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Hepatocellular carcinoma (HCC) is one of the most common malignancies and it is the fourth cause of cancer-related mortality. The treatment of HCC with traditional chemotherapeutic agents such as doxorubicin has been limited due to poor efficacy, acquired resistance of the tumors and systemic toxicity. Verapamil as a P-gp inhibitor has demonstrated anti-cancer activities both in vitro and in vivo. Natural products and plant-derived compounds, such as ginger extract, have been investigated as safe and effective anti-cancer agents. Combination therapy offers preferable prognosis with less side effects. For example, the combination of chemotherapeutics with verapamil or ginger extract has been shown to exert beneficial therapeutic effects, overcome multidrug resistance and reduce side effects through modulation of different signaling pathways in tumor cells. Nano-sized formulations are designed to increase accumulation of drugs at the tumor environment and to improve solubility/bioavailability, promote retention, specificity, efficacy and safety. This review summarizes how to overcome cardiotoxicity and multidrug resistance evolved by doxorubicin in HCC treatment.

This study aimed to investigate the impact of ginger extract (GE) loaded into chitosan nanoparticles (CNPs) in enhancing cytotoxicity and reducing cardiotoxicity of doxorubicin (DXN) in hepatocellular carcinoma (HCC) induced mice. DXN and GE were loaded into CNPs and cytotoxicity of loaded and unloaded drugs against HepG2 cells was evaluated. HCC was induced in male albino mice by injection of diethylnitrosamine (DINA). Mice were divided into eight groups (n = 15): (1) normal control, (2) DINA, (3) CNPs, (4) free DXN, (5) CNPs DXN, (6) free GE, (7) CNPs GE, and (8) CNPs DXN + CNPs GE. Both GE and DXN loaded into CNPs showed a greater decline in cell viability of HepG2 cells than the unloaded forms. GE CNPs displayed pronounced anticancer activity In Vivo through apoptosis, greater down-regulation of multidrug resistance 1, enhancement of anti-oxidant activity and depletion of vascular endothelial growth factor content in liver tissues. GE CNPs in combination with DXN CNPs showed nearly normal hepatic lobule architecture and the greatest increase in apoptotic cell count. Co-treatment group had decreased cardiac malondialdehyde, tumor necrosis factor-α and serum activity of creatine kinase and lactate dehydrogenase. Combination of GE CNPs and DXN CNPs might be a potentially effective therapeutic approach for HCC.

Osteoarthritis [OA] is a chronic, prevalent, debilitating joint disease characterized by progressive cartilage degradation, subchondral bone remodeling, bone marrow lesions, meniscal damage, and synovitis. Joint diseases are very difficult to be treated with traditional line therapy. Hence the importance of developing new therapeutic methods such as stem cell therapy. Mesenchymal Stem Cells [MSCs] isolated from multiple tissues as bone marrow, adipose tissue, dental pulp, placenta and umbilical cord. They possess ability of self-renewal and multilineage differentiation which is a hoping tool for treatment of multiple diseases. The aim of this study is to assess the ability of stem cells to differentiate into chondrocytes and the ability of those chondrocytes to induce cartilage repair and suppresses cartilage degeneration in Monosodium iodoacetate [MIA] induced osteoarthritis in rats' model. In this experimental study Wharton jelly separated from umbilical cord was used to isolate MSCs then differentiated to chondrocytes and injected into MIA induced osteoarthritis in rat's model. The rats divided into three groups; control group, MIA-treated group and MIA- Chondrocytes treated group. Results: MIA- Chondrocytes treated group appeared healthy with no signs of inflammation. On microscopic examination: the articular cartilage of injected limbs showed observable restoration of surface continuity, chondrocytes density, boundaries between layers and matrix basophilia. Conclusion: Intra-articular injection of chondrocytes improves, inhibits the progression of degeneration of the affected cartilage and induces cartilage repair.

