Pentoxifylline as Add-On Treatment to Donepezil in Copper Sulphate-Induced Alzheimer's Disease-Like Neurodegeneration in Rats.

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by behavioral, cognitive, and progressive memory impairments. Extensive neuronal loss, extracellular accumulation of insoluble senile amyloid-ß (Aß) plaques, and intracellular neurofibrillary tangles (NFTs) are the major pathological features. The present study aimed to investigate the therapeutic effect of donepezil (DON) and pentoxifylline (PTX) in combination to combat the neurodegenerative disorders (experimental AD) induced by CuSO4 intake in experimental rats. Thirty adult male Wistar rats (140-160 g) were used in this study. AD was first induced in rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. The AD group received no further treatment. Oral treatment with DON (10 mg/kg/day), PTX (100 mg/kg/day), or DON + PTX for the other three groups was started from the 10th week of CuSO4 intake for 4 weeks. Cortex markers like acetylcholine (ACh), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) and hippocampus markers like ß-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), Clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 were measured. The histopathology studies were done by using hematoxylin and eosin and Congo red stains as well as immunohistochemistry for neurofilament. CuSO4 induced adverse histological and biochemical changes. The histological injury in the hippocampus was inhibited following the administration of the DON and PTX. The brain tissue levels of AChE, MDA, BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α were significantly increased, while brain tissue levels of ACh, TAC, and Bcl-2 were significantly decreased in CuSO4-treated rats as compared with the untreated control group. The effects induced by either DON or PTX on most studied parameters were comparable. Combined treatment of DON and PTX induced remarkable results compared with their individual use. However, more clinical and preclinical studies are still required to further confirm and prove the long-term efficacy of such combination.

Vitamin D alleviates cognitive dysfunction and brain damage induced by copper sulfate intake in experimental rats: focus on its combination with donepezil.

This study aimed to demonstrate the potential benefits of donepezil (DPZ) and vitamin D (Vit D) in combination to counteract the neurodegenerative disorders induced by CuSO4 intake in experimental rats. Neurodegeneration (Alzheimer-like) was induced in twenty-four male Wistar albino rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. AD rats were divided into four groups: untreated AD group (Cu-AD) and three treated AD groups; orally treated for 4 weeks with either DPZ (10 mg/kg/day), Vit D (500 IU/kg/day), or DPZ + Vit D starting from the 10th week of CuSO4 intake. Another six rats were used as normal control (NC) group. The hippocampal tissue content of ß-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 and the cortical content of acetylcholine (Ach), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured. Cognitive function tests (Y-maze) and histopathology studies (hematoxylin and eosin and Congo red stains) and immunohistochemistry for neurofilament. Vit D supplementation alleviated CuSO4-induced memory deficits including significant reduction hippocampal BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α and cortical AChE and MDA. Vit D remarkably increased cortical Ach, TAC, and hippocampal Bcl-2. It also improved neurobehavioral and histological abnormalities. The effects attained by Vit D treatment were better than those attained by DPZ. Furthermore, Vit D boosted the therapeutic potential of DPZ in almost all AD associated behavioral and pathological changes. Vit D is suggested as a potential therapy to retard neurodegeneration.

Infliximab substantially re-silenced Wnt/ß-catenin signaling and ameliorated doxorubicin-induced cardiomyopathy in rats.

The release of inflammatory cytokines, namely tumor necrosis factor-α (TNF-α), plays an important role in the pathogenesis of cardiomyopathy. TNF-α increases in plasma and in myocardium of heart failure patients. We aimed to investigate the role of TNF-α inhibitor (infliximab; IFX) in regulating dilated cardiomyopathy (DCM) induced in rats. DCM was induced in rats by doxorubicin (DOX; 3.5 mg. kg-1 , i.p) twice weekly for 3 weeks (21 mg. kg-1 cumulative dose). DCM rats were treated with RPL (1 mg. kg-1 orally, daily), IFX (5 mg. kg-1 ; i.p. once) or their combination for 4 weeks starting next day of last DOX dose. Echocardiography was conducted followed by a collection of blood and left ventricle (LV) for biochemical and histological investigations. DCM rats revealed deteriorated cardiac function (increased CK-MB activity, LVIDs, LVIDd, ESV, and EDV, while decreased EF% and FS%), hypertrophy (increased HW/TL, ß-MHC, and α-actin), inflammation (increased IL-1ß, IL-6, and TNF-α). The activation of Wnt/ß-catenin along with increased gene expression of RAS components (RENIN, ACE, and AT1) were evident. LV architecture also revealed abnormalities and some degree of fibrosis. Treatment with RPL and/or IFX suppressed TNF-α and consequently improved most of these parameters suppressing Wnt/ß-catenin/RAS axis. Combined RPL and IFX treatment was the best among all treatments. In conclusion, Wnt/ß-catenin/RAS axis is implicated in DOX-induced cardiomyopathy. The upstream TNF-α was proved for the first time in-vivo to stimulate this axis where its inhibition by RPL or IFX prevented DCM. Targeting this axis at two points using RPL and IFX showed better therapeutic efficacy.

