Search

Thymoquinone (TQ) is the main active constituent of Nigella Sativa. The present study aimed to investigate the effect of TQ on apoptotic parameters and MMP-9 expression in isoproterenol (ISP)-induced myocardial infarction (MI). TQ was given once daily for 7 days at doses of 10 and 20 mg/kg orally with ISP (86 mg/kg; s.c.) administered on the 6th and 7th days. TQ pretreatment protected against ISP-induced MI as approved by normalization of electrocardiogram (ECG) and b (CK)-MB, minimal histopathological changes, and reduction of the infarction size. Effects of TQ could be supported by its antioxidant activity, evidenced by the increase of cardiac reduced glutathione and total serum antioxidant capacity, and the inhibition of ISO-induced lipid peroxidation. TQ anti-inflammatory activity was associated with reduced expression of NF-κB and TNF-α. TQ ameliorated cardiomyocytes, apoptotic pathways by inhibiting both the intrinsic pathway, via reducing cytoplasmic cytochrome C, and the extrinsic pathway, by inhibiting TNF-α and caspases, and the effect of TQ was dose-dependent. Moreover, TQ reduced the expression of metalloproteinase (MMP)-9, which is considered as a prognostic marker of ventricular remodeling, recommending that TQ can be used as a possible supplement to minimize post-MI changes. So, we conclude that TQ antiapoptotic activity and the inhibitory modulation of MMP-9 expression contribute to TQ protective effects in MI. Up to our knowledge, this is the first study reporting the effect of TQ on cytochrome c activity and MMP-9 expression in MI.

Background:Transarterial chemoembolization(TACE)is the most widely used treatment worldwide for intermediate unresectable hepatocellular carcinoma(HCC).New systemic therapies have shown survival benefits but looking ahead to the future of systemic therapies is necessary to overcome low response rates, relatively high toxicity. Aim:The present study aimed to assess efficacy& safety of viscum album in Egyptian patients with intermediate Barcelona Clinic Liver Cancer (BCLC) stage HCC compared to TACE. Patients and methods:Forty-five naive intermediate HCC patients were enrolled in this prospective open label study. Patients were randomly assigned into 3 groups,viscum Group I,TACE/Viscum Group II and TACE Group III.Viscum has been prepared as an injectable aqueous solution containing one milliliter of viscum.Two viscum ampoules per week were subcutaneously administered for 8 weeks.All patients underwent laboratory investigations including liver function tests to assess deterioration in liver functions and triphasic spiral computed tomography to assess radiological response according to modified response evaluation criteria in solid tumors (mRECIST). Results:In all cases, chronic hepatitis C virus infection was the cause of liver disease.Stable disease was achieved in all patients.Toxicity,primarily in the form of local reaction&fever,was generally mild &well tolerated.No discontinuation or toxic deaths associated with drugs were observed.In HCC patients, serum levels of vascular endothelial cell growth factor(VEGF)&Tumour necrosis factor alpha(TNF-α)were significantly elevated,whereas levels of Transforming growth factor-B(TGF-β)were lower compared to pretreatment values. Conclusion:In patients with intermediate HCC,Viscum Album is a secure treatment.For efficacy elucidation,Further randomized controlled trials with large numbers of patients are recommended.Treatment with TACE&viscum is associated with modulation of HCC patients with serum angiogenic,inflammatory cytokines.

Cardioprotective agents are compounds that provide heart protection and decrease cardiotoxicity incidence. Cardiotoxicity is a serious condition that results in diminishing the heart's ability to pump blood throughout the body and can be developed into heart failure. Oxidative stress is an important pathogenic event in cardiotoxicity where the generated reactive oxygen species (ROS) cause myocardial cellular destruction. Moreover, apoptosis, fibrosis, and inflammatory cascades play major roles in cardiotoxicity pathogenesis. Recently, much attention has been paid to the cardioprotective effects of natural products. Methyl palmitate (MP) is a naturally occurring methyl ester that can be also synthesized. This review article aimed to elucidate the potential cardioprotective effects of MP as well as the underlying possible mechanisms. Indeed, MP showed effective cytoprotective roles in various experimental models. In this regard, MP showed potent antioxidant activity which was proven by the decreased production of oxidative stress markers and the increased activity of the endogenous antioxidant enzymes. It also exhibited anti-inflammatory activity which was evidenced by the reduced expression of the pro-inflammatory cytokines and the elevated expression of the anti-inflammatory cytokines. Moreover, MP showed anti-apoptotic activity evidenced by the elevated anti-apoptotic protein expression and the mitigated pro-apoptotic protein expression. Besides, further studies proved the anti-fibrotic and vasodilatation activities of MP. Thus, MP could provide major cardioprotective activities through its antioxidant, anti-inflammatory, anti-apoptotic, anti-fibrotic, and vasodilatation properties.

Introduction: Doxorubicin is a highly effective anticancer agent with serious cardiotoxic effects. Hypertension is considered as a major risk factor for doxorubicin cardiotoxicity. It should be noted that about one-third of cancer patients have hypertension, and melatonin can have cardio-protective effects. The present study aimed to further investigate the possible beneficial effects of melatonin co-administration to perindopril against doxorubicin cardiotoxicity in hypertensive rats. Method: Rats were randomly assigned to naive group and N-Omega-Nitro-L-Arginine Methyl Ester Hydrochloride (L-NAME) hypertensive group. L-NAME group was further subdivided into untreated, doxorubicin, doxorubicin / perindopril, doxorubicin/melatonin and doxorubicin/ perindopril / melatonin subgroups. Cardiac functions, CK-MB, malondialdehyde, superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and cardiac percentage area of collagen fibers were evaluated. Results: Combining melatonin with perindopril to doxorubicin produced significant decreases in left ventricular end diastolic pressure, malondialdehyde, TNF-α, and TGF-β. It resulted in significant increases in left ventricular dP/dtmax and SOD, in addition to apparent improvement in cardiac histopathology with a significant decrease in percentage area of collagen deposition compared to perindopril alone. Conclusion: Co-administration of melatonin to perindopril in hypertensive rats who received doxorubicin alleviated doxorubicin cardiac toxicity more than using perindopril alone. These effects could be explained by the reported antihypertensive, anti-inflammatory, anti-oxidant, and anti-fibrotic effects of melatonin.

