Mechanisms of Bushen Tiaoxue Granules against controlled ovarian hyperstimulation-induced abnormal morphology of endometrium based on network pharmacology.

Bushen Tiaoxue Granules (BTG) is an empirical Chinese herbal formula that has been used for the treatment of subfertility. The protective effect of BTG on controlled ovarian hyperstimulation (COH)-induced impaired endometrial receptivity has been reported in our previous study. This study aims to explore the mechanisms of BTG on ameliorating abnormal morphology of endometrium based on network pharmacology. Active compounds of BTG were identified via the traditional Chinese medicine systems pharmacology and UPLC-MS technology. The SwissTargetPrediction platform and HERB database were used to screen out the putative targets of BTG. Potential targets of endometrial dysfunction caused by COH were obtained from three GEO databases. Through the STRING database, the protein-protein interaction was carried out according to the cross-common targets of diseases and drugs. GO terms and KEGG pathways enrichment analyses were conducted via the Metascape database. AutoDock Vina was used for docking validation of the affinity between active compounds and potential targets. Finally, in vivo experiments were used to verify the potential mechanisms derived from network pharmacology study. A total of 141 effective ingredients were obtained from TCMSP and nine of which were verified in UPLC-MS. Six genes were selected through the intersection of 534 disease related genes and 165 drug potential targets. Enrichment analyses showed that BTG might reverse endometrial dysfunction by regulating adherens junction and arachidonic acid metabolism. Hematoxylin-eosin staining revealed that BTG ameliorated the loose and edematous status of endometrial epithelium caused by COH. The protein expression of FOXO1A, ß-Catenin and COX-2 was decreased in the COH group, and was up-regulated by BTG. BTG significantly alleviates the edema of endometrial epithelium caused by COH. The mechanisms may be related to adheren junctions and activation of arachidonic acid metabolism. The potential active compounds quercetin, taxifolin, kaempferol, eriodictyol, and isorhamnetin identified from the BTG exhibit marginal cytotoxicity. Both high and low concentrations of kaempferol, eriodictyol, and taxifolin are capable of effectively ameliorating impaired hESC cellular activity.

Application of mesenchymal stem cell therapy for premature ovarian insufficiency: Recent advances from mechanisms to therapeutics.

The incidence of premature ovarian insufficiency (POI) is increasing worldwide, particularly among younger women, posing a significant challenge to fertility. In addition to menopausal symptoms, POI leads to several complications that profoundly affect female reproductive function and overall health. Unfortunately, current clinical treatment strategies for this condition are limited and often yield unsatisfactory outcomes. These approaches typically involve hormone replacement therapy combined with psychological support. Recently, mesenchymal stem cell (MSC) therapies for POI have garnered considerable attention in global research. MSCs can restore ovarian reproductive and endocrine functions through diverse mechanisms, including controlling differentiation, promoting angiogenesis, regulating ovarian fibrosis, inhibiting apoptosis, enhancing autocrine and paracrine effects, suppressing inflammation, modulating the immune system, and genetic regulation. This editorial offers a succinct summary of the application of MSC therapy in the context of POI, providing evidence for groundbreaking medical approaches that have potential to enhance reproductive health and overall well-being for women.

Burden and attributable risk factors of ischemic stroke in China from 1990 to 2019: an analysis from the Global Burden of Disease Study 2019.

Background: The epidemiologic characteristics and attributable risk factors of ischemic stroke in China have changed over the past three decades. An up-to-date analysis on deaths, disability-adjusted life-years (DALYs), prevalence, incidence, and attributable risk factors of ischemic stroke for China is needed. This study aims to provide a comprehensive analysis of burden and attributable risk factors of ischemic stroke at national level in China by sex from 1990 to 2019. Methods: This is a secondary analysis of the Global Burden of Disease (GBD) study 2019. All data used in this study was derived from the 2019 GBD study. Deaths, DALYs, prevalence, incidence, and attributable risk factors of ischemic stroke in China by sex from 1990 to 2019 were analyzed. Results: From 1990 to 2019, the age-standardized deaths rate decreased by 3.3%, age-standardized DALYs rate decreased by 4%, age-standardized prevalence rate increased by 33.5%, and age-standardized incidence rate of ischemic stroke in China increased by 34.7%. In 2019, ambient particulate matter pollution became an important risk factor, whereas household air pollution from solid fuels was no longer a major risk factor for ischemic stroke in China. Burden of ischemic stroke was higher in China compared to other regions. Ambient particulate matter pollution among men, and diet high in sodium, smoking, household air pollution from solid fuels among women account for the increased deaths/DALYs due to ischemic stroke in China. Conclusion: Our study revealed that great changes have occurred in burden and attributable risk factors of ischemic stroke in China in the past three decades. Distinct sex-specific differences are observed in burden and attributable risk factors.

