Retinal microcirculatory disorder is a key factor in the occurrence and development of diabetic retinopathy （DR）， and also an important link in the prevention and treatment of DR. The theory of "Gaozhuo" holds that the microcirculatory disorder in DR is based on the deficiency of spleen Qi and is characterized by the obstruction caused by "Gaozhuo" and blood stasis. The deficiency of spleen Qi is an essential precondition for the endogenous formation and accumulation of Gaozhuo， while Gaozhuo invasion is the direct cause of microcirculatory disorders in DR. The deficiency of spleen Qi and the endogenous formation of Gaozhuo mean the process in which glucose metabolism dysfunction induces an excessive production of inflammatory factors and lipid metabolites. The obstruction caused by "Gaozhuo" and blood stasis is the direct pathogenesis of microcirculatory disorders in DR， encompassing two stages： Gaozhuo obstruction and turbidity and stasis stagnation. Gaozhuo obstruction and turbidity and stasis stagnation represent the process in which inflammatory factors and lipid metabolites damage the retinal microcirculation and induce thrombosis， thus mediating microcirculatory disorders. Turbidity and stasis stagnation and blood extravasation outside the vessels reveal the progression to microvascular rupture and hemorrhage resulting from the microcirculatory disorders. According to the pathogenesis evolution of the theory of "Gaozhuo"， microcirculatory disorders in DR can be divided into deficiency of spleen Qi with Gaozhuo obstruction， deficiency of spleen Qi with turbidity and stasis stagnation， and turbidity and stasis stagnation with blood extravasation outside the vessels. Clinically， treatment principles should focus on strengthening the spleen and benefiting Qi， resolving turbidity， and dispersing stasis. Different syndrome patterns should be addressed with tailored therapies， such as enhancing the spleen and benefiting Qi while regulating Qi and reducing turbidity， strengthening the spleen and benefiting Qi while resolving turbidity and dispelling stasis， and strengthening the spleen and resolving turbidity while removing stasis and stopping bleeding. Representative prescriptions include modified Wendantang， modified Buyang Huanwutang， modified Danggui Buxuetang， Zhuixue Mingmu decoction， Tangmuqing， Shengqing Jiangzhuo Tongluo Mingmu prescription， Danhong Huayu decoction， and Yiqi Yangyin Huoxue Lishui formula.

ObjectiveTo investigate the efficacy of Xingpi capsules （XPC） in treating diarrhea-predominant irritable bowel syndrome （IBS-D） with spleen deficiency and elucidate its potential molecular mechanisms. MethodsA rat model of IBS-D with spleen deficiency was established by administering senna leaf in combination with restrained stress and swimming fatigue for 14 d. Ten specific pathogen free （SPF）-grade healthy rats were used as the normal control group. After successful modeling， SPF-grade rats were randomly divided into a model group， a pinaverium bromide group （1.5 mg·kg^-1）， and low- and high-dose XPC groups （0.135 and 0.54 g·kg^-1）， with 10 rats in each group. Rats in the normal control group and the model group were given distilled water by gavage， while the remaining groups were administered corresponding drug solutions by gavage once a day for 14 consecutive days. The rat body weights and fecal condition were observed every day， and the Bristol score was recorded. Enzyme-linked immunosorbent assay （ELISA） was used to determine the levels of 5-hydroxytryptamine （5-HT） in serum and colon tissue. Transmission electron microscopy was used to observe the microvilli and tight junctions in the colon. The integrity of the colonic barrier， intestinal motility， and expression of related pathway proteins were evaluated by hematoxylin-eosin （HE） staining， immunohistochemistry， and Western blot. ResultsCompared with those in the normal control group， rats in the model group showed a significantly decreased body weight and increased diarrhea rate， diarrhea grade， and Bristol score （P<0.01）. HE staining revealed incomplete colonic mucosa in the model group， with