Potential cardioprotective and anticancer effects of carvedilol either free or as loaded nanoparticles with or without doxorubicin in solid Ehrlich carcinoma-bearing mice.

AIM: The aim of this study was to investigate the potential cardioprotective and anti-cancer effects of carvedilol (CAR) either free or as loaded nano-formulated with or without doxorubicin (DOX) in solid Ehrlich carcinoma (SEC)-bearing mice. It focused on assessment of cardiac damage, drug resistance, apoptosis, oxidative stress status, angiogenesis and proliferation. METHODS: CAR was loaded into poly-D,L lactic-co-glycolic acid)PLGA(or Niosomes. SEC was induced in female albino mice as an experimental model of breast cancer. Seventy-two mice were randomly divided into 9 equal groups (Normal control, Untreated-SEC, SEC + DOX, SEC + CAR-free, SEC + CAR-PLGA, SEC + CAR-Niosomes, SEC + DOX + CAR-free, SEC + DOX + CAR-PLGA and SEC + DOX + CAR-Niosomes). Tumor volume and survival rate were recorded. On day 28 from tumor inoculation, mice were sacrificed, and blood samples were collected for determination of serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB). One part from tumor tissues was prepared for assessment of multidrug resistance protein-1 (MDR-1), caspase-3, reduced glutathione (GSH) and malondialdehyde (MDA), while the other part was processed for histopathological examination and immunohistochemical expression of vascular endothelial growth factor (VEGF) and Ki-67. RESULTS: There was non-significant difference between CAR-free, CAR-PLGA and CAR-Niosomes as anticancer either alone or when combined with DOX. However, CAR-free demonstrated potential cardioprotective effects against cardiac damage mediated by cancer or DOX that have been enhanced using CAR-PLGA or CAR-Niosomes, but that of Niosomes outperformed them both. CONCLUSION: CAR could be used as an adjuvant therapy with DOX, especially when nanoformualted with PLGA and even better with Niosomes, without compromising its cytotoxicity against cancer cells and preventing its cardiotoxic impacts.

Thymidine phosphorylase as a molecular target for quercetin-incorporated collagen matrix in the prevention of hand-foot syndrome induced by capecitabine in rats.

Hand-foot syndrome (HFS) is a common adverse effect of capecitabine affecting the quality of life of cancer patients. To enhance the tolerability of capecitabine, this work evaluated the incorporation of quercetin into topical collagen matrix formula to target thymidine phosphorylase enzyme, oxidative stress, and apoptosis underlying HFS. Forty Sprague Dawley rats were allocated to four equal groups. The control group received distilled water orally. HFS was induced by oral capecitabine (200 mg/kg/day) for 21 days. The untreated HFS group received no treatment. In the treated groups, topical collagen and quercetin-incorporated collagen matrix formula were administered concomitantly with the HFS induction protocol. Treatment with quercetin-incorporated collagen matrix showed a significant decrease in thymidine phosphorylase level compared with the untreated and collagen-treated groups. Treatment with quercetin-incorporated collagen matrix showed a significant decrease in malondialdehyde and caspase-3 levels, and a significant increase in the total antioxidant capacity of the skin and B cell lymphoma/leukemia 2 levels compared with the untreated group. Additionally, a significant improvement in the gross picture and histopathological score of HFS was observed. In conclusion, the quercetin-incorporated collagen matrix is a promising formula for the prevention of HFS, due to the targeted effect on thymidine phosphorylase and subsequent antioxidant and antiapoptotic effects.

Artesunate effect on schistosome thioredoxin glutathione reductase and cytochrome c peroxidase as new molecular targets in schistosoma mansoni-infected mice.

