The interplay between hypovitaminosis D and the immune dysfunction in the arteriovenous thrombotic complications of the sever coronavirus disease 2019 (COVID-19) infection.

Thromboembolic complications including cerebrovascular accidents, pulmonary embolism, myocardial infarction, deep vein thrombosis and disseminating intravascular coagulopathy are serious encounters in sever coronavirus disease 2019 (COVID-19) infected patients. This worsens the prognosis and may lead to death or life long morbidities. The laboratory finding of the disturbed haemostasias and the hyperinflammatory response are almost invariably present in COVID-19 patients. Multiple treatment modalities are utilized by the healthcare professionals to overcome the cytokine storm, oxidative stress, endothelial dysfunction, and coagulopathy in these patients. The combined actions of vitamin D (VitD) as a steroid hormone with anti-inflammatory, immunomodulatory, and antithrombotic properties increase the potential of the possible involvement of hypovitaminosis D in the thromboembolic complications of COVID-19 infection, and stimulated researchers and physicians to administer VitD therapy to prevent the infection and/or overcome the disease complications. The current review highlighted the immunomodulatory, anti-inflammatory, antioxidative and hemostatic functions of VitD and its interrelation with the renin-angiotensin-aldosterone system (RAAS) pathway and the complement system. Additionally, the association of VitD deficiency with the incidence and progression of COVID-19 infection and the associated cytokine storm, oxidative stress, hypercoagulability, and endothelial dysfunction were emphasized. Normalizing VitD levels by daily low dose therapy in patients with hypovitaminosis D below (25 nmol/l) is essential for a balanced immune response and maintaining the health of the pulmonary epithelium. It protects against upper respiratory tract infections and decreases the complications of COVID-19 infections. Understanding the role of VitD and its associated molecules in the protection against the coagulopathy, vasculopathy, inflammation, oxidative stress and endothelial dysfunction in COVID-19 infection could lead to new therapeutic strategies to prevent, treat, and limit the complications of this deadly virus infection.

Activation of the Peroxisome Proliferator-Activated Receptors (PPAR-α/γ) and the Fatty Acid Metabolizing Enzyme Protein CPT1A by Camel Milk Treatment Counteracts the High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease.

Camel milk (CM) has a unique composition rich in antioxidants, trace elements, immunoglobulins, insulin, and insulin-like proteins. Treatment by CM demonstrated protective effects against nonalcoholic fatty liver disease (NAFLD) induced by a high-fat cholesterol-rich diet (HFD-C) in rats. CM dampened the steatosis, inflammation, and ballooning degeneration of the hepatocytes. It also counteracted hyperlipidemia, insulin resistance (IR), glucose intolerance, and oxidative stress. The commencement of NAFLD triggered the peroxisome proliferator-activated receptor-α (PPAR-α), carnitine palmitoyl-transferase-1 (CPT1A), and fatty acid-binding protein-1 (FABP1) and decreased the PPAR-γ expression in the tissues of the animals on HFD-C. This was associated with increased levels of the inflammatory cytokines IL-6 and TNF-α and leptin and declined levels of the anti-inflammatory adiponectin. Camel milk treatment to the NAFLD animals remarkably upregulated PPARs (α, γ) and the downstream enzyme CPT1A in the metabolically active tissues involved in cellular uptake and beta-oxidation of fatty acids. The enhanced lipid metabolism in the CM-treated animals was linked with decreased expression of FABP1 and suppression of IL-6, TNF-α, and leptin release with augmented adiponectin production. The protective effects of CM against the histological and biochemical features of NAFLD are at least in part related to the activation of the hepatic and extrahepatic PPARs (α, γ) with consequent activation of the downstream enzymes involved in fat metabolism. Camel milk treatment carries a promising therapeutic potential to NAFLD through stimulating PPARs actions on fat metabolism and glucose homeostasis. This can protect against hepatic steatosis, IR, and diabetes mellitus in high-risk obese patients.

