Nermin A. H. Sadik

Cytoprotective effects of DL-alpha-lipoic acid or squalene on cyclophosphamide-induced oxidative injury: An experimental study on rat myocardium, testicles and urinary bladder

The present study aimed to evaluate the role of DL-alpha-lipoic acid (LA) and squalene (SQ) on oxidative cardiac, testicular and urotoxic damage induced by cyclophosphamide (CP). Male Wistar rats were divided into four groups; three groups received a single intraperitoneal injection of CP (200mg/kg BW) to induce toxicity, and two of these groups received either LA (35 mg/kg BW) or SQ (0.4 ml/rat) orally 7 days before and 7 days after CP injection. A vehicle-treated control group was also included. Oxidative damage was observed by decreased serum total antioxidant capacity (TAC) level and abnormal alterations in glutathione peroxidase (GPx) and glutathione reductase (GR) activities, levels of glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO) and calcium (Ca(+2)) in the heart, testes and urinary bladder of CP-administered rats. Cardiac marker enzyme activities; creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and aspartate transaminase (AST) showed severe declines whereas testicular markers; sorbitol dehydrogenase (SDH), gamma-glutamyl transferase (gamma-GT), acid and alkaline phosphatases (ACP and ALP), serum testosterone (T) level and haemoglobin (Hb) absorbance were abnormal. Histopathological observations were also altered. These CP-induced pathological alterations were attenuated by treatment with LA or SQ. These findings highlight the efficacy of LA and SQ as cytoprotectants in CP-induced toxicity.

Polymorphisms in interleukin‐10 and interleukin‐28B genes in Egyptian patients with chronic hepatitis C virus genotype 4 and their effect on the response to pegylated interferon/ribavirin‐therapy

Recently, it has been suggested that single nucleotide polymorphisms (SNPs) in some cytokine genes may influence the production of the associated cytokines that affect the host immune response to pegylated interferon‐α (Peg‐IFN‐α) with ribavirin (RBV) in hepatitis C virus (HCV) patients. The aim of the present study was to investigate the possible role of the SNPs of IL‐10 and Il‐28B and their serum levels in predicting the response to treatment of HCV‐4.

Role of sulfurous mineral water and sodium hydrosulfide as potent inhibitors of fibrosis in the heart of diabetic rats

This study examined the downstream signaling whereby hyperglycemia may lead to myocardial fibrosis and apoptosis in the left ventricle of diabetic rats. The effects of sulfurous mineral water or sodium hydrosulfide (NaHS) as possible modulators were also examined. Sulfurous mineral water (as drinking water) and NaHS (14μmol/kg/day, IP) were administered for 7 week to rats with streptozotocin (STZ)-induced diabetes. Hyperglycemia, overproduction of glycated hemoglobin (HbA1C) and serum decline in insulin, C-peptide and insulin like growth factor-I (IGF-I) were observed in diabetic rats. Up-regulation of gene expressions of nuclear factor (NF-κB), profibrogenic growth factor such as transforming growth factor-β1 (TGF-β1), matrix metalloproteniase-2 (MMP-2), procollagen-1 and Fas ligand (Fas-L) were observed in the left ventricle of diabetic rats. A linear positive correlation between TGF-β1 and MMP-2 was also detected in diabetic group. An increase in hydroxyproline level and a disturbance in oxidative balance were detected in heart of diabetic rats. Sulfurous mineral water and NaHS treatment possibly, by improving cardiac GSH level, counteracted the enhanced expression of NF-κB, the profibrogenic and apoptotic parameters. Histopathological examination was in accordance with the biochemical and molecular findings of this study. We suggest a novel therapeutic approach of sulfurous mineral water and exogenous supplementation of H(2)S in diabetic cardiomyopathy.

