BACKGROUND:Osteoporotic fracture is the most serious complication of osteoporosis.Previous studies have demonstrated that gut microbiota has a regulatory effect on skeletal tissue and that gut microbiota has an important relationship with osteoporotic fracture,but the causal relationship between the two is unclear. OBJECTIVE:To explore the causal relationship between gut microbiota and osteoporotic fractures using Mendelian randomization method. METHODS:The genome-wide association study(GWAS)datasets of gut microbiota and osteoporotic fracture were obtained from the IEU Open GWAS database and the Finnish database R9,respectively.Using gut microbiota as the exposure factor and osteoporotic fracture as the outcome variable,Mendelian randomization analyses with random-effects inverse variance weighted,MR-Egger regression,weighted median,simple model,and weighted model methods were performed to assess whether there is a causal relationship between gut microbiota and osteoporotic fracture.Sensitivity analyses were performed to test the reliability and robustness of the results.Reverse Mendelian randomization analyses were performed to further validate the causal relationship identified in the forward Mendelian randomization analyses. RESULTS AND CONCLUSION:The results of this Mendelian randomization analysis indicated a causal relationship between gut microbiota and osteoporotic fracture.Elevated abundance of Actinomycetales[odds ratio(OR)=1.562,95%confidence interval(CI):1.027-2.375,P=0.037),Actinomycetaceae(OR=1.561,95%CI:1.027-2.374,P=0.037),Actinomyces(OR=1.544,95%CI:1.130-2.110,P=0.006),Butyricicoccus(OR=1.781,95%CI:1.194-2.657,P=0.005),Coprococcus 2(OR=1.550,95%CI:1.068-2.251,P=0.021),Family ⅩⅢ UCG-001(OR=1.473,95%CI:1.001-2.168,P=0.049),Methanobrevibacter(OR=1.274,95%CI:1.001-1.621,P=0.049),and Roseburia(OR=1.429,95%CI:1.015-2.013,P=0.041)would increase the risk of osteoporotic fractures in patients.Elevated abundance of Bacteroidia(OR=0.660,95%CI:0.455-0.959,P=0.029),Bacteroidales(OR=0.660,95%CI:0.455-0.959,P=0.029),Christensenellacea(OR=0.725,95%CI:0.529-0.995,P=0.047),Ruminococcaceae(OR=0.643,95%CI:0.443-0.933,P=0.020),Enterorhabdus(OR=0.558,95%CI:0.395-0.788,P=0.001),Eubacterium rectale group(OR=0.631,95%CI:0.435-0.916,P=0.016),Lachnospiraceae UCG008(OR=0.738,95%CI:0.546-0.998,P=0.048),and Ruminiclostridium 9(OR=0.492,95%CI:0.324-0.746,P=0.001)would reduce the risk of osteoporotic fractures in patients.We identified 16 gut microbiota associated with osteoporotic fracture by the Mendelian randomization method.That is,using gut microbiota as the exposure factor and osteoporotic fracture as the outcome variable,eight gut microbiota showed positive causal associations with osteoporotic fracture and another eight gut microbiota showed negative causal associations with osteoporotic fracture.The results of this study not only identify new biomarkers for the early prediction of osteoporotic fracture and potential therapeutic targets in clinical practice,but also provide an experimental basis and theoretical basis for the study of improving the occurrence and prognosis of osteoporotic fracture through gut microbiota in bone tissue engineering.

