Pomegranate juice attenuates acetaminophen induced hepatotoxicity in rat model of experiment

Background: Pomegranate fruit has high contents of various polyphenols and antioxidants due to which it possesses variety of therapeutic properties. In particular, pomegranate fruit peel and flowers have exhibited high antioxidant activity in different studies. Acetaminophen (APAP) overdose is the most common cause of drug induced liver toxicity including both accidental and intentional types. In our study, we investigated the protecting mechanism of pomegranate fruit juice (PJ) against toxicity caused by APAP in Wistar rats.Methods: Rats were fed with 0.2% (w/v) pomegranate fruit extract as prophylaxis to counter single dose of APAP (2 g/kg, p.o). After that variation in levels of glutathione, glutathione peroxidase (GPx), and glutathione reductase (GR) were marked.Results: A single dose of APAP elevated serum toxicity markers including lipid peroxidation. A simultaneous sharp depletion of glutathione and its metabolizing enzymes glutathione peroxidase (GPx), glutathione reductase (GR) was observed. Oral doses of PJ at (0.1% & 0.2% w/v) caused a significant (P<0.001) reduction in toxicity marker enzymes. A striking elevation in antioxidant armory was seen as in response to PJ.Conclusion: The results provide a clear picture of the defensive effect of PJ against APAP induced hepatic toxicity

Toxicity of Vernonia anthelmintica Linn. (Asteracea) seeds against mosquitoes vectors

The Toxicological activity (larvicidal, adulticidal and repellent toxicity) of Vernonia anthelmintica seeds fraction was tested against different species of mosquito vectors viz, malaria (Anopheles culicifacies and Anopheles stephensi), filaria (Culex quinquefasciatus) and dengue (Aedes aegypti). The larvicidal toxicity of Vernonia anthelmintica seeds fraction was evaluated against the early 4th instars larvae of different mosquitoes species. Mean LC50 value of the column fraction KAL-4 from seeds of V. anthelmintica against the larvae of An. culicifacies, An. stephensi, Culex quinquifaciatus and Aedes aegpyti were found to be 64 ppm, 70 ppm, 143 ppm and 166 ppm respectively. The larvicidal toxicity was more against An. culicifacies, An. stephensi than Culex quinquifaciatus and Aedes aegypti. The seed extracts did not show any adulticidal toxicity and repellent toxicity even at 10% concentrated impregnated paper and 5% on human hand, respectively

Antidiabetic potential of Moringa oleifera Lam. leaf extract in type 2 diabetic rats, and its mechanism of action

Purpose: To explore the antidiabetic potential of Moringa oleifera leaf extract in type 2 diabetic rats, and the underlying mechanisms.Methods: Streptozotocin (STZ) at a dose of 40 mg/kg was given to high fat diet (HFD)- fed rats to induce type 2 diabetes. M. oleifera leaf extract at doses 100, 200 and 400 mg/kg were given to 3 groups of type 2 diabetic rats. The area under curve (AUC) of glucose and homeostasis model assessment of insulin resistance (HOMA-R) were calculated using appropriate formulas, whereas levels of glucose,insulin, peroxisome proliferator activated receptor-γ (PPARγ, dipeptidyl peptidase-IV (DPP-IV) and inflammatory cytokines (IL-6, IL-1β and TNFα) were assayed using ELISA kits.Results: The leaf extract of M. oleifera significantly reduced the levels of glucose, insulin and cytokines in treated type 2 diabetic groups (p &lt; 0.05). DC group had significantly increased AUC for glucose, whereas the extract-treated groups showed significant&nbsp; decrease in glucose AUC. There was significant decrease in insulin sensitivity parameters, as indicated by increase in HOMA-R and decrease in PPARγ levels in the DC group (p &lt; 0.05). However, treatment with the M. oleifera extract reversed this trend via marked decrease in HOMA-R level and significant rise in PPARγ level. In contrast, the extract had no effect on DPP-IV concentration in diabetic treated groups (p &lt; 0.05).Conclusion: These results indicate that M. oleifera leaf extract mitigates hyperglycemia in type 2 DM by modulating hyperinsulinemia, PPARγ and inflammatory cytokines. Thus, the extract is a potential source of drug for the management of type 2 DM. Keywords: Moringa oleifera, Diabetes mellitus, Streptozotocin, Peroxisome proliferator activated receptor-γ, Dipeptidyl peptidase I

