This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

Aiming at the current situation of insufficient integration of medical humanities teaching and clinical practice,as well as the need for further research and improvement in the teaching system,guided by the concept of medicine and humanistic literacy integration advocated by the new medical science,this paper deeply discussed the construction of clinical medical humanities teaching system from four aspects,including the selection of clinical medical humanities teachers and team building;the teaching path that combines theoretical education,narrative medicine,and clinical skill training infused with medical humanities content;curriculum ideological and political construction with the goal of establishing the core concept and value orientation of"patient-centered";the teaching assessment and evaluation method characterized by formative evaluation.The clinical medical humanities teaching system emphasizes the practicality,experiential,and emotional aspects of medical humanities teaching,deeply integrating medical humanities with clinical practice teaching content throughout the clinical internship period of medical education,with a view to enhancing the humanistic practice ability and literacy of medical students.

Collagen is the building component of temporomandibular joint (TMJ) discs and is often affected by inflammation in temporomandibular disorders.The macromechanical properties of collagen are deteriorated by chronic inflammation.However,the mechanism by which inflammation influences disc function remains unknown.The relationship between the ultrastructure and nanomechanical properties of collagen in inflamed discs should be clarified.Seven-week-old female Sprague-Dawley rats were randomly divided into two groups.Chronic TMJ inflammation was induced by intra-articular injection of complete Freund's adjuvant,and samples were harvested after 5 weeks.Picrosirius staining revealed multiple colours under polarized light,which represented alternative collagen bundles in inflamed discs.Using atomic force microscopy scanning,the magnitude of Young's modulus was reduced significantly accompanied with disordered collagen fibril arrangement with porous architecture of inflamed discs.Transmission electron microscopy scanning revealed a non-uniform distribution of collagen fibres,and oversized collagen fibrils were observed in inflamed discs.Fourier transform infrared microspectroscopy revealed a decrease in 1 338 cm-1/amide Ⅱ area ratio of collagen in different regions.The peak positions of amide Ⅰ and amide Ⅱ bands were altered in inflamed discs,indicating collagen unfolding.Our results suggest that sustained inflammation deteriorates collagen structures,resulting in thedeterioration of the ultrastructure and nanomechanical properties of rat TMJ discs.

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disorder with high mortality. Accumulating evidence shows that toll-like receptor 2 (TLR2) plays a critical role in the regulation of wound-repairing process after tissue injury. We wondered if TLR2 signaling contributed to the pathogenesis of AAA and that targeting TLR2 would attenuate AAA development and progression. In this study, enhanced expression of TLR2 and its ligands were observed in human AAA tissue. Neutralization of TLR2 protected against AAA development and caused established AAA to regress in mouse models of AAA. In addition, TLR2-deficient mice also failed to develop AAA. The prophylactic and therapeutic effects of blocking TLR2 were accompanied by a significant resolution of inflammation and vascular remodeling, as indicated by the decreased expression or activity of MMP-2/9, α-SMA, inflammatory cytokines, and transcription factors NF-κB, AP-1 and STAT1/3 in AAA tissue. Mechanistically, blocking TLR2 decreased the expression and interaction of TLR2 and several endogenous ligands, which diminished chronic inflammation and vascular remodeling in the vascular tissue of AAA. Our studies indicate that the interactions between TLR2 and its endogenous ligands contribute to the pathogenesis of AAA and that targeting TLR2 offers great potential toward the development of therapeutic agents against AAA.

Objective:To compare the effect of TiO 2 nanoparticles on antioxidant function and element content of liver and kidney tissues in young and adult rats .Methods:Forty-eight SD male rats , half in 4-week (youth) old and half in 9-week (adult) old rats, were randomly divided into 8 groups, which were exposed to TiO2 nanoparticles [(75 ±15) nm, anatase] through intragastric administration at 0, 10, 50 and 200 mg/kg body weight every day for 30 days.The liver and kidney tissues were collected for antioxidant function and element content analysis .Results: 200 mg/kg TiO2 nanoparticles exposure significantly increased the liver total superoxide dismutase ( T-SOD ) activity and the kidney reduced glutathione (GSH)/oxidized glutathione (GSSG) ratios in young rats, and significantly decreased the liver Mo, Co, Mn and P contents and the kidney Rb and Na contents in young rats .200 mg/kg TiO2 nanoparticles exposure significantly increased GSH/GSSG ratios and Rb contents and decreased Na con-tents in the liver of adult rats .No significantly difference was found in antioxidant indexes and elements content in the kidney of adult rats between three experimental groups and control group .Conclusion:TiO2 nanoparticles can enhance the antioxidant capacity and decrease the elements content in rat liver and kidney tissues .The liver is the more sensitive target organ and the young animals are more susceptible to TiO2 nanoparticles toxicity by the oral routes .

This paper reported that the activation of oncogenes in human fetal esopha geal epithelium treated by alternariol (AOH). It was found that NIH/3T3 cells were transformed via transfeetion of DNA extracted from human fetal esophageal epithelium which was cultured and treated by 10?g/ml AOH in a short term in vitro. The efficiency of primary loci was 0.17 focus per ?g of DNA. In the secondary transfection, the efficiency was 0.58 focus per ?g of DNA (P

Objective: To study the effects of genistein on the proliferation and cell cycle progression of human gastric carcinoma cells. Methods: 3H TdR incorporation test was used to investigate the cell proliferation. Flow cytometry was used to analyze the cell cycle arrest. Immunocytochemistry technique and Western blotting were used to observe the cyclin B and P21 waf1/cip1 protein expression. Results: Genistein inhibited the proliferation of tumor cells significantly, arrested cell cycle progression at G 2/M phase, and enhanced cyclin B and P21 waf1/cip1 protein expression in dose dependent manner. Conclusion:Proliferatory inhibition and G 2/M arrest of human gastric carcinoma cells after treated with genistein may be due to increased stability of cyclin B protein and the expression of P21 waf1/cip1 .