ObjectiveTo study the mechanism of compound Xishu granules （CXG） in inhibiting the proliferation of hepatocellular carcinoma cells by regulating ferroptosis. MethodsThe transplanted tumor model of human Huh7 was established with nude mice and the successfully modeled mice were randomized into model， Fufang Banmao （0.21 g·kg^-1）， low-dose （1.87 g·kg^-1） CXG， medium-dose （3.74 g·kg^-1） CXG， and high-dose （7.49 g·kg^-1） CXG groups. Mice were administrated with drinking water or CXG for 28 days， and the body weight and tumor volume were measured every 4 days. Hematoxylin-eosin staining was employed to observe the histopathological changes of tumors. The cell-counting kit-8 （CCK-8） was used to examine the survival rate of Huh7 cells treated with different concentrations （0， 31.25， 62.5， 125， 250， 500， 1 000 mg·L^-1） of CXG for 24 h and 48 h. CA-AM， DCFH-DA， and C11-BODIPY^581/591 fluorescent probes were used to determine the intracellular levels of ferrous ion （Fe²⁺）， reactive oxygen species （ROS）， and lipid peroxide （LPO）， respectively. The colorimetric method was employed to measure the levels of glutathione （GSH） and superoxide dismutase （SOD）. Western blot was employed to determine the protein levels of glutathione peroxidase 4 （GPX4）， transferrin receptor 1 （TFR1）， and ferritin heavy chain 1 （FTH1）， respectively. ResultsIn the animal experiment， compared with the model group， the drug treatment groups showed reductions in the tumor volume from day 12 （P<0.01）. After treatment， the Fufang Banmao and low-， medium-， and high-dose CXG groups had lower tumor volume， relative tumor volume， and tumor weight than the model group （P<0.05）， with tumor inhibition rates of 48.99%， 79.93%， 91.38%， and 97.36%， respectively. Moreover， the CXG groups had lower tumor volume and relative tumor volume （P<0.05 in all the three dose groups） and lower tumor weight （P<0.05 in medium-dose and high-dose groups） than the Fufang Banmao group. Compared with the model group， the drug treatment groups showed reduced number of tumor cells， necrotic foci with karyopyknosis， nuclear fragmentation， and nucleolysis， and the high-dose CXG group showed an increase in the proportion of interstitial fibroblasts. In the cell experiment， compared with the blank group， CXG reduced the survival rate of Huh7 cells in a dose-dependent manner after incubation for 24 h and 48 h （P<0.05）. Compared with the blank group， the RSL3 group and the low-， medium-， and high-dose CXG groups showed a decrease in the relative fluorescence intensity of CA-AM and increases in the fluorescence intensity of DCFH-DA and fluorescence ratio of C11-BODIPY^581/591， which indicated elevations in the levels of Fe²⁺ （P<0.01）， ROS （P<0.05）， and LPO （P<0.01）， respectively. Compared with the blank group， the RSL3 and low-， medium-， and high-dose CXG groups showed lowered levels of GSH and SOD （P<0.05）. In addition， the RSL3 group and the medium- and high-dose CXG groups showed down-regulated expression of GPX4 and FTH1 （P<0.05）， and the low- and high-dose CXG groups presented up-regulated expression of TFR1 （P<0.05）. ConclusionCXG suppresses the proliferation of hepatocellular carcinoma cells by inducing ferroptosis via downregulating the GSH-GPX4 signaling axis and increasing intracellular Fe²⁺and LPO levels.

Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

ObjectiveTo evaluate the efficacy of Shuanghua drink in treating primary dysmenorrhea in the rat model and explore its mechanism of action. MethodsAn oxytocin-induced writhing mouse model was established to evaluate the analgesic effect of Shuanghua drink. Forty-eight non-pregnant female institute of cancer research （ICR） mice were randomly divided into six groups， including a blank group， a model group， an ibuprofen group （85.00 mg·kg^-1）， a low-dose group of Shuanghua drink （7.14 mL·kg^-1）， a medium-dose group of Shuanghua drink （14.28 mL·kg^-1）， and a high-dose group of Shuanghua drink （28.57 mL·kg^-1）. Each group consisted of eight mice. All treatment groups received daily intragastric administration at corresponding doses for 10 consecutive days. One hour after the final administration， 2 U of oxytocin was intraperitoneally injected per mouse. The writhing latency and number of writhing within 20 minutes were recorded. A primary dysmenorrhea rat model was established by using estradiol benzoate and oxytocin to evaluate the inhibitory effect of Shuanghua drink on the contraction of uterine smooth muscle. Forty-eight non-pregnant female Sprague-Dawley （SD） rats were divided into six groups， including a blank group， a model group， an ibuprofen group （51.00 mg·kg^-1）， a low-dose group of Shuanghua drink （4.28 mL·kg^-1）， a medium-dose group of Shuanghua drink （8.57 mL·kg^-1）， and a high-dose group of Shuanghua drink （17.10 mL·kg^-1）. Each group consisted of eight rats. Rats received subcutaneous injections of estradiol benzoate for 10 consecutive days to enhance uterine sensitivity. On the eleventh day， oxytocin （2 U/rat） was intraperitoneally administered to induce abnormal uterine contractions for establishing the primary dysmenorrhea model. All treatment groups received daily intragastric administration from the second day of modeling for 10 days. The effects of Shuanghua drink were evaluated by using parameters including uterine motility and the variation rate of uterine motility. The mechanism of action was investigated in rats with primary dysmenorrhea. The content of prostaglandin F_2α （PGF_2α）， prostaglandin E₂ （PGE₂）， thromboxane B₂ （TXB₂）， prostacyclin metabolite （6-keto-PGF_1α）， and β-endorphin （β-EP） in uterine tissue of rats was detected by using enzyme-linked immunosorbent assay （ELISA）. The changes in the content of nitric oxide （NO） and inducible nitric oxide synthase （iNOS） were analyzed via colorimetric assay. Western blot was performed to determine the content of phosphorylated inhibitor of kappa B kinase beta （p-IKKβ）/IKKβ， phosphorylated inhibitor of kappa B alpha （p-IκBα）， IκBα， phosphorylated p65 （p-p65）， p65， and cyclooxygenase-2 （COX-2） proteins in uterine tissue of rats. ResultsIn the oxytocin-induced writhing mouse model， the model group exhibited significantly shortened writhing latency and increased writhing frequency compared to the control group （P<0.01）. Both the ibuprofen group and the high-dose group of Shuanghua drink displayed prolonged writhing latency （P<0.05）， while the ibuprofen group and the low-dose， medium-dose， and high-dose groups of Shuanghua drink exhibited reduced writhing frequency （P<0.01）. In the primary dysmenorrhea rat model， the uterine motility and its variation rate in the model group were significantly higher than those in the blank group （P<0.01）. These parameters were markedly suppressed by ibuprofen and Shuanghua drink at all tested doses （P<0.01）. For the mechanism of action， the model group showed significantly increased PGF_2α/PGE₂， TXB₂/6-keto-PGF_1α， NO， and iNOS in uterine tissue （P<0.05， P<0.01） and significantly decreased β-EP （P<0.01）. These parameters were significantly attenuated in the ibuprofen group and the low-dose， medium-dose， and high-dose groups of Shuanghua drink. The PGF_2α/PGE₂ （P<0.01）， TXB₂/6-keto-PGF_1α （P<0.01）， NO （medium-dose group P<0.05）， and iNOS （P<0.01） were reduced， and the β-EP （medium-dose group P<0.05） was up-regulated. Compared to the model group， the ibuprofen group and medium-dose group of Shuanghua drink showed significantly increased content of β-EP in the serum of rats （P<0.05）. Compared to the blank group， the model group showed significantly elevated expressions of COX-2， p-IKKβ/IKKβ， p-IκBα/IκBα， and p-p65/p65 proteins （P<0.01） and significantly reduced anti-inflammatory protein IκBα （P<0.05）. Compared to the model group， the ibuprofen group and the low-dose， medium-dose， and high-dose groups of Shuanghua drink showed significantly reduced expressions of COX-2 （P<0.01）， p-IKKβ/IKKβ （P<0.01）， p-IκBα/IκBα （P<0.05， P<0.01）， and p-p65/p65（P<0.01） and up-regulated expression of IκBα protein （P<0.05， P<0.01）. ConclusionShuanghua drink effectively alleviates primary dysmenorrhea through analgesia and suppression of abnormal contractions of uterine smooth muscle. Its mechanism may be mediated by reduced levels of PGF_2α/PGE₂， TXB₂/6-keto-PGF_1α， iNOS， and NO， elevated β-EP level， and inhibited COX-2/NF-κB signaling pathway.