OBJECTIVE: To investigate the possible effect of artesunate (ART) on schistosome thioredoxin glutathione reductase (TGR) and cytochrome c peroxidase (CcP) in Schistosoma mansoni-infected mice. METHODS: A total of 200 laboratory bred male Swiss albino mice were divided into 4 groups (50 mice in each group). Group I: infected untreated group (Control group) received a vehicle of 1% sodium carbonyl methylcellulose (CMC-Na); Group II: infected then treated with artesunate; Group III: infected then treated with praziquantel, and group IV: infected then treated with artesunate then praziquantel. Adult S. mansoni worms were collected by Animal Perfusion Method, tissue egg counted, TGR, and CcP mRNA Expression were estimated of in S. mansoni adult worms by semi-quantitative rt-PCR. RESULTS: Semi-quantitative rt-PCR values revealed that treatment with artesunate caused significant decrease in expression of schistosome TGR and CcP in comparison to the untreated group. In contrast, the treatment with praziquantel did not cause significant change in expression of these genes. The results showed more reduction in total worm and female worm count in combined ART-PZQ treated group than in monotherapy treated groups by either ART or PZQ. Moreover, complete disappearance (100%) of tissue eggs was recorded in ART-PZQ treated group with a respective reduction rate of 95.9% and 68.4% in ART- and PZQ-treated groups. CONCLUSION: The current study elucidated for the first time that anti-schistosomal mechanisms of artesunate is mediated via reduction in expression of schistosome TGR and CcP. Linking these findings, addition of artesunate to praziquantel could achieve complete cure outcome in treatment of schistosomiasis.

Mechanism of the neuroprotective role of coenzyme Q10 with or without L-dopa in rotenone-induced parkinsonism.

Current treatment options for parkinsonism as a neurodegenerative disease are limited and still mainly symptomatic and lack significant disease-modifying effect. Understanding its molecular pathology and finding the cause of dopaminergic cell loss will lead to exploring therapies that could prevent and cure the disease. Mitochondrial dysfunction was found to stimulate releasing of reactive oxygen species (ROS) with subsequent induction of apoptotic neuronal cell death. The aim of the present study was to throw the light on the role of coenzyme Q10 with or without L-dopa in an experimental model of parkinsonism induced by rotenone in rats. The present work showed that rotenone (2.5 mg/kg/day i.p. for 60 days) induced a model of parkinsonism (group II) resembling the basic findings in human characterized by bradykinesia and rigidity manifested as an increase in catalepsy score (detected after 20 days with bad prognosis after 60 days) with marked decrease in striatal dopamine levels. This model confirmed the implication of mitochondrial-apoptotic pathway in the pathogenesis of parkinsonism as there was a decrease in levels of striatal complex I activity and ATP as well as extreme overexpression of the antiapoptotic protein Bcl-2, and also exhibited the role of coenzyme Q10 where its plasma and striatal levels were found to be decreased in comparison to the normal control rats (group I). This proposed pathogenesis was evidenced by the significant correlation between catalepsy score and the neurochemical parameters obtained in the current work. The treated groups started to receive the drug(s) after 20 days from induction of parkinsonism and continued to complete for 60 days. Oral administration of Co Q10 in a low dose 200 mg/kg/day (group III) or a high dose 600 mg/kg/day (group IV), resulted in amelioration of the mitochondrial induced apoptosis by dose-dependent restoration of striatal complex I activity, ATP levels with temperate increase in expression of Bcl-2 as well as decrease in catalepsy score. Although both low and high doses of Co Q10 resulted in significant increase in its plasma and striatal levels, but only the high dose was shown to reach the recommended therapeutic levels. As a current replacement therapy, oral administration of levodopa 10 mg/kg/day (group V), caused symptomatic improvement in the form of reduction of catalepsy score with restoration of striatal dopamine levels, but it did not show any significant effects on either striatal complex I activity, ATP levels or the expression of Bcl-2, pointing to the lack of its disease-modifying role. On the other hand, its administration with high dose of coenzyme Q10 caused the most marked symptomatic improvement in catalepsy score when compared to its administration with low dose of coenzyme Q10, or when compared to either coenzyme Q10 high dose or L-dopa, respectively. Moreover, administration of high dose coenzyme Q10 with L-dopa provided a significant increase in striatal complex I activity, ATP levels and Bcl-2 expression in comparison to group administered coenzyme Q10 low dose with L-dopa, in addition to the significant restoration of striatal dopamine levels and both plasma and striatal Co Q10 levels. Regarding that L-dopa is viewed as a replacement therapy in parkinsonism, it could be concluded that addition of coenzyme Q10 in a high dose in early parkinson's disease could be recommended based on its proved disease-modifying role on several levels of the proposed mechanisms, including improvement of respiratory chain activity and intervention with neuronal apoptosis. A further research to investigate other apoptosis-targeted compounds will open a new era in the treatment of parkinsonism.

The possible anti-apoptotic and antioxidant effects of acetyl l-carnitine as an add-on therapy on a relapsing-remitting model of experimental autoimmune encephalomyelitis in rats.

