Chinese medicine is a complex system guided by traditional Chinese medicine (TCM) theories, which has proven to be especially effective in treating chronic and complex diseases. However, the ...underlying modes of action (MOA) are not always systematically investigated. Herein, a systematic study was designed to elucidate the multi-compound, multi-target and multi-pathway MOA of a Chinese medicine, QiShenYiQi (QSYQ), on myocardial infarction. QSYQ is composed of Astragalus membranaceus (Huangqi), Salvia miltiorrhiza (Danshen), Panax notoginseng (Sanqi), and Dalbergia odorifera (Jiangxiang). Male Sprague Dawley rat model of myocardial infarction were administered QSYQ intragastrically for 7 days while the control group was not treated. The differentially expressed genes (DEGs) were identified from myocardial infarction rat model treated with QSYQ, followed by constructing a cardiovascular disease (CVD)-related multilevel compound-target-pathway network connecting main compounds to those DEGs supported by literature evidences and the pathways that are functionally enriched in ArrayTrack. 55 potential targets of QSYQ were identified, of which 14 were confirmed in CVD-related literatures with experimental supporting evidences. Furthermore, three sesquiterpene components of QSYQ, Trans-nerolidol, (3S,6S,7R)-3,7,11-trimethyl-3,6-epoxy-1,10-dodecadien-7-ol and (3S,6R,7R)-3,7,11-trimethyl-3,6-epoxy-1,10-dodecadien-7-ol from Dalbergia odorifera T. Chen, were validated experimentally in this study. Their anti-inflammatory effects and potential targets including extracellular signal-regulated kinase-1/2, peroxisome proliferator-activated receptor-gamma and heme oxygenase-1 were identified. Finally, through a three-level compound-target-pathway network with experimental analysis, our study depicts a complex MOA of QSYQ on myocardial infarction.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Ulcerative colitis (UC) is a chronic, incurable condition characterized by mucosal inflammation and intestinal epithelial cell (IEC) damage. The circadian clock gene NR1D1, implicated in ...UC and the critical mitophagy process for epithelial repair, needs further exploration regarding its role in mitophagy regulation in UC. Methods: We created a jet lag mouse model and induced colitis with dextran sulfate sodium (DSS), investigating NR1D1’s role. Intestinal-specific Nr1d1 knockout mice were also generated. RNA sequencing, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays helped ascertain NR1D1’s regulatory effect on BNIP3 expression. The mitochondrial state in IECs was assessed through transmission electron microscopy, while confocal microscopy evaluated mitophagy-associated protein expression in colon tissue and CCD841 cells. Cell apoptosis and reactive oxygen species (ROS) were measured via flow cytometry. Results: We observed reduced NR1D1 expression in the IECs of UC patients, accentuated under jet lag and DSS exposure in mice. NR1D1 ablation led to disrupted immune homeostasis and declined mitophagy in IECs. NR1D1, usually a transcriptional repressor, was a positive regulator of BNIP3 expression, leading to impaired mitophagy, cellular inflammation, and apoptosis. Administering the NR1D1 agonist SR9009 ameliorated colitis symptoms, primarily by rectifying defective mitophagy. Conclusions: Our results suggest that NR1D1 bridges the circadian clock and UC, controlling BNIP3-mediated mitophagy and representing a potential therapeutic target. Its agonist, SR9009, shows promise in UC symptom alleviation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Many common diseases like diabetes, cardiovascular disease, and cancer are caused or exacerbated by disparate physiological, pathological, environmental, and lifestyle factors. However, the chief aim ...of current drug discovery approaches is to search for single-entity drugs that interact with well-defined molecular targets (a single receptor or enzyme). The concept of multi-target drugs or multi-component therapy is gaining increased attention with the discovery that many diseases (like hypertension) are best treated by multi-drug or multi-target therapies. Traditional medicines, such as traditional Chinese medicine (TCM) and Indian Ayurveda, have been re-evaluated and are becoming important resources for the discovery of bioactive molecules with therapeutic effects and for designing multi-targets drugs. This article provides an overview of new strategies and techniques to design therapeutic regimes that comprise more than one active ingredient to produce synergistic effects by simultaneously interacting with multiple molecular targets. Advances in phytochemistry, high throughput screening, DNA sequencing, systems biology, and bioinformatics can reveal the chemical composition and molecular mechanisms of TCM and together provide a new template for the early stages of drug discovery. Meanwhile, clinical knowledge of TCM provides a promising framework for multi-component drug design. A renaissance of multi-component drug discovery inspired by traditional medicine is possible.
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► A new assay based on ultrafiltration HPLC–DAD–MS has been developed for rapid screening and identification of ligands for tyrosinase. ► Twelve compounds with tyrosinase binding ...activity were found from extract of mulberry leaves. ► Two malonyl-glycosylflavones were identified as new tyrosinase inhibitors.
