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Background: Hepatic ischemia/reperfusion (I/R) is a frequent and major complication during liver transplantation. Baicalein, a plant flavonoid, has anti-inflammatory and antioxidant effects. However, whether these effects mediate its protective effects in liver I/R injury remains poorly understood. Objective: This study was designed to investigate the effects of baicalein preconditioning on liver I/R in rats and the underlying mechanisms. Methods: Baicalein (300 mg/kg) was intraperitoneally injected 30 min before 45 min of ischemia followed by 1 h of reperfusion. Results: Baicalein preconditioning attenuated liver I/R injury, as indicated by a reduction in serum aminotransferase activities and an improvement of histopathological abnormalities. Baicalein also significantly reduced the activity of the cellular hepatic proapoptotic enzyme caspase-3 in response to I/R injury. Moreover, baicalein significantly reduced nuclear factor kappa-B expression and the subsequent proinflammatory cytokine production, tumor necrosis factor alpha (TNF-α) level, increased interleukin-10 (IL-10), an anti-inflammatory cytokine, reduced the TNF-α/IL-10 ratio, and suppressed leukocyte infiltration. It increased hepatic antioxidants and reduced lipid peroxidation. Conclusion: Taken together, bai­calein preconditioning would seem to protect against liver I/R injury via antioxidant, antiapoptotic, and anti-inflam­matory effects.

Aluminum is well recognized as a nephrotoxic agent. Its hazardous effects arise from the high risk of daily exposure. The consumption of fructose also represents a critical health issue that might negatively impact different organs, including the kidneys. To pursue our previous work, this study aimed to investigate the potential renoprotective effects of glycyrrhizic acid (GLYA) on aluminum-induced nephrotoxicity in insulin-resistant rats. Insulin resistance (IR) was induced by adding fructose (10%) in drinking water for 18 weeks. Male Wistar rats were divided into five groups: control (CTRL), aluminum chloride (ALM, 34 mg/kg/day), fructose (FRCT), aluminum plus fructose (AL/FR), and GLYA (rats received AL/FR and treated with 40 mg/kg GLYA daily). AL/FR resulted in abnormal renal function tests and renal tissue injury. This was associated with increased oxidative stress and inflammation in the renal tissue. Moreover, the expressions of the toll-like receptor 4 (TLR4) and its adaptor proteins were increased in AL/FR group. The administration of GLYA mollified AL/FR-induced renal injury, oxidative stress, activation of the TLR4 signaling pathway, and inflammation. In conclusion, we provide evidence for the promising renoprotective effect of GLYA against AL/FR-induced kidney damage in rats. The renoprotection is attributed to the suppression of oxidative stress and inhibition of the TLR4/NF-κB signaling pathway in the kidneys.

Aims Diabetic nephropathy is a major cause of chronic kidney disease and end-stage renal failure worldwide. Dapagliflozin Sodium-glucose co-transporter 2 (SGLT2) inhibitor is a new class of diabetic medications prescribed for the treatment of type 2 diabetes. The current study investigates the possible impact of dapagliflozin (DAPA) on inflammations, apoptosis, angiogenesis and fibrosis in early-stage diabetic nephropathy using a rat model of type 2 diabetes. Main methods Rats were divided into five groups, group1: normal vehicle group, group 2: diabetic group, group 3: diabetic+ DAPA (0.75 mg/kg), group 4: diabetic+DAPA (1.5 mg/kg), group 5: diabetic+DAPA (3 mg/kg). At the end of the study, Blood glucose level was measured. Serum insulin, BUN, and SCr were measured. Insulin resistance was determined using the homeostasis model assessment for insulin resistance (HOMA-IR) index. Renal tissue homogenization was done for assessment of inflammatory markers TNF-α, PEDF, and PTX-3, In addition to apoptosis markers BCL-2 and BAX. Histopathological examinations were done for tubular renal cells and immunohistochemical examination for fibrosis marker α-SMA and angiogenic factor VEGF. Key findings Treatments with dapagliflozin showed improvements in histopathological examinations, inflammatory and apoptotic markers compared to diabetic vehicles in a dose-dependent manner. Significance Thus, dapagliflozin may have renoprotective effects, which be promising in diabetic patients suffered from nephropathy.