evident congestion and edema observed. Electron microscopy results indicated decreased density and integrity of the colonic barrier， shedding and disappearance of microvilli， and significant widening of tight junctions. The expression levels of colonic tight junction proteins Occludin and Claudin-5 were downregulated （P<0.01）， and the levels of 5-HT in serum and colon tissue were elevated （P<0.01）. The small intestine propulsion rate significantly increased （P<0.01）， and the expression of contractile proteins Ras homolog family member A （RhoA） and Rho-associated coiled-coil containing protein kinase 2 （ROCK2） in colon and phosphorylation of myosin light chain （MLC₂₀） were upregulated （P<0.01）. Compared with the model group， the treatment groups showed alleviated diarrhea， diarrhea-associated symptoms， and pathological manifestations of colon tissue to varying degrees. Specifically， high-dose XPC exhibited effectively relieved diarrhea， promoted recovery of colonic mucosal structure， significantly reduced congestion and edema， upregulated expression of Occludin and Claudin-5 （P<0.01）， decreased levels of 5-HT in serum and colon tissue （P<0.05，P<0.01）， significantly slowed small intestine propulsion rate （P<0.01）， and significantly downregulated expression of contractile proteins RhoA and ROCK2 in colon and phosphorylation of MLC₂₀ （P<0.05，P<0.01）. ConclusionXPC effectively alleviates symptoms of spleen deficiency and diarrhea and regulates the secretion of brain-gut peptide. The characteristics of XPC are mainly manifested in alleviating IBS-D with spleen deficiency from the aspects of protecting intestinal mucosa and inhibiting smooth muscle contraction， and the mechanism is closely related to the regulation of the 5-HT-RhoA/ROCK2 pathway expression.

ObjectiveTo investigate the ameliorative effect of Xingpi capsules on functional dyspepsia（FD） and the potential mechanism. MethodsSixty SPF-grade male SD neonatal rats（7 days old） were randomly divided into the normal group（n=12） and the modeling group（n=48）， and the FD model was prepared by iodoacetamide gavage in the modeling group. After the model was successfully prepared， the rats in the modeling group were randomly divided into the model group， the low-dose and high-dose groups of Xingpi capsules（0.135， 0.54 g·kg^-1） and the domperidone group（3 mg·kg^-1）， with 12 rats in each group. Rats in the normal and model groups were gavaged with distilled water， and rats in the rest of the groups were gavaged with the corresponding medicinal solution， once a day for 7 d. The general survival condition of the rats was observed， and the water intake and food intake of the rats were measured， the gastric emptying rate and the small intestinal propulsion rate were measured at the end of the treatment， the pathological damage of the rat duodenum was examined by hematoxylin-eosin（HE） staining， and the expressions of colonic tight junction protein（Occludin） and zonula occludens protein-1（ZO-1） were detected by immunofluorescence. The differentially expressed genes in the duodenal tissues of the model group and the normal group， and the high-dose group of Xingpi capsules and the model group were detected by transcriptome sequencing after the final administration， and Gene Ontology（GO） and Kyoto Encyclopedia of Genes and Genomes（KEGG） enrichment analyses were carried out. The transcriptomic results were validated by Western blot， immunofluorescence， and real-time fluorescence quantitative polymerase chain reaction（Real-time PCR）， and the active ingredients of Xingpi capsules were screened for molecular docking with the key targets. ResultsCompared with the normal group， the general survival condition of rats in the model group was poorer， and the water intake， food intake， gastric emptying rate and small intestinal propulsion rate were all significantly reduced（P<0.05）， inflammatory infiltration was seen in duodenal pathology， and the fluorescence intensities of Occludin and ZO-1 in the colon were significantly reduced（P<0.01）. Compared with the model group， the general survival condition of rats in the high-dose group of Xingpi