Effects of diallyl sulfide and zinc on testicular steroidogenesis in cadmium‐treated male rats

Cadmium (Cd) is one of the environmental pollutants that affect various tissues and organs including testis. Harmful effect of cadmium on testis is known to be germ cell degeneration and impairment of testicular steroidogenesis. In the present study, the effect of diallyl sulfide (DAS), a sulfur‐containing volatile compound present in garlic, and zinc (Zn) was investigated on cadmium‐induced testicular toxicity in rats. Male adult Wistar rats treated with cadmium (2.5 mg/kg body wt, five times a week for 4 weeks) showed decreased body weight, paired testicular weight, relative testicular weight, serum testosterone, luteinizing hormone, follicle‐stimulating hormone, and testicular total antioxidant capacity (TAC) and protein levels. Testicular steroidogenic enzymes, such as 3β‐hydroxysteroid dehydrogenase (3β‐HSD) and 17β‐hydroxysteroid dehydrogenase (17β‐HSD), and marker enzymes, such as sorbitol dehydrogenase (SDH), lactate dehydrogenase (LDH), acid phosphatase (ACP), alkaline phosphatase (ALP), and glucose‐6‐phosphate dehydrogenase (G6PD), showed a significant decrease in activities whereas that of γ‐glutamyl transferase was significantly increased after cadmium exposure. The results have revealed that concurrent treatment with DAS or zinc restored key steroidogenic enzymes, SDH, LDH, and G6PD and increased testicular weight significantly. DAS restored the TAC level and increased testosterone level and relative testicular weight significantly. Zinc restored testicular protein level and body weight. It can be concluded that cadmium causes testicular toxicity and inhibits androgen production in adult male rats probably by affecting pituitary gonadotrophins and that concurrent administration of DAS or zinc provides protection against cadmium‐induced testicular toxicity.

The significance of serum levels of adiponectin, leptin, and hyaluronic acid in hepatocellular carcinoma of cirrhotic and noncirrhotic patients:

It is well established that hepatocellular carcinoma (HCC) develops in a multistep process, from chronic hepatitis, cirrhosis to HCC. Adipose tissue is not simply an energy storage organ but also a secretory organ, producing a variety of bioactive molecules known as adipokines, including adiponectin and leptin. Hyaluronic acid (HA) is an extracellular matrix protein, often associated with a variety of human cancers. Our retrospective study determines serum levels of adiponectin, leptin, and HA in HCC of cirrhotic and noncirrhotic patients and compares these levels to patients with cirrhosis and normal subjects. Noncirrhotic HCC (n = 19), cirrhotic HCC (n = 50), cirrhosis (n = 36) patients and twenty one age-, sex-, and body mass index (BMI)-matched normal healthy controls were subjected in the present study. Serum adiponectin, leptin, and HA levels were determined using enzyme-linked immunosorbent assay technique. Levels of serum adiponectin were significantly higher in the cirrhosis and cirrhotic HCC groups than in the normal subjects, whereas serum HA levels were found to significantly increase in all three patients groups. The elevation of serum leptin in our HCC patients, regardless of being cirrhotic or noncirrhotic, but not in the patients with cirrhosis, may shed some light on the significance of serum leptin level in HCC. Further studies are recommended to evaluate the prognostic value of serum leptin level in HCC.

The Therapeutic Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Simvastatin in a Rat Model of Liver Fibrosis

Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins including collagen that occurs in most types of chronic liver diseases. Studies concerning the capacity of mesenchymal stem cells (MSCs) and simvasatain (SIMV) to repair fibrotic tissues through reducing inflammation, collagen deposition, are still controversial. This study aimed to investigate the therapeutic efficacy of bone marrow (BM)-derived MSCs and SIMV on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Rats were divided into: normal, CCl4, CCl4/MSCs, CCl4/SIMV, CCl4/MSCs/SIMV, and SIMV groups. BM-derived MSCs were detected by RT-PCR of CD29 and were then infused into the tail vein of female rats that received CCl4 injection to induce liver fibrosis. Sex-determining region Y (SRY) gene on Y-chromosome gene was assessed by PCR to confirm homing of the male stem cells in liver tissue of the female recipients. Serum liver function tests, liver procollagens I and III, tissue inhibitors of metalloproteinase-1 (TIMP-1), endoglin, matrix metalloproteinase-1 (MMP-1) gene expressions, transforming growth factor-beta (TGF-β1) immunostaining, and histopathologicl examination were performed. MSCs and SIMV decreased liver procollagens I and III, TIMP-1 and endoglin gene expressions, TGF-β1 immunostaining, and serum liver function tests compared with the CCl4 group. MMP-1 expression was increased in the CCl4/MSCs group. Histopathological examination as well as fibrosis score supports the biochemical and molecular findings. It can be concluded that MSCs and SIMV were effective in the treatment of hepatic CCl4-induced fibrosis-rat model. Treatment with MSCs was superior to SIMV. This antifibrotic effect can be attributed to their effect on the MMPs/TIMPs balance which is central in fibrogenesis.

Inhibitory Effect of a Standardized Pomegranate Fruit Extract on Wnt Signalling in 1, 2-Dimethylhydrazine Induced Rat Colon Carcinogenesis

BackgroundDe-regulation of Wnt signalling is increasingly being implicated in both experimental and human carcinogenesis including colon cancer.AimsOur goal was to identify possible dietary agents that block Wnt signalling as a step toward investigating new strategies for suppression of colon cancer. Pomegranate extract has emerged as an intriguing candidate due to its polyphenolic content.MethodsWe used a 1,2-dimethylhydrazine dihydrochloride (DMH)-induced rat colon carcinogenesis model to investigate the expression pattern of the main key players in Wnt signalling by reverse transcription polymerase chain reaction (RT-PCR) analysis.ResultsOur results showed that many Wnt-target genes, e.g., Wnt5a, frizzled receptor (FRZ)-8, β-catenin, T cell factor/lymphoid enhancer binding protein (Tcf4/Lef1), c-myc and cyclin D1, were up-regulated whereas adenomatous polyposis coli (APC) and axin1 exhibited down-regulation in colonic tissues of our DMH-colon cancer group compared with the normal group. Standardized pomegranate extract minimised all the aberrant alterations observed in the studied Wnt genes in colonic tissues of the DMH + pomegranate group as compared with the DMH-induced colon cancer group. This effect was also confirmed by the normalization of survival rate, inhibition of tumour incidence and a reduction of serum tumour marker carcinoembryonic antigen (CEA) level. Histopathological observations provided supportive evidence for the biochemical and molecular analyses.ConclusionsStandardized pomegranate extract holds great promise in the field of colon cancer prevention by dietary agents.

Resveratrol and curcumin ameliorate di-(2-ethylhexyl) phthalate induced testicular injury in rats.

The present study aimed to evaluate the protective role of resveratrol and curcumin on oxidative testicular damage induced by di-(2-ethylhexyl) phthalate (DEHP). Male Wistar rats were divided into six groups; three groups received oral daily doses of DEHP (2g/kgBW) for 45days to induce testicular injury. Two of these groups received either resveratrol (80mg/kgBW) or curcumin (200mg/kgBW) orally for 30days before and 45days after DEHP administration. A vehicle-treated control group was also included. Another two groups of rats received either resveratrol or curcumin alone. Oxidative damage was observed by decreased levels of total antioxidant capacity (TAC) and glutathione (GSH) and increased malondialdehyde (MDA) level in the testes of DEHP-administered rats. Serum testosterone level as well as testicular marker enzymes activities; acid and alkaline phosphatases (ACP and ALP) and lactate dehydrogenase (LDH) showed severe declines. DEHP administration caused significant increases in the testicular gene expression levels of Nrf2, HO-1, HSP60, HSP70 and HSP90 as well as a significant decrease in c-Kit protein when compared with the control group. Histopathological observations provided evidence for the biochemical and molecular analysis. These DEHP-induced pathological alterations were attenuated by pretreatment with resveratrol and curcumin. We conclude that DEHP-induced injuries in biochemical, molecular and histological structure of testis were recovered by pretreatment with resveratrol and curcumin. The chemoprotective effects of these compounds may be due to their intrinsic antioxidant properties along with boosting Nrf2, HSP 60, HSP 70 and HSP 90 gene expression levels and as such may be useful potential tools in combating DEHP-induced testicular dysfunction.

