Ondansetron attenuates cisplatin-induced behavioral and cognitive impairment through downregulation of NOD-like receptor inflammasome pathway.

Cisplatin is an effective and commonly used chemotherapeutic drug; however, its use is accompanied by several adverse effects, including chemobrain. Ondansetron is a 5-HT3 antagonist, commonly used in prophylactic against chemotherapy-induced nausea and vomiting. Moreover, it has been identified as a novel neuroprotective agent in different animal models. However, its protective role against chemotherapy-induced chemobrain has not been investigated. The current study was the first study that explored the potential neuroprotective effect of ondansetron against cisplatin-induced chemobrain in rats. Cisplatin (5 mg/Kg) was injected intraperitoneally, once weekly, for 4 weeks with the daily administration of ondansetron (0.5 and 1 mg/Kg). Compared to the cisplatin-treated group, ondansetron administration showed a significant decrease in the latency time and a significant increase in ambulation, rearing, and grooming frequency in the open field test (OFT). Moreover, a significant improvement in the latency time in the rotarod and passive avoidance tests, following ondansetron administration. In addition, ondansetron treatment increased the percentage of alternation in the Y-maze test. Also, ondansetron showed a remarkable enhancement in the biochemical parameters in the hippocampus. It increased the acetylcholine (Ach) level and decreased the level of the acetylcholine esterase enzyme (AchE). Ondansetron significantly decreased interleukin-1ß (Il-1ß), tumor necrosis factor-alpha (TNF-α), toll-like receptor-4 (TLR-4), NOD-like receptor-3 (NLRP3) inflammasome as well as caspase-1 and caspase-3 levels. Furthermore, ondansetron significantly decreased the levels of copper transporter-1(CTR1) expression in the hippocampus. Collectively, these findings suggest that ondansetron may exhibit a neuroprotective and therapeutic activity against cisplatin-induced chemobrain.

Neuroprotective effects of indole-3-carbinol on the rotenone rat model of Parkinson's disease: Impact of the SIRT1-AMPK signaling pathway.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder. Although mounting studies have been conducted, no effective therapy is available to halt its progression. Indole-3-carbinol (I3C) is a naturally occurring compound obtained by ß-thioglucosidase-mediated autolysis of glucobrassicin in cruciferous vegetables. Besides its powerful antioxidant activity, I3C has shown neuroprotection against depression and chemically induced neurotoxicity via its anti-inflammatory and antiapoptotic effects. This study aimed to investigate the neuroprotective effects of I3C against rotenone (ROT)-induced PD in male albino rats. The possible protective mechanisms were also explored. PD was induced by subcutaneous administration of ROT (2 mg/kg) for 28 days. The effects of I3C (25, 50, and 100 mg/kg/day) were assessed by catalepsy test (bar test), spontaneous locomotor activity, rotarod test, weight change, tyrosine hydroxylase (TH) expression, α-synuclein (α-Syn) expression, striatal dopamine (DA) content, and histological examination. The highest dose of I3C (100 mg/kg) was the most effective to prevent ROT-mediated motor dysfunctions and amend striatal DA decrease, weight loss, neurodegeneration, TH expression reduction, and α-Syn expression increase in both the midbrain and striatum. Further mechanistic investigations revealed that the neuroprotective effects of I3C are partially attributed to its anti-inflammatory and antiapoptotic effects and the activation of the sirtuin 1/AMP-activated protein kinase pathway. Altogether, these results suggested that I3C could attenuate biochemical, molecular, and functional changes in a rat PD model with following repeated rotenone exposures.

Nebivolol elicits a neuroprotective effect in the cuprizone model of multiple sclerosis in mice: emphasis on M1/M2 polarization and inhibition of NLRP3 inflammasome activation.