A modified mouse model of haemorrhagic transformation associated with tPA administration after thromboembolic stroke.

Objective: To establish a new mouse model of haemorrhagic transformation associated with delayed tissue-type plasminogen activator (tPA) treatment to provide a novel tool to study therapeutic strategies for haemorrhagic transformation. Methods: Male C57BL/6 mice were subjected to carotid artery thrombosis stimulated with ferric chloride. The thrombus was then mechanically detached to induce migration toward the intracranial circulation. To induce haemorrhagic transformation, mice were intravenously injected with 10 mg/kg tPA 4.5 h after the onset of ischaemia and were sacrificed 24 h after tPA treatment. Results: In this new model, administration of tPA 4.5 h after stroke exacerbated the risk of intracerebral haemorrhage. Thrombolysis with tPA also exacerbated cerebral infarction, brain oedema, blood-brain barrier breakdown, and neurological deficits. However, cerebral blood flow was not significantly affected. Conclusion: The present model is reproducible, easy to perform, and mimics the clinical situation of haemorrhagic transformation after tPA treatment in humans. This modified model can be used as a new tool to test experimental drugs for haemorrhagic transformation associated with delayed tPA administration after an ischaemic stroke.

Investigation of the mechanisms and experimental verification of Cuscuta-Salvia in the treatment of polycystic ovary syndrome (PCOS) via network pharmacology.

Polycystic ovary syndrome (PCOS) is an endocrine disease associated with reproduction. The Cuscuta-Salvia formula has been widely used to treat for PCOS in clinic. However, its chemical and pharmacological properties remain unclear. We identified the active components and related targets of Cuscuta-Salvia using UHPLC-ESI-Q-TOF-MS and TCMSP database. Disease targets were obtained from the DisGeNET and GeneCards databases. Subsequently, common targets between Cuscuta-Salvia and PCOS were identified using a Venn diagram. PPI network was established. Core genes were selected using a Cytoscape software plugin. GO and KEGG enrichment analyses were performed for common targets using the "pathview" package in R. Several core targets were verified using molecular and Immunological methods. By combining UHPLC-ESI-Q-TOF-MS with a network pharmacology study, 14 active components and a total of 80 common targets were obtained. Ten core genes were regulated by Cuscuta-Salvia in PCOS, including IL6, AKT1, VEGFA, TP53, TNF, MAPK1, JUN, EGF, CASP3, and EGFR. GO results showed that cellular response to drugs, response to oxygen levels, response lipopolysaccharides, and response to molecule of bacterial origin in BP category; membrane, transcription regulator complex, nuclear chromatin, postsynaptic membrane, and vesicle lumen in CC category; DNA-binding transcription factor binding, RNA polymerase II-specific DNA-binding transcription factor binding, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription activator activity, and cytokine receptor binding in MF terms. The KEGG enrichment pathway was mainly involved in the PI3K - Akt, MAPK, TNF, IL-17 signalling pathways, and in cellular senescence. Furthermore, the results of the experimental study showed that Cuscuta-Salvia ameliorated the pathological changes in the ovaries, liver and adipose tissue. And it improved the expressions of the genes or proteins. Our results demonstrate that Cuscuta-Salvia may provide a novel pharmacological basis in an experimental model of PCOS by regulating gene expression. This study provides a basis for future research and clinical applications.

Efficacy of Chinese herbal medicine for tPA thrombolysis in experimental stroke: A systematic review and meta-analysis.

