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1.
Br J Pharmacol ; 181(12): 1768-1792, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38355288

RESUMEN

BACKGROUND AND PURPOSE: Panax ginseng is widely applied in the adjuvant treatment of cardiometabolic diseases in clinical practice without clear mechanisms. This study aims to clearly define the efficacy and underlying mechanism of P. ginseng and its active components in protecting against atherosclerosis. EXPERIMENTAL APPROACH: The anti-atherogenic efficacy of total ginseng saponin extract (TGS) and its components was evaluated on Ldlr-/- mice. Gut microbial structure was analysed by 16S rRNA sequencing and PCR. Bile acid profiles were revealed using targeted metabolomics with LC-MS/MS analysis. The contribution of gut microbiota to atherosclerosis was assessed by co-housing experiments. KEY RESULTS: Ginsenoside Rb1, representing protopanaxadiol (PPD)-type saponins, increased intestinal Lactobacillus abundance, resulting in enhanced bile salt hydrolase (BSH) activity to promote intestinal conjugated bile acid hydrolysis and excretion, followed by suppression of enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signal, and thereby increased cholesterol 7α-hydroxylase (CYP7A1) transcriptional expression and facilitated metabolic elimination of cholesterol. Synergistically, protopanaxatriol (PPT)-type saponins, represented by ginsenoside Rg1, protected against atherogenesis-triggered gut leak and metabolic endotoxaemia. Ginsenoside Rg1 directly induced mucin production to nutritionally maintain Akkermansia muciniphila, which reciprocally inhibited gut permeation. Rb1/Rg1 combination, rather than a single compound, can largely mimic the holistic efficacy of TGS in protecting Ldlr-/- mice from atherogenesis. CONCLUSION AND IMPLICATIONS: Our study provides strong evidence supporting TGS and ginsenoside Rb1/Rg1 combinations as effective therapies against atherogenesis, via targeting different signal nodes by different components and may provide some elucidation of the holistic mode of herbal medicines.


Asunto(s)
Aterosclerosis , Microbioma Gastrointestinal , Ginsenósidos , Homeostasis , Ratones Noqueados , Panax , Animales , Ginsenósidos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Homeostasis/efectos de los fármacos , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Masculino , Ratones , Panax/química , Ratones Endogámicos C57BL , Ácidos y Sales Biliares/metabolismo , Receptores de LDL/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Amidohidrolasas/metabolismo , Colesterol 7-alfa-Hidroxilasa/metabolismo
2.
Eur J Pharmacol ; 928: 174976, 2022 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-35487253

RESUMEN

Gastritis is a common inflammation of stomach with multiple pathogenesis. This study was designed to investigate the protective effects of oral octreotide (OCT) against ethanol-induced acute gastric injury and H. pylori-induced chronic gastritis via promoting gastric mucosa restoration, reducing gastric acid secretion and inflammation. Male C57BL/6J mice were randomly divided and treated with three doses of OCT (0.5, 2.5, 10 mg/kg) alone or combined respectively with 10 mg/kg omeprazole (OME), 0.2 g/L metronidazole (MTZ)/0.1 g/L clarithromycin (CLR) in drinking water. Oxidative stress analysis, bacterial load analysis, qPCR, gastric histopathology examinations were performed in our study. Ethanol-induced acute gastric ulcer was restored by OCT alone at doses of 2.5 mg/kg, or combined with OME as indicated by markedly reducing Gastrin, Il-6 and Il1b expression through induction of Muc5ac and Occludin, significantly improving hyperacidity and gastric bleeding. As well, OCT combined with MTZ/CLR restored the integrity of gastric mucosa damaged by H. pylori via elevating the expression of Muc5ac and somatostatin receptor 2, decreasing inflammation and increasing the number of chorionic or glands. Besides, OCT is more suitable for long-term medication in the treatment of chronic gastritis than OME. In conclusion, our results proved that the newly developed oral OCT-based therapies were more effective to reverse gastric mucosa damage and inflammation in ethanol and H. pylori infection-induced gastric injury, it is of great significance for supplementing new clinical regimens for the treatment of acute and chronic gastritis.


Asunto(s)
Gastritis Atrófica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Animales , Claritromicina/metabolismo , Claritromicina/farmacología , Claritromicina/uso terapéutico , Etanol/farmacología , Mucosa Gástrica , Gastritis/tratamiento farmacológico , Gastritis/prevención & control , Gastritis Atrófica/tratamiento farmacológico , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Octreótido/farmacología , Octreótido/uso terapéutico , Omeprazol/farmacología , Omeprazol/uso terapéutico
3.
J Ethnopharmacol ; 266: 113394, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-32941971

