RESUMEN
Cold-heat combination is a common method in the treatment of ulcerative colitis, which is represented by classic drug pair, Coptidis Rhizoma and Zingiberis Rhizoma.The present study explored the synergetic effects of berberine and 6-shogaol, the primary components of Coptidis Rhizoma and Zingiberis Rhizoma, respectively, on intestinal inflammation and intestinal flora in mice with ulcerative colitis to reveal the effect and mechanism of cold-heat combination in the treatment of ulcerative colitis.The ulcerative colitis model was induced by dextran sulfate sodium(DSS) in mice.The model mice were administered with berberine(100 mg·kg~(-1)), 6-shogaol(100 mg·kg~(-1)), and berberine(50 mg·kg~(-1)) combined 6-shogaol(50 mg·kg~(-1)) by gavage, once per day.After 20 days of drug administration, mouse serum, colon tissues, and feces were sampled.Hematoxylin-eosin(HE) staining was used to observe histopathological changes in colon tissues.Alcian blue/periodic acid-Schiff(AB/PAS) staining was used to observe the changes in the mucus layer of colon tissues.Enzyme-linked immunosorbent assay(ELISA) was employed to detect the serum content of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), and interleukin-6(IL-6).Immunohistochemical method was adopted to detect the protein expression of macrophage surface markers F4/80, mucin-2, claudin-1, and zonula occludens-1(ZO-1) in colon tissues.High-throughput Meta-amplicon library sequencing was used to detect changes in the intestinal flora of mice.The results indicated that the 6-shogaol group, the berberine group, and the combination group showed significantly relieved intestinal injury, reduced number of F4/80-labeled positive macrophages in colon tissues, increased protein expression of mucin-2, claudin-1, and ZO-1, and decreased serum le-vels of TNF-α, IL-1ß, and IL-6.Shannon, Simpson, Chao, and Ace indexes of the intestinal flora of mice in the 6-shogaol group and the combination group significantly increased, and Chao and Ace indexes in the berberine group significantly increased.As revealed by the bioinformatics analysis of intestinal flora sequencing, the relative abundance of Verrucomicrobia at the phylum, class, and order levels decreased significantly in all treatment groups after drug administration, while that of Bacillibacteria gradually increased.In the 6-shogaol group and the combination group, Akkermansia muciniphila completely disappeared, but acid-producing bacillus still existed in large quantities.As concluded, both 6-shogaol and berberine can inhibit intestinal inflammation, reduce the infiltration and activation of macrophages, relieve intestinal damage, reduce intestinal permeability, improve the structure of flora, and promote intestinal microecological balance.The combined application of berberine and 6-shogaol has a significant synergistic effect.
Asunto(s)
Berberina , Colitis Ulcerosa , Colitis , Medicamentos Herbarios Chinos , Animales , Berberina/farmacología , Berberina/uso terapéutico , Catecoles , Claudina-1/metabolismo , Claudina-1/farmacología , Claudina-1/uso terapéutico , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colon , Sulfato de Dextran/efectos adversos , Sulfato de Dextran/metabolismo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Inflamación/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos C57BL , Mucina 2/metabolismo , Mucina 2/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Objective To investigate the association of pancreatic steatosis with coronary atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Methods Patients with T2DM who underwent coronary computed tomography angiography(CCTA)in our center due to chest pain were enrolled from January 2016 to February 2019. According to the CCTA findings,patients were divided into normal group,mild-to-moderate coronary atherosclerosis group and severe coronary atherosclerosis group. CT attenuation of pancreas and spleen was measured on abdominal non-enhanced CT,and the CT attenuation indexes including the difference between pancreatic and splenic attenuation (P-S) and the ratio of pancreas-to-spleen attenuation (P/S) were calculated. Analysis of variance or Kruskal-Wallis rank test were used to assess differences among each group. Logistic regression analysis was used to analyze the risk factors of severe coronary stenosis. The accuracy of P/S in predicting severe coronary artery stenosis was assessed by receiver operator characteristic (ROC) curve analysis. Results A total of 173 consecutive T2DM patients were enrolled. These patients included 27 patients with normal coronary artery (15.6%),124 patients with mild to moderate stenosis (71.7%),and 22 patients with severe stenosis (12.7%). There were significant differences in CT attenuation of pancreas (Z=11.543,P=0.003),P-S (Z=11.152,P=0.004) and P/S (Z=11.327,P=0.004) among normal coronary artery group,mild and moderate stenosis group,and severe stenosis group. The CT attenuation of pancreatic head,body,and tail significantly differed in patients with coronary artery stenosis (Z=14.737,P=0.001). After adjusting for confounding factors,multiple Logistic regression showed that P/S (OR=0.062,95%CI=0.008-0.487,P=0.008) was still significantly associated with the severe coronary artery stenosis. The area under the ROC curve of P/S for the diagnosis of severe coronary artery stenosis was 0.701,and the optimal cutoff point was 0.660. Conclusion CT attenuation of pancreas and CT attenuation indexes are associated with the severity of coronary stenosis in T2DM patients,suggesting that pancreatic steatosis may be used as one of the indicators for predicting severe coronary artery stenosis.
