Search Results (36,880)

Soil-transmitted helminths (STHs) and Herpes Simplex Virus type 2 (HSV-2) are highly prevalent infections with overlapping distribution, particularly in resource-poor regions. STH/HSV-2 co-infections may impact female reproductive health. However, many aspects of STH/HSV-2 co-infections, including the role of microRNAs (miRNAs) in regulating female genital tract (FGT) immunity and their potential contribution to pathologies such as chronic inflammation, impaired mucosal defense, and reproductive tract cancers remain unclear. In this study we investigated the miRNA expression profiles in murine FGT tissues following single or co-infection with Nippostrongylus brasiliensis (Nb) and HSV-2 and explored predicted miRNA-mRNA targets and pathways. An analysis of miRNA sequencing data was conducted to determine differentially expressed (DE) miRNAs between infected FGT tissues and uninfected controls. Ingenuity Pathway Analysis was conducted to predict the immune-related target genes of the DE miRNAs and reveal enriched canonical pathways, top diseases, and biological functions. Selected representative DE miRNAs were validated using RT-qPCR. Our results showed a total of eight DE miRNAs (mmu-miR-218-5p, mmu-miR-449a-5p, mmu-miR-497a-3p, mmu-miR-144-3p, mmu-miR-33-5p, mmu-miR-451a, mmu-miR-194-5p, and mmu-miR-192-5p) in the comparison of Nb-infected versus uninfected controls; nine DE miRNAs (mmu-miR-451a, mmu-miR-449a-5p, mmu-miR-144-3p, mmu-miR-376a-3p, mmu-miR-192-5p, mmu-miR-218-5p, mmu-miR-205-3p, mmu-miR-103-3p, and mmu-miR-200b-3p) in the comparison of HSV-2-infected versus uninfected controls; and one DE miRNA (mmu-miR-199a-5p) in the comparison of Nb/HSV-2 co-infected versus uninfected controls (p-value < 0.05, |logFC| ≥ 1). Core expression analysis showed that, among other canonical pathways, the DE miRNAs and their predicted mRNA targets were involved in neutrophil degranulation, interleukin-4 and interleukin-13 signaling, natural killer cell signaling, interferon alpha/beta signaling, and ISGylation. Additionally, cancer was predicted as one of the significantly enriched diseases, particularly in the co-infected group. This is the first study to provide insights into the FGT miRNA profiles following Nb and HSV-2 single and co-infection, as well as the predicted genes and pathways they regulate, which may influence host immunity and pathology. This study highlights the role of miRNAs in regulating FGT immunity and pathology in the context of STH/HSV-2 co-infection. Full article

Coxsackievirus B3 (CV-B3) infection causes inflammatory conditions such as viral myocarditis and meningitis, and incidence rates are rising annually. While children are more likely to be affected by severe manifestations, the molecular basis of this age-dependent susceptibility is poorly understood. In this study, we used young Balb/c mice at three developmental stages (7-, 14-, and 30-day-old mice) to investigate CV-B3 pathogenesis. Our findings revealed that 7-day-old mice exhibited substantial infection susceptibility and pathological severity compared to older mice. Critically, an age-dependent analysis showed a progressive decline in the expression of CV-B3-binding Coxsackievirus and Adenovirus Receptor (CAR) splice variants (CAR1 and CAR2) at both the transcriptional and translational levels as the mice matured from 7 to 30 days. These receptor isoforms demonstrated a direct correlation with viral replication efficiency in younger hosts. Concurrently, aging was associated with a rise in non-binding CAR variants (CAR3 and CAR4). During CV-B3 infection, the abundance of CAR1/CAR2 in young mice facilitated accelerated viral proliferation, coupled with the hyperactivation of the NLRP3 inflammasome and the expansion of IL-17-producing γδT cells (γδT17 cells). This cascade triggered excessive production of proinflammatory cytokines (IL-1β, IL-18, and IL-17), culminating in pronounced inflammatory infiltrates within cardiac and cerebral tissues. These findings establish NLRP3 inflammasome dysregulation as a critical determinant of CV-B3-induced tissue damage and provide novel insights into the heightened susceptibility to CV-B infection during early life and its associated severe disease rates. Full article