Increased fructose consumption predisposes to nonalcoholic steatohepatitis (NASH).There no effective treatment to be used as the second line when lifestyle modification is insufficient .So, the aim of this study was to evaluate the effect of Curcumin on some biochemical markers in fructose induced NASH . Sixty male albino rats were divided randomly and equally into three groups. Group I (control group). Group II (NASH group), received 70% fructose for 5 weeks .Group III (curcumin treated NASH group), fed as group II followed by daily administration of curcumin at a dose of 50 mg/kg orally for 6 weeks. Blood samples were collected to measure lipid profile, and liver enzymes activities . Liver tissues samples were collected for estimation of mRNA expression levels of nuclear factor E2-related factor-2 (Nrf2) using quantitative real-time PCR ,levels of Beclin 1, AMPK, IL6 and Nrf2 DNA-binding activity by ELISA method, and oxidative stress markers malondialdehyde (MDA), superoxide dismutase (SOD) ,GSH spectrophotometrically. NASH was confirmed by histopathology as well as increased activity of liver enzymes and marked dyslipidemia .Curcumin ameliorated biochemical disturbance in NASH by upregulating autophagy process through increasing Beclin 1, increasing AMPK and hampered IL6 levels in the liver . It also restored redox balance as evident by suppressing MDA formation and preservation of intracellular antioxidants status via increasing GSH, activating SOD and Nrf2 signaling pathway. Results suggested that curcumin has an effective role in counteracting both abnormalities in autophagy process and redox balance, supporting the potential utility of this natural product in effective treatment of NASH.

Autophagy is necessary for neuronal homeostasis and its dysfunction has been implicated in Parkinson's disease (PD) as it can exacerbate endoplasmic reticulum (ER) stress and ER stress-induced apoptosis. Quercetin is a flavonoid known for its neuroprotective and antioxidant effects. The present study investigated the protective, autophagy-modulating effects of quercetin in the rotenone rat model of PD. Rotenone was intraperitoneally injected at dose of 2 ml/kg/day for 4 weeks. Simultaneous intraperitoneal injection of quercetin was given at a dose of 50 mg/kg/day also for 4 weeks. Neurobehavioral changes were studied. Oxidative/antioxidant status, C/EBP homologous protein (CHOP), Beclin-1, and dopamine levels were assessed. DNA fragmentation and histopathological changes were evaluated. This research work revealed that quercetin significantly attenuated rotenone-induced behavioral impairment, augmented autophagy, ameliorated ER stress- induced apoptosis with attenuated oxidative stress. From the current study, quercetin can act as an autophagy enhancer in PD rat model and modulates the microenvironment that leads to neuronal death.

The mechanisms leading to neuronal death in Parkinson's disease (PD) are not fully elucidated; however, mounting evidence implicates endoplasmic reticulum (ER) stress, oxidative damage, and inflammatory changes are the crucial factors in its pathogenesis. This study was undertaken to investigate the modulatory effects of resveratrol on ER stress-mediated apoptosis, inflammatory and oxidative stress markers in a rat model of rotenone-induced PD. mRNA expression levels of ER stress markers; C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), were estimated in the rat brain using quantitative real-time PCR. Caspase-3 activity, IL-1β levels and Nuclear Factor Erythroid 2-related factor (Nrf2) DNA-binding activity were estimated by ELISA, while glutathione peroxidase and Xanthine oxidase activities, as well as protein carbonyl contents in the rat brain were evaluated spectrophotometrically. Our data revealed that Resveratrol ameliorated rotenone-induced ER stress by downregulating CHOP and GRP78 genes expression and hampered caspase-3 activity in the brain of rotenone exposed rats. It also restored redox balance as evident by suppressing Xanthine oxidase activity and protein carbonyls formation; in addition to preservation of intracellular antioxidants status via activating glutathione peroxidase and Nrf2 signaling pathway. In conclusion; our study launched promising avenues for the potential use of resveratrol as a neuroprotective therapeutic agent in Parkinson's disease.

Objective Our study aimed to investigate the possible protective effects of quercetin (QCT) on doxorubicin (DOX)-induced cardiotoxicity in rats. Background DOX is an antineoplastic drug that produces cardiotoxicity; it generates highly cytotoxic-free radicals that damage the cardiomyocytes. QCT is a plant flavonoid. QCT pretreatment reduces DOX-induced oxidative stress. Materials and methods Fifty-five adult rats were divided into four groups: group 1 (control) received saline (5 ml/kg) orally for 4 weeks; group 2 (DOX) received six doses of DOX intraperitoneally (2.5 mg/kg) on alternative days in the last 2 weeks; group 3 (QCT + DOX) received QCT orally (10 mg/kg once daily) for 4 weeks and DOX intraperitoneally (2.5 mg/kg) in the last 2 weeks as group 2, and group 4 (QCT) received QCT (10 mg/kg once daily) orally for 4 weeks. We measured the body weight, heart weight, and ECG parameters. Serum cardiac troponin-I (cTn-I), serum malondialdehyde (MDA), and total serum antioxidant capacity (TAC) have been estimated. In addition, histopathological changes of the rat heart were assessed. Results The DOX group showed significant ECG changes, significant increase in serum cTn-I (P Conclusion QCT may be a promising cardioprotective agent against DOX-induced cardiotoxicity due to its inhibition of cardiac apoptosis and oxidative stress.

