Anti-viral Effects of Pavetta indica Methanolic Extract and Acyclovir on Behavioral and Biochemical Parameters in Streptozotocin-induced Alzheimer's Disease in Rats.

BACKGROUND: Alzheimer's disease is a neurological dysfunction of the brain caused by neurodegeneration and oxidative stress. Some viruses, such as herpes viruses, HSV-1, and HSV-2, are causative agents of Alzheimer's disease and result in ß-amyloid peptide and tau protein accumulation in the brain. Some antiviral drugs, such as valacyclovir, acyclovir, and foscarnet, reduce amyloid-beta and P-tau. Pavetta indica leaves are also reported for their antiviral properties. The current study aimed to find out the significance of using Pavetta indica methanolic extract and acyclovir against Alzheimer's disease induced by streptozotocin. METHODS: Wistar rats received acyclovir and Pavetta indica methanolic extract orally at different dose ranges (50, 150, 450 mg/kg) and (125, 250, 500 mg/kg), respectively. The standard therapy, Rivastigmine (2 mg/kg), was given orally. RESULTS: Intracerebroventricular-streptozotocin produced significant alternations in behavioral assessments, including locomotor activity test, Morris water maze test, and elevated plus maze test. Moreover, intracerebroventricular-streptozotocin ameliorated the antioxidant defense activity by decreasing levels of catalase, superoxide dismutase, and reduced glutathione while enhancing the oxidative stress markers, including malondialdehyde, and total nitrite levels. Finally, the main findings showed that intracerebroventricular-streptozotocin significantly increased the inflammatory marker, tumor necrosis factor-α, and disturbed neurotransmitter mediators, including levels of acetylcholinesterase, glutamate, and γ-amino butyric acid. CONCLUSION: In a dose-dependent manner, acyclovir and Pavetta indica methanolic extract treatments abrogated the streptozotocin-induced behavioral and neurological abnormalities in rats. The potential therapeutic effects of PIME and acyclovir administration in intracerebroventricular-streptozotocin-treated rats may be attributed to its potential antiviral, antioxidant, and anti-inflammatory effects. The current study suggests that Pavetta indica methanolic extract and acyclovir are promising therapeutic targets against Alzheimer's disease.

Comparative effects of incretin-based therapy on doxorubicin-induced nephrotoxicity in rats: the role of SIRT1/Nrf2/NF-κB/TNF-α signaling pathways.

Introduction: Nephrotoxicity represents a major complication of using doxorubicin (DOX) in the management of several types of cancers. Increased oxidative stress and the activation of inflammatory mediators play outstanding roles in the development of DOX-induced kidney damage. This study aimed to investigate whether the two pathways of incretin-based therapy, glucagon-like peptide-1 receptor agonist (presented as semaglutide, SEM) and dipeptidyl peptidase-4 inhibitor (presented as alogliptin, ALO), differentially protect against DOX-induced nephrotoxicity in rats and to clarify the underlying molecular mechanisms. Methods: Adult male rats were divided into six groups: control (received the vehicle), DOX (20 mg/kg, single I.P. on day 8), DOX + ALO (20 mg/kg/day, P.O. for 10 days), DOX + SEM (12 µg/kg/day, S.C. for 10 days), ALO-alone, and SEM-alone groups. At the end of the study, the animals were sacrificed and their kidney functions, oxidative stress, and inflammatory markers were assessed. Kidney sections were also subjected to histopathological examinations. Results: The co-treatment with either ALO or SEM manifested an improvement in the kidney functions, as evidenced by lower serum concentrations of creatinine, urea, and cystatin C compared to the DOX group. Lower levels of MDA, higher levels of GSH, and increased SOD activity were observed in either ALO- or SEM-treated groups than those observed in the DOX group. DOX administration resulted in decreased renal expressions of sirtuin 1 (SIRT1) and Nrf2 with increased NF-κB and TNF-α expressions, and these effects were ameliorated by treatment with either ALO or SEM. Discussion: Co-treatment with either ALO or SEM showed a renoprotective effect that was mediated by their antioxidant and anti-inflammatory effects via the SIRT1/Nrf2/NF-κB/TNF-α pathway. The fact that both pathways of the incretin-based therapy demonstrate an equally positive effect in alleviating DOX-induced renal damage is equally noteworthy.