Multiple sclerosis (MS) is a progressive inflammatory autoimmune demyelinating disease of the brain and spinal cord. Glucocorticoids (GCs) are the standard treatment of MS, however they have several drawbacks like oxidative stress and apoptosis. This study was designed to evaluate some possible antioxidant, anti-apoptotic and immune modulatory effects of Acetyl-l-carnitine (ALCAR) when used either alone or as an add-on therapy with dexamethasone for treatment of a relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) as a model of MS. This experiment was performed on 50 female Sprague Dawley rats divided into; normal control group, untreated EAE group, EAE group treated by dexamethasone, EAE group treated by ALCAR, and EAE group treated by both dexamethasone and ALCAR. The clinical score of the motor deficit of EAE was recorded daily. At the end of experiment, rats were sacrificed and the brain and spinal cord were processed for assessment of reduced glutathione (GSH), malondialdehyde (MDA) and caspase-3 activity. Histopathological changes and immunohistochemical expression of Bcl-2 and CD4+ T cell were carried out. Combination of both dexamethasone and ALCAR provided marked antioxidant and anti-apoptotic effects represented by significant decrease in MDA, caspase-3 and significant increase in GSH, Bcl-2 expression, and it also exhibited marked immunosuppressive effect represented by significant decrease in CD4+ T cells expression with significant improvement in clinical outcome when compared to untreated EAE group or to dexamethasone treated group. These findings pave the way for using ALCAR as an adjuvant therapy during long-term use of dexamethasone in MS.

Randomized controlled trial of polyethylene glycol versus lactulose for the treatment of overt hepatic encephalopathy.

BACKGROUND: Overt hepatic encephalopathy (HE) is a frequent complication of cirrhosis and one of the most debilitating manifestations that necessitates hospitalization. Although many treatment modalities are being investigated, none of them are satisfactory. So, newer treatment modalities have to be tried. OBJECTIVE: To evaluate the safety and efficacy of polyethylene glycol (PEG) versus lactulose in the management of HE. PATIENTS AND METHODS: This clinical trial included 100 patients with post-hepatitis C cirrhosis who were admitted with HE. Patients were randomized into two equal groups: group I patients received lactulose and group II patients received PEG. The clinico-epidemiological characteristics of patients, Child-Pugh score, and HE scoring algorithm were registered before and 24 h after administration of the drug. Moreover, any suspected adverse effects were recorded. RESULTS: All 100 patients received treatment. Three patients died within 24 h of admission and did not complete the follow-up period. According to intention-to-treat approach, they were considered as treatment failure. On analysis, 36/50 (72%) patients improved one grade or more in HE scoring algorithm score after 24 h of lactulose therapy versus 47/50 (94%) of those on PEG therapy (P<0.05). The time needed for resolution of HE and length of hospital stay were significantly lower in PEG group versus lactulose group (P<0.001). Both therapies were tolerated, and no significant adverse events were reported. CONCLUSION: Both lactulose and PEG were safe and effective in the treatment of HE. PEG significantly decreased the time needed for resolution of HE and significantly shortened the hospital stay.

Neurotrophic and antioxidant effects of silymarin comparable to 4-methylcatechol in protection against gentamicin-induced ototoxicity in guinea pigs.

BACKGROUND: Despite that gentamicin is a very effective aminoglycoside, its potential ototoxicity which is of irreversible nature makes a challenge and limitation for its use. This study was designed to investigate possible neurotrophic and antioxidant effects of silymarin comparable to 4-methylcatechol in protection against gentamicin-induced ototoxicity. METHODS AND RESULTS: Twenty pigmented guinea pigs were divided into four equal groups, where group I served as normal control group. The other groups received gentamicin (120 mg/kg/day, ip) for 19 days where group II given vehicle of 1% CMC, group III and group IV were pre-treated 2h before gentamicin by 4-methylcatechol (10 µg/kg, ip) and silymarin (100mg/kg, oral gavage), respectively. The main findings indicated that silymarin exhibited restoration of nerve growth factor (NGF) levels and increased tropomyosin-related kinase receptors-A (Trk-A) m-RNA expression in cochlear tissue and preservation of hair cells of organ of Corti by scanning electron microscopy (SEM) with significant decrease in auditory brainstem response (ABR) threshold compared to 4-methylcatechol. Only silymarin caused significant amelioration in oxidative stress state by reducing malondialdehyde (MDA) levels and increasing catalase activity. CONCLUSIONS: Silymarin exerts superiority over 4-methylcatechol when recommended as protective agent against gentamicin ototoxicity based on its efficient neurotrophic and antioxidant activities.