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disease of the gastrointestinal tract, consisting of ulcerative colitis (UC) and Crohn's disease (CD). Gut microbiota and their metabolites may play a role in the pathogen of IBD, especially of the UC. Qingchang Huashi Formula (QHF), a traditional Chinese medicine formula, has shown therapeutic effect on treating UC based on the clinical practice without clear pharmacological mechanism. AIM OF THE STUDY: The aim of this study was to clearly define the effect of QHF and its components, Baitouweng (PBR) and Baizhi (ADR) on treating UC. MATERIALS AND METHODS: Pharmacodynamic effects of QHF and single herb were evaluated in dextran sulfate sodium (DSS) induced acute or chronic colitis mice. Body weight loss, disease activity index (DAI) and colon length were estimated. Histological changes were observed by H&E staining. The number and abundance of gut microbiota were measured with 16S rRNA sequencing. LC-MS and GC-MS were used to detect the concentration of metabolites (e.g., bile acids (BAs) and short chain fatty acids (SCFAs)). The goblet cell was observed by Alcian blue/periodic acid-Schiff (AB/PAS) straining and the crypt stem cell was estimated by immunohistochemical analyses. The colorectal tissues were used to detect levels of IL-1ß, IL-6 and TNF-α by ELISA or qRT-PCR. The expression of NLRP3, Caspase 1 and IL-1ß were examined by western blotting. RESULTS: QHF significantly inhibited colitis, protected mice from the loss of body weight and colon shorten. Comparatively, ADR and PBR showed strong efficacy in inhibiting DSS-induced colitis. We verified that while ADR was responsible for QHF's effect on maintaining gut microbiota homeostasis and metabolism, PBR was more prominent in keeping crypt stem cells proliferation and colonic goblet cells function. Moreover, we demonstrated that the alleviation of colitis by QHF was associated with the restoration of gut microbiota-metabolism homeostasis, protection of intestinal epithelial barrier and regulation of NLRP3/IL-1ß pathway. CONCLUSIONS: The finding of the present study suggested that QHF is curative in DSS-induced colitis by restoring gut microbiota-metabolism homeostasis and goblet cells function. An optimized QHF was constituted by ADR and PBR, which showed comparable efficacy on colitis to that of QHF. Our work probed out the active constitutes as well as the relevant pharmacological mechanisms of QHF, shedding light on potential new drug combination for the treatment of IBD.


Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Células Caliciformes/efectos de los fármacos , Animales , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/patología , Colon/efectos de los fármacos , Colon/microbiología , Colon/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Células Caliciformes/patología , Homeostasis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Ribosómico 16S
4.
J Ethnopharmacol ; 243: 112093, 2019 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-31325602

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng (Panax ginseng C. A. Mey) has been widely used in Asian countries for thousands of years. It has auxiliary anticancer efficacy and its derived preparations (e.g. Shenmai injection) are prescribed for cancer patients as Traditional Chinese Medicines clinically in China. AIM OF THE STUDY: The involved adjuvant anticancer mechanisms of ginseng are still unknown. The present study evaluated the anti-cancer effect of total ginsenosides extract (TGS) and determined the anticancer mechanisms of TGS-induced cell death in human non-small cell lung cancer (NSCLC) cells. MATERIALS AND METHODS: The anti-cancer effect of TGS was evaluated in NSCLC by cell proliferation assay. The autophagy flux induction of TGS were tested and validated by Western blot, immunofluorescence and transmission electron microscope. The mechanisms of TGS in inducing autophagic cell death were validated by Western blot, gene knockdown and quantitative real time PCR assay. RESULTS: We found TGS could induce cell death in concentration and time dependent manners, and the cell morphology of NSCLC changed from cobblestone shape to elongated spindle shape after treated with TGS. In the study of cell autophagy, we confirm that TGS could upregulate autophagy flux and induce autophagic cell death through activation endoplasmic reticulum stress. Further investigations demonstrated this process was mediated by the ATF4-CHOP-AKT1-mTOR axis in NSCLC cells. CONCLUSION: Our findings suggested that TGS could induce autophagic cell death in NSCLC cells through activation of endoplasmic reticulum stress, disclosing another characteristic of TGS-induced cell death and a novel mechanism of TGS and its derived preparations in clinical treatment of cancer patients.


Asunto(s)
Antineoplásicos/farmacología , Muerte Celular Autofágica/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ginsenósidos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Factor de Transcripción Activador 4/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Factor de Transcripción CHOP/metabolismo
5.
Molecules ; 22(7)2017 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-28708106

