Modulatory effect of liraglutide on doxorubicin-induced testicular toxicity and behavioral abnormalities in rats: role of testicular-brain axis.

Doxorubicin (DOX) is a powerful chemotherapeutic agent used in many types of malignancies. However, its use results in testicular damage. DOX-induced testicular damage results in low level of serum testosterone which may affect cognitive function. The current study investigated the protective effect of liraglutide (50, 100 µg/kg/day) in testicular toxicity and the consequent cognitive impairment induced by DOX. DOX treatment reduced sperm count (62%) and sperm motility (53%) and increased sperm abnormalities (786%), as compared to control group. DOX also reduced serum testosterone level (85%) and the gene expression of testicular 3ß-HSD (68%) and 17ß-HSD (82%). Moreover, it increased testicular oxidative stress (MDA and GSH) by 103% and 59%, respectively, apoptotic (caspase-3 and P53) by 996% and 480%, respectively. In addition, DOX resulted in increasing autophagic markers including PAKT, mTOR, and LC3 by 48%, 56%, and 640%, respectively. Additionally, rats' behavior in Y-maze (60%) and passive avoidance task (85%) was disrupted. The histopathological results of testis and brain supported the biochemical findings. Treatment with liraglutide (100 µg/kg/day) significantly abrogated DOX-induced testicular damage by restoring testicular architecture, increasing sperm count (136%) and sperm motility (106%), and decreasing sperm abnormalities (84%) as compared to DOX group. Furthermore, liraglutide increased serum testosterone (500%) and steroidogenesis enzymes 3ß-HSD (105%) and 17ß-HSD (181%) along with suppressing oxidative stress (MDA and GSH) by 23% and 85%, respectively; apoptotic (caspase-3 and P53) by 59% and55%, respectively; and autophagic markers including PAKT, mTOR, and LC3 by 48%, 97%, and 60%, respectively. Moreover, it enhanced the memory functions in passive avoidance and Y-maze tests (132%). In conclusion, liraglutide is a putative agent for protection against DOX-induced testicular toxicity and cognitive impairment through its antioxidant, antiapoptotic, and antiautophagic effects.

Roflumilast escalates α-synuclein aggregate degradation in rotenone-induced Parkinson's disease in rats: Modulation of the ubiquitin-proteasome system and endoplasmic reticulum stress.

Perturbation of the protein homeostasis circuit is one of the principal attributes associated with many neurodegenerative disorders, such as Parkinson's disease (PD). This study aimed to explore the neuroprotective effect of roflumilast (ROF), a phosphodiesterase-4 inhibitor, in a rotenone-induced rat model of PD and investigate the potential underlying mechanisms. Interestingly, ROF (1 mg/kg, p.o.) attenuated motor impairment, prevented brain lesions, and rescued the dopaminergic neurons in rotenone-treated rats. Furthermore, it reduced misfolded α-synuclein burden. ROF also promoted the midbrain cyclic adenosine monophosphate level, which subsequently enhanced the 26S proteasome activity and the expression of the 20S proteasome. ROF counteracted rotenone-induced endoplasmic reticulum stress, which was demonstrated by its impact on activating transcription factor 6, glucose-regulated protein 78, and C/EBP homologous protein levels. Moreover, ROF averted rotenone-induced oxidative stress, as evidenced by its effects on the levels of nuclear factor erythroid 2-related factor 2, heme oxygenase-1, reduced glutathione, and lipid peroxides with a significant anti-apoptotic activity. Collectively, this study implies repurposing of ROF as a novel neuroprotective drug owning to its ability to restore normal protein homeostasis.

Glimepiride mitigates tauopathy and neuroinflammation in P301S transgenic mice: role of AKT/GSK3ß signaling.