Oxidative stress (OS) is a major concern in young poultry and livestock, prompting extensive research on OS models. This study aimed to systematically investigate the dynamic effects and temporal trends of OS induced with lipopolysaccharide (LPS) over time. Twenty-eight piglets were randomly divided into four groups and equally intraperitoneally injected with LPS at doses of 0 μg/kg (control), 50 μg/kg (L-LPS), 100 μg/kg (M-LPS) and 150 μg/kg (H-LPS) body weight, respectively. The results showed that total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), and catalase (CAT) were decreased, while malondialdehyde (MDA), nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), diamine oxidase (DAO) and D-lactic acid (D-LA) were increased in the M-LPS and H-LPS group on day 1 in comparison with the control group, but no differences were found among treatments on day 7. However, LPS treatments gave rise to varying degrees of pathological injury in the intestines, livers and spleens on day 7. Metabolomics analysis indicated that compared with the control group, glycyl-valine, histamine and lepidine F were decreased in the M-LPS group. Most differentially expressed metabolites were enriched in amino acid-related metabolism pathways on both day 1 and day 7. Microbiome analysis identified that Oscillibacter_sp._CAG:241 was decreased in the M-LPS group compared with the control group on day 1, while Bacteroides_thetaiotaomicron and Lactobacillus_amylovorus were reduced in the M-LPS group on day 7. Collectively, an LPS dose of 100 μg/kg body weight is optimal for inducing acute inflammation in Wuzhishan miniature pigs. These findings highlight the importance of considering both the duration of OS induction and the specific research objectives when establishing OS models. Full article

The recent identification of early-onset mutational signatures with geographic variations by Diaz-Gay et al. is a significant finding, since early-onset colorectal cancer has emerged as an alarming public health challenge in the past two decades, and the pathomechanism remains unclear. Environmental risk factors, including lifestyle and diet, are highly suspected. The identification of colibactin from Escherichia coli as a potential pathogenic source is a major step forward in addressing this public health challenge. Therefore, the following opinion manuscript aims to outline the likely onset of the pathomechanism and the critical role of acquired Piezo2 channelopathy in early-onset colorectal cancer, which skews proton availability and proton motive force regulation toward E. coli within the microbiota–host symbiotic relationship. In addition, the colibactin produced by the pks island of E. coli induces host DNA damage, which likely interacts at the level of Wnt signaling with Piezo2 channelopathy-induced pathological remodeling. This transcriptional dysregulation eventually leads to tumorigenesis of colorectal cancer. Mechanotransduction converts external physical cues to inner chemical and biological ones. Correspondingly, the proposed quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling, initiated by Piezo2, seems to be the principal and essential underlying novel oscillatory signaling that could be lost in colorectal cancer onset. Hence, Piezo2 channelopathy not only contributes to cancer initiation and impaired circadian regulation, including the proposed hippocampal ultradian clock, but also to proliferation and metastasis. Full article

Background/Objectives: Accurate visualization of the Achilles tendon enthesis is critical for distinguishing mechanical, degenerative, and inflammatory pathologies. Although ultrasonography is the first-line modality for suspected enthesis disease, recent technical advances may expand the role of magnetic resonance imaging (MRI). This study evaluated the utility of ultra-short echo time (UTE) and zero echo time (ZTE) sequences versus proton density-weighted imaging (PD-WI) for depicting the enthesis organ in healthy volunteers. Methods: In this institutional review board (IRB)-approved prospective single-center study, 50 asymptomatic adult volunteers underwent 3-Tesla hindfoot MRI with fat-suppressed PD-WI, UTE, and ZTE between 2018 and 2023. Four radiologists assessed image quality, signal-to-noise ratio, visibility, and abnormal high signal intensities (SIs) of the periost, sesamoid, and enthesis fibrocartilages (PCa, SCa, and ECa, respectively). Statistical tests included Chi-square, McNemar, paired Wilcoxon, and Benjamini–Hochberg adjustments for multiple comparisons. Results: The median age was 36 years (range: 20–51); 58% women were included. PD-WI and ZTE sequences were always available while UTE was unavailable in 24% of patients. PD-WI consistently failed to concomitantly visualize all fibrocartilages. ZTE and UTE visualized all fibrocartilages in 72% and 92.1% of volunteers, respectively, with significant differences favoring ZTE and UTE over PD-WI (p < 0.0001) and UTE over ZTE (p = 0.027). Inter-rater agreement exceeded 80% except for SCa on ZTE (68%, 95%CI: 53.2–80.1). Abnormal SCa findings in asymptomatic patients were more frequent with UTE (23.7%) and ZTE (34%) than with PD-WI (2%) (p = 0.0045). Conclusions: At 3-Tesla, UTE and ZTE sequences reliably depict the enthesis organ of the Achilles tendon, outperforming PD-WI. However, the high sensitivity of these sequences also presents challenges in interpretation. Full article