capsules improved significantly， and the water intake， food intake， gastric emptying rate and small intestinal propulsion rate were all significantly increased（P<0.05）， the duodenal pathology showed a decrease in inflammatory infiltration， and the fluorescence intensities of colonic Occludin and ZO-1 were significantly increased（P<0.01）. Transcriptomic results showed that Xingpi capsules might exert therapeutic effects by regulating the phosphatidylinositol 3-kinase（PI3K）/protein kinase B（Akt） through the key genes such as Slc5a1， Abhd6. The validation results showed that compared with the normal group， the phosphorylation levels of PI3K and Akt proteins， the protein expression level of interleukin（IL）-1β， and the fluorescence intensities of IL-6 and IL-1β were significantly increased in the model group（P<0.05， P<0.01）， and the mRNA levels of Slc5a1， Abhd6， Mgam， Atp1a1， Slc7a8， Cdr2， Chrm3， Slc5a9 and other key genes were significantly increased（P<0.01）. Compared with the model group， the phosphorylation levels of PI3K and Akt， the protein expression level of IL-1β and the fluorescence intensities of IL-6 and IL-1β in the high-dose group of Xingpi capsules were significantly reduced（P<0.05， P<0.01）， and the mRNA levels of Slc5a1， Abhd6， Mgam， Atp1a1， Slc7a8， Cdr2， Chrm3 and Slc5a9 were significantly reduced（P<0.05）. Weighted gene co-expression network analysis and molecular docking results showed that E-nerolidol and Z-nerolidol in Xingpi capsules were well bound to ABDH6 protein， and linarionoside A， valerosidatum and senkirkine were well bound to Slc5a1 protein. ConclusionXingpi capsules can effectively improve the general survival and gastrointestinal motility of FD rats， its specific mechanism may be related to the inhibition of PI3K/Akt signaling pathway to alleviate the low-grade inflammation of duodenum， and E-nerolidol， Z-nerolidol， linarionoside A， valerosidatum and senkirkine may be its key active ingredients.

ObjectiveTo investigate the ameliorative effect of Xingpi capsules on functional dyspepsia（FD） and the potential mechanism. MethodsSixty SPF-grade male SD neonatal rats（7 days old） were randomly divided into the normal group（n=12） and the modeling group（n=48）， and the FD model was prepared by iodoacetamide gavage in the modeling group. After the model was successfully prepared， the rats in the modeling group were randomly divided into the model group， the low-dose and high-dose groups of Xingpi capsules（0.135， 0.54 g·kg^-1） and the domperidone group（3 mg·kg^-1）， with 12 rats in each group. Rats in the normal and model groups were gavaged with distilled water， and rats in the rest of the groups were gavaged with the corresponding medicinal solution， once a day for 7 d. The general survival condition of the rats was observed， and the water intake and food intake of the rats were measured， the gastric emptying rate and the small intestinal propulsion rate were measured at the end of the treatment， the pathological damage of the rat duodenum was examined by hematoxylin-eosin（HE） staining， and the expressions of colonic tight junction protein（Occludin） and zonula occludens protein-1（ZO-1） were detected by immunofluorescence. The differentially expressed genes in the duodenal tissues of the model group and the normal group， and the high-dose group of Xingpi capsules and the model group were detected by transcriptome sequencing after the final administration， and Gene Ontology（GO） and Kyoto Encyclopedia of Genes and Genomes（KEGG） enrichment analyses were carried out. The transcriptomic results were validated by Western blot， immunofluorescence， and real-time fluorescence quantitative polymerase chain reaction（Real-time PCR）， and the active ingredients of Xingpi capsules were screened for molecular docking with the key targets. ResultsCompared with the normal group， the general survival condition of rats in the model group was poorer， and the water intake， food intake， gastric emptying rate and small intestinal propulsion rate were all significantly reduced（P<0.05）， inflammatory infiltration was seen in duodenal pathology， and the fluorescence intensities of