Cancer is a broad term used to describe a large number of diseases characterized by uncontrolled cell proliferation that leads to tumor production. Cancer is associated with mutations in genes controlling proliferation and apoptosis, oxidative stress, fatty acid synthase (FAS) expression, and other mechanisms. Currently, most antineoplastic drugs have severe adverse effects and new effective and safe drugs are needed. This study aims to investigate the possible anticancer activity of rutin and orlistat which are both safely used clinically in humans against two breast cancer models (in vivo EAC and in vitro MCF7) and the pancreatic cancer cell line (PANC-1). Our results have shown that both rutin and orlistat exerted an in vivo anticancer activity as evidenced by the decrease in tumor volume, CEA level, cholesterol content, FAS, and the exerted antioxidant action (reduced MDA level and increased GSH content) and through histopathological examination. In addition, both were cytotoxic to MCF-7 and Panc-1 cell lines by promoting apoptosis. In conclusion, the anticancer activity of rutin and orlistat makes them promising candidates for cancer treatment alone or in combination with other anticancer drugs specially that they are used clinically with an acceptable safety profile.

Stroke is the second leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. Advanced glycation endproducts (AGEs) are known to be increased in several chronic diseases and induce inflammation and protein intercalation. The only drug approved for the treatment ischemic stroke is recombinant tissue plasminogen activator (r-TPA). The current study was designed to investigate the protective effect of benfotiamine (70 mg/kg/day), perindopril (2 mg/kg/day) and alagebrium (2 mg/kg/day) on experimentally-induced ischemic brain damage. All drugs were administered daily for one week before and 2 days after middle cerebral artery occlusion (MCAO). Benfotiamine, perindopril and alagebrium ameliorated the deleterious effects of MCAO as indicated by the improvement in the performance of the animals in initiation of walking test and improvement of the deteriorated brain histology. This was associated with normalization of the level of AGEs that was increased following MCAO. The result of the current study represent a new indication for benfotiamine, perindopril, alagebrium in the management of ischemic stroke.

Aluminium is a ubiquitous element that occurs naturally in the soil making human exposure to it unavoidable. It is implicated in the aetiology of different neurodegenerative diseases and can induce liver injury. In addition, insulin resistance (IR) plays an essential role in the pathogenesis and the progression of liver disorders. The increased consumption of fructose contained in soft drinks and western pattern diet results in IR that along with the wide distribution of aluminium make the concurrent exposure conceivable and increase the risk of liver injury. Therefore, the present study explores the hepatotoxic effects of aluminium and fructose administered concurrently and evaluates the possible protection by monoammonium glycyrrhizinate (MAG). Liver injury was induced by the administration of aluminium chloride (34 mg/kg/d) plus 10% (w/v) fructose in drinking water. Male rats were treated with either MAG (40 mg/kg/d) or silymarin (SIL, 100 mg/kg/d). The concurrent administration of aluminium and fructose (FRUAL) induced liver injury manifested as a significant elevation of serum liver enzymes activities, bilirubin level, and prothrombin time, as well as reduction of albumin level. On the other hand, the administration of MAG improved the FRUAL-induced aberrations of liver function tests and hepatic cytoarchitecture. We assume that the MAG-induced suppression of oxidative stress, toll-like receptor 4 pathway activation, inflammation, and apoptosis might play a crucial role in the hepatoprotective effect of MAG in this model. Intriguingly, the hepatoprotective effect MAG against FRUAL-induced liver injury surpasses that of the gold standard SIL, suggesting MAG as a better alternative to SIL.