Tyrosinase is a key enzyme in melanin synthesis. Its inhibitor may be used to efficiently treat hyperpigmentation and widely applied in cosmetic products and food supplements. In the present study, a new assay based on ultrafiltration high-performance liquid chromatography coupled with diode array detector and mass spectrometry (HPLC–DAD–MS) was developed for the rapid screening and identification of ligands for tyrosinase. Experiments were carried out to select the optimal binding conditions, tyrosinase concentration, and incubation time. Non-specific binding to the denatured tyrosinase was also investigated. Twelve compounds with tyrosinase binding activity were found in mulberry leaf extracts. The identities of these compounds were characterised by HPLC–DAD–MSn. Particularly, two compounds, namely, quercetin-3-O-(6-O-malonyl)-β-d-glucopyranoside and kaempferol-3-O-(6-O-malonyl)-β-d-glucopyranoside, were identified as new tyrosinase inhibitors. The screening results were verified by tyrosinase inhibition assays. Experimental results proved that the proposed method could rapidly screen tyrosinase inhibitors in complex mixtures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Drawing on the theories of Kim’s racial triangulation and Allport’s intergroup contact, this study examined ideological and experiential predictors of Asian Americans’ interracial attitudes and ...solidarity with Black Americans. In a community sample of 249 Asian Americans, hierarchical multiple regression analyses revealed that the ideological variables of internalized racism and model minority myth were associated with greater anti-Black attitudes. Internalized model minority myth of unrestricted mobility was also related to reduced intergroup solidarity. Conversely, the experiential variables of close and general contact with Black Americans were respectively related to greater pro-Black attitudes and intergroup solidarity. Additionally, higher quality of general contact buffered the negative association between internalized model minority myth and intergroup solidarity. The findings highlight the importance of deconstructing internalized racial beliefs rooted in White supremacy and cultivating quality intergroup contact between Black and Asian Americans. Implications for practice, community intervention, training, and research are discussed.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
In patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. Here we show that the convection-enhanced delivery of ...nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumour) and encapsulating an oxaliplatin prodrug and a cationic DNA intercalator inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human glioblastoma tumours in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signalling and metabolic pathways altered by each drug. Our findings suggest that the combination of anticancer drugs with distinct mechanisms of action with selective drug release and convection-enhanced delivery may represent a translational strategy for the treatment of TMZ-resistant gliomas.
PD-1 inhibitors, as one of commonly used immune checkpoint inhibitors, enable T-cell activation and prevent immune escape by blocking the PD-1/PD-L1 signaling pathway. They have transformed the ...treatment landscape for cancer in recent years, due to the advantages of significantly prolonging patients' survival and improving their life quality. However, the ensuing unpredictable immune-related adverse effects (irAEs) plague clinicians, such as colitis and even potentially fatal events like intestinal perforation and obstruction. Therefore, understanding the clinical manifestations and grading criteria, underlying mechanisms, available diverse therapies, accessible biomarkers, and basis for risk stratification is of great importance for the management. Current evidence suggests that irAEs may be a marker of clinical benefit to immunotherapy in patients, so whether to discontinue PD-1 inhibitors after the onset of irAEs and rechallenge after remission of irAEs requires further evaluation of potential risk-reward ratios as well as more data from large-scale prospective studies to fully validate. At the end, the rare gastrointestinal toxicity events caused by PD-1 inhibitors are also sorted out. This review provides a summary of available data on the gastrointestinal toxicity profile caused by PD-1 inhibitors, with the aim of raising clinicians' awareness in daily practice, so that patients can safely benefit from therapy.
Abstract A pressing challenge in spatially resolved transcriptomics (SRT) is to benchmark the computational methods. A widely-used approach involves utilizing simulated data. However, biases exist in ...terms of the currently available simulated SRT data, which seriously affects the accuracy of method evaluation and validation. Herein, we present scCube ( https://github.com/ZJUFanLab/scCube ), a Python package for independent, reproducible, and technology-diverse simulation of SRT data. scCube not only enables the preservation of spatial expression patterns of genes in reference-based simulations, but also generates simulated data with different spatial variability (covering the spatial pattern type, the resolution, the spot arrangement, the targeted gene type, and the tissue slice dimension, etc.) in reference-free simulations. We comprehensively benchmark scCube with existing single-cell or SRT simulators, and demonstrate the utility of scCube in benchmarking spot deconvolution, gene imputation, and resolution enhancement methods in detail through three applications.
For a weighted projective line X, a wide subcategory of the category coh-X of coherent sheaves over X is called c→-invariant if it is closed under the grading shift of the canonical element c→. We ...proved that a c→-invariant wide subcategory of coh-X containing a vector bundle is the perpendicular category of a torsion exceptional sequence. If X is of domestic type, then the poset of wide subcategories of coh-X is the union of the poset of wide subcategories generated by an exceptional sequence and the poset of c→-invariant wide subcategories.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders of the gastrointestinal tract, mainly including Crohn's disease and ulcerative colitis. Epidemiological findings suggest ...that inadequate dietary fibers intake may be a risk factor for IBD. Oat beta-glucan is a type of fermentable dietary fiber and has been proved to reduce experimental colitis. However, the mechanism remains unclear. The aim of this study was to explore the role and possible mechanism of oat beta-glucan in reducing experimental colitis. We used a dextran sulfate sodium (DSS)-induced mice acute colitis model to explore the potential mechanism of oat beta-glucan in reducing experimental colitis. As a result, oat beta-glucan upregulated the expressions of Erythropoietin-producing hepatocyte receptor B6 (EPHB6) and transcription factor EB (TFEB), promoted autophagy flux and downregulated the expressions of interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in intestinal epithelial cells (IECs). The role of the EPHB6-TFEB axis was explored using a lipopolysaccharide-induced HT-29 cells inflammation model. The results revealed that EPHB6 regulated the expression of TFEB, and knockdown of EPHB6 decreased the protein level of TFEB. When EPHB6 or TFEB was knocked down, autophagy flux was inhibited, and the anti-inflammatory effect of sodium butyrate, a main metabolite of oat beta-glucan in the gut, was blocked. In summary, our findings demonstrated that oat beta-glucan reduced DSS-induced acute colitis in mice, promoted autophagy flux via EPHB6-TFEB axis and downregulated the expressions of IL-1β, IL-6 and TNF-α in IECs, and this effect may be mediated by butyrate.
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