Occludin and ZO-1 in the colon were significantly reduced（P<0.01）. Compared with the model group， the general survival condition of rats in the high-dose group of Xingpi capsules improved significantly， and the water intake， food intake， gastric emptying rate and small intestinal propulsion rate were all significantly increased（P<0.05）， the duodenal pathology showed a decrease in inflammatory infiltration， and the fluorescence intensities of colonic Occludin and ZO-1 were significantly increased（P<0.01）. Transcriptomic results showed that Xingpi capsules might exert therapeutic effects by regulating the phosphatidylinositol 3-kinase（PI3K）/protein kinase B（Akt） through the key genes such as Slc5a1， Abhd6. The validation results showed that compared with the normal group， the phosphorylation levels of PI3K and Akt proteins， the protein expression level of interleukin（IL）-1β， and the fluorescence intensities of IL-6 and IL-1β were significantly increased in the model group（P<0.05， P<0.01）， and the mRNA levels of Slc5a1， Abhd6， Mgam， Atp1a1， Slc7a8， Cdr2， Chrm3， Slc5a9 and other key genes were significantly increased（P<0.01）. Compared with the model group， the phosphorylation levels of PI3K and Akt， the protein expression level of IL-1β and the fluorescence intensities of IL-6 and IL-1β in the high-dose group of Xingpi capsules were significantly reduced（P<0.05， P<0.01）， and the mRNA levels of Slc5a1， Abhd6， Mgam， Atp1a1， Slc7a8， Cdr2， Chrm3 and Slc5a9 were significantly reduced（P<0.05）. Weighted gene co-expression network analysis and molecular docking results showed that E-nerolidol and Z-nerolidol in Xingpi capsules were well bound to ABDH6 protein， and linarionoside A， valerosidatum and senkirkine were well bound to Slc5a1 protein. ConclusionXingpi capsules can effectively improve the general survival and gastrointestinal motility of FD rats， its specific mechanism may be related to the inhibition of PI3K/Akt signaling pathway to alleviate the low-grade inflammation of duodenum， and E-nerolidol， Z-nerolidol， linarionoside A， valerosidatum and senkirkine may be its key active ingredients.

BACKGROUND: Post-stroke disability diminishes the physical activity (PA) level of survivors, potentially affecting their long-term prognosis. This study endeavors to explore the correlation between daily PA level and the all-cause mortality in patients with a history of stoke in the United States. METHODS: Data of stroke survivors were sourced from the National Health and Nutritional Examination Survey (NHANES) 2007-2018. The population was stratified into three groups based on their PA level. Kaplan-Meier method with log-rank tests for significance was used for survival analysis. Weighted Cox proportional hazards regression models were employed to estimate the hazard ratios (HRs) for all-cause mortality. Subgroup analysis was conducted to strengthen the results. RESULTS: A total of 1395 participants were recruited, comprising 679 males and 716 females, with a median age of 68 years. Based on their PA levels, 779 individuals were classified as inactive, 156 as insufficiently active, and 460 as sufficiently active. Following a median observation period of 59 months, there were 476 recorded deaths, with 349, 47, and 80 cases in the three respective groups. Compared to the inactive group, the HRs and 95% confidence intervals (CIs) for all-cause mortality in participants who were insufficiently active and sufficiently active were 0.58 (0.40, 0.84) and 0.47 (0.33, 0.67), respectively. The Kaplan-Meier curve revealed a significant difference in overall survival between the three groups, as confirmed by the log-rank test (P < 0.0001). Subgroup analysis further validated our results and demonstrated that the protective impact of PA on stroke prognosis varies according to distinct characteristics. CONCLUSIONS The results indicate that increased levels of PA are associated with a protective effect on long-term mortality among stroke survivors. Further prospective longitudinal studies are necessary to elucidate the optional PA level and special exercise guideline targeting this population.
