Pentoxifylline and its association with kaempferol improve NASH-associated manifestation in mice through anti-apoptotic, anti-necroptotic, antioxidant, and anti-inflammatory mechanisms.

OBJECTIVE: Non-alcoholic fatty liver disorders (NAFLD), particularly non-alcoholic steatohepatitis (NASH), have emerged as a leading cause of liver transplantation and mortality. However, the pathophysiology of NASH remains unknown. Oxidative stress, apoptosis, and necroptosis pathways are heavily linked to NASH. Therefore, the current study aimed to investigate the underlying mechanism for Pentoxifylline's (PTX) activity in NASH management, either alone or in combination with Kaempferol (KP). MATERIALS AND METHODS: A total of 32 male C57BL/6J mice were divided into four groups: the mice in the control group were fed a standard chow diet and given a vehicle; the mice in NASH group were maintained on NASH protocol for 25 days; the mice in the PTX group were kept on NASH protocol for 25 days and given PTX (100 mg/kg), and PTX+KP mice group were given NASH protocol along with KP (50 mg/kg) and PTX (100 mg/kg) simultaneously. RESULTS: The LDL-C, total cholesterol, triglycerides, glutathione peroxidase (GPx), superoxide dismutase (SOD), malondialdehyde (MDA), glucose, insulin, and HOMA-IR levels were considerably decreased in the PTX and PTX+KP treated groups. AMP-activated protein kinase (AMPK) Gene expression of the liver was significantly increased in the other treated groups, but peroxisome proliferator-activated receptor (PPAR), phosphorylated mixed lineage kinase-like protein (pMLKL), and sterol regulatory element binding protein 1 (SREBP1) were reduced significantly. Caspase-8 and receptor-interacting serine/threonine protein kinase (RIPK3) protein expression were significantly decreased in the PTX and PTX+KP groups compared to NASH group and nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) immunohistochemistry expression. CONCLUSIONS: Our current study suggests that PTX and its combination with KP have a significant ameliorative effect against NASH via novel mechanisms involving the regulation of apoptosis and necroptosis, as well as decreased oxidative stress, lipogenesis, proinflammatory cytokines, and modulation of histopathological manifestation.

Effect of co-treatment with doxorubicin and verapamil loaded into chitosan nanoparticles on diethylnitrosamine-induced hepatocellular carcinoma in mice.

This study aimed to investigate the potential role of co-treatment with doxorubicin (DOX) and verapamil (VRP) nanoparticles in experimentally induced hepatocellular carcinoma in mice and to investigate the possible mechanisms behind the potential favorable effect of the co-treatment. DOX and VRP were loaded into chitosan nanoparticles (CHNPs), and cytotoxicity of loaded and unloaded drugs against HepG2 cells was evaluated. Male albino mice were divided into eight groups (n = 15): (1) normal control, (2) diethylnitrosamine, (3) CHNPs, (4) free DOX, (5) CHNPs DOX, (6) free VRP, (7) CHNPs VRP, and (8) CHNPs DOX + CHNPs VRP. Either VRP or DOX loaded into CHNPs showed stronger growth inhibition of HepG2 cells than their free forms. DOX or VRP nanoparticles displayed pronounced anticancer activity in vivo through the decline of vascular endothelial growth factor and B cell lymphoma-2 contents in liver tissues, upregulation of antioxidant enzymes, and downregulation of multidrug resistance 1. Moreover, reduced cardiotoxicity was evident from decreased level of tumor necrosis factor-α and malondialdehyde in heart tissues coupled with decreased serum activity of creatine kinase-myocardial band and lactate dehydrogenase. Co-treatment with CHNPs DOX and CHNPs VRP showed superior results versus other treatments. Liver sections from the co-treatment group revealed the absence of necrosis, enhanced apoptosis, and nearly normal hepatic lobule architecture. Co-treatment with CHNPs DOX and CHNPs VRP revealed enhanced anticancer activity and decreased cardiotoxicity versus the corresponding free forms.

Serum LINC00305 expression and its genetic variant rs2850711 are associated with clinical and laboratory features of rheumatoid arthritis.

BACKGROUND: Long intergenic non-protein coding (lnc) RNA 00305 (LINC00305) is a pro-inflammatory atherosclerosis-associated lncRNA. We hypothesised that LINC00305 expression and its variant rs2850711 (A/T) are implicated in rheumatoid arthritis (RA) and linked with clinical and routine laboratory markers. METHODS: 100 RA patients and 100 healthy controls were recruited. LINC00305 genotyping and expression were performed using allelic-discrimination PCR and quantitative real-time PCR. LINC00305 diagnostic power was evaluated using area under the receiver operating characteristic curve (AUC). Serum nuclear factor- κB (NF-κB) and matrix metalloproteinase-3 (MMP-3) levels were determined by ELISA, standard laboratory markers by routine methods. RESULTS: LINC00305 expression was significantly increased in RA patients and positively correlated with DAS28, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor and anti-cyclic citrullinated peptide antibody. In multivariate analysis, NF-κB, MMP-3 and LINC00305 were significant predictors of RA (P< 0.0001). Individuals carrying AT and TT genotypes of rs2850711 polymorphism had significantly more likely to have RA than AA genotype carriers (P< 0.05). LINC00305 expression, DAS28 score and serum levels of NF-κB and MMP-3 were significantly increased in the patients carrying LINC00305 AT and TT genotypes as compared with AA genotype patients (P< 0.01). CONCLUSION: Increased expression level of LINC00305 and its rs2850711 genetic variant may play a role in the diagnosis and management of RA, and its severity and activity.

