In recent years, there have been frequent reports on the adverse effects of synthetic cannabinoid (SC) abuse. SCs cause psychoactive effects, similar to those caused by marijuana, by binding and activating cannabinoid receptor 1 (CB1R) in the central nervous system. The aim of this study was to establish a reliable quantitative structure-activity relationship (QSAR) model to correlate the structures and physicochemical properties of various SCs with their CB1R-binding affinities. We prepared 15 SCs and their derivatives (tetrahydrocannabinol [THC], naphthoylindoles, and cyclohexylphenols) and determined their binding affinity to CB1R, which is known as a dependence-related target. We calculated the molecular descriptors for dataset compounds using an R/CDK (R package integrated with CDK, version 3.5.0) toolkit to build QSAR regression models. These models were established and statistical evaluations were performed using the mlr and plsr packages in R software. The most reliable QSAR model was obtained from the partial least squares regression method via external validation. This model can be applied in vivo to predict the addictive properties of illicit new SCs. Using a limited number of dataset compounds and our own experimental activity data, we built a QSAR model for SCs with good predictability. This QSAR modeling approach provides a novel strategy for establishing an efficient tool to predict the abuse potential of various SCs and to control their illicit use.

Background: Skin is exposed to ultraviolet radiation (UV) and air pollution and recent works demonstrated these factors have additive effects in the disturbance of skin homeostasis. Nuclear factor erythroid 2-related factor 2 (Nrf2) and aryl hydrocarbon receptor (AHR) appears appropriate targets in the management of combined environmental stressors. The protective effects of Silymarin (SM), an antioxidant and anti-inflammatory complex of flavonoids, were evaluated. Methods: Reactive oxygen species (ROS) and interleukin 1-alpha (IL-1a) were quantified in UV+urban dust stressed reconstructed human epidermis (RHE) treated with SM. Gene expression study was conducted on targets related to AHR and Nrf2. SM agonistic activity on cannabinoid receptor type 2 (CB2R) was evaluated on mast cells. Clinical study quantified the performance of SM and cannabidiol (CBD), in skin exposed to solar radiation and air pollution. Results: SM decreased morphological alterations, ROS and IL-1a in UV+urban dust stressed RHE. AHR and Nrf2 related genes were upregulated that control antioxidant effector and barrier function. Interleukin 8 gene expression was decreased. Clinical study confirmed SM to improve homogeneity and perceived well-being of urban skins exposed to UV, outperforming CBD. SM activated CB2R and release of β-endorphin from mast cells. Conclusions: SM provides protection of skin from oxidative stress and inflammation caused by two major factors of exposome and appears mediated by AHR-Nrf2. SM activation of CB2R opens a new understanding of SM anti-inflammatory properties.

Objective: Type I interferon receptor (IFNAR) signaling contributes to several autoimmune and vascular diseases such as atherosclerosis and stroke. The purpose of this study was to assess the influence of IFNAR1 deficiency on the formation and progression of experimental abdominal aortic aneurysms (AAAs). Methods: AAAs were induced in type I interferon receptor subunit 1 (IFNAR1) deficient and wild type control male mice via intra-infrarenal aortic infusion of porcine pancreatic elastase. Immunostaining for IFNAR1 was evaluated in experimental and clinical aneurysms. The initiation and progression of experimental AAAs was assessed via ultrasound imaging prior to (day 0) and 3-, 7-, and 14-days following elastase infusion. Aneurysmal histopathology was analyzed at sacrifice. Results: Increased aortic medial and adventitial IFNAR1 expression was present in both clinical AAAs harvested at surgery and experimental AAAs. Following AAA initiation, wild type mice experienced progressive, time-dependent infrarenal aortic enlargement. This progression was substantially attenuated in IFNAR1 deficient mice. On histological analyses, medial elastin degradation, smooth muscle cell depletion, leukocyte accumulation and neoangiogenesis were markedly diminished in IFNAR1 deficient as compared to wild type mice. Conclusion: IFNAR1 deficiency limited experimental AAA progression in response to intra-aortic elastase infusion. Combined with clinical observations, these results suggest a regulatory role for IFNAR1 activity in AAA pathogenesis.

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 involvement of the angiotensin II type 1 receptor in the Frank-Starling Law of the Heart, where the various activations are very limited, allows simple analysis of the kinase systems involved and thence extrapolation of the mechanism to that of angiotensin control of activation of cardiac and skeletal muscle contraction. The involvement of phosphorylation of the myosin light chain in the control of contraction is accepted but not fully understood. The involvement of troponin-I phosphorylation is also indicated but of unknown mechanism. There is no known signal for activation of myosin light chain kinase or Protein Kinase C-βII other than Ca²⁺/calmodulin but the former is constitutively active and thus has to be under control of a regulated inhibitor, the latter kinase may also be the same. Ca²⁺/calmodulin is not activated in Frank-Starling, i.e. there are no diastolic or systolic [Ca²⁺] changes. I suggest here that that the regulated inhibition is by myosin light chain phosphatase and/or β-arrestin. Angiotensin activation is by translocation of the β-arrestin from the sarcoplasm to the PM thus reducing its kinase inhibition action in the sarcoplasm, this reduced inhibition has been wrongly attributed to a mythical downstream agonist property of β-arrestin.

Despite the effectiveness of insulin injections in managing hyperglycemia in Type 1 Diabetes, they fall short in addressing autoimmunity and regenerating damaged islets. This review aims to explore the potential of various treatment modalities for T1DM, including mesenchymal stem cells (MSCs), MSC-derived exosomes, gene therapy, islet allotransplantation, and pancreatic islet cell transplantation. Results: MSCs demonstrate efficacy in T1DM treatment through immunomodulation and tissue regeneration, although further research is warranted to optimize their therapeutic potential. Gene therapy presents a promising approach despite challenges such as donor shortage and immune rejection. Pancreatic islet cell transplantation emerges as a viable option, albeit with associated risks including graft rejection and the need for immunosuppression. Teplizumab, an FDA-approved humanized monoclonal antibody, revolutionizes the treatment landscape of Type 1 Diabetes by significantly delaying its onset, offering a paradigm shift since the discovery of insulin Conclusion: Ongoing studies and technological advancements in T1DM management offer a promising outlook for improved treatments and possibly even eradication on a global scale. MSCs, MSC-derived exosomes, gene therapy, and pancreatic islet transplantation hold considerable potential.

Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the “classical” protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage independent growth of etoposide resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide resistant RB cells, impacts mirroring PTPRE KD effects and indicating PTPRE regulation via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and - dependent on the cell line - also AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma.

Our recent study detected the expression of a tissue Renin-Angiotensin System (tRAS) in human intervertebral discs (IVDs). The present study sought to investigate the impact of angiotensin II receptor type 1 (AGTR1) antagonist losartan on human nucleus pulposus (NP) cell inflammation and degeneration induced by tumor necrosis factor-α (TNF-α). Human NP cells (4 donors, Pfirrmann grade 2-3, 30-37 years old, male) were isolated and expanded. TNF-α (10 ng/mL) was used to induce inflammation and degeneration. We examined the impact of losartan supplementation and measured gene expression of tRAS, anabolic, catabolic, and inflammatory markers in NP cells after 24 h and 72 h of exposure, respectively. T0070907, a PPAR-gamma antagonist, was applied to examine the regulatory pathway of losartan. Losartan (1 mM) significantly impaired TNF-α induced increase of pro-inflammatory (nitric oxide and TNF-α), catabolic (matrix metalloproteinases), and tRAS (AGTR1a and Angiotensin Converting Enzyme) markers. Further, losartan maintained the NP cell phenotype by upregulating aggrecan and downregulating collagen type I expression. In summary, losartan showed anti-inflammatory, anti-catabolic, and positive phenotype modulating effects on human NP cells. These results indicate that tRAS signaling plays an important role in IVD degeneration, and tRAS modulation with losartan could represent a novel therapeutic approach.

Spinocerebellar ataxia type 3 is a neurodegenerative disease caused by an abnormal expansion of CAG repeats in the disease gene ATXN3, leading to prolonged polyglutamine (polyQ) tracts in the respective protein ataxin-3. The polyQ-expanded protein forms polyQ-containing aggregates in several brain regions which leads to neuronal cell loss. Autophagy is thought to play a significant role in clearing these polyQ-containing protein aggregates. Therefore, the autophagy mechanism was investigated in SCA3 with focus on the autophagic protein p62/sequestosome-1. Human and mouse RNA sequencing data were analyzed to determine RNA expression level of autophagic genes. Additionally, autophagy was studied in the SCA3 304Q knock-in mouse model and through several cell culture experiments using HEK-293T cells transfected with ATXN3 of differ-ent polyQ lengths. For cell culture experiments, autophagy was induced with rapamycin treat-ment, proteasomal degradation was blocked with MG132 and degradation of autophagic pro-teins was investigated using cycloheximide treatment. Here, we report an increased autophagy impairment with SCA3 disease progression seen in HEK-293T cells transfected with ATXN3 plasmid with expanded polyQ tracts, higher aged 304Q-knock-in mice, or human post-mortem brain material. Furthermore, co-localized aggregation of the autophagic protein p62 and the dis-ease protein ATXN3 was observed in the course of SCA3 disease. Therefore, we suggest a signifi-cant role for p62 in aggregate formation seen in the neurodegenerative disease SCA3.

Background This study aimed to identify the prominent risk factors that may trigger danger signals of early onset of vascular deregulation in T1D. The risk factors we have identified may serve as dual-purpose biomarkers of rapid diagnosis that offer prospective tailor-made resolution therapeutics. Methods The healthy control (HC) was compared with individuals diagnosed with T1D for the risk factors of vascular deregulation in published research studies from year 2013 to 2023. The PubMed, Web of Science and Google Scholar databases were searched from 1/1/2013 to 1/9/2023. The risk of bias was assessed with the Cochrane (ROBINS-I ) tool, which is relevant to clinical subjects. A random effect model for continuous data was followed and analysed by RevMan 5.4 and GraphPad Prism software. Results 80 relevant case-control studies having 5293 HC and 7492 T1D patients were included. The age and sex-matched HC consisted of persons free of disease and not under any medication while clinical subjects of all age groups were included. 28 risk factors were grouped into six primary outcome models, all of which favoured the T1D synonymous with a high risk of CVD. Conclusions Our findings have strong implications for improving the quality of life and health economics related to vascular disease in T1D. HbA1c% is the most effective biomarker, followed by FBG, LDL-C, and AI% which the clinicians could evaluate using a simple blood test or non-invasive techniques. (Protocol registered at https://www.crd.york.ac.uk/prospero/ CRD42022384636).

The sexual reproduction of ascomycetes is controlled by the mating-type(MAT) locus. (Pseudo)homothallic reproduction has been hypothesized based on genetic data from Hirsutella sinensis (Genotype #1 of Ophiocordyceps sinensis). In this study, the differential occurrence of the mating-type genes in the MAT1-1 and MAT1-2 idiomorphs, which constitute the genetic control of O. sinensis reproduction, was analyzed in 237 strains and 5 genomes of H. sinensis. The mating-type genes were differentially transcribed in H. sinensis Strain L0106, and the MAT1-2-1 transcript in H. sinensis Strain 1229 was alternatively spliced, with an unspliced intron I containing stop codons; these findings constitute O. sinensis reproduction controls at the transcriptional and coupled transcriptional-translational levels. The occurrence of the mating-type genes and a-/α-pheromone receptor genes differed among the 5 H. sinensis genomes. The differential occurrence and transcription of these genes are inconsistent with self-fertilization under (pseudo)homothallism but suggest self-sterility of H. sinensis, which therefore needs a mating partner to achieve sexual outcrossing under heterothallism or hybridization. Consistent occurrence and transcription of the mating-type genes of both the MAT1-1 and MAT1-2 idiomorphs have been reported in natural and cultivated Cordyceps sinensis, but these findings are insufficient to determine the reproduction mode(s) because of the co-occurrence of >90 fungal species and multiple genomically independent genotypes of O. sinensis. The mutant MAT1-1-1 and α-pheromone receptor transcripts in natural C. sinensis result in the N-terminus or middle-truncated proteins, with changes in hydrophobicity and secondary structures of the proteins, suggesting heterogeneous fungal source(s) of the proteins and hybridization reproduction.

Steroidogenic factor 1 (SF-1) is a nuclear receptor that regulates steroidogenesis and reproductive development. NR5A1/SF-1 variants are associated with a broad spectrum of phenotypes across individuals with disorders of sex development (DSD). Oligogenic inheritance has been suggested as an explanation. However, testing the impact of specific gene variants involved in a network remains difficult. To confirm the hypothesis that NR5A1/SF-1-related DSD follow an oligogenic mode of inheritance, we investigated a constellation of gene variants identified in a 46,XY severely undervirilized individual. Candidate genes were revealed by whole exome sequencing, and pathogenicity was predicted by different in silico tools. We found variants in NR1H2 and INHA associated with steroidogenesis, sex development, and reproduction. Functional testing was conducted in cell models. Novel SF-1 and NR1H2 binding sites in the AR and INHA gene promoters were found. Transactivation studies showed that wild-type NR5A1/SF-1 regulates INHA and AR gene expression, while the NR5A1/SF-1 variant had decreased transcriptional ac-tivity. NR1H2 was found to regulate AR gene transcription; however, the NR1H2 variant showed normal activity. This study expands the NR5A1/SF-1 network of interacting partners while strengthening the hypothesis that the broad phenotype observed in 46,XY DSD individuals may be caused by oligogenic pathogenicity.

The vomeronasal system serves as a pivotal element in mammalian sensory biology, allowing the perception of chemical signals essential for social communication via the activation of two main receptor families, V1R and V2R. The expression of V1Rs and V2Rs is linked with that of the G-protein alpha-subunits, Gαi2 and Gαo, respectively. The exploration of the evolutionary pathways of V1Rs and V2Rs across all mammalian species remains a main challenge, juxtaposing available genomic data against emerging immunohistochemical evidence. However, recent investigations, in contrast to what is predicted by the currently annotated genomic sequences, have revealed the expression of Gαo in the vomeronasal neuroepithelium of wild canids, including wolves and foxes. In the present study, the employment of a specific antibody raised against the mouse V2R2, member of the C-family of vomeronasal receptors, V2Rs, has confirmed the expression of this receptor in the fox and wolf, but it has revealed the lack of expression in the dog. This may reflect the impact of domestication on the regression of the VNS in this species, in contrast to their wild counterparts, and underscores the effects of artificial selection on sensory functions. Thus, these findings suggest a more refined chemical detection capability in wild species.