BACKGROUND: Tissue-type plasminogen activator (tPA) remains the sole FDA approved thrombolytic drug for ischemic stroke. But delayed thrombolytic therapy with tPA may increase the risk of hemorrhagic transformation. Many Chinese herbal medicines have been used as tPA helpers to enhance the capacity of tPA and minimize the risk of hemorrhagic transformation. The efficacy of Chinese herbal medicines on tPA thrombolysis is not systematically analyzed. METHODS: We searched the following three databases up to January 2022: Web of Science, PubMed, and Scopus. Studies that reported the efficacy and safety of Chinese herbal medicines on tPA thrombolysis in experimental stroke were included. The efficacy outcomes were neurological score and infarct volume, the safety outcomes were cerebral hemorrhage and blood brain barrier (BBB) damage. We used the checklist of CAMARADES to assess the quality of included studies. Standardized mean difference (SMD) with 95% confidence intervals were used to assess all the outcomes. Subgroup analyses were performed to explore the sources of heterogeneity. Trim and fill method and Egger's test were used to assess the potential publication bias. Sensitivity analyses were used to identify the stability of the results. RESULTS: A total of nine studies including 11 Chinese herbal medicines fulfilled the inclusion criteria and were subsequently analyzed. The pooled data demonstrated that Chinese herbal medicines improved neurological score (2.23 SMD, 1.42-3.04), infarct volume (1.08 SMD, 0.62-1.54), attenuated cerebral hemorrhage (1.87 SMD, 1.34-2.4), and BBB dysfunction (1.9 SMD, 1.35-2.45) following tPA thrombolysis in experimental stroke. Subgroup analysis indicated that the route of drug delivery, dosage of tPA, and stroke model used may be factors inducing heterogeneity and influencing the efficacy. CONCLUSION: Treatment with Chinese herbal medicines significantly improved neurological score and infarct volume, reduced cerebral hemorrhage and BBB damage after tPA thrombolysis. This study supports Chinese herbal medicine as an adjuvant therapy in reducing the side effects of tPA thrombolysis after acute ischemic stroke. The results should be interpreted with more caution since this article was based on animal studies.

Antithrombotic Agents for tPA-Induced Cerebral Hemorrhage: A Systematic Review and Meta-Analysis of Preclinical Studies.

Background tPA (tissue-type plasminogen activator) remains the only approved drug for acute ischemic stroke, with a potentially serious adverse effect: hemorrhagic transformation. The effects of antithrombotic agents on tPA-induced hemorrhagic transformation after ischemic stroke are not clearly defined. We performed a systematic review and meta-analysis in preclinical studies aiming to evaluate the efficacy of antithrombotic agents on tPA-induced hemorrhagic transformation after ischemic stroke. Methods and Results We conducted a systematic review and meta-analysis of studies testing antithrombotic agents in animal models of tPA-induced hemorrhagic transformation. The pooled effects were calculated using random-effects models, and heterogeneity was explored through meta-regression and subgroup analyses. Publication bias was assessed using trim and fill method and the Egger test. The efficacy of 18 distinct interventions was described in 22 publications. The pooled data showed a significant improvement in cerebral hemorrhage, infarct size, and neurobehavioral outcome in treated compared with control animals (standardized mean difference, 0.45 [95% CI, 0.11-0.78]; standardized mean difference, 1.18 [95% CI, 0.73-1.64]; and standardized mean difference, 0.91 [95% CI, 0.49-1.32], respectively). Subgroup analysis indicated that quality score, random allocation, control of temperature, anesthetic used, stroke model used, route of drug delivery, time of drug administration, and time of assessment were significant factors that influenced the effects of interventions. Conclusions Administration with antiplatelet agents revealed statistically significant improvement in all the outcomes. Anticoagulant agents showed significant effects in infarct size and neurobehavioral score, but fibrinolytic agents did not show any significant improvement in all the outcomes. The conclusions should be interpreted cautiously given the heterogeneity and publication bias identified in this analysis.

The Protective Role of Immunomodulators on Tissue-Type Plasminogen Activator-Induced Hemorrhagic Transformation in Experimental Stroke: A Systematic Review and Meta-Analysis.