Objective The present work was designed to investigate whether fenofibrate could ameliorate olanzapine deleterious effect on insulin resistance via its effect on fibroblast growth factor-21 (FGF-21)-adiponectin axis without affecting olanzapine antipsychotic effect in postweaning socially isolated reared female rats. Method Treatment with olanzapine (6 mg/kg, intraperitoneally) or fenofibrate (100 mg/kg, orally) have been started 5 weeks after isolation, then behavioral tests, hippocampal content of neurotransmitters, and brain-derived neurotrophic factor (BDNF) were assessed. Moreover, insulin resistance, lipid profile, FGF-21, adiponectin, inflammatory, and oxidative stress markers of adipose tissue were assessed. Results Treatment of isolated-reared animals with olanzapine, or fenofibrate significantly ameliorated the behavioral and biochemical changes induced by postweaning social isolation. Co-treatment showed additive effects in improving hippocampal BDNF level. Besides, fenofibrate reduced the elevation in weight gain, adiposity index, insulin resistance, lipid profile, and FGF-21 level induced by olanzapine treatment. Also, fenofibrate increased adiponectin level which was reduced upon olanzapine treatment. Moreover, fenofibrate improved both adipose tissue oxidative stress and inflammatory markers elevation as a result of olanzapine treatment. Conclusion Fenofibrate could ameliorate olanzapine-induced insulin resistance without affecting its central effect in isolated reared rats via its action on FGF-21-adiponectin axis.

Alzheimer disease (AD) is a chronic and progressive neurodegenerative disorder characterized by memory loss and cognition impairment. A link has been established between AD and epilepsy sharing multiple mechanisms and pathogenesis. Similar Hippocampal changes have been found between both diseases. Choosing antiepileptic drug in AD patient represent a great a challenge especially with increase seizure risk in AD patients. Lacosamide, antiepileptic drug, was reported to have a neuroprotective effect in animal models and a histone deacetylase inhibition activity. This study was designed to investigate the potential effect of chronic lacosamide treatment in Streptozotocin induced AD in male Wistar rats. Methods AD animal model was induced with single bilateral intracerebroventricular injection of STZ (3 mg/kg) on day one. Lacosamide (30 mg/kg orally, once daily) was administrated for 21 days. Cognitive function assessment was done with Morris Water Maze (MWM) and Y Maze tasks. APP and MAPT mRNA level were measured. Results ICV-STZ caused significant prolongation in Escape latency time and reduction in time spent in target quadrant in MWM and reduction in spontaneous alteration ratio in Y Maze compared to control group. STZ induced Up-regulation in Amyloid precursor protein and Microtubule associated protein tau gene expression. Chronic Lacosamide treatment attenuated STZ induced cognitive impairment and mitigated APP and MAPT induced expression with STZ. Conclusion Lacosamide has a neuroprotective effect against STZ induced cognitive deficits ameliorating Aβ and Tau pathology.

Background Liver cirrhosis is considered the terminal stage of many hepatic diseases of different etiologies. Liver cirrhosis was associated with increased incidence rates of some extrahepatic manifestations such as osteoporosis. Regardless of the liver disease etiology, the presence of cirrhosis implies a twofold risk of bone fractures higher than non-cirrhotic patients. The liver is the main storage depot for iron and is the primary organ that is responsible for clearing excess iron in conditions of iron overload. When the iron storage and antioxidant capacity of the liver is overwhelmed, iron overload can lead to marked oxidantmediated liver and bone injury and iron overload was a risk factor for osteoporosis via affecting osteoblast survival. Aim of the work to examine the possible protective effect of Deferoxamine (DFO) on liver cirrhosis rat model induced osteoporosis. Material and Method rats was divided into 4 groups Animal Groups: Naïve control, DFO-treated group, TAA-treated group received Thioacetamide (TAA) ip (200 mg/kg/rat) twice weekly for 12 weeks, TAA+DFO treated group received TAA intra-peritoneal in addition to DFO intraperitoneal injections (300 mg/kg/3 times/week, for the last 4 weeks of TAA injections. Results and Conclusion Deferoxamine produced significant improvement in bone mineralization alongside its significant effect on liver function test in a rat model of liver cirrhosis induced osteoporosis.

Clinical observations recognized the co-existence and interactions of pain and depression a long time, ago. The aim of this work was to study the effect of ibuprofen and fluoxetine on BCGinduced depressive-like behaviour, on formalin-induced pain, as well as on mechanical allodynia after planter incision in mice. BCG induced a depressive behaviour that was seen in the forced swim test (FST) and the tail suspension test (TST). It also induced a decrease in pain-related behaviour in the formalin test, and an increase in the baseline in mechanical allodynia test compared to the control group. Fluoxetine (80 mg/L of drinking water) showed a significant decrease in the immobility time in the FST and TST and enhanced pain related behaviour in formalin test in the BCG-inoculated group. However, it did not affect the increase in the pain threshold in the planter incision allodynia model. Adding ibuprofen to drinking water (0.2 g/L of drinking water), reversed the depressive like behaviour induced by BCG and enhanced pain-related behaviour in formalin test, in both the total pain-related behaviour and phase 2. It also prevented the increase in the base line induced by BCG. On the other hand, the incisional pain model was not affected by BCG inoculation except at the 2-hour time point, where it showed hypoalgesia, as well.

