Study on the differential hepatotoxicity of raw polygonum multiflorum and polygonum multiflorum praeparata and its mechanism.

BACKGROUND: Polygonum multiflorum (PM), a widely used traditional Chinese medicine herb, is divided into two forms, namely raw polygonum multiflorum (RPM) and polygonum multiflorum praeparata (PMP), according to the processing procedure. Emerging data has revealed the differential hepatotoxicity of RPM and PMP, however, its potential mechanism is still unclear. METHODS: In our study, we investigated the differential hepatotoxicity of RPM and PMP exerted in C57BL/6 mice. First, sera were collected for biochemical analysis and HE staining was applied to examine the morphological alternation of the liver. Then we treated L02 cells with 5 mg / mL of RPM or PMP. The CCK8 and EdU assays were utilized to observe the viability and proliferation of L02 cells. RNA sequencing was performed to explore the expression profile of L02 cells. Western blotting was performed to detect the expression level of ferroptosis-related protein. Flow cytometry was used to evaluate ROS accumulation. RESULTS: In our study, a significant elevation in serum ALT, AST and TBIL levels was investigated in the RMP group, while no significant differences were observed in the PMP group, compared to that of the CON group. HE staining showed punctate necrosis, inflammatory cell infiltration and structural destruction can be observed in the RPM group, which can be significantly attenuated after processing. In addition, we also found RPM could decrease the viability and proliferation capacity of L02 cells, which can be reversed by ferroptosis inhibitor. RNA sequencing data revealed the adverse effect of PM exerted on the liver is closely associated with ferroptosis. Western blotting assay uncovered the protein level of GPX4, HO-1 and FTL was sharply decreased, while the ROS content was dramatically elevated in L02 cells treated with RPM, which can be partially restored after processing. CONCLUSIONS: The hepatotoxicity induced by RPM was significantly lower than the PMP, and its potential mechanism is associated with ferroptosis.

Ziyuglycoside II attenuated OVX mice bone loss via inflammatory responses and regulation of gut microbiota and SCFAs.

BACKGROUND AND PURPOSE: Osteoporosis (OP) is a frequent clinical problem for the elderly. Traditional Chinese Medicine (TCM) has achieved beneficial results in the treatment of OP. Ziyuglycoside II (ZGS II) is a major active compound of Sanguisorba officinalis L. that has shown anti-inflammation and antioxidation properties, but little information concerning its anti-OP potential is available. Our research aims to investigate the mechanism of ZGS II in ameliorating bone loss by inflammatory responses and regulation of gut microbiota and short chain fatty acids (SCFAs) in ovariectomized (OVX) mice. METHODS: We predicted the mode of ZGS II action on OP through network pharmacology and molecular docking, and an OVX mouse model was employed to validate its anti-OP efficacy. Then we analyzed its impact on bone microstructure, the levels of inflammatory cytokines and pain mediators in serum, inflammation in colon, intestinal barrier, gut microbiota composition and SCFAs in feces. RESULTS: Network pharmacology identified 55 intersecting targets of ZGS II related to OP. Of these, we predicted IGF1 may be the core target, which was successfully docked with ZGS II and showed excellent binding ability. Our in vivo results showed that ZGS II alleviated bone loss in OVX mice, attenuated systemic inflammation, enhanced intestinal barrier, reduced the pain threshold, modulated the abundance of gut microbiota involving norank_f__Muribaculaceae and Dubosiella, and increased the content of acetic acid and propanoic acid in SCFAs. CONCLUSIONS: Our data indicated that ZGS II attenuated bone loss in OVX mice by relieving inflammation and regulating gut microbiota and SCFAs.

Anthocyanin biosynthesis in goji berry is inactivated by deletion in a bHLH transcription factor LrLAN1b promoter.

