Modulation of IR as a therapeutic target to prevent NASH using NRF from Diceratella elliptica (DC.) jonsell. Strong Nrf2 and leptin inducer as well as NF-kB inhibitor.

BACKGROUND: Insulin resistance (IR) and lipotoxicity were evidenced as the major nonalcoholic steatohepatitis (NASH) initiators. However, absence of the effective treatment against NASH progression raised our aim to discover a new promising insulin modulator and NSH preventer. PURPOSE: Our study aimed to extract and prepare a nitriles rich fraction (NRF) from Diceratella elliptica (DC.) Jonsell, investigate its insulin-sensitizing & anti-NASH potentialities and address its molecular targets in IR-NASH pathogenesis. STUDY DESIGN: NRF was prepared using natural autolysis method and compounds were identified. Then, seventy male Wistar rats were feed high fat diet (HFD) or normal pellets for 35 days. In day 14th, HFD rats were injected by Streptozotocin (STZ) once and treatment was started in day 21st with either NRF (30, 60 and 120 mg/kg; orally) or pioglitazone (PioG) (10 mg/kg; i.p) beside HFD. While, NRF-alone rats were treated with NRF (120 mg/kg; orally) beside the normal pellets. Body weight, glucose homeostasis, hepatopathological examinations were performed. METHODS: Gas liquid chromatography-mass spectrophotometry (GLC/MS) was used for compounds' identification while spectrophotometer was used for total glucosinolates (GLS) quantification. Also, the biochemical and molecular investigations concerned with liver lipotoxicity, oxidative stress, inflammation and insulin signaling pathway were investigated and confirmed with the computational prediction of the major compounds' targets. RESULTS: Butenyl and benzyl GLS were the major along with other volatile compounds. NRF had significantly increased the insulin sensitivity and improved NASH-hisptopathology showing hepatoprotective effect. While, the fraction's anti-NASH potentiality was evidenced in the normalized hepatic steatosis markers, inflammation and oxidative stress key transcriptional factors resulting in induction of insulin receptor substrates (IRSs) phosphorylation and its downstream effectors. CONCLUSION: NRF has reversed IR, stimulated leptin secretion and prevented NASH initiation showing promising anti-NASH and anti-fibrotic effects.

Bidirectional transcription of Linc00441 and RB1 via H3K27 modification-dependent way promotes hepatocellular carcinoma.

The retinoblastoma gene (RB1), a known tumor-suppressor gene (TSG), was decreased in multiple cancers including hepatocellular carcinoma (HCC). Here we focused on the bidirectional transcripted long noncoding RNA (Linc00441) with neighbor gene RB1 to investigate whether Linc00441 is involved in the suppression of RB1 in HCC. We found that aberrant upregulated intranuclear Linc00441 was reversely correlated with RB1 expression in human HCC samples. The gain- and loss-of-function investigation revealed that Linc00441 could promote the proliferation of HCC cells in vitro and in vivo with an apoptosis suppression and cell cycle rearrangement. Furthermore, RNA pull-down assay indicated the decreased level of RB1 induced by Linc00441 was associated with the incidental methylation by DNMT3A recruited by Linc00441. On the contrary, the transcription factor (TCF-4) enhanced H3K27 acetylation and direct transcription factor for Linc00441 was responsible for the upregulation of Linc00441 in HCC. In conclusion, the epigenetic interaction between Linc00441 and bidirectional transcripted neighbor RB1 may be a de novo theory cutting-point for the inactivation of RB1 in HCC and may serve as targeting site for tumor therapy in the future.

Spontaneous pneumomediastinum following pneumonia in a 23-year-old male patient.

Spontaneous pneumomediastinum (SPM) is defined as the presence of interstitial air in the mediastinum without any apparent precipitating factor. We present a case of 23 year old male patient, who has been referred to our outpatient clinic with the complaints of sudden chest pain, dyspnea followed by pneumonia and was diagnosed as SPM. The patient was treated with ampicillin sulbactam (4 gr/day) and methylprednisolon (20 mg/day) for 4 days. and oral intake was stopped during treatment. Post treatment, it was observed that the crepitations were disappeared thoroughly and vesicular sounds were heard by oscultation. The control values of arterial blood gas was as following: pH:7,39 pO2:95 mmHg, pCO2:37 mmHg, SaO2: %97. In the 5th day his oral intake was started and he was discharged.

Protective effect of Caralluma fimbriata against high-fat diet induced testicular oxidative stress in rats.

