Binary Bacillus subtilis protects the intestinal mucosa barrier and alleviates nonalcoholic steatohepatitis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is characterized by liver steatosis, inflammation, and even fibrosis. NASH is likely to develop into cirrhosis and liver cancer, the major causes of liver related deaths. We aimed to study the effect of probiotics on NASH via the gut-liver axis. METHODS: Thirty male Sprague-Dawley rats were divided into three groups. A control group of 10 rats was fed on a standard chow for 16 weeks. Twenty rats fed on a high-fat diet for 8 weeks were separated to two groups: a model group (10 rats) fed on vehicle for 8 weeks and a treatment group (10 rats) supplemented with binary Bacillus subtilis for 8 weeks. Hepatic expression of IL-6 and TNF-ɑ and ileum expression of IL-17 and occludin were measured. RESULTS: The high-fat diet caused inflammation of the liver and ileum in rats. Binary Bacillus subtilis treatment reduces liver inflammation through the intestinal liver axis. Increased levels of IL-6 and TNF-α were detected in rats fed a high-fat diet, which were reduced to lower levels after treatment with binary Bacillus subtilis. In rats on the high-fat diet, elevated IL-17 levels and decreased occludin levels were observed. Treatment with Bacillus subtilis reduced IL-17 levels and restored the expression of occludin. CONCLUSION: Binary Bacillus subtilis has a beneficial effect on liver inflammation and intestinal damage.

Effect of ambient temperature on daily hospital admissions for acute pancreatitis in Nanchang, China: A time-series analysis.

The aim of this study was to evaluate the short-term effect of temperature on the risk of acute pancreatitis (AP) in southern China. We performed a time-series study of 2822 patients admitted with a first episode of AP in Nanchang between May 2014 and June 2017. A generalized additive model combined with a distributed lag non-linear model was applied to assess the association of temperature and AP. In subgroup analysis, according to different etiologies of pancreatitis, significant associations were found between daily average temperature and non-biliary pancreatitis hospitalization at lags of 0-7 days, but not for biliary pancreatitis or total AP. Higher daily average temperature tended to increase the occurrence of non-biliary pancreatitis at lags of 0-7 days. These findings suggest that high temperature is associated with higher non-biliary pancreatitis risk in Nanchang, China. In the context of global warming, the morbidity of non-biliary pancreatitis may increase.

Clinical characteristics and diagnosis of a rare case of systemic AL amyloidosis: a descriptive study.

Systemic amyloidosis is a rare disease involving multiple organs. It is difficult to establish diagnosis as the symptoms is diverse and non-specific. And without specific therapy the prognosis is very poor. We analyzed detailed clinical and laboratorial data of a 53-year-old male patient. The characteristic features included refractory pleural effusion, extraordinary hepatomegaly and cardiac failure. The illness lasted 9 months and therapy period spanned 4 months. Fine needle biopsy of liver, lung, heart, pancreas and kidney was performed. Immunohistochemistry, immunofluorescence, Congo staining and hematoxylin and eosin staining were performed. All specimens were stained pink with haematoxylin and eosin staining. Amorphous deposits of eosinophilic material were visible within the Congo red dye stained liver tissue whereas under cross-polarized light pathognomonic apple-green birefringence of amyloid deposits was visible. At last systemic AL amyloidosis diagnosis was confirmed. The report showed an unusual AL amyloidosis case in detail which would be helpful for physician in clinical work.

Adenovirus-mediated expression of orphan nuclear receptor NR4A2 targeting hepatic stellate cell attenuates liver fibrosis in rats.

Liver fibrosis is a wound-healing response characterized with the accumulation of extracellular matrix (ECM). And hepatic stellate cells (HSCs) are the principal cell source of ECM. NR4A2 (Nurr1) is a member of orphan nuclear receptor NR4A family and acts as transcription factor. It participates in regulating cell differentiation, proliferation and apoptosis. We previously demonstrated that NR4A2 expression in fibrotic liver reduced significantly compared with normal liver and NR4A2 knockout in HSCs promoted ECM production. In the present study we explored the role of NR4A2 on liver fibrosis. Studies in cultured HSCs demonstrated that NR4A2 over-expression suppressed the activation of HSCs, such as ECM production and invasion ability. Moreover cell cycle was arrested, cell apoptosis was promoted and cell signaling pathway was influenced. Adenovirus-mediated delivery of NR4A2 in rats ameliorated significantly dimethylnitrosamine (DMN) induced liver fibrosis. The In vivo experiments produced results consistent with in vitro experiments. Taken together these results demonstrate NR4A2 enhancement attenuates liver fibrosis via suppressing the activation of HSCs and NR4A2 may be an ideal target for anti-fibrotic therapy.

