Metabolic dysfunction-associated fatty liver disease (MAFLD) poses a significant challenge in modern medicine due to its high prevalence. The pathogenesis of MAFLD involves a complex dysmetabolic process consistent with the “multiple-hit” hypothesis. This process includes excessive triglyceride (TC) accumulation within hepatocytes, lipotoxicity, insulin resistance (IR), chronic low-grade inflammation, and increased oxidative stress. The role of leptin in the liver has been extensively studied, demonstrating both direct effects on hepatic cells and indirect actions mediated through the central nervous system (CNS). In MAFLD, leptin modulates several physiological processes: it improves glucose metabolism by enhancing insulin sensitivity and lowering glucose levels; regulates lipid metabolism by promoting β-oxidation and TC export while inhibiting lipogenesis; and contributes to fibrogenesis by upregulating transforming growth factor-β (TGF-β) expression and activating hepatic stellate cells (HSCs) and the immune response. This review explores the structure of leptin, its primary physiological functions, its potential role in MAFLD pathogenesis, and its promise as a novel therapeutic target.

Immunoinflammatory skin diseases are characterized by an imbalance in immune homeostasis, and their chronic inflammatory processes involve a complex regulatory network of CD4+ T cell differentiation. With the widespread use of biologics (e.g., interleukin-17/interleukin-23 inhibitors) in psoriasis, atopic dermatitis, and other diseases, the adverse effects triggered by the phenomenon of CD4+ T cell-mediated immune drift have attracted significant attention, with the skin being the primary target as an immune organ. In this paper, we provide a review of the clinical features of the skin and the mechanisms of immune drift caused by different types of biologics, as well as the therapeutic modalities.

Gastrointestinal complications are common in patients after ischemic stroke. Gastric motility is regulated by gastric pace-making activity (also called gastric myoelectrical activity (GMA)) and autonomic function. The aim of this study was to evaluate GMA, assessed by noninvasive electrogastrography (EGG), and autonomic function, measured via spectral analysis of heart rate variability derived from the electrocardiogram in patients with ischemic stroke.

EGG and electrocardiogram were simultaneously recorded in both fasting and postprandial states in 14 patients with ischemic stroke and 11 healthy controls. Multi-channel surface EGG was used to measure GMA, and autonomic function was evaluated by heart rate variability spectral analysis.

Compared to healthy subjects, patients with ischemic stroke, especially those with a modified Rankin scale ≥ 4, had impaired GMA in both fasting and postprandial states. This included a lower percentage of normal gastric slow waves (the basic rhythmic waves of GMA) and a higher percentage of tachygastria, bradygastria, or arrhythmia. Patients with ischemic stroke also showed a decrease in the dominant frequency and power of the gastric slow waves. Autonomic functions were altered in ischemic stroke patients with a modified Rankin scale ≥ 4, as reflected by increased sympathetic activity and reduced parasympathetic activity.

Gastric pace-making activity is impaired in patients with severe ischemic stroke, as evidenced by a reduced percentage of normal gastric slow waves and a lower frequency of gastric slow waves, likely due to impaired autonomic functions.

The incidence of early-onset pancreatic cancer (EOPC) is rising, yet optimal treatment strategies remain unclear. While adjuvant chemotherapy (ACT) has shown survival benefits in pancreatic ductal adenocarcinoma, its specific role in EOPC patients following neoadjuvant chemotherapy (NACT) and surgery remains underexplored. This study aimed to assess the clinical benefit of ACT in EOPC patients after NACT.

This retrospective cohort study analyzed pancreatic ductal adenocarcinoma patients from the SEER database (2006–2019) who received NACT followed by curative resection. Propensity score matching (1:1) was used to balance covariates such as tumor, lymph node, metastasis stage, chemotherapy, and radiotherapy. Overall survival (OS) and cancer-specific survival (CSS) were compared between patients with EOPC (<50 years) and average-onset pancreatic cancer (AOPC, ≥50 years). Multivariate Cox regression analysis was performed to identify prognostic factors.