High-fat diet (HFD) promotes the oxidative stress formation, which in turn has hazardous effects on reproductive system and fertility. The objective of this study was to evaluate the protective effect of Caralluma fimbriata on high-fat diet-induced oxidative stress in the testis of rat. Male Wistar rats were randomly divided into five groups: Control (C), Control treated with CFE (C+ CFE), High fat diet fed (HFD), High fat diet fed treated with CFE (HFD+CFE) and High fat diet fed treated with Metformin (HFD+Met). CFE was orally administered (200mg/kg body weight) for 90days to groups-C+CFE and HFD+CFE rats. The effects of HF-diet on the reproductive organs were determined by measuring relative and absolute testes and epididymal fat pads weights. Regarding testes antioxidant status, high-fat fed rats showed higher levels of lipid peroxidation, protein oxidation, polyol pathway enzymes and lower GSH levels and lower activities of antioxidants, while CFE treatment prevented all these observed abnormalities. The present study clearly indicates that CFE offers a significant protection against HF-diet induced testicular oxidative stress in rats.

Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease.

OBJECTIVE: Recent studies have suggested that endotoxin-induced cytokines play an important role in nonalcoholic fatty liver disease (NAFLD). Rifaximin is a nonabsorbable antibiotic that might act on Gram-negative bacteria, thereby inhibiting endotoxin proinflammatory cytokine production in patients with NAFLD. Our aim was to investigate the efficacy of rifaximin on NAFLD. METHODS: Forty-two patients with biopsy-proven NAFLD [15 steatosis, 27 nonalcoholic steatohepatitis (NASH)] were included in this prospective, open-label, observational cohort study. BMI and serum aspartate aminotransferase, alanine aminotransferase (ALT), gamma glutamyl transferase, lipid profile, ferritin, C-reactive protein, glucose, insulin, homeostatic model assessment as well as endotoxin, serum Toll-like receptor 4 (TlR4), interleukin-1α (IL-1α), IL-6, IL-10, IL-12, and tumor necrosis factor-α (TNF-α) levels were measured before and after a 28-day administration of rifaximin (1200 mg/daily). Results were analyzed using nonparametric Wilcoxon signed-rank tests. RESULTS: A mild reduction in the mean BMI (32.3 ± 6.9 vs. 31.9 ± 6.8, P = 0.02) and a significant reduction in the endotoxin (0.9 ± 0.34 vs. 0.8 ± 0.13, P = 0.03) and IL-10 (4.08 ± 0.9 vs. 3.73 ± 0.7, P = 0.006) levels in the NASH group were noted. A significant reduction was observed in serum aspartate aminotransferase (50.4 ± 39 vs. 33 ± 14, P = 0.01), ALT (72 ± 48 vs. 45.2 ± 26.3, P = 0.0001), gamma glutamyl transferase (52 ± 33 vs. 41.2 ± 21.1, P = 0.02), LDL (137 ± 34 vs. 127 ± 27.5, P = 0.03), and ferritin (142 ± 214 vs. 89.3 ± 123, P = 0.0001) in the NASH group, but only in ALT (50.4 ± 26 vs. 35.5 ± 23.25, P = 0.01), and ferritin (73.6 ± 83 vs. 55 ± 76, P = 0.004) levels decreased significantly in the steatosis group. Treatment with rifaximin did not exert a significant effect on serum levels of TLR-4, IL-1, IL-6, IL-12, or TNF-α in either group. CONCLUSION: In NAFLD and especially in NASH, short-term administration of rifaximin appears to be safe and effective.

Serum and biliary MMP-9 and TIMP-1 concentrations in the diagnosis of cholangiocarcinoma.

AIM: Cholangiocarcinoma is generally detected late in the course of disease, and current diagnostic techniques often fail to differentiate benign from malignant disease. Ongoing biomarker studies for early diagnosis of cholangiocarcinoma are still continues. By this study, we analyzed the roles of serum and biliary MMP-9 and TIMP-1 concentrations in the diagnosis of cholangiocarcinoma. MATERIALS AND METHODS: The 113 patients (55 males, 58 females) were included; 33 diagnosed with cholangiocarcinoma (malignant group) and 80 diagnosed with choledocholithiasis (benign group). MMP-9 and TIMP-1 concentrations were analyzed in serum and bile and compared in the malignant and benign groups. Results were evaluated statistically. RESULTS: Biliary MMP-9 concentrations were significantly higher (576 ± 209 vs. 403 ± 140 ng/ml, p < 0.01) and biliary TIMP-1 concentrations were significantly lower (22.4 ± 4.9 vs. 29.4 ± 6.1 ng/ml, p < 0.01) in the malignant than in the benign group. In contrast, serum MMP-9 and TIMP-1 concentrations were similar in the two groups. Receiver operating curve analysis revealed that the areas under the curve of bile MMP-9 and TIMP-1 were significantly higher than 0.5 (p < 0.001). The sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios and accuracy were 0.94, 0.32, 0.36, 0.93, 1.40, 0.19 and 0.5 for biliary MMP-9, respectively, and 0.97, 0.36, 0.39, 0.97, 1.5, 0.08 and 0.54 for biliary TIMP-1, respectively. CONCLUSION: Serum and biliary MMP-9 and TIMP-1 tests do not appear to be useful in the diagnosis of cholangiocarcinoma.

