Epigenetics refers to the DNA chemistry changes that result in the modification of gene transcription and translation independently of the underlying DNA coding sequence. Epigenetic modifications are reported to involve various molecular mechanisms, including classical epigenetic changes affecting DNA methylation and histone modifications and small RNA-mediated processes, particularly that of microRNAs. Epigenetic changes are reversible and are closely interconnected. They are recognised to play a critical role as mediators of gene regulation, and any alteration in these mechanisms has been identified to mediate various pathophysiological conditions. Moreover, genetic predisposition and environmental factors, including dietary alterations, lifestyle or metabolic status, are identified to interact with the human epigenome, highlighting the importance of epigenetic factors as underlying processes in the etiology of various diseases such as MetS. This review will reflect on how both the classical and microRNA regulated epigenetic changes are associated with the pathophysiology of Metabolic syndrome. We would then focus on the various aspects of epigenetic-based strategies used to modify MetS outcomes, including epigenetic diet, epigenetic drugs, epigenome editing tools, and miRNA-based therapies.

Autism Spectrum Disorders (ASD) are neurodevelopmental disturbances affecting social skills, whose incidence worldwide is dramatically increasing. Together with the rise of ASD prevalence, several immune conditions are following the same trend, including Atopic Dermatitis (AD), with a possible clinical relationship with ASD. To date, their pathogenesis is still unknown, but several studies highlighted the relevance of gene-environment interactions to the onset of both disorders. Among potential contributing factors, microRNAs (miRNAs), small molecules capable of controlling gene expression and targeting mRNA transcripts, might represent one of the major circulating link, unraveling the connections between neurodevelopmental and immune conditions. We conducted a systematic literature review, under the PRISMA guidelines, trying to define the panel of common miRNAs involved in both ASD and AD. The review retrieved articles published until December 13, 2018, in PubMed, ScienceDirect, PsycARTICLES and Google Scholar. We found a handful works dealing with miRNAs in ASD and AD, with the most overlapping dysregulated miRNAs being miR-146 and miR-155. Two possible compounds are abnormally regulated in both ASD and AD subjects, possibly cross-contributing to the interactions between the two disorders, setting the basis to investigate more precisely the possible link between ASD and AD from another, not just clinical, perspective.

MicroRNAs (MiRNAs) are a class of non-coding single-stranded RNA molecules of approximately 20-24 nucleotides in plants that play an important regulatory role in a variety of biological processes such as plant growth and development and response to various abiotic stresses. For example Drought, Salt, Cold, High temperature, Heavy metals and Nutrition. MiRNAs affect gene expression by manipulating the cleavage, translational expression or DNA methylation of target mRNAs. This review describes the current progress made on the way miRNAs are produced and regulated and the way miRNA/target gene is used in plant responses to abiotic stresses. Studying the molecular mechanism of action of miRNAs downstream target genes can optimize the genetic manipulation of crop growth and development conditions that provide a more theoretical basis for improving crop production.

Opioids have served as a cornerstone in pain management for decades. However, the emergence of increasingly potent synthetic analogs brings forth a range of side effects, including respiratory depression, tolerance, dependence, constipation, and, more importantly, the development of severe and debilitating opioid use disorder (OUD). Search for therapeutics to mitigate OUD has been challenging and this has called for novel approaches that include design of small molecules targeting neuronal circuits involved in addiction (opioid, dopamine, serotonin, norepinephrine, and glutamate receptors, etc.) and development of biologics that target circulating opioids/opiates. In this review, we retrieved and discussed over two dozen of relevant patents filed in the past twelve (12) years that focus on novel approaches to produce therapeutics for OUD. The current review excluded patents on biologics and concentrated on small molecules, which will be discussed separately in a subsequent sequel. The chemical entities disclosed were highlighted and specific examples were provided where necessary. Although the number of patents in the realm of drug discovery for OUD is currently limited, we foresee a continued expansion in the quest for therapeutics for OUD in the years to come.

Over the past few decades, phototherapy, encompassing the utilization of both natural and artificial light, has emerged as a dependable and non-invasive strategy for addressing a diverse range of illnesses, diseases, and infections. This therapeutic approach, primarily known for its efficacy in treating skin infections such as herpes and acne lesions, involves the synergistic use of specific light wavelengths and photosensitizers like methylene blue. Photodynamic therapy, as it is termed, relies on the generation of antimicrobial reactive oxygen species (ROS) through the interaction between light and externally applied photosensitizers. Recent research, however, has highlighted the intrinsic antimicrobial properties of light itself, marking a paradigm shift in focus from exogenous agents to the inherent photosensitivity of molecules found naturally within pathogens. Chemical analyses have identified specific organic molecular structures and systems, including porphyrins and conjugated C=C bonds, as pivotal components in molecular photosensitivity. Given the prevalence of these systems in organic life forms, there is an urgent need to investigate the potential impact of phototherapy on individual molecules expressed within pathogens and discern their contributions to the antimicrobial effects of light. This review delves into the recently unveiled key molecular targets of phototherapy, offering insights into their potential downstream implications and therapeutic applications. By shedding light on these fundamental molecular mechanisms, we aim to advance our understanding of phototherapy's broader therapeutic potential and contribute to the development of innovative treatments for a wide array of microbial infections and diseases.

Biofilm formation by unicellular eukaryotes presents major challenges in healthcare, agriculture, and food industries, primarily due to enhanced resistance to environmental stressors and antimicrobial agents. Understanding the regulatory mechanisms of biofilm formation, such as quorum sensing (QS) and cyclic di-GMP signaling, has led to the discovery of novel compounds that can inhibit biofilm development. In 2024, significant advancements were made in identifying compounds like betulinic acid, methyl anthranilate, and pulmonarin B analogues that target these pathways. This review explores the potential applications of these compounds, especially in Vietnam's agriculture and food industries, where biofilm formation contributes to contamination and antimicrobial resistance. The findings underscore the global relevance of biofilm-disrupting technologies and their role in combating biofilm-associated infections and resistance.

Aberration in microRNA (miRNA) expression or DNA methylation is a causal factor for polycystic ovarian syndrome (PCOS), a common endocrine disorder and leading cause of infertility. However, the epigenetic interactions between miRNA and DNA methylation remain unexplored in PCOS. In this study, we conducted an integrated analysis of RNA-seq, miRNA-seq and MBD-seq on ovarian granulosa cells of PCOS and control groups to reveal the epigenetic interactions involved in the pathogenesis of PCOS. Firstly, we identified 830 genes and 30 miRNAs that were expressed differently in PCOS, and seven miRNAs were found to negatively regulate targeted mRNA expression. Next, in total, 130 miRNAs were found to be significantly differently methylated in promoter regions, while 13 were found to be associated with miRNA expression. Furthermore, the promoter hypermethylation of miR-429, miR-141-3p, and miR-126-3p was proven to suppress miRNA expression and therefore upregulate their corresponding genes, including XIAP, BRD3, MAPK14 and SLC7A5. Our results demonstrate that DNA methylation regulates miRNA expression and therefore controls its corresponding gene expression. The reactivation of the transcription of epigenetically silenced genes may be one of the key elements in PCOS pathogenesis. Meanwhile, the epigenetic mechanisms underlying the regulation of miRNA expression can provide a potential therapeutic target for PCOS in the future.

The influenza virus has been the primary cause of the pandemic, posing a constant threat to human society. Due to its genetic evolution and continuous outbreak, antiviral research currently focuses on exploring a novel lead agent. A comprehensive antiviral screening discovered a marine bacterium whose extract exerted excellent efficacy against influenza viruses. Parerythrobacter sp. M20A3S10, a novel strain under the family Erythrobacteraceae, could produce carotenoids exhibiting antiviral and anticancer activity by enhancing the cellular immune system. Post-treatment of M20A3S10 extract showed outstanding therapeutic indexes: against influenza virus A/PR8 (H1N1) [selectivity index (SI) = 24.0], A/Wisconsin/15/2009 (H3N2) (SI = 30.1) and B/Florida/78/2015 (SI = 38.2). Comparably, the effectiveness was demonstrated against Zika virus (ZIKV) and dengue virus type 2 (DENV2) with an SI of 22.5 and 24.1, respectively, namely broad-spectrum activity. Of note, the antiviral responses resulted from the common replication mechanism between IAV, ZIKV, and DENV2. The stimulation of apoptosis-mediated cellular immunity prevented the viral release and protected the host, suggesting that switching from necroptosis to apoptosis is a novel antiviral target. Although the specific compound affecting the antiviral activity was not identified, its promising efficacy with broad activity will contribute to developing a strategy for preventing future pandemics.

As yin and yang, cancer and diabetes are metabolic disorders characterized by deregulated, yet opposing, metabolic alterations. These metabolic shifts reflect a complex network of defective underlying signaling pathways, which ultimately orchestrate both disease pathogenesis and progression. The Warburg effect portrays the chief metabolic phenotype in cancer and is reflected by the dominance of aerobic glycolysis over minimal-to-no viable oxidative phosphorylation in cancer. Conversely, during the pathogenesis of type 2 diabetes (T2D), oxidative phosphorylation is constantly heightened. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, with exacerbating metabolic alterations affecting oxidative phosphorylation in a tissue-specific manner. Promising nutritional adjuvants, such as alpha-lipoic acid and flavonoids, can reprogram metabolism and exert antitumor and antidiabetic effects. Other pharmacological agents, such as metformin, have therapeutic effects on cancer and T2D. Herein, we discuss the molecular mechanisms and signaling pathways involved in the metabolic shifts in cancer and T2D, and explore the therapeutic strategies under investigation that aim to reverse the metabolic shift in both disease scenarios.

