Search Results (1,110)

Background: Connexins (Cx) are a family of transmembrane proteins that form gap junctions and connexin hemichannels (HCs), enabling direct intercellular communication within the nervous system. Connexin 43 (Cx43), the principal astrocytic connexin, exhibits a context-dependent dual role: under physiological conditions it maintains tissue homeostasis and metabolic support, whereas under pathological conditions excessive activation of Cx43 hemichannels promotes neuroinflammation, excitotoxicity, blood–brain barrier disruption, and secondary neural tissue damage. Other connexin isoforms also contribute to the pathogenesis of neurological and psychiatric disorders through alterations in neuronal synchronization, glial signaling, and myelin integrity. Objective: To systematize current evidence on the role of key connexin isoforms in acute nervous system injuries—including stroke, traumatic brain injury, spinal cord injury, and peripheral nerve injury—as well as chronic disorders such as neurodegenerative diseases, epilepsy, and psychiatric disorders, with particular emphasis on the functional duality of connexin channels and the therapeutic potential of their selective modulation. Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases in accordance with the PRISMA framework and the PRISMA Extension for Scoping Reviews guidelines. The review included data from experimental models, postmortem brain studies, genetic association analyses, and pharmacological intervention studies. The retrieved studies were screened, assessed for eligibility, and integrated using a qualitative narrative synthesis approach. Results: In acute neural injuries, hyperactivation of Cx43 hemichannels amplifies inflammatory signaling, edema formation, and neuronal death, whereas selective HCs inhibitors reduce lesion volume and improve functional outcomes in experimental models. Connexin 36 (Cx36) contributes to cortical spreading depolarization and seizure propagation, while Connexin 32 (Cx32) and Connexin 47 (Cx47) are critically involved in oligodendrocyte function and white-matter demyelination. In PNI, Cx43 upregulation contributes to neuropathic pain, whereas mutations in Cx32 cause hereditary demyelinating neuropathies. In neurodegenerative diseases—including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis—Cx43 hemichannel activity promotes neuroinflammation and pathological protein accumulation, while reduced Cx32/Cx47 expression disrupts metabolic support of axons. In psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia, decreased astrocytic connexin expression (Cx43 and Cx30) has been associated with impaired glial–neuronal communication and cognitive–emotional dysfunction. In epilepsy, increased Cx43/Cx30 expression contributes to neuronal hypersynchronization and blood–brain barrier dysfunction, whereas selective hemichannel blockade suppresses seizure activity. Conclusions: Cx—particularly Cx43—occupies a central position in the molecular mechanisms of secondary neural injury and network dysfunction. The dual functional properties of gap junctions and hemichannels determine their context-dependent effects across neurological and psychiatric diseases. Selective inhibition of pathological HCs activity shows significant neuroprotective and anticonvulsant potential and represents a promising direction for the development of targeted therapeutic strategies. Further studies are required to determine optimal therapeutic time windows, tissue-specific effects, and the long-term safety of Cx modulation. Full article

Introduction: Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, with several proposed pathogenic mechanisms. Given the established role of mitochondrial dysfunction in PD, this study seeks to investigate the enrichment of rare genetic variants tied to mitochondrial metabolism in cases of early-onset and familial PD. Methods: We performed a retrospective analysis on 248 early-onset and familial PD patients and 1622 control individuals. We assessed both pathway-level and gene-level burden of germline rare variants detected using exome sequencing in 467 nuclear genes related to mitochondrial metabolism. Results: Gene-set mutation burden analysis indicated an increased burden in genes associated with mtDNA maintenance. In addition, gene-level analysis identified a possible association between PD and rare variant burden in 14 mitochondrial metabolism-related genes under dominant or recessive inheritance models. Conclusions: Our findings support a potential contribution of rare germline variants affecting mitochondrial metabolism to the susceptibility in early-onset and familial PD. Full article