Single-nucleotide polymorphism in the promoter region of the osteopontin gene at nucleotide −443 as a marker predicting the efficacy of pegylated interferon/ribavirin-therapy in Egyptians patients with chronic hepatitis C

Osteopontin (OPN) is an extracellular matrix glycophosphoprotein produced by several types of cells including the immune system. The present study examined the possibility that single-nucleotide polymorphisms (SNP) in the promoter region of the OPN at nt -443 is a marker predicting the therapeutic efficacy of pegylated interferon (peg-IFN-α2b)-ribavirin combination therapy in Egyptian patients with chronic hepatitis C. Blood was collected from 95 patients with chronic hepatitis C who had received peg-IFN-α2b-ribavirin combination therapy and 100 age and sex matched controls. SNP in OPN at nucleotide (nt) -443 and its serum protein level were analyzed. Sustained virological response (SVR) was higher in patients with T/T at nt -443 than in those with C/C or C/T. A univariate logistic regression analysis showed that fibrosis grade, serum OPN protein level and T/T homozygotes of SNP at -443 were significant predictors for response. Receiver operating characteristics (ROC) analysis revealed the diagnostic and prognostic efficacy of serum OPN. It can be concluded that SNP in the promoter region of OPN at nt -443 and serum OPN protein level are predictors of response to the efficacy of peg-IFN-α2b-ribavirin therapy in Egyptian patients with chronic hepatitis C.

Transforming growth factor beta 1 and monocyte chemoattractant protein-1 as prognostic markers of diabetic nephropathy

We aimed to find the relationship between serum transforming growth factor beta 1(TGF-β1) and urinary monocyte chemoattractant protein-1 (MCP-1) throughout the course of diabetic nephropathy (DN) and to assess the relationship between both levels and other parameters of renal injury such as albumin/creatinine ratio and estimated glomerular filtration rate (eGFR). Serum TGF-β1, urinary MCP-1, eGFR, and glycosylated hemoglobin (HbA1c) were measured in 60 patients with type II diabetes mellitus with different degrees of nephropathy (20 patients with normoalbuminuria, 20 patients with microalbuminuria, and 20 patients with macroalbuminuria) and compared with 20 matched healthy control subjects. Both the levels of serum TGF-β1 and urinary MCP-1 were significantly higher in patients with micro- and macroalbuminuria (137.8 ± 69.5 and 329.25 ± 41.46 ng/dl, respectively, for TGF-β1 and 167.41 ± 50.23 and 630.87 ± 318.10 ng/g creatinine, respectively, for MCP-1) compared with normoalbuminuric patients and healthy controls (33.25 ± 17.5 and 29.64 ± 10.57 ng/dl, respectively, for TGF-β1 and 63.85 ± 21.15 and 61.50 ± 24.81 ng/g creatinine, respectively, for MCP-1; p < 0.001). There was a positive significant correlation between the levels of serum TGF-β1 and those of urinary MCP-1 (r = 0.73, p < 0.001). Also, serum TGF-β1 and urinary MCP-1 correlated positively with HbA1c (r = 0.49 and 0.55, respectively, p < 0.05 for both) and inversely with eGFR (r = −0.69 and −0.60, respectively, p < 0.001 for both). We can conclude that serum TGF-β1 and urinary MCP-1 can be used as the markers for detection of progression of DN. Antagonizing TGF-β1 and MCP-1 might be helpful in attenuating the progression of nephropathy in diabetic patients.