Background: Recanalization with tissue plasminogen activator (tPA) is the only approved agent available for acute ischemic stroke. But delayed treatment of tPA may lead to lethal intracerebral hemorrhagic transformation (HT). Numerous studies have reported that immunomodulators have good efficacy on tPA-induced HT in ischemic stroke models. The benefits of immunomodulators on tPA-associated HT are not clearly defined. Here, we sought to conduct a systematic review and meta-analysis of preclinical studies to further evaluate the efficacy of immunomodulators. Methods: The PubMed, Web of Science, and Scopus electronic databases were searched for studies. Studies that reported the efficacy of immunomodulators on tPA-induced HT in animal models of stroke were included. Animals were divided into two groups: immunomodulators plus tPA (intervention group) or tPA alone (control group). The primary outcome was intracerebral hemorrhage, and the secondary outcomes included infarct volume and neurobehavioral score. Study quality was assessed by the checklist of CAMARADES. We used standardized mean difference (SMD) to assess the impact of interventions. Regression analysis and subgroup analysis were performed to identify potential sources of heterogeneity and evaluate the impact of the study characteristics. The evidence of publication bias was evaluated using trim and fill method and Egger's test. Results: We identified 22 studies that met our inclusion criteria involving 516 animals and 42 different comparisons. The median quality checklist score was seven of a possible 10 (interquartile range, 6-8). Immunomodulators improved cerebral hemorrhage (1.31 SMD, 1.09-1.52); infarct volume (1.35 SMD, 0.95-1.76), and neurobehavioral outcome (0.9 SMD, 0.67-1.13) in experimental stroke. Regression analysis and subgroup analysis indicated that control of temperature and time of assessment were important factors that influencing the efficacy of immunomodulators. Conclusion: Our findings suggested that immunomodulators had a favorable effect on tPA-associated intracerebral hemorrhage, cerebral infarction, and neurobehavioral impairments in animal models of ischemic stroke.

[Erectile dysfunction and psychological status in infertile males].

OBJECTIVE: To investigate the relationship of erectile dysfunction (ED) with psychological factors in male patients with infertility. METHODS: We conducted a questionnaire investigation among 252 male patients with infertility, which involved the general condition, results of semen routine examination, sexual life, and scores in IIEF-5, self-reported 9-item patient health questionnaire (PHQ-9) and 7-item generalized anxiety disorder scale (GAD-7). We analyzed the prevalence of ED, depression, and anxiety and their correlations among the patients in comparison with 100 fertile male controls. RESULTS: In 245 of the infertility patients, the most common symptoms of depression and anxiety were "feeling tired or no vitality" and "easily getting worried or impatient", 20.4% of them with depression disorder and 42.9% with anxiety disorder. The PHQ-9 and GAD-7 scores were significantly higher in the infertile males than in the normal fertile controls (P <0.05), and so was the incidence of ED (28.6% vs 12.4%, P <0.05), while the IIEF-5 scores were markedly lower in the former than in the latter group (P <0.01), and so were sex frequency and sexual satisfaction (P <0.05). The PHQ-9 and GAD-7 scores were remarkably higher in the infertility patients with ED than in those without (P <0.01). Logistic regression analysis showed that the level of libido and results of semen routine examination were the risk factors for depression disorder, while age, education level, disease course and experience of assisted reproduction were those for anxiety disorder. CONCLUSIONS: Male infertility patients have a poorer mental health and a higher incidence of ED than normal fertile men, and there is some interaction between psychological status and ED prevalence.

Circulating microRNAs in patients with polycystic ovary syndrome.

AIM: To explore the pattern of expression of circulating miRNAs in patients with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: Microarray and qRT-PCR were used to investigate circulating miRNAs in PCOS during clinical diagnosis. The targets of dys-regulated miRNAs were predicted using bioinformatics, followed by function and pathway analysis using the databases of Gene Ontology and the KEGG pathway. RESULTS: BMI, triglyceride, HOMA-IR, Testosterone and CRP levels were significantly higher, while estradiol was significantly lower in PCOS than in control groups. After SAM analysis, 5 circulating miRNAs were significantly up-regulated (let-7i-3pm, miR-5706, miR-4463, miR-3665, miR-638) and 4 (miR-124-3p, miR-128, miR-29a-3p, let-7c) were down-regulated in PCOS patients. Hierarchical clustering showed a general distinction between PCOS and control samples in a heat map. After joint prediction by different statistical methods, 34 and 41 genes targeted were up-and down-regulated miRNAs, in PCOS and controls, respectively. Further, GO and KEGG analyses revealed the involvement of the immune system, ATP binding, MAPK signaling, apoptosis, angiogenesis, response to reactive oxygen species and p53 signaling pathways in PCOS. CONCLUSIONS: We report a novel non-invasive miRNA profile which distinguishes PCOS patients from healthy controls. The miRNA-target database may provide a novel understanding of PCOS and potential therapeutic targets.