Pre-eclampsia is a hypertension disorder during pregnancy, significantly affects maternal morbidity and mortality worldwide. A Case-control research was done on 100 pregnant mothers as respondents: 50 case (pre-eclampsia) and 50 control groups (healthy pregnant mothers). Selected case the following characteristics: were patients that visited the Syamrabu Bangkalan Public Hospital; were third-generation Madura natives; aged between 20-40 years old; had a gestational age of over 20mgg; had blood pressure above 140/90mmHg; and single pregnancies. Control had the following characteristics: were healthy pregnant women without pre-eclampsia or chronic hypertension; were third-generation Madura natives; had a gestational age of over 20mgg; aged between 20-40 years; and without pregnancy complications. The results showed of those with PE, 45 had the AA genotype (homozygote) (90%), five had AC (heterozygote) (8%) and one had CC (homozygote) (2%). As for those without PE, 33 had the AA genotype (homozygote) (73.3%), 11 had AC (heterozygote) (26.7%), none had CC (homozygote) (0%). PE and non-PE cases mostly had the AA genotype (homozygote) and A alleles. AT1R 1166 A/C polymorphism was found to be a significant risk factor for pre-eclampsia, while potassium level had no significant effect on it. Meaning further research is needed on different ethnicities and races.

Background and Objectives Neurofibromatosis 1 (NF1 MIM # 162200), also known as von Recklinghausen disease, is among the most common autosomal dominantly transmitted disorders characterized mainly by neurocutaneous manifestations such as café au lait spots, intertriginous freckling, various types of neurofibromas (cutaneous neurofibromas or plexiform tumors), neurological manifestations, and bone abnormalities. It occurs with an incidence of 1:3000–1:4000 cases. Cone-rod dystrophies belong to the large group of retinal dystrophies, a highly heterogeneous group of disorders clinically manifested mainly by damage to cone and rod cells and have a broad spectrum of clinical manifestations. Many genes are involved in their etiology, with more than 100 currently identified, including the CRX gene responsible for the autosomal dominant form of cone-rod dystrophy (ad CORD). Materials and Methods: The authors present an intriguing case of a patient diagnosed with Neurofibromatosis type 1 (NF1) as an infant and ocular involvement (myopia and astigmatism onset at age 15), which yielded a surprising molecular testing result. Results: Molecular DNA analysis identified a rare occurrence of two mutational variants, including a pathogenic variant in the NF1 gene, c.3871-2A, and a likely pathogenic variant in the CRX gene c.119G>A. Conclusions: The authors present this case to highlight the surprises offered by molecular testing in a condition where the diagnosis is usually based on clinical criteria, thus providing patients with competent genetic advice.

Melanocortins play crucial roles in regulating the stress response, inflammation, and skin pigmentation. In this review, we focus on the melanocortin 1 receptor (MC1R), a G protein-coupled receptor primarily known for regulating skin pigmentation and exhibiting anti-inflammatory effects. First, we provide an overview of the structure, signaling pathways, and related diseases of MC1R. Next, we discuss the potential therapeutic use of synthetic peptides and small molecule modulators of MC1R, highlighting the development of various drugs that enhance stability through amino acid sequence modifications and small molecule drugs to overcome limitations associated with peptide characteristics. Notably, MC1R-targeted drugs have applications beyond skin pigmentation-related diseases, which predominantly affect MC1R in melanocytes. These drugs can also be useful in treating inflammatory diseases with MC1R expression present in various cells. Our review underscores the potential of MC1R-targeted drugs to treat a wide range of diseases and encourages further research in this area.

The transient vanilloid receptor potential type 1 (TRPV1) regulates neuronal and vascular functions mediated by nitric oxide (NO) and by the calcitonin gene-related peptide (CGRP). Here we study the participation of TRPV1 in the regulation of myocardial injury caused by ischemia-reperfusion and in the regulation of NO, tetrahydrobiopterin (BH4), the cGMP pathway, CGRP, total antioxidant capacity (TAC), malondialdehyde (MDA) and phosphodiesterase-3 (PDE-3). Isolated hearts of Wistar rats were used (according to Langendorff) to study the effects of capsaicin (CS), capsazepine (CZ) and CZ+CS treatments. The hearts were divided into three subgroups; 1) perfusion, 2) ischemia and 3) ischemia-reperfusion. In all groups we studied cardiac work and levels of NO, cGMP, BH4, CGRP, TAC, MDA and PDE-3 in ventricular tissue. Western blots were used to determine the expressions of eNOS, iNOS and phosphorylated NOS (pNOS). Structural changes were determined by histological evaluation. CS prevented damage caused by ischemia-reperfusion by improving cardiac work and the levels of NO, cGMP, BH4, TAC and CGRP. TRPV1 and iNOS expression were increased under ischemic conditions, while eNOS and pNOS were not modified. We conclude that the activation of TRPV1 constitutes a therapeutic possibility to counteract the damage caused by ischemia and reperfusion by regulating the NO pathway through CGRP.

(1) Background: Patients with type 2 diabetes mellitus (T2DM) are at higher risk of cancer but how these two diseases associate is still debated. The goal was the assessment of the overall incidence of cancer among patients with newly diagnosed T2DM in Hungary. Summarizing, incident T2DM is associated with a significantly higher overall risk of incident cancer, with a reverse correlation of age. Newly registered T2DM patients were suggested to be screened for cancer within 6 months. (2) Methods: A nationwide, retrospective, longitudinal study was performed using a Hungarian database. The incident T2DM and diabetes free Hungarian population were included in the study. The primary endpoints were the overall and site-specific incidence and annual percentage change of the incidence of cancer in both populations. (3) Results: The overall incidence of cancer in patients amounted to 29.4/1000 and 6.6/1000 with or without T2DM, respectively, and the OR (95%CI) of cancer of the T2DM group was 4.32 (4.14-4.53), p<0.0001. The risk of having cancer was age-dependent, having the highest odd in the age group 18-39. The incidence of cancer was declining in the non-diabetic but was unchanged in T2DM population. The average lag time of diagnosing a cancer after the detection of T2DM was 3.86 months.; (4) Conclusions: Iincident T2DM is associated with a significantly higher overall risk of incident cancer, with a reverse correlation of age. Newly registered T2DM patients were suggested to be screened for cancer within 6 months.

The periodontal ligament (PDL) is a complex connective tissue that connects the tooth root to the dental alveolar bone and plays crucial mechanical roles. PDL also exhibits regenerative roles and regulatory functions to maintain per-iodontium integrity and homeostasis. While PDL exposure to oral microbial pathogens is common, virtually nothing is known regarding viral infections of PDL. In particular, human herpes simplex virus type 1 (HSV-1) persistently infects the oral cavity through infections of the oral epithelium, connective tis-sue and neurons. While the oral spread of HSV-1 is generally asymptomatic, this virus has also been implicated in various oral pathologies. In this study, using a primary cell model derived from PDL (PDL-cells), and whole surgical fragments of PDL, we provide evidence supporting the efficient infection of PDL by HSV-1 and the promotions of cytopathic effects. Infection of PDL by HSV-1 was also associated with an acute innate inflammatory response, as il-lustrated by the production of the antiviral interferons and pro-inflammatory cytokines. Furthermore, this inflammatory response to HSV-1 was exacerbated in the presence of bacterial-derived products, such as peptidoglycans. This work therefore highlights the ability of HSV-1 to infect mesenchymal cells from PDL, suggesting that PDL may serve as a viral reservoir for the perio-dontal spread of HSV-1. Moreover, this raises questions about HSV-1 oral pathogenesis, as HSV-1-associated cytopathic and inflammatory effects may contribute to profound alterations of PDL integrity and functioning.

Background: Since cytokine receptor like factor 1 (CRLF1) has been implicated in tissue regeneration, we hypothesized that CRLF1 released by mesenchymal stem cells can promote the repair of osteochondral defects. Methods: The degree of a femoral osteochondral defect repair in rabbits after intra-articular injections of bone marrow derived mesenchymal stem cells (BMSCs) that were transduced with empty adeno associated virus (AAV) or AAV containing CRLF1 was determined by morpholog-ical, histological and microCT analyses. The effects of CRLF1 on chondrogenic differentiation of BMSCs or catabolic events of interleukin-1beta-treated chondrocyte cell line TC28a2 were deter-mined by alcian blue staining, gene expression levels of cartilage and catabolic marker genes us-ing real time PCR analysis, and immunoblot analysis of Smad2/3 and STAT3 signaling. Results: Intra-articular injections of BMSCs overexpressing CRLF1 markedly improved repair of a rabbit femoral osteochondral defect. Overexpression of CRLF1 in BMSCs resulted in the release of a homodimeric CRLF1 complex that stimulated chondrogenic differentiation of BMSCs via enhancing Smad2/3 signaling, whereas the suppression of CRLF1 expression inhibited chondro-genic differentiation. In addition, CRLF1 inhibited catabolic events in TC28a2 cells cultured in an inflammatory environment, while a heterodimeric complex of CRLF1 and Cardiotrophin like Cytokine (CLC) stimulated catabolic events via STAT3 activation. Conclusion: A homodimeric CRLF1 complex released by BMSCs enhanced the repair of osteochondral defects via the inhibition of catabolic events in chondrocytes and the stimulation of chondrogenic differentiation of precursor cells.

Anti-islet autoantibodies serve as key markers in immune-mediated type 1 diabetes (T1D) and slowly-progressive T1D (SPIDDM), also known as latent autoimmune diabetes in adults (LADA). Autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), tyrosine phosphatase-like protein IA-2 (IA-2A), and zinc transporter 8 (ZnT8A) are currently employed in the diagnosis, pathological analysis, and prediction of T1D. GADA can also be detected in non-diabetic patients with autoimmune diseases other than T1D and may not necessarily reflect insulitis. Conversely, IA-2A and ZnT8A serve as surrogate markers of pancreatic β-cell destruction. Combinatorial analysis of these four anti-islet autoantibodies demonstrated that 93-96% of acute-onset T1D and SPIDDM cases were diagnosed as immune-mediated T1D, while the majority of fulminant T1D cases were autoantibody-negative. Evaluating the epitopes and immunoglobulin subclasses of anti-islet autoantibodies help distinguish between diabetes-associated and non-diabetes-associated autoantibodies and is valuable for predicting future insulin deficiency in SPIDDM (LADA) patients. Additionally, GADA in T1D patients with autoimmune thyroid disease reveals the polyclonal expansion of autoantibody epitopes and immunoglobulin subclasses. Recent advancements in anti-islet autoantibody assays include nonradioactive fluid-phase assays and the simultaneous determination of multiple biochemically defined autoantibodies. Developing a high-throughput assay for detecting epitope-specific or immunoglobulin isotype-specific autoantibodies will facilitate more accurate diagnosis and prediction of autoimmune disorders.

Equine herpesvirus type 1 (EHV-1) causes rhinopneumonitis, abortion and neurological outbreaks (equine herpesvirus myeloencephalopathy, EHM) in horses. EHV-1 also causes lethal encephalitis in laboratory small animals such as mice and hamsters experimentally. EHV-1 ORF76 is a homologue of HSV-1 US9, which is a herpesvirus kinase. Starting with an EHV-1 bacterial artificial chromosome clone of neuropathogenic strain Ab4p (pAb4p BAC), we constructed an ORF76 deletion mutant (Ab4p∆ORF76) by replacing ORF76 with the rpsLneo gene. Deletion of ORF76 had no influence on replication, cell-to-cell spread in cultured cells or replication in primary neuronal cells. In western blots of EHV-1-infected cell lysates, an EHV-1 Us9-specific polyclonal antibody detected multiple bands ranging from 35 to 42-kDa. In a CBA/N1 mouse infection model following intranasal inoculation, the parent and Ab4p∆ORF76 revertant caused the same histopathology in the brain and olfactory bulbs. The parent, Ab4p∆ORF76 and revertant mutant replicated similarly in the olfactory mucosa, although Ab4p∆ORF76 was not transported to the olfactory bulbs and was unable to infect the CNS. These results indicated that the ORF76 (US9) plays an essential role in the anterograde spread EHV-1.

Background: Ventilator-associated pneumonia (VAP) is among the most common healthcare-associated infections in Pediatric Intensive Care Units (PICUs). Because of the lack of a gold-standard diagnostic test, early diagnosis of VAP is challenging. We investigated whether bronchial biomarkers interleukin-4 (IL-4), plasminogen activator inhibitor-1 (PAI-1) and soluble receptor for advanced glycation end products (RAGE) could contribute in early VAP diagnosis through their fluctuation in time in critically ill pediatric patients. Methods: Bronchial secretions were collected from PICU patients with VAP on days 1 and 6. PAI-1, RAGE and IL-4 levels were measured by ELISA. Protein concentrations between high and low VAP suspicion patients were compared using unpaired Student’s t or Mann–Whitney U tests. Results: Twenty PICU patients, with median age 7.75yrs (range 0.5-15.3), mechanically ventilated for ≥48hrs with increased oxygenation requirements and VAP clinical/laboratory signs were enrolled. They were divided in VAP high-suspicion (n=12) or low-suspicion (n=8) groups based on Clinical Pulmonary Infection Score (cutoff:6). ΡΑΙ-1 και RAGE levels did not differ between high- or low-VAP suspicion groups the 1st or 6th days (p-value>0.05). IL-4 was not detected in bronchial secretions. Conclusion: Bronchial concentrations of IL-4, PAI-1 and RAGE in critically ill children are not correlated with high- or low-VAP suspicion.