Dihydromyricetin protects against gentamicin-induced nephrotoxicity via upregulation of renal SIRT3 and PAX2.

AIM: Gentamicin-induced nephrotoxicity limits its widespread use as an effective antibacterial agent. Oxidative stress, inflammatory cytokines and apoptotic cell death are major participants in gentamicin-induced nephrotoxicity. We therefore, investigated whether dihydromyricetin (DHM), the antioxidant and anti-inflammatory flavonoid, could protect against the nephrotoxic effects of gentamicin. METHODS: Male Wistar rats administrated gentamicin (100 mg/kg/day, i.p.) for 8 days. DHM (400 mg/kg, p.o.) was concurrently given with gentamicin for 8 days. Control group received the vehicle of DHM and gentamicin. Histopathological examinations, biochemical measurements and immunohistochemical analyses were done at the end of the study. KEY FINDINGS: Treatment with DHM improved the gentamicin induced deterioration of renal functions; serum levels of urea, creatinine and cystatin-C as well as urinary levels of Kim-1 and NGAL, the sensitive indicators for early renal damage, were declined. Additionally, DHM abrogated gentamicin-induced changes in kidney morphology. These nephroprotective effects were possibly mediated via decreasing renal gentamicin buildup, activating the antioxidant enzymes GSH, SOD and CAT and decreasing lipid peroxidation and nitric oxide levels. Further, DHM suppressed renal inflammation and apoptotic cell death by decreasing the expression of nuclear factor-kappa B (NF-κB), TNF-alpha and caspase-3. These effects were correlated to the upregulation of renal SIRT3 expression. Also, DHM activated the regeneration and replacement of injured tubular cells with new ones via enhancing PAX2 expression. SIGNIFICANCE: DHM is a promising therapeutic target that could prevent acute renal injury induced by gentamicin and help renal tubular cells to recover through its antioxidant, anti-inflammatory and antiapoptotic properties.

Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity.

BACKGROUND: Methotrexate (MTX) is an effective anticancer, anti-inflammatory, and immunomodulatory agent. However, it induces a serious pneumonitis that leads to irreversible fibrotic lung damage. This study addresses the protective role of the natural flavonoid dihydromyricetin (DHM) against MTX-induced pneumonitis via modulation of Nrf2/NF-κB signaling crosstalk. METHODS: Male Wistar rats were divided into 4 groups: control, which received the vehicle; MTX, which received a single MTX (40 mg/kg, i.p) at day 9 of the experiment; (MTX + DHM), which received oral DHM (300 mg/kg) for 14 days and methotrexate (40 mg/kg, i.p) on the 9th day; and DHM, which received DHM (300 mg/kg, p.o) for 14 days. RESULTS: Lung histopathological examination and scoring showed a decline in MTX-induced alveolar epithelial damage and decreased inflammatory cell infiltration by DHM treatment. Further, DHM significantly alleviated the oxidative stress by decreasing MDA while increasing GSH and SOD antioxidant levels. Additionally, DHM suppressed the pulmonary inflammation and fibrosis through decreasing levels of NF-κB, IL-1ß, and TGF-ß1 while promoting the expression of Nrf2, a positive regulator of antioxidant genes, and its downstream modulator, HO-1. CONCLUSION: This study identified DHM as a promising therapeutic target against MTX-induced pneumonitis via activation of Nrf2 antioxidant signaling while suppressing the NF-κB mediated inflammatory pathways.

Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis.