RESUMEN

Evodiamine is one of the main components isolated from Evodia rutaecarpa, and it has been reported to exert inhibitory effects on cancers by anti-proliferative and apoptosis-inducing activities. Although the anti-cancer activity of evodiamine has been identified, the precise mechanisms of this action remain obscure. While previous studies indicated that evodiamine exerts anti-tumor effects through inhibiting ß-catenin activity, and WW domain-containing oxidoreductase (WWOX) regulates ß-catenin accumulation in cytoplasm, the effects of evodiamine on the expression of WWOX are still unknown. In this study, we provide evidence that evodiamine dose- and time-dependently inhibits both Mus musculus and Homo sapiens hepatocellular carcinoma (HCC) cells, as well as Hepa1-6 and HepG2 cell proliferation. We further tested the therapeutic effects of evodiamine in Hepa1-6 hepatoma-bearing mice, and we found that treatment of evodiamine by oral gavage significantly decreased the tumor size of the mice. Moreover, the expressions of WWOX were dose-dependently increased in HCC cell lines as well as in Hepa1-6 hepatoma-bearing mice after the treatment with evodiamine. Knockdown of WWOX in HepG2 and Hepa1-6 cells diminished the effects of evodiamine on the inhibitory effect of cancer cell growth, indicating that evodiamine induced anti-cancer activity through a WWOX-dependent pathway. As such, evodiamine activated WWOX to exert an anti-HCC activity, and might be a potential therapeutic or preventive candidate for HCC treatment.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Evodia/química , Quinazolinas/química , Quinazolinas/farmacología , Oxidorreductasa que Contiene Dominios WW/efectos de los fármacos , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Técnicas de Silenciamiento del Gen/métodos , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Extractos Vegetales/química , Quinazolinas/administración & dosificación , beta Catenina
6.
Drug Metab Dispos ; 44(5): 720-31, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26965985

RESUMEN

Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in Western countries. Glycyrrhizin (GL), a potent hepatoprotective constituent extracted from the traditional Chinese medicine liquorice, has potential clinical use in treating APAP-induced liver failure. The present study determined the hepatoprotective effects and underlying mechanisms of action of GL and its active metabolite glycyrrhetinic acid (GA). Various administration routes and pharmacokinetics-pharmacodynamics analyses were used to differentiate the effects of GL and GA on APAP toxicity in mice. Mice deficient in cytochrome P450 2E1 enzyme (CYP2E1) or receptor interacting protein 3 (RIPK3) and their relative wild-type littermates were subjected to histologic and biochemical analyses to determine the potential mechanisms. Hepatocyte death mediated by tumor necrosis factorα(TNFα)/caspase was analyzed by use of human liver-derived LO2 cells. The pharmacokinetics-pharmacodynamics analysis using various administration routes revealed that GL but not GA potently attenuated APAP-induced liver injury. The protective effect of GL was found only with intraperitoneal and intravenous administration and not with gastric administration. CYP2E1-mediated metabolic activation and RIPK3-mediated necroptosis were unrelated to GL's protective effect. However, GL inhibited hepatocyte apoptosis via interference with TNFα-induced apoptotic hepatocyte death. These results demonstrate that GL rapidly attenuates APAP-induced liver injury by directly inhibiting TNFα-induced hepatocyte apoptosis. The protective effect against APAP-induced liver toxicity by GL in mice suggests the therapeutic potential of GL for the treatment of APAP overdose.


Asunto(s)
Acetaminofén/efectos adversos , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Ácido Glicirrínico/farmacología , Hígado/efectos de los fármacos , Sustancias Protectoras/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Activación Metabólica/efectos de los fármacos , Animales , Línea Celular , Citocromo P-450 CYP2E1/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo
7.
Toxicol Appl Pharmacol ; 227(2): 291-8, 2008 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-18078970

RESUMEN

Antrodia camphorata (A. camphorata) is a fungus commonly used for treatment of viral hepatitis and cancer in Chinese folk medicine. Extract of A. camphorate is reported to possess anti-inflammatory, antihepatitis B virus and anticancer activities. In this study, we tested the in vivo effects of polysaccharides derived from A. camphorata (AC-PS) on immune function by detection of cytokine expression and evaluation of the immune phenotype in a T1/T2 doubly transgenic mouse model. The protective effect of AC-PS in mice was tested by infection with Schistosoma mansoni. The induction of large amounts of IFN-gamma, IL-2 and TNF-alpha mRNA were detected after 2 and 4 weeks of oral AC-PS administration in BALB/c and C57BL/6 mice. In transgenic mice, 3 to 6 weeks of oral AC-PS administration increased the proportion of CD4(+) T cells and B cells within the spleen. More specifically, there was an increase of Th1 CD4(+) T cells and Be1 cells among spleen cells as observed by detection the of Type1/Type2 marker molecules. By using a disease model of parasitic infection, we found that AC-PS treatment inhibited infection with S. mansoni in BALB/C and C57BL/6 mice. AC-PS appears to influence the immune system of mice into developing Th1 responses and have potential for preventing infection with S. mansoni.


Asunto(s)
Factores Inmunológicos , Polyporales/química , Polisacáridos/farmacología , Esquistosomiasis mansoni/genética , Esquistosomiasis mansoni/prevención & control , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , ADN Complementario/biosíntesis , ADN Complementario/genética , Citometría de Flujo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Polisacáridos/química , ARN/biosíntesis , ARN/genética , Esquistosomiasis mansoni/parasitología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Transgenes
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