Potential therapeutic efficacy of pachymic acid in chronic kidney disease induced in rats: role of Wnt/ß-catenin/renin-angiotensin axis.

OBJECTIVES: Chronic kidney disease (CKD) is a major public health problem associated with high mortality. The therapeutic effects of pachymic in CKD management and its underlying mechanisms have not been studied. Therefore, we aimed to investigate the possible inhibitory effect of PA on renal Wnt/ß-catenin signalling in CKD. METHODS: CKD was induced in rats by doxorubicin (DOX; 3.5 mg/kg i.p., twice weekly for 3 weeks). Rats were treated orally with PA (10 mg/kg/day), LOS (10 mg/kg/day) or their combination (PA + LOS) for 4 weeks starting after the last dose of DOX. KEY FINDINGS: DOX-induced renal injury was characterized by high serum cystatin-C, and urine albumin/creatinine ratio, renal content of podocin and klotho were decreased. Tumour necrosis factor-α, interleukin-6, interleukin-1ß, Wnt1, active ß-catenin/total ß-catenin ratio and fibronectin along with mRNA expression of RENIN, ACE and AT1 were increased in renal tissues. Treatment with either PA or LOS ameliorated all DOX-induced changes. The combined treatment was more effective in improving all changes than monotherapy. CONCLUSIONS: These results suggest a new therapeutic benefit of PA in ameliorating CKD in rats through its up-regulatory effect on renal klotho thereby preventing Wnt/ß-catenin reactivation and RAS gene expression. PA/LOS combination provided an additional inhibition of Wnt/ß-catenin signalling and its downstream targets.

Resveratrol Ameliorates Aortic Calcification in Ovariectomized Rats via SIRT1 Signaling.

Postmenopausal women are at an increased risk of vascular calcification which is defined as the pathological deposition of minerals in the vasculature, and is strongly linked with increased cardiovascular disease risk. Since estrogen-replacement therapy is associated with increased cancer risk, there is a strong need for safer therapeutic approaches. In this study we aimed to investigate the protective and therapeutic effects of the phytoestrogen resveratrol against vascular calcification in ovariectomized rats, a preclinical model of postmenopause. Furthermore, we aimed to compare the effects of resveratrol to those of estrogen and to explore the mechanisms underpinning those effects. Treatment with resveratrol or estrogen ameliorated aortic calcification in ovariectomized rats, as shown by reduced calcium deposition in the arterial wall. Mechanistically, the effects of resveratrol and estrogen were mediated via the activation of SIRT1 signaling. SIRT1 protein expression was downregulated in the aortas of ovariectomized rats, and upregulated in rats treated with resveratrol or estrogen. Moreover, resveratrol and estrogen reduced the levels of the osteogenic markers: runt-related transcription factor 2 (RUNX2), osteocalcin and alkaline phosphatase (ALP) which have been shown to play a role during vascular calcification. Additionally, the senescence markers (p53, p16 and p21) which were also reported to play a role in the pathogenesis of vascular calcification, were reduced upon treatment with resveratrol and estrogen. In conclusion, the phytoestrogen resveratrol may be a safer alternative to estrogen, as a therapeutic approach against the progression of vascular calcification during postmenopause.

The efficacy of bone marrow-derived mesenchymal stem cells and/or erythropoietin in ameliorating kidney damage in gamma irradiated rats: Role of non-hematopoietic erythropoietin anti-apoptotic signaling.

