Search Results (1,893)

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia globally. Although the direct cause of AD remains under debate, neuroinflammation and oxidative stress are critical components in its pathogenesis and progression. As a result, compounds like cannabidiol (CBD) are being increasingly investigated for their ability to provide antioxidant and anti-inflammatory neuroprotection. CBD is the primary non-psychotropic phytocannabinoid derived from Cannabis sativa. It has been found to provide beneficial outcomes in a variety of medical conditions and is gaining increasing attention for its potential therapeutic application in AD. CBD is not psychoactive and its lipophilic nature allows its rapid distribution throughout the body, including across the blood–brain barrier (BBB). CBD also possesses anti-inflammatory, antioxidant, and neuroprotective properties, making it a viable candidate for AD treatment. This review outlines CBD’s mechanism of action, the role of oxidative stress and neuroinflammation in AD, and the effectiveness and limitations of CBD in preclinical models of AD. Full article

Alterations in a mother’s metabolism and endocrine system, due to unbalanced nutrition, may increase the risk of both metabolic and non-metabolic disorders in the offspring’s childhood and adulthood. The risk of obesity in the offspring can be determined by the interplay between maternal nutrition and lifestyle, intrauterine environment, epigenetic modifications, and early postnatal factors. Several studies have indicated that the fetal bowel begins to colonize before birth and that, during birth and nursing, the gut microbiota continues to change. The mother’s gut microbiota is primarily transferred to the fetus through maternal nutrition and the environment. In this way, it is able to impact the establishment of the early fetal and neonatal microbiome, resulting in epigenetic signatures that can possibly predispose the offspring to the development of obesity in later life. However, antioxidants and exercise in the mother have been shown to improve the offspring’s metabolism, with improvements in leptin, triglycerides, adiponectin, and insulin resistance, as well as in the fetal birth weight through epigenetic mechanisms. Therefore, in this extensive literature review, we aimed to investigate the relationship between maternal diet, epigenetics, and gut microbiota in order to expand on current knowledge and identify novel potential preventative strategies for lowering the risk of obesity in children and adults. Full article

The technical difficulty of separating extracellular vesicles (EVs) from plasma proteins in human blood presents a significant hurdle in EV research, particularly during nano ultra-high-performance liquid chromatography–tandem mass spectrometric (UHPLC-MS/MS) analysis, where detecting “vesicular” proteins among abundant plasma proteins is challenging. Standardisation is a pressing issue in EV research, prompting collaborative global efforts to address it. While the MISEV guidelines offer valuable recommendations, unanswered questions remain, particularly regarding sample storage. We compared size exclusion chromatography (SEC) columns with pore sizes of 35 nm and 70 nm to identify fractions with minimal contaminating proteins and the highest concentration of small EVs (sEVs). Following column selection, we explored potential differences in the quality and quantity of sEVs isolated from platelet-free plasma (PFP) after long-term storage at −80 °C (>2.5 years) compared to freshly drawn blood. Our methodologically rigorous study indicates that prolonged storage, under correct storage and processing conditions, does not compromise sEV quality. Both columns effectively isolated vesicles, with the 70 nm column exhibiting a higher abundance of “vesicular” proteins. We propose a relatively rapid and moderately efficient protocol for obtaining a comparatively pure sEV fraction from plasma, facilitating sEV processing in clinical trials. Full article

Astrocytes in the brain contribute to various essential functions, including maintenance of the neuronal framework, survival, communication, metabolic processes, and neurotransmitter levels. Leucine-rich repeat kinase 2 (LRRK2) is associated with the pathogenesis of Parkinson’s disease (PD). LRRK2 is expressed in neurons, microglia, and astrocytes and plays diverse roles in these cell types. We aimed to determine the effects of mutant human G2019S-LRRK2 (GS-hLRRK2) in rat primary astrocytes (rASTROs). Transfection with GS-hLRRK2 significantly decreased cell viability compared to transfection with the vector and wild-type human LRRK2 (WT-hLRRK2). GS-hLRRK2 expression significantly reduced the levels of nerve growth factor and increased the levels of proinflammatory cytokines (interleukin-1β and tumor necrosis factor α) compared to the vector and WT-hLRRK2 expression. Furthermore, GS-hLRRK2 expression in rASTROs promoted astrogliosis, which was characterized by increased expression of glial fibrillary acidic protein and vimentin. Treatment with the conditioned medium of G2019S LRRK2-expressing rASTROs decreased N27 cell viability compared to treatment with that of WT-hLRRK2-expressing rASTROs. Consequently, the regulation of the dopamine synthesis pathway was affected in N27 cells, thereby leading to altered levels of tyrosine hydroxylase, dopamine transporter, Nurr1, and dopamine release. Overall, the G2019S LRRK2 mutation disrupted astrocyte function, thereby aggravating PD progression. Full article

