Journal of Physiology and Pharmacology最新文献

We investigated the effects and mechanisms of neurotrophin-3 (NT-3)-modified bone marrow mesenchymal stem cells (BMSCs) combined with a polycaprolactone (PCL) scaffold to repair denervation-induced muscle atrophy following sciatic nerve injury (SNI) in rats. An established SNI rat model was utilized to evaluate the therapeutic efficacy of BMSCs, pcDNA3.1-NT-3, and NT-3-modified BMSCs scaffold complexes. Functional recovery of peripheral nerves was assessed through serial sciatic functional index (SFI) measurements. Histopathological analyses evaluated nerve regeneration and gastrocnemius muscle preservation, complemented by quantification of muscle wet weight and fiber cross-sectional area. Molecular mechanisms were investigated via RT-qPCR and Western blot to determine expression profiles of NT-3, FasL, Cleaved Caspase-3, Bcl-2, and Bax. Both individual and combined applications of BMSCs and pcDNA3.1-NT-3 composite PCL scaffolds demonstrated therapeutic efficacy in ameliorating SNI, enhancing nerve regeneration, and restoring neurological function while attenuating denervation-induced skeletal muscle atrophy. The combinatorial BMSCs/pcDNA3.1-NT-3 intervention exhibited superior neurorestorative effects through synergistic mechanisms, suggesting clinical potential for optimizing functional recovery in peripheral nerve injury (PNI) patients. Notably, SNI rats exhibited upregulated FasL expression in neuromuscular tissues, which was significantly suppressed following BMSCs/pcDNA3.1-NT-3 scaffold treatment. Lentiviral-mediated FasL overexpression (Lv-FasL) abolished the therapeutic benefits of the composite scaffold, confirming FasL's critical role in mediating these neuroprotective effects. We found out that NT-3 modified BMSCs combined with PCL scaffolds promoted nerve regeneration, repaired nerve function, and inhibited skeletal muscle atrophy in rats after sciatic nerve injury by regulating FasL expression.

Colorectal cancer (CRC) remains a major global health challenge, with increasing incidence and limited treatment options. The antimicrobial peptide cathelicidin (LL-37) has been implicated in both tumorigenic and tumor-suppressive roles, but its precise function in CRC progression remains unclear. This study investigates the LL-37 expression in CRC and its association with key molecular pathways, including vitamin D signaling and G protein-coupled receptors (GPCRs). We analyzed LL-37 mRNA expression in 25 CRC tissue samples and matched healthy colonic mucosa using quantitative real-time PCR. Additionally, we assessed the expression of potential LL-37 target receptors, including formyl peptide receptor 2 (FPR2), toll-like receptors (TLR3, TLR4), CXC chemokine receptor 2 (CXCR2), and mas-related gene X2 (MrgX2). The correlation between LL-37 expression and clinicopathological factors, including tumor stage and nodal metastases, was also evaluated. LL-37 expression was significantly upregulated in CRC tissues compared to normal mucosa (p<0.001), with higher expression in advanced-stage CRC (AJCC stage III) and tumors with nodal metastases (p=0.006). Molecular analysis revealed significantly increased FPR2 expression and reduced TLR3 expression in CRC tissue, suggesting their involvement in tumor progression. Our findings suggest a role for LL-37 in CRC progression, potentially mediated through FPR2 activation and TLR3 suppression. The observed discrepancies in LL-37 function across studies highlight its complex, context-dependent role in tumor biology. Further research is needed to elucidate the mechanistic basis of LL-37 signaling and its potential as a therapeutic target in CRC.

Rat models of hemorrhagic shock (HS) are essential tools for investigating the pathophysiological mechanisms underlying trauma-induced hypovolemia and for evaluating therapeutic interventions. This review synthesizes established protocols across controlled (fixed-volume, fixed-pressure) and uncontrolled hemorrhage paradigms, as well as complex trauma HS models, including traumatic brain injury (TBI) combinations. Fixed-pressure models offer reproducibility by maintaining target mean arterial pressure (MAP) over extended durations, while fixed-volume approaches standardize blood loss relative to body weight, however their consistency may vary across animals due to physiological differences. On the other hand, uncontrolled hemorrhage models such as spleen or liver transection, tail amputation, and renal injury better replicate clinical pathophysiology, including unregulated bleeding and variable shock severity, but pose challenges to standardization. Combined trauma models, particularly TBI+HS, further enhance translational relevance by allowing investigation into compounded inflammation, coagulopathy, and neuro-ischemic damage. While controlled models offer precision for mechanistic studies, uncontrolled and complex models improve clinical applicability. Nevertheless, rat HS models are subject to several methodological limitations, including variability in anesthesia protocols, cannulation techniques, animal strains, and endpoint definitions. Finally, we outline future directions, including the standardization of hybrid models, optimization of resuscitation strategies, and incorporation of omics-based endpoints. This review aims to serve as a practical guide for the selection and design of rat hemorrhagic shock models in translational trauma research.