Insulin resistance and chronic alcoholism are risk factors for renal dysfunction. This study investigated the therapeutic effects of two imidazoline-1 receptor (I1R) agonists on renal dysfunction in rats after chronic, sequential fructose and ethanol administration. Daily drinking water was supplemented with fructose (10%, w/v) for 12 weeks and then with ethanol (20%, v/v) for another 8 weeks. Rats were treated with rilmenidine and clonidine in the last two weeks of the study. Blood glucose and serum insulin (sIns) levels, lipid profiles, kidney function and renal histopathology were evaluated at the end of the experiment. Additionally, renal gene expression of nischarin, phosphatidylcholine-specific phospholipase C (PC-PLC) and prostaglandin E2 (PGE2) were measured. Renal levels of superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and total NO (tNO) were detected, and we determined the relative renal gene expression levels of alpha smooth muscle actin (α-SMA), hydroxyproline, interleukin 10 (IL-10), tumour necrosis factor alpha (TNF-α) and caspase-3. The results showed significant deterioration of blood glucose, sIns, lipid profiles, kidney function and renal histopathology in fructose/ethanol-fed rats. Additionally, markers of inflammation, fibrosis, apoptosis and oxidative stress were upregulated. The administration of rilmenidine or clonidine significantly improved blood glucose and sIns levels and reduced renal dysfunction. Our work showed that chronic, sequential fructose and ethanol administration induced fasting hyperglycaemia and renal impairment, and these effects were ameliorated by I1R agonists.

Background: Methotrexate (MTX) as an antineoplastic agent inhibits dihydrofolate reductase. The frequency of high dose methotrexate (HDMTX) associated toxicity is variable. In this study we investigate the frequency of myelosuppression following 5 and 9 days of HDMTX infusion and MTX delayed elimination in subsequent MTX cycles in children with Acute lymphoblastic Leukemia (ALL). Methods: This study included 28 children diagnosed with ALLduring the period between May2014to April 2016. Complete blood counts were measured before and after 5 and 9 days of HDMTX infusion and MTX levels at 42hour in 28 children with ALL. The HD-MTX dose is 5 gm/m2 during 102 infusion of HD MTX at consolidation phase of ALL therapy. The MTX levels at 42 h in patients with and without toxicity were compared to evaluate the correlation between MTX levels and myelotoxicity. Results: MTX infusion induced significant reduction in levels of TLC, ANC, RBCs, Hb and significant elevation of PLT count after 5 days of MTX administration. Additionally, after 9 days of MTX infusion, there is significant decrease inTLC, ANC, and RBCs levels. However, no significant difference in the PLT count and Hb level occurred. There is gradual decrease in myelotoxicity after 5 days and increase after 9 days of MTX administration with regard to MTX cycles. There is no statistical difference in MTX level at 42 h between patients with and without myelotoxicity after 5 and 9 days of MTX infusion. MTX delayed elimination observed in MTX cycles 1, 2, 3 and 4 was 42.8% (n=12), 42.8% (n=12), 57.1% (n=16) and 72% (n=13) respectively. Conclusion: Myelotoxicity was decreased after 5 days of MTX administration and increased after 9 days with regard to MTX cycles. There is no correlation between MTX plasma concentration after 42 h and hematologic toxicity. Therefore, we cannot depend on MTX levels at 42 h to anticipate and predict hematologic toxicity. Keywords: HDMTX, ALL, myelosupression, blood count

Aluminum is implicated in the etiology of different neurodegenerative diseases, diabetes and cancer. The current study was conducted to evaluate the protective effects of glycyrrhizic acid (GAM) and silymarin (SLY) on AlCl