Radiation-induced multiple organ injury, including γ-radiation nephropathy, is the most common. Even with dose fractionation strategy, residual late side effects are inevitable. Bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation and erythropoietin (EPO) have shown to be effective in treating chronic kidney disease and associated anemia. This study aimed to evaluate the effect of BM-MSCs and/or EPO in fractionated γ-irradiation induced kidney damage in rats. Adult male Wistar rats were randomized into 2 groups; normal and 8 Gy (fractionated dose of 2 Gy for 4 days) γ-irradiated rats. Animal from both groups were subdivided to receive the following treatments: BM-MSCs (1 × 106 cells/rat, i.v - once), EPO (100 IU/kg, i.p - every other day for 30 days) or their combined treatment (BM-MSCs and EPO). γ-Irradiated rats showed a noticeable elevation in serum urea and creatinine, kidney malondialdehyde (MDA) and caspase 3 activity. They also revealed significant drop in kidney glutathione (GSH) and Bcl2 protein contents. Conspicuously, they revealed down-regulation of renal EPO signaling (EPO, EPOR, pJAK2, pPI3K and pAkt). Conversely, groups treated with BM-MSCs and/or EPO revealed significant modulation in most tested parameters and appeared to be effective in minimizing the hazard effects of radiation. In conclusion, BM-MSCs and/or EPO exhibited therapeutic potentials against nephrotoxicity induced by fractionated dose of γ-irradiation. An effect mediated by antioxidant and non-hematopoietic EPO downstream anti-apoptotic signaling (PI3K/Akt) pathway. EPO potentiate the repair capabilities of BM-MSCs making this combined treatment a promising therapeutic strategy to overcome radiotherapy-induced kidney damage.

Inactivation of Wnt/ß-catenin/renin angiotensin axis by tumor necrosis factor-alpha inhibitor, infliximab, ameliorates CKD induced in rats.

Infliximab (IFX), a chimeric monoclonal antibody against tumor necrosis factor-α (TNF-α), is widely used to treat autoimmune diseases and chronic diseases associated with inflammation. TNF-α was reported to inhibit klotho, reactivate ß-catenin and cause tubular cell injury in vitro. Whether the inhibition of TNF-α can regulate Wnt/ß-catenin pathway via klotho in CKD in vivo is not studied yet. We aimed to investigate the impact of IFX on Wnt/ß-catenin pathway in doxorubicin (DOX)-induced nephropathy. Doxorubicin (3.5 mg/kg; i.p., twice weekly for 3 weeks) increased serum cystatin-C, urine albumin/creatinine ratio (UACR), but depleted renal podocin. It markedly increased renal contents of TNF-α, interleukin-6 (IL-6), interleukin-1ß (IL1ß). DOX decreased the renal expression of klotho which in turn increased Wnt1, active ß-catenin/total ß-catenin ratio in renal tissue. Significant increase in renal gene expression of RENIN, ACE, and AT1 was observed. Moreover, renal fibronectin and collagen deposition increased in renal tissue. Treatment with either IFX (5 mg/kg, once; i.p.), losartan (LOS, 10 mg/kg/day, orally) or their combination significantly improved renal function, inhibited inflammatory cytokines and fibrosis. Renal TNF-α was negatively correlated with renal klotho. On the hand, it was positively correlated with renal Wnt1 and active ß-catenin/total ß-catenin ratio. The combined IFX and LOS treatment was the most effective in improving all studied parameters. In conclusion, this study proved, for the first time, the inhibitory effect of IFX on renal Wnt/ß-catenin signaling in DOX-induced nephropathy in vivo by up-regulating renal klotho. Therefore, these results suggest a new role for IFX in chronic kidney disease via targeting renal Wnt/ß-catenin/renin angiotensin axis.

Modulation of NADPH oxidase and Nrf2/HO-1 pathway by vanillin in cisplatin-induced nephrotoxicity in rats.