Toxin A and B from Clostridioides difficile are the main pathogenicity factors for clinical symptoms of C. difficile infections. Receptor-mediated endocytosis and endosomal escape are required for targeting substrate proteins of the Rho-GTPase family. We previously reported that Toxin B (TcdB) affects endo-lysosomal transport and autophagic flux of target cells. These effects are independent from pathogenic Rho inhibition. Here, we aimed at further characterization of this event by immunofluorescent characterization of the vesicular structures that are affected. We found large aggregates of damaged endolysosomal structures positive for EEA1, LAMP1, CHMP4B and TcdB, as well as an increase in perinuclear concentration of non-mature autophagosomes (amphisomes) positive for SQSTM, Rab7, and LC3B. We investigated whether Rab7, a regulator of late endosome transport, is causative for decreased lysosome function. Although TcdB induced an increase in active Rab7, as tested by an RILP pull-down assay, inhibition of Rab7 did not prevent TcdB-induced decrease in cathepsin D as a surrogate for lysosome dysfunction. It also indicates that the observed increase in Rab7 positive amphisomes is secondary to lysosomal dysfunction. By applying an autoproteolytic deficient mutant of TcdB we proved that the release of the glucosyltransferase domain is mandatory for triggering all of these effects. This suggests that after membrane perforation the toxin remnants leave an open leak in endolysosomes affecting ion homeostasis. Investigation of all large clostridial glucosyltransferases and other toxins revealed lysosomal dysfunction as a general effect of many but not of all toxins that integrate into the endosome membrane. Full article

Oligodendroglial cells are the myelinating glial cells of the central nervous system (CNS), and their morphological differentiation is a prerequisite for efficient myelin formation, which is essential for proper neuronal function. While oligodendroglial morphological changes normally proceed through tightly regulated developmental transitions, disruption of the underlying molecular mechanisms can lead to aberrant cellular phenotypes characterized by either premature, insufficient, or excessive differentiation. Although the phosphatidylinositol 3-kinase (PI3K) and its downstream Akt kinase signaling are well established as major drivers of oligodendrocyte morphological differentiation, myelination, and CNS white matter formation, how its negative regulator, phosphatase and tensin homolog (PTEN), is involved in the regulation of oligodendroglial morphogenesis remains incompletely understood. Recent genetic studies have highlighted a spectrum of disorders caused by PTEN dysfunction, conceptually established but currently evolving as PTENopathy, which has been partially associated with white matter abnormalities. Here, we report that, in an experimental model using the FBD-102b cell line, a well-established model of oligodendroglial cell differentiation, chemical inhibition of PTEN enhances pronounced morphological changes characterized by widespread membranes, accompanied by increased expression of differentiation and/or myelin marker proteins. We then focused on Rho family small GTPases, central regulators of cell morphogenesis, and examined their potential involvement downstream of this signaling. Expression of the RhoG-binding domain (RBD) of engulfment and cell motility 1 (ELMO1) attenuated the increased morphological changes. Similarly, inhibition of downstream Akt signaling also reversed these changes. Taken together, these results provide insight into how balanced regulation between PTEN and downstream signaling molecules governs oligodendroglial cell differentiation and suggest that dysregulation of this signaling equilibrium may contribute to cellular phenotypes relevant to disease-associated cellular alterations. Full article

A distinct form of chronic kidney disease of unknown etiology (CKDu) has emerged in tropical regions of Sri Lanka, predominantly affecting individuals aged 30–60 years in the North Central Province. Unlike conventional chronic kidney disease (CKD), CKDu occurs independently of diabetes or hypertension and is characterized by tubulointerstitial damage, including tubular atrophy, interstitial inflammation, and fibrosis. Epidemiological studies showed familial clustering, suggesting an underlying genetic predisposition. This study aimed to identify genetic variants associated with CKDu in Sri Lankan populations using whole-exome sequencing (WES). Eighty-six individuals (47 CKDu patients and 39 controls) were recruited from endemic and non-endemic regions. Physiological, biochemical, and geographic parameters were recorded. DNA extracted from blood was subjected to WES to identify variants associated with CKDu. Results: A total of 171 unique variants across 121 genes were identified. Among the most prevalent genes were ATXN3, LFNG, PNLDC1, LINC02456, and HLA-DRB1. In the case–control comparison, only LFNG showed statistically significant enrichment in affected individuals, whereas signals in ATXN3, PNLDC1, and LINC02456 were not statistically significant, but have an association with renal dysfunction, and thus are included as hypothesis-generating variant observations. HLA-DRB1 variants showed trends toward a protective haplotype. LFNG showed the greatest prevalence in affected individuals (71.7%), followed by PNLDC1 (63%), ATXN3 (56%), FIP1L1 (41%), and HLA-DRB1 (32%). Conclusion: Findings suggest genetic variants in combination with environmental factors may contribute to CKDu susceptibility in the Sri Lankan population. We underscore the multi-factorial nature of CKDu and highlight the need for integrative genomic and environmental research to elucidate disease mechanisms and inform targeted prevention strategies. Full article