Diabetes mellitus (DM) poses a significant challenge to global health, with its prevalence projected to rise dramatically by 2045. This narrative review explores the bidirectional relationship between periodontitis (PD) and type 1 diabetes mellitus (T1DM), focusing on cellular and molecular mechanisms derived by the interplay between oral microbiota and the host immune response. A comprehensive search of literature published between 2008 and 2023 was conducted to elucidate the association between these two diseases. Preclinical and clinical evidence suggests a bidirectional relationship, with individuals with T1DM exhibiting heightened susceptibility to periodontitis, and vice versa. The review includes recent findings from human clinical studies, revealing variations in oral microbiota composition in T1DM patients, including increases in certain pathogenic species such as Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans, along with shifts in microbial diversity and abundance. Molecular mechanisms underlying this association involve oxidative stress and dysregulated host immune responses, mediated by inflammatory cytokines such as IL-6, IL-8, and MMPs. Furthermore, disruptions in bone turnover markers, such as RANKL and OPG, contribute to periodontal complications in T1DM patients. While preventive measures to manage periodontal complications in T1DM patients may improve overall health outcomes, further research is needed to understand the intricate interactions between oral microbiota, host response, periodontal disease, and systemic health in this population.

The G-protein-coupled estrogen receptor (GPER; G protein-coupled estrogen receptor 30, also known as GPR30) is a novel estrogen receptor and has emerged as a promising target for ovarian cancer. GPER, a seven-transmembrane receptor, suppresses cellular viability and migration in studied ovarian cancer cells. However, its impact on the fallopian tube, which is the potential origin of high-grade serous (HGSC) ovarian cancer, has not been addressed. This study was conducted to evaluate the relationship of GPER, ovarian cancer subtypes, i.e., high-grade serous cell lines (OV90 and OVCAR420), as well as potential HGSC ovarian cancer origin (i.e., the fallopian tube cell line FT190). The selective ligand assessed here is the agonist G-1, which was utilized in an in vitro study to characterize its effects on cellular viability and migration. As a result, this study has addressed the effect of a specific GPER antagonist in combination with an agonist on cell viability, providing a better understanding of the effects of these compounds on our diverse group of studied cell lines. Strikingly, attenuated cell proliferation and migration behaviors were observed in the presence of G-1. Thus, our in vitro study reveals the impact of the origin of HGSC ovarian cancers and highlights the GPER agonist G-1 as a potential therapy for ovarian cancer.

Cannabinoid metabolites have been reported to be more potent than the parent compounds. Among them, Ajulemic acid (AJA) is a synthetic analogue of Δ9-THC-11-oic which will be a good template structure for discovery of more potent analogues. Herein, we optimized the key allylic oxidation step to introduce the C-11 hydroxy group with high yield. And a series of compounds were prepared with this condition applied including HU-210, 11-Nor-Δ8-Tetrahydrocannabinol-9-carboxylic acid and Δ9-THC-COOH.

For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in individuals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, and mechanistic studies of virus infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses, and summarise current unbiased efforts aimed at characterising the complete population of viruses (the “virome”) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.

Acute HSV-1 infection is associated with mild symptom, such as fever and lesions of the mouth, face and skin. This phase is followed by a latency period before reactivation which is associated with symptoms ranging from ulcers to encephalitis. Despite available anti-HSV-1 drugs, the development of new antiviral agents is sought due to the presence of resistant viruses. Melatonin, a molecule secreted by the pineal gland, has been shown to be an antioxidant, inducer of antioxidant enzymes, and regulator of various biological processes. Clinical trials have explored its therapeutic utility in conditions including infections. This study focuses on melatonin's role in HSV-1 replication and the underlying mechanisms. Melatonin was found to decrease the synthesis of HSV-1 proteins in infected Vero cells measured by inmunofluorescence indicating an inhibition of HSV-1 replication. Additionally, it regulates the activities of antioxidant enzymes and affects proteasome activity. Melatonin activates the unfolded protein response (UPR) and autophagy and suppresses apoptosis in HSV-1-infected cells. In summary, melatonin demonstrates an inhibitory role in HSV-1 replication by modulating various cellular responses, suggesting its potential utility in the treatment of viral infections.

In this paper, we extend the KdVSKR equations in (1+1)-dimension and (2+1)-dimension to fractional KdVSKR equations with modified Riemann-Liouville derivative. The (2+1)-dimensional KdVSKR equation, which is a recent extension of (1+1)-dimensional KdVSKR equation, can model the resonances of solitons in shallow water. By means of the Hirota bilinear method, finite symmetry group method and consistent Riccati expansion method, many new interaction solutions have been derived. Soliton-cnoidal interaction solution of the (1+1)-dimensional fractional KdVSKR equation has been derived for the first time. For the (2+1)-dimensional frac-tional KdVSKR equation, two-wave interaction solutions and three-wave interaction solutions, including dark-soliton-sine interaction solution, bright-soliton-elliptic interaction solution, and lump-hyperbolic-sine interaction solution, have been derived. Impact of the fractional order on the shapes of these solutions has been illustrated by figures. Three-wave interaction solutions of fractional systems have not been reported in the existing references. The research idea in this paper can be applied to other fractional differential equations.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Recent data highlight similarities between neurodegenerative diseases including PD and type 2 diabetes mellitus (T2DM) suggesting a crucial interplay between the gut–brain axis. GLP-1R agonists, known for their use in T2DM treatment, are currently extensively studied as novel PD modifying agents. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles and clinical trials regarding GLP-1R agonists and PD, published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Our research was conducted between February 2023 and February 2024. We used the terms “GLP-1”, “GLP-1 receptor”, “GLP-1R agonists”, “PD”, “T2DM”, “insulin”, “neurodegenerative disease”, “glucose”, “animal models”, “clinical trials” in different combinations. Many data on animal models and preclinical studies show that GLP1-R agonists can restore dopamine levels, inhibit dopaminergic loss, attenuate neuronal degeneration and alleviate motor and non-motor features of PD. Evidence from clinical studies are also very promising enhancing the possibility of adding GLP1-R agonists in the current armamentarium of drugs available for PD treatment.

Neurokinin-1 receptor (NK-1R) antagonists exert an antitumor action, are safe and do not cause serious side-effects. These antagonists (via the NK-1R) exerted multiple actions against cancer: antiproliferative and anti-Warburg effects, apoptosis, anti-angiogenic and antimetastatic. These multiple effects have been shown in a broad-spectrum of cancers. The drug aprepitant (an NK-1R antagonist) is currently used in clinical practice as antiemetic. In in vivo and in vitro studies, aprepitant also showed the aforementioned multiple antitumor actions against many types of cancer. A successful combination therapy (aprepitant and radiotherapy) has recently been reported in a patient suffering from lung carcinoma: the tumor mass disappeared and side-effects were not observed. Aprepitant could be considered as an intelligent bullet against cancer. The administration of aprepitant in cancer patients to prevent recurrence and metastasis after surgical procedures, thrombosis and thromboembolism is discussed as well as the possible link, through the SP/NK-1R system, between cancer and depression. Our main aim is to review the multiple antitumor actions exerted by aprepitant and the use of this drug is suggested in cancer patients. Altogether, the data support the reprofiling of aprepitant for a new therapeutic use as an antitumor agent.

Background and Aim. Since virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, post-hepatitis C virus (HCV) infection would be a cause for liver cirrhosis that would progress to HCC. Cytotoxic T cells (Tc) are known to be involved in post-HCV complications and HCC pathogenesis. The inhibitory checkpoint Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) is expressed on Tc. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression post-HCV and moreover, to evaluate LAIR-1 expression as a non-invasive biomarker for HCC progression in the context of liver cirrhosis post-HCV genotype 4 (G4) in Egyptian patients’ peripheral venous blood liquid biopsy. We studied LAIR-1 expression on Tc related to the progression of liver cirrhosis in a case-controlled study enrolled 64 patients with post-HCV G4-HCC and 37 patients with post-HCV G4-liver cirrhosis. Methods: LAIR-1 expression was analyzed by flow cytometry. Results: LAIR-1 expression on Tc and the percentage of Tc positive for LAIR-1 (LAIR-1+Tc %) were significantly higher in the post-HCV G4-HCC group compared to the post-HCV G4-liver cirrhosis

HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in brain specimens of HAND donors. Immunoblot revealed CB1 and CB2 were differentially expressed in frontal cortices from HAND brains compared to neurocognitively unimpaired (NUI) brains from PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution on neuronal processes of NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.

Diabetes may cause an increase blood levels of cytokines inducing a rising of C reactive protein (PCR) and fibrinogen stimulating a subclinical inflammation which lead to adhesive molecules expression and to endothelial disfunction. A comprehensive panel of type 1 diabetes mellitus (T1DM) interleukins polymorphisms is not provided yet. As chronic periodontitis (CP) is considered the sixth complication of DM, a clarification is needed about the inflammatory role managed by single nucleotides polymorphisms (SNPs). The goal of this review is to focus on the significant diversity of SNPs in T1DM patients with and without CP. After a digital search on PubMed and Scopus with reference to the last 5 years, 21 items were enrolled. Several ILs were analyzed. T1DM still needs to be thoroughly explored regarding the ILs polymorphisms panel, however the last 5 years have led to the increased independence of this condition, causing autonomous inflammatory effects which requires further investigations. CP and T1DM association in children and adolescents represents a severe gap in literature that should be filled, the scarce presence of studies also about adults serves as a motivation for ulterior clinical researches

Skin involvement is an overlooked aspect in the management of paediatric patients with type 1 diabetes. A comprehensive search of published literature using the PubMed database was carried out using the following key terms: “children”, “pediatric/paediatric patients”, “skin”, “skin disorders”, “type 1 diabetes”. Dermatological side effects are frequently observed among diabetic children and adolescents. Insulin-induced lipodystrophies and allergic contact dermatitis caused by insulin pumps or glycaemic sensors are the most common skin reactions in these patients. Furthermore, several diabetes-associated skin diseases such as necrobiosis lipoidica, granuloma annulare, vitiligo, and bullosis diabeticorum may already be present in paediatric age. Paediatric diabetes specialists should pay attention to their patients’ skin so as to recognize these disorders, identify the potential causes, and choose the most suitable treatment. Finally, the evaluation of skin concentrations of advanced glycation end-products using non-invasive diagnostic techniques may be used to assess the risk of chronic complications of diabetes as early as adolescence.

Cannabis is one of the oldest cultivated crops in the history for food, fiber and drugs for thousands of years. Extension of cannabis genetic variation developed in a wide- ranging choice of varieties with various complementary phenotypes and secondary metabolites. Cannabis grow practices is very diverse, especially indoor cultivation factors, such as different lighting conditions, pot size, humidity, fertilizers. These growth factors influence a lot on the production of cannabinoids. For medical or pharmaceutical purposes, ratio of CBD or THC is very important. Plants traits and metabolic compounds are related to various conditions produced by microbes. Investigating this crosstalk between plants and microbes can play a vital role not only for stimulating the biosynthetic and signaling pathways of the host plants for the production of agronomically or pharmaceutically essential metabolic compounds but also against pathogens. This study emphasis on decoding the crosstalk between cannabis and associated microbes in the belowground environmental niches that would unravel the complexity of stabilizing cannabinoid production.

Type 1 diabetes affects millions of people globally and requires careful management to avoid serious long-term complications, including heart and kidney disease, stroke, and loss of sight. The present standard-of-care for type 1 diabetes is exogenic insulin substitutional therapy. The most advanced stretegies in this area is the development of hybrid-closed loop system and the producing of long-acting insulins. Progresses in stem cell therapies have started to revolutionize the care of patients with type 1 diabetes; however, significant challenges remain including the limited islets availability, difficulties in maintaining the viability, the heterogeneity within a complex pathology and in patients’ responses to treatment. On the way, a considerable amount of efforts in maximizing the islet transplantation effectiveness by controlling the advantageous of different stem cell approaches. With the availability and the use of big data, the concept of precision medicine is gaining wide attention worldwide and could bring the dream of “presonlaized” therapies as a reality in the near future. Here we review the current range of treatments available as well as recent pre-clinical breakthroughs in the field of personlaized medicine for type 1 diabetes.

Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia associated with impaired carbohydrate, lipid and protein metabolism, with concomitant absence of insulin secretion or reduced sensitivity to its metabolic effects. Patients with diabetes mellitus have 30% more risk of developing heart failure and cardiovascular disease with respect to healthy people. Heart and cardiovascular problems are the first cause of death worldwide and the main complications which lead to high healthcare costs. Such complications can be delayed or avoided by taking prescribed medications in conjunction with a healthy lifestyle (i.e. diet and physical activity). The American College of Sports Medicine and the American Diabetes Association recommend that diabetic people reduce total sedentary time by incorporating physical activity in their weekly routine. This narrative literature review has the aim to summarize and present the main guidelines, pre-exercise cardiovascular screening recommendations, and considerations for patients with diabetes and comorbidities who are planning to participate in regular exercise regimens.

The receptor-type protein tyrosine phosphatases (RPTPs) are involved in a wide variety of physiological functions which are mediated via their diverse extracellular regions. They play key roles in cell-cell contacts, bind various ligands and are regulated by dimerization and other processes. Depending on the subgroup they have been described as everything from ‘rigid rods’ to ‘floppy tentacles’. Here we review current experimental structural knowledge on the extracellular region of RPTPs and draw on AlphaFold structural predictions to provide further insights into structure and function of these cellular signalling molecules.

Life-threatening inflammatory conditions such as acute respiratory distress syndrome or sepsis often go hand in hand with severe vascular leakage. During inflammation, endothelial cell integrity and intact barrier function are crucial to limit leukocyte and plasma extravasation. Prostaglandin D₂ (PGD₂) is a potent inflammatory lipid mediator with vasoactive properties. It has been suggested that PGD^­₂ is involved in the regulation of endothelial barrier function; however, it is unclear whether this is also true for primary human pulmonary microvascular endothelial cells. Furthermore, as PGD₂ is a highly promiscuous ligand, we set out to determine which receptors are important in human pulmonary endothelial cells. In the current study, we found that PGD₂ and the DP1 agonist BW245c potently strengthened pulmonary and dermal microvascular endothelial cell barrier function and protected against thrombin-induced barrier disruption. Yet surprisingly, these effects were mediated only to a negligible extent via DP1 receptor activation. In contrast, we observed that the EP4 receptor was most important and mediated the barrier enhancement by PGD₂ and BW245c. These data demonstrate a novel mechanism by which PGD₂ may modulate inflammation and emphasizes the role of EP4 receptors in human endothelial cell function.