Background and purpose: Insulin resistance (IR) and obesity predispose diseases such as diabetes, cardiovascular and neurodegenerative disorders. Beta-caryophyllene (BCP), a natural sesquiterpene, exerts neuroprotective, anxiolytic and antidepressant effects via its selective agonism to cannabinoid receptor 2 (CB2R). BCP was shown to have an anti-diabetic effect, however, the implication of CB2R is yet to be elucidated. A link between CB2R agonism and PPAR-γ activation has been discussed, but the exact mechanism is not well-defined. This study was designed to examine the role of BCP in improving diet-induced metabolic (insulin resistance), neurobehavioral (anxiety, depression and memory deficit), and neurochemical (oxidative, inflammatory and neurotrophic factor) alterations in the prefrontal cortex of obese rats’ brain. The involvement of CB2R and/or PPAR-γ dependent activity was also investigated. Experimental approach: Male Wistar rats were fed a high fat/fructose diet (HFFD) for 12 weeks to induce IR and obesity. Rats were treated with BCP for the last 4 weeks. Either CB2R antagonist AM630 or PPAR-γ antagonist BADGE was administered before BCP treatment to study the mechanism of BCP actions. Key results: Beta-caryophyllene alleviated HFFD-induced IR, oxidative-stress, neuroinflammation and behavioral changes. The anxiolytic, anti-oxidant and anti-inflammatory effects of BCP were mediated by both PPAR-γ and CB2R. The effects of BCP on glycemic parameters seem to be CB2R-dependent with the non-significant role of PPAR-γ. Furthermore, BCP-evoked antidepressant and memory improvement are likely mediated only via CB2R, mainly by upregulation of PGC-1α and BDNF. Conclusion: This study suggests the potential effect of BCP in treating HFFD-induced metabolic and neurobehavioral alterations. BCP seems to activate PPAR-γ in a ligand-independent manner, via upregulation and activation of PGC-1α. The BCP activation of PPAR--γ seems to be CB2R-dependent.

Beta-caryophyllene (BCP) is a phytocannabinoid possessing selective agonistic activity to cannabinoid type-2 receptors (CB2R) and peroxisome proliferator-activated receptors-α (PPAR-α). However, few studies reported the contribution of PPAR-γ receptors in BCP effects. The aim of this study was to investigate the BCP effects on diet-induced dyslipidemia and vascular inflammation as well as the involvement of CB2R and PPAR-γ receptors. Wistar rats were fed a high-fat diet and administered 10% fructose for 12 weeks. Treatment with pioglitazone, BCP, BCP + CB2R antagonist, AM630, or BCP + PPAR-γ antagonist, BADGE was started from the 9th week and continued till the 12th week. BCP significantly ameliorated all diet-induced alterations in a CB2R-dependant manner as it improved glycemic parameters, dyslipidemia, and vascular oxidative stress and inflammation. It also downregulated proatherogenic adhesion molecule (VCAM-1) and restored vascular eNOS/iNOS expression balance. PPAR-γ was involved in BCP-evoked suppression of vascular inflammation, VCAM-1 and restoration of normal vascular eNOS/iNOS balance thus normal NO level. Furthermore, part of BCP hypolipidemic effects (lowering total cholesterol, LDL, VLDL) involved both CB2R and PPAR-γ receptors. BCP treatment was superior to pioglitazone in anti-inflammatory and anti-atherosclerotic measures. BCP may represent a more potent alternate to pioglitazone avoiding its side effects in the treatment of insulin resistance and vascular inflammation.

Chronic alcoholism is a risk factor for kidney injury. Clonidine is an α2-adrenergic receptor/imidazoline-1 receptor agonist that can reduce blood pressure and maintain renal functions. This study aims to investigate the possible ameliorative effects of clonidine on ethanol induced kidney injury and its mechanism of action. Kidney injury was induced in rats by adding ethanol to drinking water for eight weeks. Clonidine effects on kidney functions and histopathology were measured. Moreover, phentolamine (α-adrenergic receptor antagonist), efaroxan (imidazoline-1 receptor antagonist) and rilmenidine (imidazoline-1 receptor agonist) were used to clarify the role of imidazoline-1 receptor in mediating renal ameliorative effects. Also, the effect of clonidine on liver functions and metabolic changes, in addition to renal oxidative stress, inflammatory and apoptotic pathways were measured. Results showed that, clonidine improved renal functions and reduced ethanol induced renal inflammation and fibrosis. On the other hand, efaroxan, only, blocked clonidine effects on kidney functions. Rilmenidine decreased kidney injury like clonidine. Both clonidine and rilmenidine increased renal nischarin gene expression. Furthermore, clonidine improved liver functions, increased serum insulin and decreased serum advanced glycation end products (metabolic markers). Also, clonidine reduced renal oxidative stress as reflected by decreased myeloperoxidase, malondialdehyde, inducible nitric oxide synthase and total nitric oxide levels and increased superoxide dismutase level. Moreover, clonidine reduced renal tumor necrosis factor-α (inflammatory marker) and caspase-3 (apoptotic marker) levels, while increased renal prostaglandine E2 and interleukin-10 levels (anti-inflammatory markers). In conclusion, clonidine can reduce ethanol induced kidney injury, at least in part, by stimulating imidazoline-1 receptor signaling.