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Enfermedad de la Arteria Coronaria/complicaciones , Estenosis Coronaria , Diabetes Mellitus Tipo 2/complicaciones , Páncreas/patología , Angiografía Coronaria , Humanos , Valor Predictivo de las PruebasRESUMEN
BACKGROUND: Gastric precancerous lesions (GPL) precede the development of gastric cancer (GC). They are characterized by gastric mucosal intestinal metaplasia and dysplasia caused by various factors such as inflammation, bacterial infection, and injury. Abnormalities in autophagy and glycolysis affect GPL progression, and their effective regulation can aid in GPL treatment and GC prevention. Xiaojianzhong decoction (XJZ) is a classic compound for the treatment of digestive system diseases in ancient China which can inhibit the progression of GPL. However, its specific mechanism of action is still unclear. AIM: To investigate the therapeutic effects of XJZ decoction on a rat GPL model and the mechanisms underlying its effects on autophagy and glycolysis regulation in GPLs. METHODS: Wistar rats were randomly divided into six groups of five rats each and all groups except the control group were subjected to GPL model construction for 18 wk. The rats' body weight was monitored every 2 wk starting from the beginning of modeling. Gastric histopathology was examined using hematoxylin-eosin staining and Alcian blue-periodic acid-Schiff staining. Autophagy was observed using transmission electron microscopy. The expressions of autophagy, hypoxia, and glycolysis related proteins in gastric mucosa were detected using immunohistochemistry and immunofluorescence. The expressions of the following proteins in gastric tissues: B cell lymphoma/Leukemia-2 and adenovirus E1B19000 interacting protein 3 (Bnip-3), microtubule associated protein 1 light chain 3 (LC-3), moesin-like BCL2-interacting protein 1 (Beclin-1), phosphatidylinositol 3-kimase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), p53, AMP-activated protein kinase (AMPK), and Unc-51 like kinase 1 (ULK1) were detected using western blot. The relative expressions of autophagy, hypoxia, and glycolysis related mRNA in gastric tissues was detected using reverse transcription-polymerase chain reaction. RESULTS: Treatment with XJZ increased the rats' body weight and improved GPL-related histopathological manifestations. It also decreased autophagosome and autolysosome formation in gastric tissues and reduced Bnip-3, Beclin-1, and LC-3II expressions, resulting in inhibition of autophagy. Moreover, XJZ down-regulated glycolysis-related monocarboxylate transporter (MCT1), MCT4, and CD147 expressions. XJZ prevented the increase of autophagy level by decreasing gastric mucosal hypoxia, activating the PI3K/AKT/mTOR pathway, inhibiting the p53/AMPK pathway activation and ULK1 Ser-317 and Ser-555 phosphorylation. In addition, XJZ improved abnormal gastric mucosal glucose metabolism by ameliorating gastric mucosal hypoxia and inhibiting ULK1 expression. CONCLUSION: This study demonstrates that XJZ may inhibit autophagy and glycolysis in GPL gastric mucosal cells by improving gastric mucosal hypoxia and regulating PI3K/AKT/mTOR and p53/ AMPK/ULK1 signaling pathways, providing a feasible strategy for the GPL treatment.