Black goji berry (Lycium ruthenicum Murray) contains a rich source of health-promoting anthocyanins which are used in herbal medicine and nutraceutical foods in China. A natural variant producing white berries allowed us to identify two key genes involved in the regulation of anthocyanin biosynthesis in goji berries: one encoding a MYB transcription factor (LrAN2-like) and one encoding a basic helix-loop-helix (bHLH) transcription factor (LrAN1b). We previously found that LrAN1b expression was lost in the white berry variant, but the molecular basis for this phenotype was unknown. Here, we identified the molecular mechanism for loss of anthocyanins in white goji berries. In white goji, the LrAN1b promoter region has a 229 bp deletion that removes three MYB-binding elements and one bHLH-binding element, which are key to its expression. Complementation of the white goji berry LrAN1b allele with the LrAN1b promoter restored pigmentation. Virus-induced gene silencing of LrAN1b in black goji berry reduced fruit anthocyanin biosynthesis. Molecular analyses showed that LrAN2-like and another bHLH transcription factor LrJAF13 can activate LrAN1b by binding directly to the MYB-recognizing element and bHLH-recognizing element of its promoter-deletion region. LrAN1b expression is enhanced by the interaction of LrAN2-like with LrJAF13 and the WD40 protein LrAN11. LrAN2-like and LrAN11 interact with either LrJAF13 or LrAN1b to form two MYB-bHLH-WD40 complexes, which hierarchically regulate anthocyanin biosynthesis in black goji berry. This study on a natural variant builds a comprehensive anthocyanin regulatory network that may be manipulated to tailor goji berry traits.

Analyzing the molecular mechanism of xuefuzhuyu decoction in the treatment of pulmonary hypertension with network pharmacology and bioinformatics and verifying molecular docking.

BACKGROUND: XueFuZhuYu (XFZY), a typical Chinese herbal formula, has remarkable clinical effects for treating Pulmonary Hypertension (PH) with unclear mechanisms. Our research involved the utilization of network pharmacology to explore the traditional Chinese herbal monomers and their related targets within XFZY for PH treatment. Furthermore, molecular docking verification was performed. METHODS: The XFZY's primary active compounds, along with their corresponding targets, were both obtained from the TCMSP, ChEMBL, and UniProt databases. The target proteins relevant to PH were sifted through OMIM, GeneCards and TTD databases. The common "XFZY-PH" targets were evaluated with Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses with the assistance of R software. The Protein-Protein Interaction (PPI) network and compound-target-pathway network were constructed and a systematic analysis of network parameters was performed by the powerful software Cytoscape. Molecular docking was employed for assessing and verifying the interactions between the core targets and the top Chinese herbal monomer. RESULTS: The screening included 297 targets of active compounds in XFZY and 8400 PH-related targets. DO analysis of the above common 268 targets indicated that the treatment of the diseases by XFZY is mediated by genes related to Chronic Obstructive Pulmonary Disease (COPD), Obstructive Lung Disease (OLD), ischemia, and myocardial infarction. The findings from molecular docking indicated that the binding energies of 57 ligand-receptor pairs in PH and 20 ligand-receptor pairs in COPD-PH were lower than -7kJ•mol-1. CONCLUSIONS: This study indicates that XFZY is a promising option within traditional Chinese medicine compound preparation for combating PH, particularly in cases associated with COPD. Our demonstration of the specific molecular mechanism of XFZY anti-PH and its effective active ingredients provides a theoretical basis for better clinical application of the compound.

Decoding the mechanism of Eleutheroside E in treating osteoporosis via network pharmacological analysis and molecular docking of osteoclast-related genes and gut microbiota.