The study was designed to investigate the potential anti-arthritic effects of methyl palmitate in an adjuvant arthritis model in rats that shares many histopathological similarities with human RA. The underlying mechanism and its effect on CD68 macrophages were investigated, as a further argument to its possible efficacy in RA treatment. A normal control group was injected only with saline, arthritic group, and three treatment groups with CFA induced arthritis received methyl palmitate (MP) at three different doses (75, 150, 300 mg/kg/week for 3 weeks, intraperitoneal). The degree of ipsilateral paw swelling, ankle diameter, spleen index, thymus index and the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β were measured. In addition, the underlying molecular mechanism was investigated using CD68 expression. Methyl palpitate significantly and dose dependently decreased the arthritic symptoms as measured by ipsilateral paw volume and ankle diameter. It showed no effect on body weight but significantly decreased splenic, thymus index, serum TNF-α and IL-1β. CD68 macrophages expression and the overall synovial inflammatory cellularity were halted. Methyl palmitate exhibits significant anti-inflammatory and exerts a potential anti-arthritic effect in a rat model of adjuvant induced arthritis. Furthermore, it inhibits expression of synovial CD68 macrophage that validate its therapeutic potential adjuvant arthritis.

Background MAP kinases, CREB, and Tau are signaling molecules among downstream synaptic targets involved in synaptic function, memory formation and cognition. Purpose Here we investigate the neuro-protective effect of selenium in HFHCD induced tauopathy and cognitive impairment in rats. The study was focused on the effects on synaptic plasticity related molecules in hippocampus, which in turn may be the mechanism responsible for underlying behavior alterations. Method Rats were divided into 2 main groups: one fed with normal rat chow diet and the other with HFHCD for 6 weeks. Every group was subdivided into three subgroups, non-treated, low dose Se (200 μg/kg) and high dose Se (400 μg/kg). The cognitive behaviors of the rats were tested using the Morris Water Maze test, hole board and conditioned avoidance tests. Results Daily administration of Se decreased the observed memory impairment induced by HFHCD as measured by behavioral tests. It significantly alleviated oxidative stress and restored protein expression of cyclic AMP response element protein (CREB) and brain derived neurotrophic factor (BDNF) and reduced p-Tau in the hippocampus. Conclusion Se reversed HFHCD-induced cognitive impairments via decrease expression of p38 MAPK that phosphorylate and aggregate Tau protein. Addition, It restored neuronal plasticity through increasing the expression of BDNF, and CREB in the hippocampus; thus, it can be considered as a possible beneficial therapeutic approach for prevention and treatment of HFHCD induced tauopathy and cognitive impairment, further studies are warranted in this field.

Background Lowbush blueberry extract (Vaccinium angustifolium) is abundant with polyphenols (such as chlorogenic acid) with high antioxidant profile. It has received great interest due to its protective role in many disorders such as heart diseases and neurological disorders. Hypothesis We hypothesized that blueberry leaf extract might have a protective effect against cardiac hypertrophy via suppressing oxidative stress, inflammation and fibrosis. Method Blueberry leaf nutraceutical extract was administered orally to male albino rats at three different doses (25, 50 and 100 mg/kg/day of the extract, equivalent to 3.4, 6.8 and 13.6 mg of chlorogenic acid, respectively) once daily for 28 consecutive days against a dose of isoprenaline (ISO) (5 mg/kg) for 14 days. Results The results indicated that isoprenaline induced significant myocardial damage, characterized by conduction abnormalities, increased heart-to-body weight ratio, increased serum CKMB, AST, c-TnI and LDH. Pretreatment with blueberry extract at a dose of 50 mg/kg/day (equivalent to 6.8 mg chlorogenic acid) protected against ISO-induced ECG changes, leakage of cardiac enzymes and histopathological changes. Also, ISO caused significant glutathione depletion, lipid peroxidation and reduction in activities of antioxidant catalase enzyme. These effects were prevented by pretreatment with blueberry extract. Additionally, ISO elicited inflammatory effects by increasing the expression of NF-κB, COX-2, TNF-α and IL-6 while pretreatment with blueberry extract significantly inhibited these inflammatory responses. Furthermore, ISO induced fibrosis by increasing the level of TGF-β while pretreatment with blueberry extract significantly reduced it. Conclusion These findings indicate that blueberry leaf extract possessed a potent protective effect against ISO-induced cardiac hypertrophy via suppressing oxidative stress, inflammation and fibrosis.

Background Myocardial injury is considered as a worldwide main cause of morbidity and mortality. The present study aimed to investigate the probable cardioprotective activity of the naturally occurring endogenous fatty acid ester methyl palmitate (MP) against isoproterenol (ISO)-induced myocardial injury in rats and the possible underlying molecular mechanisms. The study was carried out in two consecutive sets of experiments; the first set screened the cardioprotective dose of MP in ISO-intoxicated rats. In the second set, forty male Sprague Dawley rats received either MP (150 mg/kg, p.o) three times/week for 2 weeks and/or 2 consecutive doses of ISO separated by 24 h (85 mg/kg, s.c) on the 13th and 14th days. Different cardiotoxicity and oxidative stress markers were assessed. Furthermore, endothelial nitric oxide synthase (eNOS) levels were determined. For detection of apoptosis, Bax, Bcl-2, and caspase 3 were estimated. To assess inflammation, toll-like receptor 4 (TLR-4) and tumor necrosis factor-alpha (TNF-α) were measured using ELISA. Meanwhile, nuclear factor kappa B (NF-kB) and cyclooxygenase-2 (COX-2) were detected immunohistochemically. Results Pretreatment with MP significantly ameliorated the cardiotoxicity and oxidative stress markers. It also markedly elevated eNOS content, decreased apoptotic marker expression, and mitigated TLR-4 activation and other inflammatory markers. Electrocardiography and histopathological examination also confirmed the cardioprotective effect of MP. Conclusion The findings of this study indicated that MP possesses a potent cardioprotective activity against ISO-induced myocardial injury through its significant antioxidant, anti-apoptotic, anti-inflammatory, and vasodilatation activities. Graphical abstract

