Objective To evaluate the safety and efficacy of valve-in-valve transcatheter mitral valve replacement(ViV-TMVR)in patients with bioprosthetic valve degeneration who are at high surgical risk.Methods This study is a multi-center,retrospective cohort analysis of 20 consecutive patients who underwent transseptal ViV-TMVR using the Edwards SAPIEN 3 transcatheter heart valve(THV).The primary endpoints include technical success and procedural success,both defined according to the Mitral Valve Academic Research Consortium(MVARC)criteria,as well as mortality and functional change assessed based on New York Heart Association(NYHA)classification at 30-days and six months post-procedure.Clinical follow-up assessments are conducted at 30-days and six months.Results From February 2021 to October 2022,a total of 20 patients with symptoms of bioprosthetic valve degeneration were enrolled across nine sites in China.The patients had a mean age of(73.5±5.5)years,with 85.0％being females and 70.0％classified as NYHA class Ⅲ/Ⅳ.The study achieved a 100.0％technical success rate and a 90.0％procedural success rate finally.All patients remained alive during the 30-day follow-up period.However,six months post-intervention,two patients(10.0％)were re-hospitalized due to heart failure,and sadly,one of them(5.0％)died.None of the patients reported any adverse events related to ViV-TMVR during the follow-up period.Notably,there was a significant improvement in NYHA class compared to baseline(P=0.0004)at six-month follow-ups.Conclusions The transseptal ViV-TMVR technique proved to be highly successful and was associated with significant improvement in NYHA class function.These findings strongly suggest that it serves as a safe and efficient treatment alternative for high-risk patients suffering from bioprosthetic valve degeneration.

Aim To investigate the role of FRMD4A in autophagy of placental trophoblast cells in preeclampsia(PE).Methods The placental tissues and clinical data of normal pregnancy and PE were obtained,and the histopathological changes were observed by HE staining.An in vitro model of hypoxia-induced HTR-8/SVneo trophoblast cells was established.The expres-sions of LC3B Ⅱ/Ⅰ and p62 in placental tissues and hypoxic cell models were analyzed by Western blot.The expression of FRMD4A was detected by qRT-PCR,Western blot and immunofluorescence,and the correlation between the expression level of FRMD4A and the clinical characteristics of the subjects was ana-lyzed by Pearson correlation analysis.Hypoxia induced trophoblast cells were transfected with si-FRMD4A,and the expression of LC3 B Ⅱ/Ⅰ and p62 was analyzed by Western blot.Results Compared with the normal group,the expression of LC3B Ⅱ/Ⅰ in PE placental tissues and hypoxia-induced trophoblast models was significantly upregulated,while the expression of p62 was significantly downregulated.Meanwhile,the ex-pression of FRMD4A increased significantly.Moreo-ver,its expression was positively correlated with the maternal systolic blood pressure,diastolic blood pres-sure,and platelet count,but negatively correlated with the neonatal weight(P＜0.01).In addition,hypoxia-induced trophoblast cells transfected with si-FRMD4A showed a significant decrease in LC3B Ⅱ/Ⅰ and an increase in p62 expression.Conclusions The expres-sion of FRMD4A is upregulated in PE placenta and hy-poxia-induced trophoblast cell model.Interfering with it can significantly hinder the autophagy process of trophoblast cells,suggesting that it may serve as a po-tential molecular target to participate in the pathologi-cal process of PE.