In a wide range of lymphoid neoplasms, the process of malignant transformation is associated to somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes. In the last two decades, the field has made a major effort to develop therapies that target these epigenetic alterations. In this review, we discuss which epigenetic alterations occur in non-Hodgkin B-cell lymphoma. Furthermore, we aim to present in close to comprehensive manner the current state-of-the-art in the preclinical and clinical development of epigenetic drugs. We focus on therapeutic strategies interfering with histone methylation and acetylation as these are most advanced in being deployed from the bench-to-bedside and have greatest potential to improve the prognosis of lymphoma patients.

A “watch and wait” strategy, delaying treatment until active disease manifests, is adopted for most CLL cases; however prognostic models incorporating biomarkers have shown to be useful to predict treatment requirement. In our prospective O-CLL1 study including 224 patients, we investigated the predictive role of 513 microRNAs (miRNAs) on time to first treatment (TTFT). In the context of this study six well-established variables (i.e., Rai stage, beta-2-microglobulin levels, IGVH mutational status, del11q, del17p, and NOTCH1 mutations) maintained significant associations with TTFT in a basic multivariable model, collectively yielding a Harrell's C-index of 75% and explaining 45.4% of the variance in the prediction of TTFT. Concerning miRNAs, 73 out of 513 were significantly associated with TTFT in a univariable model; of these, 16 retained an in-dependent relationship with the outcome in a multivariable analysis. For 8 of these (i.e., miR-582-3p, miR-33a-3p, miR-516a-5p, miR-99a-5p, and miR-296-3p, miR-502-5p, miR-625-5p, and miR-29c-3p) a lower expression correlated with a shorter TTFT, whereas in the remaining eight (i.e., miR-150-5p, miR-148a-3p, miR-28-5p, miR-144-5p, miR-671-5p, miR-1-3p, miR-193a-3p, and miR-124-3p) the higher expression was associated with shorter TTFT. Integrating these miRNAs into the basic model significantly enhanced predictive accuracy, raising the Harrell’C index to 81.1% and the explained variation in TTFT to 63.3%. Moreover, the inclusion of the miRNA scores enhanced the Integrated Discrimination Improvement (IDI) and the Net Reclassification Index (NRI), underscoring the potential of miRNAs to refine CLL prognostic models and providing insights for clinical decision-making. In silico analyses on the differently expressed miRNAs revealed their potential regulatory functions of several pathways, including those involved in the therapeutic responses. To add a bio-logical context to the clinical evidence, a miRNA-mRNA correlation analysis revealed at least one significant negative correlation between 15 of the identified miRNAs and a set of 50 Artificial Intelligence (AI) selected genes, previously identified by us as relevant for TTFT prediction in the same cohort of CLL patients. In conclusion, the identification of specific miRNAs as predictors of TTFT holds promise for enhancing risk stratification in CLL to predict therapeutic needs. However, further validation studies and in-depth functional analyses are required to confirm the robustness of these observations and to facilitate their translation into meaningful clinical utility.

Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in the regulation of idiopathic pulmonary fibrosis (IPF) is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein-1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 has yet to be investigated. In addition, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual luciferase reporter system assay were used to identify the target gene of miR-30a, and cell transfection was used to confirm this relationship. Ten-eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and the transfection of miR-30a mimic/inhibitor significantly reduced/increased the expression of TET1 protein. Further experiment verified that the interference on TET1(siRNA) could inhibit the hydroxymethlation of the Drp-1 promoter. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit the TET1 expression by base pairing with complementary sites in the 3′ untranslated region to regulate the hydroxymethlation of the Drp-1 promoter. Furthermore, miR-30a could act as a potential therapeutic target for IPF.

To discover potential micro(mi)RNAs biomarkers of SARS-CoV-2 infection and disease progression, large-scale deep sequencing analysis of small RNA expression was performed on plasma samples from 40 patients hospitalized for SARS-CoV-2 infection (median 13.50 [IQR 9–24] days since symptoms initiation) and 21 healthy noninfected individuals. A totally of 1218 different miRNAs were identified. When compared with healthy noninfected donors, SARS-CoV-2 infected patients showed significantly (fold change [FC] >1.2 and adjusted p [padj] <0.05) altered expression of 190 miRNAs. The top 10 differentially expressed (DE) miRNAs were miR-122-5p, let-7b-5p, miR-146a-5p, miR-342-3p, miR-146b-5p, miR-629-5p, miR-24-3p, miR-12136, let-7a-5p, and miR-191-5p, which displayed FC and padj values ranging from 153 to 5 and 2.51 × 10-32 to 2.21 × 10-21, respectively, which unequivocally diagnosed SARS-CoV-2 infection. No differences in blood cell counts and biochemical plasma parameters, including interleukin 6, ferritin and D-dimer, were observed between COVID-19 patients on high-flow oxygen therapy, low-flow oxygen therapy, or not requiring oxygen therapy. Notably, 31 significantly deregulated miRNAs were found when patients on high- and low-flow oxygen therapy were compared. SARS-CoV-2 infection generates a specific miRNA signature in hospitalized patients. Specific miRNA profiles are associated with COVID-19 prognosis in patients requiring oxygen flow.

Serine/threonine kinase (AKT) signaling regulates diverse cellular processes and is one of the most important aberrant cell survival mechanisms associated with tumorigenesis, metastasis, and chemoresistance. Targeting AKT has become an effective therapeutic strategy for the treatment of many cancers. AKT3 (PKBγ), the least studied isoform of the AKT family, has emerged as a major contributor to malignancy. AKT3 is frequently overexpressed in human cancers, and many regulatory oncogenic or tumor suppressor small non-coding RNAs (ncRNAs), including microRNAs (miRNAs), have recently been identified to be involved in regulating AKT3 expression. Therefore, a better understanding of regulatory miRNA/AKT3 networks may reveal novel biomarkers for diagnosis of patients with cancer and provide invaluable information for developing more effective therapeutic strategies. The aim of this review is to summarize current research progress in the isoform-specific functions of AKT3 in human cancers and the roles of dysregulated miRNA/AKT3 in specific types of human cancers.

Oncological changes in the prostate are a common cause of death among elderly men. Malignant cells are difficult to identify at early stages, which are asymptomatic. The patient often seeks medical assistance when the disease has already progressed, and the treatment is less effective. Early diagnosis of prostate cancer (PC) is thus one of the priority tasks of modern urology and healthcare in general. The aim of this study is the detection of microRNAs (miRNAs), which are known to be associated with PC. The detection of the target miRNAs in human plasma samples has been performed with a nanoribbon biosensor system, which was based on "silicon-on-insulator" structures (SOI-NR biosensor). In order to provide biospecific detection of the target miRNAs, the surface of individual nanoribbons has been modified with DNA oligonucleotide probes (oDNA probes), whose nucleotide sequences were complementary to those of the target miRNAs. The high detection sensitivity has been demonstrated with the use of model oDNAs, which are complementary to nanoribbon-immobilized oDNA probes, in buffer solutions. The sensitivity threshold was 1.1 × 10^-17 M. The successful detection of target miRNAs, isolated from real plasma samples of PC patients, has also been demonstrated. We believe that the development of highly sensitive nanotechnology-based biosensors for PC markers is a step towards personalized medicine.

Malignancy is a fatal disease with an increasing incidence with each passing year, and the early diagnosis of malignancy can significantly improve the cure rate of patients, which has profound implications for saving patients' lives. The changes of miRNA are closely related to the occurrence of malignant tumors. The expression of miRNA in many malignant tumors is obviously different and unique from that in normal tissues. In this study, a strategy for amplifying microRNA (miRNA) signal was designed using duplex specific nuclease (DSN), which was then combined with Peptide nucleic acid (PNA) probe hybridization technology to prepare a sensitive and efficient paper-based lateral flow biosensor (LFB) for the detection of pancreatic cancer (PC) associated microRNA-10b. The performance evaluation results of the LFB showed that the detection limit of miR-NA-10b is 5 nM/mL, and carries demonstrated well specificity, stability, reproducibility. The biosensor prepared in this paper can provide accurate and rapid detection of miRNA-10b. The detection results play a guiding role in the early diagnosis of PC. Meeting the clinical need for largescale screening of individuals at high risk of PC. Providing new avenues to achieve early mass screening in individuals at high risk of PC.

Technology-based approaches for upper limb (UL) motor rehabilitation after stroke are designed mostly for severely affected patients to increase their recovery chances. However, the available randomised controlled trials (RCTs) focused on efficacy of technology-based interventions often include patients with a wide range of motor impairment. This scoping review aims at overviewing the actual severity of stroke patients enrolled in RCTs which claim to specifically address UL severe motor impairment. The literature search was conducted on Scopus and PubMed databases and included articles from 2008 to May 2024, specifically RCTs investigating the impact of technology-based interventions on UL motor functional recovery after stroke. Forty-eight studies were selected. They showed that upon patients’ enrolment the values of the UL Fugl-Meyer Assessment and Action Research Arm Test covered the whole range of both scales, thus revealing the non-selective inclusion of severe impaired patients. Heterogeneity in terms of numerosity, characteristics of enrolled patients, trial design, implementation, and reporting were present across studies. No clear difference in the severity of the included patients according to the intervention type was found. Patient stratification upon enrolment is crucial to best direct resources to those patients who will benefit the most from a given technology-assisted approach (personalised rehabilitation).