Objective: Eleutheroside E (EE) is an anti-inflammatory natural compound derived from the edible medicinal herb Acanthopanax senticosus. This study aims to investigate the underlying mechanism of the anti-osteoporosis action of EE through network pharmacology, molecular docking and gut microbiota. Materials and methods: Network pharmacology was used to explore the potential core targets and main pathways mediated by EE in osteoporosis (OP) treatment. Molecular docking was exploited to investigate the interactions between the active anti-OP compounds in EE and the potential downstream targets. Following the multi-approach bioinformatics analysis, ovariectomy (OVX) model was also established to investigate the in vivo anti-OP effects of EE. Results: The top 10 core targets in PPI network were TP53, AKT1, JUN, CTNNB1, STAT3, HIF1A, EP300, CREB1, IL1B and ESR1. Molecular docking results that the binding energy of target proteins and the active compounds was approximately between -5.0 and -7.0 kcal/mol, which EE has the lowest docking binding energy with HIF1A. Enrichment analysis of GO and KEGG pathways of target proteins indicated that EE treatment could potentially alter numerous biological processes and cellular pathways. In vivo experiments demonstrated the protective effect of EE treatment against accelerated bone loss, where reduced serum levels of TRAP, CTX, TNF-α, LPS, and IL-6 and increased bone volume and serum levels of P1NP were observed in EE-treated mice. In addition, changes in gut microbiota were spotted by 16S rRNA gene sequencing, showing that EE treatment increased the relative abundance of Lactobacillus and decreased the relative abundance of Clostridiaceae. Conclusion: In summary, these findings suggested that the characteristics of multi-target and multi-pathway of EE against OP. In vivo, EE prevents the onset of OP by regulating gut microbiota and inflammatory response and is therefore a potential OP drug.

Development and External Validation of a Nomogram for Predicting the Effect of RTX on the Treatment of Membranous Nephropathy.

Introduction: Rituximab (RTX) has been shown to be effective in inducing immunological remission in patients with membranous nephropathy (MN). Some patients required more than one course of RTX to achieve immunological remission. Identifying patients who need more courses of RTX to achieve immunological remission is beneficial for better physician-patient communication, the assessment of treatment course, and the evaluation of medical costs. This study aims to establish a practical model to predict the probability of immunological remission after receiving one cycle of RTX. Methods: This study enrolled 106 patients from the First Affiliated Hospital of Zhengzhou University in the modeling group and 30 patients from Henan Provincial Hospital of Traditional Chinese Medicine in the external validation group. Patients in the modeling group were divided into responders or nonresponders according to whether they achieved immunological remission or not after following up for 6 months. A nomogram was established based on the results of logistic regression analysis. The predictive performance of the nomogram was evaluated by the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis (DCAs). Results: In the modeling group, 75 (70.8%) patients achieved immunological remission within 6 months after receiving one cycle of RTX. Significant differences were observed between nonresponders and responders. Risk factors used in nomogram included PLA2R antibody, hemoglobin, and gender. The AUC value of nomogram was 0.797 (95% CI 0.701-0.894, P<0.001). The calibration curves demonstrated acceptable agreement between the predicted outcomes by the nomogram and the actual values. DCA curves showed good positive net benefits in the predictive model. The external validation also demonstrated the reliability of the prediction nomogram. Conclusion: A predictive nomogram including PLA2R antibody, hemoglobin, and gender may provide a basis to predict the doses of RTX needed in MN patients.

[Active components and potential mechanism of Taohong Siwu Decoction in regulating ischemic stroke based on target cell trapping combined with network pharmacology, molecular docking, and experimental validation].

The potential anti-stroke active components in Taohong Siwu Decoction(THSWD) were identified by target cell trapping coupled with ultra-high performance liquid chromatography-quadrupole-time of flight mass spectrometry(UPLC-Q-TOF-MS). The underlying mechanism of active components in THSWD in the treatment of ischemic stroke(IS) was explored by network pharmacology, molecular docking, and experimental validation. The UPLC-Q-TOF-MS technology combined with the UNIFI data analysis platform was used to analyze the composition of the cellular fragmentation fluid after co-incubation of THSWD with target cells. The targets of potential active components and IS were collected by network pharmacology, and the common targets underwent protein-protein interaction(PPI), Gene Ontology(GO), and Kyoto Encyclopedia of Genes and Genomes(KEGG) signaling pathway enrichment analyses. The target cell trapping component-core target-signaling pathway network was constructed, and the active components were molecularly docked to the top targets in the PPI network, followed by pharmacodynamic validation in vitro. Fifteen active components were identified in the target cellular fragmentation fluid, including bicyclic monoterpenes, cyanoglycosides, flavonols, quinoid chalcones, phenylpropanoids, and tannins. As revealed by the analysis of network pharmacology, THSWD presumably regulated PI3K-AKT, FoxO, MAPK, Jak-STAT, VEGF, HIF-1, and other signaling pathways to affect inflammatory cascade reaction, angiogenesis, oxidative stress, pyroptosis, apoptosis, and other pathological processes via paeoniflorin, butylphthalide, dehydrated safflower yellow B, 3,4-dicaffeoylquinic acid, amygdalin, paeoniflorin, and ligusticolactone. Molecular docking and in vitro pharmacodynamic validation revealed that the target cell trapping active components could promote neovascularization in rat brain microvascular endothelial cells(rBMECs) in the oxygen-glucose deprivation/reoxygenation(OGD/R) model. The application of target cell trapping coupled with UPLC-Q-TOF-MS technology can rapidly screen out the potential active components in THSWD. The active components of THSWD can be predicted to intervene in the pathogenesis of IS through network pharmacology, and molecular docking combined with experimental validation can further clarify the efficacy, thus providing a theoretical basis for research ideas on the pharmacodynamic substance basis of traditional Chinese medicine compounds.