In metastatic breast cancer (MBC), the conventional doxorubicin (DOX) has various problems due to lack of selectivity with subsequent therapeutic failure and adverse effects. DOX- induced cardiotoxicity is a major problem that necessitates the presence of new forms to decrease the risk of associated morbidity. Nanoparticles (NPs) are considered an important approach to selectively increase drug accumulation inside tumor cells and thus decreasing the associated side effects. Tumor cells develop resistance to chemotherapeutic agents through multiple mechanisms, one of which is over expression of efflux transporters. Various NPs have been investigated to overcome efflux mediated resistance. To date, only liposomal doxorubicin (LD) and pegylated liposomal doxorubicin (PLD) have entered phase II and III clinical trials and FDA- approved for clinical use in MBC. This review addresses the effects of LD and PLD on the hematological and palmar-plantar erythrodysesthesia (PPE) in anthracycline naïve and pretreated MBC patients. For evidence, studies to be included in this review were identified through PubMed, Cochrane and Google scholar databases. The results derived from: four phase III clinical trials that compared LD with the conventional DOX in naïve MBC patients, and ten non-comparative clinical trials investigated LD and PLD as monotherapy or combination in pretreated MBC. This work confirmed the cardiac tolerability profile of LD and PLD versus DOX, while hematological and skin toxicities were more common. Other DOX-NPs in preclinical trials were discussed in a chronological order. Finally, the modern preclinical development framework for DOX includes exosomal DOX (exo-DOX). Exosomal NPs are non-toxic, non-immunogenic, and can be engineered to have high cargo loading capacity and targeting specificity. These NPs have not been investigated clinically. Our study shows that the full clinical potentiality of DOX-NPs remains to be addressed to move the field forward.

Carvedilol is a drug of choice in treatment of portal hypertension. The present study was designed to elucidate the potential role of antifibrotic effects of carvedilol in improving hepatic efficiency and the carvedilol oral pharmacokinetic changes during induction of liver fibrosis. Rats were given CCl4 (1 ml/kg, intraperitoneal) twice weekly for 6 weeks and/or co-treated with carvedilol (10 mg/kg, orally) three times weekly on alternating days. Indocyanine green (ICG) clearance test was used as a modality for the measurement of hepatic blood flow. In addition, assessment of serum albumin as a marker of synthetic capacity and immunohistochemical staining of P-glycoprotein (P-gp) expression as a marker of metabolic capacity were done. Furthermore, hydroxyproline and TGF-β1 were detected as markers of liver fibrosis. The area under plasma concentration–time curve of a single dose of carvedilol was significantly increased, associated with decreased the clearance in rats intoxicated with CCl4 compared to control group. Carvedilol co-treatment in CCl4-intoxicated rats for 6 weeks significantly counteracted the changes in hepatotoxicity markers and histopathological lesions induced by CCl4. In addition, there were no significant alterations in carvedilol pharmacokinetics between control and CCl4-intoxicated rats. Furthermore, carvedilol treatment restored liver efficiency, including synthetic and metabolic capacity as well as hepatic blood flow. The present study provides evidence underlying the antifibrotic effects of carvedilol and enhancement of hepatic efficiency. In addition, the pharmacokinetic parameters of a single dose of carvedilol are altered in liver fibrosis, manifested as delayed clearance. This was attributed to the reduction of both hepatic blood flow and CYP2D6 expression in the liver. Carvedilol co-treatment in CCl4-intoxicated rats for 6 weeks recovered its pharmacokinetic profile, which is mainly attributed to the impact of pharmacodynamic antifibrotic effects of carvedilol on its own kinetics.

Background & aim Schizophrenia is a chronic, disabling neurological illness. This study investigated the effect of rosuvastatin (RSU) addition to the antipsychotic drug: olanzapine (OLZ) in treatment of post-weaning isolation rearing (IR) damaging effect and assessed behavioral impairment, metabolic and hepatic abnormalities, oxidative stress, and inflammatory markers. Methods Treatment with OLZ (6 mg/kg, P.O.) and/or RSU (10 mg/kg, I.P.) have been started 6 weeks after isolation. We assessed behavioral tests, serum cortisol level, and hippocampal content of neurotransmitters. In addition, we assessed histopathology, inflammatory and oxidative stress markers of hippocampus, liver and adipose tissue Results Treatment of IR animals with OLZ, and/or RSU significantly counteracted the changes in hippocampus, liver and adipose tissue induced by post-weaning IR. Co-treatment of IR rats with both OLZ and RSU showed additive effects in some areas like improving both tumor necrosis factor alpha (TNFα) in both hippocampus and liver, histopathology of liver, oxidative stress markers of adipose tissue, β3 adrenergic receptors (ADRβ3), serum cortisol and total cholesterol. In addition, RSU alone alleviated the damage of IR rats by the same efficacy as OLZ with more benefit in cognition and exploration. Conclusion post-weaning IR as a model has behavioral, hippocampal, hepatic and marked metabolic changes more relevant to schizophrenia than drug-induced models. These effects were ameliorated by RSU and/or OLZ that are explained by their antioxidant, anti-inflammatory, anti-stress and anti-hyperlipidemic properties. Interestingly, co-treatment with both drugs showed a better effect.

