Effects of omega-3 fatty acids and pioglitazone combination on insulin resistance through fibroblast growth factor 21 in type 2 diabetes mellitus

AbstractFibroblast growth factor 21 (FGF21) is an effective regulator of glucose and lipid metabolism. It is mainly regulated by peroxisome proliferator activated receptors, and is widely associated with cases of insulin resistance as obesity and type 2 diabetes (T2D). Our study aimed to investigate the potential effects of omega-3 fatty acids, pioglitazone, and their combination on serum and liver FGF21 concentrations, and its hepatic gene expression in a rat model of T2D. We also studied the modulating effects of these treatments on blood glucose, lipid profile, and insulin resistance. T2D was induced in male Sprague–Dawley rats by combination of high fat diet and low dose streptozotocin (35 mg/kg). Diabetic rats were treated with omega-3 fatty acids (10%W/W diet), pioglitazone (20 mg/kg), and their combination for a period of 4 weeks. Serum FGF21 concentration was significantly increased in diabetic rats. In contrast, hepatic FGF21 concentration, and gene expression were significantly decreased. Omega-3 fatty acids, pioglitazone, and their combination significantly decreased serum FGF21. Omega-3 fatty acids and combination therapy significantly decreased liver FGF21 concentration, with non-significant changes in gene expression. On the other hand, pioglitazone significantly increased hepatic FGF21 concentration and gene expression. Omega-3 fatty acids, pioglitazone and their combination significantly improved lipid profile. Pioglitazone and combination significantly decreased blood glucose levels and improved insulin resistance. In conclusion, this study introduces the first evidence regarding the antidiabetic effects of omega-3 fatty acids and pioglitazone combination, such effects are mediated through FGF21

Expression of RFC/SLC19A1 is Associated with Tumor Type in Bladder Cancer Patients

Urinary bladder cancer (UBC) ranks ninth in worldwide cancer. In Egypt, the pattern of bladder cancer is unique in that both the transitional and squamous cell types prevail. Despite much research on the topic, it is still difficult to predict tumor progression, optimal therapy and clinical outcome. The reduced folate carrier (RFC/SLC19A1) is the major transport system for folates in mammalian cells and tissues. RFC is also the primary means of cellular uptake for antifolate cancer chemotherapeutic drugs, however, membrane transport of antifolates by RFC is considered as limiting to antitumor activity. The purpose of this study was to compare the mRNA expression level of RFC/SLC19A1 in urothelial and non-urothelial variants of bladder carcinomas. Quantification of RFC mRNA in the mucosa of 41 untreated bladder cancer patients was performed using RT-qPCR. RFC mRNA steady-state levels were ∼9-fold higher (N = 39; P<0.0001) in bladder tumor specimens relative to normal bladder mRNA. RFC upregulation was strongly correlated with tumor type (urothelial vs. non-urothelial; p<0.05) where median RFC mRNA expression was significantly (p<0.05) higher in the urothelial (∼14-fold) compared to the non-urothelial (∼4-fold) variant. This may account for the variation in response to antifolate-containing regimens used in the treatment of either type. RFC mRNA levels were not associated with tumor grade (I, II and III) or stage (muscle-invasive vs. non-muscle invasive) implying that RFC cannot be used for prognostic purposes in bladder carcinomas and its increased expression is an early event in human bladder tumors pathogenesis. Further, RFC can be considered as a potential marker for predicting response to antifolate chemotherapy in urothelial carcinomas

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Vitamin D potentiates anti-tumor activity of 5-fluorouracil via modulating caspase-3 and TGF-β1 expression in hepatocellular carcinoma-induced in rats