Background Chronic renal failure (CRF) is a major public health problem worldwide. The pathophysiological basis of the disease and its complication include inflammation and oxidative stress, which are similar in humans and animals. In this study, we seek to develop new therapeutic modalities for CRF. Objective This study aimed to investigate the nephroprotective effects of curcumin (CUR) and/or sildenafil in adenine (AD) model of CRF. Materials and methods Rats were divided into five groups as follows: control naive group, AD group received AD 200 mg/kg/day orally to induce CRF, CUR group received CUR 200 mg/kg/day in addition to AD, sildenafil group received sildenafil 0.5 mg/kg/day in addition to AD, and combination group received combination of CUR 200 mg/kg/day and sildenafil 0.5 mg/kg/day in addition to AD. After consecutive 28 days of treatment, body weight, kidney index, and Doppler on renal artery assessments were done for all groups. In addition, kidney function tests and markers of oxidative stress were evaluated. Histopathological assessment of renal tissues and immunohistochemical staining for tumor necrosis factor-α were performed. Results CUR, sildenafil, and their combination significantly decreased body weight loss and urine volume and improved renal hemodynamic changes caused by AD. In addition, they significantly improved kidney function tests and biomarkers of oxidative stress. A significant down-regulation of tumor necrosis factor-α immunohistochemical expression was noted. They also brought histopathological changes induced by AD toward normal. Conclusion CUR and sildenafil may play a role in renal protection in AD-induced nephrotoxicity. The combined treatment showed better nephroprotective effect than either treatment alone did.

The aim of this study was to investigate the protective effect of montelukast (MTK) against prednisolone-induced hepatic injury in rats. Twenty-eight male albino rats were categorized into four equal groups. Group I served as the control group; group II: rats orally received prednisolone (5 mg·kg-1 ·d-1 ) for 30 days; groups III and IV: rats orally received MTK at 10 and 20 mg·kg-1 ·d-1 , respectively, simultaneously with prednisolone for 30 days. Serum liver enzymes, hepatic mitochondrial function, oxidative/nitrosative stress, and inflammatory and apoptotic markers were evaluated, and the results were confirmed by histopathological examination. MTK showed significant hepatic protection evidenced by alleviated histological lesion and improvement of mitochondrial function, oxidative/nitrosative stress, and inflammatory and apoptotic changes induced by prednisolone, with more profound protection in higher MTK dose (20 mg·kg-1 ). In view of these findings, we can conclude that MTK may have hepatoprotective potential, beyond its therapeutic value for asthmatic patients during their course of corticosteroid therapy.

Diabetes mellitus is accompanied by hormonal and neurochemical changes that can be associated with anxiety and depression. I investigated the antidepressant effect of simvastatin (SMV) on diabetic rats. Rats were divided into control (CTR) and streptozotocin-induced diabetic (STZ) groups and were orally administered 0, 5, or 10 mg/kg of SMV daily for 14 days, then exposed to the forced swimming test (FST). Our results showed that diabetic rats had higher immobility duration than the CTR rats, and SMV decreased this depressive-like behavior in the diabetic rats. However, clomipramine lowered the immobility time in the CTR and STZ rats. STZ decreased serotonin concentration in the hippocampus, which was reversed by SMV and clomipramine. The dopamine concentration in the hippocampus decreased in the STZ groups compared with the CTR groups. However, SMV and clomipramine had no significant effect on the dopamine levels in either the CTR or STZ groups. Corticosterone levels were increased in the untreated STZ group; SMV and clomipramine significantly decreased corticosterone levels in the STZ groups, but had no effect on the CTR groups. In conclusion, SMV exerts an antidepressant-like effect on diabetic rats that are submitted to the FST. The antidepressant-like effect of SMV in the FST appears to be mediated, at least in part, by the biochemical changes to the blood levels of corticosterone and of serotonin concentration in the hippocampus.

