Background & Aims: Although water channel aquaporin-8 (AQP8) has been implicated in hepatic bile formation and liver diseases associated with abnormal bile flow in human and animal studies, direct evidence of its involvement in bile secretion is still lacking. This study aimed to determine the role of AQP8 in bile secretion and gallstone formation.
Methods: We generated various transgenic knock-in and knockout mouse models and assessed liver AQP8 expression by immunostaining and immunoblotting, hepatic bile secretion by cannulation of the common bile duct, cholesterol gallstone formation by feeding a high-fat lithogenic diet, and identified regulatory small molecules by screening the organic fractions of cholagogic Chinese herbs and performing biochemical characterization.
Background: The gut virome has been implicated in inflammatory bowel disease (IBD), yet a full understanding of the gut virome in IBD patients, especially across diverse geographic populations, is lacking.
Results: In this study, we conducted a comprehensive gut virome-wide association study in a Chinese cohort of 71 IBD patients (15 with Crohn's disease and 56 with ulcerative colitis) and 77 healthy controls via viral-like particle (VLP) and bulk virome sequencing of their feces. By utilizing an integrated gut virus catalog tailored to the IBD virome, we revealed fundamental alterations in the gut virome in IBD patients.
Necroptotic immunogenic cell death (ICD) can activate the human immune system to treat the metastasis and recurrence of triple-negative breast cancer (TNBC). However, developing the necroptotic inducer and precisely delivering it to the tumor site is the key issue. Herein, we reported that the combination of shikonin (SHK) and chitosan silver nanoparticles (Chi-Ag NPs) effectively induced ICD by triggering necroptosis in 4T1 cells.
View Article and Find Full Text PDFN-acylethanolamine acid amidase (NAAA) is a nucleophilic lysosomal cysteine hydrolase, which primarily mediates the hydrolytic inactivation of endogenous palmitoylethanolamide (PEA), which further influences the inflammatory process by regulating peroxisome proliferator-activated receptor-α (PPAR-α). Herein, a novel lysosome (Lyso)-targeting fluorescent probe (i.e.
View Article and Find Full Text PDFMelatonin (Mel) is an endogenous active molecule whose metabolism progress significantly influences its bioactivity. However, the detailed metabolic pathway of Mel in the pathological state has not yet been fully illustrated. In this study, 16 metabolites of Mel in cancer cells and human liver microsomes were identified, of which seven novel metabolites were newly discovered.
View Article and Find Full Text PDFUridine-disphosphate glucuronosyltransferase 1A9 (UGT1A9), an important detoxification and inactivation enzyme for toxicants, regulates the exposure level of environmental pollutants in the human body and induces various toxicological consequences. However, an effective tool for high-throughput monitoring of UGT1A9 function under exposure to environmental pollutants is still lacking. In this study, 1,3-dichloro-7-hydroxy-9,9-dimethylacridin-2(9H)-one (DDAO) was found to exhibit excellent specificity and high affinity towards human UGT1A9.
View Article and Find Full Text PDFP23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it translocates into the nucleus. The molecular nature underlying how this HSP90-independent p23 function is achieved remains as a biological mystery. Here, we found that p23 is a previously unidentified transcription factor of COX-2, and its nuclear localization predicts the poor clinical outcomes.
View Article and Find Full Text PDFBDE47 (2,2,4,4-tetrabromodiphenyl ether) is a member of the most important congeners of polybrominated diphenyl ethers (PBDEs) and has been identified as a developmental, reproductive and nervous system toxicant and endocrine system disruptor due to its frequent detection in human tissue and environmental samples. Our preliminary work suggested that high- and low-level of bromodiphenyl ethers have different effects on neuronal cells with differential targets of actions on neural tissues. In this study, we presented the underlying mechanism of BDE47 neurotoxicity from the perspective of thyroid hormone (TH) metabolism using in vitro model of human SK-N-AS neuronal cells.
View Article and Find Full Text PDFCytochrome P450 1A is one of the vital subfamilies of heme-containing cytochrome P450 enzymes belonging to an important exogenous metabolizing CYP in human. The abnormal of endoplasmic reticulum (ER) may directly affect the functional activity of ER-located CYP1A and be associated with the occurrence and development of various diseases. In the present study, we constructed a selective two-photon fluorescent probe for rapid and visual detection of endogenous CYP1A that was localized in the ER.
View Article and Find Full Text PDFA novel near-infrared (NIR) fluorescent probe CHC-CES1 based on a hemi-cyanine skeleton for detecting carboxylesterase 1 (CES1) activity was developed. Herein, CHC-CES1 could be specifically hydrolysed to CHC-COOH along with a significant NIR fluorescence signal enhancement at 670 nm. Systematic evaluation indicated that CHC-CES1 possessed an outstanding selectivity and sensitivity towards CES1, and possessed good chemical stability in complex biosamples.
View Article and Find Full Text PDFEthnopharmacological Relevance: Jinhongtang as a traditional Chinese medicine (TCM) formula, has been widely used as a clinical adjuvant in the treatment of acute abdominal diseases and sepsis. Clinical benefits of the concurrent use of Jinhongtang and antibiotics have been observed, however, the mechanism has not been fully understood.
Aim Of The Study: The present study aimed to explore the effect of Jinhongtang on the antibacterial activity of Imipenem/Cilastatin and to clarify the underlying mechanism of herb-drug interaction (HDI).
An endoplasmic reticulum targeting NIR fluorescent probe (ERBM) was developed for real-time monitoring of carboxylesterase 1 (CES1) and exhibited excellent ER location in living cell imaging. In addition, ERBM was applied to illustrate the regulation characteristics of CES1 under ER stress and acute liver injury models at the cell and animal level.