We investigated the role of vitamin D (Vit D) alone and in combination with 5-fluorouracil (5-FU) in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) in rats. Fifty male Sprague–Dawley rats were randomized into a control group and 4 groups that received TAA (200 mg/kg, i.p.) twice per week for 16 weeks. These 4 groups were further divided as follows: HCC group; 5-FU group (75 mg/kg, i.p., once weekly for 3 weeks starting from the 12th week); Vit D group (200 IU/kg daily by oral tube for 16 weeks); and 5-FU + Vit D group (received the previously mentioned dosage regimens of 5-FU and Vit D). HCC was detected by histopathological changes in liver sections and the elevation of serum α-fetoprotein (AFP). Treatment with 5-FU + Vit D significantly decreased gene expression of nuclear factor erythroid 2-related factor 2 (NrF2) and transforming growth factor β1 (TGF-β1) at both the gene and protein level and serum AFP concentrations in comparison with their corresponding monotherapy. Moreover, 5-FU + Vit D treatment enhanced apoptosis by increasing caspase-3 gene and protein expression. Conclusively, Vit D enhances antitumor activity of 5-FU in an HCC-induced model and improves liver function of treated animals. Combination therapy in a TAA-induced HCC rat model was more effective than 5-FU or Vit D through the modulation of TGF-β1, caspase-3, and NrF2 expressions.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Hepatoprotective Effect of Curcumin on Hepatocellular Carcinoma Through Autophagic and Apoptic Pathways

Background and rationale: Microtubule-associated protein light chain 3-II (LC3-II), and Sequestosome-1 (SQSTM1) are proteins that can be used as markers for autophagic pathway. Bcl-2 protein is reported to be inversely correlated with apoptosis. We aimed to investigate the effects of curcumin on liver inflammation and fibrosis up to the first dysplastic stage of Hepatocellular carcinoma (HCC) induced by Thioacetamide (TAA) in rats and to clarify the effects of curcumin on LC3-II, SQSTM1, and Bcl-2. Male Sprague-Dawley rats were randomized into four groups: Control group, TAA group, Curcumin low-dose group, and Curcumin highdose group. The last three groups received TAA 200 mg/kg i.p. twice weekly for 18 weeks. Oxidative stress markers as hepatic malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity were measured by colorimetric methods. Hepatic SQSTM1 concentration was measured by ELISA, and gene expression levels of Bcl-2, and LC3-II were measured by RT-PCR.We also investigated the in vitro effect of curcumin on HepG2 cells viability through MTT assay, and the involvement of autophagy in this effect. Results: Curcumin increased the survival percent in rats, decreased -fetoprotein (AFP) concentration, and serum aspartate aminotransferase (AST) activity, and increased serum albumin concentration. Curcumin also significantly reduced oxidative stress in liver, inhibited apoptosis, and induced autophagy. In vitro, curcumin (50 μM) decreased HepG2 cells viabilityand the concentration of SQSTM1. Conclusions: Curcumin leads to protection against TAA induced HCC up to the first dysplastic stage through activating autophagic pathway and inhibiting apoptosis. Also, the antioxidant activity of curcumin almost prevents liver fibrosis

Thrombopoietin level in patients with chronic liver diseases

Thrombocytopenia and oxidative stress are the most frequent problems in patients with chronic liver diseases as viral cirrhosis and schistosomiasis. So, this study aimed to evaluate the role of thrombopoietin (TPO) on the occurrence of thrombocytopenia and in differentiation between these diseases. It also aimed to investigate the relation between TPO, oxidative stress and antioxidant status in these two types of chronic liver disease. So, We measured serum TPO level, lipid peroxide (MDA) and serum total antioxidant activity (TAO) in 40 patients with cirrhosis caused by hepatitis C virus and 37 patients with schistosomiasis from The Specialized Medical Hospital, Mansoura University. Results: Both serum TPO level and serum TAO activity were significantly lower (p < 0.05) in thrombocytopenic patients with viral cirrhosis when compared to both non thrombocytopenic and control groups. In contrast, TPO level was within the normal range in the patients with scistosomiasis either thrombocytopenic or not. while serum TAO activity was significantly lower (p < 0.05) in both thrombocytopenic and non thrombocytopenic patients with schistosomiasis in comparison to control subjects with no significant difference between these two subgroups. Serum MDA concentration was increased significantly (p < 0.05) in all diseased groups when compared to controls with significant increase in thrombocytopenic patients as compared to non thrombocytopenic. Conclusion: TPO hypoproduction played a role in the pathogenesis and treatment of viral cirrhosis associated with thrombocytopenia. Also, total antioxidant activity and MDA are useful markers for monitoring patients with these chronic liver diseases