After propensity score matching (124 EOPC vs. 124 AOPC), EOPC patients had significantly longer median OS (41.0 vs. 29.0 months, P = 0.042) and CSS (48.0 vs. 30.0 months, P = 0.016). ACT was an independent prognostic factor for EOPC (OS: hazard ratio = 0.495, 95% confidence interval 0.271–0.903, P = 0.022; CSS: hazard ratio = 0.419, 95% confidence interval 0.219–0.803, P = 0.009), but not for AOPC (P > 0.05). Subgroup analysis revealed that EOPC patients with tumor, lymph node, metastasis stage II disease or those receiving ACT derived the greatest survival benefit.

EOPC patients exhibit superior survival following NACT and surgical resection compared to AOPC, with ACT further enhancing outcomes in this subgroup. These findings support the use of tailored ACT for EOPC and underscore the need for prospective validation.

Despite advancements in diagnostic and therapeutic strategies, hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality. Antioxidant-1 (ATOX1) has been implicated in oncogenic processes across various cancer types; however, its specific role in HCC remains unclear. This study aimed to investigate the function of ATOX1 and its underlying molecular mechanisms in HCC.

Immunohistochemical analysis was conducted to assess ATOX1 expression in HCC tissues. Cell Counting Kit-8, colony formation, Transwell migration, flow cytometry, and reactive oxygen species (ROS) assays were employed to evaluate the malignant behaviors of tumor cells. A xenograft mouse model was employed to assess the effects of ATOX1 knockdown on tumor growth in vivo. DCAC50 treatment was performed to inhibit the copper transport function of ATOX1. RNA sequencing was conducted to explore the potential molecular mechanisms of ATOX1 in HCC.

ATOX1 expression was significantly elevated in HCC tumor tissues. ATOX1 promoted cell proliferation, colony formation, and migration. Knockdown of ATOX1 suppressed tumor growth in vivo. Mechanistically, ATOX1 activated c-Myb, and thus enhanced the malignant phenotype of HCC cells via activation of the PI3K/AKT signaling pathway. Additionally, ATOX1 reduced intracellular copper accumulation and inhibited ROS production and apoptosis. Inhibition of ATOX1 by DCAC50 decreased cell proliferation while increasing ROS levels and apoptosis in HCC cells. Notably, acetylcysteine reversed the reduction in c-Myb expression induced by ATOX1 knockdown.

ATOX1 may promote HCC carcinogenesis through the activation of the c-Myb/PI3K/AKT pathway and the inhibition of copper accumulation and oxidative stress.

Huo Xue Tong Luo Capsule (HXTL) has been clinically used to treat osteonecrosis of the femoral head, osteoporosis, and other bone and joint diseases with promising effects. Our previous study has shown that HXTL can promote osteogenesis in mesenchymal stem cells by inhibiting lncRNA-Miat expression through histone modifications. However, the mechanism by which HXTL treats postmenopausal osteoporosis (PMOP) remains unclear. In this study, we used network pharmacology-based mechanism prediction, molecular docking, and pharmacological validation to investigate the mechanism of HXTL in treating PMOP.

The key candidate targets and relevant signaling pathways of HXTL for PMOP treatment were predicted using network pharmacology and molecular docking analysis. RAW264.7 cells were used for Western blot to validate the predicted mechanistic pathways. The ovaries of mice were surgically removed to simulate PMOP. The effect of HXTL on PMOP was evaluated using tartrate-resistant acid phosphatase staining and immunohistochemical assays in vivo.

Network pharmacology analysis suggested that HXTL interacted with 215 key targets linked to PMOP, primarily affecting the PI3K-AKT signaling pathway. Molecular docking showed that the main components of HXTL exhibited strong binding affinity to NFATc1, p-PI3K, and p-AKT1. Furthermore, our in vitro results confirmed that HXTL suppressed the PI3K-AKT signaling pathway. In vivo, HE and tartrate-resistant acid phosphatase staining results showed that HXTL inhibited osteoclast formation and protected bone mass.

