Exploring the anti-ferroptosis mechanism of Kai-Xin-San against Alzheimer's disease through integrating network pharmacology, bioinformatics, and experimental validation strategy in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai Xin San (KXS), first proposed by Sun Simiao during the Tang Dynasty, has been utilized to treat dementia by tonifying qi and dispersing phlegm. AIM OF THE STUDY: This study aimed to elucidate the mechanism by which KXS exerts its therapeutic effects on Alzheimer's disease (AD) by targeting ferroptosis, using a combination of network pharmacology, bioinformatics, and experimental validation strategies. MATERIALS AND METHODS: The active target sites and the further potential mechanisms of KXS in protecting against AD were investigated through molecular docking, molecular dynamics simulation, and network pharmacology, and combined with the validation of animal experiments. RESULTS: Computational and experimental findings provide the first indication that KXS significantly improves learning and memory defects and inhibits neuronal ferroptosis by repairing mitochondria damage and upregulating the protein expression of ferroptosis suppressor protein 1 (FSP1) in vivo APP/PS1 mice AD model. According to bioinformatics analysis, the mechanism by which KXS inhibits ferroptosis may involve SIRT1. KXS notably upregulated the mRNA and protein expression of SIRT1 in both vivo APP/PS1 mice and in vitro APP-overexpressed HT22 cells. Additionally, KXS inhibited ferroptosis induced by APP-overexpression in HT22 cells through activating the SIRT1-FSP1 signal pathway. CONCLUSIONS: Collectively, our findings suggest that KXS may inhibit neuronal ferroptosis through activating the SIRT1/FSP1 signaling pathway. This study reveals the scientific basis and underlying modern theory of replenishing qi and eliminating phlegm, which involves the inhibition of ferroptosis. Moreover, it highlights the potential application of SIRT1 or FSP1 activators in the treatment of AD and other ferroptosis-related diseases.

Diastereoselective Synthesis of Chromeno[3,2-d]isoxazoles via Brønsted Acid Catalyzed Tandem 1,6-Addition/Double Annulations of o-Hydroxyl Propargylic Alcohols.

A Brønsted acid catalyzed tandem process to access densely functionalized chromeno[3,2-d]isoxazoles with good to excellent yields and diastereoselectivities was disclosed. The procedure is proposed to involve a 1,6-conjugate addition/electrophilic addition/double annulations process of alkynyl o-quinone methides (o-AQMs) in situ generated from o-hydroxyl propargylic alcohols with nitrones. Mild conditions, good functional group compatibility, easy scale-up of the reaction, and further product transformation demonstrated its potential application.

Renshen Baidu Powder Attenuated Intestinal Inflammation and Apoptosis in Ulcerative Colitis Rats through the Inhibition of PI3K/AKT/NF-κB Signaling Pathway.

Objective: Renshen Baidu Powder (RBP) is a famous classic compound of traditional Chinese medicine (TCM) and is commonly used for treating ulcerative colitis (UC). However, the pharmacological mechanism of RBP in treating UC remains unclear. This study investigates the possible mechanism of RBP for UC treatment by network pharmacological analysis and rat validation. Methods: First, the main chemical constituents of RBP were identified using ultrahigh-performance liquid chromatography quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-HRMS). Then, we obtained targets of identified compounds from the SwissTargetPrediction database and targets associated with UC from GeneCards database. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the metabolism-related signaling pathways affected by RBP. Hematoxylin-eosin (HE) staining was used to observe the pathological change of colon in UC rats after treating RBP, and terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP Nick end labeling (TUNEL) staining was used to detect apoptosis after RBP treatment. The enzyme-linked immunosorbent assay (ELISA) was employed to evaluate cytokine levels of TNF-α, IL-1ß, and IL-6. The protein expressions of Bax, Bcl-2, PI3K, AKT, and NF-κB in colonic tissue were detected using immunohistochemistry (IHC). Real-time quantitative polymerase chain reaction (RT-QPCR) was employed to evaluate mRNA expression of PI3K, AKT, and NF-κB. Results: We found a total of 24 main compounds and 329 potential targets related to UC. According to KEGG results, 3 main pathways were identified as responsible for UC, including PI3K-AKT, HIF-1, and VEGF signaling pathway. Animal experiments showed that RBP treatment significantly attenuated colon damage in rats with UC. Mechanistically, RBP could inhibit PI3K/AKT/NF-κB pathway; decrease cell apoptosis; and downregulate the expression of TNF-α, IL-1ß, and IL-6. Conclusions: This study demonstrated that RBP may exert anti-inflammatory and antiapoptotic therapeutic benefits in UC by regulating the PI3K/AKT/NF-κB signaling pathways, providing a scientific basis for understanding the mechanism of RBP against UC.