The anticancer drug methotrexate (MTX) is known to cause hepatotoxicity as a possibly fatal adverse effect that hinders its clinical application. Although the natural flavonoid, dihydromyricetin (DHM), has antioxidant and anti-inflammatory effects; its role against MTX-induced hepatotoxicity has not been explored yet. For this, rats were administrated DHM orally for two weeks at a dose of 300 mg/kg per day, with or without a single i.p. injection of 40 mg/kg MTX on the 9th day of the experiment. MTX caused deterioration in liver structure and function, depicted by an increase in liver enzymes; ALT and AST. Moreover, MTX induced oxidative stress, shown by increasing malondialdehyde and decreasing reduced glutathione and total antioxidant capacity, initiated the inflammatory response via upregulated expression of Toll-like receptor 4 (TLR4) and its downstream transcription factor, nuclear factor-kappa B (NF-κB p65). Consequent to TLR4 signaling cascade, Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammosome was activated and caused caspase 1 mediated transformation of proinflammatory cytokines interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) into their active forms. Interestingly, administering DHM with MTX improved liver structure and function, as well as significantly decreased all oxidative stress and inflammatory signaling. Collectively, DHM possesses antioxidant and anti-inflammatory properties that can ameliorate MTX-induced hepatotoxicity, through down-regulation of liver TLR4/NF-κB and therefore prohibit activation of NLRP3/caspase 1 pathway.

Protective effects of menthol against sepsis-induced hepatic injury: Role of mediators of hepatic inflammation, apoptosis, and regeneration.

Liver dysfunction in sepsis is a major complication that amplifies multiple organ failure and increases the risk of death. Inflammation and oxidative stress are the main mediators in the pathophysiology of sepsis. Therefore, we investigated the role of menthol, a natural antioxidant, against sepsis-induced liver injury in female Wistar rats. Sepsis was induced by cecal ligation and puncture (CLP). Menthol (100 mg/kg) was given intragastric 2 h after CLP. Blood samples and liver tissues were collected 24 h after surgery. Menthol significantly (p < 0.05) attenuated the sepsis-induced elevation in serum liver enzymes and improved the hepatic histopathological changes. Menthol treatment significantly (p < 0.05) decreased hepatic levels of tumor necrosis factor-alpha, malondialdehyde, total nitrite, and cleaved caspase-3. It restored the hepatic levels of superoxide dismutase and reduced glutathione. Additionally, menthol significantly (p < 0.05) increased hepatic levels of B-cell lymphoma 2 (Bcl-2); an anti-apoptotic factor, and proliferating cell nuclear antigen (PCNA), a biomarker of regeneration and survival. Our results showed the therapeutic potential of menthol against liver injury induced by sepsis.

Protective effect of empagliflozin on gentamicin-induced acute renal injury via regulation of SIRT1/NF-κB signaling pathway.

Gentamicin is a highly effective antibiotic. However, its major complication is nephrotoxicity. This study investigated the beneficial effects of empagliflozin against gentamicin-induced nephropathy. Kidney damage was induced in male Wistar rats by administration of gentamicin (100 mg/kg/day, i.p.) for 8 days. Two doses of empagliflozin (10 and 20 mg/kg, p.o.) were concomitantly given with gentamicin for 8 days. Gentamicin administration increased serum creatinine, urea, and cystatin C concentrations. Empagliflozin in both doses ameliorated these changes via mitigation of gentamicin-induced increase in renal oxidative stress, inflammation, and apoptosis. Empagliflozin added to GM treatment led to lower measured levels of TGF-B, NF-κB and caspase 3, and only the higher dose increased PAX2 levels indicating an improvement in tubular regeneration. Additionally, empagliflozin (20 mg/kg/day) markedly prevented gentamicin-induced histopathological changes. The protective effects of empagliflozin may be mediated by decreasing gentamicin concentration in renal tissue and possibly other effects like antioxidant and antiapoptotic effects.

Cardioprotective effect of allyl isothiocyanate in a rat model of doxorubicin acute toxicity.

