Hala A. Attia

Aqueous Date Flesh or Pits Extract Attenuates Liver Fibrosis via Suppression of Hepatic Stellate Cell Activation and Reduction of Inflammatory Cytokines, Transforming Growth Factor-β1 and Angiogenic Markers in Carbon Tetrachloride-Intoxicated Rats

Previous data indicated the protective effect of date fruit extract on oxidative damage in rat liver. However, the hepatoprotective effects via other mechanisms have not been investigated. This study was performed to evaluate the antifibrotic effect of date flesh extract (DFE) or date pits extract (DPE) via inactivation of hepatic stellate cells (HSCs), reducing the levels of inflammatory, fibrotic and angiogenic markers. Coffee was used as reference hepatoprotective agent. Liver fibrosis was induced by injection of CCl4 (0.4 mL/kg) three times weekly for 8 weeks. DFE, DPE (6 mL/kg), coffee (300 mg/kg), and combination of coffee + DFE and coffee + DPE were given to CCl4-intoxicated rats daily for 8 weeks. DFE, DPE, and their combination with coffee attenuated the elevated levels of inflammatory cytokines including tumor necrosis factor-α, interleukin-6, and interleukin-1β. The increased levels of transforming growth factor-β1 and collagen deposition in injured liver were alleviated by both extracts. CCl4-induced expression of α-smooth muscle actin was suppressed indicating HSCs inactivation. Increased angiogenesis was ameliorated as revealed by reduced levels and expression of vascular endothelial growth factor and CD31. We concluded that DFE or DPE could protect liver via different mechanisms. The combination of coffee with DFE or DPE may enhance its antifibrotic effects.

Preventive Effects of Selenium Yeast, Chromium Picolinate, Zinc Sulfate and their Combination on Oxidative Stress, Inflammation, Impaired Angiogenesis and Atherogenesis in Myocardial Infarction in Rats

PURPOSE Accumulating evidences suggest a critical role of trace metal dyshemostasis in oxidative stress and cardiac dysfunction after myocardial infarction (MI). This study investigated the cardioprotective effects of selenium yeast (Se), chromium picolinate Cr(pic)3, zinc sulfate (Zn) and their combination on isoproterenol (ISO)-induced MI. METHODS Rats were divided into six groups: normal control, ISO control, Se-pretreated (0.1 mg/kg), Cr(pic)3-pretreated (400 µg/kg), Zn-pretreated (30 mg/kg) and metal combination-pretreated groups. All metals were administered for 28 days and at the 27th day, MI was induced by subcutaneous injection of ISO (85 mg/kg) once for two consecutive days. RESULTS ISO control group showed hyperlipidemia, elevation of cardiac biomarkers and lipid peroxidation and increased immunostaining of p47 phox NADPH oxidase subunit in addition to decreased levels of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Cardiac levels of tumor necrosis factor-α (TNF-α) were increased, while vascular endothelial growth factor (VEGF, the major angiogenic factor) was decreased. Pretreatment with Se normalized the cardiac enzymes, lipid peroxidation, GSH, SOD, CAT, GPx, TNF-α and VEGF (P<0.001) and reduced the immunostaining of p47 phox subunit. However, Se failed to correct the dyslipidemia. Cr(pic)3 significantly improved lipid profile (P<0.001) and all other biochemical deviations except for VEGF. Zn, but to lesser extent, reduced the oxidative damage and TNF-α levels and improved both dyslipidemia and angiogenesis. Combination therapy exhibited less prominent protection compared to individual metals. CONCLUSION Daily supplementation with trace metals is promising for improving myocardial performance via preventing oxidative damage, induction of angiogenesis, anti-inflammatory and/or anti-hyperlipidemic mechanisms.

Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways.

To investigate whether ruboxistaurin (a selective PKC‐β inhibitor) mediates renoprotective effect via interference with TGF‐β1/Smad‐GRAP cross‐signalling.