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Objective: To investigate underlying mechanism involving Roumudan(RMD) formulation (Z20160012) suppressed liver fibrosis induced by CCl4 injection in mice by inhibiting TGF-ß1/Smad4 pathway. Methods: Male BALB/c mice were randomly divided into control group, liver fibrosis model group and RMD-treated group(n=11). Mice in liver fibrosis model and RMD-treaded groups were injected intraperitoneally with CCl4 (20% in olive oil) at the dose of 2.5 mL/kg two times for one week and 5 mL/kg two times for 4 weeks. Mice in control group were treated intraperitoneally with the same volume of olive oil at the same time intervals. From sixth week, Mice in liver fibrosis model group were administrated with CCl4 (20% in olive oil, 1.5 ml/kg once per week) intraperitoneally and given distilled water by intragastric gavage. Mice in the RMD-treated group were administrated with CCl4 (20% in olive oil, 1.5 ml/kg/mouse once per week) intraperitoneally and given RMD(6.2 g/kg everyday) by intragastric gavage. Mice in the control group were administrated with olive oil (1.5 ml/kg/mouse once per week) intraperitoneally and given distilled water by intragastric gavage. The serum AST and ALT levels were estimated for assessment of liver function. The pathologic changes of mice' livers were examined by the HE, Masson, immunohistochemical staining, Western Blot, Q-PCR and so on. Results: After intraperitoneally injected with CCl4 in mice, the pathological characteristics of liver fibrosis were observed compared with the control group at the sixth week. Compared with the liver fibrosis model group, RMD improved the liver function significantly through reducing liver index(Pï¼0.01) and the levels of ALT(Pï¼0.01), AST(Pï¼0.01) and HYP(Pï¼0.05). The expression of TGF-ß1(Pï¼0.05), α-SMA(Pï¼0.05), COL1A1(Pï¼0.01) and COL3A1(Pï¼0.01) were decreased by RMD. The positive expression area of Smad4 mRNA in RMD treated group was lower than that in liver fibrosis model group. Conclusion: The RMD formulation could attenuate liver fibrosis by inhibiting TGF-ß1/Smad4 pathway and extracellular matrix (ECM) production in mice.
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Tetracloruro de Carbono , Factor de Crecimiento Transformador beta1 , Animales , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
OBJECTIVE: To observe the regulatory effect of 6-Shogaol on Notch signal pathway in colonic epithelial cells of mice with ulcerative colitis. METHODS: Forty Kunming mice were randomly divided into normal group (n=10) and model group (n=30). The model of ulcerative colitis was induced by free drinking of 2% dextran sulfate sodium salt(DSS). After 15 days, the mice were divided into model group, 6-gingerenol group and positive control group with 10 mice in each group. Normal group and model group were treated with normal saline, 6-gingerenol group was treated with 6-Shogaol 100 mg/(kg·d), positive control group was treated with sulfasalazine 100 mg/(kg·d), for 20 days. The histopathological changes of colon were observed, and the expressions of Hes-1 and Math-1protein in colonic epithelial cells were detected by immunofluorescence double labeling method. The expressions of Notch-1, Hes-1 and Math-1 mRNA in colonic epithelial tissue were detected by RT-PCR. The expressions of Notch-1, Hes-1 and Math-1 protein in colonic epithelial tissue was detected by Western blot. RESULTS: Compared with the normal group, the expression of Notch-1 and Hes-1 protein and the relative expression of mRNA in colonic epithelium of model group were significantly increased (Pï¼0.01), while the relative expressions of Math-1 mRNA and protein were decreased significantly (Pï¼0.01). Compared with the model group, the expressions of Notch-1 and Hes-1 protein and the relative expression of mRNA in colonic epithelium of 6-Shogaol group and sulfasalazine group were decreased significantly(Pï¼0.01), while the relative expressions of Math-1 mRNA and protein were increased significantly(Pï¼0.01). CONCLUSION: 6-Shogaol can inhibit the over activation of Notch pathway and regulate the balance of differentiation between colonic epithelialabsorptive cell line and secretory cell line and repair damaged mucosal tissue.
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Catecoles/farmacología , Colitis Ulcerosa , Células Epiteliales/efectos de los fármacos , Transducción de Señal , Animales , Colon/citología , Modelos Animales de Enfermedad , Mucosa Intestinal/patología , Ratones , Receptores Notch/metabolismoRESUMEN
OBJECTIVE: To evaluate the correlating clinical factors of coronary artery calcification score (CACS). METHODS: 141 patients suspected of coronary artery disease were included. They underwent multi-slice row computed tomography, pulse wave velocity (PWV), UCG and blood biochemistry within a period of 3 months. The subjects were divided into three groups according to CAC score: A (CACS = 0 - 10), B (CACS = 11 - 400), C (CACS > 400). RESULTS: CACS was significantly associated with age, history of hypertension and diabetes mellitus. It was also associated with the presence of mitral annular calcification and aortic valve calcification, low ankle brachial pressure index (ABI) and high mean artery pressure (MAP) as well as high values of brachial ankle PWV (baPWV) and Upstroke time (UT). Multifactorial logistic regression analysis showed that the presence of aortic valve calcification and mitral annular calcification, the history of diabetes mellitus and high value of UT were independently correlated with severe coronary artery calcification. CONCLUSIONS: Aortic valve calcification, mitral annular calcification, history of diabetes mellitus, high value of UT were independently correlated with severe coronary artery calcification. Measurement of PWV and UCG should be performed before multi-slicerow computed tomography, because the assessment of coronary artery lumen narrowing with multi-slice row computed tomography can not be carried out accurately in the presence of severe coronary artery calcification.