Objectives: Epidemiologic and experimental animal studies have shown that stress can alter tumor growth and that adrenergic fibers from the sympathetic nervous system, acting through stromal β2-adrenergic receptors, promote tumor cell survival during the initial phases of cancer development. Recent epidemiological data suggest that beta blocker intake improves survival of prostate cancer patients. Methods: Signaling mediated by β-adrenergic receptors promotes neuroendocrine differentiation in prostate cancer cell line. Although neuroendocrine cells are a minor population in the epithelial compartment of normal prostate glands, the population of neuroendocrine-like cells that express markers such as SYN, Bcl-2, Dll-3, and AMACR correlates with cancer progression, androgen-independent state, and poor prognosis in prostate cancer patients. As recent studies show that an increase in neuroendocrine cell density occurs before development of benign prostatic hyperplasia (BPH), a non-lethal disease affecting the transition zone, in hypertensive rats, we investigated whether neuroendocrine differentiation is associated with BPH. Results: Our results showed that isobutyl-methyl-xanthine and forskolin leading to sustained activation of the cAMP/PKA pathway led to an increase in neuroendocrine differentiation markers in BPH-1 cell line. Similar results were observed by combining the β-adrenergic receptors agonist isoproterenol with forskolin. These treatments reduced BPH-1 cell proliferation rates by 40% and 60%, respectively. Effects on neuroendocrine markers expression and cell proliferation were fully reversed by the β2 blocker carvedilol. Conclusion: These data suggest that β-adrenergic receptors are linked to the development of neuroendocrine-like cells in BPH. As 20% of the prostate cancer tumors occur in this zone, this observation warrants further investigation.

In the last decades, studies on the inflammatory signaling pathways in multiple pathological contexts revealed new targets for novel therapies. Among the family of G-protein-coupled Proteases Activated Receptors, PAR2 was identified as a driver of the inflammatory cascade in many pathologies, ranging from autoimmune disease to cancer metastasis. For this reason, many efforts have been focused on the development of potential antagonists of PAR2 activity. This work focuses on a small molecule, 1-Piperidine Propionic Acid (1-PPA), previously described to be active against inflammatory processes, but whose target is still unknown. Stabilization effects observed by cellular thermal shift assay coupled to in-silico investigations, including molecular docking and Molecular Dynamics simulations, suggested that 1-PPA binds PAR2 in an allosteric pocket of the receptor inactive conformation. In addition, this compound was found able to inhibit platelet aggregation, a process mediated by PAR family members, including PAR2. Since the allosteric pocket binding 1-PPA is highly conserved in all the members of the PAR family, the evidence reported here suggests that 1-PPA could represent a promising new small molecule targeting PARs with antagonistic activity.

The Cannabis plant (Cannabis sativa L.) produces an estimated 545 chemical compounds of different biogenetic classes. In addition to economic value, many of these phytochemicals have medicinal and physiological activity. The plant is most popularly known for its two most prominent and most studied secondary metabolites— Δ9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD). Both Δ9-THC and CBD have a wide therapeutic window across many ailments and form part of a class of secondary metabolites called cannabinoids—of which approximately over 104 exist. This review will focus on non-cannabinoid metabolites of Cannabis sativa that also have therapeutic potential, some of which share medicinal properties similar to those of cannabinoids. The most notable of these non-cannabinoid phytochemicals are flavonoids and terpenes. We will also discuss future directions in cannabis research and development of cannabis-based pharmaceuticals. Caflanone, a flavonoid molecule with selective activity against the human viruses including the coronavirus SARS-COV2, and certain cancers, is one of the most promising non-cannabinoid molecules that is being advanced into clinical trials. As validated by thousands of years of the use of cannabis for medicinal purposes, vast anecdotal evidence abounds on the medicinal benefits of the plant. These benefits are attributed to the many phytochemicals in this plant, including non-cannabinoids. The most promising non-cannabinoids with potential to alleviate global disease burdens are discussed.

This work is a review of the current situation of type 1a diabetes mellitus in childhood. With a quick read, the reader will discover the current and immediate future challenges.

Malignant melanoma is one of the most aggressive and resistant tumor types which is often accompanied by poor prognosis when spread to nearby or distant tissues. Even though an increasing number of second-line therapies are available for cancer patients, the 5-year survival rate of melanoma patients with regional and distant metastases is still rather low. Therefore, there is an urgent need to develop new, highly efficient treatments. Melanocortin-1-receptor (MC1R) is a cell surface receptor for α-MSH. It is responsible for melanogenesis and is shown to be overexpressed on the surface of cancer cells in a subset of melanoma patients. Here, we designed and synthesized α-MSH analogs and conjugated them to daunomycin through oxime linkage. Using our peptide-drug conjugates (Dau-α-MSHs), we performed comparative in vitro and in vivo evaluations to reveal their suitability for tumor targeting. Firstly, the expression level of MC1R was determined in various melanoma cell lines via RT-qPCR. Then, we examined the antiproliferative effect of our Dau-α-MSHs, moreover we determined the cellular uptake profile and intracellular localization of Dau-α-MSHs. The most efficient Dau-α-MSHs were investigated in vivo using a murine xenograft melanoma model. We found that various cell lines show differential expression on the mRNA levels. We also showed that healthy primary cells have lower expression of MC1R compared to tumor cell lines. Moreover, the concentration-dependent cellular uptake profile of Dau-α-MSHs was detected and the compounds exhibited a great antiproliferative effect on melanoma cell lines. We also provided evidence that our novel Dau-α-MSHs can inhibit tumor expansion significantly and are suitable for targeted tumor therapy.

Aims/Hypothesis): Type 1 diabetes is an immune-mediated disease with destruction of the pancreatic β-cells, a process that is conditioned by multiple genes and other factors. HLA counts as the major susceptibility gene. Significant variations in HLA genetic susceptibility to type 1 diabetes between Caucasians, African and Asian and other ethnic groups may have led to the variation in incidence of type 1 diabetes globally. Type 1 diabetes is characterized upon HLA identification. In this chapter we discuss global variations in genetic susceptibility of HLA with regard to type 1 diabetes globally with a particular attention to Arab population. Methods): Haplotype configuration of HLA class I A, B, C and Class II –DR/DQ/DP were studied in Caucasians, African and Asian and in Arab population to see if that is responsible for the exponential rise in the rate of type 1 diabetes. Results): Although Arabs have one of the highest global incidence and prevalence rates of type 1 diabetes, unfortunately, there is a dearth amount of information regarding HLA genetic susceptibility to type 1 diabetes in the Arab world. HLA haplotype configurations contribute to its risk value. However, out of an insufficient present study there are examples of misjudgment of HLA risk according to HLA alleles rather than haplotypes. Conclusion): To date HLA outlooks for the characterization of type 1 diabetes. There is an ethnicity difference in HLA characteristics which is responsible for variation in type 1 diabetes. Although Arab population have contributed heavily in the rise of burden of type 1 diabetes, however, there is significantly a dearth amount of studies on HLA in Arab population. Obviously, any future prediction, prevention or cure of the disease will be based on the HLA genetics. There is a dire need for a systematic screening of HLA for Arab population with type 1 diabetes, identification of Arab HLA-risk values and identify those who are prone to get the disease.

Incretin effect helps in regulating glucose homeostasis and maintaining glycaemic control within the human body. This effect is achieved by the two naturally occurring incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Such hormones released by specialized entero-endocrine cells of the gastrointestinal tract cause insulin augmentation after food consumption. However, incretin effects are impaired in type 2 diabetic, primarily attributed to the deterioration of GLP-1 function along with decreased GLP-1 receptor expression. Targeting this hormone has, therefore, become an important therapeutic approach to treat this diabetic condition. Native GLP-1’s brief half-life and rapid proteolytic degradation have generated significant enthusiasm in uncovering the long-acting GLP-1 receptor (GLP-1R) agonists to manage type 2 diabetes. These synthetic peptides mimic the natural GLP-1 to activate GLP-1R and effectively exert various physiological benefits in terms of weight management, blood pressure, lipid profile, obesity and major adverse cardiovascular event. This review paper provides insights into the structure, function and expression of GLP-1 and its receptor. It also summarizes existing literature regarding different types of GLP-1 receptor agonists, their effects on blood pressure and how they exert their actions. While animal models have contributed significantly to this area of study, the scarcity of human studies is noted, indicating a need for more investigation in this domain. Expanding research in humans will help in comprehending the impact of GLP-1 receptor agonists on blood pressure regulation and their underlying mechanisms.

In recent years, numerous approaches have been developed to comprehend the molecular altera-tions underlying thyroid cancer (TC) oncogenesis and explore novel therapeutic strategies for TC. It is now well established that the neurokinin-1 receptor (NK-1R) is overexpressed in cancer cells and that NK-1R is essential for viability of cancer cells. The binding of substance P (SP) to NK-1R in neoplastic cells plays a pivotal role in cancer progression by promoting neoplastic cell growth, protecting tumour cells from apoptosis, triggering invasion and metastasis through enhanced migration of cancer cells, and stimulating endothelial cell proliferation for tumour angiogenesis. Remarkably, all types of human TC (papillary, follicular, medullary, anaplastic), as well as met-astatic lesions, exhibit overexpression of SP and NK-1R compared to the normal thyroid gland. TC cells synthesize and release SP, which exerts its multiple functions through autocrine, para-crine, intracrine, and neuroendocrine processes, including the regulation of tumour burden. Con-sequently, the secretion of SP from TC results in increased SP levels in plasma, which are signifi-cantly higher in TC patients compared to controls. Additionally, NK-1R antagonists have demonstrated a dose-dependent antitumour action. They impair cancer cell proliferation on one side and induce apoptosis of tumour cells on the other side. Furthermore, it has been demonstrat-ed that NK-1R antagonists inhibit neoplastic cell migration, thereby impairing both invasiveness and metastatic abilities, as well as angiogenesis. Given the consistent overexpression of NK-1R in all types of TC, targeting this receptor represents a promising therapeutic approach for TC. Therefore, NK-1R antagonists, such as the drug aprepitant, may represent novel drugs for TC treatment.

Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autosomal recessive autoinflammatory disease with symptoms including but not limited to osteomyelitis, periostitis, and systemic inflammation. DIRA is developed from the loss-of-function mutations of IL1RN gene that encodes IL-1 receptor antagonist (IL-1RA), leading to the unchecked pro-inflammatory signaling and subsequent systemic inflammation. Thus, Anakinra as the recombinant IL-1RA has become the primary drug to treat DIRA. Although Anakinra has been effective for complete remission of DIRA, it also showed various side effects. To further address its efficacy and safety in treating DIRA, a review of literature was conducted in this study. We have identified 15 papers with 25 patients studied, making it possible to conduct reliable statistical analyses. The literature review found that continual treatment with Anakinra is effective to cause clinical remission of DIRA. Statistical analyses found that after the treatment with Anakinra, patients had improved Hemoglobin, Erythrocyte Sedimentation Rate, and C-reactive Protein levels. All known cytogenetic abnormalities were also analyzed to inform clinicians for genetic screening and rapid diagnosis of DIRA. The results from this study provide a comprehensive view for further improving the treatment of DIRA by Anakinra.

The Mediterranean diet (MED) is highly recommended. Medical nutrition therapy is the cornerstone of diabetes treatment. We assessed adherence to the MED, and resultant micronutrient intake and glycemic control in youth with type 1 diabetes. Twenty adolescents, median age 18 years (interquartile range: 15.5-21), median diabetes duration 9 years (7-14), using continuous glucose monitoring devices, received personalized diet regimes based on MED. At 6 months post-intervention, the caloric intake remained unchanged; however, the carbohydrate proportion was lower (p=0.058) and the intakes of some monounsaturated fats increased (p=0.049). Sodium intake exceeded the recommended daily allowance by 250% (p=0.653), before and after the intervention. For blood glucose, the percent time-in-range 70-180 mg/dL improved from 52% (38-60) to 63% (47-71) (p=0.047). The total insulin dose decreased marginally, from 0.76 u/kg (0.64-0.97) to 0.72u/kg (0.61-0.89) (p=0.067). BMI z-score and waist circumference did not change (p=0.316 and p=0.161, respectively). Diastolic blood pressure percentile decreased from 73% (68-88) to 69% (50-79) (p=0.028), and LDL cholesterol from 114mg/ dl (105-134) to 104mg/dl (96-124) (p=0.059). The Israeli Mediterranean diet screener score increased, from 8 (7-11) to 13 points (12-14) (p=<0.001). The MED-based intervention demonstrated feasibility and improvements in glycemic outcomes and in certain nutritional parameters.

The incidence of Type 1 Diabetes (T1D) in the Arab world, particularly, oil and gas rich Gulf Cooperative Council (GCC) countries has more than doubled in the last twenty years. Therefore, there is a dire need for careful systematic familial cohort studies, especially in high-risk populations. Several immunogenetic factors affect the pathogenesis of the disease. Genes in the human leukocyte antigen (HLA) account for the major genetic susceptibility to the disease. The triggering agents initiate disease onset by destruction of pancreatic β-cells. The autoantibodies against glutamic acid decarboxylase (GADA), insulinoma antigen-2 (IA-2A), insulin (IAA), and zinc transporter-8 (ZnT-8A) comprise the most reliable biomarkers for T1D in both children and adults. Although three of the GCC countries, namely Kuwait, Saudi Arabia and Qatar are among the top 10 countries with high incidence rate of T1D, no proper diagnostic and prediction tools were applied in the region. Understanding the disease sequelae in a homogenous gene pool with high consanguinity in the GCC could help solve the challenges in understanding pathogenesis, as well as hasten the prevention of T1D. Arab states must incorporate T1D predictive and intervention policies on a war-footing basis to minimize the burden of this serious disease.