Doxorubicin (DOX) is an effective anthracycline chemotherapeutic drug. Nevertheless, the cardiotoxicity adverse effect restricts its clinical benefit. Allyl isothiocyanate (AITC) is a natural antioxidant and anti-inflammatory agent. In the present study, we investigated the effect of AITC on cardiotoxicity of DOX. Thirty-two adult male albino rats were divided into four groups; control, AITC, DOX, and AITC + DOX. AITC was administrated orally (25 mg/kg/day) for 7 days, and DOX was given as a single i.p. injection (15 mg/kg) on the third day. Mortality rate was observed during the experiment. Cardiac toxicity markers (lactate dehydrogenase (LDH), creatine kinase (CK-MB), and cardiac Troponin I (cTn-I)) were evaluated in serum samples obtained from all groups after 48 hours of DOX injection. DOX-treated group showed 40% mortality and a significant increase in cardiac enzymes. This increase was accompanied by degenerated cardiomyocytes, and inflammatory cells infiltrates. Interestingly, AITC administration alleviated myocardial oxidative stress induced by DOX as attenuated the increase in malondialdehyde (MDA), and nitric oxide (NO) while resulted in elevations of the antioxidant reduced glutathione (GSH) level as well as superoxide dismutase (SOD) activity. Furthermore, the inflammatory cytokine, TNF-α, was reduced upon administration of AITC with DOX. The cardio-protection of AITC is attributed to increase the expression of cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2). Subsequently, heme oxygenase 1 (HO-1) level was elevated by AITC to correct the oxidative stress induced by DOX in the heart. Accordingly, AITC ameliorated acute cardiotoxicity associated with DOX treatment via attenuation of oxidative stress and the induced-tissue inflammatory injury. Abbreviations: DOX: doxrubicin; Nrf2: nuclear factor erythroid 2-related factor 2; HO-1: heme oxygenase 1; AITC: ally isothiocyanate; MDA: malondialdehyde; SOD: superoxide dismutase; GSH: reduced glutathione; TNF-α: tumor necrosis factor alpha.

Optimized Self-Nanoemulsifying Delivery System Based on Plant-Derived Oil Augments Alpha-Lipoic Acid Protective Effects Against Experimentally Induced Gastric Lesions.

Peptic ulcer disease is an injury of the alimentary tract that leads to a mucosal defect reaching the submucosa. Alpha-lipoic acid (ALA), a natural potent antioxidant, has been known as a gastroprotective drug yet its low bioavailability may restrict its therapeutic efficacy. This study aimed to formulate and optimize ALA using a self-nanoemulsifying drug delivery system (SNEDDS) with a size of nano-range, enhancing its absorption and augmenting its gastric ulcer protection efficacy. Three SNEDDS components were selected as the design factors: the concentrations of the pumpkin oil (X1, 10-30%), the surfactant tween 80 (X2, 20-50%), and the co-surfactant polyethylene glycol 200 (X3, 30-60%). The experimental design for the proposed mixture produced 16 formulations with varying ALA-SNEDDS formulation component percentages. The optimized ALA-SNEDDS formula was investigated for gastric ulcer protective effects by evaluating the ulcer index and by the determination of gastric mucosa oxidative stress parameters. Results revealed that optimized ALA-SNEDDS achieved significant improvement in gastric ulcer index in comparison with raw ALA. Histopathological findings confirmed the protective effect of the formulated optimized ALASNEDDS in comparison with raw ALA. These findings suggest that formulation of ALA in SNEDDS form would be more effective in gastric ulcer protection compared to pure ALA.

Abnormal cannabidiol confers cardioprotection in diabetic rats independent of glycemic control.

