Assessing the impact of tear direction in coronary artery dissection on thrombosis development: A hemodynamic computational study.

OBJECTIVE: Iatrogenic coronary artery dissection is a complication of coronary intimal injury and dissection due to improper catheter manipulation. The impact of tear direction on the prognosis of coronary artery dissection (CAD) remains unclear. This study examines the hemodynamic effects of different tear directions (transverse and longitudinal) of CAD and evaluates the risk of thrombosis, rupture and further dilatation of CAD. METHODS: Two types of CAD models (Type I: transverse tear, Type II: longitudinal tear) were reconstructed from the aorto-coronary CTA dataset of 8 healthy cases. Four WSS-based indicators were analyzed, including time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), relative residence time (RRT), and cross flow index (CFI). A thrombus growth model was also introduced to predict the trend of thrombus growth in CAD with two different tear directions. RESULTS: For most of the WSS-based indicators, including TAWSS, RRT, and CFI, no statistically significant differences were observed across the CAD models with varying tear directions, except for OSI, where a significant difference was noted (p < 0.05). Meanwhile, in terms of thrombus growth, the thrombus growing at the tear of the Type I (transverse tear) CAD model extended into the true lumen earlier than that of the Type II (longitudinal tear) model. CONCLUSIONS: Numerical simulations suggest that: (1) The CAD with transverse tear have a high risk of further tearing of the dissection at the distal end of the tear. (2) The CAD with longitudinal tear create a hemodynamic environment characterized by low TAWSS and high OSI in the false lumen, which may additionally increase the risk of vessel wall injury. (3) The CAD with transverse tear may have a higher risk of thrombosis and coronary obstruction and myocardial ischemia in the early phase of the dissection.

Antibacterial Ingredients and Modes of the Methanol-Phase Extract from the Fruit of Amomum villosum Lour.

Epidemics of infectious diseases threaten human health and society stability. Pharmacophagous plants are rich in bioactive compounds that constitute a safe drug library for antimicrobial agents. In this study, we have deciphered for the first time antibacterial ingredients and modes of the methanol-phase extract (MPE) from the fruit of Amomum villosum Lour. The results have revealed that the antibacterial rate of the MPE was 63.64%, targeting 22 species of common pathogenic bacteria. The MPE was further purified by high performance liquid chromatography (Prep-HPLC), and three different constituents (Fractions 1-3) were obtained. Of these, the Fraction 2 treatment significantly increased the cell membrane fluidity and permeability, reduced the cell surface hydrophobicity, and damaged the integrity of the cell structure, leading to the leakage of cellular macromolecules of Gram-positive and Gram-negative pathogens (p < 0.05). Eighty-nine compounds in Fraction 2 were identified by ultra HPLC-mass spectrometry (UHPLC-MS) analysis, among which 4-hydroxyphenylacetylglutamic acid accounted for the highest 30.89%, followed by lubiprostone (11.86%), miltirone (10.68%), and oleic acid (10.58%). Comparative transcriptomics analysis revealed significantly altered metabolic pathways in the representative pathogens treated by Fraction 2 (p < 0.05), indicating multiple antibacterial modes. Overall, this study first demonstrates the antibacterial activity of the MPE from the fruit of A. villosum Lour., and should be useful for its application in the medicinal and food preservative industries against common pathogens.

Mendelian randomization and colocalization analysis reveal novel drug targets for myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is a complex autoimmune disease affecting the neuromuscular junction with limited drug options, but the field of MG treatment recently benefits from novel biological agents. We performed a drug-targeted Mendelian randomization (MR) study to identify novel therapeutic targets of MG. METHODS: Cis-expression quantitative loci (cis-eQTL), which proxy expression levels for 2176 druggable genes, were used for MR analysis. Causal relationships between genes and disease, identified by eQTL MR analysis, were verified by comprehensive sensitivity, colocalization, and protein quantitative loci (pQTL) MR analyses. The protein-protein interaction (PPI) analysis was also performed to extend targets, followed by enzyme-linked immunosorbent assay (ELISA) to explore the serum level of drug targets in MG patients. A phenome-wide MR analysis was then performed to assess side effects with a clinical trial review assessing druggability. RESULTS: The eQTL MR analysis has identified eight potential targets for MG, one for early-onset MG and seven for late-onset MG. Further colocalization analyses indicated that CD226, CDC42BPB, PRSS36, and TNFSF12 possess evidence for colocalization with MG or late-onset MG. pQTL MR analyses identified the causal relations of TNFSF12 and CD226 with MG and late-onset MG. Furthermore, PPI analysis has revealed the protein interaction between TNFSF12-TNFSF13(APRIL) and TNFSF12-TNFSF13B(BLyS). Elevated TNFSF13 serum level of MG patients was also identified by ELISA experiments. This study has ultimately proposed three promising therapeutic targets (TNFSF12, TNFSF13, TNFSF13B) of MG. CONCLUSIONS: Three drug targets associated with the BLyS/APRIL pathway have been identified. Multiple biological agents, including telitacicept and belimumab, are promising for MG therapy.