Ischemia reperfusion (IR) injury occurs in many clinical situations such as organ transplantation and hepatectomies resulting in oxidative stress and immune activation. Heme oxygenase-1(HO-1) is the rate-limiting step in the heme-degradation pathway and has a critical cytoprotective role. Induction of HO-1 improves liver I/R injury. Quercetin, a plant pigment (flavonoid), is an antioxidant and HO-1 inducer. Tin protoporphyrin (SnPP) is a HO-1 inhibitor. This study was designed to investigate the protective effect of quercetin in hepatic I/R injury and the role of HO-1. Wister rats were randomly divided into four groups (sham, I/R, quercetin, and SnPP). Liver ischemia was induced for 45 min then reperfusion was allowed for 1 h. Quercetin and surprisingly SnPP ameliorate the deleterious effect of I/R by reducing the oxidative stress and hepatocyte degeneration. Both agents decreased the elevated inflammatory cytokines and improved the inhibition of the antiapoptotic marker, Bcl2. They induced HO-1 content and expression. Quercetin has better cytoprotective effect than SnPP. These findings suggest that quercetin has a hepatoprotective effect against I/R injury via HO-1 induction and unexpectedly, SnPP showed the similar effect. Quercetin has more prominent protective effect than SnPP because of its superior ability to induce HO-1.

Anxiety disorders are among the most prevalent mental disorders in the general population. Nearly 30 million persons are affected in the United States, with women affected nearly twice as frequently as men. These disorders are frequently treated using benzodiazepines (Diazepam) and non-benzodiazepines (Zaleplon). Non-benzodiazepines have replaced the benzodiazepines for anxiety treatment due to low risk of dependence and CNS effects encouraging drug abuse. This work was designed to investigate the toxicological overdose effect of zaleplon and diazepam on behavior, blood pressure, heart rate, brain neurotransmitter content and liver & kidney functions in rats. Rats were divided into five groups: 1% Tween 80, p.o. (control), diazepam (1 & 4 mg/kg, p.o.) and zaleplon (1 & 4 mg/kg, p.o.). All groups were injected daily for four weeks to perform the following: behavioral study (assessment of motor co-ordination and anxiety performance), measurement of blood pressure & heart rate, determination of the free amino acid and monoamine contents in the whole brain, determination of serum aminotransferases activity, total protein, total and direct billirubin, creatinine & blood urea nitrogen of experimental rats. Zaleplon decreased motor co-ordination, blood pressure and heart rate with extent lesser than diazepam. However, it decreased anxiety performance and brain monoamine content with extent more than diazepam. While, diazepam increased brain amino acid content, serum aminotransferases activity, total protein, total & direct billirubin, creatinine and blood urea nitrogen by magnitude more than zaleplon.

Cancer refers to a disorder of cell proliferation that leads to tumor production. Cancer is usually treated by surgery, chemotherapeutic drugs, and radiation. Despite the presence of many anticancer drugs, cancer is still an uncontrolled disease and is a major cause of death worldwide. In addition, most anticancer drugs have severe side effects that can limit their use in some patients. This study aims to investigate the possible anticancer activity of two clinically used drugs: a natural antioxidant agent (salicin) and an antihyperlipidemic agent (fenofibrate) against two breast cancer models (in vivo EAC and in vitro MCF7) and the pancreatic cancer cell line (Panc-1).Our results have shown that both salicin and fenofibrate exerted an in vivo anticancer activity as evidenced by the decrease in tumor weight, tumor volume, CEA level, and reduced tumor cholesterol content through an antioxidant (reduced MDA level and increased GSH and catalase content) and an antiinflammatory activity (reduced TNF-∝ level). In addition, both salicin and fenofibrate were shown to be cytotoxic to MCF-7 and Panc-1 cell lines through activation of the caspase 3/7 apoptotic pathway.In conclusion, salicin and fenofibrate are promising anticancer drugs that are already used clinically with acceptable safety profile which can be incorporated into clinical trials to determine their possible application in cancer treatment.