The roles of apolipoprotein E3 and CYP2D6 (rs1065852) gene polymorphisms in the predictability of responses to individualized therapy with donepezil in Han Chinese patients with Alzheimer's disease.

AIM: Polymorphisms in the apolipoprotein E and CYP2D6 genes are widely reported to be related to Alzheimer's disease. However, few studies have focused on the relationship between polymorphisms in apolipoprotein E and CYP2D6 (rs1065852) genes and therapeutic responses to donepezil (DNP). This study explored the influence of apolipoprotein E3 and CYP2D6 (rs1065852) gene polymorphisms on therapeutic responses to donepezil in Han Chinese patients with Alzheimer's disease. MATERIALS AND METHODS: A total of 85 patients with mild to moderate Alzheimer's disease who were treated with 2.5-10mg of DNP per day for at least 3 months were enrolled. Mini-Mental State Examination scores were measured before and after DNP treatment, and the apolipoprotein E3 and CYP2D6 (rs1065852) genotypes of the patients were determined. RESULTS: We found that ApoE E3 non-carriers responded better to DNP treatment than E3 carriers (p=0.000) and that CYP2D6*10/*10 patients (MMSE score change: 0.29±3.27) exhibited better therapeutic responses to DNP than did CYP2D6*1/*1 and CYP2D6*1/*10 patients (p=0.033). Patients who were ApoE E3 non-carriers and who had the CYP2D6*10/*10 genotype exhibited a trend toward better clinical responses to DNP therapy. CONCLUSIONS: The ApoE E3 allele and the CYP2D6 rs1065852 polymorphism may provide clinically relevant information for predicting therapeutic responses to DNP therapy.

Chinese Herbal Medicines as an Adjunctive Therapy for Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Pancreatic cancer is a common malignancy with a high mortality. Most patients present clinically with advanced pancreatic cancer. Moreover, the effect of radiotherapy or chemotherapy is limited. Complementary and alternative medicines represent exciting adjunctive therapies. In this study, we ascertained the beneficial and adverse effects of Chinese herbal medicine (CHM) in combination with conventional therapy for inoperable pancreatic cancer by using meta-analysis methods for controlled clinical trials. We extracted data for studies searched from six electronic databases that were searched and also assessed the methodological quality of the included studies. We evaluated the following outcome measures: 6-month and 1-year survival rate, objective response rate, disease control rate, quality of life, and adverse effects. The final analysis showed CHM is a promising strategy as an adjunctive therapy to treat advanced or inoperable pancreatic cancer and that CHM in combination with conventional therapy is a promising strategy for resistant disease. However, convincing evidence must be obtained and confirmed by high-quality trials in future studies.

Orphan nuclear receptor NR4A2 inhibits hepatic stellate cell proliferation through MAPK pathway in liver fibrosis.

Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis, which is a pathological process characterized by extracellular matrix accumulation. NR4A2 is a nuclear receptor belonging to the NR4A subfamily and vital in regulating cell growth, metabolism, inflammation and other biological functions. However, its role in HSCs is unclear. We analyzed NR4A2 expression in fibrotic liver and stimulated HSCs compared with control group and studied the influence on cell proliferation, cell cycle, cell apoptosis and MAPK pathway after NR4A2 knockdown. NR4A2 expression was examined by real-time polymerase chain reaction, Western blotting, immunohistochemistry and immunofluorescence analyses. NR4A2 expression was significantly lower in fibrotic liver tissues and PDGF BB or TGF-ß stimulated HSCs compared with control group. After NR4A2 knockdown α-smooth muscle actin and Col1 expression increased. In addition, NR4A2 silencing led to the promotion of cell proliferation, increase of cell percentage in S phase and reduced phosphorylation of ERK1/2, P38 and JNK in HSCs. These results indicate that NR4A2 can inhibit HSC proliferation through MAPK pathway and decrease extracellular matrix in liver fibrogenesis. NR4A2 may be a promising therapeutic target for liver fibrosis.

Stereoselective metabolism of donepezil and steady-state plasma concentrations of S-donepezil based on CYP2D6 polymorphisms in the therapeutic responses of Han Chinese patients with Alzheimer's disease.