Background/Objectives: Nonalcoholic fatty liver disease (NAFLD), also referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), affects roughly one-quarter of the global population and represents a major public health concern. Despite its rising prevalence and potential for serious complications, NAFLD remains underrecognized and poorly understood in many communities. This study aimed to assess knowledge of NAFLD and its determinants among adults in the Northern Border Region of Saudi Arabia. Methods: A descriptive, population-based cross-sectional study was conducted using a previously validated online questionnaire adapted from published NAFLD awareness instruments, administered to adults residing in the Northern Border Region of Saudi Arabia. Data were analyzed using Python (statsmodels, version 0.14), and non-parametric tests, correlation analyses, and multivariable linear regression were used to examine NAFLD knowledge and its associated determinants. Results: A total of 1016 adults (mean age 34.7 ± 11.8 years) were included in the analysis. The mean NAFLD knowledge score was 14.6 ± 8.3 out of 30 (48.7% correct responses), with a median of 16 (interquartile range 8–21). Overall, 59.2% of participants had poor knowledge, 26.8% had moderate knowledge, and 14% had good knowledge. In bivariate analyses, educational level (χ² = 15.62, p < 0.001), family history of liver disease (p = 0.001), body weight category (p = 0.003), and smoking status (p = 0.007) were significantly associated with NAFLD knowledge. In multivariable linear regression, university education (B = 2.783, 95% CI 0.627–4.940, p = 0.011) was an independent positive predictor of higher knowledge scores. Current smoking (B = −1.857, 95% CI −3.477 to −0.237, p = 0.025), private-sector employment (B = −1.934, 95% CI −3.867 to −0.001, p = 0.050), and overweight status (B = −4.119, 95% CI −7.337 to −0.901, p = 0.012) were independently associated with lower knowledge scores. The final model explained 2.2% of the variance in knowledge (adjusted R² = 0.022). Conclusions: This study demonstrates generally low levels of NAFLD knowledge among adults in the Northern Border Region of Saudi Arabia, with only a minority achieving good knowledge scores. The findings underscore the need for targeted health promotion initiatives, educational interventions, and public campaigns to improve awareness of NAFLD and to support its prevention and management. Full article

Mitochondrial dysfunction plays a central role in the pathogenesis of bronchopulmonary dysplasia (BPD). Solute carrier family 25 member 28 (SLC25A28) is an iron transporter located in the inner mitochondrial membrane. In this study, we aimed to explore the role and underlying molecular mechanisms of SLC25A28 in BPD. Hyperoxia (85% O₂) was used to establish a neonatal murine model of BPD, and mouse lung epithelial cells (MLE-12 cells) were used in vitro. SLC25A28 expression and activity were downregulated under hyperoxic conditions, both in vivo and in vitro. SLC25A28 overexpression restored hyperoxia-induced mitochondrial oxidative phosphorylation (OXPHOS) dysfunction, and further enhanced the proportion of Ki67-positive cells by 37% (p < 0.05) and increased migration by 33% (p < 0.01) in MLE-12 cells. In contrast, SLC25A28 knockdown exacerbated these impairments in MLE-12 cells, with reduced the proportion of Ki67 positive cells by 71% (p < 0.01) and a 35% reduction in the migration rate. SLC25A28 was also knocked down in vivo, which further aggravated alveolar simplification in BPD mice. Furthermore, the mitochondrial-targeted peptide SS-31 could potentially interact with SLC25A28 and preserve its protein abundance. SS-31 administration mitigated hyperoxia-induced alveolar simplification, with the radical alveolar count (RAC) increasing by 28% (p < 0.05) and the mean linear intercept (MLI) decreasing by 20% (p < 0.001). In summary, this study revealed that SLC25A28 ameliorated hyperoxic lung injury by improving mitochondrial OXPHOS in alveolar epithelial cells, suggesting that it may serve as a potential therapeutic target for BPD. Full article