Background: Atypical carcinoid of the thymus is an exceptionally rare neuroendocrine tumor originating from neuroendocrine cells within the thymus. These tumors often present with no symptoms or with nonspecific clinical signs, making early diagnosis particularly challenging. Despite their rarity, atypical carcinoids are clinically significant due to their aggressive nature and relatively poor prognosis. Early detection and appropriate management are therefore crucial to improving patient outcomes. Results: In this report, we present the case of a 64-year-old patient in whom an atypical carcinoid of the thymus was incidentally discovered following a thoracic computed tomography scan performed for unrelated reasons. Imaging revealed a suspicious anterior mediastinal mass, which was subsequently surgically resected. Histopathological examination, supported by immunohistochemical analysis, confirmed the diagnosis of an atypical carcinoid of the thymus. The tumor demonstrated coexpression of epithelial and neuroendocrine markers, consistent with this rare entity. Conclusions: This case adds to the limited body of literature on atypical carcinoid of the thymus and highlights the importance of considering this diagnosis when evaluating anterior mediastinal masses. It also underscores the value of thorough radiological and pathological assessment in identifying early-stage disease, which may significantly influence prognosis and therapeutic strategies. Full article

Background and Objectives: Meniscal pathologies are common abnormalities of the knee joint and a frequent cause of knee pain. Prompt and accurate diagnosis is essential to ensure appropriate treatment. Ultrasonography is increasingly used due to its accessibility, cost- and time-efficiency, and capacity for dynamic assessment. This study aimed to evaluate the usefulness of ultrasonography in identifying specific types of meniscal tears and to assess their frequency of occurrence. Materials and Methods: A retrospective study was conducted to assess the frequency and sonographic appearance of various meniscal pathologies. The study population included all patients who underwent ultrasonographic examination of the knee in our clinic over one year for various indications (n = 430). Archived ultrasound images were retrospectively reviewed and analyzed. Results: Meniscal pathologies were identified in 134 patients. The findings included 95 cases of degenerative lesions (70.9%), 18 meniscal cyst-related pathologies (13.4%), 8 complex tears (6.0%), 5 flap tears (3.7%), 3 vertical pericapsular tears (2.2%), 3 partial thickness tears (2.2%), and 2 bucket-handle-type tears (1.5%). Each lesion type was characterized and illustrated through representative ultrasound images. Conclusions: Ultrasound imaging of meniscal pathology offers a valuable diagnostic option. By characterizing and visually documenting different meniscal lesions, this study highlights the practical potential of ultrasonography in routine clinical settings. These findings may enhance diagnostic accuracy and guide more targeted management strategies. Moreover, the results contribute to the expanding body of research on musculoskeletal ultrasonography and may encourage broader adoption of ultrasound in orthopedic diagnostics. Full article

Short-chain fatty acids (SCFAs) are metabolites derived from the fermentation of dietary fibre by gut bacteria. SCFAs function as essential regulators of host-microbiome interactions by participating in numerous physiological and pathological processes within the gastrointestinal (GI) tract. In recent years, the depletion of SCFAs has been increasingly linked to the pathogenesis of GI diseases. In this review, we summarize the current understanding of the therapeutic mechanisms of SCFAs in GI diseases, including inflammatory bowel disease, irritable bowel syndrome, metabolic dysfunction-associated steatotic liver disease, and acute pancreatitis. We next highlight potential therapeutic approaches that increase the endogenous production of SCFAs, including prebiotics, probiotics, and fecal microbiota transplantation. We conclude that, although SCFAs are promising therapeutic agents, further research is necessary due to variability in treatment efficacy, inconsistent clinical outcomes, and a limited understanding of SCFAs’ mechanisms of action. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a range of liver conditions, from simple hepatic steatosis to its more severe inflammatory form known as metabolic dysfunction-associated steatohepatitis (MASH). Despite its growing clinical significance and association with cirrhosis and cancer, there are currently few pharmacological treatments available for MASLD, highlighting the urgent need for new therapeutic strategies. This narrative review aims to elucidate the molecular mechanisms of lipophagy in MASLD progression, emphasizing how its dysfunction contributes to hepatic steatosis and lipotoxicity. We also explore the intersection of lipophagy failure with oxidative stress and inflammation in the liver, focusing on key signaling pathways, such as mTORC1 and AMPK, and discuss the therapeutic potential of targeting these pathways by systematically reviewing the literature from PubMed, Scopus, and Google Scholar databases. Recent studies suggest that lipophagy, the selective autophagic degradation of lipid droplets, is crucial for maintaining hepatic lipid homeostasis. Indeed, some vital components of the lipophagy machinery seem to be functionally inhibited in MASLD, resulting in the accumulation of intracellular triacylglycerol (TAG), lipotoxicity, and subsequent oxidative stress, all of which contribute to disease progression. In summary, impaired lipophagy is a central pathological mechanism in MASLD, making it an important therapeutic target. A deeper understanding of these mechanisms may offer new strategic insights for combating the progression of MASLD/MASH. Full article