Expression of Krüppel–like factor 15 (KLF15), a stress induced transcription factor, is induced during bovine herpesvirus 1 (BoHV-1) reactivation from latency, and KLF15 stimulates BoHV-1 replication. Transient transfection studies revealed KLF15 and glucocorticoid receptor (GR) cooperatively transactivate the BoHV-1 immediate early transcription unit 1 (IEtu1), herpes sim-plex virus type 1 (HSV-1) infected cell protein 0 (ICP0), and ICP4 promoter. The IEtu1 promoter drives expression of bICP0 and bICP4, two key BoHV-1 transcriptional regulatory proteins. Based on these studies, we hypothesized infection is a stressful stimulus that increases KLF15 ex-pression and enhances productive infection. New studies demonstrated that silencing KLF15 impaired HSV-1 productive infection and KLF15 steady state protein levels were increased at late stages of productive infection. KLF15 was primarily localized to the nucleus following in-fection of cultured cells with HSV-1, but not BoHV-1. When cells were transfected with a KLF15 promoter construct and then infected with HSV-1, promoter activity was significantly increased. The ICP0 gene and to a lesser extent bICP0 transactivated the KLF15 promoter in the absence of other viral proteins. In contrast, BoHV-1 or HSV-1 encoded VP16 had no effect on KLF15 pro-moter activity. Collectively, these studies revealed HSV-1 and BoHV-1 productive infection in-creased KLF15 steady state protein levels, which correlated with increased virus production.

Background/Objectives: The disparities in internalizing and externalizing symptoms between individuals with versus without neurofibromatosis type 1 (NF1) are poorly understood, based on mixed evidence in the literature. The current meta-analysis aimed to synthesize existing findings on the topic and explore moderators of the group disparities. Method: Electronic databases were searched from inception to March 26th 2024, which identified 59 eligible studies (N of NF1 = 3,182, mean ages 2.38 to 46.4 years). The primary outcome was differences in internalizing and externalizing symptoms between individuals with and without NF1. Data were analyzed using robust variance estimation and random-effects models. Results: Compared with unaffected controls, individuals with NF1 showed more severe depressive (k = 21; g = 0.43; 95% CI [0.21, 0.65]), anxiety (k = 24; g = 0.27; 95% CI [0.01, 0.54]), somatic (k = 27; g = 0.56; 95% CI [0.30, 0.83]), total internalizing (k = 75; g = 0.50; 95% CI [0.33, 0.67]), aggression (k = 33; g = 0.33; 95% CI [0.08, 0.58]), delinquency, (k = 37; g = 0.43; 95% CI [0.26, 0.60]), and total externalizing symptoms (k = 47; g = 0.24; 95% CI [0.13, 0.35]). Studies that included more participants with NF1 who had ADHD or a lower verbal IQ reported greater group disparities in total internalizing symptoms or aggression. Conclusions: Findings highlight the importance of including psychosocial needs in monitoring and treating NF1. Future research should identify predictors of internalizing and externalizing symptoms within the NF1 population to inform our knowledge and intervention development.

Background: Sarcopenia is a progressive muscle disorder characterized by muscle wasting, decreased strength, and a substantially elevated risk of developing severe and potentially life-threatening health complications. For decades, muscle wasting has been recognized as a clinical symptom in various severe diseases and conditions. However, with increasing life expectancy and an aging population, sarcopenia has emerged as a prominent age-related condition in primary care, significantly contributing to disability and mortality rates. Aim and Objective: Our goal was to elucidate the clinical characteristics associated with sarcopenia prevalence in postmenopausal women with type 1 osteoporosis. Methodology: 370 postmenopausal osteoporosis patients who routinely visited the physiotherapy department at Ali Fatima Hospital were examined in this cross-sectional investigation. Mean age 64.59 ± 5.85 years, it was discovered that the patients' quality of life, postural stability, muscular strength, and balance were related to the existence of sarcopenia. Conclusion: In summary, among postmenopausal female patients with type 1 osteoporosis, the incidence of sarcopenia was relatively high (90.35%), affecting quality of life in 39.82% of patients, postural instability in 92.21% of patients, and balance in 39.92% of patients.

This study aimed to present a systematic meta-analysis examining the association between Helicobacter pylori (H. pylori) infection, hemoglobin A1c levels, and the development of type 1 diabetes mellitus. The initial search identified 451 articles related to the association between H. pylori infection and T1DM. Among them, 14 articles had 2,971 participants meeting the inclusion criteria for advanced meta-analysis. A significant association was observed between H. pylori infection and T1DM, with an odds ratio (OR) of 1.87 (95% confidence interval [CI]: 1.27–2.78, p = 0.002). A subgroup analysis on H. pylori status showed that a longer duration of diabetes diagnosis and higher hemoglobin A1c levels were significantly associated with H. pylori infection (p < 0.001 for both). However, there was no significant association between H. pylori infection and the diagnostic age of diabetes (p = 0.306). These findings contribute to the understanding of the association between H. pylori infection and T1DM, thereby highlighting the potential role of H. pylori in influencing the duration and glycemic control of diabetes.

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that, occasionally, may spread to the central nervous system (CNS), being the most common cause of sporadic encephalitis. One of the main neurovirulence factors of HSV-1 is the protein ICP34.5 that, although initially seemed to be relevant only in neuronal infections, it can also promote viral replication in non-neuronal cells. New ICP34.5 functions have been discovered during the recent years, and some of them have been questioned. This review describes the mechanisms of ICP34.5 to control cellular antiviral responses and debates its most controversial functions. One of the most discussed roles of ICP34.5 is autophagy inhibition. Although autophagy is considered a defense mechanism against viral infections, current evidence suggests that this antiviral function is only one side of the coin. Different types of autophagic pathways interact with HSV-1 impairing or enhancing the infection, and both the virus and the host cell modulate these pathways to tip the scales in its favor. In this review, we will summarize the recent progress on the interplay between autophagy and HSV-1, focusing on the intricate role of ICP34.5 in the modulation of this pathway to gain the battle against cellular defenses.

Introduction: Type 1 diabetes mellitus is a chronic disease of autoimmune etiology that is highly prevalent in childhood. In the last decade, the possibility of using the Bacillus Calmette-Guérin vaccine for the treatment of this disease has been studied thanks to its immunomodulatory action . Objectives: The objective of this work is to carry out a systematic review of the available scientific evidence on the relationship between the tuberculosis vaccine and the treatment of diabetes in childhood. Secondarily, the aim is to study the incidence of Type 1 Diabetes Mellitus in a cohort of children from the Basque Country according to whether or not they have received the vaccine. Methods: An exhaustive bibliographic search has been carried out on the evidence available to date. For the epidemiological study in Euskadi, a comparison of accumulated incidences between vaccinated and unvaccinated population groups was made. Results: According to the literature analyzed, There is more and more evidence about the possible use of the tuberculosis vaccine in Type 1 Diabetes Mellitus. The results of our study were not conclusive, but we believe that it is necessary to continue with long-term studies to eliminate biases. Conclusions: The Bacillus Calmette-Guérin vaccine could be used for the treatment of autoimmune, allergic, infectious or oncological processes, although more studies are still necessary in this regard.

Omicron SARS-CoV-2 variants have dominated the strains of COVID-19 circulating worldwide for the last two years. Although the mortality rate of the COVID-19 Omicron variants is only approximately half that of previous variants, vaccines effective against Omicron are needed. Demonstrating that a SARS-CoV-2 vaccine can protect against Omicron in an in vivo infection model, particularly in that of Syrian hamsters, is important for the preclinical characterization of SARS-CoV-2 vaccines. Here, we report on the evaluation of W-PreS-O for its ability to protect Syrian hamsters against infection by Omicron. W-PreS-O is a chimeric vaccine based on a single fusion protein (W-PreS-O), combining RBDs from Wuhan hu-1 wild-type and Omicron adsorbed to aluminum hydroxide. The Syrian hamsters were immunized three times at three-week intervals with W-PreS-O or with aluminum hydroxide (placebo), and then they were infected with Omicron BA.1. Non-infected and non-vaccinated animals served as controls. Neutralizing antibody (nAB) titers, weight, lung symptoms (i.e., edema and pneumonia index), and viral loads, as measured using RT-PCR in the upper and lower respiratory tracts, were determined. In addition, infectious virus titers from the lungs were measured using a plaque-forming assay. W-PreS-O-vaccinated hamsters developed robust nABs against Omicron, showed almost no development of pneumonia, and had significantly reduced infectious virus titers in the lungs. Importantly, the viral loads in the nasal cavities of W-PreS-O-vaccinated hamsters were close to or above the PCR cycle threshold considered to be non-infectious. Our data provide compelling evidence demonstrating that the W-PreS-O vaccine has protective effect against Omicron in a Syrian hamster in vivo infection model. W-PreS-O is therefore a highly promising candidate vaccine for Omicron infections, and it should be further evaluated in clinical studies.

HIV-1, like other viruses, represents an open thermodynamic system. This is why it is important to know its thermodynamic properties. Virus-host interactions are performed at the membrane as antigen-receptor binding. Antigen-receptor binding represents a chemical reaction, similar to protein-ligand interactions. The driving force for antigen-receptor binding is Gibbs energy of binding. Knowing Gibbs energy of binding, it is possible to estimate the rate of virus binding and entry into host cells. In this paper, binding equilibrium constants and standard Gibbs energies of binding between the HIV-1 gp120 antigen and the CD4 receptor have been reported at 4°C, 22°C and 37°C.

Several studies have shown promising treatments for type 1 diabetes mellitus (T1DM) using developing gene therapy methods. This review article focuses on summarizing possible new treatment options and outlining their pros and cons, since there is no cure for T1DM as of yet. New treatments involve islet and stem cell transplantation, genetic vaccination, and immunological precursor cell-mediated therapy. Since most of these methods are still in their early stages, efficacy in human trials of this type of treatment is still largely unknown, however, researchers are hopeful after numerous successes in trials with non-obese diabetic (NOD) mice.

Chronic kidney disease (CKD) bears a heavy burden on patients and the health care system as whole. The incidence of CKD has been increasing in the Arab world over the years due to increases in Diabetes and hypertension which are the most prominent causes of CKD. Syrians are at higher risk for diabetes and hypertension due to the crisis that the country has been going through. 297 patients’ charts were examined in the kidney surgical hospital in Damascus Syria to determine risk factors for CKD, prevalence of diabetes among them and its associating demographic factors along with changes in serum creatinine, urea, fasting blood glucose levels and MDRD score among diabetic CKD patients. 64.6% of patients were above 50, 61.6% were males and 35.4% were diabetic. Patients with diabetes had lower creatinine levels upon admission than non-diabetics. The correlation between fasting blood glucose level and serum creatinine, urea and MDRD was not statistically significant. This paper shows that the prevalence of diabetes among CKD patients is similar in Syrians to the rest of the world despite the increase of diabetes incidence.

Mapping forest extent and forest cover classification are important for the assessment of forest resources in socio-economic as well as ecological terms. Novel developments in the availability of remotely sensed data, computational resources, and advances in areas of statistical learning have enabled fusion of multi-sensor data, often yielding superior classification results. Most former studies of nemoral forests fusing multi-sensor and multi-temporal data have been limited in spatial extent and typically to a simple classification of landscapes into major land cover classes. We hypothesize that multi-temporal, multi-censor data will have a specific strength in further classification of nemoral forest landscapes owing to the distinct seasonal patterns of the phenology of broadleaves. This study aimed to classify the Danish landscape into forest/non-forest and further into forest types (broadleaved/coniferous) and species groups, using a cloud-based approach based on multi-temporal Sentinel 1 and 2 data and machine learning (random forest) trained with National Forest Inventory (NFI) data. Mapping of non-forest and forest resulted in producer accuracies of 99% and 90 %, respectively. The mapping of forest types (broadleaf and conifer) within the forested area resulted in producer accuracies of 95% for conifer and 96% for broadleaf forest. Tree species groups were classified with producer accuracies ranging 34-74%. Species groups with coniferous species were the least confused whereas the broadleaf groups, especially Oak, had higher error rates. The results are applied in Danish National accounting of greenhouse gas emissions from forests, resource assessment and assessment of forest biodiversity potentials.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that acts on the pancreas to increase insulin and decrease glucagon secretion. Albuminuria is the pivotal marker for diabetic nephropathy, which is the leading microvascular complication of diabetes mellitus. Most of the previous studies mainly focused on the clinical trials of the therapeutic renal protective effect after administration of GLP-1 receptor agonists (GLP-1 RAs), not prior to administration. Therefore, this study aimed to investigate the association between fasting plasma GLP-1 levels and albuminuria before GLP-1 RA administration. A cross-sectional study was designed to evaluate the association between fasting plasma GLP-1 levels and albuminuria in patients with type 2 diabetes mellitus (T2DM). A total of 68 T2DM participants were analyzed from the data at Wonkwang University Hospital in Iksan, Korea. Logistic regression analysis was performed to evaluate the odds ratio (OR) and 95% confidence interval (CI) of the incidence of albuminuria between the GLP-1 low group (Group L) and the high group (Group H). The OR (95% CI) for the incidence of albuminuria comparing the Group L with the Group H of fasting plasma GLP-1 levels was 3.410 (1.160-10.023), p = 0.026 after adjustment for age, gender, fasting plasma glucose, HbA1c, C-peptide, the use of ACE inhibitors or ARBs, SGLT-2 inhibitors, and DPP-4 inhibitors. As a continuous variable, the OR (95% CI) for the incidence of albuminuria associated with the reduction of each 1 pmol/L in fasting plasma GLP-1 levels was 1.673 (1.173-1.870), p = 0.018, after full adjustment. This study showed the negative association between fasting plasma GLP-1 levels and the incidence of albuminuria in Korean patients with T2DM, before GLP-1 RA administration. This result suggests that endogenous GLP-1 may play a role in attenuating albuminuria.