Angiotensin-I Converting Enzyme Inhibition and Antioxidant Activity of Papain-Hydrolyzed Camel Whey Protein and Its Hepato-Renal Protective Effects in Thioacetamide-Induced Toxicity.

Papain hydrolysis of camel whey protein (CWP) produced CWP hydrolysate (CWPH). Fractionation of CWPH by the size exclusion chromatography (SEC) generated fractions (i.e., SEC-F1 and SEC-F2). The angiotensin converting enzyme inhibitory activity (ACE-IA) and free radical scavenging actions were assessed for CWP, CWPH, SEC-F1, and SEC-F2. The SEC-F2 exerted the highest ACE-IA and scavenging activities, followed by CWPH. The protective effects of CWPH on thioacetamide (TAA)-induced toxicity were investigated in rats. The liver enzymes, protein profile, lipid profile, antioxidant enzyme activities, renal functions, and liver histopathological changes were assessed. Animals with TAA toxicity showed impaired hepatorenal functions, hyperlipidemia, and decreased antioxidant capacity. Treatment by CWPH counteracted the TAA-induced oxidative tissue damage as well as preserved the renal and liver functions, the antioxidative enzyme activities, and the lipid profile, compared to the untreated animals. The current findings demonstrate that the ACE-IA and antioxidative effects of CWPH and its SEC-F2 fraction are worth noting. In addition, the CWPH antioxidative properties counteracted the toxic hepatorenal dysfunctions. It is concluded that the hydrolysis of CWP generates a wide range of bioactive peptides with potent antihypertensive, antioxidant, and hepatorenal protective properties. This opens up new prospects for the therapeutic utilization of CWPH and its fractions in the treatment of oxidative stress-associated health problems, e.g., hypertension and hepatorenal failure.

Clopidogrel Prophylaxis Abates Myocardial Ischemic Injury and Inhibits the Hyperlipidemia-Inflammation Loop in Hypercholestrolemic Mice.

BACKGROUND: Platelet hyper adhesiveness orchestrates with inflammation and vascular muscle proliferation leading to atheroma formation and endothelial dysfunction. OBJECTIVES: The current study aims to compare the prophylactic role of Aspirin and Clopidogrel therapy against isoproterenol-induced acute myocardial infarction (AMI), in mice on high-fat, cholesterol-rich diet (HFD-C). METHODS: The animals received HFD-C with Aspirin or Clopidogrel for 8 weeks and were subjected to AMI by isoproterenol. The blood lipids, inflammatory cytokines, myocardial enzymes, redox state, long pentraxin (PTX3), and matrix metalloproteinases (MMP-2 and MMP-9) activities were investigated. RESULTS: Antiplatelet therapy moderated the hyperlipidemia induced by HFD-C in the current study. Essentially, the total cholesterol and LDL-C levels were lower with Aspirin than with Clopidogrel therapy. Yet Aspirin and Clopidogrel each comparably lowered CK-MB, AST, MMP-2, MMP-9, and the lipid peroxidation product malondialdehyde (MDA) in the hyperlipidemic animals exposed to AMI. However, the decline in cTn-T, LDH and PTX3 levels was greater after Clopidogrel than Aspirin administration. Therefore, Clopidogrel provides greater protection against AMI than Aspirin in the hyperlipidemic mice. This could be explained by the suppression of the proinflammatory cytokines IL-6, TNF-α, TGF-1ß and stabilization of the extracellular matrix through the inhibition of MMP-2 and MMP-9 activities. Furthermore, Clopidogrel demonstrated significant antioxidative action in the AMI animals, resulting in diminished MDA production and preserved CAT activity. CONCLUSION: Beside its therapeutic role in the thrombotic vascular events, Clopidogrel confers significant protection against ischemic myocardial injury by counteracting the platelet-mediated inflammation and oxidative stress associated with HFD-C consumption in animals.