Modulatory effect of celastrol on Th1/Th2 cytokines profile, TLR2 and CD3+ T-lymphocyte expression in a relapsing-remitting model of multiple sclerosis in rats.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of brain and spinal cord that has an increasing incidence worldwide and classically presents in a relapsing-remitting form. This study was designed to induce a relapsing-remitting model of experimental autoimmune encephalomyelitis (EAE) to investigate the possible modulatory effect of celastrol on Th1/Th2 cytokines profile, immunohistochemical expression of TLR2, and CD3+T-lymphocytic count. Eighteen female Sprague Dawley rats were divided into 3 groups; where group I served as normal control, group II as EAE+vehicle, and group III as EAE treated by celastrol (1mg/kg/day, i.p.) started at 10th day till 42nd day post-immunization. The clinical score of rats in group II (EAE+vehicle) was relapsed after the re-challenge at the 35th day post-immunization and exhibited significant positive association with serum TNF-α, NF-κB expression and nitrites levels in brain and spinal cord, and CD3+ T-lymphocytic count in brain tissues while serum IL-10 showed significant negative association. Treatment of EAE by celastrol caused amelioration of the clinical score and inhibited the relapse. It caused significant shift in cytokines profile from Th1 by decrease in TNF-α towards Th2 pattern by increase in IL-10. Moreover, celastrol treatment resulted in significant reduction in NF-κB expression, nitrites levels, as well as immunohistochemical expression of TLR2 and CD3+ T-lymphocytic count. The beneficial effect of celastrol was further confirmed histopathologically by reduction in H&E score. Collectively, these results provide a promising pre-clinical evidence and conclusion about use of celastrol in treatment of multiple sclerosis that must be accessed in further clinical studies.

Effect of propranolol on IL-10, visfatin, Hsp70, iNOS, TLR2, and survivin in amelioration of tumor progression and survival in Solid Ehrlich Carcinoma-bearing mice.

BACKGROUND: ß-Adrenergic signaling could contribute to initiation and progression of breast cancer. This research investigated some potential mechanisms of propranolol in amelioration of progression and survival in breast cancer. METHODS AND RESULTS: Solid Ehrlich Carcinoma (SEC) xenograft model was induced in 30 mice divided into 3 groups; where group I served as untreated SEC group. In groups II and III, propranolol treatment i.p. in low (5mg/kg) and high dose (10mg/kg) caused significant increase in interleukin-10 (IL-10) and decrease in heat shock protein 70 (Hsp70) and inducible nitric oxide synthase (iNOS) activity with non significant change in visfatin in tumor tissues compared to untreated SEC. In untreated SEC, tumor volume (V) exhibited significant negative correlation with IL-10 levels and toll like receptor 2 (TLR2) expression with significant positive correlation with Hsp70 levels and iNOS activity. While propranolol in either doses caused reduction of tumor volume (V), and improved percentage tumor growth inhibition (% TGI) only its high dose exhibited significant impact on survival rate. Propranolol dose-dependent effect was evident for IL-10 and Hsp70, and even only the high dose significantly increased and decreased TLR2 and survivin, respectively. This comes in favor of recommending high dose of propranolol in cancer therapy. Nonetheless, use of low dose cannot be ignored when benefit to risk balance have to be considered. CONCLUSIONS: Propranolol could provide palliative effects in progression and survival of breast cancer that are mainly mediated via direct immunomodulatory and apoptotic mechanisms and probably associated with indirect anti-angiogenic activity.

Targeting sphingosine kinase 1 (SphK1) and apoptosis by colon-specific delivery formula of resveratrol in treatment of experimental ulcerative colitis in rats.