Neurological dysfunction during ischemic stroke can lead to severe neural damage. Curcumin, a natural polyphenolic compound, has shown significant neuroprotective effects in the context of cerebral ischemia, though the detailed mechanisms remain insufficiently understood. This study aims to determine whether curcumin pre-treatment provides neuroprotection against ischemic stroke (IS) and to elucidate the underlying molecular pathways. A middle cerebral artery occlusion (MCAO) model was induced and pre-treated with 50, 100, or 200 mg/kg of curcumin. The impact of curcumin on ischemic injury was evaluated by assessing neurological deficits, cerebral edema, and blood-brain barrier (BBB) permeability using neurological scoring, brain water content analysis, and Evans blue staining. Neuronal morphology and apoptosis were assessed. An oxygen-glucose deprivation/reperfusion (OGD/R) model was employed using HT-22 cells. Cell viability and apoptosis were measured. Oxidative stress and inflammation were determined, as well as iron levels in brain tissue and cells. Curcumin pre-treatment significantly improved neurological scores, reduced neuronal morphological damage, and ameliorated cerebral edema and BBB disruption in MCAO/R rats. Furthermore, curcumin enhanced cell viability in HT-22 cells following OGD/R, reduced apoptosis, and alleviated ferroptosis, oxidative stress, and inflammation through activation of the melatonin receptor 2 (MT2)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/inositol-requiring enzyme 1 (IRE1) signaling pathway. We conclude that curcumin enhances neuron survival and provides neuroprotection against IS by activating the MT2/cAMP/PKA/IRE1 pathway.

Inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are characterized by chronic intestinal inflammation, immune dysregulation and altered microbiota. This review underscores the significance of rodent models of experimental colitis in understanding the complex interplay between intestinal inflammation with special focus to contribution of neutrophils, proinflammatory and anti-inflammatory cytokines, intestinal microbiota as well as other disorders associated with IBD, such as neurodegenerative diseases, including Alzheimer's disease, offering insights into potential therapeutic targets and underlying mechanisms. Furthermore, the review identified interleukin-8 (IL-8) as a key factor of inflammation and by compiling experimental results and reviewing literature from databases such as PubMed and Medline, it provided a comprehensive overview of the influence of the immune system and intestinal microbiota on IBD and proposed targeted therapies to better treat the disease.

This study investigated the mechanism of the RNA-binding protein Epiplakin 1 (EPPK1) in ovarian cancer (OC). EPPK1 expression in OC tissues was analyzed using gene expression profiling interactive analysis (GEPIA). The association between EPPK1 expression and patient overall survival (OS) and progression-free survival (PFS) was evaluated through Kaplan-Meier analysis. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot were performed to quantify EPPK1 levels in 25 clinical OC specimens. An EPPK1-knockdown xenograft model was established to examine tumor growth and distant metastasis in vivo. The roles of EPPK1 and Yes-associated protein (YAP) in OC cell proliferation, migration, and immune escape were assessed in vitro. The EPPK1-YAP interaction was characterized. Analysis of the GEPIA database revealed elevated EPPK1 expression in ovarian serous cystadenocarcinoma, with Kaplan-Meier survival curves demonstrating significantly shorter OS and PFS in patients with high EPPK1 expression over a 5-year period. RT-qPCR and Western blot analyses confirmed EPPK1 upregulation in clinical OC specimens. Functional studies demonstrated that altered EPPK1 and YAP expression modulated OC cell proliferation, migration, invasion, and immune escape capabilities both in vitro and in vivo. Mechanistically, EPPK1 binds to and enhances YAP mRNA stability. Notably, YAP overexpression rescued the inhibitory effects of EPPK1 knockdown on OC cell proliferation, migration, invasion, and immune evasion in vitro. The results indicate that EPPK1 promotes immune evasion and distant metastasis in OC by stabilizing YAP RNA.

Bladder cancer continues to represent a considerable global health burden, characterized by increasing incidence and mortality rates. Despite its prevalence as one of the most common urological malignancies, diagnosis remains challenging due to the scarcity of dependable, non-invasive biomarkers. Consequently, the imperative to identify novel biomarkers for effective diagnosis becomes evident. This study included 101 hospital patients, whose were stratified according to biopsy-confirmed histopathological diagnosis into the bladder cancer group (n=69) and the non-cancer group (n=32). Serum angiopoietin-like 4 (ANGPTL4) concentrations were quantified using an enzyme-linked immunosorbent assay (ELISA). Significantly lower serum ANGPTL4 levels (approximately 28% lower) were observed in the bladder cancer cohort compared to the non-cancer group (p=0.043). The optimal cut-off value was 16.95 ng/ml, yielding a sensitivity of 74% and a specificity of 53%. The Youden Index was established at 0.2704. The presented findings indicate that ANGPTL4 poorly differentiates patients with bladder cancer from non-cancer patients.