This study presents a detailed computational investigation aimed at identifying and evaluating potential small organic molecular scaffolds as inhibitors targeting the Pks13 protein, a critical enzyme in tuberculosis (TB) drug discovery. Our approach integrates multiple computational techniques, including quantitative structure-activity relationship (QSAR) modelling, compound library generation, molecular docking, biological activity prediction, re-evaluation of screened compounds, molecular dynamics (MD) analysis, and binding free energy estimation using the MM-GBSA approach. We developed a robust QSAR model using multiple linear regression (MLR) techniques, specifically tailored to predict the minimum inhibitory concentration (MIC) values of potential anti-TB agents. This model demonstrated excellent predictive performance, validated through rigorous internal and external validation procedures. Through molecular docking simulations, we identified five promising inhibitors Ethyl (R,Z)-2-(2-((2-chlorobenzyl) oxy)benzylidene)-5-(4-chlorophenyl)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylate (PKD1), (7R,9aR)-7-(2-hydroxyphenyl)-4-(2-methoxyphenyl)-3-methyl-7,8,9,9a-tetrahydroisoxazolo[5,4-b]quinolin-5(6H)-one (PKD2), (7-(4-methoxy phenyl)-2-methyl-3-phenylpyrazolo[1,5-a]pyrimidin-5-yl)(4-(3-(trifluoromethyl)phenyl) piperazin-1-yl)methanone (PKD3), (8S,10S)-10-(((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl tetrahydro-2H-pyran-2-yl)oxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetra-hydrotetracene-5,12-dione (PKD4), 3-(3,4-dimethylphenyl)-5-((2-(4-fluorophenyl)-2-oxoethyl) thio)-6-phenyl-2-thioxo-2,3,5,7a-tetrahydrothiazolo[4,5-d]pyrimidin-7(6H)-one (PKD5)with high binding affinities, prioritizing them based on their binding energies. These selected compounds were further assessed for their biological activity predictions, guiding the selection of candidates for experimental validation. Subsequent re-evaluation using absolute binding free energy estimation and MD simulations provided insights into the stability and dynamics of the protein-ligand complexes over time. Our findings highlighted the potential of identified compounds as stable binders within the Pks13-TE domain binding pocket, underscoring their viability as drug candidates. Additionally, binding free energy analysis using MM-GBSA reaffirmed the strong affinity of the proposed compounds towards Pks13. Our integrated computational approach offers a systematic and detailed framework for the identification and characterization of potential Pks13 inhibitors with specific relevance to TB drug discovery.

Amyloids result from the aggregation of several unrelated proteins, due to either specific mutations or promoting intra- or extra-cellular conditions. Structurally, they are rich in intermolecular β-sheets and are the causative agents of several diseases, both neurodegenerative and systemic. It is believed that the most toxic species are small aggregates, referred to as oligomers, rather than the final fibrillar assemblies. Their mechanisms of toxicity are mostly mediated by aberrant interactions with the cell membranes, with resulting derangement of membrane-related functions. Much effort is being put in the search for natural antiamyloid agents, and/or in the development of synthetic molecules. Actually, it is well documented that the prevention of amyloid aggregation results in several cytoprotective effects. Here, we portray the state of the art in the field. Several natural compounds are effective antiamyloid agents, notably tetracyclines and polyphenols. They are generally non-specific, as documented by their partially overlapping mechanisms, and the capability to interfere with the aggregation of several unrelated proteins. Among rationally designed molecules, we mention the prominent examples of β-breakers peptides, whole antibodies and fragments thereof, and the special case of drugs contrasting transthyretin aggregation. In this framework, we stress the pivotal role of the computational approaches. When combined with biophysical methods, in several cases they have helped clarify in detail the protein/drug modes of interaction, which make it plausible that more effective drugs will be developed in the future.

Abstract Background: Occipital neuralgia is a debilitating condition and traditional treatments often provide limited or temporary relief. Recently, ultrasound-guided hydrodissection of the greater occipital nerve (GON) has emerged as a promising minimally invasive approach. Objectives: To describe two novel ultrasound-guided hydrodissection with 5% dextrose for GON and discuss their advantages, disadvantages, and considerations. Methods: Two case reports are presented. Case 1 describes a lateral decubitus approach for hydrodissecting the GON between the semispinalis capitis (SSC) and obliquus capitis inferior (OCI) muscles. Case 2 details a cranial-to-caudal approach for hydrodissecting the GON within the SSC and upper trapezius (UT) muscles when the GON pass through these two muscles. Results: Both patients experienced significant and sustained pain relief with improvements in function and quality of life. Conclusions: Ultrasound-guided GON hydrodissection using 5% dextrose is a promising treatment for occipital neuralgia. The lateral decubitus and cranial to caudal approaches provide additional options to address patient-specific anatomical considerations and preferences.

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease due to the absence of effective therapies. A more comprehensive understanding of molecular events, encompassing the dysregulation of microRNAs (miRs) and metabolic reprogramming, holds the potential to unveil precise mechanisms underlying mCRPC. This study aims to assess the expression of selected serum exosomal miRs (miR-15a, miR-16, miR-19a-3p, miR-21, and miR-141a-3p) alongside serum metabolomic profiling and their correlation in patients with mCRPC and benign prostate hyperplasia (BPH). Blood serum samples from mCRPC patients (n=51) and BPH patients (n=48) underwent metabolome analysis through 1H-NMR spectroscopy. The expression levels of serum exosomal miRs in mCRPC and BPH patients were evaluated using quantitative real-time polymerase chain reaction (qRT‒PCR). The 1H-NMR metabolomics analysis revealed significant alterations in lactate, acetate, citrate, 3-hydroxybutyrate, and branched-chain amino acids (BCAAs, including valine, leucine, and isoleucine) in mCRPC patients compared to BPH patients. MiR-15a, miR-16, miR-19a-3p, and miR-21 exhibited a down-regulation of more than twofold in the mCRPC group. Significant correlations were predominantly observed between lactate, citrate, acetate, and miR-15a, miR-16, miR-19a-3p, and miR-21. The importance of integrating metabolome analysis of serum with selected serum exosomal miRs in mCRPC patients has been confirmed, suggesting their potential utility as clinical diagnostic markers.

Human arteries show structural and functional peculiarities according to the nutrient and oxygen needs of a specific vascular district. This architectural heterogeneity is reflected in the pathological setting of cardiovascular diseases (CVDs). Indeed, the responsiveness to cardiovascular risk factors, the morphological and molecular patterns are discriminating factors among CVDs affecting different vascular beds. Micro-RNAs (miRNAs) are endogenous regulators of gene expression and fine tuners of vascular cell differentiation, thus these non-coding RNAs can modulate the arterial heterogeneity. The identification of a miRNA signature artery-specific would be promising in the therapy of CVDs, especially in frail elderly patients. In the present review we will provide a concise description of the arterial tree heterogeneity on structural and cellular basis, mainly in the pathological context. Secondly, we will address the miRNA potential as crucial mediators of arterial heterogeneity focusing on abdominal aorta and femoral artery, with the final goal of strengthening the search of more targeted therapies in CVDs and stratification approaches in frail elderly patients.

Recently concluded, large-scale cancer genomics studies involving multiregion sequencing of primary tumors and paired metastases appear to indicate that many or most cancer patients have one or more “clonal" mutations in their tumors. Clonal mutations are those that are present in all of a patient’s cancer cells. Clonally mutated proteins can potentially be targeted by inhibitors or E3 ligase small molecule glues, but developing new small molecule drugs for each patient is not feasible currently. Achilles Therapeutics is currently the only company specifically targeting clonal mutations. However, they are doing so with tumor-derived T cells. To address the potential limitations of immunotherapy, I have devised another approach for exploiting clonal mutations, which I call “Oncolytic Vector Efficient Replication Contingent on Omnipresent Mutation Engagement” (OVERCOME). The ideal version of OVERCOME would likely employ a bioengineered facultative intracellular bacterium. The bacterium would initially be attenuated, but (transiently) reverse its attenuation upon clonal mutation detection.

Melanoma is the most aggressive form of skin cancer. In the advanced stage of development it is resistant to currently available therapeutic modalities. Increased invasiveness and metastatic potential depend on a number of proteins involved in various signal transduction pathways. Hippo signaling plays an important role in malignant transformation. Dysfunctions of the Hippo pathway initiate the expression of tumor growth factors and is associated with tumor growth and metastasis formation. This review summarizes the recent achievements in studying the role of the Hippo pathway in melanoma pathogenesis and points to the potential specific targets for anti-melanoma therapy.

Claudins are a family of 27 proteins that have an important role in the formation of tight junc-tions. They also have an important function in ions exchange, cell mobility, and in in the epitheli-al-to-mesenchymal transition, the latter being very important in cancer invasion and metastasis. Therapeutic targeting of claudins has been investigated to improve cancer outcomes. Recent evi-dence shows improved outcomes when combining monoclonal antibodies against Claudin 18.2 with chemotherapy for patients with gastroesophageal junction cancer. Currently Chimeric anti-gen receptor T-cells targeting Claudin 18 are under investigation.

Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas’ associated with poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas’ still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained under-represented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa.

The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer.