Efficacy Analysis of Wandai Decoction Combined with Traditional Chinese Medicine Fumigation and Washing in Patients with Chronic Vaginitis After Sintilimab Treatment for Small Cell Lung Cancer.

Objective: To investigate the effect of Wandai decoction combined with traditional Chinese medicine fumigation and washing in patients with chronic vaginitis after sintilimab treatment for small cell lung cancer. Methods: We recruited 80 patients who developed chronic vaginitis after sintilimab treatment for small cell lung cancer from Hainan General Hospital from January 2020 to June 2022; using a random number table, 40 were assigned to a control group and 40 were assigned to an observation group. The control group was treated with Wandai decoction, and the observation group was treated with Wandai decoction combined with traditional Chinese medicine fumigation and washing. The 2 groups were compared for improvement of the symptoms of vulvar pruritus subsidence time, leukorrhea recovery time, and traditional Chinese medicine symptom score; levels of the vaginal microecological environment factors immunoglobulin G, secretory immunoglobulin A, and pH; levels of the serum inflammatory factors C-reactive protein, tumor necrosis factor, and interleukin-6; and clinical efficacy. Results: After treatment, the observation group had significantly higher vulvar pruritus subsidence time, leukorrhea recovery time, traditional Chinese medicine symptom score, and pH value; significantly lower levels of C-reactive protein, tumor necrosis factor, and interleukin-6; and significantly higher levels of immunoglobulin G, secretory immunoglobulin A, and total effective rate compared with the control group (all P < .0.001). Conclusions: Wandai decoction combined with traditional Chinese medicine fumigation and washing was effective in treating chronic vaginitis after sintilimab treatment for small cell lung cancer. The treatment ameliorated symptoms of leukorrhea abnormalities, vulvar pruritus, and local inflammation, and promoted the recovery of the vaginal microbial environment. Despite the limitations of our study (small sample size and lack of comparison between different types of chronic vaginitis, which hinders the confirmation of extensive efficacy), we consider Wandai decoction combined with traditional Chinese medicine fumigation and washing worthy of promotion and application in clinical practice.

Concurrent chemoradiotherapy followed by adjuvant cisplatin-gemcitabine versus cisplatin-fluorouracil chemotherapy for N2-3 nasopharyngeal carcinoma: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma. METHODS: We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up. FINDINGS: From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths. INTERPRETATION: Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.

Age is Not the Most Important Factor in the Prognosis of Femoral Neck Fracture: An Analysis of Long-Term Clinical Follow-Up.