Catha edulis active principle, cathinone, suppresses motor coordination, accelerates the anxiety and alters the levels of dopamine and its metabolites in the limbic areas of male Swiss albino mice

Cathinone, the active principle of khat (Catha edulis), stimulates, excites and produces euphoric feelings in khat users. Locomotor and rearing activities, either individual or in groups, of male Swiss albino mice were decreased significantly compared to the control. Motor coordination tests (rotarod, rope climb and grip tests) have shown decreased motor performance in the mice treated with cathinone compared to the control. The elevated plus maze test has shown significant anxiety in the mice compared to the control. Contents of dopamine and its metabolite, homovanillic acid, were increased in the limbic areas compared to the control group. In contrast, contents of 3,4-dihydroxyphenyl acetic acid were depleted significantly and dose dependently compared to the control group in the limbic areas of mice. In conclusion, natural cathinone has depleted motor coordination, accelerated anxiety in mice and altered the contents of dopamine and its metabolites

Enhancement of antifungal activity and transdermal delivery of 5-flucytosine via tailored spanlastic nanovesicles: statistical optimization, in-vitro characterization, and in-vivo biodistribution study

Aim and background: This current study aimed to load 5-flucytosine (5-FCY) into spanlastic nanovesicles (SPLNs) to make the drug more efficient as an antifungal and also to load the 5-FCY into a hydrogel that would allow for enhanced transdermal permeation and improved patient compliance.Methods: The preparation of 5-FCY-SPLNs was optimized by using a central composite design that considered Span 60 (X1) and the edge activator Tween 80 (X2) as process variables in achieving the desired particle size and entrapment efficiency. A formulation containing 295.79 mg of Span 60 and 120.00 mg of Tween 80 was found to meet the prerequisites of the desirability method. The optimized 5-FCY-SPLN formulation was further formulated into a spanlastics gel (SPG) so that the 5-FCY-SPLNs could be delivered topically and characterized in terms of various parameters.Results: As required, the SPG had the desired elasticity, which can be credited to the physical characteristics of SPLNs. An ex-vivo permeation study showed that the greatest amount of 5-FCY penetrated per unit area (Q) (mg/cm2) over time and the average flux (J) (mg/cm2/h) was at the end of 24 h. Drug release studies showed that the drug continued to be released until the end of 24 h and that the pattern was correlated with an ex-vivo permeation and distribution study. The biodistribution study showed that the 99mTc-labeled SFG that permeated the skin had a steadier release pattern, a longer duration of circulation with pulsatile behavior in the blood, and higher levels in the bloodstream than the oral 99mTc-SPNLs. Therefore, a 5-FCY transdermal hydrogel could possibly be a long-acting formula for maintenance treatment that could be given in smaller doses and less often than the oral formula

Nephroprotective Effect of Zingerone against CCl4-Induced Renal Toxicity in Swiss Albino Mice: Molecular Mechanism

The protective effects of Zingerone against CCl4 induced nephrotoxicity in Swiss albino mice via modulation of metabolizing enzyme, oxidative stress, inflammatory cytokines, and apoptosis. The biochemical estimation indicated that the BUN and creatinine were significantly increased in group 2 (CCl4) compared to group 1 (normal) which was significantly reduced after treatment with Zingerone in group 3 when compared with group 2. The CCl4 treatment has significantly increased TBARS levels and reduced the antioxidant enzyme such as GSH, GPx, GR, GST, CAT, and SOD in group 2 compared to group 1, while the Zingerone treatment showed significant reduction in TBARS levels and increased the antioxidant enzymes in group 3 (CCl4 + Zingerone) as compared to group 2. Similarly, it was observed that CCl4 significantly increased the cytokines such as IL-1β, IL-2, and TNFα levels in group 2 as compared to group 1. The treatment with Zingerone significantly attenuated the levels of IL-1β, IL-2, and TNFα in group 3 compared to group 2. Caspase 3 and caspase 9 were also significantly increased in CCl4-treated group 2, whereas Zingerone treatment significantly reduced the elevated levels of caspases 3 and 9 in group 3 compared to group 2