The effect of Gegen Qinlian Decoction on clinical prognosis and islet function for type 2 diabetic mellitus: A protocol for systematic review and meta-analysis.

BACKGROUND: With the development of social economy, people's lives are improving day by day. Chronic diseases represented by diabetes have gradually entered people's field of vision. At present, about 415 million people in the world suffer from diabetes, of which more than 90% are Type 2 diabetic mellitus (T2DM), which causes severe physical and mental pain to patients and their families, and also imposes a huge burden on the health care system. Animal experiments and clinical studies both show that Gegen Qinlian Decoction (GQD) cannot only reduce the blood glucose of T2DM, but also improve the islet function of patients, reduce the insulin resistance index and insulin secretion index, and have no adverse reactions. Therefore, we designed this protocol to evaluate the effect of GQD on clinical Prognosis and islet function for T2DM. METHODS: This review was conducted from January 1, 2000 to October 1, 2020, sourced from the Cochrane Library, Pubmed, Excerpt Medica Database, Science Direct, World Health Organization, International Clinical Trials Registration Platform, Web of Science, Chinese Biomedical Literature, the China National Knowledge Infrastructure Database, Wanfang Database, Chinese Scientific Journal Database. In this study clinical randomized controlled trial is used and we set inclusion criteria and exclusion criteria for screening. The primary outcomes include Fasting plasma glucose,2 h plasma glucose, Hemoglobin A1c, fasting plasma insulin, insulin resistance index and insulin secretion index. Review Manager 5.3 software will be used for data analysis. RESULTS: This study will provide the systematic evidence of the effect of GQD on Clinical Prognosis and islet function for T2DM. CONCLUSION: The findings of this meta-analysis will provide evidence to evaluate the effect of GQD on Clinical Prognosis and islet function for type 2 diabetic mellitus. INPLASY REGISTRATION NUMBER: INPLASY2020110083.

Gancao Xiexin decoction combined with mesalazine in the treatment of ulcerative colitis: A protocol for a systematic review and meta-analysis.

BACKGROUD: Ulcerative colitis (UC) is a chronic inflammatory disease that involves the rectum, colon and ileum. Gancao Xiexin decoction (GCXXD) is a classic herbal formula in Shanghanlun. More and more research evidence shows that GCXXD has a certain therapeutic effect on UC. Therefore, we designed this study protocol aim to evaluate the efficacy and safety of GCXXD combine with mesalazine for UC. METHODS: We will systematically search 6 databases, including PubMed, the Cochrane Library, EMBASE, CNKI, VIP, Wang-fang database up to July 2020 to obtain eligible studies. The primary outcomes will focus on the clinical effectiveness. Review Manager 5.3 software will be used for data analysis. RESULTS: This study will provide the systematic evidence of UC treated with GCXXD combine with mesalazine. CONCLUSION: The findings of this meta-analysis will provide evidence to judge whether GCXXD combine with mesalazine is a more effective intervention compare to mesalazine only for patient of UC. INPLASY REGISTRATION NUMBER: INPLASY202080008.

1H nuclear magnetic resonance-based metabolic profiling of cerebrospinal fluid to identify metabolic features and markers for tuberculosis meningitis.