The diagnosis of attention-deficit/hyperactivity disorder (ADHD) in high-functioning adults is challenging, often relying on subjective reports which can be confounded by compensatory mechanisms. Quantitative electroencephalography (QEEG) is an objective neurophysiological tool that can identify biomarkers associated with attentional dysregulation. This case report aims to illustrate the clinical utility of QEEG in characterizing the neural correlates of suspected ADHD in a high-functioning adult female. A 31-year-old high-functioning female with chronic symptoms of inattention and executive dysfunction underwent an eight-channel resting-state QEEG assessment under both eyes-open (EO) and eyes-closed (EC) conditions. Data were analyzed using the Fast Fourier Transform (FFT) to determine the absolute and relative power of spectral bands and to compute key frequency ratios, including the theta/beta ratio (TBR). To confirm the clinical diagnosis of ADHD and exclude comorbid psychiatric or neurodevelopmental disorders, standardized diagnostic tools were employed, including the DIVA 2.0 structured interview. Data analysis revealed a marked excess of relative theta power in frontal and central regions, which persisted and amplified in the EC condition (e.g., F3: 21.37% in EO vs. 27.10% in EC). The TBR in frontal leads surpassed the clinical threshold of 1.5. Notably, a paradoxical alpha response was observed, with a decrease in posterior Alpha power upon eye closure. A mild rightward frontal asymmetry was also present. We found that the patient's QEEG profile provided objective, quantifiable evidence that supports her subjective clinical presentation and is consistent with neurophysiological subtypes of adult ADHD. This case highlights the value of QEEG as an adjunctive diagnostic tool for illustrating potential neural correlates of ADHD in high-functioning individuals and for suggesting potential targets for therapeutic strategies. While this single-case study highlights QEEG's potential, the findings underscore the need for larger-scale research to validate these neuromarkers for broader clinical application.

Chronic low-grade inflammation associated with obesity is increasingly recognized as a modifier of epithelial homeostasis within the female reproductive system. However, its early molecular consequences in physiologically relevant large-animal models remain insufficiently defined. To examine whether obesity-linked systemic inflammation is accompanied by alterations in epithelial stress markers in the Fallopian tube and ovarian surface epithelium of slaughterhouse-derived sows. Animals were retrospectively classified into lean (75-100 kg, n=3) and obese (200-250 kg, n=3) groups based on post-mortem body weight and circulating inflammatory markers. Plasma concentrations of CRP, IL-6, IL-1β, and TNF-α were measured via ELISA. TP53 and PAX8 transcript abundance was assessed using RT-qPCR, while protein levels and localization were evaluated by Western blotting and immunofluorescence. Obese sows exhibited elevated plasma CRP (+22.9%, p<0.05), IL-6 (+85.7%, p<0.05), and IL-1β (+140.2%, p<0.01), alongside a marked decrease in TNF-α (-73.1%, p<0.001), confirming a distinct inflammatory profile. TP53 mRNA levels were higher in both the Fallopian tube and ovarian cortex, whereas PAX8 expression showed a trend toward reduction in the Fallopian tube, although without statistical significance. Western blotting revealed significantly increased p53 protein levels in the Fallopian tube (p<0.05). Immunofluorescence demonstrated enhanced p53 and PAX8 signals in the Fallopian tube epithelium (p<0.01 and p<0.001, respectively), and a focal increase in p53 abundance in the ovarian surface epithelium (p<0.01). Concluding, obesity-associated inflammation is accompanied by molecular stress signatures in porcine reproductive epithelia, particularly within the Fallopian tube. Although these alterations should not be interpreted as preneoplastic, they may represent early adaptive or dysregulated responses to chronic metabolic burden, warranting further validation in larger cohorts.

Lung cancer remains a leading cause of cancer-related mortality worldwide, emphasizing the urgent need for innovative therapeutic approaches. This study explores the anticancer potential of ethanolic extract of Bacopa monnieri (B. monnieri) against A549 lung cancer cells. Treatment with various concentrations of B. monnieri for 24 and 48 hours significantly reduced cell viability in a dose- and time-dependent manner, as demonstrated by MTT assays. Mechanistically, B. monnieri treatment elevated reactive oxygen species (ROS) levels, depleted antioxidant defenses, disrupted mitochondrial membrane potential (ΔΨm), and triggered cytochrome C release, culminating in apoptosis. Apoptotic cell death was confirmed using acridine orange/ethidium bromide (AO/EtBr) dual staining. Additionally, Western blot and mRNA analysis showed downregulation of the anti-apoptotic protein Bcl-2 and upregulation of pro-apoptotic markers, including Bax, caspase-3, and PARP, indicating activation of the intrinsic apoptotic pathway. These results suggest that B. monnieri exerts its anticancer effects by modulating critical molecular pathways involved in cell survival and apoptosis. This study underscores the potential of B. monnieri as a promising therapeutic agent for lung cancer treatment. Further research is warranted to investigate its pharmacokinetics, bioavailability, and therapeutic efficacy in preclinical models.