Comparison of the hypoglycemic and antithrombotic (anticoagulant) actions of whole bovine and camel milk in streptozotocin-induced diabetes mellitus in rats.

People with diabetes are at higher risk of fatal thromboembolic accidents in the cerebral and coronary circulations, especially stroke and ischemic heart disease. We have previously described the hypoglycemic, hypolipidemic, and anticoagulant activity of orally administered camel milk in streptozotocin-induced diabetic rats. In the present study in the same animal model, we extended these observations by comparing camel milk and the more available and widely consumed bovine milk with respect to their antidiabetic and antithrombotic actions. Rats were rendered diabetic by intraperitoneal streptozotocin (65 mg/kg), and then camel milk or bovine milk was administered orally for 8 wk. We evaluated the changes in body weight, fasting blood glucose, glucose tolerance, blood coagulation profile, and platelet function. Diabetic rats developed weight loss, hyperglycemia, glucose intolerance, inhibition of platelet aggregation responses to arachidonic acid and adenosine diphosphate, a marked decrease (>50%) in plasma fibrinogen levels, and short activated partial thromboplastin time. Treatment with camel milk or bovine milk reversed these abnormalities, resulting in weight gain, decreased blood glucose levels, and improved glucose tolerance. Despite the more remarkable antidiabetic action of camel milk, treatment with bovine milk was more effective in correcting plasma fibrinogen levels and restoring inhibited platelet aggregation responses. Long-term administration of camel milk or bovine milk counteracted streptozotocin-induced metabolic manifestations in rats, maintained platelet function, and abolished coagulopathy-associated fibrinogen consumption. Notably, the antidiabetic effect of camel milk was more pronounced than that of bovine milk, but bovine milk exhibited more potent anticoagulant activity than camel milk. These findings should encourage further clinical trials to assess the efficiency of camel milk and bovine milk or their derived peptides as food supplements or potential nonpharmacological therapies for dysglycemia and the vascular complications of diabetes mellitus.

Camel milk attenuates the biochemical and morphological features of diabetic nephropathy: inhibition of Smad1 and collagen type IV synthesis.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus (DM) that worsens its morbidity and mortality. There is evidence that camel milk (CM) improves the glycemic control in DM but its effect on the renal complications especially the DN remains unclear. Thus the current study aimed to characterize the effects of CM treatment on streptozotocin (STZ)-induced DN. Using STZ-induced diabetes, we investigated the effect of CM treatment on kidney function, proteinuria, renal Smad1, collagen type IV (Col4), blood glucose, insulin resistance (IR), lipid peroxidation, the antioxidant superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH). In addition renal morphology was also examined. The current results showed that rats with untreated diabetes exhibited marked hyperglycemia, IR, high serum urea and creatinine levels, excessive proteinuria, increased renal Smad1 and Col4, glomerular expansion, and extracellular matrix deposition. There was also increased lipid peroxidation products, decreased antioxidant enzyme activity and GSH levels. Camel milk treatment decreased blood glucose, IR, and lipid peroxidation. Superoxide dismutase and CAT expression, CAT activity, and GSH levels were increased. The renoprotective effects of CM were demonstrated by the decreased serum urea and creatinine, proteinuria, Smad1, Col4, and preserved normal tubulo-glomerular morphology. In conclusion, beside its hypoglycemic action, CM attenuates the early changes of DN, decreased renal Smad1 and Col4. This could be attributed to a primary action on the glomerular mesangial cells, or secondarily to the hypoglycemic and antioxidant effects of CM. The protective effects of CM against DN support its use as an adjuvant anti-diabetes therapy.

Camel milk ameliorates steatohepatitis, insulin resistance and lipid peroxidation in experimental non-alcoholic fatty liver disease.