BACKGROUND AND AIM: Multiple sclerosis (MS) is a demyelinating neurodegenerative inflammatory disease affecting mainly young adults. Microgliosis-derived neuroinflammation represents a key hallmark in MS pathology and progression. Nebivolol (Neb) demonstrated antioxidant, anti-inflammatory and neuroprotective properties in several brain pathologies. This study was conducted to investigate the potential neuroprotective effect of Neb in the cuprizone (Cup) model of MS. METHODS: C57Bl/6 mice were fed 0.2% Cup mixed into rodent chow for 5 weeks. Neb (5 and 10 mg/kg/day) was administered by oral gavage during the last 2 weeks. RESULTS: Neb prevented Cup-induced weight loss and motor deficits as evidenced by increased latency to fall in the rotarod test and enhanced locomotor activity as compared to Cup-intoxicated mice. Neb reversed Cup-induced demyelination as confirmed by Luxol fast blue staining and myelin basic protein western blotting. Administration of Neb modulated microglial activation status by suppressing M1 markers (Iba-1, CD86, iNOS, NO and TNF-α) and increasing M2 markers (Arg-1 and IL-10) as compared to Cup-fed mice. Furthermore, Neb hindered NLRP3/caspase-1/IL-18 inflammatory cascade and alleviated oxidative stress by reducing lipid peroxidation, as well as increasing catalase and superoxide dismutase activities. CONCLUSION: These findings suggest the potential neuroprotective effect of Neb in the Cup-induced model of MS in mice, at least partially by virtue of shifting microglia towards M2 phenotype, mitigation of NLRP3 inflammasome activation and alleviation of oxidative stress.

Rosuvastatin and low-dose carvedilol combination protects against isoprenaline-induced myocardial infarction in rats: Role of PI3K/Akt/Nrf2/HO-1 signalling.

Rosuvastatin has been shown to activate PI3K/Akt/Nrf2/HO-1 pathway, which promotes cell survival in the myocardium. This study investigated the therapeutic benefit of adding rosuvastatin to low-dose carvedilol in protection against myocardial infarction (MI). Rosuvastatin (RSV) and carvedilol (CAR) were given for 7 consecutive days with concurrent administration of two doses of isoprenaline (ISP) on 6th and 7th days to induce MI. Isoprenaline injections caused detrimental alterations in the myocardial architecture and electrocardiogram (ECG) pattern and significantly increased the infarct size, heart index and serum levels of cardiotoxicity markers compared to the control group. ISP induced oxidative damage, inflammatory and apoptotic events and downregulated PI3K/Akt/Nrf2/HO-1 signalling pathway compared to the control values. Treatment with low-dose CAR and/or RSV prevented the ECG and histopathological alterations induced by ISP, and also reduced the infarct size, heart index, serum creatine kinase-MB, cardiac troponin-I and C-reactive protein levels compared to ISP group. CAR and/or RSV treatment restored the activity of superoxide dismutase and total antioxidant capacity with a consequent reduction in lipid peroxides level. Further, they decreased the expression of nuclear factor (NF)-κB (p65) and increased the phosphorylated PI3K and Akt, which may activate the anti-apoptotic signalling as evidenced by the decreased active caspase 3 level. The combination therapy has a more significant effect in the most studied parameters than their monotherapy, which may be because of the activation of PI3K/Akt Nrf2/HO-1 pro-survival signalling pathway. This study highlights the potential benefits of combining RSV with low-dose CAR in case of MI.

Pre-treatment with cardamonin protects against cisplatin-induced nephrotoxicity in rats: impact on NOX-1, inflammation and apoptosis.