Ulcerative colitis (UC) is a chronic inflammatory bowel disorder (IBD) that has an elevated risk of developing into colon cancer. In trials to develop new therapeutic alternatives for UC, it is important to fulfill modifying effects on pathogenic targets and to reach the colon in a high concentration. Thus, the current work has investigated a colon-specific delivery formula of resveratrol in targeting sphingosine kinase 1 (SphK1) and apoptotic pathways to control pathogenesis and its progression to any expected neoplasm. This work was conducted on 40 Wister albino rats equally divided into 4 groups where group I served as the normal control group. The untreated oxazolone-induced colitis in group II exhibited significant increase in SphK1 activity as well as activity of both myeloperoxidase (MPO) and caspase-3 with concomitant mild DNA fragmentation in colonic tissue. Colonic SphK1 activity showed significant positive correlation with the disease activity index (DAI) and histopathological score in this group. Comparable with treatment by the native resveratrol formula, nRes (group III), treatment by the colon-specific delivery resveratrol formula, cRes (group IV) caused significant decrease in the activity of SphK1 and MPO with massive DNA fragmentation in colonic tissue and non significant change in caspase-3 activity. The lowest DAI and histopathological score have been recorded in the group treated by the colon-specific delivery resveratrol formula. In conclusion, the anti-inflammatory and apoptotic effects of resveratrol could be attributed to its inhibitory effect on sphingosine kinase 1 (SphK1) providing a useful therapeutic tool to break the link between inflammation and carcinogenesis risk in ulcerative colitis.

Effect of atorvastatin with or without prednisolone on Freund's adjuvant induced-arthritis in rats.

Rheumatoid arthritis is a chronic systemic inflammatory disease where cardiovascular diseases have been recognized as major determinants of early morbidity and mortality. Recently, there has been renewed interest in medication with glucocorticoids to decrease joint damage, but in long-term they incur substantial increase in the risk of cardiovascular diseases and their overall risk/benefit ratio is deemed unfavorable. So, the proposed role of statins in treatment of rheumatoid arthritis when corticosteroids indicated as traditional therapy needs to be investigated. Fifty albino rats were divided into 5 equal groups; normal control group, Freund's adjuvant induced arthritis group, group of induced arthritis treated with atorvastatin, group of induced arthritis treated with prednisolone, and group of induced arthritis treated with atorvastatin and prednisolone. The change in paw volume, serum levels of malondialdehyde (MDA), paraoxonase1 (PON1) activity, nitrites, C-reactive protein (CRP) and lipid profile was determined. The results revealed that treatment by atorvastatin in combination with prednisolone produced better satisfactory results than in either remedy alone evidenced by significant decrease in volume of hind paw, levels of MDA, nitrites, CRP, significant increase in PON1 activity and HDL and amelioration of other lipid profile parameters that were impaired by prednisolone. The present work demonstrated that statins exert beneficial anti-inflammatory and antioxidant effects beyond their basic cholesterol-lowering activity. Thus, we suggest that if corticosteroid therapy is indicated in rheumatoid arthritis, atorvastatin could be added to get benefit from its pleiotropic effects. However, further studies are needed to verify to what extent statin therapy contribute to clinical benefits in human.

Intervention of mitochondrial dysfunction-oxidative stress-dependent apoptosis as a possible neuroprotective mechanism of α-lipoic acid against rotenone-induced parkinsonism and L-dopa toxicity.

The current study evidenced hypothesis that mitochondrial dysfunction-oxidative stress-dependent apoptotic pathways play a critical role in degeneration of dopaminergic neurons in Parkinson's disease. Model of rotenone-induced parkinsonism in rats produced decrease in striatal complex I activity and reduced glutathione with increase in nitrites concentration and caspase-3 activity. This was confirmed by significant correlation of catalepsy score with neurochemical parameters. Moreover, electron microscopic examination of striatal neurons displayed ultrastructure affection as hyperchromatic nuclei and disrupted mitochondria that are typical features of undergoing apoptosis. Administration of L-dopa as replacement therapy, although caused symptomatic improvement in catalepsy score, but further worsening in neurochemical parameters. Therefore, efforts are not only to improve effect of L-dopa, but also to introduce drugs provide antiparkinsonian and neuroprotective effects. In this study, α-lipoic acid exhibited noticeable neuroprotective effects by a mechanism via intervention of mitochondrial dysfunction-oxidative stress-dependent apoptotic pathways. Combination of α-lipoic acid efficiently halting deleterious toxic effects of L-dopa, revealed normalization of catalepsy score in addition to amelioration of neurochemical parameters and apparent preservation of striatal ultrastructure integrity, indicating benefit of both symptomatic and neuroprotective therapy. In conclusion, α-lipoic acid could be recommended as a disease-modifying therapy when given with L-dopa early in course of Parkinson's disease.

Effects of rosiglitazone and aspirin on experimental model of induced type 2 diabetes in rats: focus on insulin resistance and inflammatory markers.