ObjectiveTo evaluate the efficacy of Shuanghua drink in treating primary dysmenorrhea in the rat model and explore its mechanism of action. MethodsAn oxytocin-induced writhing mouse model was established to evaluate the analgesic effect of Shuanghua drink. Forty-eight non-pregnant female institute of cancer research （ICR） mice were randomly divided into six groups， including a blank group， a model group， an ibuprofen group （85.00 mg·kg^-1）， a low-dose group of Shuanghua drink （7.14 mL·kg^-1）， a medium-dose group of Shuanghua drink （14.28 mL·kg^-1）， and a high-dose group of Shuanghua drink （28.57 mL·kg^-1）. Each group consisted of eight mice. All treatment groups received daily intragastric administration at corresponding doses for 10 consecutive days. One hour after the final administration， 2 U of oxytocin was intraperitoneally injected per mouse. The writhing latency and number of writhing within 20 minutes were recorded. A primary dysmenorrhea rat model was established by using estradiol benzoate and oxytocin to evaluate the inhibitory effect of Shuanghua drink on the contraction of uterine smooth muscle. Forty-eight non-pregnant female Sprague-Dawley （SD） rats were divided into six groups， including a blank group， a model group， an ibuprofen group （51.00 mg·kg^-1）， a low-dose group of Shuanghua drink （4.28 mL·kg^-1）， a medium-dose group of Shuanghua drink （8.57 mL·kg^-1）， and a high-dose group of Shuanghua drink （17.10 mL·kg^-1）. Each group consisted of eight rats. Rats received subcutaneous injections of estradiol benzoate for 10 consecutive days to enhance uterine sensitivity. On the eleventh day， oxytocin （2 U/rat） was intraperitoneally administered to induce abnormal uterine contractions for establishing the primary dysmenorrhea model. All treatment groups received daily intragastric administration from the second day of modeling for 10 days. The effects of Shuanghua drink were evaluated by using parameters including uterine motility and the variation rate of uterine motility. The mechanism of action was investigated in rats with primary dysmenorrhea. The content of prostaglandin F_2α （PGF_2α）， prostaglandin E₂ （PGE₂）， thromboxane B₂ （TXB₂）， prostacyclin metabolite （6-keto-PGF_1α）， and β-endorphin （β-EP） in uterine tissue of rats was detected by using enzyme-linked immunosorbent assay （ELISA）. The changes in the content of nitric oxide （NO） and inducible nitric oxide synthase （iNOS） were analyzed via colorimetric assay. Western blot was performed to determine the content of phosphorylated inhibitor of kappa B kinase beta （p-IKKβ）/IKKβ， phosphorylated inhibitor of kappa B alpha （p-IκBα）， IκBα， phosphorylated p65 （p-p65）， p65， and cyclooxygenase-2 （COX-2） proteins in uterine tissue of rats. ResultsIn the oxytocin-induced writhing mouse model， the model group exhibited significantly shortened writhing latency and increased writhing frequency compared to the control group （P<0.01）. Both the ibuprofen group and the high-dose group of Shuanghua drink displayed prolonged writhing latency （P<0.05）， while the ibuprofen group and the low-dose， medium-dose， and high-dose groups of Shuanghua drink exhibited reduced writhing frequency （P<0.01）. In the primary dysmenorrhea rat model， the uterine motility and its variation rate in the model group were significantly higher than those in the blank group （P<0.01）. These parameters were markedly suppressed by ibuprofen and Shuanghua drink at all tested doses （P<0.01）. For the mechanism of action， the model group showed significantly increased PGF_2α/PGE₂， TXB₂/6-keto-PGF_1α， NO， and iNOS in uterine tissue （P<0.05， P<0.01） and significantly decreased β-EP （P<0.01）. These parameters were significantly attenuated in the ibuprofen group and the low-dose， medium-dose， and high-dose groups of Shuanghua drink. The PGF_2α/PGE₂ （P<0.01）， TXB₂/6-keto-PGF_1α （P<0.01）， NO （medium-dose group P<0.05）， and iNOS （P<0.01） were reduced， and the β-EP （medium-dose group P<0.05） was