Cisplatin is an effective anti-cancer drug; however, its clinical use is usually associated with nephrotoxicity as a dose-limiting side effect. Several molecular mechanisms have been found to be involved in this nephrotoxicity such as oxidative stress, inflammation and apoptosis. The aim of this study was to explore the potential nephroprotective effect of cardamonin, a flavone found in Alpinia plant, in a rat model of cisplatin-induced nephrotoxicity. The possible mechanisms underlying this nephroprotective effect were investigated. Cardamonin was given at two different doses; 10 and 30mg/kg orally for two weeks, starting one week before giving a single nephrotoxic dose of cisplatin (7mg/kg). Acute nephrtoxicity was evident by significantly increased blood urea nitrogen and serum creatinine levels. Also, cisplatin increased lipid peroxidation and depleted reduced glutathione level and superoxide dismutase. Additionally, cisplatin showed a marked pro-inflammatory response as evidenced by significant increase in tissue levels of IL-1ß, TNF-α, NF-kB, iNOS, ICAM-1 and MCP-1. Pre-treatment with cardamonin significantly attenuated the nephrotoxic effects, oxidative stress and inflammation induced by cisplatin, in a dose-dependent manner. Also, cardamonin decreased caspase-3 expression and Bax/Bcl-2 ratio as compared to cisplatin group. Besides, cradamonin reversed cisplatin-induced decrease in EGF. Furthermore, up-regulation of NOX-1 was found to be involved in cisplatin-induced nephrotoxicity and its expression was significantly reduced by cardamonin. Histopathological examination further confirmed the nephroprotective effect of cardamonin. Moreover, pre-treatment with subtoxic concentration of cardamonin has significantly enhanced cisplatin cytotoxic activity in four different human cancer cell lines; hela, hepG2, PC3 and HCT116 cancer cell lines. In conclusion, these findings suggest that cardamonin improves therapeutic index of cisplatin and that NOX-1 is partially involved in the pathogenesis of cispaltin-induced nephrotoxicity.

Neuroprotective effect of empagliflozin against doxorubicin-induced chemobrain in rats: Interplay between SIRT-1/MuRF-1/PARP-1/NLRP3 signaling pathways and enhanced expression of miRNA-34a and LncRNA HOTAIR.

Chemobrain, a challenging side effect of doxorubicin (DOX)-based chemotherapy, impairs cognitive abilities in cancer survivors. DOX triggers chemobrain via oxidative stress, leading to inflammation and apoptosis. Empagliflozin (EMPA), a sodium glucose co-transporter-2 inhibitor, demonstrated neuroprotective effects by reducing reactive oxygen species (ROS) and inflammation, but its protective mechanisms against DOX-induced chemobrain is not fully known. Thus, this study aimed to investigate EMPA's neuroprotective effects on DOX-induced chemobrain in rats and to uncover the underlying protective mechanisms. Fifty male Wistar rats were divided into control, EMPA, DOX (2 mg/kg, IP, once/week for 4 weeks), and two treated groups (DOX+ EMPA 5 and 10 mg/kg/day, PO, for 4 weeks). Behavioral tests showed improved memory, motor performance, and reduced anxiety in EMPA-treated groups compared to DOX, with superior results at the higher dose. Histopathological analysis revealed increased intact neurons in the cortex and hippocampus in EMPA-treated groups, with 346.4 % increase in CA3 (p < 0.0001), 19.1 % in dentate gyrus (p = 0.0006), and 362.6 % in cortex (p < 0.0001) in the high-dose EMPA group. Biochemical investigations of the high-dose EMPA group revealed significant decreases in inflammatory and apoptotic markers (JNK/PARP-1/NLRP3/MuRF-1/FOXO-1), increased SIRT-1 protein expression by 389.9 % (p < 0.0001), and reduced miRNA-34a and LncRNA HOTAIR gene expression (50.4 % and 53.4 % respectively, p < 0.0001) relative to DOX group. Conclusively, EMPA demonstrated superior behavioral and histopathological outcomes particularly at higher dose, positioning it as a promising neuroprotective candidate against DOX-induced chemobrain, possibly through modulating SIRT-1, NF-κb, NLRP3, and oxidative stress pathways.

Coenzyme Q10 ameliorates cyclophosphamide-induced chemobrain by repressing neuronal apoptosis and preserving hippocampal neurogenesis: Mechanistic roles of Wnt/ ß-catenin signaling pathway.

