Physiological research最新文献

Gouty arthritis is a type of inflammatory arthritis that is mediated by the deposition of monosodium urate crystals and is an important burden on healthcare worldwide. The aim of this comprehensive review is to discuss the most recent advances regarding the mechanisms of treatment for gout, from classic pharmacological interventions to emerging therapeutic strategies. The chapter dissects the pathophysiology of gout through hyperuricemia, crystal deposition, and inflammatory responses to form a basis for the discussion of current treatment approaches; pharmacological interventions are described-side by side with lifestyle modifications-including NSAIDs, colchicine, and xanthine oxidase inhibitors. Newer approaches to management are discussed, including the use of biologics targeting IL-1beta, newer agents in development, and personalized medicine. It also outlines the future directions in gout research, focusing on the development of novel imaging techniques, biomarkers for treatment response, and targeting novel pathways. This review serves as an overall guide for clinicians and researchers and all other stakeholders interested in further advancing the specialty of gouty arthritis. Key words Gouty arthritis " Serum urate " Hyperuricemia " Crystal deposition " Colchicine.

The Social Brain is a distributed network of neuroanatomical regions and neurochemical systems that underpins the human capacity for social cognition, empathy, and interpersonal behavior. Social isolation (SI), defined as the objective reduction in social interaction, poses a significant threat to the integrity of this system. In this review, we synthesize evidence from human and animal studies to elucidate the biological, cognitive, and behavioral consequences of SI on the social brain. We describe how SI acts as a chronic stressor, disrupting structural connectivity, and altering neurotransmitter systems critical for social cognition. These disruptions manifest in altered social behavior, mentalization processes, and emotional reactivity, significantly contributing to increased vulnerability to psychiatric and neurodegenerative disorders, including depression, schizophrenia, substance use disorders, and Alzheimer's disease. Converging findings from studies of evolutionarily conserved mechanisms in rodent and primate models demonstrate that SI compromises neurodevelopment, attenuates neuroplasticity, and triggers maladaptive stress responses, highlighting that social deprivation has profound neurobiological and behavioral consequences that greatly overlap with the pathophysiological changes seen in neuropsychiatric disorders. Furthermore, we explore the role of indirect stressors resulting from SI such as touch deprivation and digital-era social disconnection as contemporary amplifiers of SI's neurobiological impact. In light of public health challenges such as the COVID-19 pandemic, we propose that SI should be recognized not only as a psychosocial condition but as a modifiable risk factor with transdiagnostic significance across psychiatry, neurology, and preventive medicine. Addressing SI through targeted interventions and policy measures is essential for promoting mental resilience and well-being. Key words Chronic Stress " Loneliness " Social Cognition " Socialization " Social Stress.

The proliferation and migration of vascular smooth muscle cells (VSMCs) are the initial contributors to restenosis in patients undergoing percutaneous coronary intervention (PCI). MicroRNA-145 (miR-145) plays a significant role in this pathological process. Although carvedilol has been shown to inhibit VSMC proliferation and migration, the underlying mechanisms are not fully understood. The aim of our study is to examine whether carvedilol regulates the expression of miR-145 and thereby inhibits the proliferation and migrative capacity of VSMCs. VSMCs were cultured and transfected with either miR-145 mimics or miR-145 inhibitors. Cell proliferation was evaluated using the Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2?-deoxyuridine (EdU) assays, while wound healing and Transwell assays were used to assess the migration capacity. Protein expression levels were quantified using western blot analysis, and additionally, a luciferase reporter assay was performed to identify the target gene of miR-145. We found that carvedilol upregulated the expression of miR-145 and decreased the expression of Krüppel-like factor 4 (KLF4). Furthermore, miR-145 inhibited VSMC proliferation and migration. KLF4 was identified as a direct target of miR-145. Importantly, the inhibition of miR-145 attenuated the suppressive effects of carvedilol on VSMCs. In summary, our results in this study demonstrate that carvedilol exerts its inhibitory effects on VSMC proliferation and migration, at least in part, through the upregulation of miR-145. These findings suggest that miR-145 may be a key mediator in the therapeutic effects of carvedilol on VSMCs.

This study aimed to examine the protective and antioxidant properties of a Teucrium polium leaf extract against acute kidney damage caused by nicotine in male mice. A total of 24 male Swiss albino mice were divided into four groups. The control group (oral solution of 0.9 % NaCl), the positive control group (injections of nicotine at a dosage of 2.5 mg/kg b.w.), the third group (received 100 mg/kg b.w. ethanolic extract of T. polium), and the fourth group (nicotine injections at a dosage of 2.5 mg/kg b.w + 100 mg/kg b.w. ethanolic extract of T. polium). GC-MS analysis of the plant extract revealed the presence of 16 active compounds. Nicotine administration resulted in a significant increase in kidney biomarkers, namely urea, uric acid, and creatinine, by 50 %, 207 %, and 129 %, respectively, compared to the control group, indicating nephrotoxicity. However, treatment with the T. polium extract improved these parameters by 77 %, 79 %, and 83 %, respectively. Furthermore, the nicotine group exhibited elevated levels of nitric oxide (NO) and malondialdehyde (MDA), which are indicators of oxidative stress, as well as decreased levels of glutathione (GSH) and reduced activity of superoxide dismutase (SOD). Conversely, the administration of the T. polium extract reversed these effects, suggesting its potential to enhance the antioxidant defense system. This finding was also supported by the improvements observed in the kidney TUNEL assay sections and the preservation of histopathological integrity. In conclusion, the T. polium extract demonstrates protective effects against nicotine-induced kidney damage by modulating oxidative stress and antioxidant defense mechanisms.