Aim To investigate the intervention effect of Rehmannia radix water extract on bleomycin(BLM)-induced pulmonary fibrosis in mice combined with metabolomics and to reveal the potential mechanism,in order to provide new ideas for clinical treatment of pul-monary fibrosis.Methods Male C57BL/6N mice were randomly divided into the control group,model group,pirfenidone group(positive control,PFD,270 mg·kg-1),and low dose(DH-L,4.55 g·kg-1)group,medium dose(DH-M,9.1 g·kg-1)group and high dose(DH-H,18.2 g·kg-1)group of Rehman-nia.Except for the control group,BLM(5 mg·kg-1)was instilled into the trachea to establish the model of pulmonary fibrosis in the other groups.The survival rate,lung index and blood oxygen saturation of mice in each group were evaluated.HE and Masson staining were used to observe the pathological changes of lung tissue.WBP was used to detect lung function.Flow cytometry was used to detect the apoptosis of primary lung cells,ROS and immune cells.ELISA was used to detect the levels of fibrosis markers and inflammatory factors(α-SMA,collagen Ⅰ,collagen Ⅲ,TGF-β1,TNF-α,IL-1 β,and IL-6).Biochemical method was employed to detect the contents of GSH-Px,T-SOD and MDA.Liquid chromatograph mass spectrometer(LC-MS)metabolomics was used to analyze the changes of serum metabolic profile.Results Water extract of Re-hmannia significantly increased the survival rate,oxy-gen saturation and lung function of mice with pulmona-ry fibrosis,reduced the lung coefficient,ameliorated pathological damage and collagen deposition in lung tissue,reduced the levels of apoptosis and oxidative stress,and down-regulated the levels of inflammatory factors in lung tissue.It regulated the levels of metabo-lites such as bile acid metabolism,sphingolipid metabo-lism,and unsaturated fatty acid metabolism.Conclu-sions Water extract of Rehmannia inhibits lung injury and collagen deposition in mice with pulmonary fibrosis by inhibiting inflammatory response,which may be a-chieved by regulating the levels of inflammatory factors through the metabolic pathways of bile acid and sphin-golipid.

Poly(lactic-co-glycolide)(PLGA)is a key excipient in long-acting sustained-release preparations,and its degradation properties directly affect the drug release behavior.In this study,PLGA microspheres were prepared by microfluidic techniques,and the morphology changes of the microspheres were observed by scanning electron microscopy(SEM).In alkaline environment,due to the accelerated hydrolysis of ester bonds,the surface of the microspheres was rapidly dissolved and eroded,and the degradation rate was significantly higher than that in acidic environment.High temperature accelerated the degradation of PLGA microspheres.Under neutral and alkaline conditions,the microspheres showed aggregation and adhesion.Under acidic conditions,the microspheres gradually decomposed into irregular fragments.The high ionic strength further promoted the surface corrosion of the microspheres,especially under extreme pH conditions.Simultaneously,PLGA microspheres encapsulating coumarin were prepared to simulate the microsphere formulation.The release rate of coumarin after degradation of the microspheres under different conditions was observed by measuring the absorbance with ultraviolet-visible spectrophotometry.The results were consistent with those of the blank microspheres.This study revealed that the degradation of PLGA microspheres was significantly pH-dependent,temperature sensitive and ion strength responsive.These findings not only helped to understand and optimize the long-term stability and controlled release performance of drug-carrying microspheres,but also provided a theoretical basis for further improvement of PLGA-based drug carrier design.

Near infrared spectroscopy(NIRS)analysis technology has become an important process analysis tool in industrial and agricultural production,and has been widely used for qualitative and quantitative analysis in the fields of tobacco,agriculture,and pharmaceuticals.To address issues such as poor generalization ability and low prediction accuracy in NIRS modeling,a two-dimensional convolutional neural network(2DCNN)quantitative analysis model based on competitive adaptive reweighted sampling(CARS)and Gramian angular difference field(GADF)(CARS-GADF-2DCNN)was proposed.CARS-GADF-2DCNN used the CARS method to select an optimal wavelength set from the full spectrum,then employed GADF to encode the selection results into two-dimensional images,and finally used 2DCNN for prediction analysis.The 2DCNN model consisted of convolutional layers,parallel convolution modules,flattening layer,and fully connected layers.Simulation experiments were conducted on three public near-infrared(NIR)spectral datasets encompassing soil,tablet,and grain datasets to evaluate the CARS-GADF-2DCNN model.The results demonstrated that,compared to the one-dimensional convolutional neural network(1DCNN),the GADF-2DCNN model achieved 16.74％,23.40％,and 7.13％improvement in prediction accuracy for the soil,tablet,and grain datasets,respectively.Compared to GADF-2DCNN,VCPA-GADF-2DCNN,and IRIV-GADF-2DCNN models,the CARS-GADF-2DCNN model further improved prediction accuracy.For the soil dataset,prediction accuracy improved by 39.00％,30.78％and 4.13％;for the tablet dataset,the improvements were 9.52％,6.94％and 2.56％;for the grain dataset,the improvements were 20.57％,9.85％and 15.66％.In conclusion,CARS-GADF-2DCNN effectively selected the optimal wavelength subset from near infrared spectra,and revealed the latent features between different wavelengths.CARS-GADF-2DCNN addresses the issues of high complexity in prediction models and low prediction accuracy in near infrared spectral modeling,and could be effectively applied to near infrared spectral prediction analysis of different substances.