Both insulin resistance and decreased insulin secretion are major features of the pathophysiology of type 2 diabetes. Inflammatory pathways are found to be critical in mechanisms underlying insulin resistance, which is a major determinant of increased risk of cardiovascular complications in type 2 diabetes, and so, it is a potential therapeutic target. Thiazolidinediones (e.g., rosiglitazone) act primarily as insulin sensitizers and were discovered to have anti-inflammatory effects leading to reevaluation of their potential use in treatment of diabetes. Acetyl salicylic acid (aspirin), which is currently recommended for cardiovascular disease (CVD) or even CVD risk factors, is shown to ameliorate diabetic process. This work aimed to study correlation between homeostasis model assessment estimate of insulin resistance (HOMA-IR) with serum levels of inflammatory markers tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), C-reactive protein (CRP), and free fatty acids (FFAs) in experimental model of induced type 2 diabetes in rats, with evaluation of effects of rosiglitazone and aspirin (low or high dose), alone or in combination. There is significant elevation of insulin resistance and serum levels of fasting glucose, insulin, TNF-alpha, IL-6, CRP, and FFAs in the diabetic group when compared to the normal group, with positive significant correlation between levels of each of TNF-alpha, IL-6, CRP, and FFAs with insulin resistance (HOMA-IR). Administration of rosiglitazone, low-dose aspirin, or high-dose aspirin to diabetic rats caused nonsignificant lowering in insulin level with significant reduction of levels of other parameters when compared to the diabetic group. Also, there is no significant difference in the measured parameters between diabetic rats administered a combination of rosiglitazone with high-dose aspirin and those administered a combination of rosiglitazone with low-dose aspirin. It was concluded that aspirin and rosiglitazone offer unique approaches for treatment of type 2 diabetes due to their insulin-sensitizing and anti-inflammatory properties, and their combination was found to provide augmented beneficial effects. Also, in view of the potential dose-dependent adverse effects of aspirin, with no achievement of further benefit by high dose in this study, it is strongly recommended to use low-dose aspirin as a safe and effective medication for diabetes.

Modulating effect of atorvastatin on paraoxonase 1 activity in type 2 diabetic Egyptian patients with or without nephropathy.

The aim of this study was to investigate the modulating effect of atorvastatin on serum paraoxonase 1 enzyme (PON1) activity in type 2 diabetic Egyptian patients with or without nephropathy. The present study was carried out on the following groups: control group, which consisted of 30 healthy persons; Group I, which consisted of 20 type 2 diabetic patients without nephropathy; and Group II, which consisted of 20 type 2 diabetic patients with nephropathy. All the patients selected were under an antidiabetic regimen of insulin, and patients receiving antihypertensive agents were excluded from the follow-up study to avoid drug interaction fallacies. Twenty-two patients (15 without nephropathy and seven with nephropathy) received atorvastatin in individually adjusted oral dosage (range 10-20 mg) once per day for 12 weeks. All cases were subjected to thorough clinical examination and history taking and measurement of serum levels of PON1 activity, malondialdehyde (MDA), glutathione reductase activity, fasting glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), urea, and creatinine. Urine samples were collected for determination of proteinuria. The obtained results showed that PON1 activity and HDL significantly decreased and fasting glucose significantly increased in Group I and Group II when compared to the control group, with significant difference in their levels between Group II and Group I. MDA, total cholesterol, and LDL levels significantly increased and glutathione reductase activity significantly decreased in Group I and Group II when compared to the control group. Urea, creatinine, and proteinuria levels showed significant increase in Group II when compared to the control group and Group I, with nonsignificant difference between control group and Group I. Atorvastatin therapy caused a significant increase in PON1 activity, and serum levels of MDA and glutathione reductase activity were significantly decreased and increased, respectively. Also, total cholesterol, triglyceride and LDL-cholesterol levels were significantly reduced with a significant increase in HDL-cholesterol levels. There was a significant modest reduction in serum urea and creatinine levels as well as in proteinuria level. Fasting glucose level was significantly reduced under the antidiabetic regimen of insulin through the follow-up period. PON1 activity showed a significant negative correlation with glucose and LDL, and a significant positive correlation with HDL in all the studied groups. It could be concluded that atorvastatin with its pleiotropic effects could provide optimal therapeutic intervention to control not only dyslipidemia, but also oxidative stress status with consequent improvement in the course of type 2 diabetes and diabetic nephropathy. More specifically, restoration of PON1 activity by atorvastatin opens a window to investigate other drugs that could provide a new adjuvant therapeutic line for better control of diabetes and diabetic nephropathy. Further research is also recommended to study the distribution of PON1 genetic polymorphism among the Egyptian population to explain the variability in its activity and its relationship with other factors that associate diabetes and its complications.