Deterioration in the neurocognitive function of cancer patients referred to as "Chemobrain" is a devastating obstacle associated with cyclophosphamide (CYP). CYP is an alkylating agent, clinically utilized as an efficient anticancer and immunosuppressant. Coenzyme Q10 (CoQ10) is a worthwhile micronutrient with diverse biological activities embracing antioxidant, anti-apoptotic, and neuroprotective effects. The current experiment was designed for investigating the neuroprotective capability of CoQ10 versus CYP-elicited chemobrain in rats besides elucidating the causal molecular mechanisms. Male Sprague Dawley rats received CoQ10 (10 mg/kg, orally, once daily, for 10 days) and/or a single dose of CYP (200 mg/kg i.p. on day 7). CoQ10 counteracted CYP-induced cognitive and motor dysfunction as demonstrated by the findings of neurobehavioral tests (passive avoidance, Y maze, locomotion, and rotarod tests). Histopathological analysis further affirmed the neuroprotective abilities of CoQ10. CoQ10 effectually diminished CYP-provoked oxidative injury by restoring the antioxidant activity of catalase (CAT) enzyme while reducing malondialdehyde (MDA) levels. Besides, CoQ10 efficiently repressed CYP-induced neuronal apoptosis by downregulating the expression of Bax and caspase-3 while upregulating the Bcl-2 expression. Moreover, CoQ10 hampered CYP-provoked upregulation in acetylcholinesterase (AChE) activity. Furthermore, CoQ10 considerably augmented hippocampal neurogenesis by elevating the expressions of brain-derived neurotrophic factor (BDNF) and Ki-67. These promising neuroprotective effects can be credited to upregulating Wnt/ß-catenin pathway as evidenced by the elevated expressions of Wnt-3a, ß-catenin, and Phoshpo-glycogen synthase kinase-3 ß (p-GSK-3ß). Collectively, these findings proved the neuroprotective capabilities of CoQ10 against CYP-induced chemobrain through combating oxidative injury, repressing intrinsic apoptosis, boosting neurogenesis, and eventually upregulating the Wnt/ß-catenin pathway.

Lycopene and Chrysin through Mitigation of Neuroinflammation and Oxidative Stress Exerted Antidepressant Effects in Clonidine-Induced Depression-like Behavior in Rats.

Depression is a severely debilitating psychiatric disorder that influences more than 15% of the population worldwide. It has been demonstrated that it is associated with a high risk of developing other diseases such as cardiovascular diseases, diabetes, stroke, epilepsy, and cancer. The current study examines the possibility of chrysin and lycopene having an antidepressant effect in a rat model of depression induced by clonidine, as well as the mechanisms underlying this effect, including the role of neuroinflammation and oxidative stress. Rats were allotted into seven groups. The rats in group 1 served as a control. Group 2 received lycopene only. Group 3 was provided chrysin only. Group 4 was administered clonidine and served as the model. Group 5 was offered lycopene and clonidine. Group 6 was administered chrysin and clonidine. Group 7 was given FLX and clonidine and represented the standard. The experiment lasted two weeks, during which behavioral, biochemical, histopathological, and immunohistochemical measurements were performed. Lycopene and chrysin were used to correct the concentrations of noradrenaline and serotonin hippocampal tissue concentrations. These findings were also improved by immunohistochemical analysis of GFAP, VEGF, caspase3, and histopathological examinations, in which pretreatment of rats with lycopene and chrysin reversed all clonidine-induced alterations. The current research demonstrates that lycopene and chrysin have an auspicious antidepressant effect against clonidine that provoked behavioral hopelessness in rats. Manipulating oxidative stress, inflammation, and apoptosis may partially represent the corrective mechanism for the neuroprotective actions against the depressive effect of clonidine.

Forskolin alleviates cisplatin-induced acute renal toxicity in rats.

CONTEXT: Renal toxicity correlated with cisplatin administration curbs its clinical application. Accordingly, the identification of novel protective agents is important. Forskolin provides anti-inflammatory, anti-oxidant as well as anti-cancer effects. OBJECTIVES: This study aimed to explore the nephroprotective effect of forskolin in a model of cisplatin-induced acute renal toxicity in rats in addition to exploring the possible mechanisms. METHODS: Rats were sorted into four groups: control group, cisplatin group, cisplatin/forskolin group that was given forskolin (10 mg/kg, i.p.) 1 week before cisplatin and forskolin-only group. Nephrotoxicity markers were tested in the blood. Tissues were used to assess histopathology, oxidative stress, inflammation and apoptosis. KEY FINDINGS: In cisplatin-injected rats, the nephrotoxicity indices were particularly increased. Cisplatin markedly reduced the levels of reduced glutathione and superoxide dismutase. Also, malondialdehyde and Nicotinamide adenine dinucleotide phosphate oxidase were increased. In addition, the pro-inflammatory cytokines and caspase-3 were elevated. Moreover, the epidermal growth factor expression was significantly reduced. Furthermore, marked histopathological changes were noted in the tissues of cisplatin-injected rats. Forskolin attenuated nephrotoxicity markers, inflammation, oxidative stress and apoptotic insults provoked via cisplatin. Moreover, cisplatin cytotoxic activity was not modulated by forskolin in human cultured cancerous cell lines. CONCLUSION: Forskolin provides significant protection from cisplatin-evoked nephrotoxicity enhancing its therapeutic index.

