PFAS (per- and polyfluorinated alkyl substances) as EDCs (endocrine-disrupting chemicals) - Identification of compounds with high potential to bind to selected terpenoids NHRs (nuclear hormone receptors)

Article

作者: Stępnik, Maciej ; Kowalska, Dominika ; Sosnowska, Anita ; Bulawska, Natalia ; Puzyn, Tomasz

The objective of the subsequent study was to examine the probability of PFAS (per- and polyfluorinated alkyl substances) binding to various NHRs (nuclear hormone receptors) and to identify their structural features that contribute most to the binding score (BS). We evaluated the BS for PFAS in relation to 7 selected NHRs - 4 with additional antagonist forms (Retinoid X receptor alpha - RXRα, Liver X receptor alpha - LXRα, Liver X receptor beta - LXRβ, Estrogen receptor alpha - ERα, Estrogen receptor alpha antagonist - anti-ERα, Estrogen receptor beta - ERβ, Estrogen receptor beta antagonist - anti-ERβ, Glucocorticoid receptor - GR, Glucocorticoid receptor antagonist - anti-GR, Androgen receptor - AR, Androgen receptor antagonist - anti-AR). We based our study on the results of molecular docking, which we used to develop MLR-QSAR (Multiple Linear Regression - Quantitative Structure-Activity Relationship) models. The models we developed allowed us to predict the BS for an extensive set of PFAS compounds from the NORMAN database (more than 4000) - virtual screening. The probability of PFAS binding to selected receptors was determined by structural features such as particle size, branching, and fluorine content. These variables were also identified in the literature reports of experimental studies as the most important for this group of compounds. The research focused on receptors from the terpenoid group. The RXRα, LXRα and β, GR, and anti-GR receptors were shown to be the group less likely to be affected by PFAS. Sex hormones such as AR, anti-AR, ERα and ERβ with their antagonist forms are the most affected.

2024-11-01·Combinatorial Chemistry & High Throughput Screening

Gegen Qinlian Decoction Modulates Atherosclerosis and Lipid Metabolism Through Cellular Interplay and Signaling Pathways

Article

作者: Shen, Li ; Miao, Qing ; Gao, Kun ; Lv, Qin ; Zhang, Zhiwei ; Zhou, Yu ; Li, Zhiguo

Objective:The objective of this study is to investigate Gegen Qinlian decoction (GQD) effects on lipid metabolism and explore its mechanism for preventing and treating atherosclerosis.Methods:An atherosclerotic rat model was established;, and after an 8-week high-fat diet, atherosclerosis and non-alcoholic fatty liver disease were assessed. Subsequently, GQD was administered at low and high doses. Histopathological aortic wall changes, hepatic lipid deposition, and blood lipid changes were evaluated. ELISA indicated the influence of TNF-α and IL-13, and Western blotting revealed MerTK, ABCA1, and LXR-α expression. A foam macrophage model was established, and Cell activity was detected by the MTT method. ELISA indicated the influence of PPAR-γ. The expression of ABCA1, ABCA7, ABCG1, GAS6, MerTK, SCARB1, LXR- α and LXR-β mRNA were detected by qPCR， and Western blotting revealed MerTK and LXR-α expression. The impact of drug-containing serum of GQD on efferocytosis-related factors was studied.Results:GQD improved atherosclerosis and non-alcoholic fatty liver disease and reduced serum low-density lipoprotein levels in the high-dose group. The high- and low-dose groups showed upregulated ABCA1, MerTK, and LXR-α expression in blood vessels and the liver, respectively. GQD decreased serum TNF-α and increased IL-13 levels. PPAR-γ expression was elevated in the high-, and low-dose groups. In the high-and low-dose groups, ABCA7, GAS6, SCARB1, and LXR-α, ABCA1 and MerTK, and ABCG1 gene expression were upregulated, respectively. Both low- and high-dose serum-containing drugs promoted LXR-β gene expression, and LXR-α protein expression was improved in the high-dose group.Conclusion:GQD improves rat atherosclerosis and hepatic lipid metabolism by regulating PPAR-γ, LXR-α, LXR-β, ABCA1, ABCA7, and ABCG1 expression and augmenting cellular intercalation through the GAS6/TAM pathway

2024-01-01·Phytomedicine

QiShenYiQi pill inhibits atherosclerosis by promoting TTC39B-LXR mediated reverse cholesterol transport in liver

