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BACKGROUND AND AIM: Considering the limitation of varying acid suppression of proton pump inhibitors, this study was aimed to assess the efficacy, safety, and dose-effect relationship of keverprazan, a novel potassium-competitive acid blocker, in the treatment of duodenal ulcer (DU) compared with lansoprazole. METHODS: A randomized, double-blind, double-dummy, multicenter, low-dose, high-dose, and positive-drug parallel-controlled study was conducted to verify the non-inferiority of keverprazan (20 or 30 mg) to lansoprazole of 30 mg once daily for 4 to 6 weeks and dose-effect relationship of keverprazan in the treatment of patients with active DU confirmed by endoscopy. RESULTS: Of the 180 subjects randomized, including 55 cases in the keverprazan_20 mg group, 61 cases in the keverprazan_30 mg group, and 64 cases in the lansoprazole_30 mg group, 168 subjects (93.33%) completed the study. The proportions of healed DU subjects in the keverprazan_20 mg, keverprazan_30 mg, and lansoprazole_30 mg groups were respectively 87.27%, 90.16%, and 79.69% at week 4 (P = 0.4595) and were respectively 96.36%, 98.36%, and 92.19% at week 6 (P = 0.2577). The incidence of adverse events in the keverprazan_20 mg group was lower than that in the lansoprazole_30 mg (P = 0.0285) and keverprazan_30 mg groups (P = 0.0398). CONCLUSIONS: Keverprazan was effective and non-inferior to lansoprazole in healing DU. Based on the comparable efficacy and safety data, keverprazan of 20 mg once daily is recommended for the follow-up study of acid-related disorders. (Trial registration number: ChiCTR2100043455.).
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Antiulcerosos , Úlcera Duodenal , Humanos , Úlcera Duodenal/tratamiento farmacológico , Úlcera Duodenal/inducido químicamente , Antiulcerosos/uso terapéutico , Estudios de Seguimiento , Lansoprazol/efectos adversos , Inhibidores de la Bomba de Protones/efectos adversos , Método Doble Ciego , 2-Piridinilmetilsulfinilbencimidazoles/efectos adversosRESUMEN
OBJECTIVE: To investigate the changes in expression of the ACE2/Ang(1-7)/Mas receptor axis' components that occur during progression of liver fibrosis using a rat model system. METHODS: Thirty-six adult male Wistar rats, were randomly assigned to groups of normal control (n = 6; no manipulation) and liver fibrosis (n = 30; given a subcutaneous injection of 40% chronic carbon tetrachloride (CCl4)). At post-injection days 15, 30, 45, 60 and 75, 1 control rat and 6 modeled rats were sacrificed for analysis. Histopathological analysis of liver tissue was performed with hematoxylin-eosin and rapid Masson staining. Protein expression level of Ang(1-7) was determined by enzyme-linked immunosorbent assay, and of ACE2 and Mas receptor was evaluated by immunohistochemistry. Real-time PCR was used to measure the mRNA expression levels of ACE2 and Mas receptor. RESULTS: The expression levels of ACE2, Ang(1-7) and Mas receptor showed a statistically significant upward trend that followed the progression of fibrosis up to post-injection day 60 (P less than 0.01), but the significant increase was not seen from day 60 to day 75. CONCLUSION: Each component of the ACE2/Ang(1-7)/Mas receptor axis shows differential expression during the development of liver fibrosis and may contribute to disease progression.