Background/Aims: Screening for gestational diabetes mellitus (GDM) are currently done at 24 - 28 weeks of conception, missing out on the most vulnerable period of organogenesis and thus preventing clinicians from starting treatments until the late second or third trimester. MicroRNAs (miR) are small non-coding RNA molecules that could aid in detecting or predicting GDM through establishing a novel non-invasive prenatal testing (NIPT) tool. The objective of this study was to summarize the most recent updates on plasma microRNAs as GDM diagnostic biomarkers. Methods: Between April and June 2021, a PubMed literature search was undertaken to review recent articles on human plasma miR associated with GDM. Animal studies and papers that are written in languages other than English were excluded. Only plasma miRNAs were used to avoid coagulation biases. Results: A total of 31 miRNAs were found significantly upregulated in the plasma samples of patients with GDM. It was found mainly during the 2nd or 3rd trimester except for miR-223 and miR-23a that were upregulated at 9 – 11 weeks of gestation. Conclusion: Though extensive prospective cohort studies are required, miR-223 and miR-23a should be considered the most promising to develop a successful NIPT tool because they were found to be upregulated earliest, during the first trimester.

Cell membrane-derived liposomes, termed Memposomes, serve as promising carriers for drug delivery due to their ability to closely mimic cells and efficiently target specific cells. Liposomes derived from cancer cell membranes, in particular, exhibit homologous targeting capabilities, making them potential candidates for cancer-specific drug delivery. However, the underlying mechanisms and specific proteins responsible for this homologous targeting phenomenon remain debated. This study focuses on the role of E-cadherin, a cell adhesion molecule implicated in homophilic adhesion, in influencing the homologous targeting ability of Memposomes derived from cancer cell membranes. E-cadherin expression patterns were assessed in various cell lines, categorizing them into E-cadherin-positive and -negative groups. Memposomes were produced for each group, and their targeting tendencies were evaluated. The study confirmed that E-cadherin expression significantly influenced the homologous targeting ability of Memposomes. Cell lines with higher E-cadherin expression levels exhibited a more pronounced homologous targeting effect. This research demonstrates that cell adhesion molecules, particularly E-cadherin involved in homophilic adhesion, play a pivotal role in influencing the cell targeting ability of Memposomes. The study further validates the stability, safety, and purity of Memposomes, emphasizing their potential as effective drug delivery vehicles for the development of cell-specific therapies.

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), and nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres, 100-300 nm in size, loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than nonspecific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study shows the potential for anticancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labelling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier for precisely targeting tumors. This combination has the potential to produce anti-tumor effects in active targeted therapy of GBM.

Cachexia is a complex metabolic syndrome characterized by loss of skeletal muscle, leading to a significant weight loss that impacts patient morbidity and mortality. Given the complexity of gene regulatory networks that control gene expression, our objective was to perform an integrative mRNA and miRNA profiling to identify genetic programs that capture essential mechanistic details that promote muscle atrophy in cancer cachexia. Here, we used RNA sequencing to analyze miRNAs and mRNAs expression profiles in tibialis anterior (TA) muscles of the Lewis lung carcinoma model of cancer cachexia. In addition, we compared these findings with RNA-Seq data from C2C12 myotubes treated in vitro with the cachectic factors tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). Extracellular matrix (ECM) alterations were validated by picrosirius staining, western blot, and fractal dimension analyses. We found 1,008 mRNAs and 18 miRNAs differentially expressed in cachectic mice. This set of genes was associated with the ECM, proteolysis, and inflammatory response. Enrichment analysis of transcriptional factor binding sites revealed activation of the atrophy-related transcriptional factors: NF-κB, Stat3, AP-1, and FoxO. Furthermore, the integration of mRNA and miRNA expression profiles identified post-transcriptional regulation by miRNAs of genes involved in ECM organization, cell migration, transcription factors binding, ion transport, and FoxO signaling pathway. C2C12 myotubes treated with TNF-α and IFN-γ similarly down-regulate subsets of ECM genes, including collagens. Our integrative analysis of miRNA-mRNA co-profiles comprehensive characterized regulatory relationships of molecular pathways and revealed miRNAs targeting ECM-associated genes in cancer cachexia. We also confirmed in C2C12 myotubes that changes in ECM-associated genes are dependent on inflammatory signaling of the cytokines TNF-α and IFN-γ.

MicroRNAs (miRNAs) play a pivotal role in important biological processes by regulating posttranscriptional gene expression and exhibit differential expression patterns during development, immune responses, and stress challenges. The diamondback moth causes significant economic damage to crops worldwide. Despite substantial advancements in understanding the molecular biology of this pest, our knowledge regarding the role of miRNAs in regulating key immunity-related genes remains limited. In this study, we leveraged whole transcriptome resequencing data from P. xylostella infected with Metarhizium anisopliae to identify specific miRNAs targeting the prophenoloxidase-activating protease1 (PAP1) gene through bioinformatic analysis. Seven miRNAs (pxy-miR-375-5p, pxy-miR-4448-3p, pxy-miR-279a-3p, pxy-miR-3286-3p, pxy-miR-965-5p, pxy-miR-8799-3p and pxy-miR-14b-5p) were identified and validated. Luciferase reporter assays confirmed that pxy-miR-279a-3p binds to the open reading frame (ORF) and pxy-miR-965-5p to the 3’ untranslated region (3’ UTR) of PAP1. Our experiments demonstrated that injecting a pxy-miR-965-5p mimic significantly reduced PAP1 expression in P. xylostella larvae, suppressing PO activity and increasing larval mortality rate. Conversely, the injection of inhibitors obtained opposite results. Furthermore, we identified four LncRNAs (MSTRG.32910.1, MSTRG.7100.1, MSTRG.6802.1, and MSTRG.22113.1) that potentially interact with pxy-miR-965-5p. Interference assays using antisense oligonucleotides (ASO) revealed that silencing MSTRG.7100.1 and MSTRG.22113.1 increased the expression of pxy-miR-965-5p. These findings shed light on the potential role of pxy-miR-965-5p in the immune response of P. xylostella to M. anisopliae infection and provide a theoretical basis for biological control strategies targeting the immune system of this pest.

Numerous proteomic and transcriptomic studies have been carried out to better understand the current multi-variant SARS-CoV-2 virus mechanisms of action and effects. However, they are mostly centered on mRNAs and proteins. The effect of the virus on human post-transcriptional regulatory agents such as microRNAs (miRNAs) involved in the regulation of 60% of human gene activity remains poorly explored. Similar to what we have previously done with other viruses such as Ebola and HIV, in this study we investigated the miRNA profile of lung epithelial cells following infection with SARS-CoV-2. At the 24 and 72 hours post-infection, SARS-CoV-2 did not drastically alter the miRNome. About 90% of the miRNAs remained non-differentially expressed. The results revealed that miR-1246, miR-1290 and miR-4728-5p were the most upregulated over time. miR-196b-5p and miR-196a-5p were the most downregulated at 24 h while at 72 h, miR-3924, miR-30e-5p and miR-145-3p showed the highest level of downregulation. In the top significantly enriched KEGG pathways of genes targeted by differentially expressed miRNAs we found, among others, MAPK, RAS, P13K-Akt and renin secretion signaling pathways. By RT-qPCR, we also showed that SARS-CoV-2 may regulate several predicted host mRNA targets involved in the entry of the virus into host cells (ACE2, TMPRSS2, ADAM17 and FURIN), in renin–angiotensin system (RAS) (Renin, Angiotensinogen, ACE), innate immune response (IL-6, IFN1β, CXCL10, SOCS4) and fundamental cellular processes (AKT, NOTCH, WNT). Finally, we demonstrated by dual luciferase assay a direct interaction between miR-1246 and ACE-2 mRNA. This study highlights the modulatory role of miRNAs in the pathogenesis of SARS-CoV-2.

Atrial fibrillation (AF) is a form of sustained cardiac arrhythmia and microRNAs (miRs) play crucial roles in pathophysiology of AF. To identify novel miR-mRNA pairs, we performed RNAseq from atrial biopsies of AF and non-AF patients. Differentially expressed miRs (11-down and 9-up) and mRNAs (95-up and 82-down) were identified and hierarchically clustered in a heat-map. Subsequently, GO, KEGG, and GSEA analyses were run to identify deregulated pathways. Then, miR targets were predicted in miRDB database, and a regulatory network of negatively correlated miR-mRNA pairs was constructed using Cytoscape. To select potential candidate genes from GSEA analysis, top-50 enriched genes in GSEA were overlaid with predicted targets of differentially deregulated miRs. Besides, protein-protein-interaction (PPI) network of enriched genes in GSEA was constructed, and subsequently GO and canonical pathway analyses were run for genes in PPI network. Our analyses showed that TNF-α, p53, EMT, and SYDECAN1 signaling were among the highly affected pathways in AF samples. SDC-1 (syndecan-1) was the top-enriched gene in p53, EMT, and SYDECAN1 signaling. Consistently, SDC-1 mRNA and protein levels were significantly higher in atrial samples of AF patients. Among negatively correlated miRs, miR-302b-3p was experimentally validated to suppress SDC-1 transcript levels. Overall, our results suggested that miR-302b-3p/SDC-1 axis may involve in pathogenesis of AF.