The ameliorative effect of niclosamide on bile duct ligation induced liver fibrosis via suppression of NOTCH and Wnt pathways.

Liver fibrosis is the conjoint consequence of almost all chronic liver diseases. Cholestatic liver injury is a significant stimulus for fibrotic liver. This study was conducted to investigate the hepatoprotective effect of niclosamide as a NOTCH inhibitor and on the Wnt pathway against cholestatic liver fibrosis (CLF) which was experimentally induced by bile duct ligation (BDL). Rats were randomly divided into five main groups (6 per group): sham, BDL, BDL/niclosamide 5, BDL/niclosamide 10 and niclosamide 10 only group. Niclosamide was administered intraperitoneally (i.p.) for 4 weeks starting at the same day of surgery at doses 5 and 10 mg/kg. Liver function, cholestasis, oxidative stress, inflammation, liver fibrosis, NOTCH signaling pathway and Wnt pathway markers were assessed. Niclosamide (5 and 10 mg/kg) significantly reduced liver enzymes levels, oxidative stress, inflammation and phosphorylated signal transducer and activator of transcription3 (p-STAT3). Niclosamide (5 and 10 mg/kg) also significantly reduced NOTCH pathway (Jagged1, NOTCH2, NOTCH3, HES1, SOX9), Wnt pathway (Wnt5B, and Wnt10A), and fibrosis (transforming growth factor-beta1 (TGF-ß1), alpha smooth muscle actin (α-SMA) and collagen deposition with more prominent effect of the higher dose 10 mg/kg. So, this study presents nicloamide as a promising antifibrotic agent in CLF through inhibition of NOTCH and Wnt pathways.

Saxagliptin ameliorated the depressive-like behavior induced by chronic unpredictable mild stress in rats: Impact on incretins and AKT/PI3K pathway.

Depression is a widespread, withering illness, resulting in a massive personal suffering and economic loss. The chronic exposure to stress may be involved in the etiology of human psychiatric disorders; such as depression. In the current study, the animals were subjected to chronic unpredictable mild stress (CUMS) for 14 days. Saxagliptin (SAXA) is a member of dipeptidyl peptidase-4 (DPP-4) inhibitors class. The current study was the first one to examine the anti-depressive effect of SAXA in an experimental model of CUMS-induced depression in rats and the possible underlying mechanisms. Animals were orally treated with SAXA (0.5, 1 and 2 mg/kg) for 14 days. SAXA treatment reversed the CUMS-induced alterations in the behavioral, biochemical as well as histopathological parameters. Moreover, it hindered the CUMS-induced increase in the oxidative stress, inflammatory, and apoptotic markers. On the other hand, it increased the monoamines levels and the neurogenic brain derived neurotrophic factor (BDNF). In addition, SAXA treatment increased the incretin hormones, glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which are linked to the activation of protein kinase B (AKT)/phosphatidylinositol3-kinase (PI3K) pathway. In conclusion, the current study revealed that the modulation of the interplay between the key events involved in depression, including oxidative stress, inflammation, and GLP-1/PI3K/AKT signaling pathway, can explain the anti-depressant activity of SAXA.

Mechanistic insights into the protective effect of paracetamol against rotenone-induced Parkinson's disease in rats: Possible role of endocannabinoid system modulation.