Autophagy is necessary for neuronal homeostasis and its dysfunction has been implicated in Parkinson's disease (PD) as it can exacerbate endoplasmic reticulum (ER) stress and ER stress-induced apoptosis. Quercetin is a flavonoid known for its neuroprotective and antioxidant effects. The present study investigated the protective, autophagy-modulating effects of quercetin in the rotenone rat model of PD. Rotenone was intraperitoneally injected at dose of 2 ml/kg/day for 4 weeks. Simultaneous intraperitoneal injection of quercetin was given at a dose of 50 mg/kg/day also for 4 weeks. Neurobehavioral changes were studied. Oxidative/antioxidant status, C/EBP homologous protein (CHOP), Beclin-1, and dopamine levels were assessed. DNA fragmentation and histopathological changes were evaluated. This research work revealed that quercetin significantly attenuated rotenone-induced behavioral impairment, augmented autophagy, ameliorated ER stress- induced apoptosis with attenuated oxidative stress. From the current study, quercetin can act as an autophagy enhancer in PD rat model and modulates the microenvironment that leads to neuronal death.

The endocannabinoid signalling system is widely accepted to play a role in controlling the affective state. Plant cannabinoids are well known to have behavioural effects in animals and humans and the cannabinoid CB(1) receptor antagonist rimonabant has recently been shown to precipitate depression-like symptoms in clinical trial subjects. The aim of the present study was to investigate the behavioural and neurochemical effects of chronic administration of Δ⁹-tetrahydrocannabinol (THC) and rimonabant on intact and olfactory bulbectomised (OB) rats used as a model of depression. As expected, OB rats were hyperactive in the open field. Repeated THC (2 mg/kg, i.p. once every 48 h for 21 days) and rimonabant (5 mg/kg, i.p. once every 48 h for 21 days) reduced this hyperactivity, which is typical of clinically effective antidepressant drugs. In intact animals, chronic THC increased brain derived neurotrophic factor (BDNF) expression levels in the hippocampus and frontal cortex but rimonabant had no effect. Rimonabant increased the levels of phosphorylated extracellular signal regulated kinases (p-ERKs(1/2)) in the hippocampus and prefrontal cortex and THC also increased expression in frontal cortex. OB did not affect BDNF or p-ERK(1/2) expression in the hippocampus or frontal cortex and in, contrast to the intact animals, neither THC nor rimonabant altered expression in the OB rats. These findings indicate antidepressant-like behavioural properties of both THC and rimonabant in OB rats although additional studies are required to clarify the relationship between the chronic effects of cannabinoids in other pre-clinical models and in human depression.

Recent findings indicate that CB1 receptor blockade might be relevant to the action of antidepressant drugs as inhibition of endocannabinoid function can increase synaptic availability of neurotransmitters; an effect also seen with chronic antidepressant drug treatment. Chronic treatments with established antidepressants also lead to raised brain BDNF levels. The aim of this study was to compare the effects of rimonabant (an inverse agonist/antagonist of CB1 receptors) with those of the antidepressant tranylcypromine (TCP), on behaviour and expression of BDNF/CREB signalling pathways in rat brain. Daily (i.p.) injections of vehicle or TCP (10 mg/kg) or rimonabant (2 mg/kg) were given for 14 days. Locomotor activity (LMA) and a conditional emotional response (CER) were measured in addition to levels of BDNF and CREB/phospho-CREB, using immunoblotting, in the frontal cortex, hippocampus, striatum and cerebellum. The velocity of movement was increased significantly on the 3rd, but not 9th, day of TCP treatment versus vehicle-treated rats (p0.05) while rimonabant had no effect. There were no significant changes in grooming or freezing behaviours after rimonabant or TCP compared to vehicle-treated rats. Rearing was significantly reduced by TCP treatment on the 3rd, but not 9th, day of treatment (p0.001) while rimonabant had no effect. BDNF levels were significantly increased in the frontal cortex after TCP (p0.05) but not by rimonabant. Neither TCP nor rimonabant significantly affected CREB or p-CREB expression. In conclusion, chronic administration of TCP to rats increased BDNF expression in the frontal cortex but no similar effect was observed with rimonabant indicating that rimonabant does not show antidepressant drug-like responses after chronic treatment.