ABSTRACT: Objectives: Oncostatin M (OSM), a member of the interleukin (IL)-6 family of cytokines, is known to elicit pathogenic effects involving disruption of the epithelial barrier function as a part of immunological response networks. It is not yet known how these integrated cytokine signals influence inflammation and other physiological processes in the pathology of chronic rhinosinusitis (CRS). We investigated the expression and distribution of OSM and OSM receptor (OSMR) in sinonasal specimens of CRS patients, and we compared the results with a panel of inflammatory cytokine levels and clinical features. Materials and Methods: We classified CRS patients as eosinophilic (ECRS, n=36) or non-eosinophilic (non-ECRS, n=35) based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) phenotypic criteria, and we compared their cases with those of 68 non-CRS subjects. We also examined stimulatory effects of OSM on the expression levels of cytokine receptors by using the human bronchial epithelium cell line BEAS-2B. Results: An RT-PCR showed that the OSM mRNA levels were significantly increased in the ethmoid sinus mucosa of the CRS patients. The OSM mRNA levels were positively correlated with those of TNF-α, IL-1β, IL-13, and OSMR-β. In BEAS-2B cells, OSM treatment induced significant increases in the OSMR-β, IL-1R1, and IL-13Ra mRNA levels. Conclusions: Our findings indicate that OSM is involved in the pathogenesis of CRS in both type 1 and type 2 inflammation, suggesting the OSM signaling pathway as a potential therapeutic target for modulating epithelial stromal interactions.

This study aimed to identify and differentiate the factors that may affect the incidence of temporomandibular joint (TMJ) dysfunction in children with type 1 diabetes. We analyzed the TMJ symptoms, clinical and laboratory parameters of type 1 diabetes in a cohort of 101 consecutive patients. The participants were evaluated regarding the presence of pain in the masticatory muscles, TMJ sounds, mouth opening, maximum mouth opening, lateral and protrusive excursions, and Fonseca scores. The overall cohort showed a mean Fonseca score of 20 ± 13.89, referred to mild TMJ dysfunction. Of patients, 34.65% presented at least one clinical symptom and were defined as having dysfunction. The most frequently recorded symptom was TMJ sounds, presented in 16.8% of children. In subjects with dysfunction compared to those without dysfunction, a significant difference was found at height standard deviation scores, Fonseca scores and maximum mouth opening (p&lt;0.001). HbA1c levels, diabetes duration, age and gender did not reveal any significant differences between the patients with and without dysfunction. Type 1 diabetes is often associated with limited mouth opening and mild TMJ dysfunction. This dysfunction may reflect a more chronic condition and possibly exceeds the prevalence of cheiroartropathy. This study could be a starting point towards enhancing our understanding of clinically evident TMJ involvement in type 1 diabetes.

Recent studies have shown that the endogenous cannabinoid system (ECS) of the brain is essentially involved in the pathogenesis of Parkinson's disease (PD), influencing its symptoms by regulating the level of endogenous cannabinoids and altering the activation of cannabinoid receptors (CBR). Therefore, modulation of ECS with new drugs developed for this purpose may prove to be a promising strategy in the treatment of PD. However, fine regulation of ECS is quite a challenge due to the functional diversity of CBR in the basal ganglia. Our review analyses the effects of ECS modulators on experimental PD models and in patients with PD, as well as presents the outlooks for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD.

Alphaherpesviruses cause genital lesions and reproductive failure in both humans and animals. Their control is mainly based on prevention by hygienic prophylactic measures, due to the ab-sence of vaccines and limitations of antiviral drug therapy. Ozone is an oxidating gas showing a strong microbicidal activity on bacteria, fungi, viruses, and protozoa. The present study assessed the in vitro virucidal and antiviral activity of ozone against Caprine herpesvirus type 1. Virucidal activity of a gaseous mixture containing O3 at 20 and 50 μg /mL was assessed against the virus for different contact times (30 s, 60s, 90s, 120s, 180s and 300s). Antiviral activity of a gaseous mix-ture containing O3 at 20 and 50 μg /mL was evaluated against the virus to for 30s and 60s. Ozone displayed significant virucidal activity when used at all the tested concentrations whilst signifi-cant antiviral activity was observed using ozone at 50 μg/ml. The gaseous mixture, tested in the present study, showed virucidal and antiviral activity against CpHV-1 with a dose- and a time-contact -dependent fashion. Ozone therapy could be evaluated in vivo for the treatment of CpHV-1-induced genital lesions in goats, through topical applications.

Corrosive burns lead to progressive esophageal stricture and dysphagia. There are many trials to prevent Esophageal stricture formation after corrosive burn. This study aimed to access the effects of EW-7197 on prevention for esophageal stricture formation after corrosive esophageal burn. animal study were classified divided into three groups: a healthy group, a control group (corrosive burn without EW-7197), and a treatment group (corrosive burn with EW-7197). Corrosive esophageal burns were produced using 30% NaOH on the lower esophagus. For 3 weeks, the control group received vehicle and the treatment group received 20 mg/kg/day EW-7197. Treatment efficacy was assessed by measuring the stenosis ratio by esophagogram with contrast media on day 21. histologic staining was performed to evaluate the fibrosis area ratio, and western blotting was performed to evaluate fibrotic markers. Among 20 rats that underwent surgery, 14 survived. Three in the treatment group died because of esophageal perforation, and three in the control group died due to their debilitating status. The esophageal stenosis ratio was significantly lower in the treatment group than in the control group (12.1 ± 9.5% and 42.2 ± 8.3%, respectively; p = 0.001). The histologic fibrosis area ratio was also significantly lower in the treatment group (12.5 ± 3.0% and 21.6 ± 2.1%, respectively; p = 0.001). The treatment group showed lower expressions of profibrogenic proteins such as TGF-β1, pSmad3, and α-SMA. EW-7197 may be a good alternative for the prevention esophageal stricture formation after corrosive burn.

Background: Although autophagy is a pro-survival process of tumor cells, in particular conditions and when differently regulated by specific signals it can stimulate cell death. We previously demonstrated that the selective stimulation of the M2 muscarinic receptor subtype (M2 mAChR) negatively controls cell proliferation and survival and causes oxidative stress and cytotoxic and genotoxic effects in both GBM cell lines and GBM stem cells (GSCs). In this work, we have evaluated whether autophagy was induced as a downstream mechanism of the observed cytotoxic processes induced by M2 mAChR activation by the orthosteric agonist APE or the dualsteric agonist N-8-Iper. Methods: To assess the activation of autophagy, we analyzed the expression of LC3B by Western blot analysis and in LC3B-EGFP transfected cell lines. Apoptosis was assessed by Caspases 3 and 9 protein expression. Results: Our data indicate that activation of M2 mAChR by N-8-Iper promotes autophagy in both U251 and GB7 cells lines as suggested by the LC3B-II expression level and analysis of the transfected cells by fluorescence microscopy. Autophagy induction by M2 mAChRs is regulated by the decreased activity of the PI3K/AKT/mTORC1 pathway and upregulated by the pAMPK expression. Downstream autophagy activation, the increase of apoptosis was also observed in both cell lines after treatment with the two M2 agonists. Conclusions: N-8-Iper treatment causes autophagy via pAMPK upregulation, followed by apoptosis in both investigated cell lines. In contrast, the absence of autophagy in APE-treated GSC cells seems to indicate that cell death could be triggered by mechanisms alternative to those observed for N-8-Iper.

Liraglutide, a glucagon-like peptide 1 analog used to treat type 2 diabetes and obesity, is a po-tential new treatment modality for bile acid (BA) diarrhea. Here, we show that administration of liraglutide significantly decreased total BAs, especially the primary BAs, including cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, and β-muricholic acid, in the liver and feces. In addition, liraglutide significantly decreased trypto-phan metabolites, including L-tryptophan, serotonin, 5-hydroxy indole-3-acetic acid, L-kynurenine, and xanthurenic acid, in the colon, whereas it significantly increased in-dole-3-propionic acid. Moreover, the administration of liraglutide remarkably decreased the ex-pression of apical sodium-dependent bile acid transporter, which mediates BA uptake across the apical brush border member in the ileum, ileal BA binding protein, and fibroblast growth factor 15 in association with decreased expression of the BA-activated nuclear receptor farnesoid X receptor and the heteromeric organic solute transporter Ostα/β, which induces BA excretion, in the ileum. Liraglutide acutely decreased body weight and blood glucose levels in association with decreases in plasma insulin and serotonin levels in food-deprived mice. These findings suggest the potential of liraglutide as a novel inhibitor of primary BAs and serotonin in the colon, which may be in-volved in the improvement of BA diarrhea.

Secretory and membrane proteins are vital for cell activities, including intra- and intercellular communication. Therefore, protein quality control in the endoplasmic reticulum (ER) is an essential and crucial process for eukaryotic cells. Endoplasmic reticulum-associated degradation (ERAD) targets misfolded proteins during the protein maturation process in the ER and leads to their disposal. This process maintains the ER productive function and prevents misfolded protein stress (i.e., ER stress). The ERAD-stimulating factor ER degradation-enhancing α mannosidase-like 1 protein (EDEM1) acts on misfolded proteins to accelerate ERAD, thereby maintaining the productivity of the ER. However, the detail mechanism underlying the function of EDEM1 in ERAD is not completely understood due to lack of established physiological substrate proteins. In this study, we attempted to identify substrate proteins for EDEM1 using siRNA. The matrix component thrombospondin-1 (TSP1) and epidermal growth factor receptor (EGFR) were identified as candidate targets of EDEM1. Their protein maturation status and cellular localization were markedly affected by knockdown of EDEM1. We also showed that EDEM1 physically associates with EGFR and enhances EGFR degradation via ERAD. Our data highlight the physiological role of EDEM1 in maintaining specific target proteins and provide a potential approach to the regulation of expression of clinically important proteins.

Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is expressed on microglia. AZ683 has high affinity for CSF1R (K_i = 8 nM; IC₅₀ = 6 nM) and >250-fold selectivity over 95 other kinases and, in this paper, we report the radiosynthesis of [¹¹C]AZ683 and initial evaluation of its use in CSF1R PET. [¹¹C]AZ683 was synthesized by ¹¹C-methylation of the desmethyl precursor with [¹¹C]MeOTf in 3.0% non-corrected activity yield (based upon [¹¹C]MeOTf), >99% radiochemical purity and high specific activity. Preliminary PET imaging with [¹¹C]AZ683 revealed no brain uptake in rodents and nonhuman primates suggesting that [¹¹C]AZ683 is a poor candidate for imaging neuroinflammation, but that it could still be useful for peripheral imaging of inflammation.

The study aimed to determine the relationship between glucose, C-peptide, BDNF, and leptin between mother and fetus and neonatal weight. Methods: In the prospective observational cohort study, we included 66 women with T1DM. According to the z-score for neonatal weight, patients were divided into Healthy weight neonates (n=42) and Overweight neonates (n=24). The maternal blood samples were taken during pregnancy and cesarean section when the umbilical vein blood sample was also withdrawn. The maternal vein sera were analyzed for fasting glucose, CRP, leptin, BDNF, TSH, FT3, and FT4. The umbilical vein sera were analyzed for glucose, C-peptide, leptin, TSH, FT3, FT4, and BDNF concentration. The neonatologist measured the skinfold thickness on the third day of neonatal life. Results: A strong correlation was confirmed between maternal and umbilical vein glucose concentration and maternal glucose and C-peptide in umbilical vein blood. A negative correlation was found between the concentration of BDNF in the umbilical vein and glucose in maternal blood. A strong correlation was seen between BMI and maternal blood leptin concentration, neonatal fat body mass, and umbilical vein blood leptin concentration. Increased odds for Overweight neonates were BMI, BDNF, and TSH in the first trimester of pregnancy. Maternal leptin concentration decreased the odds of Overweight neonates. Conclusions: Maternal glucose concentrations affect the fetus’s glucose, C-peptide, and BDNF concentrations. Leptin levels increase in maternal blood due to increased body mass index, and in the neonate, its fat body mass is responsible for increased leptin concentrations.

Diabetes Mellitus (DM) is a chronic metabolic disease consisting of Type 1 or Type 2 diabetes. Although treatment of Type 1 diabetes primarily involves insulin therapy, inhibitors of sodium glucose co-transporters (SGLT’s) are a promising new therapeutic. Of particular interest are the two family members, SGLT1 and SGLT2 that collectively contribute to 100% of filtered glucose reabsorption within the kidneys. Consequently, sole SGLT2 inhibitors (SGLT2i) and dual SGLT1/2 inhibitors (SGLT1/2i) contribute to reducing blood glucose levels by reducing glucose reabsorption and promoting glucosuria and natriuresis. Research from our team on SGLT2i, showed that there is a compensatory mechanism whereby SGLT1 is upregulated. This therefore may warrant the combined use of SGLT1/2i. Our in vitro results demonstrated that whilst both the sole SGLT2i empagliflozin (EMPA) and dual SGLT1/2i sotagliflozin (SOTAG) significantly reduce glucose uptake within HK2 cells, the latter was more effective. In addition, our in vitro results indicate significantly more pronounced upregulation of SGLT1 protein with EMPA compared to SOTAG. Our in vivo mechanistic findings demonstrated that SGLT1/2i significantly increased renal SOD1 levels, whilst SGLT2i significantly elevated renal SOD2 levels. Therefore, our study highlighted that SGLT2i and SGLT1/2i differentially regulate protective anti-oxidant proteins in the kidney.

A flavonoid Astragalin (kaempferol-3-O-β-D-glucopyranoside, Ast) has several biological activities including anti-oxidant, anti-HIV, and anti-allergic effects. Nonetheless, its insolubility in hydrophilic solvents imposes restrictions on its therapeutic applications. In this study, we investigated the effects of water-soluble astragalin-galactoside (kaempferol-3-O- β-D-isomaltotrioside, Ast-Gal) on dendritic cell (DC) maturation and T helper (Th) cell-mediated immune responses. Ast-Gal significantly increased maturation and activation of DCs through up-regulation of surface markers, such as CD80, CD86, and MHC II in a dose-dependent manner, while Ast had little effects. Also, Ast-Gal-treated DCs markedly secreted immune-stimulating cytokines such as IL-1β, IL-6, and IL-12. Importantly, Ast-Gal strongly increased expression of IL-12, a polarizing cytokine of Th1 cells. In a co-culture system of DCs and CD4+ T cells, Ast-Gal-treated DCs preferentially differentiates naïve CD4+ T cells into Th1 cells. The addition of neutralizing IL-12 mAb to cultures of Ast-Gal-treated DCs and CD4+ T cells significantly increased IFN- γ production, thereby indicating that Ast-Gal-stimulated DCs enhance the Th1 response through IL-12 production by DCs. Injection with Ast-Gal-treated DCs in mice increased IFN-γ-secreting Th1 cell population. Collectively, these findings indicate that hydrophilically modified astragalin can enhance Th1-mediated immune responses via DCs, and point to a possible application of water-soluble astragalin-galactoside as an immune adjuvant.