Parkinson's disease (PD) is a disabling progressive neurodegenerative disease. So far, PD's treatment remains symptomatic with no curative effects. Aside from its blatant analgesic and antipyretic efficacy, recent studies highlighted the endowed neuroprotective potentials of paracetamol (PCM). To this end: the present study investigated: (1) Possible protective role of PCM against rotenone-induced PD-like neurotoxicity in rats, and (2) the mechanisms underlying its neuroprotective actions including cannabinoid receptors' modulation. A dose-response study was conducted using three doses of PCM (25, 50, and 100 mg/kg/day, i.p.) and their effects on body weight changes, spontaneous locomotor activity, rotarod test, tyrosine hydroxylase (TH) and α-synuclein expression, and striatal dopamine (DA) content were evaluated. Results revealed that PCM (100 mg/kg/day, i.p.) halted PD motor impairment, prevented rotenone-induced weight loss, restored normal histological tissue structure, reversed rotenone-induced reduction in TH expression and striatal DA content, and markedly decreased midbrain and striatal α-synuclein expression in rotenone-treated rats. Accordingly, PCM (100 mg/kg/day, i.p.) was selected for further mechanistic investigations, where it ameliorated rotenone-induced oxidative stress, neuro-inflammation, apoptosis, and disturbed cannabinoid receptors' expression. In conclusion, our findings imply a multi-target neuroprotective effect of PCM in PD which could be attributed to its antioxidant, anti-inflammatory and anti-apoptotic activities, in addition to cannabinoid receptors' modulation.

Protective effects of morin against depressive-like behavior prompted by chronic unpredictable mild stress in rats: Possible role of inflammasome-related pathways.

Depression is a common mental illness that possesses a noteworthy effect on patients' lives. Many theories are recently studied for their plausible involvement in depression pathogenesis, especially oxidative stress and inflammation. Morin (2',3,4',5,7-pentahydroxyflavone), a natural flavonoid, is characterized by its potent anti-inflammatory, and anti-oxidant activities. Accordingly, the aim of the current study was to investigate its potential protective anti-depressant effect in the model of chronic unpredictable mild stress (CUMS) in experimental rats. Moreover, the conceivable neuro-protective mechanisms, especially those related to the inflammasome pathway, were explored. Several, mild, unpredictable stressors were applied for 4 weeks concomitantly with the oral administration of morin (15 and 30 mg/Kg). Morin hydrate supplementations exhibited a significant improvement in the scores of the forced swimming and sucrose preference tests. In addition, it prompted a marked elevation in the ambulation, rearing as well as grooming scores of the open field test. The morin-treated groups showed a great improvement in the biochemical parameters in both the cortex and hippocampus, where it significantly elevated the serotonin, epinephrine, and norepinephrine levels. Also, it significantly increased reduced glutathione levels and decreased malondialdehyde levels. Regarding the inflammasome pathway, morin significantly decreased the tissue levels of tumor necrosis factor-alpha, toll-like receptor-4, interleukin-1beta, NOD-like receptor pyrin domain-containing protein-3, and caspase-1 levels. Morin also significantly decreased the level of the key apoptotic marker, caspase-3. In conclusion, these findings propose that morin might show a promising anti-depressant effect.

Dibenzazepine Attenuates Against Cisplatin-Induced Nephrotoxicity in Rats: Involvement of NOTCH Pathway.