Circular RNA Vaccines against Monkeypox Virus Provide Potent Protection against Vaccinia Virus Infection in mice.

Since the outbreak of mpox in 2022, widespread concern has been placed on imposing an urgent demand for specific vaccines that offer safer and more effective protection. Using an efficient and scalable circular RNA (circRNA) platform, we constructed four circRNA vaccines that could induce robust neutralizing antibodies as well as T-cell responses by expressing different surface proteins of monkeypox virus (MPXV), resulting in potent protection against vaccinia virus (VACV) in mice. Strikingly, the combination of the four circular RNA vaccines demonstrated the best protection against VACV challenge among all the tested vaccines. Our study provides a favorable approach for developing MPXV-specific vaccines by using a circular mRNA platform and opens up novel avenues for future vaccine research.

Effects of Cu2O nanoparticles on the kinetic characteristics of rapid chlorophyll fluorescence induction and related genes in wheat seedlings.

Metal nanoparticles could be accumulated in soils, which threatens the ecological stability of crops. Investigating the effects of cuprous oxide nanoparticles (Cu2O-NPs) on photosystem Ⅱ (PSⅡ) of wheat seedling leaves holds considerable importance in comprehending the implications of Cu2O-NPs on crop photosynthesis. Following the hydroponic method, we investigated the effects of 0, 10, 50, 100, and 200 mg·L-1 Cu2O-NPs on chlorophyll fluorescence induction kinetics and photosynthetic-related genes in wheat seedlings of "Zhoumai 18". The results showed that, with the increases of Cu2O-NPs concentrations, chlorophyll contents in wheat leaves decreased, and the standardization of the OJIP curve showed a clearly K-phase (ΔK＞0). Cu2O-NPs stress increased the parameters of active PSⅡ reaction centers, including the absorption flux per active RC (ABS/RC), the trapping flux per active RC (TRo/RC), the electron transport flux per active RC (ETo/RC), and the dissipation flux per active RC (DIo/RC). Cu2O-NPs stress decreased the parameters of PSⅡ energy distribution ratio including the maximum quantum yield of PSⅡ (φPo), the quantum yield of electron transport from QA (φEo), and the probability that a trapped exciton moved an electron further than QA (Ψo), while increased the quantum ratio for heat dissipation (φDo). Moreover, there was a decrease in photosynthetic quantum yield Y(Ⅱ), photochemical quenching coefficient (qP), net photosynthetic rate (Pn), stomatal conductance (gs), intercellular CO2 concentration (Ci), and transpiration rate (Tr) of leaves with the increases of Cu2O-NPs concentration. Under Cu2O-NPs stress, the expression levels of genes which included PSⅡ genes (PsbD, PsbP, Lhcb1), Rubisco large subunit genes (RbcL), cytochrome b6/f complex genes (PetD, Rieske), and ATP synthase genes (AtpA, AtpB, AtpE, AtpI) were downregulated. These results indicated that Cu2O-NPs stress altered the activity and structure of PSⅡ in wheat seedlings, affected the activity of PSⅡ reaction centers, performance parameters of PSⅡ donor and acceptor sides. PSⅡ related genes were downregulated and exhibited significant concentration effects.

[Review of clinical effects of disk-up sinus reamer(DSR)-based internal sinus floor elevation with implantation in 10 years].