BACKGROUND AND OBJECTIVE: Tauopathy is a group of neurodegenerative diseases in which the pathogenesis processes are related to tau protein. The imbalances between the activities of kinases and phosphatases of tau protein lead to tau hyperphosphorylation and subsequent neurodegeneration. Numerous studies suggest a strong linkage between type 2 diabetes mellitus (T2D) and neurodegenerative diseases. Therefore, finding a drug with a dual therapeutic activity against T2D and neuroprotective will be a promising idea. Hence, the potential neuroprotective effect of Glimepiride (GPD) against tauopathy was evaluated in the current study. METHODS: P301S mice model was employed for tauopathy and C57BL/6 wild type mice (WT) was used as control. Phosphorylated and acetylated tau protein levels was assessed in cortex and hippocampus by western blot. Effect of GPD on tauopathy related enzymes, neuroinflammation, apoptotic markers were evaluated. Furthermore, the neuroprotective effects against anxiety like behavior and motor impairment was analyzed using Parallel rod floor and Open field tests. RESULTS: GPD significantly ameliorates motor impairment, anxiety like behavior and neurodegeneration in P301S mice. Phosphorylated tau and acetylated tau were significantly decreased in both cortex and hippocampus of P301S mice via decreasing GSK3ß, increasing ratio of phosphorylated-AKT to total-AKT, increasing PP2A and normalization of CDK5 levels. Furthermore, GPD treatment also decreased neuroinflammation and apoptosis by reducing NF-kB, TNF-α and caspase 3 levels. CONCLUSION: The current data suggests that GPD exerts a protective effect against tauopathy, behavioural consequences, neurodegeneration, neuroinflammation and apoptosis. GPD is therefore a promising agent for the treatment of neurodegenerative diseases associated with tauopathy.

Potential role of Drug Repositioning Strategy (DRS) for management of tauopathy.

Tauopathy is a term that has been used to represent a pathological condition in which hyperphosphorylated tau protein aggregates in neurons and glia which results in neurodegeneration, synapse loss and dysfunction and cognitive impairments. Recently, drug repositioning strategy (DRS) becomes a promising field and an alternative approach to advancing new treatments from actually developed and FDA approved drugs for an indication other than the indication it was originally intended for. This paradigm provides an advantage because the safety of the candidate compound has already been established, which abolishes the need for further preclinical safety testing and thus substantially reduces the time and cost involved in progressing of clinical trials. In the present review, we focused on correlation between tauopathy and common diseases as type 2 diabetes mellitus and the global virus COVID-19 and how tau pathology can aggravate development of these diseases in addition to how these diseases can be a risk factor for development of tauopathy. Moreover, correlation between COVID-19 and type 2 diabetes mellitus was also discussed. Therefore, repositioning of a drug in the daily clinical practice of patients to manage or prevent two or more diseases at the same time with lower side effects and drug-drug interactions is a promising idea. This review concluded the results of pre-clinical and clinical studies applied on antidiabetics, COVID-19 medications, antihypertensives, antidepressants and cholesterol lowering drugs for possible drug repositioning for management of tauopathy.

Pharmacology of Diosmin, a Citrus Flavone Glycoside: An Updated Review.

Flavonoids are phytochemicals that are well known for their beneficial pharmacological properties. Diosmin is a flavone glycoside derived from hesperidin, a flavanone abundantly found in citrus fruits. Daflon is an oral phlebotonic flavonoid combination containing diosmin and hesperidin (9:1) that is commonly used for the management of blood vessel disorders. After oral administration, diosmin is converted to diosmetin, which is subsequently absorbed and esterified into glucuronide conjugates that are excreted in the urine. Pharmacological effects of diosmin have been investigated in several in vitro and in vivo studies, and it was found to possess anti-inflammatory, antioxidant, antidiabetic, antihyperlipidemic, and antifibrotic effects in different disease models. Diosmin also demonstrated multiple desirable properties in several clinical studies. Moreover, toxicological studies showed that diosmin has a favorable safety profile. Accordingly, diosmin is a potential effective and safe treatment for many diseases. However, diosmin exhibits inhibitory effects on different metabolic enzymes. This encourages the investigation of its potential therapeutic effect and safety in different diseases in clinical trials, while taking potential interactions into consideration.

Piceatannol ameliorates behavioural, biochemical and histological aspects in cisplatin-induced peripheral neuropathy in rats.

Peripheral neurotoxicity is a dose-limiting and a potentially lifelong persistent toxicity of cisplatin. This study investigated the possible protective effect of piceatannol (PIC) in a model of cisplatin-induced peripheral neuropathy in rats. PIC (10 mg/kg, i.p.) was given for 7 days, starting 2 days before cisplatin single injection (7 mg/kg, i.p.). Behavioural, biochemical and histological examinations were conducted. Cisplatin administration resulted in thermal hypoalgesia evidenced by increased paw and tail withdrawal latency times in the hotplate and tail flick tests, respectively, and reduced the abdominal constrictions in response to the acetic acid injection. Moreover, cisplatin treatment decreased rat locomotor activity and grip strength. These behavioural alterations were reversed by PIC coadministration. In addition, PIC decreased cisplatin-induced elevation in serum neurotensin and platinum accumulation in sciatic nerve. Also, PIC reversed, to a large extent, cisplatin-induced microscopical alterations in nerve axons and restored normal myelin thickness. Therefore, PIC may protect against cisplatin-induced peripheral neuropathy.