Trimethylamine N-oxide (TMAO) is involved in the development of kidney disease. However, the specific mechanism by which it leads to kidney injury is unclear. This study explored the role of regulated cell death in TMAO-induced kidney injury. We constructed a TMAO-induced chronic kidney injury model by intraperitoneal injection of TMAO (100 micromol/kg/day for three months). Plasma creatinine (Cre) and urea nitrogen (BUN) levels were measured to evaluate kidney function. Masson staining was used to evaluate kidney pathological changes. The expression levels of regulated cell death-related proteins were measured using western blotting. Plasma Cre and BUN, the area of kidney fibrosis in the TMAO group significantly increased. The western blotting results showed cleaved-Caspase-8, Caspase-8, Caspase-1, NOD-like receptor protein 3 (NLRP3), interleukin-1beta (IL-1beta), cleaved-gasdermin D (cleaved-GSDMD), Z-DNA binding protein 1 (ZBP1), phosphorylation of receptor-interacting protein kinase 3 (RIP3) and mixed-lineage kinase domain-like pseudokinase (MLKL) significantly elevated in the TMAO group. The transferrin receptor 1 (TFR1), ferritin heavy chain (FTH), ferroportin (FPN), nuclear factor erythroid 2-related factor 2 (NRF2), and glutathione peroxidase 4 (GPX4) protein expression in kidney tissue of the TMAO group significantly up-regulated. However, there was no change in iron and MDA levels. The results suggested that PANoptosis, including pyroptosis, apoptosis, and necroptosis components, might be involved in TMAO-induced chronic kidney injury.

Paclitaxel (PTX), a commonly used chemotherapeutic, frequently leads to chemotherapy-induced peripheral neuropathy (CIPN), characterized by persistent pain and neuronal hypersensitivity. While its effects on peripheral nerves are well-documented, paclitaxel also influences central nervous system pathways, particularly spinal synaptic transmission, through Toll-like receptor 4 (TLR4) activation and subsequent sensitization of transient receptor potential vanilloid 1 (TRPV1) receptors. In this study, we used an in vitro model of paclitaxel-induced neuropathic pain to investigate the role of glial activation in TRPV1 receptor function. Using whole-cell patch-clamp recordings from superficial dorsal horn neurons in acute spinal cord slices, we evaluated the effects of minocycline (MX), a glial cell inhibitor, and ISO-1, a macrophage migration inhibitory factor (MIF) antagonist, on paclitaxel-induced synaptic changes. Our results demonstrate that acute paclitaxel application enhances nociceptive signaling and impairs capsaicin-induced TRPV1 receptor tachyphylaxis, leading to sustained hyperactivity. Minocycline preincubation effectively mitigated paclitaxel-induced sensitization, restoring normal nociceptive signaling, whereas acute minocycline treatment failed to prevent these changes. ISO-1 in vitro co-incubation with paclitaxel did not affect the paclitaxel-induced changes. These findings offer novel insight into the intricate interactions among neuroinflammatory mediators, glial cell activation, and TRPV1 receptor sensitization in paclitaxel-induced neuropathic pain. The differential effects of acute versus prolonged pre-incubation minocycline application suggest the importance of sustained glial inhibition for effective outcomes and neuropathic pain management.

This minireview describes recent advances in high-tech innovations on virtual reality (VR) aiding physical and cognitive recovery from neuromuscular disorders, notably useful for post-stroke rehabilitation. VR is a computer-generated technique that engulfs users in 3D multisensory interactive feedback. This technique creates simulations of realistic situations that can be manipulated by a user. It provides a spectrum of benefits in both physical and cognitive rehabilitation in the wake of neuromuscular episodes. VR engages and motivates patients to endure the unpleasant sequela of disease. Further, it enhances the acquisition of rehabilitative skills by caregivers and trains them in psychophysical health preservation. The benefits and user-friendliness of VR make it an increasingly welcome assistive neurological therapy tool. However, VR standardization, mechanisms, and, particularly, the long-term effects appear not to keep pace with its popularity and fast-progressing technical advances. Evidence-based studies on large groups of individuals are needed to settle these issues.