BACKGROUND: Camel milk (CM) is gaining increasing recognition due to its beneficial effects in the control and prevention of multiple health problems. The current study aimed to investigate the effects of CM on the hepatic biochemical and cellular alterations induced by a high-fat, cholesterol-rich diet (HCD), specifically, non-alcoholic fatty liver disease (NAFLD). METHODS: Seventy male Wistar rats were divided into four groups: the Control (C) Group fed a standard diet; the Control + camel milk (CCM) Group fed a standard diet and CM, the Cholesterol (Ch) Group fed a HCD with no CM, and the Cholesterol + camel milk (ChM) Group fed a HCD and CM. The following parameters were investigated in the studied groups; basal, weekly random and final fasting blood glucose levels, intraperitoneal glucose tolerance test (GTT) and insulin tolerance test (ITT), serum insulin, serum lipids, liver functions, lipid peroxidation products, the antioxidant activity of catalase (CAT) and the levels of reduced glutathione (GSH). In addition, HOMA-IR as an index of insulin resistance (IR) and the histopathology of the hepatic tissue were assessed. RESULTS: The Ch Group developed features similar to those of non-alcoholic steatohepatitis (NASH), characterized by hepatic steatosis; inflammatory cellular infiltration in liver tissue; altered liver functions; and increased total cholesterol, triglycerides, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, atherogenic index (AI), blood glucose, IR, and malondialdehyde (MDA) levels. Additionally, feeding the HCD to animals in the Ch Group decreased CAT activity and the GSH and high-density lipoprotein (HDL) cholesterol levels. Camel milk intake for eight weeks decreased hepatic fat accumulation and inflammatory cellular infiltration, preserved liver function, increased the GSH levels and CAT activity, decreased the MDA levels, and ameliorated the changes in the lipid profile, AI, and IR in animals from the ChM Group. CONCLUSIONS: CM has a unique composition that is rich in minerals; vitamins, insulin and insulin-like protein, and it increased HDL-cholesterol and ameliorated the biochemical and cellular features of NAFLD in rats that received a HCD. The antioxidant effect of CM is a likely mechanism for the altered metabolism and absorption of HCD in the presence of CM. Regular consumption of CM could provide a natural way to protect against NAFLD induced by a high-fat diet.

Magnesium sulfate therapy of preeclampsia: an old tool with new mechanism of action and prospect in management and prophylaxis.

A disturbed balance between angiogenic and antiangiogenic growth factors is a highly accepted mechanism in the pathogenesis of pregnancy-induced hypertension and proteinuria, which is clinically known as preeclampsia (PE). We investigated the effect of magnesium sulfate (MgSO4) therapy on vascular endothelial growth factor (VEGF), placental growth factor (PlGF), nitric oxide (NO) metabolites, soluble fm-like tyrosine kinase-1 (sFlt-1) and endoglin levels in PE rats and the effect of this treatment on the feto-maternal outcome. The PE group showed hypertension, proteinuria and decreased number and weight of live pups relative to the control group. This result was associated with increased sFlt-1, VEGF receptor-2 (VEGFR-2), VEGFR-3 and endoglin levels but decreased NO metabolites. MgSO4 therapy ameliorated systolic hypertension and proteinuria and decreased sFlt-1, VEGFR-2, VEGFR-3 and endoglin levels but increased NO metabolites in the treated group. Physiological and biochemical changes and improved pup weight and viability were observed in the treated group. The vasodilator action of MgSO4 and increased NO production are expected to increase placental blood flow and help fetal nutrition and development. Relief of placental ischemia decreases the production of antiangiogenic growth factors and restores the bioavailability of angiogenic factors (PlGF and VEGF). These changes resulted in better fetal outcome and an improved clinical picture of PE. These findings are promising and encourage further study of the mechanism of action of MgSO(4) to support its widespread use in the prevention and management of the etiopathological changes underlying the vast majority of the manifestations and complications of PE.

The possible role of estrogen and selective estrogen receptor modulators in a rat model of Parkinson's disease.