up-regulated. Compared to the model group， the ibuprofen group and medium-dose group of Shuanghua drink showed significantly increased content of β-EP in the serum of rats （P<0.05）. Compared to the blank group， the model group showed significantly elevated expressions of COX-2， p-IKKβ/IKKβ， p-IκBα/IκBα， and p-p65/p65 proteins （P<0.01） and significantly reduced anti-inflammatory protein IκBα （P<0.05）. Compared to the model group， the ibuprofen group and the low-dose， medium-dose， and high-dose groups of Shuanghua drink showed significantly reduced expressions of COX-2 （P<0.01）， p-IKKβ/IKKβ （P<0.01）， p-IκBα/IκBα （P<0.05， P<0.01）， and p-p65/p65（P<0.01） and up-regulated expression of IκBα protein （P<0.05， P<0.01）. ConclusionShuanghua drink effectively alleviates primary dysmenorrhea through analgesia and suppression of abnormal contractions of uterine smooth muscle. Its mechanism may be mediated by reduced levels of PGF_2α/PGE₂， TXB₂/6-keto-PGF_1α， iNOS， and NO， elevated β-EP level， and inhibited COX-2/NF-κB signaling pathway.

The efficacy and safety of different Chinese patent medicines in the treatment of stable chronic obstructive pulmonary disease(COPD) were evaluated by network Meta-analysis. The randomized controlled trial(RCT) of Chinese patent medicines for stable COPD were retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library with the time interval from inception to February 2024. The quality of the included RCT was evaluated by the Cochrane's risk of bias assessment tool. RevMan 5.4 and Stata 16.0 were used to establish the risk of bias diagram and perform the network Meta-analysis. A total of 113 RCTs were included, involving 8 265 patients and 14 Chinese patent medicines. The network Meta-analysis yielded the following results based on the surface under the cumulative ranking curve(SUCRA).(1) In terms of improving the forced expiratory volume in 1 second to forced vital capacity(FEV1/FVC) ratio, the top three treatments were Jingshuibao Capsules + conventional western medicine, Yupingfeng San + conventional western medicine, and Sanzi Zhike Capsules + conventional western medicine.(2) In terms of improving the clinical efficacy, the top three treatments were Yifei Capsules + conventional western medicine, Yupingfeng Granules + conventional western medicine, and Bufei Huoxue Capsules + conventional western medicine.(3) In terms of improving the percentage of predicted FEV1(FEV1%pred), the top three treatments were Jingshuibao Capsules + conventional western medicine, Bufei Granules + conventional western medicine, and Bailing Capsules + conventional western medicine.(4) In terms of improving the distance in 6 min walking test(6MWT), the top three treatments were Jingshuibao Capsules + conventional western medicine, Bailing Capsules + conventional western medicine, and Jianpi Yifei Oral Liquid + conventional western medicine.(5) In terms of reducing the COPD assessment test(CAT), the top three treatments were Bufei Granules + conventional western medicine, Yifei Capsules + conventional western medicine, and Yifei Huoxue Granules + conventional western medicine.(6) In terms of reducing the frequency of acute exacerbation of chronic obstructive pulmonary disease(AECOPD) within 1 year, the top three treatments were Yupingfeng Capsules + conventional western medicine, Yupingfeng San + conventional western medicine, and Jianpi Yifei Oral Liquid + conventional western medicine.(7) In terms of safety, 28 RCTs have reported adverse reactions, mainly involving the digestive system, circulatory system, and nervous system. The results showed that Chinese patent medicines combined with conventional western medicine improved FEV1/FVC, FEV1%pred, clinical efficacy, and 6MWT, while reducing CAT and the frequency of AECOPD within 1 year. However, due to the limitations of the included studies and the lack of direct comparisons between different interventions, these results need further validation.