Non-alcoholic fatty liver disease: An overview of risk factors, pathophysiological mechanisms, diagnostic procedures, and therapeutic interventions.

Non-alcoholic fatty liver disease (NAFLD) is a disorder of excessive fat accumulation in the liver, known as steatosis, without alcohol overconsumption. NAFLD can either manifest as simple steatosis or steatohepatitis, known as non-alcoholic steatohepatitis (NASH), which is accompanied by inflammation and possibly fibrosis. Furthermore, NASH might progress to hepatocellular carcinoma. NAFLD and NASH prevalence is in a continuous state of growth, and by 2018, NAFLD became a devastating metabolic disease with a global pandemic prevalence. The pathophysiology of NAFLD and NASH is not fully elucidated, but is known to involve the complex interplay between different metabolic, environmental, and genetic factors. In addition, unhealthy dietary habits and pre-existing metabolic disturbances together with other risk factors predispose NAFLD development and progression from simple steatosis to steatohepatitis, and eventually to fibrosis. Despite their growing worldwide prevalence, to date, there is no FDA-approved treatment for NAFLD and NASH. Several off-label medications are used to target disease risk factors such as obesity and insulin resistance, and some medications are used for their hepatoprotective effects. Unfortunately, currently used medications are not sufficiently effective, and research is ongoing to investigate the beneficial effects of different drugs and phytochemicals in NASH. In this review article, we outline the different risk factors and pathophysiological mechanisms involved in NAFLD, diagnostic procedures, and currently used management techniques.

Protective and therapeutic effects of the flavonoid "pinocembrin" in indomethacin-induced acute gastric ulcer in rats: impact of anti-oxidant, anti-inflammatory, and anti-apoptotic mechanisms.

Peptic ulcer including gastric and duodenal ulcers is a common gastro-intestinal disorder worldwide, associated with a significant mortality due to bleeding and perforation. Numerous efforts are being exerted to look for natural drugs that lack the potential side effects but still keep beneficial effects for treatment and/or prevention of gastric ulcer. Pinocembrin (PINO) is a natural flavonoid retaining anti-microbial, anti-oxidant, and anti-inflammatory activities. The present study was conducted to investigate the protective and therapeutic effects of PINO against indomethacin (INDO)-induced gastric ulcer in rats and the possible underlying mechanisms. PINO (25 and 50 mg/kg) promoted mucus secretion, decreased ulcer index, and inhibited histopathological changes induced by INDO. Further investigation of possible mechanisms showed that PINO significantly attenuated INDO-induced oxidative and inflammatory responses in both doses when administrated before or after ulcer induction. PINO downregulated mRNA expression level of p38-mitogen-activated protein kinase (p38-MAPK) which subsequently inhibited NF-κB activation and inflammatory cytokine release including tumor necrosis factor-α (TNF-α) and interleukin-1beta (IL-1ß). Additionally, PINO inhibited apoptotic activity which was confirmed by downregulation of caspase-3 transcription. The current results demonstrated the promising therapeutic activity of PINO against INDO-induced gastric ulcer due to-at least partly-its anti-oxidant, anti-inflammatory, and anti-apoptotic effects.

Diosmin ameliorates inflammation, insulin resistance, and fibrosis in an experimental model of non-alcoholic steatohepatitis in rats.