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BACKGROUND: Alcohol-associated hepatic fibrosis is a widespread liver disease with no effective treatment. Recent studies have indicated that interleukin-22 (IL-22) can ameliorate alcohol-associated liver disease. However, the mechanism underlying the role of IL-22 in alcohol-associated hepatic fibrosis remains unclear. Therefore, we investigated the effect of IL-22 in a mouse model of alcohol-associated hepatic fibrosis and its underlying mechanisms. METHODS: Alcohol-associated hepatic fibrosis was induced by feeding male C57BL/6J mice with a Lieber-DeCarli liquid diet containing 4% ethyl alcohol for 8 weeks and injecting them with 5% tetrachloromethane (CCl4 ) intraperitoneally for the last 4 weeks. During the last 4 weeks, IL-22 was also administered. We investigated the role of IL-22 in autophagy and the PI3K/AKT/mTOR signaling pathway using a 3-methyladenine intraperitoneal injection in the mice treated with IL-22. The effects of IL-22 on alcohol-associated hepatic fibrosis, autophagy-related gene expression, and PI3K/AKT/mTOR activity were assessed using histopathology, biochemical analysis, transmission electron microscopy, quantitative real-time PCR, immunohistochemistry, and western blotting. RESULTS: Mice treated with ethanol and CCl4 displayed distinct liver injuries, including hepatocyte necrosis, inflammatory cell infiltration, and hepatic fibrosis, which were substantially attenuated by IL-22 treatment. In addition, we found that IL-22 regulated the expression of autophagy-related genes and inhibited the PI3K/AKT/mTOR pathway, as evidenced by the reduction in p-PI3K, p-AKT, and p-mTOR expression after IL-22 treatment. CONCLUSIONS: IL-22 exerts a marked protective effect against alcohol-associated hepatic fibrosis. Its effect may be partly related to the alteration of autophagy-related gene expression and inhibition of the PI3K/AKT/mTOR pathway in the liver.
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Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratones , Masculino , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones Endogámicos C57BL , Serina-Treonina Quinasas TOR/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/prevención & control , Etanol/toxicidad , Autofagia , Interleucina-22RESUMEN
AbstractObjective: To analyze the liver injury and coagulation dysfunction in COVID-19 severe/critical type patients. METHODS: The clinical data of 53 COVID-19 patients were collected from a single center in Wuhan from February 8, 2020 to March 25, 2020. The patients were divided into severe type group (38 patients) and critical type group (15 patients). The clinical characteristics, indexes of liver function, coagulation function and inflammatory markers were analyzed retrospectively. According to the degree of abnormal liver function in the process of diagnosis and treatment, the patients were divided into three groups: combined liver injury, mild abnormal liver function and normal liver function group. Statistical analysis was performed by using Student t test, Mann-Whitney U test, Kruskal-Wallis test and Chi-square test. RESULTS: Among the 53 patients, 29 were male (54.7%) and 24 were female (45.3%), the median age was 57(27ï¼80) years old. The time from onset to admission was (11.5±7.7) days. The levels of AST, TBIL, DBIL, ALP, GGT, LDH, D-dimer, PCT and hsCRP in critical patients were higher than those in severe patients (P<0.05). The levels of Alb in critical patients was lower than those in severe patients (P<0.05). Among the 53 patients, 34 (64%) patients showed abnormal elevation of ALT, AST or TBIL, while 4 (7.5%) patients showed the criteria of COVID-19 with liver injury. After the patients were grouping according to the degree of liver dysfunction, the levels of ALP, GGT and D-dimer of the patients in the liver injury group were significantly higher than those in the normal liver function group, D-dimer levels of the patients in the liver injury group was significantly higher than those in the mild abnormal liver function group, while the levels of ALP and GGT in the mild abnormal liver function group were significantly higher than those in the normal liver function group, and the differences were statistically significant(P<0.05). CONCLUSION: In this group, the patients with COVID-19 severe/critical type have a certain proportion of liver injury accompanied by significantly increased D-dimer levels, critical type patients have more severe liver function and coagulation dysfunction, which may promote the progression of COVID-19.
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Trastornos de la Coagulación Sanguínea , COVID-19 , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hígado , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , SARS-CoV-2RESUMEN
Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder characterised by gastrointestinal (GI) hamartomatous polyposis and mucocutaneous pigmentations. PJS is associated with an increased cancer risk, including GI and various extra-GI malignancies. In this study, we tracked this family for 8 years, and analyzed the clinical data of the PJS pedigree including two generations. In our research, the studied family members, including the proband, older daughter and younger daughter, all detected to have three heterozygous mutations in the RET gene that were inherited from the proband. The existed three mutant spots included exon 5 (GTG>ATG, Val292Met), exon 2 (CGC>CAC, Arg67His) and exon 18 (CGC>TGC, Arg982Cys) in RET. Our study provides an observation of the genetic heterogeneity of PJS. This pedigree investigation showed that it is critical to establish a long-term follow-up system for PJS patients and their families.