Background Alzheimer disease (AD) initially presents with cognitive decline that affects the affected individual’s daily activities. Cognitive decline reversal represents an important medical need, where Phosphodiesterase-5 inhibitors (PDE-5Is) might play a role. Aim This systematic review was performed to verify the efficacy of PDE-5Is in preventing cognitive impairment and to elucidate the underlying mechanism. Methods Preclinical animal studies assessing the efficacy of PDE-5Is in preventing cognitive impairment and pathological changes by measuring Aβ-42 β42 and p-Tau were included in the analysis. CAMARADES Checklist was used to assess study quality. Further, various signaling pathways in different studies were examined. Results and outcomes Data of behavioral tests were extracted and a meta-analysis was conducted. Fifteen animal trials met the inclusion criteria, and all reported the prevention of cognitive deficits by PDE-5Is in Alzheimer’s disease. A significant effect of PDE-5Is in increasing the time spent in the target quadrant was reported in four of seven studies using the water maze. Four studies showed significant improvement in contextual fear memory freezing time, and three studies showed improvement in the 14 unit maze number of errors. Conclusions Cognitive decline in preclinical AD finds tauopathy has a more impact than Aβ-42. This systematic review showed that PDE-5 inhibitors might help prevent cognitive impairment in AD, and while its mechanism of action is non-related to Aβ-42, it might include decrease p-Tau, increase CREB and BDNF or suppressing apoptosis and inflammation. However, the efficacy of PDE-5 inhibitors in preventing cognitive impairment remains unclear due to various limitations, such as the small number of included studies, the high risk of bias, the lack of an integrated study design, and low reporting quality.

Nonalcoholic steatohepatitis (NAFLD) is a progressive form of liver disease that leads to advanced fibrosis. The present study was designed to assess the hepatoprotective effect of thymoquinone (TQ) on liver functions, insulin resistance, and PPAR-γ expression in NAFLD. Rats were divided into two main groups: one fed with normal rat chow diet and the other with high-fat high-cholesterol diet group for 6 weeks. Every group was subdivided into three subgroups (n = 8): treated with saline, low dose TQ (10 mg/kg), high dose TQ (20 mg/kg). High fat high cholesterol diet caused marked liver damage as noted in histopathology and significant increase in liver index, liver enzymes. There was significant increase in the insulin resistance, serum cholesterol, triglyceride, PPAR-γ gene overexpression with significant decrease in HDL. Additionally, oxidative stress increased by measuring MDA associated with significant decrease in serum total antioxidant capacity. As markers of inflammation, hepatic TNF-α was significantly increased with decrease in IL10. Further, there was increase in BAX protein with decrease in Bcl as compared to control group. This model of 6 weeks high-fat high-cholesterol diet showed minimal fibrosis as noticed by increase MMP2 and Masson trichrome satin. Co-treatment with TQ improved all previous parameters. High dose was more effective, although mostly non-statistically significant. TQ may have a promising agent to improve hepatic steatosis, oxidative stress; inflammatory, apoptotic status, fibrosis and so prevent liver damage in patients with NAFLD. Although PPAR-γ was significantly under-expressed by TQ, insulin resistance was improved significantly suggesting a role of liver damage.

Doxorubicin (DOX) is an effective anticancer drug; however, its clinical use is limited by its cardiotoxic effect. Adenosine was proved to mediate anti-inflammatory effects and protected from myocardial ischemia/reperfusion injury. So the present work was designed to examine the effectiveness of a selective A3 adenosine receptor agonist (Cl-IB-MECA) in DOX-induced cardiotoxicity and to elucidate the underlying mechanisms via studying its effect on different oxidative stress, inflammatory and apoptotic markers. Firstly the potential cardioprotective dose of Cl-IB-MECA was screened in male Wistar rats at different doses (20, 40 and 80 µg/kg; i.v) against a single dose of DOX (15 mg/kg; i.p). Secondly, the dose of 40 µg/kg Cl-IB-MECA was selected for further assessment of the cardioprotective mechanisms. Cl-IB-MECA at a dose 40 µg/kg (i.v) protects against DOX-induced bradycardia, elevated creatine kinase isoenzyme-MB and histopathological changes. Also, it significantly ameliorates oxidative stress injury evoked by DOX as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme activities. Additionally, DOX provoked inflammatory responses by increasing the expressions of nuclear factor kappa B and the levels of tumor necrosis factor alpha. Cl-IB-MECA pretreatment significantly inhibited these inflammatory responses. Furthermore, DOX induced apoptotic tissue damage by increasing cytochrome c expressions which was suppressed by Cl-IB-MECA pretreatment. Cl-IB-MECA protects against DOX-induced cardiotoxicity through restoration of the oxidant/antioxidant status and consequential suppression of DOX-induced inflammatory responses and abrogation of the resultant apoptotic signals.