PURPOSE: To analyze the bone remodeling around the implant 10 years after disk-up sinus reamer(DSR)-based internal sinus floor elevation with implantation and to investigate the influence of different factors on implant retention. METHODS: The clinical and imaging data of patients undergoing DSR-based sinus floor elevation with simultaneous implantation were collected from the Department of Dental Implantology, Affiliated Hospital of Qingdao University from January 2008 to December 2011. Panoramic film and CBCT were used to measure the changes of bone mass around implant in different periods. Kaplan-Meier and Log-rank tests were used to analyze the effects of different factors on implant retention with SPSS 26.0 software package. RESULTS: The study included 98 patients with a total of 128 implants. During the follow-up of 0-168 months, 7 implants failed, and the remaining formed good osseointegration and functioned, with a 10-year cumulative retention rate of 94.53%. The height of bone formation was (0.29±0.15) mm at the top and (2.74±0.66) mm in the sinus of 75 implant sites with complete imaging data obtained ten years after surgery. Kaplan-Meier and Log-rank tests showed that 8 factors including initial bone height, elevated bone height, mucosal perforation, implant length, implant torsion, diabetes, smoking and periodontitis had significant effects on implant retention. CONCLUSIONS: The DSR-based internal sinus floor elevation with implantation is a reliable and stable bone augmentation operation for vertical bone defect in maxillary posterior region, with a 10-year cumulative retention rate of no less than 94%. Initial bone height, elevated bone height, mucosal perforation, implant length, implant torsion, diabetes, smoking and periodontitis are the important factors affecting the long-term retention rate of implants.

Adjuvant Transarterial Chemoembolization Plus Immunotherapy for Huge Hepatocellular Carcinoma: A Propensity Score Matching Cohort Study.

Purpose: The prognosis of patients with huge hepatocellular carcinoma (huge HCC, diameter ≥10 cm) is poor owing to the high early recurrence rate. This study aimed to explore the clinical value of postoperative adjuvant transarterial chemoembolization (PA-TACE) plus programmed cell death-1 (PD-1) inhibitors for huge HCC. Patients and Methods: Data from consecutive huge HCC patients treated with hepatectomy during June 2017 and July 2022 were retrospectively collected. Baseline differences were balanced between huge HCC patients who underwent PA-TACE with (AIT group) or without PD-1 inhibitors (AT group) by propensity-score matching (PSM). We compared recurrence-free survival (RFS), overall survival (OS) and recurrence patterns between the two groups. Independent risk factors for RFS and OS were confirmed by Cox regression analysis, and subgroup analysis was also conducted. Results: A total of 294 patients were enrolled, and 77 pairs of patients in the AIT and AT groups were matched by PSM. The 1-year and 2-year RFS were 49.9% and 35.7% in the AIT group compared to 24.7% and 15.5% in the AT group respectively (p<0.001). The 1-year and 2-year OS were 83.6% and 66.9% in the AIT group compared to 50.6% and 36.8% in the AT group respectively (p<0.001). There were no significant differences in recurrence patterns between the two groups. Multivariable analysis demonstrated that combined therapy of PA-TACE plus PD-1 inhibitors was a protective factor related to both RFS and OS. Conclusion: PA-TACE plus PD-1 inhibitors could improve survival outcomes for huge HCC patients.

Primary cilia restrict autoinflammation by mediating PD-L1 expression.

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Engineering an (R)-selective transaminase for asymmetric synthesis of (R)-3-aminobutanol.

(R)-selective transaminases show promise as catalysts for the asymmetric synthesis of chiral amines, which are building blocks of various small molecule drugs. However, their application is limited by poor substrate acceptance and low catalytic efficiency. Here, a potential (R)-selective transaminase from Fodinicurvata sediminis (FsTA) was identified through a substrate truncating strategy, and used as starting point for enzyme engineering toward catalysis of 4-hydroxy-2-butanone, a substrate that poses challenges in catalysis. Molecular docking and dynamics simulations revealed Y90 as the key residue responsible for poor substrate binding. Starting from the variant (Y90F, mut1) with initial activity, FsTA was systematically modified to improve substrate-binding through active site reshaping and consensus sequence strategy, yielding three variants (H30R, V152K, and Y156F) with improved activity. A quadruple mutation variant H30R/Y90F/V152K/Y156F (mut4) was also found to show a 7.95-fold greater catalytic efficiency (kcat/KM) than the initial variant mut1. Furthermore, mut4 also enhanced the thermostability of enzyme significantly, with the Tm value increasing by 10 °C. This variant also exhibited significantly improved activity toward a series of ketones that are either not accepted or poorly accepted by the wild-type. This study provides a basis for the rational design of an active to creating variants that can accommodate novel substrates.