Pulmonary Disease, Chronic Obstructive/physiopathology* ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Randomized Controlled Trials as Topic ; Nonprescription Drugs/therapeutic use*

Objective To investigate the correlation between the level of N-terminal pro-Brain natriuretic peptide(NT-proBNP)and cardiorespiratory fitness following acute exposure to high altitude.Methods Forty-six subjects were recruited from the Second Affiliated Hospital of Army Medical University in June 2022,including 19 males and 27 females.After completing cardiopulmonary exercise test(CPET),serological detection of myocardial cell-related markers,and multiple metabolites at a plain altitude(300 meters above sea level),all subjects flew to a high-altitude location(3900 meters above sea level).Biomarker testing and CPET were repeated on the second and third days after arrival at high altitude.Changes in serum biomarker and key CPET indicators before and after rapid ascent to high altitude were compared,and the correlation between serum levels of various myocardial cell-related markers and metabolites and high altitude cardiorespiratory fitness was analyzed.Results Compared with the plain altitude,there was a significant decrease in maximal oxygen uptake after rapid ascent to high altitude[(25.41±6.20)ml/(kg.min)vs.(30.17±5.01)ml/(kg.min),P<0.001].Serum levels of NT-proBNP,Epinephrine(E),plasma renin activity(PRA),angiotensin Ⅱ(Ang Ⅱ),angiotensin-converting enzyme 2(ACE2)and leptin(LEP)significantly increased,with all differences being statistically significant(P<0.05)after acute high altitude exposure.In contrast,no statistically significant differences were observed for creatine kinase MB(CK-MB),cardiac troponin I(cTnI),myoglobin(Myo)and norepinephrine(NE)(P>0.05).Correlation analysis showed a significant negative correlation between NT-proBNP at plain altitude(r=-0.768,P<0.001)and at high altitude(r=-0.791,P<0.001)with maximal oxygen uptake at high altitude.Multivariate linear regression analysis indicated that maximal oxygen uptake at plain altitude(t=2.069,P=0.045),NT-proBNP at plain altitude(t=-2.436,P=0.020)and at high altitude(t=-3.578,P=0.001)were independent influencing factors of cardiorespiratory fitness at high altitude.Conclusion Cardiorespiratory fitness significantly decreases after rapid ascent to high altitude,and the baseline NT-proBNP level at plain altitude is closely related to cardiorespiratory fitness at high altitude,making it a potential predictor indicator for high altitude cardiorespiratory fitness.