Background: Retrograde cricopharyngeus dysfunction (RCPD) is a recently described upper esophageal sphincter motility disorder caused by the inability of the cricopharyngeus muscle to relax, prohibiting belching. While clinical features and treatment have been reported, early-life experiences remain unclear. This study aimed to explore childhood experiences, comorbidities, and family history in adults reporting symptoms consistent with RCPD. Methods: This cross-sectional survey included adults recruited through an online community focused on RCPD who reported cardinal symptoms consistent with RCPD. The survey collected and descriptively analyzed demographics, symptom profile, family history, neonatal and childhood experiences, psychological factors, and physician visits. Results: Of 225 respondents, 207 met inclusion criteria (mean age 32 years; 69% female). Nearly all experienced abdominal bloating (98%), gurgling noises (98%), flatulence (90%), and inability to belch (100%). Painful hiccupping, a newer described symptom, was reported by 80%. Symptoms began before age 25 in 97%, and 29% reported a first-degree relative affected. Common early-life experiences included emetophobia (39%), anxiety (38%), and difficulty being burped as an infant (20%). No statistically significant crude differences were detected in symptom severity, frequency, gender, or age of onset by presence of experiences. Only 36% felt that any physician understood their condition, and 18% reported their gastroenterologist improved their symptoms. Conclusions: Psychological early-life experiences and family history were common, but exploratory analyses did not detect statistically significant differences in symptom burden by their presence. These findings provide a foundation for future studies investigating the disorder’s pathophysiology. Limited physician recognition highlights the need for greater clinical awareness of this emerging esophageal motility disorder. Full article

G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors and are critical regulators of β-cell physiology. Nearly 300 GPCRs are expressed in human islets, where they integrate metabolic, hormonal, neuronal, and inflammatory cues to control insulin secretion, proliferation, and survival. Altered GPCR signaling contributes to β-cell dysfunction and the pathogenesis of both type 1 and type 2 diabetes. This review provides an overview of GPCR functions in β-cell biology, highlighting receptors that stimulate or inhibit glucose-stimulated insulin secretion, as well as those influencing β-cell fate. We also examine GPCR biosynthesis, trafficking, and subcellular localization—processes that shape receptor availability and signaling specificity. Aberrant folding, retention, or misrouting of GPCRs can disrupt β-cell function and contribute to metabolic disease. Thus, beyond receptor pharmacology, understanding the molecular mechanisms governing GPCR biogenesis and spatial distribution is essential for designing targeted strategies to preserve β-cell function and improve glucose homeostasis. Full article

The liver produces the majority of plasma proteins, maintaining the metabolic homeostasis. The dysregulation of liver protein synthesis underlies many systemic conditions. Therefore, there is a great potential in therapies that inhibit the hepatic protein production. This is the mechanism of action of antisense oligonucleotides (ASOs) and small interfering RNA (siRNA). These therapeutics have undergone rapid development and are revolutionizing the pharmacological landscape of many liver-related diseases (e.g., inclisiran in familial hypercholesterolemia). Furthermore, gene-editing technologies that allow a direct correction of impaired genes in the liver are currently being evaluated. They hold a promise for future advances in treatment, especially of monogenic disorders such as hereditary transthyretin amyloidosis or alpha-1 antitrypsin deficiency. In this review, we describe the most relevant systemic diseases caused by dysfunction of protein synthesis in liver cells, in which significant therapeutic progress has been made over the last decades. Moreover, we present currently available drugs and their mechanisms of action, including six siRNA agents and five ASOs that have been approved to date. Finally, we discuss emerging strategies, focusing on novel RNA-based therapeutics that are the subjects of ongoing clinical trials. Full article