Objective: The prognosis of femoral neck fractures is affected by factors including age and type of fracture. This study aimed to explore the associations among postsurgical outcomes of internal fixation for femoral neck fracture (healing rate, necrosis rate, and joint function score) and age and type of fracture. Methods: We retrospectively analyzed 297 cases of femoral neck fracture treated with internal fixation between February 2008 and October 2018. The postoperative femoral neck nonunion rate (a measure of healing) and femoral head necrosis rate were determined by x-ray and computed tomography. The Harris hip score (a measure of joint function and pain) was calculated. The effects of age and fracture type on these factors were analyzed. Results: There was no significant difference in the rate of femoral head necrosis and postoperative joint function scores among the different age groups. There was a significant difference in the postoperative rate of femoral head necrosis by Garden (P = .001) and Pauwels (P = .01) fracture types. No significant differences were noted for the Harris hip score for fractures characterized by the Pauwels classification (P = .09). However, the Harris hip scores differed significantly among groups for fractures categorized by the Garden classification (P = .001). Conclusions: Fracture type but not age is closely related to femoral head necrosis and Harris hip score after internal fixation of femoral neck fractures.

External Application of Traditional Chinese Medicine in the Prevention and Treatment of Nausea and Vomiting Caused by Chemotherapy of Non-Small-Cell Lung Cancer: A RCT Study.

Objective: To investigate the external application of traditional Chinese medicine in the prevention and treatment of nausea and vomiting caused by chemotherapy of non-small-cell lung cancer. Methods: This is a prospective trial. A total of 114 patients with non-small-cell lung cancer who were hospitalized in our hospital from October 2020 to March 2022 were selected and randomly divided into the research group and the control group at the ratio of 1 : 1. The control group received chemotherapy + tropisetron 4 mg intravenous drip 30 minutes before chemotherapy./day × 3 days. The research group received chemotherapy + intravenous infusion of tropisetron 4 mg 30 minutes before chemotherapy, once a day for 3 days + external application of traditional Chinese medicine for 5 days. The therapeutic effects of the two groups of patients were compared. Results: After treatment, the serum creatinine, urea nitrogen, and endogenous creatinine in the research group were better than those in the control group (t = 15.943, 12.005, and 13.325; P=0.001, 0.005, and 0.005). After treatment, ALT and TBIL in the research group were superior to those in the control group (t = 11.583, 10.012, and 9.426; P=0.001, 0.002, and 0.001). After treatment, the physiological status, social/family status, emotional status, and family status of the research group were significantly better than those in the control group (t = 16.274, 5.379, 5.142, and 8.153; P=0.005, 0.000, 0.002, and 0.001). After treatment, the ECOG score and KPS score (82.46 ± 4.61) of the research group were significantly different from those of the control group (t = 11.913 and 9.357; P=0.035 and 0.001). The effective rate (χ 2 = 11.724; P=0.000) of the research group was higher but the incidence of adverse reaction (χ 2 = 4.294; P=0.001) was lower than that of the control group. Conclusion: External application of traditional Chinese medicine can significantly reduce nausea and vomiting caused by chemotherapy of non-small-cell lung cancer and can improve the patient's body and quality of life, which is worthy of clinical research and promotion.

A Distinct Hibiscus sabdariffa Extract Prevents Iron Neurotoxicity, a Driver of Multiple Sclerosis Pathology.

Iron deposition in the brain begins early in multiple sclerosis (MS) and continues unabated. Ferrous iron is toxic to neurons, yet the therapies used in MS do not counter iron neurotoxicity. Extracts of Hibiscus sabdariffa (HS) are used in many cultures for medicinal purposes. We collected a distinct HS extract and found that it abolished the killing of neurons by iron in culture; medications used in MS were ineffective when similarly tested. Neuroprotection by HS was not due to iron chelation or anthocyanin content. In free radical scavenging assays, HS was equipotent to alpha lipoic acid, an anti-oxidant being tested in MS. However, alpha lipoic acid was only modestly protective against iron-mediated killing. Moreover, a subfraction of HS without radical scavenging activity negated iron toxicity, whereas a commercial hibiscus preparation with anti-oxidant activity could not. The idea that HS might have altered properties within neurons to confer neuroprotection is supported by its amelioration of toxicity caused by other toxins: beta-amyloid, rotenone and staurosporine. Finally, in a mouse model of MS, HS reduced disability scores and ameliorated the loss of axons in the spinal cord. HS holds therapeutic potential to counter iron neurotoxicity, an unmet need that drives the progression of disability in MS.