Iron-overload is a well-known factor of hepatotoxicity and liver fibrosis, which found to be a common finding among hepatitis C virus patients and related to interferon resistance. We aimed to elucidate the potential antifibrotic effect of deferoxamine; the main iron chelator, and its additional usefulness to interferon-based therapy in concanavalin A-induced immunological model of liver fibrosis. Rats were treated with deferoxamine and/or pegylated interferon-α for 6 weeks. Hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed. Concanavalin A induced a significant increase in hepatotoxicity indices and lipid peroxidation accompanied with a significant depletion of total antioxidant capacity, glutathione level and superoxide dismutase activity. Besides, it increased CD4(+) T-cells content and the downstream inflammatory cascades, including NF-κB, TNF-α, iNOS, COX-2, IL-6 and IFN-γ. Furthermore, α-SMA, TGF-β1 and hydroxyproline were increased markedly, which confirmed by histopathology. Treatment with either deferoxamine or pegylated interferon-α alone reduced liver fibrosis markers significantly and improved liver histology. However, some of the hepatotoxicity indices and oxidative stress markers did not improve upon pegylated interferon-α treatment alone, besides the remarkable increase in IL-6. Combination therapy of deferoxamine with pegylated interferon-α further improved all previous markers, ameliorated IL-6 elevation, as well as increased hepcidin expression. In conclusion, our study provides evidences for the potent antifibrotic effects of deferoxamine and the underlying mechanisms that involved attenuating oxidative stress and subsequent inflammatory cascade, as well as the production of profibrogenic factors. Addition of deferoxamine to interferon regimen for HCV patients may offer a promising adjuvant modality to enhance therapeutic response.

Doxorubicin (DOX) is a widely used chemotherapeutic agent however its clinical use is limited by cumulative cardiotoxicity. Epigallocatechin-3-gallate (EGCG), a main catechin in green tea, possesses a potent antioxidant, anti-apoptotic and anticancer properties. The current study aimed to investigate the potential protective effect of EGCG against DOX-induced cardiotoxicity. Firstly the potential cardioprotective dose of EGCG was screened at different doses (10, 20 and 40 mg/kg/day) against a single dose of DOX (15 mg/kg; i.p.). EGCG protected against DOX-induced ECG changes, leakage of cardiac enzymes (creatine kinase isoenzyme-MB, and lactate dehydrogenase) and histopathological changes. The dose of 40 mg/kg EGCG was selected for further assessment to address the EGCG cardioprotective mechanisms. EGCG was given orally 3 times/week for 4 consecutive weeks and DOX (2.5 mg/kg; i.p.) 3 times/week on the last 2 weeks. EGCG significantly ameliorated oxidative stress injury evoked by DOX as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme activities. DOX caused down-regulation of ErbB2 expression while EGCG pretreatment significantly increased ErbB2 expression indicating its effect on pro-survival pathway. Furthermore, DOX provoked apoptotic responses evidenced by increasing the expression of nuclear factor kappa-B, tumor suppressor protein p53, calpain 2, caspases 3 and 12. Additionally basal level of Hsp70 was reduced in DOX-intoxicated group. EGCG pretreatment significantly ameliorated these apoptotic signals indicating its anti-inflammatory and anti-apoptotic actions. In conclusion, EGCG possesses cardioprotective action against DOX-induced cardiotoxicity by suppressing oxidative stress, inflammation and apoptotic signals as well as activation of pro-survival pathways.

Sitaglebtin, dipeptidyl peptidase 4 inhibitors, has been investigated and proved to improve triglycerides, low density lipoprotein and blood pressure, which are important risk factors for cardiovascular diseases. Aim: The present study was designed to investigate the potential protective effect of sitaglebtin in isoproterenol induced myocardial injury. Further assessment was done to address the cardioprotective mechanism. Method: Male Wister rats were treated with sitaglebtin (30 mg/kg/day for 2 weeks by gavage) and/ or isoproterenol (85mg /kg; i.p. 24 hours apart at day 14th and 15th of the experiment). Results: Isoproternol induced a significant ECG changes, several pathological changes and elevated cardiac enzymes. These changes were significantly attenuated by pre-treatment of rats with sitaglebtin. As a marker of oxidative stress, isoproterenol caused significant decrease in reduced glutathione level and superoxide dismutase with increase in malondialdhyde compared to the control group. Sitaglebtin pretreatment restored these markers toward normal values. Energy decline was assessed by measuring ATP/ADP, which decreased significantly in isoproterenol group and significantly increased by sitaglebtin pretreatment. Isoproternol caused inflammatory effects indicated by up-regulation of tumor necrosis factor-α expression in the myocardial tissue. Sitaglebtin also counteracted inflammatory cell infiltration, other histopathological changes, and the overexpression tumor necrosis factor-α in myocardial tissue. Collectively, these findings suggest that sitaglebtin, an anti-diabetic agent, has cardioprotective effect against isoproterenol induced myocardial injury that could be through antioxidant properties, TNF-α inhibition, and an enhancement of myocardial energy state .

Doxorubicin (DOX) is the mainstay chemotherapeutic agent against a variety of human neoplasmas. However, its clinical utility is limited by its marked cardiotoxicity. Chrysin, is a natural flavone which possesses antioxidant, anti-inflammatory and anti-cancer properties. The current study aimed to investigate the potential protective effect of chrysin against DOX-induced chronic cardiotoxicity and the underlying molecular mechanisms. Male Sprague-Dawley rats were treated with either DOX (5 mg/kg, once a week) and/or chrysin (50 mg/kg, four times a week) for four weeks. Chrysin prevented DOX-induced cardiomyopathy which was evident by conduction abnormalities, elevated serum CKMB and LDH and histopathological changes. Chrysin also ameliorated DOX-induced oxidative stress by decreasing lipid peroxidation and upregulating the antioxidant enzymes. Moreover, chrysin attenuated DOX-induced apoptosis via decreasing expression of p53, Bax, Puma, Noxa, cytochrome c and caspase-3 while increasing expression of Bcl-2. DOX induced activation of MAPK; p38 and JNK and increased expression of NF-κB. Meanwhile, DOX suppressed AKT pathway via decreasing expression of its upstream activator VEGF and increasing expression of PTEN. Conversely, chrysin effectively neutralised all these effects. Collectively, these findings indicate that chrysin effectively protected against DOX-induced cardiomyopathy via suppressing oxidative stress, p53-dependent apoptotic pathway, MAPK and NF-κB pathways while augmenting the VEGF/AKT pathway.