Several pre-clinical and human-based studies have shown that acutely administered cannabidiol (CBD) can produce anxiolytic-like effects The present study investigated the effects of chronic administration of CBD on rat behaviour and on the expression of brain proteins. Male Lister-hooded rats (150–200 g, n = 8 per group) received daily injections of CBD (10 mg/kg, i.p.) for 14 days. The rats were subjected to two behavioural tests: locomotor activity and conditioned emotional response (CER). The expression of brain-derived neurotrophic factor (BDNF), its receptor tyrosine kinase B (Trk B), extracellular signal-regulated kinases (ERK1/2) and phospho-ERK1/2 and the transcription factor cyclic AMP response element binding protein activation (CREB) and phospho-CREB were determined in brain regions such as the frontal cortex and hippocampus using Western immunoblotting. CBD significantly increased the time spent freezing in the CER test with no effect on locomotor activity. CBD significantly reduced BDNF expression in the hippocampus and frontal cortex with no change in the striatum. In addition, CBD significantly reduced TrkB expression in the hippocampus with a strong trend towards reduction in the striatum but had no effect in the frontal cortex. In the hippocampus, CBD had no effect on ERK1/2 or phospho-ERK2, but in the frontal cortex, CBD significantly reduced phospho-ERK1/2 expression without affecting total ERK. Chronic administration of CBD produced an anxiogenic-like effect in clear opposition to the acute anxiolytic profile previously reported. In addition, CBD decreased the expression of proteins that have been shown to be enhanced by chronic treatment with antidepressant/anxiolytic drugs.

The endocannabinoid signalling system is widely accepted to play a role in controlling the affective state. Plant cannabinoids are well known to have behavioural effects in animals and humans and the cannabinoid CB(1) receptor antagonist rimonabant has recently been shown to precipitate depression-like symptoms in clinical trial subjects. The aim of the present study was to investigate the behavioural and neurochemical effects of chronic administration of Δ⁹-tetrahydrocannabinol (THC) and rimonabant on intact and olfactory bulbectomised (OB) rats used as a model of depression. As expected, OB rats were hyperactive in the open field. Repeated THC (2 mg/kg, i.p. once every 48 h for 21 days) and rimonabant (5 mg/kg, i.p. once every 48 h for 21 days) reduced this hyperactivity, which is typical of clinically effective antidepressant drugs. In intact animals, chronic THC increased brain derived neurotrophic factor (BDNF) expression levels in the hippocampus and frontal cortex but rimonabant had no effect. Rimonabant increased the levels of phosphorylated extracellular signal regulated kinases (p-ERKs(1/2)) in the hippocampus and prefrontal cortex and THC also increased expression in frontal cortex. OB did not affect BDNF or p-ERK(1/2) expression in the hippocampus or frontal cortex and in, contrast to the intact animals, neither THC nor rimonabant altered expression in the OB rats. These findings indicate antidepressant-like behavioural properties of both THC and rimonabant in OB rats although additional studies are required to clarify the relationship between the chronic effects of cannabinoids in other pre-clinical models and in human depression.

In reply to Dr. Gururajan's comments on our manuscript (Elbatsh et al. 2012) about the anxiogenic-like effects of chronic cannabidiol administration in rats, we accept that the use of a wider ranging dose/response design would have been desirable. We emphasised the need for additional longterm multi-dose studies of the drug in models of affective disease in the discussion which present constraints of finance and time have not allowed. Moreover, given that cannabidiol (CBD) is being reported almost as a panacea, we consider it of value to show, even if only at a single dose, that CBD can provoke potentially deleterious behavioural responses. Secondly, in terms of the behavioural changes in the context of anxiety, not only total distance travelled was reported in the activity boxes, but also rearing and grooming as possible markers of anxiety-related behaviour. Locomotor activity in a neutral environment was measured to detect any hypoactivity associated with CBD treatment that could have interfered with the interpretation of behavioural changes in the conditioned emotional response (CER). We used the CER test which had previously been used to show anxiolytic effects of acute CBD (Bitencourt et al. 2008; Resstel et al. 2006), but we agree that the elevated plus maze could also be an appropriate test, given that it would be useful to find converging effects in a number of anxiety test procedures. Maha Elbatsh for the authors