Objective:To investigate the protective effect of achyranthes bidentata(AB)on sperm quality in mice with sper-matogenic disorder through the glycolytic metabolic pathway and its action mechanism.Methods:We equally randomized 40 Kun-ming mice into a normal control,a model control,a low-dose AB(3.5 g/kg)and a high-dose AB group(7.0 g/kg),and established the model of spermatogenic disorder in the latter three groups of mice by intraperitoneal injection of doxorubicin(30 mg/kg).Two days after modeling,we collected the testis and kidney tissues and blood samples from the mice for observation of the pathological changes in the testis tissue by HE staining,detection of perm motility with the sperm quality analyzer,examination of the apoptosis of testis cells by flow cytometry,measurement of the levels of testosterone(T),malondialdehyde(MDA),superoxide dismutase(SOD)and cata-lase(CAT)in the serum and testis tissue by ELISA,and determination of expressions of the key enzymes of glycolysis hexokinase Ⅱ(HK2),pyruvate kinase M2(PKM2),platelet phosphofructokinase(PFKP),lactate dehydrogenase A(LDHA)and the meiosis pro-teins REC8 and SCP3 by Western blot,and the mRNA expressions of glycolytic phosphofructokinase 1(PFK1),phosphoglycerate ki-nase 1(PGK1),tumor necrosis factor-α(TNF-α)and interleukin-1 β(IL-1β)by fluorescence quantitative PCR(FQ-PCR).Results:Compared with the model controls,the mice in the AB groups showed significant increases in the testis coefficient,kidney in-dex,sperm concentration,sperm motility,spermatogonia,primary spermatocytes,spermatids,sperm count and the serum T level(P＜0.05 orP＜0.01),but dramatic decreases in the apoptosis of testis cells and percentage of morphologically abnormal sperm(P＜0.01).Achyranthes bidentata also significantly elevated the levels of SOD and CAT,and down-regulated the mRNA expressions of MDA,TNF-α and IL-1β(P＜0.05 or P＜0.01),and up-regulated the protein expressions of HK2,PKM2,PFKP,LDHA,REC8 and SCP3,and expressions of the glycolysis key genes Pfk1 and Pgk1(P＜0.05 orP＜0.01).Conclusion:Achyranthes bidentata ameliorates doxorubicin-induced spermatogenic disorder in mice by regulating the glycolytic pathway and reducing oxidative stress and the expressions of inflammatory factors.

Depression is a highly heterogeneous psychiatric disorder with complex pathogenesis influenced by the interplay of biological,psychological,and social-environmental factors.Based on the 2021 edition of the Chinese Guidelines for the Prevention and Treatment of Depressive Disorders,which explicitly identify gender as a significant risk factor for depression onset,this paper systematically reviews the gender-differentiated pathogenesis and therapeutic advances in depression from both traditional Chinese medicine(TCM)and Western medical perspectives.In Western medicine,a large number of studies have demonstrated the sex-specific mechanism of estrogen/testosterone fluctuations and monoamine transmitter system regulation.While in TCM,although the constitution theory proposes that there are significant gender differences in congenital constitution and that qi depression and qi deficiency are associated with susceptibility to depression,current evidence primarily relies on cross-sectional surveys and lacks validation through high-quality RCTs.Compared with Western medicine,the direct research on gender-differentiated antidepressant effects in TCM remains relatively underdeveloped.In future study,it may be possible to deepen and improve the research on anti-depression in TCM from the biological markers of particular constitutions in the gender dimension.This paper advocates establishing a bio-psycho-social integrated intervention model,advancing mechanistic exploration through prospective cohort studies and multi-omics technologies,and promoting precision diagnosis and treatment systems based on gender differences,and to form a three-dimensional diagnosis and treatment and research system that covers biomarkers,social role assessment,and TCM constitution identification,in order to provide a new theoretical framework and a practical pathway for the precise medical treatment of depression.