A novel hybrid machine learning model for auxiliary diagnosing myocardial ischemia.

Introduction: Accurate identification of the myocardial texture features of fat around the coronary artery on coronary computed tomography angiography (CCTA) images are crucial to improve clinical diagnostic efficiency of myocardial ischemia (MI). However, current coronary CT examination is difficult to recognize and segment the MI characteristics accurately during earlier period of inflammation. Materials and methods: We proposed a random forest model to automatically segment myocardium and extract peripheral fat features. This hybrid machine learning (HML) model is integrated by CCTA images and clinical data. A total of 1,316 radiomics features were extracted from CCTA images. To further obtain the features that contribute the most to the diagnostic model, dimensionality reduction was applied to filter features to three: LNS, GFE, and WLGM. Moreover, statistical hypothesis tests were applied to improve the ability of discriminating and screening clinical features between the ischemic and non-ischemic groups. Results: By comparing the accuracy, recall, specificity and AUC of the three models, it can be found that HML had the best performance, with the value of 0.848, 0.762, 0.704 and 0.729. Conclusion: In sum, this study demonstrates that ML-based radiomics model showed good predictive value in MI, and offer an enhanced tool for predicting prognosis with greater accuracy.

Target and Semitarget Analysis of Advanced Glycation End Products Using a New Pair of Permanently Positively Charged Stable Isotope Labeling Agents.

A pair of positively charged stable isotope labeling (SIL) agents, (4-carbonochloridoylphenyl)-trimethylazanium iodide (d0-CCPTA) and d6-CCPTA, were designed and synthesized. These agents were employed in the precolumn labeling of advanced glycation end products (AGEs) within 5 min under mild conditions. Through derivatization, the mass spectrometry response of the AGEs was enhanced by approximately 2 orders of magnitude. The detection and quantitation limits were in the ranges of 3.1-7.1 and 10.0-23.7 ng/kg, respectively. The recoveries were in the range of 90.1-94.3%, and the matrix effect ranged from -6.6 to -3.5%. CCPTA produced "CCPTA-specific production ions", and all analytes were analyzed by common multiple reaction monitoring (MRM) parameters. The common MRM parameters were applied to the semitarget analysis of 41 types of AGE candidates in the absence of standards, with 13 AGEs identified.

Downregulation of the CD151 protects the cardiac function by the crosstalk between the endothelial cells and cardiomyocytes via exosomes.

BACKGROUND: Heart failure (HF) is the last stage in the progression of various cardiovascular diseases. Although it is documented that CD151 contributes to regulate the myocardial infarction, the function of CD151 on HF and involved mechanisms are still unclear. METHOD AND RESULTS: In the present study, we found that the recombinant adeno-associated virus (rAAV)-mediated endothelial cell-specific knockdown of CD151-transfected mice improved transverse aortic constriction (TAC)-induced cardiac function, attenuated myocardial hypertrophy and fibrosis, and increased coronary perfusion, whereas overexpression of the CD151 protein aggravated cardiac dysfunction and showed the opposite effects. In vitro, the cardiomyocytes hypertrophy induced by PE were significantly improved, while the proliferation and migration of cardiac fibroblasts (CFs) were significantly reduced, when co-cultured with the CD151-silenced endothelial cells (ECs). To further explore the mechanisms, the exosomes from the CD151-silenced ECs were taken by cardiomyocyte (CMs) and CFs, verified the intercellular communication. And the protective effects of CD151-silenced ECs were inhibited when exosome inhibitor (GW4869) was added. Additionally, a quantitative proteomics method was used to identify potential proteins in CD151-silenced EC exosomes. We found that the suppression of CD151 could regulate the PPAR signaling pathway via exosomes. CONCLUSION: Our observations suggest that the downregulation of CD151 is an important positive regulator of cardiac function of heart failure, which can regulate exosome-stored proteins to play a role in the cellular interaction on the CMs and CFs. Modulating the exosome levels of ECs by reducing CD151 expression may offer novel therapeutic strategies and targets for HF treatment.

Identification of End-Binding 1 Protein as Novel α-4 Giardin-Binding Partners in Giardia lamblia Trophozoites.