Fenofibrate attenuates diabetic nephropathy in experimental diabetic rat's model via suppression of augmented TGF-β1/Smad3 signaling pathway

Abstract Context: Fibrates, the ligands of peroxisome profileferator-activated receptor-α have been shown to have a renal protective action in diabetic nephropathy (DN). Objective: This study aimed to elucidate the effect of fenofibrate on renal transforming growth factor-β1 (TGF-β1) and Smad3 in Streptozotocin (STZ)-induced DN. Methods: Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were given fenofibrate (100 mg/kg, p.o.). After 12 weeks, diabetic nephropathy biomarkers were assessed. The mRNA expression of collage I and III, TGF-β1 and Smad3 and were detected by RT–PCR. Results: Fenofibrate reduced significantly serum creatinine, kidney/body weight ratio, serum albumin excretion Collage I & III, TGF-β1 and Smad3 mRNA expression. Conclusions: Our results give further insights into the mechanisms underlying the protective role of fenofibrate in DN, suggesting that interference with TGF-β1/Smad3 signaling pathway may be a useful therapeutic approach to prevent DN.

Date fruits inhibit hepatocyte apoptosis and modulate the expression of hepatocyte growth factor, cytochrome P450 2E1 and heme oxygenase-1 in carbon tetrachloride-induced liver fibrosis

Abstract Context: Date fruits have protective effects against liver fibrosis; however their anti-apoptotic effects have not been investigated. Objective: To investigate the modulating effects of date fruits on pro- and anti-apoptotic markers, cytochrome P450 2E1 (CYP2E1) and hepatocyte growth factor (HGF) in liver fibrosis. Materials and methods: Liver fibrosis was induced by injection of carbon tetrachloride (CCl4) for eight weeks. Date flesh extract (DFE) and pits extract (DPE) were taken daily concomitant with CCl4. Hepatocyte apoptosis was determined by measuring the expression of Fas, caspase-3, Bax, Bcl2 and hemeoxygenase-1 (HO-1). Hepatic levels of HGF and CYP2E1 were determined. Results: Treatment with DFE and DPE significantly attenuated the elevated levels of Fas, caspase 3, Bax and CYP2E1 induced by CCl4. In addition, they alleviated the reduction in Bcl2, HGF and HO-1, the cytoprotective and anti-apoptotic factors in liver. Conclusions DFE and DPE treatment can ameliorate liver fibrosis by inhibiting hepatocyte apoptosis.

Pulmonary prophylactic impact of melatonin and/or quercetin: A novel therapy for inflammatory hypoxic stress in rats

Abstract The study aims to compare, through histological and biochemical studies, the effects of quercetin, melatonin and their combination in regulation of immuno-inflammatory mediators and heat shock protein expressions in sodium nitrite induced hypoxia in rat lungs. The results revealed that NaNO2 injection caused a significant decrease in Hb in rats, while serum levels of TNF-α, IL-6 and CRP, VEGF and HSP70 were elevated compared to the control group. Administration of melatonin, quercetin or their combination before NaNO2 injection markedly reduced these parameters. Histopathological examination of the lung tissue supported these biochemical findings. The study suggests that melatonin and/or quercetin are responsible for lung tissue protection in hypoxia by downregulation of immuno-inflammatory mediators and heat shock protein expressions. Pre-treatment of hypoxic animals with a combination of melatonin and quercetin was effective in modulating most of the studied parameters to near-normal levels.

Quercetin inhibits sodium nitrite‐induced inflammation and apoptosis in different rats organs by suppressing Bax, HIF1‐α, TGF‐β, Smad‐2, and AKT pathways

The objective of this work is to study the protective effects of Quercetin against sodium nitrite‐induced hypoxia on liver, lung, kidney and cardiac tissues, also to explore novel mechanism of this compound. Male albino rats were injected with sodium nitrite (75 mg/kg). Quercetin (200 mg kg−1,‐ i.p.) was administrated 24 and 1 h respectively prior to sodium nitrite intoxication, hypoxia significantly decreased hemoglobin concentration, while increased expressions of HIF, Bax, Smad‐2, TGF‐β, and AKT. However, administration of Quercetin played a modulatory role against the previous mentioned apoptotic factors protein expressions in all the studied tissues. On the other hand, Bcl‐2 was downregulated by NaNO2, whereas concurrent treatment with Quercetin increased its expression. It was concluded that Quercetin possesses an anti‐apoptotic action induced by NaNO2‐intoxication via different mechanisms. Quercetin administration is recommended in areas of high altitudes to combat the hazard effect of hypoxia in different organs and in some diseases accompanied by hypoxic stress.