Leukodystrophies represent a large and complex group of inherited disorders affecting the white matter of the central nervous system. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare leukodystrophy which still needs the proper identification of diagnostic, prognostic, and monitoring biomarkers. The aim of this study was to determine the diagnostic and prognostic value of chitinases and neurofilament light chain as biomarkers for ALSP. A cross-sectional study was performed to analyze cerebrospinal fluid levels of chitinases (chitotriosidase and chitinase 3-like 2) and neurofilament light chain in five different groups: (i) normal health individuals; (ii) patients with definitive diagnosis of ALSP and genetic confirmation; (iii) asymptomatic patients with CSF1R variants; (iv) patients with other adult-onset leukodystrophies; and (v) patients with amyotrophic lateral sclerosis (external control group). Chitinase levels showed a statistical correlation with clinical assessment parameters in ALSP patients. Chitinase levels were also distinct between ALSP and the other leukodystrophies. Significant differences were noted in the levels of chitinases and neurofilament light chain comparing symptomatic (ALSP) and asymptomatic individuals with CSF1R variants. This study is the first to establish chitinases as a potential biomarker for ALSP and confirms neurofilament light chain as a good biomarker for primary microgliopathies. Full article

Coronaviruses represent a significant class of viruses that affect both animals and humans. Their replication cycle is strongly associated with the endoplasmic reticulum (ER), which, upon virus invasion, triggers ER stress responses. The activation of the unfolded protein response (UPR) within infected cells is performed from three transmembrane receptors, IRE1, PERK, and ATF6, and results in a reduction in protein production, a boost in the ER’s ability to fold proteins properly, and the initiation of ER-associated degradation (ERAD) to remove misfolded or unfolded proteins. However, in cases of prolonged and severe ER stress, the UPR can also instigate apoptotic cell death and inflammation. Herein, we discuss the ER-triggered host responses after coronavirus infection, as well as the pharmaceutical targeting of the UPR as a potential antiviral strategy. Full article

Galectins are a group of β-galactoside-binding proteins with several roles in immune response, cellular adhesion, and inflammation development. Current evidence suggest that these proteins could play a crucial role in many respiratory diseases such as pulmonary fibrosis, lung cancer, and respiratory infections. From this standpoint, an increasing body of evidence have recognized galectins as potential biomarkers involved in several aspects of asthma pathophysiology. Among them, galectin-3 (Gal-3), galectin-9 (Gal-9), and galectin-10 (Gal-10) are the most extensively studied in human and animal asthma models. These galectins can affect T helper 2 (Th2) and non-Th2 inflammation, mucus production, airway responsiveness, and bronchial remodeling. Nevertheless, while higher Gal-3 and Gal-9 concentrations are associated with a stronger degree of Th-2 phlogosis, Gal-10, which forms Charcot–Leyden Crystals (CLCs), correlates with sputum eosinophilic count, interleukin-5 (IL-5) production, and immunoglobulin E (IgE) secretion. Finally, several galectins have shown potential in clinical response monitoring after inhaled corticosteroids (ICS) and biologic therapies, confirming their potential role as reliable biomarkers in patients with asthma. Full article

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with complex carcinogenesis. Although there has been significant progress in the treatment of HCC over the past decades, drug resistance to chemotherapy remains a major obstacle in its successful management. In this study, we were able to reduce chemoresistance in cisplatin-resistant HepG2 cells by either silencing the expression of transglutaminase type 2 (TG2) using siRNA or by the pre-treatment of cells with the TG2 enzyme inhibitor cystamine. Further analysis revealed that, whereas the full-length TG2 isoform (TG2-L) was almost completely cytoplasmic in its distribution, the majority of the short TG2 isoform (TG2-S) was membrane-associated in both parental and chemoresistant HepG2 cells. Following the induction of cisplatin toxicity in non-chemoresistant parental cells, TG2-S, together with cisplatin, quickly relocated to the cytosolic fraction. Conversely, no cytosolic relocalisation of TG2-S or nuclear accumulation cisplatin was observed, following the identical treatment of chemoresistant cells, where TG2-S remained predominantly membrane-associated. This suggests that the deficient subcellular relocalisation of TG2-S from membranous structures into the cytoplasm may limit the apoptic response to cisplatin toxicity in chemoresistant cells. Structural analysis of TG2 revealed the presence of binding motifs for interaction of TG2-S with the membrane scaffold protein LC3/LC3 homologue that could contribute to a novel mechanism of chemotherapeutic resistance in HepG2 cells Full article