Doxorubicin (DOX) is one of the most effective chemotherapeutic drugs; however, its incidence of cardiotoxicity compromises its therapeutic index. Chrysin, a natural flavone, possesses multiple biological activities, such as antioxidant, anti-inflammatory and anti-cancer. The present study was designed to investigate whether chrysin could protect against DOX-induced acute cardiotoxicity; and if so, unravel the molecular mechanisms of this protective effect. Chrysin was administered to male albino rats once daily for 12 consecutive days at doses of 25 and 50mg/kg orally. DOX (15 mg/kg; i.p.) was administered on day 12. Chrysin pretreatment significantly protected against DOX-induced myocardial damage which was characterized by conduction abnormalities, increased serum creatine kinase isoenzyme-MB (CK-MB), and lactate dehydrogenase (LDH) and myofibrillar disarrangement. As indicators of oxidative stress, DOX caused significant glutathione depletion, lipid peroxidation and reduction in activities of antioxidant enzymes; catalase (CAT) and superoxide dismutase (SOD). Chrysin pretreatment significantly attenuated DOX-induced oxidative injury. Additionally, DOX provoked inflammatory responses by increasing the expressions of nuclear factor kappa-B (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and the levels of tumor necrosis factor-alpha (TNF-α) and nitric oxide while chrysin pretreatment significantly inhibited these inflammatory responses. Furthermore, DOX induced apoptotic tissue damage by increasing Bax and cytochrome c expressions and caspase-3 activity while decreasing the expression of Bcl-2. Chrysin pretreatment significantly ameliorated these apoptotic actions of DOX. Collectively, these findings indicate that chrysin possesses a potent protective effect against DOX-induced acute cardiotoxicity via suppressing oxidative stress, inflammation and apoptotic tissue damage.

Objectives This study aimed to elucidate the effect of bupropion (BUP) on high-fat diet (HFD)-treated rats that is to say the action of BUP on diabetes and hyperlipidemia with its consequences on liver and endothelial function. Methods Male Wistar rats were fed HFD or normal chow for 15 weeks then given either BUP (50 mg/kg) or distilled water by gavage for 4 weeks. The effect of BUP on diabetes, hyperlipidemia, hepatic and vascular functions as well as tumour necrosis factor-alpha (TNF)-α were assessed. The intima-media thickness of the aorta was evaluated. Key findings BUP significantly decreased serum lipid, liver enzyme, homeostasis model assessment for insulin resistance (HOMA-IR), serum TNF-α and the impaired glucose tolerance. Liver from rats with non-alcoholic steatohepatitis (NASH) demonstrated significant higher TNF-α level, inflammatory cell infiltration, ballooning and steatosis which significantly ameliorated by BUP treatment. Neither intima/media ratio nor vascular reactivity to acetylcholine is improved by BUP treatment. Conclusions NASH induced by a HFD was associated with hyperlipidemia, insulin resistance, endothelial dysfunction and increase in liver TNF-α. All of these may contribute to the pathogenesis of NASH. BUP has potential role in improving metabolic and hepatic function with negative vascular effect. Since BUP is a well-known antidepressant, it will be a candidate drug in treatment of depression in hepatic diseased or metabolic disturbed patients.

Pulmonary fibrosis is one of the most common chronic interstitial lung diseases with high mortality rate after diagnosis and limited successful treatment. The present study was designed to assess the potential antifibrotic effect of thymoquinone (TQ) and whether TQ can attenuate the severity of oxidative stress and inflammatory response during bleomycin-induced pulmonary fibrosis. Male Wister rats were treated intraperitoneally with either bleomycin (15 mg/kg, 3 times a week for 4 weeks) and/or thymoquinone (5mg/kg/day, 1 week before and until the end of the experiment). Bleomycin significantly increased lung weight and the levels of Lactate dehydrogenase, total leucocytic count, total protein and mucin in bronchoalveolar lavage and these effects were significantly ameliorated by TQ treatment. As markers of oxidative stress, bleomycin caused a significant increase in the levels of lipid peroxides and nitric oxide accompanied with a significant decrease in the antioxidant enzyme activity of superoxide dismutase and glutathione transferase. TQ treatment restored these markers toward normal values. TQ also counteracted emphysema in air alveoli, inflammatory cell infiltration, lymphoid hyperplastic cells activation surrounding the bronchioles and the over expression of activated form of nuclear factor kappa-B (NF-B) in lung tissue that was induced by bleomycin. Fibrosis was assessed by measuring hydroxyproline content, which increased markedly in the bleomycin group and significantly reduced by concurrent treatment with TQ. Furthermore, histopathological examination confirmed the antifibrotic effect of TQ. Collectively these findings indicate that TQ has potential antifibrotic effect beside its antioxidant activity that could be through NF-κB inhibition.