Cisplatin is one of the standard anti-cancer agents that are used to treat variety of solid tumors. Nevertheless, due to the accumulation of cisplatin in the renal epithelial cells, nephrotoxicity was found to be the main side effect that limits its clinical use. The current study was conducted to assess the potential nephroprotective effect of dibenzazepine, a Notch inhibitor, against cisplatin-induced nephrotoxicity in rats as well as the possible mechanisms underlying this nephroprotection. The rats were pre-treated with 2 mg/kg dibenzazepine for 7 days before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Cisplatin induced acute nephrotoxicity, where blood urea nitrogen and serum creatinine levels were significantly increased. Besides, lipid peroxidation was markedly elevated and the levels of reduced glutathione and catalase were significantly reduced. Also, the tissue levels of the pro-inflammatory mediators; IL-1ß, TNF-α, and NF-kB, were significantly increased in the cisplatin group. The pre-treatment with dibenzazepine significantly mitigated the nephrotoxic effects of cisplatin, the oxidative stress and inflammatory status as well as decreased caspase-3 expression, as compared to the cisplatin group. Furthermore, the up-regulation of Notch-1 and Hes-1 was found to be involved in cisplatin-induced nephrotoxicity and their expression was significantly reduced by dibenzazepine. The nephroprotective effect of dibenzazepine was further confirmed by the histopathological assessment. Moreover, dibenzazepine pre-treatment of hela and PC3 cells in vitro did not antagonize the cisplatin anti-cancer activity. In conclusion, these findings show that dibenzazepine provides protection against cisplatin-induced nephrotoxicity. Moreover, the up-regulation of the Notch pathway was shown to play a role in the pathogenesis of cisplatin-induced renal injury.

Hepatoprotective Effect of Cranberry Nutraceutical Extract in Non-alcoholic Fatty Liver Model in Rats: Impact on Insulin Resistance and Nrf-2 Expression.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a pathological accumulation of triglycerides (TGs) in the hepatocyte in the absence of alcohol intake. Untreated NAFLD is expected to progress into liver fibrosis. Cranberry is rich in polyphenols with antioxidant and anti-inflammatory activities. HYPOTHESIS: The present study was performed to evaluate our hypothesis of the possible anti-fibrotic effect of cranberry nutraceuticals in a high fat cholesterol diet induced (HFCD)-NAFLD in rats, focusing on improving insulin sensitivity and modulating the expression of nuclear factor erythroid-2-related factor-2 (Nrf2) (a transcription factor responsible for regulating cellular redox balance). METHOD: Male albino wistar rats (12 weeks) received HFCD and/or cranberry (50 and 100 mg/kg/day, three times/week) orally for 8 consecutive weeks. RESULTS: In comparison to the HFCD group, cranberry treated groups (50 and 100 mg/kg) showed marked hepatoprotection, where it significantly decreased liver enzymes (alanine transaminases by 49 and 64% and aspartate transaminases by 45 and 64%; respectively), TGs, and ameliorated the histopathological alterations (such as inflammatory cells infiltration and ballooning degeneration) induced by HFCD. Cranberry also alleviated oxidative stress (malondialdehyde, glutathione, catalase and superoxide dismutase) and inflammation (tumor necrosis factor- alpha, interleukine-6 and nuclear factor kappa-b) and significantly reduced the HOMA-IR and TyG index. On the other hand, cranberry treated groups (50 and 100 mg/kg) showed a marked increase in the expression of adiponectin, by 8 and 13-fold, insulin receptor substrate-2 by 21 and 79%, and Nrf2 by 13 and 61%, respectively. Notably, cranberry significantly reduced the fibrotic markers, TGF-ß and α-SMA expression and collagen deposition. CONCLUSION: The present study showed that cranberry significantly attenuated NAFLD, in a dose dependent manner, which could be partially recognized by its antioxidant, anti-inflammatory activities, and its ability to improve insulin sensitivity. Notably, our study proves for the first time that the anti-fibrotic activity of cranberry is promising.

Cytotoxic effects of 2-methoxyestradiol in the hepatocellular carcinoma cell line HepG2.

AIM: The study was designed to examine the potential cytotoxicity of 2-methoxyestradiol (2ME2), a natural 17beta-estradiol metabolite, in hepatocellular carcinoma and the possible underlying mechanisms for this cytotoxicity. METHODS: The cell line HepG2 was treated with different concentrations of 2ME2 for 48 and 72 h. RESULTS: Using the sulforhodamine B assay, HepG2 was sensitive to the cytotoxic effect of 2ME2. 2ME2 induced cell arrest at the G(2)/M phase and a significant high percentage of apoptotic cells compared to the control group. Also, 2ME2 induced a significant increase in caspase 9 enzymatic activity after 48 and 72 h of treatment compared with control values. The DNA laddering was observed only in cells treated for 72 h. Furthermore, 2ME2 induced a significant decrease in the expression levels of vascular endothelial growth factor (VEGF) gene compared to the control values. CONCLUSION: 2ME2 exerts cytotoxic activity in the HepG2 cell line by preferential cell blocking at the G(2)/M phase as well as induction of apoptosis as evidenced by increased caspase 9 enzymatic activity and observed DNA laddering in 2ME2-treated HepG2 cells. In addition, a reduction in hypervascularity is an important postulated mechanism as indicated by the significant reduction in the expression of VGEF, one of the most important angiogenic factors.