View Article and Find Full Text PDFEthnopharmacological Relevance: Jinhongtang, a traditional Chinese medicine (TCM) formula consisting of dry stems of Rheum palmatum L. (Polygonaceae) and Sargentodoxa cuneata (Oliv.) Rehder & E.
View Article and Find Full Text PDFIntroduction: Viruses in the human gut have been linked to health and disease. Deciphering the gut virome is dependent on metagenomic sequencing of the virus-like particles (VLPs) purified from the fecal specimens. A major limitation of conventional viral metagenomic sequencing is the low recoverability of viral genomes from the metagenomic dataset.
View Article and Find Full Text PDFInhibition of ferroptosis in intestinal epithelial cells ameliorates clinical symptoms and improves endoscopic presentations in inflammatory bowel disease (IBD). Licorice is used worldwide in food and medicine fields. Liquiritin, a flavonoid component in licorice, is an effective substance used as an anti-inflammatory, antioxidant food that has been shown to improve chemically induced colitis.
View Article and Find Full Text PDFBackground: Shaoyao Decoction (SYD) is a canonical herbal medicine prescription formulated by Liu Wan-Su in AD 1186. SYD has been widely used to treat inflammatory bowel disease by clearing heat and damp, removing stasis toxin in the intestine; however, the precise mechanisms and therapeutic material basis remain largely unclear. In the present study, we measured the effects of SYD on colitis symptom, epithelial barrier function, epithelial ferroptosis, colonic protein and mRNA expression of glutathione peroxidase 4 (GPX4) in colitis model, and determined whether SYD restored barrier loss in colitis by modulation of GPX4-regulated ferroptosis pathway.
View Article and Find Full Text PDFTuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which is a major threat to global public health. Currently, β-lactam antibiotics are rarely used in the treatment of TB, since Mtb naturally expresses β-lactamase (Blac) which renders Mtb resistant to such antibiotics due to β-lactam cleavage. Fortunately, antibiotic resistance can be overcome when β-lactam antibiotics are combined with a Blac inhibitor.
View Article and Find Full Text PDFJinhongtang granule (JHT) is a traditional Chinese medicine formula used for treatment of infection diseases including severe COVID-19. However, pharmacokinetics of JHT was unknown, especially in infection condition. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to simultaneously quantify ten active components form JHT in rat plasma.
View Article and Find Full Text PDFCurrently, the development of selective fluorescent probes toward targeted enzymes is still a great challenge, due to the existence of numerous isoenzymes that share similar catalytic capacity. Herein, a double-filtering strategy was established to effectively develop isoenzyme-specific fluorescent probe(s) for cytochrome P450 (CYP) which are key enzymes involving in metabolism of endogenous substances and drugs. In the first-stage of our filtering approach, near-infrared (NIR) fluorophores with alkoxyl group were prepared for the screening of CYP-activated fluorescent substrates using a CYPs-dependent incubation system.
View Article and Find Full Text PDFCYP2J2 as an endoplasmic reticulum (ER)-expressed vital cytochrome P450 isoform participates in the metabolism of endogenous polyunsaturated fatty acids. Its abnormal expression and function are closely related to the progress of cancer and cardiovascular diseases. Herein, an ER-targeting near-infrared (NIR) fluorescent probe was developed for monitoring CYP2J2 activity, which possessed a high selectivity and sensitivity toward CYP2J2 among various CYP450 isoforms and exhibited excellent subcellular localization for ER.
View Article and Find Full Text PDFTwo new nor-triterpenoids ganodrenol A (), B (), and a new natural product ganodrenol C (), along with three known nor-triterpenoids (-) were isolated from the fruiting bodies of The chemical structures of these isolates were determined by 1 D and 2 D NMR, HRESIMS, and X-ray crystallography analysis. The inhibitory effects of isolated triterpenoids (-) against FAAH were evaluated by an in assay, and compound showed an inhibition rate of 70.27%.
View Article and Find Full Text PDFCYP3A4-mediated Phase I biotransformation is the rate-limiting step of elimination for many commonly used clinically agents. The modulatory effects of herbal medicines on CYP3A4 activity are one of the risk factors affecting the safe use of drug and herbal medicine. In the present study, the inhibitory effects of nearly hundred kinds of herbal medicines against CYP3A4 were evaluated based on a visual high-throughput screening method.
View Article and Find Full Text PDFSignal Transduct Target Ther
March 2022
NEMO/IKKβ complex is a central regulator of NF-κB signaling pathway, its dissociation has been considered to be an attractive therapeutic target. Herein, using a combined strategy of molecular pharmacological phenotyping, proteomics and bioinformatics analysis, Shikonin (SHK) is identified as a potential inhibitor of the IKKβ/NEMO complex. It destabilizes IKKβ/NEMO complex with IC of 174 nM, thereby significantly impairing the proliferation of colorectal cancer cells by suppressing the NF-κB pathway in vitro and in vivo.
View Article and Find Full Text PDFMonoamine oxidase A (MAO-A), as a vital drug target for various central nervous system diseases, locates in mitochondria and is mainly responsible for the oxidative inactivation of neurotransmitter amines. In the present work, a Mito-targeting fluorescent probe (HCCP) was developed to selectively and sensitively detect MAO-A activity, and successfully applied for the real-time monitoring endogenous MAO-A in living cells and tissues. Additionally, a high-throughput screening platform was established using HCCP and the inhibitory effects of 210 kinds of Herbal medicines toward MAO-A were evaluated.
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