Despite significant strides in prevention, diagnosis, and treatment, cardiovascular diseases remain the number one cause of mortality in the United States, with rates climbing at an alarming rate in the developing world. Targeted delivery of therapeutics to the heart has been a lofty goal to achieve with strategies ranging from direct intra-cardiac or intra-pericardial delivery, intra-coronary infusion, to adeno-associated viral vectors which have preference, if not complete cardio-selectivity, for cardiac tissue. Cell penetrating peptides (CPP) are 5-30 amino acid long peptides that are able to breach cell membrane barriers while carrying cargoes up to several times their size, in an intact functional form. Identified nearly three decades ago, the first of these CPPs came from the HIV coat protein transactivator of transcription. Although a highly efficient CPP, its clinical utility is limited by its robust ability to cross any cell membrane barrier, including crossing the blood-brain barrier and transducing neuronal tissue non-specifically. Several strategies have been utilized to identify cell or tissue specific CPPs, one of which is phage display. Using this latter technique, we identified a cardiomyocyte targeting peptide (CTP) more than a decade ago, a finding that has been corroborated by several independent labs across the world that have utilized CTP for myriad different purposes in pre-clinical animal models. The goal of this publication is to provide a comprehensive review of the identification, validation, and application of CTP, and outlining its potential in diagnostic and therapeutic applications especially in the field of targeted RNA interference.

Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment of non-small cell lung cancer (NSCLC) with MET mutations. It is also being investigated as a treatment for breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. In both preclinical and clinical studies, it has demonstrated efficacy in lung, kidney, and stomach cancers. Savolitinib is an oral anti-cancer medication taken as a 600 mg dose once daily. It can be used as a monotherapy in patients with non-small cell lung cancer with MET mutations, and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who have developed resistance to them. Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer.

Overexpression of BRF2, a selective subunit of RNA polymerase III, has been shown to be crucial in the development of several types of cancers, including breast cancer and lung squamous cell carcinoma . Predominately, BRF2 acts as a central redox-sensing transcription factor (TF) and is involved in rescuing oxidative stress (OS) -induced apoptosis. Here, we showed a novel link between BRF2 and DNA damage response. Due to the lack of BRF2 specific inhibitors, through virtual and molecular dynamics screening, we identified potential drug candidates that interfere with BRF2-TATA-binding Protein (TBP)-DNA complex interactions based on binding energy, intermolecular, and torsional energy parameters. We experimentally tested Bexarotene as a potential BRF2 inhibitor. We found that Bexarotene (Bex) treatment resulted in a dramatic decline in oxidative stress (Tert-butylhydroquinone (tBHQ))-induced levels of BRF2 and consequently, lead to a decrease in cellular proliferation of cancer cells which may in part be due to drug pretreatment induced reduction of ROS generated by the oxidizing agent. Our data thus, provide the first experimental evidence that BRF2 is a novel player in DNA damage response pathway and Bexarotene can be used as a potential inhibitor to treat cancers with the specific elevation of oxidative stress.

Abstract: Age-related macular degeneration (AMD) is the leading cause of central blindness in developed countries. It affects people mainly over the age of 50 years. It is a disease of the macula, an area of the retina responsible for sharp central vision. It particularly affects the Bruch’s membrane (BM); a layer in the retina that acts as the basement upon which retinal pigment epithelial cells (RPE) attach and survive. The pathology of AMD is not fully understood, but age is considered the main risk factor. There are two forms; nonexudative, leading to the end-stage of the disease, called nonexudative (or dry) AMD (90% of cases) where fatty deposits called drusen form under the RPE on top of the BM lifting off the RPE, and neovascular (or wet) AMD (10% of cases) where abnormal new blood vessels grow and push through the BM, bleeding in and disrupting the RPE. Neovascular AMD is well controlled with regular antiangiogenic drug injections of anti-vascular endothelial growth factor (anti-VEGF) into the eye, whereas there is no current treatment for nonexudative AMD. Many research groups across the world are working on a treatment for nonexudative AMD. This review discusses the research currently being conducted including cell therapies, development of cell transplantation membranes, targeting other disease structures in affected retina (i.e. drusen), and drug delivery to the retina using nanoparticles. Finally, we include our research contributing to the field; developing a bioactive membrane intended to function two-fold: target diseased structures and transplant healthy RPE to the desired area.

The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of ‘checkpoint blockade’ and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient’s own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function. The production of extracellular adenosine is mediated by the cell surface ectoenzymes CD73, CD39 and CD38 and therapeutic agents have been developed to target these as well as the downstream adenosine receptors (A₁R, A_2AR, A_2BR, A₃R) to enhance anti-tumor immune responses. This review will discuss the role of adenosine and adenosine receptor signaling in tumor and immune cells with a focus on their cell-specific function and their potential as targets in cancer immunotherapy.

During last decades multiple therapeutic approaches have been explored for improved management of peritoneally disseminated malignancies – a grim condition known as peritoneal carcinomatosis (PC). Intraperitoneal administration can be used to achieve elevated local concentration and extended half-life of the drugs in the peritoneal cavity to improve their anticancer efficacy. However, IP-administered chemotherapeutics have a short residence time in the IP space, and are not tumor selective. An increasing body of work suggests that functionalization of drugs and nanoparticles with targeting peptides increases their peritoneal retention and provides a robust and specific tumor binding and penetration that translates into improved therapeutic response. Here we review a progress in affinity targeting of intraperitoneal anticancer compounds, imaging agents and nanoparticles with tumor homing peptides. We review classes of tumor homing peptides relevant for PC targeting, payloads for peptide-guided precision delivery, applications for targeted compounds and the effects of nanoformulation of drugs and imaging agents on affinity-based tumor delivery.

Due to the complexity of Alzheimer's disease, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted lipid nanoemulsion) are available. Versatile small molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted LCM/ND lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly SR-BI), making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such film-stabilized microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient.

Emerging evidence has shown that microRNAs play pivotal roles in wound healing. MicroRNA-21 (miR-21) was previously found to upregulate in order to fulfill an anti-inflammation role for wounds. Exosomal miRNAs have been identified and explored as essential markers for diagnostic medicine. However, the role of exosomal miR-21 in wounds has yet to be well studied. In order to facilitate the early management of poorly healing wounds, we developed an easy-to-use, rapid, paper-based microfluidic-exosomal miR-21 extraction device to determine wound prognosis in a timely manner. We isolated and then quantitatively examined exosomal miR-21 in wound fluids from normal tissues, acute and chronic wounds. Eight improving wounds displayed lower levels of exosomal miR-21 expression after wound debridement. However, four instances of increased exosomal miR-21 expression levels were notably associated with patients with poor healing wounds despite aggressive wound debridement, indicating a predictive role of tissue exosomal miR-21 for wound outcome. Paper-based nucleic acid extraction device provides a rapid and user-friendly approach for evaluating exosomal miR-21 in wound fluids as a means of monitoring wounds. Our data suggest that tissue exosomal miR-21 is a reliable marker for determining current wound status.

Background: Breast cancer is the leading cause of cancer mortality and morbidity among Indonesian women. Identification of biological pathways leading into therapeutic resistance through in vitro model is an important step to develop alternative effective therapy in breast cancer. Loss of PTEN expression has been associated with resistance to chemotherapy by involving PI3K/PTEN- dependent apoptosis pathway. We conducted in vitro experiment to investigate the association of hsa-miR-21 and PTEN expression in Doxorubicin-resistant MCF-7 cell line. Methods: Parental MCF-7 cells were periodically incubated with Doxorubicin to obtain specific Dox-resistant variant determined by IC50 using MTT assay. PTEN protein expression was analyzed using immunocytochemistry. Expression of mature has-miR-21 was measured using qRT-PCR. Results: The IC50 of Doxorubicin in parental MCF-7 and Doxorubicin-resistant MCF-7 cells (MCF-7/Dox) was 0.68 and 5.78 µg/ml, respectively. Hsa-miR-21 was significantly overexpressed in MCF-7/Dox cells compared to parental MCF cells (7.94 fold changes). Conclusion: PTEN and hsa-miR-21 expression levels were negatively correlated in Doxorubicin resistant-MCF cells. Further study to confirm the causal relationship of miR-21 overexpression and PTEN downregulation in MCF-7/Dox is required.

Non-alcoholic steatohepatitis (NASH) is a clinically serious stage of non-alcoholic fatty liver disease (NAFLD). Histologically characterized by hepatocyte ballooning, immune cell infiltration and fibrosis, NASH at a molecular level involves lipid induced hepatocyte death and cytokine production. Currently, there are very few diagnostic biomarkers available to screen NASH, and no pharmacological intervention is available for its treatment. In this study, we show that hepatocyte damage by lipotoxicity results in the release of extracellular RNAs (eRNAs) which serve as damage-associated molecular patterns (DAMPs) that stimulate the expression of pro-apoptotic and pro-inflammatory cytokines, aggravating inflammation, and cell death in HepG2 cells. Furthermore, the inhibition of eRNA activity by RNase 1 significantly increased cellular viability and reduced NF-kB mediated cytokine production. Similarly, RNase 1 administration significantly improved hepatic steatosis, inflammatory and injury markers in a murine NASH model. This study, therefore, for the first time, underscores the therapeutic potential of inhibiting eRNA action as a novel strategy for NASH treatment.

Advances in nanomedicine bring the attention of researchers to the molecular targets which can play a major role in the development of novel therapeutic and diagnostic modalities for cancer management. The choice of a proper molecular target can decide on the efficacy of the treatment and endorse the personalized medicine approach. Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled membrane receptor, well known to be overexpressed in numerous malignancies including pancreatic, prostate, breast, lung, colon, cervical and gastrointestinal cancers. Therefore, many research groups express a deep interest in targeting GRPR with their nanoformulations. A broad spectrum of the GRPR ligands has been described in the literature, which allows tuning of the properties of the final formulation, particularly in the field of the ligand affinity to the receptor and internalization possibilities. Hereby the recent advances in the field of applications of various nanoplatforms which are able to reach the GRPR expressing cells are reviewed.