PCR-detected fungal infection is associated with fatal outcomes in cirrhotic patients with spontaneous peritonitis

AbstractBackground & aimsThe rate of mortality from Spontaneous Peritonitis (SP) in cirrhotic patients is still high despite the development of new antibiotic treatments and intensive hospital care. The coexistence of spontaneous fungal peritonitis (SFP) is almost entirely ignored health problem, because it is difficult to be diagnosed at an early stage by conventional culture-based methods. Therefore, this study was designed to employ PCR-based method in evaluating the prevalence of fungal infection in cirrhotic patients with peritonitis who failed to respond to the recommended therapy and to determine its association with in-hospital mortality.Subjects and MethodsA total of 80 cirrhotic patients admitted to the hospital with ascitis (June-2013 to April-2015) were followed in this study.ResultsDuring hospitalization, 23 (42%) of patients had died although they received guideline-driven treatment. The demographics, clinical, hematological, and biochemical data were similar in both mortality and survival groups. However, the incidence of fungus infection was the only significantly elevated parameter in the mortality group than in the survival group (7/23;30% vs.0/32;0%, P=0.0012). This fungal infection was significantly associated with SP drug resistance development (P=0.007). Intriguingly, all the cases of fungal infection were detected by PCR-based method while culture-based diagnosis was able to detect the fungal infection in only 4 of these cases indicating a diagnostic sensitivity of 57%.ConclusionOur results reflect a strong association between SFP and in-hospital mortality in cirrhotic patients with SP that may offer a coherent explanation for the antibiotic treatment failure in such patients. Prompt PCR-detection and antifungal coverage is warranted in these cases

Correlations of folic acid, vitamin B12, homocysteine, and thrombopoietin to platelet count in HCV infection

IntroductionThe platelet count is known to decrease in proportion to the advancement of the stage of liver disease in chronic hepatitis C (CHC) viral infection. The platelet count is currently used as an index for fibrosis staging. The pathophysiology of thrombocytopenia (TCP) in patients with hepatitis C virus (HCV) infection is not completely understood. PurposeThis work aimed to study the correlations of folic acid (FA), vitamin B12 (Vit B12), homocysteine (Hcy), and thrombopoietin to the platelet count in HCV infection. Patients and methods Sixty-seven patients (51 men and 16 women) with HCV infection were included in this study. All patients were sero-negative for hepatitis B viral markers. In addition, 20 healthy volunteers, matched for sex and age, were included as a control group. All patients and control individuals were subjected to the following: assessment of medical history, thorough clinical examination, and laboratory investigations including the following: complete blood cell counts, viral hepatitis markers, liver and renal function tests, HCV-RNA by quantitative PCR, serum folate, Vit B12, thrombopoietin, and plasma Hcy. Abdominal ultrasonography and ultrasound-guided liver biopsy for histopathologic examinations were carried out for the patients. Patients were divided into two groups of 36 patients with CHC and 31 patients with cirrhosis with HCV liver cirrhosis (LC). Results The Results indicated a significant decrease in the platelet count in CHC and LC patients compared with the healthy control group. There was a highly significant decrease in the FA level in CHC and LC patients compared with the control group; also, a significant decrease in the platelet count was found in LC patients compared with CHC patients. Hcy was significantly increased in CHC and LC patients. There was a nonsignificant decrease in Vit B12 in CHC patients, whereas it was significantly increased in LC patients. There was a nonsignificant decrease in thrombopoietin in CHC patients compared with the control group, whereas in LC patients, there was a highly significant decrease. There was a highly significant positive correlation between the platelet count and FA, but an insignificant correlation between the platelet count and Hcy, Vit B12, thrombopoietin, and viral load. Conclusion This study concluded that TCP in HCV-related chronic liver diseases is multifactorial and decreased FA is involved in its pathogenesis as an independent risk factor. Increased Hcy may cause TCP through platelet activation and endothelial dysfunction