Regulating Effect Of Carnosine And /Or L- Arginine On The Expression Of Inflammatory Molecules Induced Nephropathy In The Hypoxic Rat Model

This study aimed to explore the effective role of carnosine and /or L- arginine in down regulation of the inflammatory molecule expression caused renal damage in response to sodium nitrite (NaNO2) induced hypoxia in rats . NaNO2 was administered subcutaneously (s.c.) to rats as a single dose (60 mg/kg body weight ). L-arginine (200mg/Kg body weight) and carnosine (250 mg/ Kg body weight ) were administered (i.p.) as a single dose , 24 h before NaNO2 injection. The results revealed that pre- administration of arginine and /or carnosine to NaNO2 hypoxic rats, significantly modulated the increases in serum markers of renal function (creatinine and urea) as well as the decrease in hemoglobin (Hb) level versus hypoxic rats. The two agents each alone or in a combination, markedly down regulated the serum pro-inflammatory molecules, including tumor necrosis factor-α (TNF- α) , C-reactive protein (CRP), vascular endothelial growth factor (VEGF) and heat shock protein -70 (HSP-70) as well as interleukin-6 (IL-6) in renal tissue compared to NaNO2 hypoxic rats . Also, the two agents successfully down modulated the alteration in the serum hypoxia inducible factor 1α (HIF 1α) . The present biochemical results were also supported by histopathological examination. In conclusion, the current data revealed that although the efficacy of arginine or carnosine each alone, their combination was more effective in ameliorating the renal damage induced by inflammatory molecules in response to NaNO2 hypoxia . This may support the use of this combination as an effective drug to treat hypoxic renal damage

Downregulation of flt-1 and HIF-1α Gene Expression by Some Antioxidants in Rats Under Sodium Nitrite–Induced Hypoxic Stress:

This study assessed the effect of L-arginine (L-argin), carnosine (carno), or their combination in the amelioration of certain biochemical indices induced in the liver of hypoxic rats. Hypoxia was induced via sodium nitrite (S.nit) injection at a dose of 75 mg/kg. Rats were administered L-argin (250 mg/kg) or carno (250 mg/kg), either alone or in combination, 24 hours and 1 hour prior to S.nit intoxication. Hypoxia significantly elevated serum alanine aminotransferase, in addition to a significant upregulation of hepatic heat shock protein 70 with concurrent reduction in the level of vascular endothelial growth factor. Moreover, hepatic vascular endothelial growth factor 1 (flt-1), hypoxia inducible factor-1α gene expression, and cytochrome P450 levels were elevated, compared with the normoxic group. The antioxidants, administered either alone or in combination, markedly downregulated all of the previously mentioned biomarkers, compared to the hypoxic rats. Histopathological examination revealed hepatocellular degeneration and nuclear pyknosis, in addition to inflammatory cellular infiltration in the hypoxic rats, whereas treatment with the studied antioxidants improved the liver architecture. The present data revealed the efficacy of L-argin and carno in ameliorating the hepatic damage induced via angiogenic markers in response to hypoxia, the combination regimen showing the superior effect.

Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3β and p38α/MAPK in a rat model of diabetic cardiomyopathy

The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on diabetic cardiomyopathy (DCM)-associated apoptosis and if this effect is mediated via modulating the activity of the survival kinases; AMP-activated protein kinase (AMPK) and Akt & the apoptotic kinases; glycogen synthase kinase-3 β (GSK-3β) and p38 mitogen-activated protein kinase (p38MAPK). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were treated with sitagliptin (10 mg/kg/day, p.o.) and metformin (200 mg/kg/day, p.o. as positive control) for six weeks. Chronic hyperglycemia resulted in elevation of serum cardiac biomarkers reflecting cardiac damage which was supported by H&E stain. The mRNA levels of collagen types I and III were augmented reflecting cardiac fibrosis and hypertrophy which was supported by Masson trichome stain and enhanced phosphorylation of p38MAPK. Cardiac protein levels of cleaved casapse-3, BAX were elevated, whereas, the levels of Bcl-2 and p-BAD were reduced indicating cardiac apoptosis which could be attributed to the diabetes-induced reduced phosphorylation of Akt and AMPK with concomitant augmented activation of GSK-3β and p38MAPK. Protein levels of liver kinase B-1, the upstream kinase of AMPK were also supressed. Sitagliptin administration alleviated the decreased phosphorylation of AMPK and Akt, inactivated the GSK-3β and p38 AMPK, therefore, attenuating the apoptosis and hypertrophy induced by hyperglycemia in the diabetic heart. In conclusion, sitagliptin exhibits valuable therapeutic potential in the management of DCM by attenuating apoptosis. The underlying mechanism may involve the modulating activity of AMPK, Akt, GSK-3β and p38MAPK.