Effect of pentoxifylline and/or alpha lipoic acid on experimentally induced acute pancreatitis.

Acute pancreatitis is a sudden inflammation of the pancreas that may be life threatening disease with high mortality rates; particularly in presence of systemic inflammatory response and multiple organ failure despite of the conventional antibiotic and symptomatic treatment. Oxidative stress has been shown to be involved in the pathophysiology of acute pancreatitis. This study was designed to investigate the possible effect of pentoxifylline and alpha lipoic acid respectively and in combination on rats with L-arginine induced acute pancreatitis. Rats were divided as follow; Group 1: served as control, Group 2 and Group 3: sacrificed after 24h and 7 days; respectively, from induction of acute pancreatitis by L-arginine 250 mg/100g, Group 4 and Group 5: rats treated by pentoxifylline (12 mg/kg) and sacrificed after 24h and 7 days; respectively, from induction of acute pancreatitis, Group 6 and Group 7: treated by alpha lipoic acid (1mg/kg) and sacrificed after 24h and 7 days; respectively, from induction of acute pancreatitis, Group 8 and Group 9: treated by pentoxifylline and alpha lipoic acid and sacrificed after 24h and 7 days; respectively, from induction of acute pancreatitis. Serum samples were collected to assay levels of amylase enzyme, C-reactive protein, IL-6, catalase enzyme activity, malondialdehyde and pancreases were excised for histopathological examination and assay of pancreatic myeloperoxidase. L-arginine induced-acute pancreatitis was evident by increased in serum marker enzymes and by histopathological findings compared to control group. Pentoxifylline and alpha lipoic acid respectively provided protection against L-arginine induced acute pancreatitis possibly by their antioxidant and anti-inflammatory effect. Treatment with alpha lipoic acid exhibited pronounced improvement in the course of pancreatitis when compared to treatment with pentoxifylline. Moreover, the combination of pentoxifylline and alpha lipoic acid offered the most evident protection when compared to groups that received monotherapy; pointing to the effectiveness of such combination therapy.

An experimental study on ulcerative colitis as a potential target for probiotic therapy by Lactobacillus acidophilus with or without "olsalazine".

Traditional medical treatments for ulcerative colitis (UC) are still compromised by its adverse effects and not potent enough to keep in remission for long-term periods. So, new therapies that are targeted at specific disease mechanisms have the potential to provide more effective and safe treatments for ulcerative colitis. Probiotics is recently introduced as a therapy for ulcerative colitis. In the present study, Lactobacillus acidophilus was selected as a probiotic therapy to investigate its effects in oxazolone-induced colitis model in rats that mimics the picture in human. The rats were grouped (8 rats each) as normal control group (Group I), Group II served as untreated oxazolone-induced colitis, Group III oxazolone-induced colitis treated with probiotic L. acidophilus (1×10(7) colony-forming units (CFU)/mL/day oral for 14 days), Group IV oxazolone-induced colitis treated with olsalazine (60 mg/kg/day oral for 14 days), Group V oxazolone-induced colitis treated with probiotic L. acidophilus and olsalazine in the same doses and duration. Disease activity index (DAI) was recorded, serum levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and intrleukin-6 (IL-6) was assessed as inflammatory markers and the histopathological picture of the colon of each rat was studied. Disease activity index (DAI) showed significant positive correlation with the elevated serum levels of CRP (r=0.741, p<0.05), TNF-α (r=0.802, p<0.05) and IL-6 (r=0.801, p<0.05). Treatment with either L. acidophilus (group III) or olsalazine (group IV) resulted in significant reduction in serum levels of CRP, TNF-α and IL-6, as well as disease activity index (DAI). Treatment with combination of L. acidophilus and olsalazine (group V) offered more significant reduction in serum levels of CRP, TNF-α, IL-6 and disease activity index (DAI) when compared to either group II (untreated group), group III (treated with L. acidophilus) or group IV (treated with olsalazine). So, it was concluded that L. acidophilus probiotic could be recommended as adjuvant therapy in combination with olsalazine to achieve more effective treatment for ulcerative colitis. For application in human, this needs to be verified in further clinical studies.