Humans ; Male ; Female ; Aged ; Exercise ; Middle Aged ; Nutrition Surveys ; Stroke/mortality* ; United States/epidemiology* ; Survivors/statistics & numerical data* ; Aged, 80 and over ; Mortality

Myocardial fibrosis (MF) is a common pathological hallmark of cardiovascular diseases, reflecting shared mechanisms in their progression. However, the lack of reliable MF models that accurately mimic its pathogenesis has hindered drug discovery, highlighting the urgent need for more effective therapeutic agents. Herein, a novel contractile three-dimensional (3D) myocardial tissue model integrating cardiomyocytes, cardiac-fibroblasts, and bone marrow-derived macrophages in collagen hydrogel was developed to simulate the fibrotic changes of cardiovascular disease, and facilitate the screening of anti-MF compounds. The 3D myocardial tissue model exhibited precise, visualizable, and quantifiable contractile characteristics under hypoxia and drug interventions. 76 compounds extracted from the resins of Toxicodendron vernicifluum, a traditional Chinese medicine with clear clinical benefits for fibrotic diseases, were screened for anti-fibrotic activity. Using an in vitro 3D oxygen-glucose deprivation (OGD)-treated myocardial tissue model instead of a two-dimensional transforming growth factor-β treated cardiac-fibroblasts model, two candidates including LQ-40 and SQ-3 exert impressive anti-MF activity, which was further validated in left anterior descending coronary artery ligation-induced MF mouse model. The current results demonstrate the feasibility and advantage of the novel contractile 3D tissue model with multi-cell types in discovering candidates for MF, further stressing the great potential of regulating macrophages in the treatment of MF.

[摘 要] 目的：探讨异莲心碱（Iso）通过PI3K/Akt/mTOR信号通路对结肠癌SW480细胞增殖、凋亡和自噬的影响。方法：用10、20和40 μmol/L的Iso处理结肠癌SW480细胞，CCK-8法、流式细胞术和WB法分别检测Iso对细胞增殖活力、凋亡和自噬相关蛋白LC3Ⅰ、LC3Ⅱ、p62表达的影响。然后，用20 μmol/L的Iso和25 μmol/L的PI3K激活剂740 Y-P分别处理SW480细胞，将细胞分为对照组、740 Y-P组、Iso组和Iso+740 Y-P组，流式细胞术、WB法检测Iso和740 Y-P对各组细胞凋亡及细胞中LC3Ⅰ、LC3Ⅱ、p62、PI3K、p-PI3K、 mTOR和p-mTOR蛋白表达的影响。结果：10、20和40 μmol/L的Iso处理后，SW480细胞增殖活力均显著下降（均P<0.05），细胞凋亡率均显著升高（均P<0.05），LC3Ⅱ/LC3Ⅰ表达均显著上调（均P<0.05），p26蛋白表达显著下调（P<0.05）。Iso和740 Y-P处理后，与对照组相比，740 Y-P组细胞凋亡率、LC3Ⅱ/LC3Ⅰ表达均显著下降（均P<0.05），p26、p-PI3K/PI3K和p-mTOR/mTOR表达均显著升高（均P<0.05）；Iso组细胞凋亡率、LC3Ⅱ/LC3Ⅰ表达升高（均P<0.05），p26、p-PI3K/PI3K和p-mTOR/mTOR表达均显著下降（均P<0.05）；与740 Y-P组相比，Iso+740 Y-P组细胞凋亡率、LC3Ⅱ/LC3Ⅰ表达升高（P<0.05），p26、p-PI3K/PI3K和p-mTOR/mTOR表达均显著下降（均P<0.05）；与Iso组相比，Iso+740 Y-P组细胞凋亡率、LC3Ⅱ/LC3Ⅰ表达下降（均P<0.05），p26、p-PI3K/PI3K和p-mTOR/mTOR表达均显著升高（均P<0.05）。结论：Iso通过抑制PI3K/Akt/mTOR信号通路抑制结肠癌SW480细胞增殖并诱导细胞凋亡和自噬。

Objective To compare the clinical efficacy between a direct aspiration first-pass technique(ADAPT)and stent-retriever thrombectomy(SRT)in the treatment for acute ischemic stroke(AIS)caused by intracranial atherosclerotic stenosis related large vessel occlusion(ICAS-LVO).Methods We retrospectively included patients with AIS caused by ICAS-LVO who received endovascular treatment in The First Affiliated Hospital of Xi'an Jiaotong University or The Second Affiliated Hospital of Shaanxi University of Chinese Medicine between January 2020 and January 2023.They were divided into ADAPT group and SRT group according to the first-selected device for thrombectomy.We compared the baseline data,test and examination results,operation process,clinical prognosis and follow-up data of the two groups.Results A total of 117 patients were recruited,including 48 patients in the ADAPT group and 69 patients in the SRT group.There was no significant difference in the baseline data between the two groups.The success rate of both the first-time thrombectomy(P=0.014)and the first-selected device of thrombectomy(P＜0.001)was significantly higher in the SRT group than in the ADAPT group.Meanwhile,the incidence of iatrogenic dissection(P＜0.001)and vasospasm(P=0.003)was significantly lower in the SRT group than in the ADAPT group.The proportion of patients for whom the device of thrombectomy was changed for remedial treatment in the ADAPT group was significantly higher than that in the SRT group(P＜0.001).However,the two groups did not differ significantly in the rate of successful vascular recanalization,incidence of symptomatic/asymptomatic intracranial hemorrhage or the rate of 90-day favorable prognosis.Conclusion For patients with AIS caused by ICAS-LVO of MCA,SRT has a higher rate of immediate successful vascular recanalization with a lower rate of secondary vascular injury compared with ADAPT,but the two techniques have similar efficacy on the 90-day prognosis.