AIM: The aim of the present study was to assess and compare the effect of 17ß-estradiol and two different selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, as well as a selective estrogen receptor alpha agonist, propyl-pyrazole-triol (PPT) and a selective estrogen receptor beta agonist, diarylpropionitrile (DPN), on behavioral and biochemical alterations in 6-hydroxydopamine (6-OHDA)-induced nigral dopaminergic cell death in rats. MAIN METHODS: 80 female Wister rats were used. Animals were divided into eight equal groups: Group I; Sham operated, Group II; subjected to ovariectomy (OVX), Group III; OVX rats received striatal injection of 6-OHDA, Groups IV-VIII; OVX rats received striatal injection of 6-OHDA and were injected daily with 17ß-estradiol, tamoxifen, raloxifene, PPT and DPN respectively for 5days before 6-OHDA and continued for further 2weeks. KEY FINDINGS: Results showed that striatal injection of 6-OHDA produced significant behavioral alteration suggestive of PD, together with significant decrease in striatal dopamine, homovanillic acid (HVA) and 3,4-dihydroxyphenyl acetic acid (DOPAC) concentrations. 6-OHDA-induced nigral dopaminergic cell death was characterized by oxidative stress, evidenced by significant decrease in striatal glutathione peroxidase activity, as well as apoptosis, evidenced by significant increase in nigral caspase-3 activity. Treatment with 17ß-estradiol, raloxifene, PPT, but neither tamoxifen nor DPN, resulted in significant amelioration of the behavioral and biochemical alterations induced by 6-OHDA. SIGNIFICANCE: These findings suggest that estrogen and some SERMs having estrogenic agonist activity in the brain, like raloxifene, might exert beneficial effect in PD.

Multiple antioxidants and L-arginine modulate inflammation and dyslipidemia in chronic renal failure rats.

The kidney is an important source of L-arginine, the endogenous precursor of nitric oxide (NO). Surgical problems requiring extensive renal mass reduction (RMR) decrease renal NO production, leading to multiple hemodynamic and homeostatic disorders manifested by hypertension, oxidative stress, and increased inflammatory cytokines. Using the RMR model of chronic renal failure (CRF), we assessed the effects of twelve weeks' administration of L-arginine and/or a mixture of antioxidants (L-carnitine, catechin, vitamins E and C) on plasma cytokines, soluble intercellular adhesion molecule-1 (sICAM-1), nitrate and nitrites (NO(2)/NO(3)), lipid profile, blood pressure, and renal function. CRF rats showed increased plasma IL-1 alpha, IL1-beta, IL-6, TNF-alpha, and sICAM-1 levels and decreased anti-inflammatory cytokines IL-4 and 10 levels, hypertension, and dyslipidemia. L-arginine treatment improved kidney functions, decreased systolic blood pressure, and decreased inflammatory cytokines levels. Antioxidants administration decreased inflammatory cytokines and sICAM-1 levels and increased IL-4 levels. Combined use of both L-arginine and the antioxidant mixture were very effective in their tendency to recover normal values of kidney functions, plasma cytokines, sICAM-1, blood pressure, NO(2)/NO(3), cholesterol, and triglycerides concentrations. Indeed, the effects of L-arginine and the antioxidants on the reduction of proinflammatory cytokines may open new perspectives in the treatment of uremia.

Effect of caffeic acid phenethyl ester on the hemostatic alterations associated with toxic-induced acute liver failure.

Coagulation abnormalities are common findings in acute liver failure (ALF) that underlie its fatal outcome. The present study aimed to investigate the effect of caffeic acid phenethyl ester (CAPE) on the oxidative stress and the disturbed hemostasis in lipopolysaccharide/galactosamine-induced ALF in rats. Fifty male Wistar rats were divided into control, ALF and a CAPE-treated ALF groups. Liver transaminases (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase), total bilirubin, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen level, anti-thrombin III levels, platelet count and antioxidative enzymes; catalase and superoxide dismutase activities in serum and reduced glutathione levels in serum and liver tissue were investigated. The ALF group showed increased serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and total bilirubin. Coagulation tests showed prolonged prothrombin time, activated partial thromboplastin time, thrombin time, decreased platelet count, fibrinogen and anti-thrombin III levels, and decreased activities of the antioxidative enzymes catalase and superoxide dismutase and decreased tissue and serum glutathione levels. Pretreatment with CAPE for 14 days before and a single dose after the exposure to the lipopolysaccharide/D-galactosamine reversed the abnormal liver functions and blood coagulation tests and increased the antioxidative enzymes activities and glutathione levels. CAPE is a promising compound that can support the liver, counteract oxidative stress and disturbed hemostasis in endotoxic-induced ALF.