The activity of dental caries, combined with its multifactorial etiology, alters salivary molecule composition. The present systematic review was developed to answer the following question: “Are salivary biomarkers reliable for diagnosis of dental caries?”. Following the “Preferred Reporting Item for Systematic Reviews and Meta-analysis” (PRISMA) guidelines, the review was conducted using multiple database research (Medline, Web of Science, and Scopus). Studies performed on healthy subjects with and without dental caries and providing detailed information concerning the clinical diagnosis of caries (Decayed, Missing, Filled Teeth-DMFT and International Caries Detection and Assessment System-ICDAS criteria) were included. The quality assessment was performed following a modified version of the Joanna Briggs Institute Prevalence Critical Appraisal Checklist. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD42022304505). Sixteen papers were included in the review. All studies reported statistically significant differences in the concentration of salivary molecules between subjects with and without caries (p < 0.05). Proteins were the most investigated molecules, in particular alpha-amylase and mucins. Some studies present a risk of bias, such as identifying confounding factors and clearly defining the source population. Nevertheless, the 16 papers were judged to be of moderate to high quality. There is evidence that some salivary compounds studied in this review could play an important diagnostic role for dental caries, such as salivary mucins, glycoproteins (sCD14), interleukins (IL-2RA, 4,-13), urease, carbonic anhydrase VI, and urea. Full article

The global demand for sustainable and nutritious food sources has catalyzed interest in legumes, known for their rich repertoire of health-promoting compounds. This review delves into the diverse array of bioactive peptides, protein subunits, isoflavones, antinutritional factors, and saponins found in the primary legume protein sources—soybeans, peas, chickpeas, and mung beans. The current state of research on these compounds is critically evaluated, with an emphasis on the potential health benefits, ranging from antioxidant and anticancer properties to the management of chronic diseases such as diabetes and hypertension. The extensively studied soybean is highlighted and the relatively unexplored potential of other legumes is also included, pointing to a significant, underutilized resource for developing health-enhancing foods. The review advocates for future interdisciplinary research to further unravel the mechanisms of action of these bioactive compounds and to explore their synergistic effects. The ultimate goal is to leverage the full spectrum of benefits offered by legumes, not only to advance human health but also to contribute to the sustainability of food systems. By providing a comprehensive overview of the nutraceutical potential of legumes, this manuscript sets a foundation for future investigations aimed at optimizing the use of legumes in the global pursuit of health and nutritional security. Full article

As environmental plastic waste degrades, it creates an abundance of diverse microplastic particles. Consequently, microplastics contaminate drinking water and many staple food products, meaning the oral ingestion of microplastics is an important exposure route for the human population. Microplastics have long been considered inert, however their ability to promote microbial dysbiosis as well as gut inflammation and dysfunction suggests they are more noxious than first thought. More alarmingly, there is evidence for microplastics permeating from the gut throughout the body, with adverse effects on the immune and nervous systems. Coupled with the now-accepted role of the gut-brain axis in neurodegeneration, these findings support the hypothesis that this ubiquitous environmental pollutant is contributing to the rising incidence of neurodegenerative diseases, like Alzheimer’s disease and Parkinson’s disease. This comprehensive narrative review explores the consequences of oral microplastic exposure on the gut-brain-axis by considering current evidence for gastrointestinal uptake and disruption, immune activation, translocation throughout the body, and neurological effects. As microplastics are now a permanent feature of the global environment, understanding their effects on the gut, brain, and whole body will facilitate critical further research and inform policy changes aimed at reducing any adverse consequences. Full article

Recent years have witnessed unprecedented progress in therapeutic gene editing, revolutionizing the approach to treating genetic disorders. In this comprehensive review, we discuss the progression of milestones leading to the emergence of the clustered regularly interspaced short palindromic repeats (CRISPR)-based technology as a powerful tool for precise and targeted modifications of the human genome. CRISPR-Cas9 nuclease, base editing, and prime editing have taken center stage, demonstrating remarkable precision and efficacy in targeted ex vivo and in vivo genomic modifications. Enhanced delivery systems, including viral vectors and nanoparticles, have further improved the efficiency and safety of therapeutic gene editing, advancing their clinical translatability. The exploration of CRISPR-Cas systems beyond the commonly used Cas9, such as the development of Cas12 and Cas13 variants, has expanded the repertoire of gene editing tools, enabling more intricate modifications and therapeutic interventions. Outstandingly, prime editing represents a significant leap forward, given its unparalleled versatility and minimization of off-target effects. These innovations have paved the way for therapeutic gene editing in a multitude of previously incurable genetic disorders, ranging from monogenic diseases to complex polygenic conditions. This review highlights the latest innovative studies in the field, emphasizing breakthrough technologies in preclinical and clinical trials, and their applications in the realm of precision medicine. However, challenges such as off-target effects and ethical considerations remain, necessitating continued research to refine safety profiles and ethical frameworks. Full article