Depression is a widespread psychiatric disorder with complex pathogenesis and unsatisfactory therapeutic effects. As a native flavonoid, Isorhamnetin (ISO) has been deemed to exert neuroprotective effects by antioxidation and regulation of immunity. However, no reports of anti-depressed effect of ISO have yet been found. The present study was conducted to clarify the mechanism basis of anti-depressed effect of ISO utilizing behavioral, biochemical, molecular approaches in vitro and in vivo and bio-informatics analysis. The effects of ISO on depressed mice was investigated through the SPT and FST, and the lesions were examined by H&E staining. Besides, the inflammatory factor and indicator in kynurenine pathway were assessed through detection kits, and the microbiota were checked by 16sRNA. Molecular docking study was performed to investigate the target of ISO. Additionally, Western blot was used to test the activation of PI3K/AKT signaling pathway. The results indicated that ISO could enhance the sugar water preference of mice in SPT and reduce immobility time in FST. Further more, ISO suppressed peripheral and central inflammation, regulated the changes in kynurenine pathway and gut microbiota, inhibited activation of PI3K/AKT pathway, and presented good binding patterns with target proteins on PI3K/AKT signaling pathway. Collectively, these findings demonstrate that ISO alleviated depression-like behaviour by normalizing inflammation-induced dysregulation of the crosstalk between KP and gut microbiota disorder through regulated PI3K/AKT/NF-κB pathway.

This study aims to investigate the potential effect of the water extract of fresh Rehmanniae Radix on hypercholesterolemia in mice that was induced by a high-fat and high-cholesterol diet and explore its possible mechanism from bile acid reabsorption. Male C57BL/6 mice were randomly assigned into the following groups: control, model, low-and high-dose(4 and 8 g·kg~(-1), respectively) fresh Rehmanniae Radix, and positive drug(simvastatin, 0.05 g·kg~(-1)). Other groups except the control group were fed with a high-fat and high-cholesterol diet for 6 consecutive weeks to induce hypercholesterolemia. From the 6th week, mice were administrated with corresponding drugs daily via gavage for additional 6 weeks, while continuing to be fed with a high-fat and high-cholesterol diet. Serum levels of total cholesterol(TC), triglycerides(TG), low density lipoprotein-cholesterol(LDL-c), high density lipoprotein-cholesterol(HDL-c), and total bile acid(TBA), as well as liver TC and TG levels and fecal TBA level, were determined by commercial assay kits. Hematoxylin-eosin(HE) staining, oil red O staining, and transmission electron microscopy were performed to observe the pathological changes in the liver. Three livers samples were randomly selected from each of the control, model, and high-dose fresh Rehmanniae Radix groups for high-throughput transcriptome sequencing. Differentially expressed genes were mined and KEGG pathway enrichment analysis was performed to predict the key pathways and target genes of the water extract of fresh Rehmanniae Radix in the treatment of hypercholesterolemia. RT-qPCR was employed to measure the mRNA levels of cholesterol 7α-hydroxylase(CYP7A1) and cholesterol 27α-hydroxylase(CYP27A1) in the liver. Western blot was employed to determine the protein levels of CYP7A1 and CYP27A1 in the liver as well as farnesoid X receptor(FXR), apical sodium-dependent bile acid transporter(ASBT), and ileum bile acid-binding protein(I-BABP) in the ileum. The results showed that the water extract of fresh Rehmanniae Radix significantly lowered the levels of TC and TG in the serum and liver, as well as the level of LDL-c in the serum. Conversely, it elevated the level of HDL-c in the serum and TBA in feces. No significant difference was observed in the level of TBA in the serum among groups. HE staining, oil red O staining, and transmission electron microscopy showed that the water extract reduced the accumulation of lipid droplets in the liver. Further mechanism studies revealed that the water extract of fresh Rehmanniae Radix significantly down-regulated the protein levels of FXR and bile acid reabsorption-related proteins ASBT and I-BABP. Additionally, it enhanced CYP7A1 and CYP27A1, the key enzymes involved in bile acid synthesis. Therefore, it is hypothesized that the water extract of fresh Rehmanniae Radix may exert an anti-hypercholesterolemic effect by regulating FXR/ASBT/I-BABP signaling, inhibiting bile acid reabsorption, and increasing bile acid excretion, thus facilitating the conversion of cholesterol to bile acids.
Animals ; Male ; Bile Acids and Salts/metabolism* ; Mice, Inbred C57BL ; Mice ; Diet, High-Fat/adverse effects* ; Cholesterol/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Hypercholesterolemia/genetics* ; Receptors, Cytoplasmic and Nuclear/genetics* ; Rehmannia/chemistry* ; Liver/drug effects* ; Humans ; Cholesterol 7-alpha-Hydroxylase/genetics* ; Plant Extracts