BACKGROUND: Giardia lamblia (syn. G. intestinalis, G. duodenalis) is a primitive opportunistic protozoon, and one of the earliest differentiated eukaryotes. Despite its primitive nature, G. lamblia has a sophisticated cytoskeleton system, which is closely related to its proliferation and pathogenicity. Meanwhile, α giardin is a G. lamblia-specific cytoskeleton protein, which belongs to the annexin superfamily. Interestingly, G. lamblia has 21 annexin-like α giardins, i.e., more than higher eukaryotes. The functional differences among α giardin members are not fully understood. METHODS: We took α-4 giardin, a member of α giardin family, as a research object. A morpholino-mediated knockdown experiment was performed to identify the effect of α-4 giardin on G. lamblia trophozoites biological traits. A yeast two-hybrid cDNA library of G. lamblia strain C2 trophozoites was screened for interaction partners of α-4 giardin. Co-immunoprecipitation and fluorescent colocalization confirmed the relationship between G. lamblia EB1 (gEB1) and α-4 giardin. RESULTS: α-4 Giardin could inhibit the proliferation and adhesion of G. lamblia trophozoites. In addition, it interacted with G. lamblia EB1 (gEB1). CONCLUSIONS: α-4 Giardin was involved in proliferation and adhesion in G. lamblia trophozoites, and EB1, a crucial roles in mitosis, was an interacting partner of α-4 giardin.

AZD1775 and anti-PD-1 antibody synergistically sensitize hepatoma to radiotherapy.

BACKGROUND: Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma. METHODS: The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro . A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8 + T cells in TME were analyzed by flow cytometry. RESULTS: Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro . AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1 + /CD8 + T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ) + or Ki67 + CD8 T cells and decreasing the levels of CD8 + Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8 + T cells proliferation, and weakening CD8 + T cells depletion. CONCLUSIONS: This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8 + T cells in TME.

Comparative effectiveness and safety of intravenous methylprednisolone and tacrolimus monotherapy in ocular myasthenia gravis with unsatisfactory prednisone responses: a retrospective study.

BACKGROUND: Oral prednisone has been recognized as the first-line therapy for the treatment of ocular myasthenia gravis (OMG). However, its long-term use is complicated by numerous adverse effects and is ineffective for some OMG patients in reaching remission. This study aimed to evaluate the effectiveness and safety of intravenous methylprednisolone (IVMP) and tacrolimus monotherapy for OMG patients with unsatisfactory responses to conventional prednisone therapy. METHODS: We retrospectively reviewed 57 OMG patients who had not achieved satisfactory improvement after prednisone therapy and thereby received IVMP or tacrolimus monotherapy for at least 6 months. Ocular symptoms were evaluated by the ocular-quantitative MG (QMG) score at each time point. A ≥ 2-point fall in ocular QMG score was defined as the cut-off point to indicate clinical improvement. Logistic regression analysis was performed to identify factors associated with the efficacy of IVMP at discharge. Adverse events were recorded. RESULTS: Both IVMP and tacrolimus monotherapy demonstrated significant clinical efficacy, with no statistical differences observed at the study endpoint. The proportions of patients who reached the cut-off point for efficacy evaluation were higher in the IVMP group than in the tacrolimus group (1, 3, and 6 months: 51.7% (15/29) vs 12.0% (3/25), p = 0.002; 69.0% (20/29) vs 40.0% (10/25), p = 0.033; 69.0% (20/29) vs 46.4% (13/28), p = 0.085, respectively). Multivariate logistics analysis showed that high ocular QMG scores at baseline indicated favourable responses to IVMP treatment (OR = 1.781; 95% CI 1.066-2.975; p = 0.028). All the adverse events were transient and tolerable. CONCLUSION: Our findings suggest that both IVMP and tacrolimus monotherapy hold promise as viable treatment options for OMG patients with unsatisfactory responses to oral prednisone. The study supports the safety and effectiveness of both therapies, with IVMP exhibiting faster improvement and favourable efficacy in patients with high ocular QMG scores.

Adjusted Preferential Adsorption of Intermediates via Regulation of the Electronic Structure during the Electrocatalytic CO2 Reduction Process.