BACKGROUND: Tuberculosis meningitis (TBM) is the most severe form of tuberculosis, and currently lacks efficient diagnostic approaches. Metabolomics has the potential to differentiate patients with TBM from those with other forms of meningitis and meningitis-negative individuals. However, no systemic metabolomics research has compared the cerebrospinal fluid (CSF) of these patients. METHODS: 1H nuclear magnetic resonance (NMR) was used for CSF metabolic profiling. Principal component analysis and orthogonal signal correction-partial least squares-discriminant analysis (OPLS-DA) were used to screen for important variables. The Human Metabolome Database was used to identify metabolites, and MetaboAnalyst 4.0 was used for pathway analysis and over-representation analysis. RESULTS: OPLS-DA modeling could distinguish TBM from other forms of meningitis, and several significantly changed metabolites were identified. Additionally, 23, 6, and 21 metabolites were able to differentiate TBM from viral meningitis, bacterial meningitis, and meningitis-negative groups, respectively. Pathway analysis indicated that these metabolites were mainly involved in carbohydrate and amino acid metabolism, and over-representation analysis indicated that some of these pathways were over-represented. CONCLUSIONS: The metabolites identified have the potential to serve as biomarkers for TBM diagnosis, and carbohydrate and amino acid metabolism are perturbed in the CSF of patents with TBM. Metabolomics is a valuable approach for screening TBM biomarkers. With further investigation, the metabolites identified in this study could aid in TBM diagnosis.

Mass spectrometry-based metabolomics for tuberculosis meningitis.

Tuberculosis meningitis (TBM) is a prevalent form of extra-pulmonary tuberculosis that causes substantial morbidity and mortality. Diagnosis of TBM is difficult because of the limited sensitivity of existing laboratory techniques. A metabolomics approach can be used to investigate the sets of metabolites of both bacteria and host, and has been used to clarify the mechanisms underlying disease development, and identify metabolic changes, leadings to improved methods for diagnosis, treatment, and prognostication. Mass spectrometry (MS) is a major analysis platform used in metabolomics, and MS-based metabolomics provides wide metabolite coverage, because of its high sensitivity, and is useful for the investigation of Mycobacterium tuberculosis (Mtb) and related diseases. It has been used to investigate TBM diagnosis; however, the processes involved in the MS-based metabolomics approach are complex and flexible, and often consist of several steps, and small changes in the methods used can have a huge impact on the final results. Here, the process of MS-based metabolomics is summarized and its applications in Mtb and Mtb-related diseases discussed. Moreover, the current status of TBM metabolomics is described.

Assessment of myocardial strain in children with risk factors for atherosclerosis with use of 3D speckle tracking echocardiography.

BACKGROUND: The known risk factors for atherosclerosis such as dyslipidemia, hypertension, obesity, and fasting hyperglycemia are associated with subclinical myocardial dysfunction. We assessed myocardial strain in children who had risk factors for atherosclerosis with use of 3D speckle tracking echocardiography (3DSTE). METHODS: A total of 340 eligible children (mean age [±SD]: 9.5 [±1.9] years; range, 7.1-12.2; 189 males, 151 females). Levels of serum cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI) were investigated. The parameters of left ventricular (LV) myocardial strain including global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) were measured with use of real time 3DSTE. RESULTS: Left ventricular (LV) global longitudinal strain and global circumferential strain in the groups with isolated dyslipidemia, isolated hypertension, isolated obese/overweight, and combination groups were lower than those in healthy controls (P < .01 for all). Global longitudinal strain (GLS) and GCS showed a negative correlation with the respective risk factors (TG, TC, and LDL-C; SBP and DBP; weight and BMI) (P < .05 for all). Multiple stepwise regression analysis showed a significant negative correlation of GLS and GCS with BMI, TC, TG, and SBP. The degree of myocardial strain aggravated significantly with increase in the number of risk factors in an individual subject.