ObjectiveTo investigate the association and translational mechanism between the hepatotoxicity of Xianling Gubao （XLGB） and its treatment of osteoporosis based on a zebrafish model. MethodsZebrafish were randomly selected four days after fertilization （4 dpf） and exposed to different concentrations of XLGB （0.7，0.35 mg·L^-1） for 96 h. At the endpoint of the exposure， the mortality rates of zebrafish in the treatment groups of different concentrations were counted， and the "dose-toxicity" curves were plotted. The 10% sublethal concentration （LC₁₀） was calculated. The liver area， acridine orange staining， and pathological tissue sections of transgenic zebrafish ［CZ16 （gz15Tg.Tg （fabp 10a： ds Red； ela31： EGFP）］ were used as indicators to confirm the hepatic damage caused by the sublethal concentration of XLGB. By using the prednisolone （PNSL）-induced osteoporosis model of zebrafish， the anti-osteoporosis activity of XLGB was evaluated by using the area of skull stained by alizarin red and the cumulative optical density value as indicators. Then， the toxicity difference of XLGB on the liver of zebrafish in healthy and osteoporotic states was compared， and the mechanism of the translational action of the toxicity of XLGB was predicted based on network pharmacology and real-time polymerase chain reaction（Real-time PCR）. ResultsThe LC₁₀ of XLGB on zebrafish （8 dpf） was 0.7 mg·L^-1. Compared with the blank group， the sublethal concentration （LC₁₀=0.7 mg·L^-1， 1/2 LC₁₀=0.35 mg·L^-1） of XLGB induced an increase in the number of apoptosis of hepatocytes in a dose-dependent manner， and the tissue arrangement of the liver was disordered and loose. The vacuoles were obvious， and the fluorescence area of the liver was significantly reduced （P<0.01）. Compared with the blank group， the mineralized area and cumulative optical density value of zebrafish skull in the PNSL model group were significantly reduced （P<0.01）， and those in the 0.7，0.35 mg·L^-1 XLGB treatment group were significantly increased compared with the model group （P<0.01）. Most importantly， 0.7 mg·L^-1 XLGB had no significant effect on the liver of zebrafish in the osteoporosis disease model compared with the blank group. The results of network pharmacology and real-time PCR experiments showed that the toxic transformation of XLGB might be related to the differences in the expression levels of key targets， such as tumor protein 53 （TP53）， cysteine aspartic acid specific protease-3（Caspase-3）， interleukin（IL）-6， and alkaline phosphatase（ALP） in different organismal states. ConclusionUnder certain conditions， XLGB has hepatotoxicity in normal zebrafish， but under osteoporotic conditions， XLGB not only exerts significant anti-osteoporosis activity but also alleviates hepatotoxicity significantly， which provides a reference for the safe clinical use of XLGB and real evidence for the theories of traditional Chinese medicine of attacking poison with poison and of treating disease with corresponding drugs without damage to the body.

Depression is a common psychiatric disorder characterized by persistent low mood or mental disorders. Current treatments primarily focus on regulating neurotransmitter levels， but their effectiveness is limited. The mechanisms underlying its onset are complex， and there is no unified consensus. Abnormal signaling pathway transmission plays a crucial role in the development of depression， involving multiple pathways， including Toll-like receptor 4/nucleotide-binding oligomerization domain-like receptor protein 3 （TLR4/NLRP3）， nuclear factor-κB （NF-κB）， Janus kinase/signal transducer and activator of transcription （JAK/STAT）， mitogen-activated protein kinase/extracellular signal-regulated kinase （MAPK/ERK）， brain-derived neurotrophic factor/tyrosine kinase receptor B （BDNF/TrkB）， cyclic AMP/protein kinase A/cAMP response element-binding protein （cAMP/PKA/CREB）， and others. Traditional Chinese medicine（TCM） is based on a holistic approach and the principle of treatment based on the differentiation of syndromes， regulating the balance of multiple systems and organ functions from a macroscopic perspective. This approach has shown unique advantages in the treatment of depression. TCM attributes the onset of depression to dysfunction of the organ systems， involving liver Qi stagnation， heart spirit deficiency， kidney essence depletion， and spleen dysfunction. TCM compound treatments focus on soothing the liver， strengthening the spleen， calming the heart， and replenishing essence， with formulas such as Xiaoyaosan， Zishui Qinggan Yin， and Chahu Jia Guizhi Longgu Muli Tang. The active components of Chinese herbs mainly aim to tonify and regulate Qi， such as salidroside， ginsenoside Rb₁， astragaloside， and muscone. External TCM treatments， primarily acupuncture， aim to open the orifices and invigorate the spirit. Acupoints such as Baihui， Shenting， and Yintang are commonly used. Additionally， massage and moxibustion therapy can intervene in depression by regulating signaling pathways. This article reviews the core role of signaling pathways in the development of depression and the mechanism of TCM regulation of signaling pathways to intervene in depression， aiming to discover new therapeutic approaches that can improve the symptoms of depressed patients.

Oral solid dosage forms require processes such as disintegration and dissolution to release the drug before it can be absorbed and utilized by the body. In this manuscript, imaging technology was used to continuously visualize and characterize the in vitro static drug release process of gliclazide modified release tablets from 15 manufacturers, combined with the traditional method of in vitro dissolution testing, to determine the release profile of gliclazide modified release tablets, to evaluate the similarity of the release profiles by using the similarity factor (f₂) method and based on the analysis of the release profiles fitted with a variety of mathematical models. The results indicate that the gliclazide modified release tablets produced by 14 companies are hydrophilic gel matrix tablets. Compared to the reference listed drug, the release profiles of formulations from 11 companies show high similarity (f₂ > 50) to the reference. Among these, formulations with visual characteristics similar to the reference exhibit similar release curves. This study provides an alternative method for the in vitro consistency evaluation of gliclazide modified release tablets, aiming to assess the in vitro release behaviour of generic formulations more accurately and comprehensively.