This research demonstrated that HXTL could inhibit osteoclast formation and prevent bone loss induced by ovariectomy in mice by inhibiting the PI3K-AKT signaling pathway. These findings provide important evidence for the clinical application of HXTL in treating PMOP.

Spinal cord injury (SCI) significantly impacts the central nervous system, with limited effective treatments available. Brain-derived neurotrophic factor (BDNF) plays a crucial role in neuronal growth, survival, and regeneration after SCI. MicroRNAs, particularly miR-124-3p, have been implicated in SCI pathophysiology. However, the relationship between miR-124-3p and BDNF in the context of SCI remains unclear. This study aimed to investigate the correlation between miR-124-3p expression and BDNF levels in a rat model of spinal cord injury and to assess how the timing of injury affects this relationship.

This study included 72 male Wistar rats divided into three groups: intact (n = 8), sham (n = 32), and SCI (n = 32). SCI diagnosis was confirmed through behavioral-motor function analysis using the Basso, Beattie & Brenham score and histological examination with crystal violet staining. The expression levels of miR-124-3p and BDNF were assessed using real-time polymerase chain reaction in all groups at four time points (one hour, one day, three days, and seven days post-injury).

In the SCI group, a marked reduction in miR-124-3p expression was observed relative to both the sham and intact groups. Conversely, there was a substantial elevation in BDNF expression within the SCI group in comparison to the sham and intact groups. The findings underscore a negative association between miR-124-3p expression and BDNF messenger RNA levels.

The downregulation of miR-124-3p and concurrent upregulation of BDNF suggest a potential regulatory role of miR-124-3p in modulating BDNF expression during SCI. These findings provide new insights into the molecular mechanisms underlying SCI and suggest that miR-124-3p and BDNF could serve as potential therapeutic targets. Further research is needed to explore the translational potential of these findings for developing novel diagnostic and therapeutic strategies for SCI.

Celiac disease is a chronic, immune-mediated enteropathy precipitated by gluten exposure in genetically predisposed individuals, with a global prevalence of approximately 1%. Though diagnostic workflows incorporate serologic techniques with both histologic and genetic evaluation, each approach carries key pitfalls that contribute to diagnostic inaccuracy. Serology testing is limited by selective immunoglobulin A deficiency and low-titer antibodies, in addition to interlaboratory variability of calibration standards and specimen concentrations. While duodenal biopsy is considered the gold standard for celiac diagnosis, patchy villous atrophy (e.g., ultrashort celiac disease) mimics other enteropathies, and the inherent subjectivity of histologic interpretation can compromise accuracy. Furthermore, celiac predisposition is highly correlated with two human leukocyte antigen (HLA) alleles, HLA-DQ2 and HLA-DQ8. However, nearly 30–40% of the general population expresses one of these alleles, thus introducing the risk of overdiagnosis and limiting the practical implications of genetic testing. There exist special celiac presentations, such as seronegative or potential celiac disease, overlap syndromes, and enteropathy-associated T-cell lymphoma, that introduce additional challenges to diagnostic success. The serologic-histologic discordance and nonspecific symptoms associated with these cases may require divergence from the traditional workflow, as well as supplemental investigations, such as a gluten challenge or breath testing, to confirm a celiac diagnosis. These challenges in celiac diagnosis have driven research into novel biomarkers and molecular assays that can not only enable earlier, more accurate detection but also provide longitudinal disease monitoring. Such markers include intestinal fatty acid-binding proteins, specific microRNA expression, and microbiome signatures that are strongly linked to celiac disease, which may one day serve as adjunctive screening tools to optimize diagnostic yield. This narrative review identifies the key pitfalls in adult celiac disease diagnosis — from pre-analytic serology issues to patchy histology and overinterpretation of HLA — and proposes a guideline-aligned, stepwise algorithm (with emerging biomarkers) to enhance accuracy and reduce missed or delayed cases. Ultimately, continued refinement of a comprehensive, multimodal diagnostic strategy that can integrate with emerging molecular tools is necessary for overcoming the current limitations of individual approaches to celiac diagnosis.