Biodegradable Polymer with Effective Near-Infrared-II Absorption as a Photothermal Agent for Deep Tumor Therapy.

Photothermal therapy holds great promise for cancer treatment due to its effective tumor ablation and minimal invasiveness. Herein a new class of biodegradable photothermal agents with effective adsorption in both near-infrared-I (NIR-I) and NIR-II windows is reported for deep tumor therapy. As demonstrated in a deep-seated ovarian cancer model, photothermal therapy using 1064 nm irradiation effectively inhibits tumor progression and prolongs survival spans. This work provides a new design of photothermal agents toward a more effective therapy of tumors.

Dynamic Microbial Shifts and Signatures of Long-Term Remission in Allergic Rhinitis After an Herbal Formula Treatment.

A mixed Chinese herbal formula, Xiao-Qing-Long-Decoction (XQLD), may contribute to sustained remission in allergic rhinitis (AR), but it is unknown which factors determine such long-term effect. Here, we aimed to identify bacterial signatures associated with sustained remission. To this end, samples from AR patients at four different times were analyzed to compare the dynamic bacterial community and structure shifts. Diversity indices Chao1 showed significant difference across different time (p<0.05), and the Kruskal-Wallis test identified that Dialister (OTU_31), Roseburia (OTU_36), Bacteroides (OTU_22), Bacteroides (OTU_2040), and Prevotella_9 (OTU_5) were the significant differential bacterial taxa (p<0.05). These distinctive genera were significantly associated with the change of AR clinical indices and the predicted functional pathways such as PPAR signaling pathway, peroxisome, and citrate cycle (TCA cycle) (p<0.05), indicating that they may be important bacterial signatures involving in the sustained remission in AR (p<0.05). Besides, lower Firmicutes/Bacteroidetes (F/B) ratio at 6 months follow-up may also contribute to the long-term remission of AR. No seriously adverse events and safety concerns were observed in this study. In conclusion, XQLD is a meaningful, long-term efficient and safe medication for AR treatment. The underlying mechanisms of sustained remission in AR after XQLD treatment may be associated with the dynamic alteration of featured gut bacteria taxa.

Self-Powered Photoelectrochemical Aptasensor for Oxytetracycline Cathodic Detection Based on a Dual Z-Scheme WO3/g-C3N4/MnO2 Photoanode.

With the high sensitivity and anti-interference provided by a dual Z-scheme structure photoanode and a two-electrode system, a high-performance self-powered photoelectrochemical (PEC) aptasensor for oxytetracycline (OTC) detection was established in this work. Graphitic carbon nitride (g-C3N4) with excellent photoelectric properties was used to be combined with WO3 and MnO2 to form a kind of dual Z-scheme heterojunction. The designed unique structure and the complementary performances of the three materials collectively guaranteed the highly stable photocurrent output of the photoanode due to the wide range of light absorption and the high separation rate of electron-hole pairs. The aptamer-based cathode modified with reduced graphene oxide (rGO) and Au nanoparticles (Au NPs) provided high conductivity and aptamer-binding sites, which brought excellent selective recognition of OTC as well as the self-powered capacity by receiving electrons from the photoanode. In the PEC sensing of OTC, the device presented a wide detection range from 1 pM to 150 nM and a low detection limit of 0.1 pM. Besides, the developed PEC aptasenor showed good selectivity, reproducibility, and stability, so as to be applied to real samples. The proposed PEC sensing method can be considered an effective and promising direction for the detection of antibiotics in the future.

Retrospective analysis of Tripterygium wilfordii polyglycoside combined with angiotensin receptor blockers for the treatment of primary membranous nephropathy with sub-nephrotic proteinuria.