Boule is the ancestral member of the Deleted in Azoospermia (DAZ) family and is pivotal for gametogenesis and male fertility in most animals. However, there is a dearth of information on molluscan boule. Here, we identified a counterpart (Pcbol) from the genome of Pomacea canaliculata, which has emerged as a cosmopolitan alien species and notorious pest that causes devastating damage to aquatic biodiversity, freshwater ecosystems and crop production in invaded ranges. This study aimed to investigate the biological roles of Pcbol in male reproduction and to decipher the molecular mechanisms underpinning its modulation via dsRNA-delivered RNA interference (RNAi). The bioinformatic analysis showed that the Pcbol genomic sequence is 12,934 nt in length, harboring an open reading frame of 294 nt that encodes 97 aa residues, with an RRM domain evolutionarily conserved among molluscan orthologues. Spatiotemporal expression profiling indicated the predominant abundance of Pcbol in adult males and testis tissues. dsPcbol, injected at a dose of 4 μg/per snail for 5 days, yielded optimal silencing at both transcript and translation levels of Pcbol, as revealed by qRT-PCR and Western blotting. Immunofluorescence echoed a pronounced reduction in Pcbol signal intensity following RNAi. In addition to the arrested reproductive gland phenotype, the number of sperm cells substantially dwindled upon dsPcbol treatment relative to the dsGFP control. In biochemical and fecundity assays, Pcbol depletion triggered a significant decrease in Te/SP/Arg content and suppressed the number of deposited eggs and hatchability. Furthermore, spermatogenic genes like CDC25/TSSK1/SPATA17/DDX4/Dmrt2/Sox2/Kelch10/SPO11 displayed considerable downregulation post Pcbol silencing, with molecular docking predicting a strong affinity between CDC25 and Pcbol. These molecular modules may interact with Pcbol to mediate knockdown effects on spermatogenesis dysfunction. Collectively, our findings not only confirmed that boule was indispensable for spermatogenesis and male fertility in a mollusk, but also highlighted the Pcbol-based male sterile technique (MST), which can be incorporated into precision pest management (PPM) strategies for sustainable control of P. canaliculata. Full article

Background/Objectives: The Positive Parenting Program (Triple P) is an evidence-based intervention for families including young children with neurodevelopmental disorders. Because establishing a definitive diagnosis in early childhood takes time, especially for 1–3-year-olds who have only recently shown early signs, parents often experience substantial stress. This study examines the effectiveness of the Group Triple P (GTP) program for mothers of 1–3-year-old children without a confirmed diagnosis who spent time at a community parenting support center. Methods: The participants were 41 mothers of children aged 1–3 who did not confirmed neurodevelopmental diagnosis but showed behavioral, emotional, or developmental concerns, or whose mothers reported parenting difficulties. To reflect real community practices, a non-randomized pre–post test design without a control group was adopted. Assessments were conducted at baseline, postintervention, and at a 12 weeks follow-up using the Strengths and Difficulties Questionnaire, Parenting Scale, Parenting Experience Scale, and Depression Anxiety Stress Scale. Results: GTP improved the mothers’ assessments of positive behaviors in children who may have neurodevelopmental disorders, with a medium effect size. GTP reduced dysfunctional parenting styles in mothers with a large effect size. It also enhanced mothers’ confidence and fulfilling sense in parenting, and decreased depression and stress with a medium effect size. Perceived access to parenting support improved, contributing to better parenting adaptation with a medium effect size. Conclusions: GTP may serve as an early public health intervention for mothers of young children who may have neurodevelopmental disorders by supporting maternal mental health and promoting adaptive parenting. Full article