Objectives: Tramadol is a centrally acting synthetic analgesic. It has a cardioprotective effect against myocardial ischemia-reperfusion (I/R) injury in isolated rat heart. We hypothesized that tramadol may exert a similar protective effect on hepatic I/R injury. Hence, the current investigation was designed to study the possible protective effects of tramadol on experimentally-induced hepatic I/R injury in rats. Materials and Methods: Tramadol was administered 30 min before ischemia following which the rats were subjected to 45 min of ischemia followed by 1 h of reperfusion. Results: Tramadol attenuated hepatic injury induced by I/R as evidenced by the reduction of transaminases, structural changes, and apoptotic cell death. It decreased the level of inflammatory markers such as tumor necrosis factor-alpha (TNF-α), TNF-α/interleukin-10 (IL-10) ratio, and nuclear factor-κB gene expression. It also increased the anti-inflammatory cytokine, IL-10 levels in hepatic tissues. Furthermore, it reduced oxidative stress parameters except manganese superoxide dismutase activity. Conclusion: The results suggest that tramadol has hepatoprotective effects against hepatic I/R injury via anti-inflammatory, antiapoptotic, and antioxidant effects.

Background and purpose: Disturbances in pulmonary vascular reactivity are important components of inflammatory lung disease. Haem oxygenase-1 (HO-1) is an important homeostatic enzyme upregulated in inflammation. Here we have investigated the potentially protective effect of HO-1 against cytokine-induced impairment in pulmonary artery relaxation. Experimental approach: Haem oxygenase-1 protein levels were assessed by immunofluorescence. HO activity was assessed by conversion of haemin to bilirubin. Rings of rat isolated pulmonary artery in organ baths were used to measure relaxant responses to the endothelium-dependent agent ACh and the endothelium-independent agent sodium nitroprusside (SNP). Production of nitric oxide (NO) and reactive oxygen species (ROS) was assessed by confocal fluorescence microscopy and fluorescent probes. Key results: Haem oxygenase-1 protein expression was strongly induced in pulmonary artery after 24-h incubation with either haemin (5 µM) or curcumin (2 µM), accompanied by a significant increase in HO activity. Incubation with tumour necrosis factor α (TNFα, 1 ng·mL−1, 2 h) significantly decreased relaxation of arterial rings to ACh, without affecting responses to SNP. Induction of HO-1 by curcumin or haemin protected against TNFα-induced hyporesponsiveness to ACh. The competitive HO inhibitor, tin protoporphyrin (20 µM), abolished the protective effect of haemin. HO-1 induction prevented a TNFα-induced increase in NO generation without affecting the TNFα-induced increase in ROS generation. HO-1 induction prevented the TNFα-induced decrease in ACh-stimulated NO generation. Conclusions and implications: Induction of HO-1 protected against TNFα impairment of endothelium-dependent relaxation in pulmonary artery, by a mechanism involving a reduction in inducible NO synthase-derived NO production.