Acute lymphoblastic leukemia is the most common malignancy in children and is characterized by numerous genetic and epigenetic abnormalities. Epigenetic mechanisms, which involve DNA methylations and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. Emerging studies are increasing our understanding of the epigenetic role of leukemogenesis and have demonstrated the potential of DNA methylations and histone modifications as a biomarker for lineage and subtypes classification, predicting relapse, and disease progression in ALL. Epigenetic abnormalities are relatively reversible when treated with some small molecule-based agents compared to genetic alterations. In this review, we conclude the genetic and epigenetic characteristics in ALL and discuss the future role of DNA methylation and histone modifications in predicting relapse, finally focus on the individual and precision therapy targeting epigenetic alterations.

Methotrexate (MTX), a structurally related substance to folic acid, is an important chemotherapeutic agent used for decades in the treatment of pediatric acute lymphoblastic leukemia (ALL) and other types of cancer as non Hodgkin lymphomas and osteosarcomas. Despite the successful outcomes observed, the primary drawback is the variability in the pharmacokinetics and pharmacodynamics between patients. The main adverse events related to its use are mainly nephrotoxicity, mucositis and myelosuppression especially when used in high doses. The potential adverse reactions and toxicities associated with MTX are a cause for concern and may lead to dose reduction or treatment interruption. Genetic variants in MTX transport genes have been linked to toxicity. Pharmacogenetic studies conducted in the past focused on single nucleotide polymorphisms (SNPs) in the coding and 5′-regulatory regions of genes. Recent studies have demonstrated a significant role of miRNAs in the transport and metabolism of drugs, and in the regulation of target genes. The last few years, the number of annotated miRNAs is continually rising, as well as the studies of miRNA polymorphisms and MTX toxicity. Therefore, the objective of the present study is to investigate the role of miRNA variants related to MTX adverse effects.

Abstract: (1) Background and Objective: MicroRNAs (miR) are biomarkers for assessing the extent of cardiac remodeling after myocardial infarction (MI) and important predictors of clinical outcome in heart failure. Overexpression of miR-30d appears to have a cardioprotective effect. The aim of the present study was to demonstrate whether miR-30d could be used as a potential therapeutic target to improve post-MI adverse remodeling. (2) Methods and Results: MiR profiling was performed by next generation sequencing to assess different expression patterns in ischemic vs. healthy myocardium in a rat model of MI. MiR-30d was significantly downregulated (p&lt;0.001) in ischemic myocardium and was selected as promising target. A mimic of miR-30d was administered in the respective treatment group, whereas control group received non-functional, scrambled siRNA. To measure the effect of miR-30d on infarct area size of left ventricle, rats were randomized and treated with miR-30d or scrambled siRNA. Histological planimetry was performed 72 hours and 6 weeks after induction of MI. Infarct area was significantly reduced at 72 hours and at 6 weeks by using the miR-30d (72 hours: 22.89±7.66% vs. 35.96±9.27%, p=0.0136; 6 weeks: 6.93±4.58% vs. 12.48±7.09%; p=0.0172). To gain insight into infarct healing, scratch assays were used to obtain information on cell migration in human umbilical vein endothelial cells (HUVEC). Gap closure was significantly faster in the mimic-treated cells 20h post-scratching (12.4% more than scrambled control after 20h; p=0.013). To analyze anti-apoptotic quality of miR-30d, the ratio between phosphorylated p53 and total p53 was evaluated in human cardiomyocytes using ELISA. Under the influence of miR-30d mimic, cardiomyocytes demonstrated a decreased pp53/total p53 ratio (0.66±0.08 vs. 0.81±0.17), showing a distinct tendency (p=0.055) to decrease apoptosis rate compared to the control group. (3) Conclusion: Using a mimic of miR-30d underlines the cardioprotective effect of miR-30d in MI and could reduce the risk for development of ischemic cardiomyopathy.

Locally advanced rectal cancer (LARC) has traditionally been treated with trimodality therapy consisting of neoadjuvant radiation +/- chemotherapy, surgery and adjuvant chemotherapy. There is currently a clinical need for biomarkers to predict treatment response and outcomes, especially during neoadjuvant therapy. Liquid biopsy in the form of circulating tumour cells (CTCs) and circulating nucleic acids in particular microRNAs (miRNA) are novel, highly stable and clinically relevant regulators of disease. We studied a prospective cohort of 52 patients with LARC, and obtained samples at baseline, during treatment, and post-treatment. We enumerated CTCs during chemoradiation at these three time-points, using the IsofluxTM CTC Isolation and detection platform. We then subjected the isolated CTCs to miRNA expression analyses, using a panel of 106 miRNA candidates. We identified CTCs in 73% of patients at baseline, and numbers fell during treatment and miRNA expression profiles also changed during treatment. Between baseline and during treatment (week 3) time-points three microRNAs (hsa-miR-95, hsa-miR-10a and hsa-miR-16-1*) were highly differentially expressed. Importantly, hsa-miR-19b-3p and hsa-miR-483-5p were found to correlate with good response to treatment. The latter (hsa-miR-483-5p) was also found to be differentially expressed between good responders and poor responders. They represent potential predictive biomarkers and a potential miRNA-based treatment strategy. In this study, we demonstrate that CTCs are present and can be isolated in the non-metastatic early stage cancer setting, and their associated miRNA profiles can potentially be utilized to predict treatment response.

The diagnosis and treatment of autoimmune diseases are major challenges. Their signs, symptoms, and their clinical severity change throughout the course of the disease. The available treatments for these conditions do not result in complete remission, and their long-term use generates several side effects. The main challenges in this field are the development of more sensitive diagnostic tools, and effective treatments. Studies in patients and animal models reported alterations in monocyte phenotype, activation, and function. These cells play an essential role in the pathogenesis of chronic inflammatory states and have become a target for extracorporeal monitoring and specific intervention. Nanoparticles (NPs) are ultrafine particles that can be used as contrast agents in diagnostic imaging techniques to detect specific cells in inflammatory infiltrates in tissues that are not easily accessible by biopsy. In addition, NPs can be designed to deliver drugs to a cell population or tissue. This review describes several experimental pieces of evidence demonstrating that monocytes and macrophages can specifically uptake various types of NPs, thus becoming detectable in vivo by magnetic resonance imaging and susceptible to be modulated by therapeutic agents. Hence, nanoparticles targeting mononuclear phagocytes represent promising tools for diagnosing and treatment.

Amino acid metabolism promotes cancer cell proliferation and survival by supporting building block synthesis, producing reducing agents to mitigate oxidative stress, and generating immunosuppressive metabolites for immune evasion. Malignant cells rewire amino acid metabolism to maximize their access to nutrients. Amino acid transporter expression is upregulated to acquire amino acids from the extracellular environment. Under nutrient depleted conditions, macropinocytosis can be activated where proteins from the extracellular environment are engulfed and degraded into the constituent amino acids. The demand for non-essential amino acids (NEAAs) can be met through de novo synthesis pathways. Cancer cells can alter various signaling pathways to boost amino acid usage for the generation of nucleotides, reactive oxygen species (ROS) scavenging molecules and oncometabolites. The importance of amino acid metabolism in cancer proliferation makes it a potential target for therapeutic intervention, including via small molecules and antibodies. In this review, we will delineate the targets related to amino acid metabolism and promising therapeutic approaches.

Cystic Fibrosis (CF) is an inherited monogenic disorder, amenable to gene based therapies. Because CF lung disease is currently the major cause of mortality and morbidity, and lung airway is readily accessible to gene delivery, the major CF gene therapy effort at present is directed to the lung. Although airway epithelial cells are renewed slowly, permanent gene correction through gene editing or targeting in airway stem cells is needed to perpetuate the therapeutic effect. Transcription activator-like effector nuclease (TALEN) has been utilized widely for a variety of gene editing applications. The stringent requirement for nuclease binding target sites allows for gene editing with precision. In this study, we engineered helper-dependent adenoviral (HD-Ad) vectors to deliver a pair of TALENs together with donor DNA targeting the human AAVS1 locus. With homology arms of 4 kb in length, we demonstrated precise insertion of either a LacZ reporter gene or a human CFTR minigene into the target site. Using the LacZ reporter, we determined the efficiency of gene integration to be about 5%. In the CFTR vector transduced cells, we have detected both CFTR mRNA and protein expression by qPCR and Wetern analysis, respectively. We have also confirmed CFTR function correction by flurometric Image Plate Reader (FLIPR) and iodide efflux assays. Taking together, these findings suggest a new direction for future in vitro and in vivo studies in CF gene editing.