Oxidative stress and nitric oxide deficiency in inflammation of chronic renal failure. Possible preventive role of L-arginine and multiple antioxidants.

OBJECTIVE: To evaluate the effect of L-arginine and multiple antioxidants on the inflammatory cytokines level, renal functions, blood pressure and dyslipidemia in chronic renal failure (CRF) rats. METHODS: This study was carried out between December 2007 and November 2008 in the Department of Physiology, Faculty of Medicine, King Saud University, Kingdom of Saudi Arabia. Chronic renal failure was induced in 40 rats by renal mass reduction (RMR) and 10 rats were sham operated. Renal mass reduction rats were treated for 12 weeks by L-arginine and/or a mixture of antioxidants (L-carnitine, Catechin, Vitamins E and C) and the effect of the treatments on plasma cytokines, soluble intercellular adhesion molecule-1 (sICAM-1), nitrate (NO2) and nitrites (NO3), lipid profile, blood pressure, and renal function was examined. RESULTS: Chronic renal failure increased plasma Interleukin (IL)-1alpha, IL-1beta, IL-6, tumor necrosis factor-alpha, soluble intercellular adhesion molecule-1 (sICAM-1) levels and decreased anti-inflammatory cytokines IL-4 and 10 levels. In addition, hypertension, and dyslipidemia were found. L-arginine treatment improved kidney functions, decreased systolic blood pressure and decreased inflammatory cytokines levels. Antioxidants administration decreased inflammatory cytokines and sICAM-1 levels and increased IL-4 levels. Combined use of L-arginine and the antioxidants mixture were very effective in their tendency to recover normal values of kidney functions, plasma cytokines, sICAM-1, blood pressure, NO2/NO3, cholesterol and triglycerides concentrations. CONCLUSION: Restoration of the pro-oxidant/ antioxidants balance with increased NO bio-availability counteracts inflammation, renal impairment and dyslipidemia in CRF. This may open new perspectives for the role of antioxidants and NO precursors in the treatment of uremia and its complications.

Catechin combined with vitamins C and E ameliorates insulin resistance (IR) and atherosclerotic changes in aged rats with chronic renal failure (CRF).

Aging is an inevitable biological process associated with increased oxidative stress and accumulation of asymmetric dimethylarginine (ADMA) a known endogenous inhibitor of nitric oxide synthase. Atherosclerosis and IR constitute major risk factors for cardiovascular mortality in elderly with chronic kidney disease (CKD). We investigated the impact of catechin, vitamins E and C supplementation on insulin sensitivity, redox state, ADMA, nitrate and nitrite (NO(2)(-)/NO(3)(-)) levels and histological picture of heart and large blood vessels of aged rats with CRF. Findings of the present study revealed that aging in rats is associated with hyperinsulinemia, hyperlipidemia, IR indicated by higher homeostasis model assessment (HOMA)-index, increased lipid peroxidation product malondialdehyde (MDA), ADMA, and blood pressure (BP), but decreased antioxidant capacity and NO(2)(-)/NO(3)(-) levels. CRF exaggerated all these findings and caused thickened intima of carotid arteries and myocardial hypertrophy. Treatment with catechin, vitamins E and C increases the antioxidant capacity and NO(2)(-)/NO(3)(-) production but, decreases MDA, ADMA and BP levels. Also it keeps insulin sensitivity and normal intima/media thickness of carotid arteries. We conclude that decreased nitric oxide (NO) availability due to ADMA accumulation may be responsible for IR and associated atherosclerotic changes in aged rats with CRF. Catechin, vitamins E and C supplementation may moderate oxidative stress of renal failure, prevent ADMA accumulation, and counteract IR and atherosclerotic changes in the elderly.