Bruton Tyrosine Kinase (BTK) has emerged as a critical mediator in the pathophysiology of neuroinflammation associated with neurodegenerative diseases. BTK, a non-receptor tyrosine kinase predominantly expressed in cells of the hematopoietic lineage, modulates B-cell receptor signaling and innate immune responses, including microglial activation. Recent evidence implicates aberrant BTK signaling in the exacerbation of neuroinflammatory cascades contributing to neuronal damage in disorders such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, ischemic stroke, and Huntington’s disease. Pharmacological inhibition of BTK has shown promise in attenuating microglial-mediated neurotoxicity, reducing pro-inflammatory cytokine release, and promoting neuroprotection in preclinical models. BTK inhibitors, originally developed for hematological malignancies, demonstrate favorable blood–brain barrier penetration and immunomodulatory effects relevant to central nervous system pathology. This therapeutic approach may counteract detrimental neuroimmune interactions without broadly suppressing systemic immunity, thus preserving host defense. Ongoing clinical trials are evaluating the safety and efficacy of BTK inhibitors in patients with neurodegenerative conditions, with preliminary results indicating potential benefits in slowing disease progression and improving neurological outcomes. This review consolidates current knowledge on BTK signaling in neurodegeneration and highlights the rationale for BTK inhibition as a novel, targeted therapeutic strategy to modulate neuroinflammation and mitigate neurodegenerative processes. Full article

The growing demand for accurate and efficient Chest X-Ray (CXR) interpretation has prompted the development of AI-driven systems to alleviate radiologist workload and reduce diagnostic variability. This paper introduces the Intelligent Humanized Radiology Analysis System (IHRAS), a modular framework that automates the end-to-end process of CXR analysis and report generation. IHRAS integrates four core components: (i) deep convolutional neural networks for multi-label classification of 14 thoracic conditions; (ii) Grad-CAM for spatial visualization of pathologies; (iii) SAR-Net for anatomical segmentation; and (iv) a large language model (DeepSeek-R1) guided by the CRISPE prompt engineering framework to generate structured diagnostic reports using SNOMED CT terminology. Evaluated on the NIH ChestX-ray dataset, IHRAS demonstrates consistent diagnostic performance across diverse demographic and clinical subgroups, and produces high-fidelity, clinically relevant radiological reports with strong faithfulness, relevancy, and alignment scores. The system offers a transparent and scalable solution to support radiological workflows while highlighting the importance of interpretability and standardization in clinical Artificial Intelligence applications. Full article

Background: Epidemiological studies have reported an inverse association between smoking and Parkinson’s disease (PD) risk, prompting interest in nicotine as a potential therapeutic agent. The present meta-analysis evaluated the efficacy of nicotine therapy in improving motor symptoms and activities of daily living in patients with PD. Methods: PubMed, Embase, and Cochrane Library were systematically searched to identify randomized controlled trials (RCTs) assessing nicotine therapy in PD. Clinical RCTs administering interventions extending beyond 1 week and reporting motor or nonmotor outcomes were included. Random-effects models were used to analyze short-term (<6 months) and long-term (≥6 months) outcomes by using standardized mean differences (SMDs). Results: This meta-analysis included five RCTs (346 participants). Nicotine therapy led to no significant improvement in motor outcomes in the short term (pooled SMD: −0.452, 95% confidence interval: −1.612 to 0.708) or long term (pooled SMD: 0.174, 95% confidence interval: −0.438 to 0.787). Considerable interstudy heterogeneity was noted. Furthermore, short-term nicotine therapy resulted in no significant improvement in daily functioning, cognition, or quality of life. Conclusions: This meta-analysis revealed a lack of compelling evidence suggesting that nicotine-based therapies improve motor or nonmotor outcomes in PD. The findings highlight a disconnect between epidemiological associations and clinical efficacy. Given the prodromal nature of PD pathology and the challenges of early diagnosis, future preventive strategies should be implemented before symptom onset in high-risk individuals identified using advanced biomarker panels. Full article