OBJECTIVES: To investigate the protective effect of vanillin in cisplatin (CP)-induced nephrotoxicity in rats and elucidate the role of nrf-2 and its downstream antioxidant molecules. METHODS: Rats received vanillin (100 mg/kg orally) for 10 constitutive days and CP (7.5 mg/kg, once, ip) on day 6 of vanillin administration. KEY FINDINGS: Cisplatin suppressed body weight gain, increased serum urea and creatinine and renal malondialdehyde and nitric oxide while decreased renal total antioxidant capacity. Up-regulation of NADPH oxidase-4 (NOX-4) was marked in renal tissue of CP-treated rats along with down-regulation of the antioxidant genes (nuclear factor erythroid 2-related factor2 (NRF2) and haem oxygenase-1(HO-1)). Increased tumour necrosis factor-α and decreased interleukin-10 with increased myeloperoxidase activity were apparent in renal tissue of CP-treated rats along with marked tubular injury, neutrophil infiltration and increased apoptosis (caspase-3) and some degree of interstitial fibrosis. Vanillin prophylactic administration prevented the deterioration of kidney function, oxidative and nitrosative stress. It also suppressed NOX-4 and up-regulated NRF2 and HO-1 expression in renal tissue. Inflammation, apoptosis and tubular injury were also inhibited by vanillin. CONCLUSIONS: The antioxidant mechanism by which vanillin protected against CP-induced nephrotoxicity involved the inhibition of NOX-4 along with the stimulation of Nrf2/HO-1 signalling pathway. These in turn inhibited inflammation and apoptosis.

The modulation of PCSK-9 and GAGs by 10-dehydrogingerdione and pentoxifylline in hyperlipidemic rabbits.

The hypolipidemic effect of 10-DHGD was previously reported owing to its anti-inflammatory and anti-oxidant properties. We further investigated the anti-inflammatory role of 10-DHGD in modulating atherogenicity by targeting proproteinconvertasesubtilisinkexin-9 (PCSK-9). Rabbits fed high cholesterol diet (HCD) containing 0.2% w/w cholesterol for12-weeks received either 10-DHGD (10-mg/kg), pentoxifylline (PTX, 40-mg/kg) or their combination concurrently with HCD. Lipid profile, serum PCSK-9, macrophage migration inhibitory factor (MIF), aorta tumor necrosis factor- alpha (TNF-α) and glycosaminoglycans (GAGs) were measured. Atherogenicity and increased PCSK-9, MIF and TNF-α and GAGs (p < 0.001) was proved HCD-fed rabbits. The concurrent administration of 10-DHGD or PTX with HCD feeding prevented this atheogenicity by modulating the release of PCSK-9, inflammatory markers and GAGs. The combined PTX and 10-DHGD in HCD fed rabbits not only lowered hyperlipidemia, but also targeted arterial inflammation to a better extent. In conclusion PTX and 10-DHGD can prevent hyperlipidemia and associated inflammatory process modifying factors predisposing to atherosclerosis.

Modulation of brain insulin signaling in Alzheimer's disease: New insight on the protective role of green coffee bean extract.

Objective: Alzheimer's disease (AD), a neurodegenerative disorder, involves brain insulin signaling cascades and insulin resistance (IR). Because of limited treatment options, new treatment strategies are mandatory. Green coffee bean extract (GCBE) was reported to attenuate IR and improve brain energy metabolism. We aimed to investigate the possible use of GCBE as a prophylactic strategy to delay the onset of AD or combined with pioglitazone (PIO) as a strategy to retard the progression of AD.Methods: Rats received 10% fructose in drinking water for 18 weeks to induce AD. GCBE-prophylactic group received GCBE for 22 weeks started 4 weeks prior to fructose administration. The PIO group treated with PIO for 6 weeks started on week 12 of fructose administration. The GCBE+PIO group received GCBE for 22 weeks started 4 weeks prior to fructose administration and treated with PIO for the last 6 weeks of fructose administration.Results: Pretreatment with GCBE, either alone or combined with PIO, alleviated IR-induced AD changes. GCBE improved cognition, decreased serine phosphorylation of insulin receptor substrate, increased phosphoinositol-3 kinase (PI3K) activity and protein kinase B (Akt) gene expression, decreased glycogen synthase kinase-3ß (GS3Kß) gene expression and Tau hyperphosphorylation.Discussion: GCBE exerted neuroprotective effects against IR-induced AD mediated by alleviating IR and modulating brain insulin signaling cascade.