[摘 要] 目的：探究聚丝蛋白（FLG）在黑色素瘤组织中的表达及其与患者临床病理特征、预后的关系。方法：选取2019年6月至2020年8月间山东第一医科大学附属人民医院收治的70例黑色素瘤患者为研究对象，取术中切除的瘤组织及瘤旁组织标本，用免疫组织化学法检测FLG蛋白表达，根据FLG的表达将患者分为阳性组和阴性组，比较瘤组织、瘤旁组织及不同病理特征下黑色素瘤组织中FLG的阳性表达率。随访患者3年，根据患者预后情况将患者分为生存组（n = 43）和死亡组（n = 27），比较两组患者的FLG阳性表达率，采用Kaplan-Meier法绘制生存曲线，比较两组患者生存时间。结果：黑色素瘤组织中FLG表达阳性率显著低于瘤旁组织（P < 0.05）；FLG阳性组肿瘤直径 > 1 cm、Breslow厚度 > 2 mm、局部溃疡、TNM分级Ⅲ～Ⅳ级、淋巴结转移、肿瘤侵袭占比显著低于阴性组（P < 0.05或P < 0.01）；70例患者中死亡27例，生存43例，生存率61.42%，死亡组患者FLG表达阳性率显著低于生存组（P < 0.05），FLG表达阳性患者生存时间显著长于阴性患者（P = 0.010）；多因素Cox回归分析显示，Breslow厚度 > 2 mm、TNM分级Ⅲ～Ⅳ级、淋巴结转移、肿瘤侵袭是影响黑色素瘤患者预后的危险因素（P < 0.01或P < 0.001），FLG表达阳性为保护因素（P < 0.01或P < 0.001）。结论：黑色素瘤组织中FLG显著降低，且与肿瘤Breslow厚度、分期侵袭和淋巴结转移等病理特征及预后有关。

ObjectiveTo investigate the intervention effects and mechanisms of the flavonoid hyperoside （Hyp） on lipopolysaccharide （LPS）-induced inflammation in the zebrafish model. MethodsZebrafish larvae were either microinjected with 0.5 g·L^-1 LPS or immersed in 1 g·L^-1 LPS for the modeling of inflammation. The larvae were then treated with Hyp at 25， 50， and 100 mg·L^-1 through immersion for four consecutive days. The inflammatory phenotypes were assessed by analyzing the mortality rate， malformation rate， body length， and yolk sac area ratio. Behavioral tests were conducted to evaluate the inflammatory stress responses， and macrophage migration was observed by fluorescence microscopy. Additionally， the mRNA levels of inflammation-related genes， including interleukin-1β （IL-1β）， interleukin-6 （IL-6）， chemokine C-C motif ligand 2 （CCL2）， chemokine C-X3-C motif receptor 1 （CX3CR1）， chemokine C-C motif receptor 2 （CCR2）， and genes associated with the Toll-like receptor 4 （TLR4）/myeloid differentiation factor 88 （MyD88）/nuclear factor-kappa B （NF-κB） signaling pathway， were measured by Real-time quantitative polymerase chain reaction（Real-time PCR）. ResultsCompared with the pure water injection group， the model group exhibited increased mortality， malformation rates and yolk sac area ratio （P0.01）， reduced body length （P0.01）， increased total swimming distance and high-speed swimming duration （P0.01）， and up-regulated mRNA levels of TLR4， MyD88， NF-κB， IL-1β， IL-6， CCL2， CX3CR1， and CCR2 （P0.01）. Hyp at low， medium and high doses， as well as aspirin， reduced the mortality and malformation rates （P0.05，P0.01）， increased the body length （P0.05，P0.01）， decreased the yolk sac area ratio （P0.01）， reduced the high-speed swimming duration （P0.01）， and down-regulated the mRNA levels of TLR4， MyD88， NF-κB， IL-1β， IL-6， CCL2， CX3CR1， and CCR2 （P0.05，P0.01） compared with the model group. ConclusionHyp may modulate the TLR4/MyD88/NF-κB pathway to ameliorate inflammatory phenotypes and alleviate stress conditions in zebrafish， thereby exerting the anti-inflammatory effect.