Objective:To evaluate the short-term rehabilitation effect of wearable visual training devices based on extended reality (XR) glasses in patients after macular hole surgery.Methods:A self-controlled study was conducted.Eleven patients with monocular low vision after macular hole surgery were recruited at Renmin Hospital of Wuhan University from October 2022 to March 2024.All patients underwent biofeedback training for 3 months using the independently developed visual rehabilitation training glasses LOOKBON T10.The LogMAR best corrected visual acuity (BCVA), retinal sensitivity, effective fixation rate, fixation stability, reading speed, vertical metamorphopsia (MV), horizontal metamorphopsia (MH), and Chinese version of the visual-related quality of life assessment form (CVRQoL-25) were compared before and after training.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Renmin Hospital of Wuhan University (No.WDRY2024-K263).Written informed consent was obtained from each subject.Results:After training, the patients' BCVA, retinal sensitivity, effective fixation rate, fixation stability, and reading speed were 0.69±0.19, (21.61±2.75)db, (92.43±4.06)%, (93.09±4.31)%, and (104.82±21.85) characters/minute, respectively, which were significantly improved compared to 0.85±0.28, (17.71±3.17)db, (31.83±19.05)%, (32.35±19.12)%, and (69.64±20.17) characters/minute before training ( t=5.253, -5.987, -11.561, -12.003, -11.682; all at P<0.001).After training, MV and MH were (0.29±0.20)° and (0.21±0.24)°, respectively, which were significantly reduced compared to pre-training (0.44±0.24)° and (0.43±0.41)° ( t=9.238, 4.068; both at P<0.01).After training, the CVRQoL-25 score was 1 193.18±229.43, which was significantly higher than pre-training 947.73±203.86 ( t=-11.687, P<0.001). Conclusions:The application of wearable visual training equipment based on XR glasses can effectively improve the visual function of patients with poor visual function recovery after macular hole surgery, and enhance their quality of life.

Benign prostatic hyperplasia(BPH)is one of the major chronic complications of type 2 diabetes mellitus(T2DM),and sex steroid hormones are common risk factors for the occurrence of T2DM and BPH.The profiles of sex steroid hormones are simultaneously quantified by LC-MS/MS in the clinical serum of patients,including simple BPH patients,newly diagnosed T2DM patients,T2DM complicated with BPH patients and matched healthy individuals.The G protein-coupled estrogen receptor(GPER)inhibitor G15,GPER knockdown lentivirus,the YAP1 inhibitor verteporfin,YAP1 knockdown/overexpression lentivirus,targeted metabolomics analysis,and Co-IP assays are used to investigate the molecular mechanisms of the disrupted sex steroid hormones homeostasis in the pathological process of T2DM complicated with BPH.The homeostasis of sex steroid hormone is disrupted in the serum of patients,accompanying with the proliferated prostatic epithelial cells(PECs).The sex steroid hormone metabolic profiles of T2DM patients complicated with BPH have the greatest degrees of separation from those of healthy individuals.Elevated 17β-estradiol(E2)is the key contributor to the disrupted sex steroid hormone homeostasis,and is significantly positively related to the clinical characteristics of T2DM patients complicated with BPH.Activating GPER by E2 via Hippo-YAP1 signaling exacerbates high glucose(HG)-induced PECs prolifer-ation through the formation of the YAP1-TEAD4 heterodimer.Knockdown or inhibition of GPER-mediated Hippo-YAP1 signaling suppresses PECs proliferation in HG and E2 co-treated BPH-1 cells.The anti-proliferative effects of verteporfin,an inhibitor of YAP1,are blocked by YAP1 overexpression in HG and E2 co-treated BPH-1 cells.Inactivating E2/GPER/Hippo/YAP1 signaling may be effective at delaying the progression of T2DM complicated with BPH by inhibiting PECs proliferation.

Humans ; Vascular Stiffness ; Coal Mining ; Occupational Diseases/epidemiology* ; Risk Factors ; Coal ; Miners

The occurrence of benign prostate hyperplasia(BPH)was related to disrupted sex steroid hormones,and metformin(Met)had a clinical response to sex steroid hormone-related gynaecological disease.How-ever,whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear.Here,our clinical study showed that along with prostatic epithelial cell(PEC)proliferation,sex steroid hormones were dysregulated in the serum and prostate of BPH patients.As the major contributor to dysregulated sex steroid hormones,elevated dihydrotestosterone(DHT)had a significant positive rela-tionship with the clinical characteristics of BPH patients.Activation of adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor(AR)-mediated Yes-associated protein(YAP1)-TEA domain transcription factor(TEAD4)heterodimers.Met's anti-proliferative effects were blocked by AMPK inhibitor or YAP1 over-expression in DHT-cultured BPH-1 cells.Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.