Despite significant advances in Parkinson’s disease (PD) treatment, it remains incurable, with limited therapeutic options. Currently, repurposing already tested, safe drugs has emerged as an effective therapeutic strategy against various neurodegenerative diseases, including PD. Using a drug-repurposing approach, the current study investigated the neuroregenerative potential of polysialic acid mimicking compounds, 5-nonyloxytryptamine oxalate (5-NOT) and Epirubicin (Epi), an anti-cancer drug, in 1-methyl-4-phenylpyridinium (MPP+)-treated human neuroblastoma SH-SY5Y cells as a PD model.

The excitotoxic model was established by exposing SH-SY5Y cells to 500 µM of MPP+ and subsequently treating them with the test compounds. The effect of MPP+-induced toxicity on cellular and nuclear morphology, as well as on the expression of neuroplasticity and cell survival proteins, were studied by immunostaining, gelatin zymogram, and Western blot assays.

Treatment with 5-NOT and Epi significantly promoted the survival of MPP+-challenged SH-SY5Y cells and prevented changes in their cellular and nuclear morphology by regulating the expression of microtubule-associated protein (MAP-2) and polysialylated-neural cell adhesion molecule (PSA-NCAM) and NCAM synaptic plasticity proteins. Further, 5-NOT and Epi treatment also protected SH-SY5Y cells by restoring levels of nitric oxide, matrix metalloproteinase, and stress response proteins. Interstingly, 5-NOT attenuated MPP+-induced toxicity in SH-SY5Y cells by regulating the intrinsic protein kinase AKT/BAD apoptotic pathway and the P-38 MAP kinase synaptic plasticity pathway.

These preliminary findings suggest that 5-NOT, as a potential polysialic acid glycomimetic, may serve as a promising drug candidate for targeting neurodegeneration of dopaminergic neurons, a hallmark feature of PD.

Exophiala, a genus of saprotrophic black fungi commonly found in the environment, is typically associated with cutaneous infections in immunocompromised hosts and rarely manifests as pneumonia. Here, we report the first case of Exophiala pneumonia in Pakistan, occurring in an immunocompetent, middle-aged female with interstitial lung disease.

A 56-year-old female presented with a two-week history of malaise and a cough productive of black sputum. On auscultation, fine crackles were heard in the bilateral posterior middle and lower lung fields. Chest radiography showed features of usual interstitial pneumonia with patchy and dense reticular opacities in the middle and lower lung lobes bilaterally. Bronchoscopy was performed, and bronchoalveolar lavage was sent to the microbiology laboratory for culture. Gram stain findings revealed numerous pus cells, primarily neutrophils, along with septate hyphae, which were also confirmed on potassium hydroxide smear. The results were communicated to the treating physician, and the patient was started on intravenous voriconazole. After four days of incubation at 25°C and 37°C, colonies of mold were observed on the culture, which were identified as Exophiala jeanselmei on Lactophenol Cotton Blue staining. After one week of treatment, the patient showed clinical improvement and was discharged on oral voriconazole with outpatient follow-up.

Our findings suggest that bronchoalveolar lavage with an elevated neutrophil count and abnormal pulmonary imaging should be evaluated as signs of both fungal and bacterial pneumonia. Additionally, fungal culture should be considered in such cases, as it employs specific techniques and prolonged incubation for the isolation of fungi. Since Exophiala jeanselmei is a rare yet severe cause of pneumonia, early detection and the knowledge gained from treated infections are crucial for effective management.