The potential anti-inflammatory effect of tetrahydrobiopterin administration in renal mass reduction-induced chronic renal failure in rats.

OBJECTIVE: To investigate the impact of tetrahydrobiopterin (BH4) supplementation on the markers of inflammation, and on the histological picture of the kidney in chronic renal failure C-reactive protein (CRF) induced in rats by subtotal nephrectomy (SNx). METHODS: This study was performed at the Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia during the period from December 2005 to January 2007. Chronic renal failure was induced by 5/6 SNx in 20 male Wister rats, and another 10 rats were sham operated by flank incision and served as controls. Ten SNx rats received 10mg kg-1 BH4 intraperitoneally daily for 4 weeks. Plasma C-reactive protein (CRP), interlukin-6 (IL-6), malondialdehyde (MDA), and kidney functions were measured in all rats. Histopathological examination of the kidney tissues was also performed. RESULTS: Untreated CRF rats showed significant elevation of plasma CRP, IL-6, and MDA levels, and significant decrease in plasma albumin and total protein levels, tubuloglomerular fibrosis and, interstitial tubular infiltration with inflammatory cells in comparison with the sham-operated rats. Tetrahydrobiopterin treatment decreased CRP, IL-6, and MDA levels, and decreased tubuloglomerular fibrosis and interstitial inflammation in treated CRF rats. CONCLUSION: Supplementation with exogenous BH4 decreased markers of inflammation and protected the kidney against post-renal mass reduction histologic damage. Restoration of intracellular BH4 balance could normalize nitrous oxide production. Therefore, BH4 might be a promising strategy in attenuating inflammation in CRF. This may decrease endothelial dysfunction and limit the associated cardiovascular morbidity and mortality of this disease.

The effect of vitamin E, L-arginine, N-nitro L-arginine methyl ester and forskolin on endocrine and metabolic changes of rats exposed to acute cold stress.

OBJECTIVE: It is a well documented fact that under stress conditions the hypothalamic-pituitary-adrenal axis (HPA) and the sympathetic nervous system (SNS) are stimulated. This results in a series of neural and endocrine adaptations known as the stress response. The current study assessed the effects of acute cold stress on adrenomedullin (ADM) levels in plasma and peripheral tissues (kidneys and heart) of rats, as well as on blood glucose, cholesterol, triglycerides (TG), total proteins both before and after intraperitoneal administration of each of the following: vitamin-E, L-arginine, forskolin and L-NAME. METHODS: The current study was conducted in the Department of Physiology, Faculty of Medicine, King Saud University, Saudi Arabia, between September 2003 and March 2004. We observed 6 groups of Wistar rats for their plasma ADM, tissue plasminogen activator (t-PA), total protein, glucose and cholesterol levels. Following exposure to cold stress (-10 degree C for 3 hours). RESULTS: Acute cold stress produced a significant increase in ADM levels in plasma, heart and kidney tissues of rats. Furthermore, acute cold stress produced a reduction in cholesterol and plasma protein levels. On the other hand, acute cold stress caused an increase in TG, glucose plasma levels and tissue plasminogen activator (t-PA). We found hormonal and metabolic changes caused by cold exposure to be decreased or even prevented after vitamin E treatment or after changing nitric oxide (NO) level by L-arginine or L-NAME treatment. CONCLUSION: The results suggest a regulatory or protective role for ADM in counteracting HPA activation following a variety of physiological and psychological stressors. Oxidative stress or changes in intracellular signals as NO, cyclic-AMP may play a role in explaining some of the metabolic and hormonal changes occurring during acute cold stress.