Article

作者: Wu, Ting-Chun ; Chen, Yun-Zhi ; Xu, Tao ; Yang, Cheng-Yong ; Peng, Li ; Chen, Nan-Ting ; Xie, Jing ; Li, Li ; Feng, Xue ; Wang, Tao-Tao

BACKGROUNDTetranucleotide repeat domain protein 39B (TTC39B) was found to combine with ubiquitin ligase E3, and promote the ubiquitination modification of liver X receptor (LXR), which led to the inhibition of reverse cholesterol transport and development of atherosclerosis. QiShenYiQi pill (QSYQ) is a modern Chinese patent drug for treating ischemic cardiovascular diseases, the underlying mechanism is found to promote the expression of LXR-α/ ATP-binding cassette transporter G5 (ABCG5) in the liver of atherosclerotic mice.PURPOSEThe aim of this study is to investigate the effect of QSYQ on TTC39B-LXR mediated reverse cholesterol transport in atherosclerotic mice.STUDY DESIGN AND METHODSMale apolipoprotein E gene knockout mice (7 weeks old) were fed with high-fat diet and treated with low dose of QSYQ (QSYQ-l, 0.3 g/kg·d), high dose of QSYQ (QSYQ-H, 1.2 g/kg·d) and LXR-α agonist (LXR-A, GW3965 10 mg/kg·d) for 8 weeks. C57BL/6 J mice were fed with normal diet and used as negative control. Oil red O staining, HE staining, ELISA, RNA sequencing, western blot, immunohistochemistry, RT-PCR, cell culture and RNA interference were performed to analyze the effect of QSYQ on atherosclerosis.RESULTSHE staining showed that QSYQ reduced the atherosclerotic lesion significantly when compared to the control group. ELISA measurement showed that QSYQ decreased serum VLDL and increased serum ApoA1. Oil Red O staining showed that QSYQ reduced the lipid content of liver and protect liver function. Comparative transcriptome RNA-sequence of liver showed that DEGs after QSYQ treatment enriched in high-density lipoprotein particle, ubiquitin ligase complex, bile secretion, etc. Immunohistochemical staining and western blot proved that QSYQ increased the protein expression of hepatic SR-B1, LXR-α, LXR-β, CYP7A1 and ABCG5. Targeted inhibiting Ttc39b gene in vitro further established that QSYQ inhibited the gene expression of Ttc39b, increased the protein expression of SR-B1, LXR-α/β, CYP7A1 and ABCG5 in rat hepatocyte.CONCLUSIONOur results demonstrated the new anti-atherosclerotic mechanism of QSYQ by targeting TTC39B-LXR mediated reverse cholesterol transport in liver. QSYQ not only promoted reverse cholesterol transport, but also improved fatty liver and protected liver function.

项与 LXR-α x NR1H2 相关的新闻（医药）

2023-12-20

·BioSpace

Anavex Announces First Entire Clinical Gene Pathway Data of ANAVEX®2-73 from AVATAR Study in Patients with Rett Syndrome