Background/Objectives: Enteropathogenic Escherichia coli O157:H7 infection disrupts intestinal homeostasis, causing dysbiosis, barrier dysfunction, and inflammation. This study aimed to evaluate the protective efficacy and mechanisms of a novel probiotic, Bacteroides thetaiotaomicron type strain ATCC 29148, isolated from goat feces, against E. coli O157:H7-induced colitis. Methods: This study assessed the protective potential of the probiotic strain Bacteroides thetaiotaomicronBT6 and BT7 in vitro for GI tolerance, adhesion, and no adverse effects were observed. For the in vivo experiment, male C57BL/6J mice were divided into groups treated with Bacteroides thetaiotaomicron (BT6), PBS, E. coli O157:H7, or a combination. We employed integrated analyses including 16S rRNA gene sequencing, antioxidant status, cytokine profiling, and short-chain fatty acid (SCFA) measurement. Results: In vitro, Bacteroides thetaiotaomicron (BT6 and BT7) showed high gastrointestinal tolerance (71.89–93.22% survival). In vivo, it significantly mitigated infection-associated weight loss and disease activity (p < 0.05). Probiotic treatment enhanced barrier integrity, reduced colonic inflammation, and modulated systemic immune responses, notably increasing anti-inflammatory IL-10 while decreasing pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 (p < 0.05). It also alleviated oxidative stress by reducing malondialdehyde (MDA) and elevating antioxidant enzymes (SOD, CAT, GSH) and ATP. Fecal SCFA profiling revealed increased propionic and butyric acid. 16S sequencing indicated that B. thetaiotaomicron (BT6) administration increased beneficial families (Lactobacillaceae, Muribaculaceae) and suppressed pathobionts. Conclusions: B. thetaiotaomicron (BT6) probiotic with potential for mitigating enteropathogenic infection, an effect mainly determined by its capacity to reestablish the intestinal epithelial barrier and enhance global host health, and modulating the inflammatory response. Full article

Schizophrenia has an estimated population prevalence of 1%, but the etiology of this devastating psychiatric condition remains largely uncharacterized. A pronounced genetic component underlies schizophrenia, with heritability estimates ranging from 60% to 80%. Until now, genome-wide association studies have successfully identified 287 distinct genetic loci associated with schizophrenia, but these primarily involve common variants that have minimal individual risk. The recent advent of exome sequencing and genome sequencing has identified ultra-rare sequence variants associated with schizophrenia in familial cases as well as in large cohorts. These studies have implicated multiple gene variants that individually have a large effect size in contributing to schizophrenia. A comparison indicates that these genes exhibit high expression levels in the central nervous system and their protein products participate in many converging pathways encompassing synaptic transmission, glutamatergic neurotransmission, chromatin modification processes, transcriptional regulation, and ubiquitin–proteasome degradation. Although model systems have been established for some genes, most remain to be further studied to identify how gene dysfunction correlates with disease. Full article

Two-pore domain potassium (K₂P) channels are the most recently identified family of potassium channels. They are regarded as the largest group of background “leak” channels, encoded by 15 mammalian KCNK genes, and divided into six subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). These channels have a role in stabilizing the resting membrane potential. Their widespread presence in the heart and vasculature supports cellular homeostasis by regulating cardiac rhythm, vascular tone, and protection against ischemic stress. The TASK, TWIK, and TREK subfamilies are the most abundantly expressed K₂P channel subfamilies in the cardiovascular system, and dysregulation of specific members has been strongly linked to the development of major cardiovascular diseases. Mutations in TASK-1 have been identified in patients with pulmonary arterial hypertension, providing human genetic evidence linking K₂P dysfunction to pulmonary vascular disease. While alterations in other K₂P channels, such as TREK-1, have been demonstrated in preclinical studies where reduced channel activity is associated with ischemia–reperfusion injury and promotes cardiac arrhythmias. Growing evidence suggests that K₂P channels could serve as promising therapeutic targets, with pharmacological activation of TASK-1 and TREK-1, for instance, that might help restore vascular tone, reduce remodeling, and offer cardioprotection. Their unique leak-channel properties enable the development of highly selective treatments. This review addresses the molecular biology, physiological roles, and disease relevance of K₂P channels in the cardiovascular and pulmonary systems, emphasizing their potential as targets for innovative therapies in cardiovascular diseases. Full article