Thrombotic thrombocytopenic purpura and focal segmental glomerulosclerosis associated with the use of ecstasy.

Ecstasy is a drug, which causes serious side effects and sometimes it can be lethal. These effects are due to idiosyncratic reactions as a result of various stimulations in adrenergic receptors. Here we present a case of a 36-year-old male patient who was diagnosed with thrombotic thrombocytopenic purpura associated with the use of ecstasy. Plasmapheresis along with methylprednisolone treatment restores patient condition to normal.

Role of gut microbiota: obesity and NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease in developed countries. Obesity is the most important risk factor for metabolic syndrome and NAFLD. Accumulated evidence has revealed that gut microbial compositional changes may be associated with more energy harvesting from the diet, which promotes increased fatty acid uptake from adipose tissue and shifts lipid metabolism from oxidation to de novo production. Furthermore, changes in intestinal barrier function contribute to metabolic endotoxemia in the form of low-grade microbial inflammation. Persistent inflammation exacerbates NAFLD progression. In this review, we discuss the role of gut microbiota in obesity and NAFLD.

Roles of serum and biliary CEA, CA19-9, VEGFR3, and TAC in differentiating between malignant and benign biliary obstructions.

BACKGROUND/AIMS: Despite the presence of many diagnostic methods, the differential diagnosis between benign and malignant biliary obstructions is still not easy. We aimed to evaluate the role of serum/biliary carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), vascular endothelial growth factor receptor-3(VEGFR-3), and total antioxidant capacity (TAC) tests in this differential diagnosis. MATERIALS AND METHODS: Patients (n:225; 110♂, 115♀) with diagnosis of malignant (n:96) or benign (n:129) biliary obstruction were included in this cross-sectional study. Serum and biliary CEA, CA 19-9, VEGFR-3, and TAC tests were analyzed, statistics were obtained, and significance was defined as p<0.05. RESULTS: Mean age was 54.9±16.4 for the benign and 54.2±19.6 for the malignant group (p=0.89). Head of pancreas cancer (18.2%), cholangiocarcinoma (11.4%) and choledochal stone (48%) were the most common etiologies. The area under the curve (AUC)s by ROC analysis of serum/biliary CA 19-9, VEGFR-3, and TAC and serum CEA were 0.701/0.616, 0.622/0.663, 0.602/0.581, and 0713, respectively. Serum TAC had higher sensitivity (61.1%) and CEA had lower sensitivity (42.7%), whereas CEA had higher specificity (89.9%) and TAC had lower specificity (60.5%). In biliary tumor markers, CA 19-9 had higher sensitivity (74%) and VEGFR-3 had lower sensitivity (56.2%); however, VEGFR-3 had higher specificity (79.1%) and CA 19-9 had lower specificity (34.1%). Additionally, combination of serum CEA (p<0.001), CA 19-9 (p<0.001), VEGFR-3 (p<0.001), and biliary CA 19-9 (p=0.028) markers achieved 95% estimation probability, and the sensitivity, specificity, and accuracy were 88.5%, 45.7%, and 64%, respectively. CONCLUSION: Serum and biliary CEA, CA 19-9, VEGFR-3, and TAC tests would not be useful in the differentiation between malignant and benign biliary obstructions.

Evaluation of concentrations of pro/anti-inflammatory cytokines after complication-free ECRP in cholangiocarcinoma.

BACKGROUND/AIMS: Variations in pro and anti-inflammatory cytokine levels occur commonly after ERCP procedure complications, such as in post-ERCP pancreatitis. Besides, the relationship between increased cytokine levels and multidrug resistance has been shown in cholangiocarcinoma patients. Our aim was to investigate the impact of cytokine level changes on treatment strategy after uncomplicated ERCP procedures in cholangiocarcinoma patients. MATERIALS AND METHODS: Of 75 patients enrolled in this study, 25 were cholangiocarcinoma, and 50 were choledocholithiasis patients. Levels of serum IL-1ß, IL-6, IL-8, IL-10, and TNF-α were evaluated 2 hours before and 12 hours after complication-free ERCP, and statistical analysis of the results was obtained; if p value<0.05, it was accepted as statistically significant. RESULTS: There was no statistically significant difference in the distribution of age (23-87 years; range: 59.8±16.6), gender (37 males vs 38 females), and levels of pre- and post-ERCP serum IL-1ß, IL-6, IL-8, IL-10, and TNF-α in both patient groups, despite the presence of some change in test means (p:0.179, 0.445, 0.522, 0.937, and 0.065, respectively). However, significantly decreased levels of TNF-α were observed in the benign group, when comparing pre- and post-ERCP period (p<0.05). CONCLUSION: Serum concentrations of IL-1ß, IL-6, IL-8, IL-10, and TNF-α evaluated after complication-free ERCP performed in patients with cholangiocarcinoma do not cause any change in treatment planning that would affect multidrug resistance.