Limonin has been shown to exhibit anti-inflammatory and antioxidant properties in the settings of chemically induced hepatic injury. The current study aimed to investigate the protective effects of limonin on experimentally-induced hepatic ischemia reperfusion (I/R) injury in rats. Rats were injected IP with either DMSO or limonin (100 mg/kg BW), 30 min before submission to 45 min of ischemia, followed by 1 h of reperfusion. Limonin ameliorated the deleterious effects of I/R as indicated by improvement in liver function tests, reduction of lactate dehydrogenase, reduction of oxidative stress, decrease in hepatocyte degeneration, and pyknosis. Furthermore, pretreatment of I/R rats with limonin, induced a significant down regulation in the various elements of the toll like receptor (TLR)pathway including TLR-2 and TLR-4, myeloid differentiation factor 88 (MYD88) and toll/IR-1(TIR)-domain-containing adaptor protein inducing interferon-beta (TRIF) and the downstream effectors TNF-α, TNF-α/IL-10 ratio and nuclear factor-κB (NF-κB). It also increased the anti-inflammatory cytokine IL-10 and decreased the activity of the apoptotic marker, caspase-3. These data indicate that limonin exerts antioxidant and anti-inflammatory effects in ischemic liver, thus, protecting hepatocytes against I/R injury in rats. The mechanism of these hepatoprotective effects appears to be related to the antioxidant and anti-inflammatory potential of limonin mediated by the down regulation of TLR- signaling pathway.

A perfusion system was conducted for more than 6 hours in response to glucose (16.7mM), theophylline (5 mM ) and tolbutamide (100 µg/ml) to give an insight about the B-cell secretory capacity. Continuous exposure of the isolated pancreas to glucose (16.7 mM ) caused a biphasic response. After 3 h of continuous glucose perfusion a significant sustained reduction in the insulin secretion rates to about 22% of the maximal response untill 6 h was observed .Then, after 15 min with 3 mM glucose perfusion, re-infusion of glucose 16.7 mM produced an increase in insulin secretion .Theophylline infusion for 6 h did not significanly affect the insulin secretion induced by re-infusion of theophylline after 15 min with low glucose ( 3 mM) concentration. The results also indicated that even after exposure of the pancreas to glucose 16.7 mM for 6 h, theophylline was able to restore the stimulatory effect after desensitization. Continuous exposure of the pancreas for long time (6 h) to tolbutamide significanly inhibit its ability to secrete insulin after 15 min of basal perfusion medium which demonstrated a desensitization phenomenon. The results revealed that, B-cells become desensitized, not exhausted, not only by glucose but also with tolbutamide. It seems also that CAMP system cann't be neglected in this model since, theophylline induced insulin secretion alone and even after long infusion with high glucose. The desensitization of the B-cell to tolbutamide may be due to sustained depolarization caused by continuous exposure to tolbutamide . The present study confirms that the elevation of plasma glucose concentration represents a pathogenic factor which causes a deleterious effect on islet B-cell function. This effect is reversed on cessation of glucose.

The effects of clofibrate (120 mg/kg) on the blood levels of glucose, lactate, pyruvate, free fatty acids (FFA) , triglycerides (TG), cortisol, triiodothyronine (T3), tetraiodothyronine (T4) , calcium and potassium of adult male diabetic rats were studied for four weeks . Moreover, the effects of four weeks treatment with clofibrate on the oral glucose tolerance were investigated. Results showed that administration of clofibrate significantly decreased the blood glucose levels to 190 , 165 and 160 mg/dl after the1st ,2nd ,3rd and 4th week of treatment vs 230 mg/dl of control. Moreover, clofibrate improved the glucose tolerance in STZ - diabetic rats after four weeks of treatment in comparison with the control diabetic rats. There is a reduction in the area under the glucose curve recording 59550± 3440 vs 79200 ± 5060 mg, min/ dl of control value. Clofibrate decreased the blood levels of FFA , TG, T4, whereas, it increased that of cortisol. The plasma levels of both lactate and pyruvate were reduced all over the time course of treatment. Potassium biood levels were significantly increased to 26.9, 25.8, 27.6 and 28.4 mg/dL after the 1st, 2nd, 3rd and 4th week of treatment respectiviely. In conclusion, the capability of the antihyperlipidemic agent, clofibrate, to reduce the blood glucose levels and to improve glucose tolerance in STZ- diabetic rats may be in part due to its ability to reduce the blood levels of FFA,TG, lactate and pyruvate and in part to the increasing of potassium plasma levels. All these changes could play a major role in reduction of the rate of gluconeogenesis and consequently reducing the hepatic glucose production (HGP) that may participate in the above actions of clofibrate on blood glucose.