Contribution of aorta glycosaminoglycans and PCSK9 to hyperlipidemia in experimental rabbits: the role of 10-dehdrogingerdione as effective modulator.

10-Dehydrogingerdione (10-DHGD) was previously reported to possess a hypolipidemic, anti-inflammatory and anti-oxidant properties in hyperlipidemic rabbit model. In this study, we investigated a possible new role for 10-DHGD in modulating atherogenic lipid profile by targeting proprotein convertase subtilisin kexin-9 (PCSK-9). Cholesterol (0.2% w/w)-fed rabbits received either atorvastatin (20 mg/kg) or 10-DHGD (10 mg/kg) for 12 weeks along with cholesterol feeding (HCD). Lipid profile, serum PCSK-9 and macrophage migration inhibitory factor (MIF), and aorta level of tumor necrosis factor-alpha (TNF-α) and glycosaminoglycans (GAGs) were measured. HCD-fed rabbits revealed an atherogenic lipid profile along with increased serum level of PCSK-9 (p < 0.001) and increased serum MIF and aortic TNF-α and GAGs (p < 0.001). 10-DHGD administration to HCD-fed rabbits prevented this atheogenicity by modulating the release of PCSK-9, inflammation extent (serum MIF and aortic TNF-α) and GAGs. These results provide new insights on the hypolipidemic potential of 10-DHGD. The effects of 10-DHGD was superior to that of atorvastatin in most studied parameters modulating atherogenicity. 10-DHGD is found to be able to suppress the release of PCSK-9, decrease aortic expression of GAGs in cholesterol-fed rabbits and halt the inflammation extent. These effects may provide new insights on the hypolipidemic potential of 10-DHGD.

Silymarin preconditioning protected insulin resistant rats from liver ischemia-reperfusion injury: role of endogenous H2S.

BACKGROUND: Hydrogen sulfide (H2S) can protect against hepatic ischemia-reperfusion injury (HIR). However, it is unknown whether it can protect against HIR in insulin resistance. This study investigated the protective effects of silymarin against HIR in a rat model of insulin resistance and the possible involvement of endogenous H2S. MATERIALS AND METHODS: Insulin resistance was first established using 10% fructose in drinking water for 10 weeks. HIR was conducted in fructose-fed rats treated with saline or silymarin (100 mg/kg), 15 min before HIR (30 min ischemia, followed by 1 h reperfusion). Insulin resistance and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), total nitrites (NO2(-)), and H2S were measured. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), hydroxyproline, H2S synthesizing activity, and mRNA expression of cystathionine ß-synthase (CBS) or cystathionine γ-lyase (CSE) were determined. Additionally, histopathological examination involved H&E, Sirius red, and caspase-3 immunostaining. RESULTS: Fructose-induced insulin resistance increased serum ALT, TNF-α, H2S and H2S synthesizing activity, and hepatic MDA, hydroxyproline, and CSE mRNA and decreased NO2(-) and GSH. These changes exacerbated the HIR injury in which endogenous H2S production was auxiliary increased. Silymarin preconditioning decreased ALT, AST, MDA, NO2(-), TNF-α, and TNF-α/IL-10 ratio, increased GSH, IL-10, improved hepatic architecture, and lowered caspase-3 immunostaining. Serum H2S, its hepatic synthesizing activity, and CSE and CBS mRNA expressions were all suppressed by silymarin pretreatment. CONCLUSIONS: The increases in endogenous H2S exacerbate HIR injury, whereas silymarin preconditioning protected against HIR in insulin resistant rats via powerful antioxidant, anti-inflammatory, and antiapoptotic effects along with suppressing H2S production.

The synergistic effect between vanillin and doxorubicin in ehrlich ascites carcinoma solid tumor and MCF-7 human breast cancer cell line.