Association of MicroRNA-146a rs2910164 Gene Polymorphism with Metabolic Syndrome.

Alteration in microRNA-146a (miRNA-146a) expression is an important event in the pathogenesis of many human diseases. MiRNA-146a rs2910164 is a functional polymorphism that showed association with several diseases. Metabolic syndrome is an aggregation of multiple risk factors including impaired glucose tolerance, increased highdensity lipoprotein, abdominal obesity, and high blood pressure. The aim of this study was to assess the relation of miRNA-146a rs2910164 with metabolic syndrome and its component traits in Egyptian women from the Suez Canal area. The study included 100 healthy female subjects and 100 metabolic syndrome patients. The component traits of metabolic syndrome were determined and the genotypes of the polymorphisms were assessed using the polymerase chain reaction-restriction fragment length polymorphism technique using the restriction enzyme Hpy188I. The rare C allele had a significantly higher frequency in metabolic syndrome patients (P = 0.013). The heterozygote GC and the rare CC genotypes showed a significant increase in body mass index, waist circumference, triglycerides, total cholesterol, low-density lipoprotein, systolic and diastolic blood pressure. The GC genotype was associated with higher fasting blood glucose, fasting serum insulin and insulin resistance. The carriers of CC genotype had significantly lower HDL compared with the GG genotype carriers. In conclusion, The C allele of miRNA-146a rs2910164 showed positive association with increased susceptibility to metabolic syndrome and its phenotypes in the study population.

Topiramate induces weight loss and improves insulin sensitivity in dietary obese rats: comparison to sibutramine.

BACKGROUND AND OBJECTIVES: Topiramate is newly approved as anticonvulsant that seems to promote body weight loss in humans. The present study was designed to evaluate the weight-controlling properties of topiramate in dietary obese female rats in comparison with sibutramine. MATERIALS AND METHODS: Fifty rats were assigned as normal, high fat diet (HFD), HFD + sibutramine (7.5 mg/kg, p.o.), HFD + topiramate (25 mg/kg, p.o.) and HFD + topiramate (50 mg/kg, p.o.). Body weight was registered, anxiety was tested in Vogel's test and blood pressure (BP) was measured. In addition, liver index, adipose tissue index, fasting blood glucose and serum lipid profile were measured in all groups. Further, serum insulin, leptin and adiponectin were determined. RESULTS: Feeding with HFD induced a significant increase in body weight of rats as well as insulin resistance and serum lipids as compared to normal group (p<0.05). These measurements were suppressed by sibutramine treatment. However, a significant elevation in BP and anxiety behavior were detected as compared with HFD group (p<0.05). Topiramate (50 mg/kg, p.o.) group showed weight loss, improved insulin resistance, lessened anxiety behavior without influence on BP. DISCUSSION: Our data ensures the findings that topiramate has a weight controlling properties with no anxiogenic or hypertensive effects. Further investigations are needed to determine the utility of topiramate in the clinical management of obesity.

Influence of glutathione S-transferase polymorphisms on type-2 diabetes mellitus risk.

Glutathione S-transferase (GST) protects cells against oxidative stress. We evaluated the effect of genetic polymorphisms of the GST gene family on the risk of developing type-2 diabetes mellitus and on glycemic control. We also investigated the effects of smoking combined with these polymorphisms on type-2 diabetes mellitus risk. We enrolled 100 type-2 diabetes mellitus patients and 100 healthy controls matched for age, gender and origin, from the Sinai area of Egypt. Fasting serum glucose, HbA(1c) and lipid profiles were determined. Two polymorphisms were identified by multiplex PCR within the GST genes: GSTM1 and GSTT1. The proportion of the GSTT1- and GSTM1-null genotypes was significantly greater in diabetic patients when compared to controls. Patients carrying both null polymorphisms had a 3.17-fold increased risk of having type-2 diabetes mellitus compared to those with normal genotypes of these two genes (P = 0.009). Additionally, patients with the GSTT1-null genotype had higher levels of triglycerides and very low-density lipoprotein cholesterol compared to those with the GSTT1-present genotype. On the other hand, patients with the GSTM1- null genotype had significantly higher levels of HbA(1c) and significantly higher diastolic blood pressure compared to those with the GSTM1- present genotype. The interaction between these genotypes and smoking status was not significant. These results give evidence that the GSTT1- and GSTM1-null genotypes, alone or combined, are associated with increased risk of type-2 diabetes mellitus, regardless of smoking status. Only the GSTM1-null genotype had an effect on glycemic control.