Variation in response to clopidogrel represents a significant clinical challenge in patients with ischemic stroke. Genetic polymorphisms cytochrome P450 2C19 (CYP2C19) are a known cause of resistance to clopidogrel. Platelet microRNAs (miRNAs) can modulate the efficacy of antiplatelet therapy. This study focuses solely on clopidogrel because it is the most widely used alternative to aspirin in patients with aspirin intolerance or contraindications. Our aim was to investigate its pharmacogenomic and epigenetic modulation in a targeted and homogeneous cohort. CYP2C19 genotypes are commonly reported as *1/*1 (wild type), *1/*2 (intermediate metabolizer), *2/*2 (poor metabolizer) and *2/*3 (poor metabolizer). These denote the number and type of loss-of-function alleles that affect clopidogrel metabolism. Clopidogrel treatment is typically a component of broader secondary prevention strategies, including lifestyle modifications, statins, and control of blood pressure. Relevant bibliographic references have been added to support the background statements provided in the introduction and methodology. To evaluate the expression of selected platelet miRNAs (miR-126-3p, miR-19a-3p, miR-19b-3p, miR-22-3p, miR-185-5p) in patients with ischemic stroke in relation to the CYP2C19 genotype (*1/*1 ,*1/*2, *2/*2) during clopidogrel treatment. Seventy patients treated with clopidogrel (75 mg daily) were enrolled. Patients were genotyped for the CYP2C19 *2 and *3 alleles by real-time polymerase chain reaction (polymerase chain reaction (PCR)) and miRNA expression was measured in plasma. All abbreviations used throughout the manuscript have been defined at their first appearance for the sake of clarity. No significant differences in miRNA expression were found between the genotypic groups (p > 0.05). Patients with genotype *2/*2 (poor metabolizer) showed a trend towards higher levels of miR-126-3p and miR-185-5p (approximately 1.5 to 1.7 times) compared to *1/*1 (wild type). The clinical parameters did not differ significantly between the groups. Poor clopidogrel metabolizers can exhibit upregulation of some platelet miRNAs as a potential compensatory mechanism. This pilot study suggests a possible epigenetic modulation of the response to antiplatelet therapy through platelet miRNAs.

To establish a co-culture cell model and implement high-throughput gene sequencing of exosomes, we preliminarily demonstrated that endothelial cell-derived exosomes play a role in modulating the phenotypic transformation of vascular smooth muscle cells (VSMCs) by means of differentially expressed long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). Primary rat aortic endothelial cells (ECs) and VSMCs were cultured for morphological observation, immunofluorescence (IF), and western blotting (WB). A co-culture model was established using a transwell system. A comparative analysis of ?-smooth muscle actin (?-SM actin), a marker of the contractile phenotype, and vimentin, indicative of the synthetic phenotype, was conducted to assess the expression levels in both co-culture and control setups. Isolated exosomes were obtained using an exosome-specific isolation kit, followed by detailed characterization using transmission electron microscopy (TEM) for morphological assessment, nanoparticle tracking analysis (NTA) for size distribution, and WB for protein profiling. Primary aortic ECs were isolated, cultured, and characterized. In the Transwell co-culture model, VSMCs transitioned to a contractile phenotype, exhibiting increased alpha-smooth muscle actin (?-SMA, contractile marker) and decreased Vimentin (synthetic marker). Exosomes were extracted, purified, and characterized by their morphology, diameter, concentration, and marker proteins (CD9, CD63, and CD81). RNA-seq and bioinformatic analyses were conducted on muscle cells before and after treatment. The Transwell-based ECs-VSMCs co-culture model significantly upregulates contractile phenotype protein expression in VSMCs, promoting their transition to a contractile state. Differentially expressed exosomal genes, including lncRNAs and circRNAs, modulate proliferation, differentiation, and phenotypic transformation of VSMCs.

Astaxanthin is a natural, small-molecule compound with anti-inflammatory and antioxidant properties that has broad potential for use in alleviating exercise fatigue. This study investigated whether astaxanthin can attenuate the onset of fatigue, prolong the time to exhaustion, and enhance post-exercise recovery using a rat model of chronic exercise fatigue. Twenty male rats were trained for 8 weeks to establish the chronic exercise fatigue model. During training, 10 rats were randomly assigned to receive astaxanthin intragastrically and 10 rats received soybean oil alone. After the intervention, 5 rats from each group were divided into astaxanthin (AX) and control groups. The remaining rats were divided into astaxanthin-exercise (AXE) and exercise control groups, respectively, and underwent exhaustive exercise. Astaxanthin alleviated chronic exercise fatigue by improving antioxidant capacity (^CAT, GSH-Px, GSH/GSSG; p<0.05-0.01) and mitochondrial function (^MMP, ST3/ST4; p<0.01-0.001). It prolonged exercise endurance (^time to exhaustion; p<0.001), reduced muscle damage (ˇBUN, CK; p<0.01) and accelerated recovery (^Liver glycogen, NEFA; p<0.001). Astaxanthin appears to improve skeletal muscle antioxidant capacity and mitochondrial function in chronic exercise fatigue in rats, providing a theoretical basis for fatigue management in exercise training.