Despite the remarkable anti-tumor activity of doxorubicin (DOX), its clinical application is limited due to multiple organ toxicities. Products with less side effects are therefore highly requested. The current study investigated the anti-cancer activities of vanillin against breast cancer and possible synergistic potentiation of DOX chemotherapeutic effects by vanillin. Vanillin (100mg/kg), DOX (2mg/kg) and their combination were administered i.p. to solid Ehrlich tumor-bearing mice for 21days. MCF-7 human breast cancer cell line was treated with vanillin (1 and 2mM), DOX (100µM) or their combination. Protection against DOX-induced nephrotoxicity was studied in rats that received vanillin (100mg/kg, ip) for 10days with a single dose of DOX (15mg/kg) on day 6. Vanillin exerted anticancer effects comparable to DOX and synergesticlly potentiated DOX anticancer effects both in-vivo and in-vitro. The anticancer potency of vanillin in-vivo was mediated via apoptosis and antioxidant capacity. It also offered an in-vitro growth inhibitory effect and cytotoxicity mediated by apoptosis (increased caspase-9 and Bax:Bcl-2 ratio) along with anti-metasasis effect. Vanillin protected against DOX-induced nephrotoxicity in rats. In conclusion, vanillin can be a potential lead molecule for the development of non-toxic agents for the treatment of breast cancer either alone or combined with DOX.

Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model.

Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats. Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10(6) cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks. Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA.

Pyridoxamine, an inhibitor of protein glycation, in relation to microalbuminuria and proinflammatory cytokines in experimental diabetic nephropathy.

Diabetic nephropathy (DN) is one of the major complications that develop as consequence of chronic and uncontrolled hyperglycaemia. Hyperglycaemia initiates various processes, one of which is protein glycation, leading to the formation of advanced glycation end products. Alteration of intracellular signalling, gene expression, release of proinflammatory molecules and free radicals are examples of such changes and they contribute to the initiation of diabetic complications. In the current manuscript, we studied the effect of pyridoxamine (PM) on protein glycation, oxidative stress, interleukin-1α (IL-1α), IL-6, C-reactive protein (CRP), gene expression of tumour necrosis factor-α (TNF-α) and transforming growth factor-ß1 (TGF-ß1) in relation to microalbuminuria and kidney functions in a model of alloxan-induced diabetic rats. We have observed that onset of microalbuminuria has preceded the gradual increase of blood sugar level in diabetic rats. In diabetic rats, gene expression of TNF-α and TGF-ß1 recorded a gradual increase and marked increase was observed after one and two weeks of alloxan administration, in comparison with normal rats. PM induced significant decrease in kidney malondialdehyde content and the gene expression of TNF-α and TGF-ß1, in addition to levels of serum glucose, fructosamine, urea, creatinine, IL-1α, IL-6, CRP and urine microalbumin. Histopathological examination of kidney tissues showed certain improvements as compared with diabetic control. In conclusion, our results may provide a supporting evidence for the therapeutic benefit of PM in DN.

Gastritis induced by Helicobacter pylori infection in experimental rats.

BACKGROUND: Gastritis, an inflammation of gastric mucosa, may be due to many pathological factors and infection, such as with Helicobacter pylori. The use of experimental models of gastritis is important to evaluate the biochemical changes and study chemotherapeutic intervention. In a previous study we demonstrated an acute gastritis model induced by iodoacetamide. AIMS: Our objective in this study was to evaluate a new gastritis model induced by H. pylori infection in experimental rats in terms of certain biomarkers in serum and mucosal tissues in addition to histopathological examination. METHODS: Gastritis was induced in 20 albino Wistar rats by H. pylori isolated from antral biopsy taken from a 49-year-old male patient endoscopically diagnosed as having H. pylori infection. Another ten rats were used as controls. Serum gastrin, pepsinogen I activity, interleukin-6 (IL-6) and gastric mucosal myeloperoxidase (MPO) activity and prostaglandin E(2) (PGE(2)) were measured. Immunostaining for inducible nitric oxide synthase (iNOS), nitrotyrosine and DNA fragmentation were used to further evaluate H. pylori-induced gastritis. RESULTS: Serum gastrin, IL-6, mucosal MPO activity, and PGE(2) demonstrated significant increases joined with a decreased serum pepsinogen I activity (P < 0.001). Immunohistochemistry demonstrated positive reaction for iNOS, nitrotyrosine and DNA fragmentation. CONCLUSIONS: Helicobacter pylori-induced gastritis models demonstrated massive oxidative stress and pronounced injury in mucosal tissue. Since our model in rats reflected the clinical picture of H. pylori infection, it can be considered as a consistent model to study chemotherapeutic intervention for this type of gastritis.