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AIM: To explore the effect of interleukin (IL)-22 on in vitro model of alcoholic liver fibrosis hepatic stellate cells (HSCs), and whether this is related to regulation of Nrf2-keap1-ARE. METHODS: HSC-T6 cells were incubated with 25, 50, 100, 200 and 400 µmol/L acetaldehyde. After 24 and 48 h, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect proliferation of HSCs to choose the best concentration and action time. We used the optimal concentration of acetaldehyde (200 µmol/L) to stimulate HSCs for 24 h, and treated the cells with a final concentration of 10, 20 or 50 ng/mL IL-22. The cell proliferation rate was detected by MTT assay. The cell cycle was analyzed by flow cytometry. The expression of nuclear factor-related factor (Nrf)2 and α-smooth muscle antigen was detected by western blotting and immunocytochemistry. The levels of malondialdehyde (MDA) and glutathione (GSH) were measured by spectrophotometry. RESULTS: In the MTT assay, when HSCs were incubated with acetaldehyde, activity and proliferation were higher than in the control group, and were most obvious after 48 h treatment with 200 µmol/L acetaldehyde. The number of cells in G0/G1 phases was decreased and the number in S phase was increased in comparison with the control group. When treated with different concentrations of IL-22, HSC-T6 cell activity and proliferation rate were markedly decreased in a dose-dependent manner, and cell cycle progression was arrested from G1 to S phase. Western blotting and immunocytochemistry demonstrated that expression of Nrf2 total protein was not significantly affected. Expression of Nrf2 nuclear protein was low in the control group, increased slightly in the model group (or acetaldehyde-stimulated group), and increased more obviously in the IL-22 intervention groups. The levels of MDA and GSH in the model group were significantly enhanced in comparison with those in the control group. In cells treated with IL-22, the MDA level was attenuated but the GSH level was further increased. These changes were dose-dependent. CONCLUSION: IL-22 inhibits acetaldehyde-induced HSC activation and proliferation, which may be related to nuclear translocation of Nrf2 and increased activity of the antioxidant axis Nrf2-keap1-ARE.
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Antioxidantes/metabolismo , Células Estrelladas Hepáticas/metabolismo , Interleucinas/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Cirrosis Hepática Alcohólica/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Acetaldehído/toxicidad , Animales , Elementos de Respuesta Antioxidante , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Glutatión/análisis , Cirrosis Hepática Alcohólica/etiología , Malondialdehído/análisis , Ratones , Ratas , Proteínas Recombinantes/metabolismo , Espectrofotometría , Interleucina-22RESUMEN
A 48-year-old woman was admitted with 15-mo history of abdominal pain, diarrhea and hematochezia, and 5-mo history of defecation difficulty. She had been successively admitted to nine hospitals, with an initial diagnosis of inflammatory bowel disease with stenotic sigmoid colon. Findings from computed tomography virtual colonoscopy, radiography with meglumine diatrizoate, endoscopic balloon dilatation, metallic stent implantation and later overall colonoscopy, coupled with the newfound knowledge of compound Qingdai pill-taking, led to a subsequent diagnosis of ischemic or toxic bowel disease with sigmoid colon stenosis. The patient was successfully treated by laparoscopic sigmoid colectomy, and postoperative pathological examination revealed ischemic or toxic injury of the sigmoid colon, providing a final diagnosis of drug-induced sigmoid colon stenosis. This case highlights that adequate awareness of drug-induced colon stenosis has a decisive role in avoiding misdiagnosis and mistreatment. The diagnostic and therapeutic experiences learnt from this case suggest that endoscopic balloon expansion and colonic metallic stent implantation as bridge treatments were demonstrated as crucial for the differential diagnosis of benign colonic stenosis. Skillful surgical technique and appropriate perioperative management helped to ensure the safety of our patient in subsequent surgery after long-term use of glucocorticoids.