INTRODUCTION: Primary membranous nephropathy (PMN) is one common cause of end-stage kidney disease. There is no optimal treatment for PMN patients with sub-nephrotic proteinuria currently. Tripterygium wilfordii polyglycoside (TWG) is a widely used traditional medicine in China and has been used to treat nephropathy for decades. OBJECTIVE: To investigate the effect of TWG combined with angiotensin receptor blocker (ARB) on the treatment of PMN with sub-nephrotic proteinuria. METHODS: Biopsy-proven sub-nephrotic PMN patients with normal kidney function and treated with TWG combined with ARB or ARB alone were retrospectively analyzed. The primary outcome was remission rate (complete or partial remission), and the secondary outcomes included proteinuria, serum albumin levels, estimated glomerular filtration rate (eGFR), relapse rate, and adverse events. RESULTS: The clinical trial included 55 patients. The overall remission rates for the TWG + ARB and ARB groups after 9 months of treatment were 74.3% and 35%, respectively (p = 0.004). Moreover, the complete remission (CR) rate for the TWG + ARB and ARB groups in the 9th month were 45.7% and 15%, respectively (p = 0.044). Treatment with TWG + ARB was the independent predictor of complete remission of proteinuria (p = 0.048). Besides, the remission rate was higher in the TWG + ARB group than in the ARB group among patients who were positive for anti-phospholipase A2 receptor (PLA2R) antibodies (65.4% vs. 21.4%, p = 0.02). CONCLUSIONS: These data demonstrate that TWG may be a promising treatment for PMN patients with sub-nephrotic proteinuria, whether anti-PLA2R antibody is positive or negative.

The protective effect of Veronica ciliata Fisch. Extracts on relieving oxidative stress-induced liver injury via activating AMPK/p62/Nrf2 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Veronica ciliata Fisch. existed in various Tibetan medicine prescriptions, which was recorded to treat liver diseases in the Tibetan medicine roll of Chinese materia medica. HYPOTHESIS/PURPOSE: The current study aimed to examine the effect of active constituents from V.ciliata relieving oxidative stress-mediated liver injury and clarify the underlying mechanism. MATERIALS AND METHODS: tert-Butyl hydroperoxide (BHP) induced liver injury in mice model was established to evaluate the hepatoprotective effect of ethyl acetate extract of V. ciliata (EAFVC). Serum and liver indicators, as well as the histopathological change of liver were examined. Next, the constituents of EAFVC were separated and characterized by high-speed countercurrent chromatography (HSCCC) and Ultra performance liquid chromatography-mass spectrometer (UPLC-MS), respectively. Based on the above, the antioxidant activity of EAFVC and two fractions was evaluated using 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and 2, 2'-azino-bis (3-ethylbenzothiazoli- ne-6-sulfonic acid) (ABTS) free radical scavenging assays. The hepatoprotective activity of EAFVC and its fractions/compounds attenuating ethanol-induced hepatocyte damage in BRL-3A cells was evaluated using the MTT method. The effect of the fraction and compounds with the strongest protective activity on ethanol-induced cytotoxicity, reactive oxygen species (ROS) accumulation, and glutathione (GSH) depletion was investigated. mRNA expression of nuclear factor-E2-related factor 2 (Nrf2) and nuclear factor of κB (NF-κB), as well as their downstream target genes, was determined by RT-qPCR. Finally, the potential mechanism of fraction 1 and luteolin on the AMPK/p62/Nrf2 signal pathway was studied using western blotting. RESULTS: Firstly, EAFVC could relieve liver impairment induced by t-BHP in mice. Next, fraction 1 enriched with polyphenolic compounds and luteolin derived from EAFVC were screened to yield the highest hepatoprotective activity against ethanol-induced hepatocyte damage. Further study demonstrated that fraction 1 and luteolin relieved BRL-3A cells damage by decreasing the aspartate aminotransferase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) activities, ROS accumulation, as well as the depletion of GSH. Also, we determined that fraction 1 and luteolin suppressed inflammation and apoptosis of BRL-3A cells. The mechanistic studies indicated that fraction 1 could attenuate oxidative stress, inflammation, and apoptosis by activating AMPK phosphorylation, which promotes autophagy associated protein expression (LC3-B, Beclin1 and p62) as well as promote phosphorylation of p62 -dependent autophagic degradation of Keap1, to induce Nrf2 dissociation from Keap1 and translocate to nuclear. Nrf2 in the nuclear activate cytoprotective related genes to exert hepatoprotective function. Finally, we found that luteolin activated the protein expression of p-AMPK, p-p62, p62, Nrf2, and its downstream target genes. CONCLUSIONS: This study clarified that fraction 1 enriched phenolic compounds could attenuate ethanol-induced liver injury in BRL-3A cells via activating AMPK/p62/Nrf2 pathway. Luteolin could serve as the major bioactive component in the therapeutic effect of fraction 1. These active constituents in V. ciliata could be used as the potential drugs targeted activation of AMPK or p62 for relieving oxidative stress-mediated liver disorders.