Chronic GPR18 activation by its agonist abnormal cannabidiol (trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; abn-cbd) improves myocardial redox status and function in healthy rats. Here, we investigated the ability of abn-cbd to alleviate diabetes-evoked cardiovascular pathology and the contribution of GPR18 to this effect. Four weeks after diabetes induction by streptozotocin (STZ, 55mg/kg; i.p), male Wistar rats received abn-cbd, the GPR18 antagonist (1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-,cyclohexen-1-yl]benzene;O-1918), their combination (100µg/kg/day, i.p, each) or their vehicle for 2 weeks. Abn-cbd had no effect on diabetes-evoked cardiac hypertrophy or impaired glycemic control (hyperglycemia and hypoinsulinemia), but alleviated the associated reductions in left ventricular (LV) contractility (dP/dtmax) and relaxation (dP/dtmin) indices, and the increases in LV end diastolic pressure (LVEDP) and cardiac vagal dominance. Abn-cbd also reversed myocardial oxidative stress by restoring circulating and cardiac nitric oxide (NO) and adiponectin (ADN) levels and enhancing GPR18 expression and phosphorylation of Akt, ERK1/2 and eNOS in diabetic rats' hearts. Concurrent GPR18 blockade (O-1918) abrogated all favorable effects of abn-cbd in diabetic rats. Collectively, the current findings present evidence for abn-cbd alleviation of diabetes-evoked cardiovascular anomalies likely via GPR18 dependent restoration of cardiac adiponectin-Akt-eNOS signaling and the diminution of myocardial oxidative stress.

The Effect of Chronic Activation of the Novel Endocannabinoid Receptor GPR18 on Myocardial Function and Blood Pressure in Conscious Rats.

Although acute activation of the novel endocannabinoid receptor GPR18 causes hypotension, there are no reports on GPR18 expression in the heart or its chronic modulation of cardiovascular function. In this study, after demonstrating GPR18 expression in the heart, we show that chronic (2 weeks) GPR18 activation with its agonist abnormal cannabidiol (abn-cbd; 100 µg·kg·d; i.p) produced hypotension, suppressed the cardiac sympathetic dominance, and improved left ventricular (LV) function (increased the contractility index dp/dtmax and reduced LV end-diastolic pressure, LVEDP) in conscious rats. Ex vivo studies revealed increased: (1) cardiac and plasma adiponectin (ADN) levels; (2) vascular (aortic) endothelial nitric oxide synthase (eNOS) expression, (3) vascular and serum nitric oxide (NO) levels; (4) myocardial and plasma cyclic guanosine monophosphate (cGMP) levels; (5) phosphorylation of myocardial protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) along with reduced myocardial reactive oxygen species (ROS) in abn-cbd treated rats. These biochemical responses contributed to the hemodynamic responses and were GPR18-mediated because concurrent treatment with the competitive GPR18 antagonist (O-1918) abrogated the abn-cbd-evoked hemodynamic and biochemical responses. The current findings present new evidence for a salutary cardiovascular role for GPR18, mediated, at least partly, via elevation in the levels of adiponectin.

Quercetin augments the protective effect of losartan against chronic doxorubicin cardiotoxicity in rats.

The present study aimed to examine whether the co-administration of quercetin (QRN) and losartan (LOS) can produce additional protective effects against chronic DOX cardiotoxicity. Cardiotoxicity in rats was induced by intraperitoneal injection of doxorubicin (DOX) in a cumulative dose of 15mg/kg for two weeks. Results revealed that DOX administration exhibited elevated serum levels of TNF-α, creatine kinase (CK-MB), lactate dehydrogenase (LDH) in addition to increased myocardial lipid peroxide (MDA) and nitric oxide (NO) alongside attenuating cardiac antioxidant defense system of superoxide dismutase (SOD) and catalase (CAT) activities. DOX produced leukocyte infiltration and myocardial lesions. Pretreatment with QRN (10mg/kg, orally) solely or in combination with LOS (0.7mg/kg, orally) for 6 weeks markedly ameliorated all these biochemical characteristics, and substantially reduced the myocardium peroxidative damage. The protective effects obtained by LOS were more pronounced by its combination with QRN. Our results suggest that quercetin potentially augmented the cardioprotective effect of losartan against chronic DOX cardiotoxicity via its antioxidant and anti-inflammatory properties.