Diabetic neuropathy (DN) is a common complication of diabetes mellitus that is hardly reversible at the late stages. Since treatment of neuropathic pain is predominantly symptomatic, a prophylactic measure would be useful. Both ibuprofen and L-arginine exert antiallodynic effects on chronic constriction injury (CCI)-induced cold allodynia. Furthermore, ibuprofen is effective in CCI-induced mechanical allodynia. The aim of the study was to assess the antiallodynic effect of prophylactic ibuprofen and L-arginine in streptozotocin-induced DN in rats and to further investigate the role of spinal miR-155 and nitric oxide (NO) in this effect. Tactile allodynia was assessed weekly by von Frey filaments. Oral daily administration of ibuprofen, L-arginine and their combination, for 4 weeks starting 1 week after streptozotocin injection (ie, before the development of tactile allodynia), resulted in a significant decrease of tactile allodynia compared with the control diabetic group. This was evident in the fifth week of the experiment. The 3 treatments prevented the decrease in muscle fiber diameter and epidermal thickness, seen in the control diabetic group. Furthermore, ibuprofen, L-arginine and their combination prevented the increase in the spinal NO level and miRNA-155, seen in the control diabetic group. In conclusion, both ibuprofen and L-arginine delayed the development of behavioral and histologic changes of DN, with concomitant suppression of spinal miR-155 and NO level. L-arginine being tolerable may be useful prophylactically in diabetic patients.

Several chronic liver diseases can lead to the occurrence of hepatic fibrosis through the accumulation of iron, which causes induction of oxidative stress and consequently activation of fibrogenesis. The present study was designed to investigate the potential antifibrotic and anti-oxidant effects of deferoxamine (DFO), a well-known iron chelator in an experimental rat model of liver injury using carbon tetrachloride (CCl4 ). First, the potential effective dose of DFO was screened against CCl4 -induced acute hepatotoxicity. Then, rats were co-treated with DFO (300 mg/kg, i.p.) for 6 weeks starting from the third week of CCl4 induction of chronic hepatotoxicity. Liver function was assessed in addition to histopathological examination. Furthermore, oxidative stress and fibrosis markers were assessed. It was found that treatment of animals with DFO significantly counteracted the changes in liver function; histopathological lesions and hepatic iron deposition that were induced by CCl4 . DFO also significantly counteracted the CCl4 -induced lipid peroxidation increase and reduction in antioxidant activities of superoxide dismutase and glutathione peroxidase enzymes. In addition, DFO ameliorated significantly liver fibrosis markers including hydroxyproline, collagen accumulation, and the expression of the hepatic stellate cells (HSCs) activation marker; alpha smooth muscle actin and transforming growth factor-beta (TGF-β). Together, these findings indicate that DFO possesses a potent antifibrotic effect due to its antioxidant properties that counteracted oxidative stress and lipid peroxidation and restored antioxidant enzymes activities as well as reducing HSCs activation and fibrogenesis.

The present study was designed to investigate the effect Hypericum Perforatum (HP), on behavioral changes, corticosterone, TNF-α levels and tryptophan metabolism and disposition in bilateral ovariectomized rats compared to 17α -ethinylestradiol. Behavioral analysis by measuring immobility time in forced swimming test and open field test, serum and hippocampal corticosterone and TNF-α along with hippocampal kynurenine/tryptophan ratio were determined in mature ovariectomized rats treated orally either by HP at three different doses 125, 250, and 500 mg/kg/day or by 17α-ethinylestradiol 30 μ g/kg/day for 30 days. Ovariectomized rats showed significant increase in immobility time in the forced swimming test. Along with elevation in serum and hippocampal TNF-α and corticosterone levels associated with significant increase in hippocampal kynurenine/tryptophan ratio. Immobility time in the forced swimming test was decreased in rats treated by different doses of HP in a dose dependent manner and 17α-ethinylestradiol with no concomitant changes in the open field test. Only Rats treated with HP exhibited significant decrease in the elevated serum and hippocampal TNF-α and corticosterone, which couldn't explain the associated insignificant effect on hippocampaus kynurenine/ tryptophan ratio in comparison to ovariectomized untreated rats. It is concluded that increased tryptophan metabolism toward kynurenine secondary to elevated corticosterone and TNF-α might be one of the pathohphysiological mechanisms that could explain depression like state observed in this rat model. Further, the observed attenuating effect of HP on TNF-α and corticosterone could contribute in its antidepressant effect in this animal model by other ways than their effects on tryptophankynurenine metabolism pathway.

Low dose methotrexate is the cornerstone for the treatment of rheumatoid arthritis. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Dissatisfied arthritis patients are likely to seek the option of complementary and alternative medicine such as bee venom. The combination of natural products with modern medicine poses the possibility of potential interaction between the two groups and needs investigation. The present study was aimed to investigate the modulatory effect of bee venom acupuncture on efficacy, toxicity, and pharmacokinetics and tissue disposition of methotrexate. Complete Freund's adjuvant induced arthritic rats were treated for 3 weeks with methotrexate and/or bee venom. Arthritic score, ankle diameter, paw volume and tissue expression of NF-κB and TNF-α were determined to assess anti-arthritic effects, while anti-nociceptive effects were assessed by gait score and thermal hyperalgesia. Methotrexate toxicity was assessed by measuring serum TNF-α, liver enzymes and expression of NF-κB in liver. Combination therapy of bee venom with methotrexate significantly improved arthritic parameters and analgesic effect as compared to methotrexate alone. Bee venom ameliorated serum TNF-α and liver enzymes elevations as well as over expression of NF-κB in liver induced by methotrexate. Histological examination supported the results. And for the first time bee venom acupuncture was approved to increase methotrexate bioavailability with a significant decrease in its elimination. Conclusion: bee venom potentiates the anti-arthritic effects of methotrexate, possibly by increasing its bioavailability. Also, it provides a potent anti-nociceptive effect. Furthermore, bee venom protects against methotrexate induced hepatotoxicity mostly due to its inhibitory effect on TNF-α and NF-κB.