Antioxidant interaction of α-tocopherol, γ-oryzanol and phytosterol in rice bran oil.

In this study, purified rice bran oil (RBO) was used as a lipid matrix model to study the individual and binary antioxidant capacity of the minor constituents (α-tocopherol, γ-oryzanol and phytosterol) added at different concentrations and ratios. The results revealed that concentration influenced on the oxidation stability and scavenging capacity, while ratio mainly affected the type of interaction or the degree of synergism or antagonism. It was important to notice that the antioxidant capacity of α-tocopherol would decrease under high concentration. Besides, the inhibition of phytosterol on α-tocopherol and the formation of hydrogen bond between γ-oryzanol and phytosterol were speculated by the interactions of these minor constituents. This work helps to select efficient combinations for stabilizing the anti-oxidation of nutrient enriched RBO or provide suggestions for moderate retain of minor constituents in RBO.

Protective effects of n-Butanol extract and iridoid glycosides of Veronica ciliata Fisch. Against ANIT-induced cholestatic liver injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Veronica ciliata Fisch. is a traditional medical herb that present in more than 100 types of Tibetan medicine prescriptions, most of which are used for liver disease therapy. Iridoid glycosides have been identified as the major active components of V.ciliata with a variety of biological activities. AIMS OF THE STUDY: The aim of this study is to explore the protective effect and potential mechanism of n-Butanol extract (BE) and iridoid glycosides (IG) from V.ciliata against ɑ-naphthyl isothiocyanate (ANIT)-induced hepatotoxicity and cholestasis in mice. MATERIALS AND METHODS: Mice were intragastrically (i.g.) given BE and IG at different dose or positive control ursodeoxycholic acid (UCDA) once a day for 14 consecutive days, and were treated with ANIT to cause liver injury on day 12th. Serum levels of hepatic injury markers and cholestasis indicators, liver index and liver histopathology were measured to evaluate the effect of BE and IG on liver injury caused by ANIT. The protein levels of tumor necrosis factor-α (TNF-α), nuclear factor kappa B(NF-κB), interleukin-6 (IL-6), Na+/taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and the levels of oxidative stress indicators in liver tissue were investigated to reveal the underlying protective mechanisms of BE and IG against ANIT-induced hepatotoxicity and cholestasis. RESULTS: The n-Butanol extract (BE) and iridoid glycosides (IG) isolated from V.ciliata significantly decreased serum level of cholestatic liver injury markers aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), total bile acid (TBA), total bilirubin (TBIL), and direct bilirubin (DBIL) in ANIT-treated mice. Histopathology of the liver tissue showed that pathological damages were relieved upon BE and IG treatment. Meanwhile, the results indicated BE and IG notably restored relative liver weights, inhibited oxidative stress induced by ANIT through increasing hepatic level of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and decreasing hepatic content of malondialdehyde (MDA). Western blot revealed that BE and IG inhibited the expression of pro-inflammatory factors TGF-α, IL-6 and NF-κB. Furthermore, the decreased protein expression of bile acid transporters NTCP, BSEP, MRP2 were upregulated by BE and IG in a dose-dependent manner. CONCLUSION: The results have demonstrated that BE and IG exhibited a dose-dependently protective effect against ANIT-induced liver injury with acute intrahepatic cholestasis in mice, which might be related to the regulation of oxidative stress, inflammatory response and bile acid transport. In addition, these findings pointed out that iridoid glycosides as main active components of V.ciliata play a critical role in hepatoprotective effect of V.ciliata.