NEW YORK, Dec. 20, 2023 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, today announced the first entire clinical gene pathway data from the ANAVEX®2-73-RS-002 AVATAR Rett syndrome trial. A whole genome and exome analysis comparing drug and placebo in patients with Rett syndrome was performed. We believe the results confirm that Rett syndrome is indeed a neurodevelopmental disorder with a key metabolic component, which can be addressed with therapeutic intervention and is likely relevant for other neurodevelopmental disease indications. AVATAR study was a randomized, placebo-controlled clinical trial in 33 patients with Rett syndrome which included prespecified biomarkers of response as well as Whole Exome Sequencing (WES) DNA data and full RNA exome expression (RNA-seq) data collection. The study included analysis of gene expression changes in each treatment group as well as analysis of the impact of single nucleotide polymorphisms/variants (SNPs/SNVs) on treatment response. ANAVEX®2-73 transcriptomics analysis (RNAseq) identified gene networks that are differentially expressed in Rett syndrome patients treated with ANAVEX®2-73 compared to placebo. Patient samples that were analyzed contained on average over 20 million unique reads in both placebo and ANAVEX®2-73 treated patients. Biological relevance of this pool of genes was assessed through pathway analysis and confirmed the impact of ANAVEX®2-73 treatment on pathways involved in neurodevelopmental diseases. The results highlight many significant differences between active treatment group and placebo, such as the differential expression of several genes in response to ANAVEX®2-73 treatment as shown in the following heatmap figure: Pathway analysis of the differentially expressed genes suggests ANAVEX®2-73 may, among other functions, correct metabolic alterations in patients with Rett syndrome through enhanced mitochondrial energy production and increased expression of genes involved in oxidative phosphorylation, fatty acid metabolism, developmental signaling pathways, transcription/translation, membrane trafficking, and branched-chain amino acid catabolism as shown in the following table: ANAVEX®2-73 Treatment-enriched Pathways Pathway Name Category p-value Oxidative phosphorylation Energy Metabolism 2.84E-04 Valine leucine and isoleucine degradation Metabolism 6.85E-04 Adipogenesis Energy Metabolism 1.48E-03 Fatty acid degradation Energy Metabolism 5.52E-03 Amino acid metabolism Metabolism 7.14E-03 Cysteine and methionine metabolism Metabolism 8.41E-03 Acyl chain remodeling of phosphatidylserine Metabolism 1.43E-02 Mitochondrial protein import Energy Metabolism 1.71E-02 α-Linolenic acid metabolism Metabolism 1.83E-02 PPAR-α pathway Signaling 1.98E-02 Acyl chain remodeling of phosphatidylethanolamine Metabolism 2.43E-02 TGF-β signaling pathway Signaling 2.49E-02 Deubiquitination Metabolism 2.99E-02 NOD1/2 signaling pathway Signaling 3.09E-02 Fatty acid β-oxidation Energy Metabolism 3.26E-02 Detoxification of reactive oxygen species Metabolism 3.26E-02 N-glycan trimming in ER and calnexin/calreticulin cycle Metabolism 3.44E-02 miRNAs involvement in the immune response in sepsis Transcription / Translation 3.81E-02 RHOV GTPase cycle Signaling 3.81E-02 Formation of xylulose-5-phosphate Metabolism 4.11E-02 NR1H2 and NR1H3 regulate gene expression linked to gluconeogenesis Transcription / Translation 4.11E-02 RHOU GTPase cycle Signaling 4.20E-02 Fatty acid metabolism Energy Metabolism 4.36E-02 Nucleotide-binding oligomerization domain (NOD) pathway Transcription / Translation 4.60E-02 Protein localization Membrane Trafficking 4.89E-02 Glycerophospholipid metabolism Metabolism 4.89E-02 The scope of these detected gene expression changes identified through ANAVEX®2-73 effect may represent additional potential biomarkers of disease pathology and response. Christopher U Missling, PhD, President and Chief Executive Officer of Anavex, stated, "We believe, this represents an extensive transcriptomics analysis (RNAseq) of a therapeutic agent in patients with Rett syndrome and it is very exciting to witness ANAVEX®2-73’s demonstration of its platform Precision Medicine potential for Rett syndrome with ability to compensate for expression levels of dysregulated developmental and metabolic genes, apparent within the Rett syndrome pathology. We are steadily making progress to learn more about this debilitating disorder and further analysis will be dedicated to evaluating the significance of each identified gene and gene variant and should deepen the understanding of the underlying signaling pathways involved in response to ANAVEX®2-73 treatment in patients with Rett syndrome.” About Anavex Life Sciences Corp. Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of novel therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders, including Alzheimer's disease, Parkinson's disease, Rett syndrome, and other central nervous system (CNS) diseases, pain, and various types of cancer. Anavex's lead drug candidate, ANAVEX®2-73 (blarcamesine), has successfully completed a Phase 2a and a Phase 2b/3 clinical trial for Alzheimer's disease, a Phase 2 proof-of-concept study in Parkinson's disease dementia, and both a Phase 2 and a Phase 3 study in adult patients with Rett syndrome. ANAVEX®2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer's disease. ANAVEX®2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson's Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX®2-73 for the treatment of Parkinson's disease. ANAVEX®3-71, which targets sigma-1 and M1 muscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer's disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid, and tau pathologies. In preclinical trials, ANAVEX®3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation. Further information is available at . You can also connect with the Company on Twitter,Facebook, Instagram, and LinkedIn. Forward-Looking Statements Statements in this press release that are not strictly historical in nature are forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. Actual events or results may differ materially from those projected in any of such statements due to various factors, including the risks set forth in the Company’s most recent Annual Report on Form 10-K filed with the SEC. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life Sciences Corp. undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof. For Further Information: Anavex Life Sciences Corp. Research & Business Development Toll-free: 1-844-689-3939 Email: info@anavex.com Investors: Andrew J. Barwicki Investor Relations Tel: 516-662-9461 Email: andrew@barwicki.com A photo accompanying this announcement is available at . Heatmap Heatmap

临床2期