Dietary intake of omega-3 polyunsaturated fatty acids (eicosapentaenoic acid, EPA) exerts antiarrhythmic effects, although the mechanisms are poorly understood. Here we investigated the possible beneficial actions of EPA on saturated fatty acid-induced changes of the L-type Ca2+ channel in cardiomyocytes. Cardiomyocytes were cultured with oleic acid/palmitic acid mixture (OAPA) in the presence or absence of EPA. Beating rate reduction of cardiomyocytes caused by OAPA were reversed by EPA. EPA also retrieved a reduction of Cav1.2-L-type Ca2+ current, mRNA and protein caused by OAPA. Immunocytochemical analysis revealed a distinct downregulation of the Cav1.2 channel caused by OAPA with a concomitant decrease in the phosphorylated component of a transcription factor adenosine-3’, 5’-cyclic monophosphate (cAMP) response element binding protein (CREB) in the nucleus, which were rescued by EPA. A free fatty acid receptor 4 (FFAR4) agonist TUG-891 reversed expression of Cav1.2- and CREB-mRNA caused by OAPA, whereas an FFAR4 antagonist AH-7614 abolished the effects of EPA. Excessive reactive oxygen species (ROS) accumulation caused by OAPA decreased Cav1.2- and CREB-mRNA expressions, which were reversed by an ROS scavenger. Our data suggest that EPA rescues cellular remodeling caused by OAPA lipotoxicity and oxidative stresses via both free fatty acid receptor 4-dependent and -independent pathways.

Background: Over the past years, there has been a rise in the incidence of type 1 diabetes, partic-ularly among younger individuals. This concerning trend has prompted investigations into po-tential contributing factors, with intestinal dysbiosis emerging as a likely culprit for the escalating annual rates of the disease; (2) Methods: We conducted a retrospective ecologic correlational study involving 37 children from the southern region of Romania between 2019-2021. All participants were within the first six months following the onset of the disease; (3) Results: In the microbiota of the patients we observed a dysbiosis marked by an overabundance of bacteria (Clostridium coccoides, Faecalibacterium, Bacterioides, Enterobacteriaceae) and fungi, compared to the healthy control group. The Spearman correlation revealed a positive association between the presence of Bacteroides (p=0.0442), Butyricicoccus (p=0.0164), and Clostridium leptum (p=0.0023) with recent diabetes onset. Furthermore, a significant correlation was observed between younger age at onset and the pres-ence of Butyricicoccus (p=0.019). The use of antibiotics in the month preceding admission was linked to the presence of fungi in the microbiota (Candida, p=0.0442); (4) Conclusions: The dysbiosis of Romanian type 1 diabetes children correlates with inflammation, more severe onset of the disease and other au-toimmune diseases.

The management of patients with spinal muscular atrophy type 1 (SMA1) is constantly evolving. In just a few decades the medical approach has switched from an exclusively palliative therapy to a targeted therapy, transforming the natural history of the disease, improving survival time and quality of life, and creating new challenges and goals. Many nutritional problems, gastrointesti-nal disorders and metabolic and endocrine alterations are commonly identified in patients af-fected by SMA1 during childhood and adolescence. For this reason, a proper pediatric multidis-ciplinary approach is then required in the clinical care of these patients, with a specific focus on the prevention of most common complications. The purpose of this narrative review is to provide the clinician with a practical and usable tool about SMA1 patients care, through a comprehensive insight into the nutritional, gastroenterological, metabolic and endocrine management of SMA1. Considering the possible horizons opened thanks to new therapeutic frontiers, a nutritional and endo-metabolic surveillance is a crucial element to be considered for a proper clinical care of these patients.

Receptor–ligand interactions at cell interfaces initiate signaling cascades essential for cellular communication and effector functions. Specifically, T cell receptor (TCR) interactions with pathogen-derived peptides presented by the major histocompatibility complex (pMHC) molecules on antigen-presenting cells are crucial for T cell activation. The binding duration, or dwell time, of TCR–pMHC interactions correlates with downstream signaling efficacy, with strong agonists exhibiting longer lifetimes compared to weak agonists. Traditional surface plasmon resonance (SPR) methods quantify 3D affinity but lack cellular context and fail to account for factors like membrane fluctuations. In the recent years, single-molecule Förster resonance energy transfer (smFRET) has been applied to measure 2D binding kinetics of TCR–pMHC interactions in a cellular context. Here, we introduce a rigorous mathematical model based on survival analysis to determine exponentially distributed receptor–ligand interaction lifetimes, verified through simulated data. Additionally, we developed a comprehensive analysis pipeline to extract interaction lifetimes from raw microscopy images, demonstrating the model’s accuracy and robustness across multiple TCR–pMHC pairs. Our new software suite automates data processing to enhance throughput and reduce bias. This methodology provides a refined tool for investigating T cell activation mechanisms, offering insights into immune response modulation.

The Virus HIV-1 infection still represents a serious disease even if actually it is transformed in chronic pathology. Considering the crucial role of the enzyme Protease in life cycle of HIV many efforts have been made in the research of new organic compounds showing inhibitory activity. After development of several series of non peptidic inhibitors we report here the synthesis of novel simple HIV-Protease inhibitors containing heteroaryl carboxamides and their antiviral activity in vitro and in HEK293 cells. Benzofuryl- benzothienyl- and indolyl rings as well as aryl sulfonamides with different electronic properties have been introduced by efficient synthetic procedures. All compounds showed inhibitory activity similar to the commercial drug Darunavir, effective against both wild-type HIV-1 protease and that containing the V32I or V82A mutations. ADME properties were also evaluated, showing the potential of such compounds to be developed as drugs.

Dent disease type 1 is a rare inherited renal disorder affecting mainly young males, generally leading to end-stage renal failure and for which there is no cure. It is caused by inactivating mutations in the gene encoding ClC-5, a 2Cl-/H+ exchanger found on endosomes in the renal proximal tubule. This transporter participates in reabsorbing all filtered plasma proteins which justifies why proteinuria is commonly observed when ClC-5 is defective. In the context of Dent disease type 1, a proximal tubule dedifferentiation was shown to be accompanied by a dysfunctional cell metabolism. However, the exact mechanisms linking such alterations to chronic kidney disease are still unclear. In this review, we gather knowledge from several Dent disease type 1 models to summarize the current hypotheses generated to understand the progression of this disorder. We also highlight some urinary biomarkers for Dent disease type 1 suggested in different studies.

It has been discovered that representing odd integers as modified binary expressions of the form $\sum \limits_{n > m}2^n + 2^m - 1$ for $m \geq 1$ helps in understanding the dynamics of Collatz-type sequences. Starting with the original Collatz sequence $3x + 1$, it is found that when the odd step is applied to an odd integer $\sum \limits_{n > m}2^n + 2^m - 1$, an even integer $3\left(\sum \limits_{n > m}2^{n}\right) + 2^{m + 1} + 2^m - 2$ is obtained, which is exactly once divisible by 2, unless the lowest index reduces to zero. This implies that the sequence alternates between odd and even steps $m$ times. This governs the dynamics of the Collatz-type sequences because the value of $m$ determines the number of times the integer can be divided by 2 in each even step. A shortcut method is developed based on this dynamics that states that the even integer after $m$ odd-even steps are completed is $\left(\left(\frac{3}{2}\right)^m \sum \limits_{n > m}2^n\right) + 3^m - 1$. A shortcut method of this magnitude has never been utilized anywhere. The shortcut method for the modified Collatz sequence $5x + 1$ is also presented.

Cholesterol, a crucial component of cell membranes, influences various biological processes, including membrane trafficking, signal transduction, and host-pathogen interactions. Disruptions in cholesterol homeostasis have been linked to congenital and acquired conditions, including neurodegenerative disorders such as Alzheimer’s disease (AD). Previous research from our group has demonstrated that herpes simplex virus type I (HSV-1) induces an AD-like phenotype in several cell models of infection. This study explores the interplay between cholesterol and HSV-1-induced neurodegeneration. The impact of cholesterol was determined by modulating its levels with methyl-beta-cyclodextrin (MβCD) using the neuroblastoma cell lines SK-N-MC and N2a. We have found that HSV-1 infection triggers the intracellular accumulation of cholesterol in structures resembling endolysosomal/autophagic compartments, a process reversible upon MβCD treatment. Moreover, MβCD exhibits inhibitory effects at various stages of HSV-1 infec-tion, underscoring the importance of cellular cholesterol levels not only in the viral entry pro-cess but also in subsequent post-entry stages. MβCD also alleviated several features of AD-like neurodegeneration induced by viral infection, including lysosomal impairment and intracellu-lar accumulation of amyloid-beta peptide (Aβ) and phosphorylated tau. In conclusion, these findings highlight the connection between cholesterol, neurodegeneration, and HSV-1 infection, providing valuable insights into the underlying mechanisms of AD.

Type 1 diabetes (T1D) is an autoimmune condition where the body’s immune cells destroy their insulin-producing pancreatic beta-cells leading to dysregulated glycaemia. Individuals with T1D control their blood glucose through exogenous insulin replacement therapy, often using multiple daily injections or pumps. However, failure to accurately mimic intrinsic glucose regulation results in glucose fluctuations and long-term complications impacting key organs such as the heart, kidneys, and/or the eyes. It is well-established that genetic and environmental factors contribute to the initiation and progression of type 1 diabetes, but recent studies show that epigenetic modifications are also important. Here, we discuss key epigenetic modifications associated with type 1 diabetes pathogenesis and discuss how recent research is finding ways to harness epigenetic mechanisms to prevent, reverse, or manage type 1 diabetes.

Lifestyle interventions can prevent type 2 diabetes (T2DM). However, some in-dividuals do not experience anticipated improvements despite weight loss. Bi-omarkers to identify such individuals at early stages are lacking. IGF-1 and IGFBP-1 were shown to predict T2DM onset in prediabetes. We assessed if these markers also predict the success of lifestyle interventions, thereby possibly guid-ing personalized strategies. We analyzed fasting serum levels of IGF-1, IGFBP-1 and IGFBP-2 in relation to changes in metabolic and anthropometric parameters, including intrahepatic li-pids (IHL) and visceral adipose tissue (VAT) volume measured by MRI, in 345 high-risk prediabetic participants (54% female; aged 36-80 years). Participants were enrolled in three randomized dietary intervention trials and assessed both at baseline and one year post-intervention. Statistical analyses were performed using IBM SPSS Statistics (version 28), significance set at p

This paper concentrates on the general birth-death processes with two different types of catastrophes. The Laplace transform of transition probability function for birth-death processes with two-type catastrophes are is successfully expressed with the Laplace transform of transition probability function of the birth-death processes without catastrophe. The first effective catastrophe occurrence time is considered. The Laplace transform of its probability density function, expectation and variance are obtained.

Background: The COVID-19 pandemic, caused by SARS-CoV-2, has severely impacted children with Type 1 Diabetes (T1D), placing them at high risk for severe outcomes. Despite extensive observational data suggesting a link between T1D and severe COVID-19, there is a lack of understanding regarding the causal effects. This study aims to determine whether Type 1 diabetes (T1D) influences the risk of severe COVID-19 outcomes, particularly respiratory failure, in pediatric ICU patients. Methods: This two-sample Mendelian Randomization (MR) study utilized genetic data from large-scale genome-wide association studies (GWAS). Genetic variants associated with T1D were used as instrumental variables to assess their impact on severe COVID-19 outcomes. The primary datasets included genetic data for T1D from 457,695 individuals (6,447 T1D cases) and severe COVID-19 outcomes from 3,790 individuals (1,610 severe cases). Various MR methods, including Inverse Variance Weighted (IVW), MR-Egger Regression, and Weighted Median, were employed to ensure robust causal inference and eliminate potential biases such as pleiotropy. Results: The MR analysis revealed no causal relationship between T1D and severe COVID-19 outcomes in pediatric patients. Odds ratios (ORs) obtained using MR-Egger, Weighted Median, and IVW methods varied from 0.7648 to 0.9853, with p-values greater than 0.05, indicating no significant causal effect. Sensitivity analyses confirmed the robustness of these findings, showing no evidence of heterogeneity or directional pleiotropy. Conclusion: Our findings indicate no genetic causal link between T1D and severe respiratory failure from COVID-19 in children. These results contrast with numerous observational studies and suggest that metabolic dysfunction and other non-genetic factors should be the focus in managing this susceptible group. The insights gained are crucial for developing targeted interventions and improving clinical management strategies for pediatric ICU patients with T1D during the COVID-19 pandemic.

ObjectivesAbrus precatorius (AP) is a medicinal plant seldomly studied for its beneficial effects and as such significant gap exists in understanding the basis by which AP leaf bioactives (APLBs) elicit beneficial effects against diabetes mellitus (DM) type-1. MethodsWe estimated DM type-1 related parameters - total protein (TP), direct bilirubin (DB), urea, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and serum glucose (SG) after treatment with methanol extracts of AP leaves (APMLE) for 21 days followed by histopathological analysis of kidney and liver sections. APLBs were collected from GCMS fractions, database and literature searches and common targets were cross-intersected with annotated DM type-1 genes from experimental GSE14503 microarray dataset and genecard database. Overlapping differentially expressed genes were collected, their protein-protein interaction network was constructed and analyzed using various bioinformatics tools: Enrichr, SRplot, GSEA, Cytoscape, PyRx, and Discovery Studio to provide insight into the potential molecular basis of APLBs in DM-type-1.Results 15 compounds were identified from GCMS analysis of APMLE. Antidiabetic potential of APMLE was observed with significant (p <0.05) normalization of SG, TP, DB, ALT, AST, ALP, urea & creatinine while hepatorenal photomicrographs indicated moderate safety of use. Erucic acid, oleic acid, phytol and stigmasterol interact with 25 type-1 DM biomarkers revealed to be enriched in lipid and prostaglandin metabolic processes, neuroactive ligand receptor interaction, PPAR signaling pathway, diabetic cardiomyopathy, and cAMP signaling pathway. Furthermore, PPARalpha (peroxisome proliferator-activated alpha) and SCD (stearoyl-coenzyme A desaturase) were revealed as core biotargets interacting with APLBs via hydrogen bond, hydrophobic interaction and van der Waals forces from docking study. ConclusionThis study demonstrated the potency of APLBs in vivo against type-1 DM. The potential basis of action has been studied from computational perspective. Future interests may provide additional experimental data into mechanisms by which APLBs elicit this remarkable ability.