BACKGROUND: The American Heart Association (AHA) introduced the concept of cardiovascular-kidney-metabolic (CKM) health and stage, reflecting the interaction among metabolism, chronic kidney disease (CKD), and the cardiovascular system. However, the association between CKM stage and the long-term risk of cardiovascular disease (CVD) has not been validated. This study aimed to evaluate the long-term CVD risk associated with CKM health metrics and CKM stage using data from a population-based cohort study. METHODS: In total, 5293 CVD-free participants were followed up to around 13 years in the Chinese Multi-provincial Cohort Study (CMCS). Considering the pathophysiologic progression of CKM health metrics abnormalities (comprising obesity, central adiposity, prediabetes, diabetes, hypertriglyceridemia, CKD, and metabolic syndrome), participants were divided into CKM stages 0, 1, and 2. The time-dependent Cox regression models were used to estimate the cardiovascular risk associated with CKM health metrics and stage. Additionally, broader CVD outcomes were examined, with a specific assessment of the impact of stage 3 in 2581 participants from the CMCS-Beijing subcohort. RESULTS: Among participants, 91.2% (4825/5293) had at least one abnormal CKM health metric, 8.8% (468/5293), 13.3% (704/5293), and 77.9% (4121/5293) were in CKM stages 0, 1, and 2, respectively; and 710 incident CVD cases occurred during a median follow-up time of 13.3 years (interquartile range: 12.1 to 13.6 years). Participants with each poor CKM health metric exhibited significantly higher CVD risk. Compared with stage 0, the hazard ratio (HR) (95% confidence interval [CI]) for CVD incidence was 1.31 (0.84-2.04) in stage 1 and 2.27 (1.57-3.28) in stage 2. Significant interactive impacts existed between CKM stage and age or sex, with higher CVD risk related to increased CKM stages in participants aged <60 years or females. CONCLUSION These findings highlight the contribution of CKM health metrics and CKM stage to the long-term risk of CVD, suggesting the importance of multi-component recognition and management of poor CKM health in CVD prevention.
Humans ; Female ; Male ; Cardiovascular Diseases/etiology* ; Middle Aged ; Adult ; Cohort Studies ; Renal Insufficiency, Chronic/metabolism* ; Aged ; Risk Factors ; Metabolic Syndrome/metabolism* ; China ; East Asian People

Asthma is a chronic inflammatory disease involving multiple inflammatory cells and cytokines. Its pathogenesis is complex, involving various cells and cytokines. Traditional Chinese medicine(TCM) theory suggests that the pathogenesis of asthma is closely related to the dysfunction of internal organs such as the lungs, spleen, and kidneys. In contrast, modern immunological studies have revealed the central role of T helper 1(Th1)/T helper 2(Th2) and T helper 17(Th17)/regulatory T(Treg) cellular immune imbalance in the pathogenesis of asthma. Th1/Th2 imbalance is manifested as hyperfunction of Th2 cells, which promotes the synthesis of immunoglobulin E(IgE) and the activation of eosinophil granulocytes, leading to airway hyperresponsiveness and inflammation.Meanwhile, Th17/Treg imbalance exacerbates the inflammatory response in the airways, further contributing to asthma pathology.Currently, therapeutic strategies for asthma are actively exploring potential targets for regulating the balance of Th1/Th2 and Th17/Treg immune responses. These targets include cytokines, transcription factors, key proteins, and non-coding RNAs. Precisely regulating the expression and function of these targets can effectively modulate the activation and differentiation of immune cells. In recent years,traditional Chinese medicine active ingredients have shown unique potential and prospects in the field of asthma treatment. Based on this, the present study systematically summarizes the efficacy and specific mechanisms of TCM active ingredients in treating asthma by regulating Th1/Th2 and Th17/Treg immune balance through literature review and analysis. These active ingredients, including flavonoids, terpenoids, polysaccharides, alkaloids, and phenolic acids, exert their effects through various mechanisms, such as inhibiting the activation of inflammatory cells, reducing the release of cytokines, and promoting the normal differentiation of immune cells. This study aims to provide a solid foundation for the widespread application and in-depth development of TCM in asthma treatment and to offer new ideas for clinical research and drug development of asthma.
Asthma/genetics* ; Humans ; Drugs, Chinese Herbal/chemistry* ; Th2 Cells/drug effects* ; Th17 Cells/drug effects* ; T-Lymphocytes, Regulatory/drug effects* ; Th1 Cells/drug effects* ; Animals ; Cytokines/immunology* ; Medicine, Chinese Traditional