This study aimed to explore the effects and mechanisms of total extracts from Anthriscus sylvestris on pulmonary hypertension in rats. Sixty male SD rats were divided into normal(NC) group, model(M) group, positive drug sildenafil(Y) group, low-dose A. sylvestris(ES-L) group, medium-dose A. sylvestris(ES-M) group, and high-dose A. sylvestris(ES-H) group. On day 1, rats were intraperitoneally injected with monocrotaline(60 mg·kg~(-1)) to induce pulmonary hypertension, and the rat model was established on day 28. From days 15 to 28, intragastric administration of the respective treatments was performed. After modeling and treatment, small animal echocardiography was used to detect the right heart function of the rats. Arterial blood gas was measured using a blood gas analyzer. Hematoxylin and eosin(HE) staining and Masson staining were performed to observe cardiopulmonary pathological damage. Flow cytometry was used to detect apoptosis in the lung and myocardial tissues and reactive oxygen species(ROS) levels. Western blot was applied to detect the expression levels of transforming growth factor-β1(TGF-β1), phosphorylated mothers against decapentaplegic homolog 3(p-Smad3), Smad3, tissue plasminogen activator(t-PA), and plasminogen activator inhibitor-1(PAI-1) in lung tissue. A blood routine analyzer was used to measure inflammatory immune cell levels in the blood. Enzyme-linked immunosorbent assay(ELISA) was used to detect the expression levels of P-selectin and thromboxane A2(TXA2) in plasma. The results showed that, compared with the NC group, right heart hypertrophy index, right ventricular free wall thickness, right heart internal diameter, partial carbon dioxide pressure(PaCO_2), apoptosis in cardiopulmonary tissue, and ROS levels were significantly increased in the M group. In contrast, the ratio of pulmonary blood flow acceleration time(PAT)/ejection time(PET), right cardiac output, change rate of right ventricular systolic area, systolic displacement of the tricuspid ring, oxygen partial pressure(PaO_2), and blood oxygen saturation(SaO_2) were significantly decreased in the M group. After administration of the total extract of A. sylvestris, right heart function and blood gas levels were significantly improved, while apoptosis in cardiopulmonary tissue and ROS levels significantly decreased. Further testing revealed that the total extract of A. sylvestris significantly decreased the levels of interleukin-1β(IL-1β), interleukin-6(IL-6), and PAI-1 proteins in lung tissue, while increasing the expression of t-PA. Additionally, the extract reduced the levels of inflammatory cells such as leukocytes, lymphocytes, granulocytes, and monocytes in the blood, as well as the levels of P-selectin and TXA2 in plasma. Metabolomics results showed that the total extract of A. sylvestris significantly affected metabolic pathways, including arginine biosynthesis, tyrosine metabolism, and taurine and hypotaurine metabolism. In conclusion, the total extract of A. sylvestris may exert an anti-pulmonary hypertension effect by inhibiting the TGF-β1/Smad3 signaling pathway, thereby alleviating immune-inflammatory responses and thrombosis.
Animals ; Male ; Smad3 Protein/metabolism* ; Transforming Growth Factor beta1/metabolism* ; Rats, Sprague-Dawley ; Rats ; Signal Transduction/drug effects* ; Hypertension, Pulmonary/genetics* ; Thrombosis/immunology* ; Drugs, Chinese Herbal/administration & dosage* ; Humans ; Apoptosis/drug effects*