Long gone was the time when tumors were thought to be insular masses of cells, residing independently at specific sites in an organ. Now, researchers gradually realize that tumors interact with the extracellular matrix (ECM), blood vessels, connective tissues and immune cells in their environment, which is now known as the tumor microenvironment (TME). It is found that the interactions between tumors and their surrounding promote tumor growth, invasion and metastasis. The dynamics and diversity of TME cause the tumors to be heterogeneous and thus pose a challenge for cancer diagnosis, drug design and therapy. As TME is significant in enhancing tumor progression, it is vital to identify the different components in the TME. This review explores how different factors in the TME supply tumors with the required growth factors and signaling molecules to proliferate, invade and metastasis. We also examine the development of TME-targeted nanotheranostics over the recent years for cancer therapy, diagnosis and anticancer drug delivery system. This review further discusses the limitations and future perspective of nanoparticle based theranostics when used in combination with current imaging modalities like Optical Imaging, Magnetic Resonance Imaging (MRI) and Nuclear Imaging (PET and SPECT).

Adamantinomatous Craniopharyngioma (ACP) is a rare epithelial tumor located in the craniopharyngeal duct, often associated with high morbidity and a high long-term recurrence rate. ACP is predominantly diagnosed in children below the age of 15 and accounts for a majority of Craniopharyngioma cases in the United States. It is most commonly caused by a mutation in exon 3 of the CTNNB1 gene, which promotes overaccumulation of β-Catenin in the WNT pathway. As β-Catenin accumulates, it over-activates the transcription factor, causing an over-transcription of WNT proteins and uncontrolled cell growth. Current methods of treatment for ACP are centered around surgical intervention and radiotherapy, including gross-total resection (GTR), subtotal resection (STR), and a combination of subtotal resection and adjuvant radiotherapy (STR+XTR). These methods of treatment are associated with high risk due to the proximity of ACP to critical structures near the craniopharyngeal duct. High recurrence rates and morbidity are closely associated with current methods of treatment and other methods have yet to be attempted in craniopharyngioma. This review will explore two possible methods of non-surgical and non-radiological therapeutic interventions. The use of RNAi therapy and CRISPR may provide insight and be a potential way to treat ACP with increased quality of life and decreased recurrence rates.

Fibroblast activation protein (FAP) is a serine protease characterized by its high expression in cancer-associated fibroblasts (CAFs) and near absence in adult normal tissues and benign lesions. This unique expression pattern positions FAP as a prospective biomarker for targeted tumor radiodiagnosis and therapy. The advent of FAP-based radiotheranostics is anticipated to revolu-tionize cancer management. Among various types of FAP ligands, peptides and antibodies, have shown advantages over small molecules, exemplifying prolonged tumor retention in human volunteers. Within its scope, this review summarizes the recent research progress of the FAP radiopharmaceuticals based on antibodies and peptides, on tumor imaging and therapy. Additionally, it incorporates insights from recent studies, providing valuable perspectives on the clinical utility of FAP-targeted radiopharmaceuticals.

: Crohn’s disease (CD) is a multifactorial chronic disorder that involves a combination of factors as genetic, immune response and gut microbiota. Actually, the therapy comprises salicylates, immunosuppressive agents, corticosteroids, biologic drugs. International guidelines don’t recommend the use of antibiotics except for septic complications of CD patients. The increased evidence of the implication of gut bacteria in this chronic disease support the rationale for using antibiotics as primary treatment of active CD. In the last decades several pathogens have been reported to be involved in the development of CD, but only Escherichia coli (E.coli) species and Mycobacterium avium paratubercolosis (MAP), aroused the interest due to their strong association with CD pathogenesis. Several meta-analyses have been published concerning antibiotic treatment in CD patients but randomized trials of antibiotic treatments against E.coli and MAP did not show prolonged benefits, and only generated conflicting results so much so that several questions are still unresolved regarding trial design, antibiotic dosing, the formulation used, the treatment course and the outcome measures. In this article we attempted to provide an overview and update of the trials on antibiotic treatment in active CD patients taking into account the role of pathogens, the mechanism by which the different antibiotics act on harmful pathogens, and antibiotic resistance. Finally, we also tried to draw new lines for future studies to use antibiotics to treat active CD patients

Cancer have been known as a most important global mortality reason, which in spite of novel therapeutic ways, the leading death is still considerable. Molecular targeted diagnosis and therapy using aptamers with high affinity have converted to a popular technique for pathological angiogenesis and cancer therapy scientists. In this paper several aptamer-based diagnostic and therapeutic techniques such as aptamer-nanomaterial conjugation, aptamer-drug conjugation (physically or covalently) and biosensors, which successfully designed for biomarkers, are critically reviewed. The results obviously demonstrated that aptamer have potentially incorporated with targeted delivery systems and biosensors for detection of biomarkers which expressed by cancer cells. Aptamer-based therapeutic and diagnostic methods, as the main field of medical sciences, possess high potential in cancer therapy, pathological angiogenesis and increase of community health. The clinical use of aptamer is so limited due to unreliability resulted from targets impurities, inaccuracy in SELEX stages process, and in vitro synthesis which led to the lower selectivity for in vivo targets. Moreover, size behavior, probable toxicity, low-distribution and unpredictable behavior of nanomaterials in in vivo media make critical their usage in clinical assays. This review can be helpful for implementation and designing the future studies which are effective and applicable for clinical use.

Classical antibacterial drugs were designed to target specific bacterial properties distinct from host human cells to maximize potency and selectivity. These designs were quite effective as they could be easily derivatized to bear next generation drugs. However, the rapid mutation of bacteria and their associated acquired drug resistance have led to the rise of highly pathogenic superbug bacterial strains for which treatment with first line drugs is no match. More than ever, there is a dire need for antibacterial drug design that goes beyond conventional standards. Taking inspiration by the body’s innate immune response to employ its own supply of labile copper ions in a toxic attack against pathogenic bacteria, which have a very low Cu tolerance, this review article examines the feasibility of Cu-centric strategies for antibacterial preventative and therapeutic applications. Promising results are shown for the use of Cu-containing materials in the hospital setting to minimize patient bacterial infections. Studies directed at disrupting bacterial Cu regulatory pathways elucidate new drug targets that can enable toxic increase of Cu levels and perturb bacterial dependence on iron. Likewise, Cu intracellular chelation/prochelation strategies effectively induce bacterial Cu toxicity. Cu-based small molecules and nanoparticles demonstrate the importance of the Cu ions in their mechanism and display potential synergism with classical drugs.

Migraine is a neurovascular disorder that affects approximately 12% of the global population. While its exact causes are still being studied, researchers believe that nociceptors in the trigeminal ganglia play a key role in the pain signals of migraine. These nociceptors innervate the intracranial meninges and convey pain signals from the meninges to the thalamus. Targeting these nociceptors is considered promising due to their accessibility and distinct molecular profile, which includes the expression of several transient receptor potential (TRP) channels. These channels have been linked to various pain conditions, including migraine. This review discusses the role and mechanisms of nociceptors in migraine, the challenges of current antimigraine drugs, and the evidence for well-studied and emerging TRP channels, particularly TRPC4, as novel targets for migraine prevention and treatment.

There is an overarching need to find alternative treatment options for malaria and this quest is more pressing in current times due to the morbidity and mortality data arising from most endemic countries and partially owing to the fact that the SARS-Cov-2 pandemic has diverted much public health attention. Additionally, the therapeutic options available for malaria has been severely threatened with the emergence of resistance to almost all existing drugs by the human malaria parasite. The Artemisinin Combination Therapies (ACTs) which hitherto have been the mainstay for malaria have encountered resistance in South East Asia, a notorious ground zero for the emergence of antimalarial drug resistance. This review analyses few key druggable targets of the parasite and the potential to leverage strategic inhibitors to mitigate the scourge of malaria by providing a concise assessment of the essential proteins of the malaria parasite that could serve as targets. Furthermore, this work provides a summary of the advances made in malaria parasite biology and the potential to leverage such findings for antimalarial drug production.

Many cellular functions important for tumor initiation and progression are mediated by members of the integrin family, a diverse family of cell adhesion receptors. With recent studies emphasising on the role of the tumor microenvironment (TME) in tumor initiation and progression, it is not surprising that a lot of attention is being given to integrins. Several integrins are under trial with many demonstrating appealing activity in patients with different cancers. A deeper knowledge of the functions of integrins within the tumor microenvironment is still required, and might lead to better inhibitors being discovered. Integrin expression is commonly dysregulated in many tumors with integrins playing key roles in signaling as well as promotion of tumor cell invasion and migration. This review report new data on the differential expression of integrins within solid tumors using two publicly available resources: The Cancer Genomic Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA). In this analysis, I investigated the expression of integrin alpha 2 (ITGα2), ITGα3, ITGβ4 and ITGβ6 in tumor tissues versus adjacent normal tissues. This analysis showed that integrins were differentially expressed in cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), esophageal carcinoma (ESCA) and lung adenocarcinoma (LUAD). This analysis showed that ITGα2 and ITGβ6 expression are upregulated in CESC and ESCA, ITGα3 is upregulated in HNSC and ESCA whilst ITGβ4 is highly expressed in CESC, HNSC, ESCA and LUAD tumor tissues compared to adjacent normal tissues. Integrins also play a major role in adhesion of circulating tumor cells to new sites and the resulting formation of secondary tumors. Furthermore, integrins have demonstrated the ability to promoting stem cell-like properties in tumor cells as well as drug resistance. Anti-integrin therapies rely heavily on the doses or concentrations used as these determine whether the drugs act as antagonists or as integrin agonists. This review offers the latest synthesis in terms of current knowledge of integrins functions within the tumor microenvironment and potential targets for different cancers.