Glycated hemoglobin (HbA1c) is used to assess glycemic control in Type 1 diabetes (DM1) patients. Apolipoproteins play an essential role in DM1 pathophysiology and may be associated with complications, as well as HbA1c. This cross-sectional observational study consisting of 81 children and adolescents of both sexes diagnosed with DM1 investigated the relationship between body fat distribution and lean mass with HbA1C and apolipoprotein values analyzing biochemical and body composition measurements. Shapiro-Wilk test with Lilliefors correction, non-parametric Mann-Whitney test, and others were used with a significance level of 5%. The sample had a diagnosis time of 4.32 years and high blood glucose levels (mean 178.19 mg/dL) and HbA1c (mean 8.57%). Subjects also had a moderate level of adiposity, as indicated by arm and thigh fat areas. The study also found significant differences in the distribution of patients concerning levels of apolipoproteins A and B, with a smaller proportion of patients having undesirable levels. Finally, the study found a significant difference in the distribution of patients with estimated cardiovascular risk based on the ApoB/ApoA-1 ratio. Conclusively, visceral fat in children and adolescents with DM1 may increase the risk of DM1 long-term complications owing to its association with elevated HbA1C and apolipoprotein values.

In the contemporary world of science, continuous observation of specific fixed regions is required, awaiting the emergence of targets or phenomena within those areas to locate and identify them. Astronomy requires continuous monitoring of stars, swiftly pinpointing occurrences, such as flares, and acquiring their spectral data to aid identification. In military contexts, continuous observation of specific areas is essential for promptly locating enemy movements and obtaining target spectral data for deciphering enemy disguises. Additionally, continuous observation of experimental samples in biochemistry is mandatory to pinpoint localized changes and acquire spectral data from those areas. Hence, this paper develops a novel imaging spectrometer solution to monitor localized regions continuously. Specifically, this paper first elaborates on the developed instrument’s characteristics and optical structure, followed by optical design software simulations. The instrument has an F-number of 5, a focal length of 100mm, and a field of view covering the wavelength range from 400nm to 600nm. The optical path diagram indicates that the system’s dispersion and imaging images can be separated, meeting the system’s requirements. Besides, the Modulation Transfer Function (MTF) graph confirms that the image quality meets the requirements. Furthermore, a region-monitoring type imaging spectrometer was constructed to assess the instrument’s capability for spectral observation of fixed regions. The instrument can detect a fixed area, with the target placed within the detection area. Spectral data were successfully obtained by conducting image processing on the acquired images. The correlation coefficient between this data and reference data was as high as 0.9226, indicating the instrument’s successful measurement of the target’s spectrum. Thus, the developed instrument demonstrated that it can image the observed areas and acquire spectral data from targets within those regions.

Background: Type 2 diabetes mellitus (T2DM) is associated with increased atherogenicity and inflammatory responses, which may be related to increased levels of high mobility group box 1 (HMGB1) and Dickkopf-related protein 1 (DKK1). Objective: The role of HMGB1 and DKK1 in T2DM is examined in association with lipid and insulin profiles. Methods: Serum HMGB1 and DKK1 were measured in T2DM with and without hypertension and compared with controls. Results: HMGB1 and DKK1 are significantly higher in T2DM irrespective of hypertension. T2DM was also accompanied by increased atherogenicity indices. HMGB1 and DKK1 are significantly correlated with HbA1c, glucose, indices of insulin resistance, β-cell function, and glucose toxicity, and different atherogenic indices. A large part of the variance in the β-cell index (30.5%) and glucose toxicity (34.8%) was explained by the combined effects of HMGB1 and DKK1 and hypertension. We found that 18.3% of the variance of the atherogenic index of plasma was explained by HMGB1 and DKK1 levels and that 31.2% was explained by glucose toxicity, HMGB1 and body weight. Conclusion: The higher serum HMGB1 and DKK1 levels in T2DM patients and the associations with atherogenicity indicate that low grade inflammation and disorders in the Wnt pathways are associated with T2DM and that both HMGB1 and DKK1 may contribute to increased atherogenicity in T2DM. Moreover, both biomarkers may cause more deficits in β-cell function and increase glucose toxicity leading to the development of more inflammation and diabetic complications. HMGB1 and the Wnt pathways are new drug targets in the treatment of T2DM.

Uveal melanoma (UM) poses a significant clinical challenge due to its high metastasis rate and poor prognosis. Melatonin, noted for its anti-cancer properties in various malignancies, including cutaneous melanoma, shows promise in UM treatment. This study aimed to evaluate melatonin receptor expression in primary UM and its association with UM-related mortality and prognostic factors. Immunohistochemical analysis of 47 primary UM tissues showed low expression of MTNR1A and MTNR1B receptors, with MTNR1A significantly higher in patients who succumbed to UM. Analysis of TCGA data from 80 UM patients revealed RNA expression for MTNR1A, RORα, and NQO2, but not MTNR1B or GPR50. Higher MTNR1A RNA levels were observed in patients with a BAP1 mutation, and higher NQO2 RNA levels were noted in patients with the epithelioid tumor cell type. However, Kaplan-Meier analysis did not show distinct survival probabilities based on receptor expression. The study concludes that UM clinical samples express melatonin receptors, suggesting a potential mechanism for melatonin's anti-cancer effects. Despite finding higher MTNR1A expression in patients who died of UM, no survival curve differences were observed. Further research is needed to explore additional mechanisms of melatonin’s oncostatic effects, including its antioxidant properties and immune modulation.

The building envelope has the most significant contribution in the reduction of the building energy consumption. Application of new, alternative and improved materials and systems has an important impact on the buildings performances. This paper is focused on the thermal transmittance, as an indicator of the thermal conductance of the construction element. It includes comparisons of the U-values, calculated by software, with those measured in situ on three representative façade walls. The walls have been constructed with the new wall system Fragmat NZ-1, a new product in Macedonian buildings. This research provides basic information on the thermal transmittance of the system. The results of the analysis show that the in situ measuring is a useful tool in validation of the precision of analytically calculated values, since it was difficult to obtain precise results from the analytical calculations only, especially when the layers are with non-uniform thickness.

Interactions between receptors and ligands of the tumor necrosis factor superfamily (TNFSF) provide costimulatory signals that control the survival, proliferation, differentiation, and effector function of immune cells. All components of the TNF superfamily are associated with NF-kB functions that are not limited to cell death and may promote survival in the face of adipose tissue inflammation in obesity. Inflammation and pro-inflammatory dysfunction of mitochondria are key factors associated with insulin resistance in obesity. The aim of the study was to analyze the relationship of soluble forms of receptors and ligands of the TNF superfam-ily in blood plasma with mitochondrial dynamics in adipose tissue (greater omentum (GO) and subcutaneous adipose tissue (Sat)) of obese patients with and without type 2 diabetes mellitus (T2DM). Increased plasma sTNF-R1, sTNF-R2, sTNFRSF8 receptors and ligands TNFSF12, TNFSF13, TNFSF13B are characteristic of obese patients without T2DM. Increases in TNFSF12, TNFSF13B, and sTNF-R1 levels are associated with decreased glucose concentration and decreased BMI in obese patients. The gene expression levels responsible for regulating mitochondrial dynamics were increased in obese patients without T2DM and were unbalanced in patients with obesity and T2DM.

IL1RA intron 2 86-bp repeat and IL4 intron 3 70-bp repeat are VNTRs that have been associated with various diseases, but their role in obesity is elusive. The objective of this study was to investigate the association of IL1RA and IL4 VNTRs with obesity and adiposity in 315 Malaysian subjects (128 M/187 F; 23 Malays/251 ethnic Chinese/41 ethnic Indians). The allelic distributions of IL1RA and IL4 were significantly different among ethnicities, and the alleles were associated with total body fat (TBF) classes. Individuals with IL1RA I/II genotype or allele II had greater risk of having higher adiposity - even after controlling for ethnicity [Odds Ratio (OR) of I/II genotype = 12.21 (CI = 2.54, 58.79; p = 0.002); II allele = 5.78 (CI = 1.73, 19.29; p = 0.004)]. However, IL4 VNTR B2 allele was only significantly associated with overall adiposity status before adjusting for ethnicity [OR = 1.53 (CI = 1.04, 2.23; p = 0.03)]. TBF was also significantly higher in those with IL1RA II allele compared with I allele (31.79 ± 2.52 vs. 23.51 ± 0.40; p = 0.005). Taken together, IL1RA intron 3 VNTR seems to be a genetic marker for overall adiposity status in Malaysian subjects.

Due to the SARS-CoV-2 pandemic a shortage of personal protective equipment, including surgical facemasks and Filtering Facepiece Particle Respirators has occurred. SARS-CoV-2 has a 79,5-82% homology to SARS-CoV. The SARS-CoV UVC sensitivity is described in literature. We have performed UVC transmission measurements of surgical facemasks and respirators. In addition, we performed UVC disinfection experiments of S. aureus with surgical facemasks and respirators. Results show that we can achieve an 8-log reduction of S. aureus in the inner layers of FFP1 respirators and the exterior of surgical facemasks. Furthermore, we showed a 7-log reduction of S. aureus in the inner layers of FFP2 respirators. We conclude that UVC disinfection is an effective, safe and scalable method for reuse of surgical facemask and respirators.

Background: Amyloid beta peptides (Aβ) have been identified as the main pathogenic agents in Alzheimer’s disease (AD). Soluble Aβ oligomers, rather than monomer or insoluble amyloid fibrils, show membrane-binding capacity to red blood cells (RBCs) and trigger several morphological and functional alterations in RBCs that can result in impaired oxygen transport and delivery. Since bioactive lipids have been recently proposed as potent protective agents against Aβ toxicity, we investigated the role of sphingosine-1-phosphate (S1P) in signaling pathways involved in the mechanism underlying ATP release in Aβ-treated RBCs. Methods: In RBCs following different treatments, ATP, 2,3 DPG, cAMP levels, and caspase 3 activity were determined by spectrophotometric and immunoassay. Results: S1P rescued the inhibition of ATP release from RBCs triggered by Aβ through a mechanism involving caspase-3 and restoring 2,3 DPG and cAMP levels within the cell. Conclusions: These findings reveal the molecular basis of S1P protection against Aβ in RBCs and suggest new therapeutic avenues in AD.

Myotonic dystrophy is a hereditary disorder with systemic involvement. The Italian Neuro-Cardiology Network (INCN-RNC) is a unique collaborative experience involving neurology units combined with cardio-arrhythmology units. The INCN facilitates the creation of integrated neuro-cardiac teams in Neuromuscular Disease Centers for the management of cardiovascular involvement in the treatment of MD1.

The glucose-insulin regulatory system and its glucose oscillations is a recurring theme in the literature because of its impact on human lives, mostly the ones affected by diabetes mellitus. Several approaches were proposed, from mathematical to data-based models, with the aim of modeling the glucose oscillation curve. Having such a curve, it is possible to predict, when injecting insulin in type 1 diabetes (T1D) individuals. However, the literature presents prediction horizons no longer than 6 hours, which could be a problem considering their sleeping time. This work presents Tesseratus, a model that adopts a multi-agent approach to combine machine learning and mathematical modeling to predict the glucose oscillation up to 8 hours. Tesseratus uses the pharmacokinetics of insulins and data collected from T1D individuals. Its outcome can support endocrinologists while prescripting daily treatment for T1D individuals, and provide personalized recommendations for such individuals, to keep their glucose concentration in the ideal range. Tesseratus brings pioneering results for prediction horizons of 8 hours for nighttime, in an experiment with seven real T1D individuals. It is our claim that Tesseratus will be a reference for classification of glucose prediction model, supporting the mitigation of short- and long-term complications in the T1D individuals.

Background In 2016, Global Polio Eradication Initiative (GPEI) recommended cessation of type 2 oral poliovirus vaccine (OPV) and OPV using countries switched from trivalent to bivalent OPV (bOPV) with addition of inactivated poliovirus vaccine (IPV) in the routine immunization schedule. The current GPEI strategy 2022-2026 includes bOPV cessation plan and switching to IPV standalone or the combination vaccine schedules in future. The focus of our study was to evaluate immunogenicity of monovalent OPV type 1 (mOPV1) with IPV and IPV only schedules. Methods This was a three-arm, multi-center randomized controlled trial conducted in 2016-2017 in India. Participants, at birth, were randomly assigned to bOPV-IPV (Arm A) or mOPV1-IPV (Arm B) or IPV (Arm C) schedules. Serum specimens collected at birth, 14-, 18- and 22- weeks age were analyzed with standard microneutralization assay for all three poliovirus serotypes. Results Results of 598 participants were analyzed. The type 1 cumulative seroconversion rates four weeks after completion of the schedule at 18 weeks were 99.5% (97.0-99.9), 100.0% (97.9-100.0) 96.0% (92.0-98.1) in Arms A (4bOPV+IPV), B (4mOPV1+IPV) and C (3IPV) respectively. Type 2 and type 3 seroconversion at 18 weeks were 80.0% (73.7-85.1), 76.9% (70.3-82.4), 93.2% (88.5-96.1) and 100.0% (98.0-100.0), 81.9% (75.6-86.8), 99.4% (96.9-99.9) respectively in the three arms. Conclusions This study shows high efficacy of different polio vaccines for serotype 1 in all three schedules. Type 1 seroconversion rate of mOPV1 is non-inferior to bOPV. All the vaccines provide high type specific immunogenicity. The program can adopt the use of different vaccines or schedules depending on epidemiology from time-to-time.