Today, colorectal cancer (CRC) diagnosis is performed using colonoscopy, which is the current, most effective screening method. However, colonoscopy poses risks of harm to the patient and is an invasive process. Recent research has proven metabolomics as a potential, non-invasive detection method, which can use identified biomarkers to detect potential cancer in a patient’s body. The aim of this study is to develop a machine-learning (ML) model based on chemical descriptors that will recognize CRC-associated metabolites. We selected a set of metabolites found as the biomarkers of CRC, confirmed that they participate in cancer-related pathways, and used them for training a machine-learning model for the diagnostics of CRC. Using a set of selective metabolites and random compounds, we developed a range of ML models. The best performing ML model trained on Stage 0–2 CRC metabolite data predicted a metabolite class with 89.55% accuracy. The best performing ML model trained on Stage 3–4 CRC metabolite data predicted a metabolite class with 95.21% accuracy. Lastly, the best-performing ML model trained on Stage 0–4 CRC metabolite data predicted a metabolite class with 93.04% accuracy. These models were then tested on independent datasets, including random and unrelated-disease metabolites. In addition, six pathways related to these CRC metabolites were also distinguished: aminoacyl-tRNA biosynthesis; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine biosynthesis; and alanine, aspartate, and glutamate metabolism. Thus, in this research study, we created machine-learning models based on metabolite-related descriptors that may be helpful in developing a non-invasive diagnosis method for CRC. Full article

8-oxoguanine (oxoG) is formed in DNA by the action of reactive oxygen species. As a highly mutagenic and the most common oxidative DNA lesion, it is an important marker of oxidative stress. Human 8-oxoguanine-DNA glycosylase (OGG1) is responsible for its prompt removal in human cells. OGG1 is a bifunctional DNA glycosylase with N-glycosylase and AP lyase activities. Aspects of the detailed mechanism underlying the recognition of 8-oxoguanine among numerous intact bases and its subsequent interaction with the enzyme’s active site amino acid residues are still debated. The main objective of our work was to determine the effect (structural and thermodynamic) of introducing an oxoG-clamp in model DNA substrates on the process of 8-oxoG excision by OGG1. Towards that end, we used DNA duplexes modeling OGG1-specific lesions: 8-oxoguanine or an apurinic/apyrimidinic site with either cytidine or the oxoG-clamp in the complementary strand opposite to the lesion. It was revealed that there was neither hydrolysis of the N-glycosidic bond at oxoG nor cleavage of the sugar–phosphate backbone during the reaction between OGG1 and oxoG-clamp-containing duplexes. Possible structural reasons for the absence of OGG1 enzymatic activity were studied via the stopped-flow kinetic approach and molecular dynamics simulations. The base opposite the damage was found to have a critical effect on the formation of the enzyme–substrate complex and the initiation of DNA cleavage. The oxoG-clamp residue prevented the eversion of the oxoG base into the OGG1 active site pocket and impeded the correct convergence of the apurinic/apyrimidinic site of DNA and the attacking nucleophilic group of the enzyme. An obtained three-dimensional model of the OGG1 complex with DNA containing the oxoG-clamp, together with kinetic data, allowed us to clarify the role of the contact of amino acid residues with DNA in the formation of (and rearrangements in) the enzyme–substrate complex. Full article

Osteogenesis imperfecta (OI) is a group of inherited disorders of connective tissue that cause significant deformities and fragility in bones. Most cases of OI are associated with pathogenic variants in collagen type I genes and are characterized by pronounced polymorphisms in clinical manifestations and the absence of clear phenotype–genotype correlation. The objective of this study was to conduct a comprehensive molecular–genetic and clinical analysis to verify the diagnosis of OI in six Russian patients with genetic variants in the COL1A1 and COL1A2 genes. Clinical and laboratory data were obtained from six OI patients who were observed at the Medical Genetics Center in Saint Petersburg from 2016 to 2023. Next-generation sequencing on MGISEQ G400 (MGI, China) was used for DNA analysis. The GATK bioinformatic software (version 4.5.0.0) was used for variant calling and hard filtering. Genetic variants were verified by the direct automatic sequencing of PCR products using the ABI 3500X sequencer. We identified six genetic variants, as follows pathogenic c.3505G>A (p. Gly1169Ser), c.769G>A (p.Gly257Arg), VUS c.4123G>A (p.Ala1375Thr), and c.4114A>T (p.Asn1372Tyr) in COL1A1; and likely pathogenic c.2035G>A (p.Gly679Ser) and c.739-2A>T in COL1A2. In addition, clinical cases are presented due to the presence of the c.4114A>T variant in the COL1A2 gene. Molecular genetics is essential for determining different OI types due to the high similarity across various types of the disease and the failure of unambiguous diagnosis based on clinical manifestations alone. Considering the variable approaches to OI classification, an integrated strategy is required for optimal patient management. Full article