The therapeutic response rates of patients to donepezil vary from 20% to 60%, one of the reasons is their genetic differences in donepezil-metabolizing enzymes, which directly influence liver metabolism. However, the mechanism of donepezil metabolism and that of its enantiomers is unknown. This study evaluated CYP2D6 polymorphisms to elucidate the stereoselective metabolism of donepezil and to confirm the association between the steady-state plasma concentrations of the pharmaco-effective S-donepezil and the therapeutic responses of Han Chinese patients with Alzheimer's disease. The in vitro study of the stereoselective metabolism demonstrated that CYP2D6 is the predominant P450 enzyme that metabolizes donepezil and that different CYP2D6 alleles differentially affect donepezil enantiomers metabolism. A total of 77 Han Chinese patients with Alzheimer's disease were recruited to confirm these results, by measuring their steady-state plasma concentrations of S-donepezil. The related CYP2D6 genes were genotyped. Plasma concentrations of S-donepezil (based on CYP2D6 polymorphisms) were significantly associated with therapeutic responses. This finding suggests that plasma concentrations of S-donepezil influence therapeutic outcomes following treatment with donepezil in Han Chinese patients with Alzheimer's disease. Therefore, determining a patient's steady-state plasma concentration of S-donepezil in combination with their CYP2D6 genotype might be useful for clinically monitoring the therapeutic efficacy of donepezil.

Induction of Nur77 by hyperoside inhibits vascular smooth muscle cell proliferation and neointimal formation.

Nur77 is an orphan nuclear receptor that belongs to the nuclear receptor 4A (NR4A) subfamily, which has been implicated in a variety of biological events, such as cell apoptosis, proliferation, inflammation, and metabolism. Activation of Nur77 has recently been shown to be beneficial for the treatment of cardiovascular and metabolic diseases. The purpose of this study is to identify novel natural Nur77 activators and investigate their roles in preventing vascular diseases. By measuring Nur77 expression using quantitative RT-PCR, we screened active ingredients extracted from Chinese herb medicines with beneficial cardiovascular effects. Hyperoside (quercetin 3-D-galactoside) was identified as one of the potent activators for inducing Nur77 expression and activating its transcriptional activity in vascular smooth muscle cells (VSMCs). We demonstrated that hyperoside, in a time and dose dependent manner, markedly increased the expression of Nur77 in rat VSMCs, with an EC50 of ∼0.83 µM. Mechanistically, we found that hyperoside significantly increased the phosphorylation of ERK1/2 MAP kinase and its downstream target cAMP response element-binding protein (CREB), both of which contributed to the hyperoside-induced Nur77 expression in rat VSMCs. Moreover, through activation of Nur77 receptor, hyperoside markedly inhibited both vascular smooth muscle cell proliferation in vitro and the carotid artery ligation-induced neointimal formation in vivo. These findings demonstrate that hyperoside is a potent natural activator of Nur77 receptor, which can be potentially used for prevention and treatment of occlusive vascular diseases.

Baicalin, a component of Scutellaria baicalensis, alleviates anorexia and inhibits skeletal muscle atrophy in experimental cancer cachexia.

Inflammatory responses are key contributors to cancer cachexia and foster a complex cascade of biological outcomes. Baicalin is a natural compound derived from Scutellaria baicalensis that possesses anti-inflammatory properties in many diseases; therefore, the aim of this study was to verify whether baicalin could ameliorate cachexia in a CT26 adenocarcinoma-induced model. Tumour-bearing and control mice were injected with CT26 adenocarcinoma cells and phosphate-buffered saline (PBS), respectively, and baicalin was administered intraperitoneally for 15 days. During the study, food intake, body weight, major organ weight, gastrocnemius muscle weight, tibialis muscle weight, epididymal fat weight and serum cytokine levels were measured and evaluated. Additionally, the expression of two E3 ubiquitin ligases and NF-κB pathway proteins were detected by Western blot. The total food intake in tumour-bearing mice receiving baicalin from days 1-16, as well as the average food intake on days 10-16, were less than normal but were significantly higher than in vehicle-treated tumour-bearing mice. Loss of tumour-free body mass in vehicle-treated tumour-bearing mice was significantly increased compared with control mice and tumour-bearing mice receiving baicalin. Serum cytokines, including tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were lowered in tumour-bearing mice treated with baicalin. Gastrocnemius muscle, epididymal fat, heart and kidney weight were significantly greater in the baicalin treatment groups compared with the vehicle-treated tumour-bearing mice. In addition, the expression of two E3 ubiquitin ligases, as well as phospho-p65, was significantly downregulated, whereas the expression of IκBα was up-regulated in tumour-bearing mice treated with baicalin, as determined by Western blotting. The present study demonstrates that baicalin effectively ameliorates anorexia by inhibiting cytokine expression and prevents skeletal muscle atrophy most likely by inhibiting activation of NF-κB in an experimental cancer cachexia model, suggesting that baicalin represents a promising natural medicine for treating cancer-induced cachexia.