The most recent outbreak of 2019 novel coronavirus, named as COVID-19, caused pneumonia epidemic in Wuhan with 2,121 deaths cases as of February 20^th 2020. Identification of effective antiviral agents to combat the novel coronavirus is urgently needed. Citrus fruit peel or wild citrus are rich in flavonoid, and is clinically documented for roles in relief of cough and promotion of digestive health. Therefore, citrus fruits are assumed to possess antivirus activities or enhance the host immunity. A previous study found that hesperetin could act as a high potent inhibitor of SARS-CoV 3CLpro. We determined six flavonoid compounds content of in three citrus species by using LC-MS technique. The content of naringin and naringenin was at higher levels in pummelo. Hesperetin and hesperidin were highly accumulated in mandarin and sweet orange. The subsequent in vitro and in vivo experiments indicated that naringin could inhibit the expression of the proinflammatory cytokines (COX-2, iNOS, IL-1β and IL-6) induced by LPS in Raw macrophage cell line, and may restrain cytokine through inhibiting HMGB1 expression in a mouse model. The results revealed that naringin may have a potential application for preventing cytokine storm. We simulated molecular docking to predict the binding affinity of those flavonoids to bind Angiotensin-converting enzyme 2 (ACE 2), which is a receptor of the coronavirus. Consideration of the potential anti-coronavirus and anti-inflammatory activity of flavonoids, the citrus fruit or its derived phytochemicals are promising in the use of prevention and treatment of 2019-nCoV infection.

Dengue virus (DENV) and chikungunya virus (CHIKV) are reemergent arboviruses that are transmitted by mosquitoes of the Aedes genus. During the last several decades, these viruses have been responsible for millions of cases of infection and thousands of deaths worldwide. Therefore, several investigations were conducted over the past few years to find antiviral compounds for the treatment of DENV and CHIKV infections. One attractive strategy is the screening of compounds that target enzymes involved in the replication of both DENV and CHIKV. In this review, we describe advances in the evaluation of natural products targeting the enzymes involved in the replication of these viruses.

Brain stem cells (neural stem cells or NSCs) and neurons of a chosen kind reprogramming is a potential technique for cell therapy. It is possible to reprogram non-neuronal cells, for example, by using a predetermined group of factors, nuclear transfer, and the induced transcriptional factors (TFs) expression in a related lineage of cells, and non-coding microRNAs (miRNAs). Researchers have additionally been attempting to improve reprogramming methods, whether it is by employing unique sets of biomolecules and particular TFs or by delivering relevant miRNA and Biomolecules. The technique of miRNA mediated is intriguing for its capability to quickly create a range of biologically desirable cell types for therapy from different lineages of cells. Current findings have made significant advancements towards changing the somatic cells to diverse particular neuronal subgroups with greater efficiency, using reprogramming of miRNA-mediated neural cells, despite the fact that the precise processes need to be discovered. To further understand how miRNAs might direct somatic cells to become neural, we need to look at the latest research on their function in neural reprogramming over the differentiated cells. Recent findings on the role of miRNAs in the initiation of cell reprogramming and the determination of the neuronal subtype's destiny are the primary focus of this comprehensive overview. Furthermore, we cover the far more latest results concerning certain miRNAs' activity in controlling different phases of neuronal differentiation, which contributes in comprehending the interaction network of miRNAs and their receptors.

Background: Molecular genetic events are among the numerous factors affecting the clinical course of papillary thyroid carcinoma (PTC). Recent studies have demonstrated that aberrant expression of miRNA, as well as different thyroid-related genes, correlate with the aggressive clinical course of PTC and unfavorable treatment outcome, which opens up new avenues for using them in personalization of the treatment strategy for patients with PTC. In the present work, our goal was to assess the applicability of molecular markers in preoperative diagnosis of aggressive variants of papillary thyroid cancer. Methods: The molecular genetic profile (expression levels of 34 different markers and BRAF mutation) was studied for 108 cytology specimens collected by fine-needle aspiration biopsy in patients with PTC having different clinical manifestations. Results: Statistically significant differences with adjustment for multiple comparisons (p &lt; 0.0015) for clinically aggressive variants of PTC were obtained for four markers: miRNA-146b, miRNA-221, FN1, and CDKN2A. Weak statistical correlation (0.0015&lt; р&lt;0.05) was observed for miRNA-31, -375, -551b, -148b, -125b, mtDNA, CITED1, TPO, HMGA2, CLU, NIS, SERPINA1, TFF3, and TMPRSS4. Conclusions: The recurrence risk of papillary thyroid carcinoma can be preoperatively predicted using miRNA-221, the fibronectin and cyclin-dependent kinase inhibitor 2A genes.

Nutritional management of depression has long been discussed due to the perceived benefit of a nutritional product having less side effects than pharmaceutical agents. Candidate nutrients for managing depression include Vitamin D, B-vitamins, tryptophan, branch chain amino acids, probiotics, omega-3 fatty acids, folate/methylfolate (aka Vitamin B9), and s-adenosylmethionine. This paper reviews three nutrients which have significant scientific support for the management of depression and have evidence of low levels in subjects with depression, and that correction of the nutritional deficiency provides clinical benefit. We present epidemiological evidence, mechanistic explanation and a review of interventional studies for these nutrients. Finally, relevant nutritional guidelines are presented with their conclusion for the role of each nutrient in the management of depression.

N-methyl-D-aspartate receptors (NMDARs) are the main class of ionotropic receptor for the ex-citatory neurotransmitter glutamate. It plays a crucial role in the permeability of Ca2+ ions and excitatory neurotransmission in the brain. Being heteromeric receptors, they are composed of sev-eral subunits, including two obligatory GluN1 subunits (eight splice variants) and regulatory GluN2 (GluN2A~D) and/or GluN3 (GluN3A~B) subunits. Widely distributed in the brain, they regulate other neurotransmission systems and are therefore involved in essential functions such as synaptic transmission, learning and memory, plasticity, excitotoxicity. The present review will discuss the physiopathological impacts of NMDAR and particularly GluN2A and GluN2B subu-nits in cognitive processes and neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease). The pharmacology of different NMDAR antagonists and their po-tentialities will be presented. In particular, a focus will be given on fluoroethylnormemantine (FENM), an investigational drug with very promising developments as a tomography radiotracer for NMDARs, an anxiolytic in post-traumatic stress disorder and a neuroprotective agent in Alzheimer's disease.

Solid tumors are composed of a highly complex and heterogenic microenvironment, with increasing metabolic status, playing a crucial role in the clinical therapeutic outcome of conventional treatments and innovative tumor nanomedicines. Scientists, have devoted great effort in conquering the tumor microenvironment (TME) challenges, in respect of effective drug accumulation and activity in tumor site, overcoming the obstacles of abnormal vasculature, dense stroma and extracellular matrix, hypoxia, and pH gradient acidosis. In this conquest, nanomedicines targeting distinct TME features have flourished, in order to increase site specificity and deep penetration, for effective antitumor activity, and further reprogram TME promoting suppression of cancer stem cells and metastasis. Thereby, several successful nanomedicine therapeutics have been under clinical trials, and further applied in clinical practice. Various novel strategies have been employed in preclinical studies and clinical trials, among which nanomedicines based on biomaterial, that have shown great promise in improving the therapeutic efficacy, reducing side effects, and promoting synergistic activity for TME targeting. In this review, we have focused on the targeting mechanisms for solid TME by nanomedicines based on the application of natural and synthetic biomaterials. We have described critical formulations that have been considered for the design of stimuli-responsive nanomedicines for TME. The development of such systems, has significantly advanced the application of biomaterials, in combinational therapies and in immunotherapies, for improved effectiveness.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PC) that commonly emerges through a transdifferentiation process from prostate adenocarcinoma and evades conventional therapies. Extensive molecular research has revealed factors that drive lineage plasticity, uncovering novel therapeutic targets to be explored. A diverse array of targeting agents is currently under evaluation in pre-clinical and clinical studies with promising results in suppressing or reversing the neuroendocrine phenotype and inhibiting tumor growth and metastasis. This new knowledge has the potential to contribute to development of novel therapeutic approaches that may enhance clinical management and prognosis of this lethal disease.

Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways that play central roles in hepatocarcinogenesis. In particular, the EGFR/PI3K/Akt/mTOR signaling pathway in HCC has garnered renewed attention from both basic and clinical researchers. Preclinical studies in vitro and in vivo have shown the effectiveness of targeting the key components of this signaling pathway in human HCC cells. Thus, targeting these signaling pathways with small molecule inhibitors holds promise as a potential therapeutic option for patients with HCC. In this review, we will explore recent advancements in understanding the role of the EGFR/PI3K/Akt/mTOR signaling pathway in HCC and assess the effectiveness of targeting this signaling cascade as a potential strategy for HCC therapy based on preclinical studies

Abstract: OTUD6A is a deubiquitinase that plays crucial roles in various human diseases. However, the precise regulatory mechanism of OTUD6A remains unclear. In this study, we found that OTUD6A significantly inhibited the production of type I interferon. Consistently, peritoneal macrophages and bone marrow-derived macrophages from Otud6a^-/- mice produced more type I interferon after virus infection compared to cells from WT mice. Otud6a^-/- mice also exhibited increased resistance to lethal HSV-1 and VSV infections, as well as LPS attack due to decreased inflammatory responses. Mechanistically, mass spectrometry results revealed that UBC13 was an OTUD6A-interacting protein, and the interaction significantly enhanced after HSV-1 stimulation. Taken together, our findings suggest that OTUD6A plays a crucial role in the innate immune response and may serve as a potential therapeutic target for infectious disease.