Priming of signal transducer and activator of transcription proteins for cytokine-triggered polyubiquitylation and degradation by the A_2a adenosine receptor

Here we demonstrate that overexpression of the human A2a adenosine receptor (A2AAR) in vascular endothelial cells confers an ability of interferon-α and a soluble IL-6 receptor/IL-6 (sIL-6Rα/IL-6) trans-signaling complex to trigger the down-regulation of signal transducer and activator of transcription (STAT) proteins. It is noteworthy that STAT down-regulation could be reversed by coincubation with A2AAR-selective inverse agonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385) but not adenosine deaminase, suggesting that constitutive activation of the receptor was responsible for the effect. Moreover, STAT down-regulation was selectively abolished by proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132), whereas lysosome inhibitor chloroquine was without effect. Down-regulation required Janus kinase (JAK) activity and a Tyr705→Phe-mutated STAT3 was resistant to the phenomenon, suggesting that JAK-mediated phosphorylation of this residue is required. Consistent with this hypothesis, treatment of A2AAR-overexpressing cells with sIL-6Rα/IL-6 triggered the accumulation of polyubiquitylated wild-type but not Tyr705→Phe-mutated STAT3. Support for a functional role of this process was provided by the observation that A2AAR overexpression attenuated the JAK/STAT-dependent up-regulation of vascular endothelial growth factor receptor-2 by sIL-6Rα/IL-6. Consistent with a role for endogenous A2AARs in regulating STAT protein levels, prolonged exposure of endogenous A2AARs in endothelial cells with ZM241385 in vitro triggered the up-regulation of STAT3, whereas deletion of the A2AAR in vivo potentiated STAT1 expression and phosphorylation. Together, these experiments support a model whereby the A2AAR can prime JAK-phosphorylated STATs for polyubiquitylation and proteasomal degradation and represents a new mechanism by which an anti-inflammatory seven-transmembrane receptor can negatively regulate JAK/STAT signaling

Thymoquinone Ameliorates Doxorubicin-Induced Cardiotoxicity in Swiss Albino Mice by Modulating Oxidative Damage and Cellular Inflammation

Thymoquinone is the active constituent of Nigella sativa, having antioxidant and anti-inflammatory actions. In present study, we have analyzed the effects of thymoquinone on doxorubicin (DOX) induced cardiotoxicity in mice. In this experiment, thirty mice (25–35 gm) were divided into five groups (Groups A, B, C, D, and E) each containing six animals. Normal saline was given to a control group (Group A) for 14 days. Cardiotoxicity was induced by DOX (15 mg/kg, i.p.) in Group B, once on the 13th day of the study, and Groups C and D also received DOX (15 mg/kg, i.p.) and were then treated with thymoquinone (10 and 20 mg/kg, b/w, p.o.), respectively, for 14 days. Group E was given only thymoquione (20 mg/kg b/w, p.o.). A blood serum marker (AST, ALT, CK-MB, and LDH) and oxidative stress marker (LPO, GSH, CAT, SOD, GPx, GR, and GST) were evaluated. Results revealed that serum enzyme marker like aspartate aminotransferase (AST), creatinine kinase-MB (CKMB), and lactate dehydrogenase (LDH) were significantly elevated in Group B as compare to Group A. Similarly, the oxidative stress marker lipid peroxidation (LPO) was also elevated in Group B while the antioxidant enzyme catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase (CAT, SOD, GPx, GR, and GST) were also decreased in Group B. The treatment with thymoquinone 10 and 20 mg/kg resulted in a significant decrease in the serum marker and increase in the antioxidant enzymes. In this study, we have found that thymoquinone prevented DOX-induced cardiotoxicity by accelerating heart antioxidant defense mechanisms and down regulating the LPO levels towards normalcy in Groups C and D. The effect of doxorubicin increases the inflammatory cytokine (IL2) in Group B as compared to Group A, and it overcomes by the thymoquinone in Groups C and D. Thus, thymoquinone may have utility as a potential drug for cardiomyopathy