The effects of a single dose of nifedipine (5 mg/Kg, 1.P.) alone, Cimetidine (25 mg/Kg, I.P. for 7 days) alone or their combination on the arterial blood presure, heart rate, the calculated double product, and electrocardiogram (ECG) in anaesthetized normotensive rats have been studied. Results of the present investigation showed that nifedipine, cimetidine or their combination didn't affect the heart rate. The administration of nifedipine alone produced a significant reduction in arterial blood pressure after 15 min., This effect lasted for 90 min after administration (recording 30% of the initial value). On the other hand, the administration of nifedipine to rats pretreated with cimetidine produced more significant and prolonged reduction in arterial blood pressure, this effect remained to the end of experiment (180 min.). moreover, nifedipine alone produced significant prolongation of PR-and QT intervals. While nifedipine administartion to the rats pretreated with cimetidine produced a significant and continuous prolongation of the PR-interval as well as QT interval and also produced an increase in T-wave amplitude and duration. Cimetidine did not alter any of ECG parameters. The results of the present study showed that cimetidine potentiates the action of nifedipine on blood pressure and support and extend the previous reports in several models that, cimetidine increases the plasma concentration and consequently the bioavailability of nifedipine due to its characteristic ability to inhibit the liver microsomal enzyme cytochrome P-450.

In the present investigation, the effects of different concentrations of digoxin (5x10-8 -5 x 10-6 M) on the number of premature ventricular contractions (PVCS), incidence, onset and duration of ventricular tachycardia (VT) and fibrillation (VF) have been studied on the isolated rat heart. Digoxin (5 x 10-8 - 5 x 10-6 M) had no effect on the number of premature ventricular contractions, the incidence and the duration of ventricular tachycardia. Digoxin at the high concentration (5 x 10-6 M) has significantly reduced the onset of reperfusion induced ventricular tachycardia. It also increased the incidence and duration of reperfusion induced ventricular fibrillation. The present investigation suggests that administration of high doses of digoxin may modulate the severity of arrhythmias resulting from reperfusion of ischaemic myocardium. This effect may be mediated through the effect of digoxin on the distribution of potassium and calcium ions.

Disturbances in pulmonary vascular reactivity are important components of inflammatory lung disease. Haem oxygenase-1 (HO-1) is an important homeostatic enzyme upregulated in inflammation. Here we have investigated the potentially protective effect of HO-1 against cytokine-induced impairment in pulmonary artery relaxation.Haem oxygenase-1 protein levels were assessed by immunofluorescence. HO activity was assessed by conversion of haemin to bilirubin. Rings of rat isolated pulmonary artery in organ baths were used to measure relaxant responses to the endothelium-dependent agent ACh and the endothelium-independent agent sodium nitroprusside (SNP). Production of nitric oxide (NO) and reactive oxygen species (ROS) was assessed by confocal fluorescence microscopy and fluorescent probes.Haem oxygenase-1 protein expression was strongly induced in pulmonary artery after 24-h incubation with either haemin (5 microM) or curcumin (2 microM), accompanied by a significant increase in HO activity. Incubation with tumour necrosis factor alpha (TNFalpha, 1 ng.mL(-1), 2 h) significantly decreased relaxation of arterial rings to ACh, without affecting responses to SNP. Induction of HO-1 by curcumin or haemin protected against TNFalpha-induced hyporesponsiveness to ACh. The competitive HO inhibitor, tin protoporphyrin (20 microM), abolished the protective effect of haemin. HO-1 induction prevented a TNFalpha-induced increase in NO generation without affecting the TNFalpha-induced increase in ROS generation. HO-1 induction prevented the TNFalpha-induced decrease in ACh-stimulated NO generation.Induction of HO-1 protected against TNFalpha impairment of endothelium-dependent relaxation in pulmonary artery, by a mechanism involving a reduction in inducible NO synthase-derived NO production.