The surface electronic structures of catalysts play a crucial role in CO2 adsorption and activation. Here, sulfur vacancies are introduced into CuInS2 nanosheets (Vs-CuInS2) to evaluate the effect of electronic structures at the surface-active sites on the electrochemical CO2 reduction reaction (CO2RR). Vs-CuInS2 exhibits a significant disparity in the highest FEformate/FECO (6.50) compared to that of CuInS2 (1.86). Specifically, the maximum current density (Jmax) of carbon products on Vs-CuInS2 is 78.78 mA cm-2, and a Faraday efficiency of carbon products (FEcarbon products) of ≥80% is achieved in 600 mV wide potential windows. In situ Raman measurements and density functional theory calculations elucidate the origin of the apparent alterations in the carbon product selectivity. The introduction of sulfur vacancies realizes the controllable regulation of the local electronic density around the metal active sites, inducing the transformation of *COOH and *OCHO from competitive adsorption on CuInS2 to specific adsorption on Vs-CuInS2. In addition, the regulation of electronic structures on Vs-CuInS2 inhibits *H adsorption. This work reveals the transfer of adsorption of CO2RR intermediates via regulation of the electronic structure, complementing the understanding of the mechanism for the enhanced CO2RR.

Integrated cell metabolomics and network pharmacology approach deciphers the anti-testosterone deficiency mechanisms of Bushen Zhuanggu Tang.

Testicular dysfunction is distinguished by a deficiency in testosterone levels, which can be attributed to the occurrence of oxidative stress injury in Leydig cells. The empirical prescription known as Bushen Zhuanggu Tang, developed by a highly experienced traditional Chinese medicine practitioner with six decades of clinical expertize, aligns with the traditional Chinese medicine principle of "kidney governing bone". Researchers have demonstrated that the administration of BSZGT can effectively enhance testosterone production. The objective of this study is to investigate the potential anti-testicular dysfunction effects of BSZGT and elucidate its underlying mechanism in an in vitro setting. Specifically, the impact of oxidative stress induced by H2O2 on the activity and testosterone levels of Leydig cells (TM3) was examined. Furthermore, the utilization of UPLC-QE-Qrbitrap-MS enabled the identification of the involvement of BSZGT in various metabolic pathways, including arginine biosynthesis, amino acyl-tRNA biosynthesis, Alanine, aspartate and glutamine metabolism, and Citrate Cycle, through the modulation of 25 distinct metabolites. Additionally, a network pharmacological analysis was conducted to investigate the pivotal protein targets associated with the therapeutic effects of BSZGT. The findings demonstrate the identification of six key proteins (CYP19A1, CYP1B1, ALOX5, ARG1, XDH, and MPO) that play a significant role in augmenting testicular function through their involvement in the ovarian steroid production pathway. In summary, our study presents a comprehensive research methodology that combines cell metabonomics and network pharmacology to enhance the discovery of new therapeutic agents for TD.

Study of the Mechanism of Astragali Radix in Treating Type 2 Diabetes Mellitus and Its Renal Protection Based on Enzyme Activity, Network Pharmacology, and Experimental Verification.

Astragali Radix (AR) is a common Chinese medicine and food. This article aims to reveal the active role of AR in treating Type 2 diabetes mellitus (T2DM) and its renal protective mechanism. The hypoglycemic active fraction was screened by α-glucosidase and identified by UPLC-QE-Orbitrap-MS spectrometry. The targets and KEGG pathway were determined through the application of network pharmacology methodology. Molecular docking and molecular dynamics simulation technology were used for virtual verification. Subsequently, a mouse model of T2DM was established, and the blood glucose and renal function indexes of the mice after administration were analyzed to further prove the pharmacodynamic effect and mechanism of AR in the treatment of T2DM. HA was determined as the best hypoglycemic active fraction by the α-glucosidase method, with a total of 23 compounds identified. The main active components, such as calycoside-7-O-ß-D-glucoside, methylnisoline, and formononetin, were revealed by network pharmacology. In addition, the core targets and the pathway have also been determined. Molecular docking and molecular dynamics simulation techniques have verified that components and targets can be well combined. In vivo studies have shown that AR can reduce blood sugar levels in model mice, enhance the anti-inflammatory and antioxidant activities of kidney tissue, and alleviate kidney damage in mice. And it also has regulatory effects on proteins such as RAGE, PI3K, and AKT. AR has a good therapeutic effect on T2DM and can repair disease-induced renal injury by regulating the RAGE/PI3K/Akt signaling pathway. This study provides ideas for the development of new drugs or dietary interventions for the treatment of T2DM.