Wogonin pre-treatment attenuates cisplatin-induced nephrotoxicity in rats: Impact on PPAR-γ, inflammation, apoptosis and Wnt/ß-catenin pathway.

Cisplatin, a platinum chemotherapeutic agent, is used in a diversity of malignancies; nevertheless, the excessive nephrotoxicity following cisplatin treatment is the dose-limiting devastating reaction. This study was designed to explore the possible nephroprotective impact of wogonin, a forceful anti-oxidant, anti-inflammatory, and anti-tumor agent, in a rat model of cisplatin-induced renal injury. The potential nephroprotective mechanisms were additionally investigated. Wogonin was given at a dose of 40 mg/kg. Acute nephrotoxicity was indicated by a significant rise in BUN, and serum creatinine levels in cisplatin-injected rats. Also, cisplatin enhanced the lipid peroxidation, diminished GSH, catalase, and PPAR-γ levels. Additionally, cisplatin-injected rats showed a significant rise in tissue levels of IL-1ß, TNF-α, NF-kB, and caspase-3 enzymatic activity. Notably, the pre-treatment with wogonin ameliorated the nephrotoxicity indices, oxidative stress, inflammation, and apoptosis induced by cisplatin. Also, wogonin up-regulated PPAR-γ expression. The involvement of Wnt/ß-catenin pathway was debatable; however, our findings showed that it was significantly induced by cisplatin. Wogonin pre-treatment markedly attenuated Wnt/ß-catenin pathway. Collectively, these findings imply that wogonin is a promising nephroprotective agent that improves the therapeutic index of cisplatin via reducing oxidative stress, inflammation as well as inducing PPAR-γ. Also, Wnt/ß-catenin pathway is partially involved in the pathogenesis of cisplatin nephrotoxicity.

The potential antifibrotic impact of apocynin and alpha-lipoic acid in concanavalin A-induced liver fibrosis in rats: Role of NADPH oxidases 1 and 4.

Liver fibrosis results from chronic inflammation that precipitates excessive accumulation of extracellular matrix. Oxidative stress is involved in its pathogenesis. This study aimed to elucidate the potential antifibrotic effect of the NADPH oxidase (NOX) inhibitor, apocynin against concanavalin A (ConA)-induced immunological model of liver fibrosis, and to investigate the ability of the antioxidant, alpha-lipoic acid (α-LA) to potentiate this effect. Rats were treated with apocynin and/or α-LA for six weeks. Hepatotoxicity indices, oxidative stress, insulin, NOXs, inflammatory and liver fibrosis markers were assessed. Treatment of animals with apocynin and α-LA significantly ameliorated the changes in liver functions and histopathological architecture induced by ConA. Liver fibrosis induced by ConA was evident where alpha-smooth muscle actin and transforming growth factor- beta1 were elevated, which was further confirmed by Masson's trichrome stain and increased hydroxyproline. Co-treatment with apocynin and α-LA significantly reduced their expression. Besides, apocynin and α-LA significantly ameliorated oxidative stress injury evoked by ConA, as evidenced by enhancing reduced glutathione content, antioxidant enzymes activities and decreasing lipid peroxides. ConA induced a significant elevation in serum insulin level and inflammatory markers; tumor necrosis factor-alpha, interleukin-6 and nuclear factor kappa b. Furthermore, the mRNA tissue expression of NOXs 1 and 4 was found to be elevated in the ConA group. All these elevations were significantly reduced by apocynin and α-LA co-treatment. These findings indicate that using apocynin and α-LA in combination possess marked antifibrotic effects, and that NOX enzymes are partially involved in the pathogenesis of ConA-induced liver fibrosis.