The transgender children and adolescents(TCAs)face serious social dilemmas in the process of gender identity and expression,which hinders this group from seeking reasonable and equal rights to survival and development.From the perspective of equal rights and the theoretical framework of social dilemma,by interviewing TCAs who seek help from medical social workers in a hospital's multi-disciplinary transgender clinic,this paper revealed that under the traditional system of"binary gender",TCAs lacked social inclusiveness and infrastructure,which led to the two major social dilemmas of"social traps"and"social barriers"encountered by this group in the process of gender expression and gender identity.Specifically,the social gender selection of TCAs often leads to collective irrational reactions and gender punishment,preventing their legal and effective medical services.To this end,the research team used critical methodology to construct a joint disciplinary diagnosis and treatment path for TCAs with the participation of medical social workers,as well as verified that the path has significant intervention effects in rationalizing the needs of TCAs and their families,alleviating their psychological pressure and social adaptation problems in the process of gender identity,fostering a diverse dialogue environment in their families,as well as enhancing their self-efficacy and social participation,to provide assistahce to the TCAs groups in social difficulties,assisting their rights and interests be included in the child-friendly indicator system,and improving the whole society's tolerance and understanding for TCAs group.

Objective: To evaluate the anti-fatigue effects of different extracts from Cistanche tubulosa (Schenk) Wight (C. tubulosa, Rou Cong Rong), focusing on central and exercise-induced fatigue in mice. This study investigated the pharmacological effects of the total oligosaccharides, polysaccharides, and phenylethanoid glycosides (CPhGs) extracted from C. tubulosa. Methods: Models of sleep deprivation and forced swimming fatigue were established to simulate central and exercise-induced fatigue. The mice were treated with different extracts of C. tubulosa, and their effects were assessed using behavioral tests to measure exercise capacity, learning, and memory function. Biochemical analyses were performed to evaluate the changes in serum and brain neurotransmitter levels, liver and muscle glycogen storage, and various fatigue-related biomarkers. Results: This study found that treatment with C. tubulosa extract improved exercise capacity, learning, and memory in mice. Total oligosaccharides from C. tubulosa enhanced adrenocorticotropic hormone, cholinesterase, and thyroid-stimulating hormone levels, reduced cortisol levels in central fatigue models, and ameliorated biochemical markers of exercise-induced fatigue, including lowering lactic acid, blood urea nitrogen, and malondialdehyde levels. Among the tested extracts, the total oligosaccharides showed the most comprehensive anti-fatigue effects. Conclusion The anti-fatigue effects of C. tubulosa, particularly those of its total oligosaccharides, are pronounced in both central and exercise-induced fatigue. These effects are mediated by the regulation of neurotransmitter levels, enhancement of glycogen storage, and improvement of antioxidant enzyme activity, suggesting potential therapeutic benefits in fatigue-related conditions.