Protein S-nitrosylation is a selective post-translational modification in which a nitrosyl group is covalently attached to the reactive thiol group of cysteine, forming S-nitrosothiol. This modification plays a pivotal role in modulating physiological and pathological cardiovascular processes by altering protein conformation, activity, stability, and other post-translational modifications. It is instrumental in regulating vascular and myocardial systolic and diastolic functions, vascular endothelial cell and cardiomyocyte apoptosis, and cardiac action potential and repolarization. Aberrant S-nitrosylation levels are implicated in the pathogenesis of various cardiovascular diseases, including systemic hypertension, pulmonary arterial hypertension, atherosclerosis, heart failure, myocardial infarction, arrhythmia, and diabetic cardiomyopathy. Insufficient S-nitrosylation leads to impaired vasodilation and increased vascular resistance, while excessive S-nitrosylation contributes to cardiac hypertrophy and myocardial fibrosis, thereby accelerating ventricular remodeling. This paper reviews the S-nitrosylated proteins in the above-mentioned diseases and their impact on these conditions through various signaling pathways, with the aim of providing a theoretical foundation for the development of novel therapeutic strategies or drugs targeting S-nitrosylated proteins. Full article

Background: Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), are genetically complex and often linked to structural genomic variations such as copy number variants (CNVs). Current diagnostic strategies face challenges in interpreting the clinical significance of such variants. Methods: We developed a customized, gene-oriented chromosomal microarray (CMA) targeting 6026 genes relevant to neurodevelopment, aiming to improve diagnostic yield and candidate gene prioritization. A total of 39 patients with unexplained developmental delay, intellectual disability, and/or ASD were analyzed using this custom platform. Systems biology approaches were employed for downstream interpretation, including protein–protein interaction networks, centrality measures, and tissue-specific functional module analysis. Results: Pathogenic or likely pathogenic CNVs were identified in 31% of cases (9/29). Network analyses revealed candidate genes with key topological properties, including central “hubs” (e.g., NPEPPS, PSMG1, DOCK8) and regulatory “bottlenecks” (e.g., SLC15A4, GLT1D1, TMEM132C). Tissue- and cell-type-specific network modeling demonstrated widespread gene involvement in both prenatal and postnatal developmental modules, with glial and astrocytic networks showing notable enrichment. Several novel CNV regions with high pathogenic potential were identified and linked to neurodevelopmental phenotypes in individual patient cases. Conclusions: Customized CMA offers enhanced detection of clinically relevant CNVs and provides a framework for prioritizing novel candidate genes based on biological network integration. This approach improves diagnostic accuracy in NDDs and identifies new targets for future functional and translational studies, highlighting the importance of glial involvement and immune-related pathways in neurodevelopmental pathology. Full article

Prolonged high-dose administration of synthetic glucocorticoids (GCs) leads to limb muscle atrophy and weakness, yet its underlying mechanisms remain incompletely understood. Muscle fibers and muscle satellite cells (MSCs) are essential for skeletal muscle development and associated pathologies. This study demonstrates that dexamethasone (Dex) induced MSC-derived extracellular vesicles (EVs) impair myogenesis in muscle fiber-like cells (MFLCs) via inducible nitric oxide synthase (iNOS) suppression. High-throughput sequencing revealed a marked upregulation of miR-335-5p in MSC-derived EVs following Dex treatment. Mechanistically, EV miR-335-5p targeted MAPK11, leading to iNOS downregulation and subsequent UPS activation in MFLCs, which directly promoted muscle protein degradation. Collectively, our findings identify the EV miR-335-5p/MAPK11/iNOS axis as a critical mediator of GC-induced muscle atrophy, offering novel insights into therapeutic strategies targeting EV-mediated signaling in muscle wasting disorders. Full article