Non-alcoholic steatohepatitis (NASH) is becoming of increasing significance due to its growing global prevalence and risk of progression to end-stage liver disease. This study was carried out to investigate the potential anti-inflammatory, insulin sensitizing, and antifibrotic effects of diosmin in an experimental model of NASH induced in rats using high-fat diet (HFD) and 30 mg/kg streptozotocin (STZ). Diosmin was administered orally at dose of 100 mg/kg for 8 weeks. Stained tissue sections were examined for histopathological signs of NASH, collagen deposition, and alpha smooth muscle actin (α-SMA) expression. In addition, insulin resistance, dyslipidemia, inflammation, and fibrosis markers were assessed. HFD/STZ successfully induced different NASH features such as insulin resistance seen by elevated fasting blood glucose levels and homeostasis model assessment for insulin resistance. Moreover, induced rats demonstrated dyslipidemia, a significant elevation in tumor necrosis factor alpha (TNF-α) and interleukin-6 levels, and an imbalance in the oxidative status of the liver. Those events altogether precipitated initiation of liver fibrosis as confirmed by elevated transforming growth factor beta (TGF-ß) levels. Treatment with diosmin demonstrated multiple beneficial effects as it significantly ameliorated histopathological NASH findings, lowered TNF-α, interleukin-6, and malondialdehyde levels, improved lipid and glucose metabolism, and lowered hepatic TGF-ß, α-SMA, and collagen content compared to untreated rats. The present study represents a drug repositioning scenario as diosmin is widely used for management of blood vessel disorders and is known to be well tolerated. This encourages the extension of our study to the clinical setting to explore diosmin effects in NASH patients.

The natural flavonoid galangin ameliorates dextran sulphate sodium-induced ulcerative colitis in mice: Effect on Toll-like receptor 4, inflammation and oxidative stress.

This study was carried out to investigate the potential therapeutic effect of galangin, a promising active principle of honeybee propolis, in dextran sulphate sodium (DSS)-induced colitis in mice. We explored the possible underlying mechanisms for galangin action and the therapeutic benefit of adding galangin to the standard therapy sulphasalazine. A galangin dose of 40 mg/kg was selected based on a preliminary dose-selection study for investigation in a 4-week cyclical model of DSS-induced colitis. Mice received 3% DSS in their drinking water during the first and third weeks and were administered the treatments (40 mg/kg galangin, 100 mg/kg sulphasalazine and a combination of 20 mg/kg galangin and 50 mg/kg sulphasalazine) daily starting from the second week. Galangin significantly ameliorated DSS-induced histopathological alterations and tissue injury, down-regulated Toll-like receptor 4 expression, suppressed NF-κB p65 activation, lowered inflammatory cytokine levels and demonstrated antioxidant effects. The combination of galangin and sulphasalazine at half doses yielded comparable results to either drug alone at full dose. This study highlights galangin as a promising therapy for colitis management.

Piceatannol protects against cisplatin nephrotoxicity via activation of Nrf2/HO-1 pathway and hindering NF-κB inflammatory cascade.

This study investigates the molecular mechanisms of the nephroprotective effect of piceatannol (PIC) against cisplatin-induced nephrotoxicity in rats. PIC (10 mg/kg i.p.) was given for 7 days, starting 2 days before cisplatin single injection (7 mg/kg i.p.). Serum creatinine, blood urea nitrogen (BUN), kidney injury molecule 1, and neutrophil gelatinase-associated lipocalin were used as nephrotoxicity markers. Oxidative stress, inflammatory, and apoptotic markers were determined. In addition, the role of PIC in Nrf2 activation and its subsequent induction of antioxidant enzymes, as well as its potential cross talk with nuclear factor kappa-B, were addressed. PIC reversed cisplatin-induced elevation of nephrotoxicity markers and restored the normal kidney ultrastructure. PIC attenuated cisplatin-induced reduction in Nrf2 expression and the relative mRNA level of antioxidant enzymes: hemeoxygenase-1, cysteine ligase catalytic, and modifier subunits, as well as superoxide dismutase and glutathione-S-transferase activities. Cisplatin pro-inflammatory response was reduced by PIC treatment as evidenced by the suppression of nuclear factor kappa-B activation and the subsequent decreased tissue levels of interleukin-1ß, tumor necrosis factor-α, cyclooxygenase-2, and inducible nitric oxide synthase. PIC suppressed cisplatin-induced apoptosis by decreasing p53 and cytochrome C expression and caspase-3 activity. Therefore, PIC may protect against cisplatin-induced nephrotoxicity by modulating Nrf2/HO-1 signaling and hindering the inflammatory and apoptotic pathways.

Telmisartan ameliorates carbon tetrachloride-induced acute hepatotoxicity in rats.

This study assessed the potential hepatoprotective effect of telmisartan (TLM), a selective angiotensin II type 1 (AT1 ) receptor blocker, on carbon tetrachloride (CCl4 )-induced acute hepatotoxity in rats. Intraperitoneal injection of male Wistar rats with CCl4 1 mL kg-1 , 1:1 mixture with corn oil for 3 days increased serum alanine transaminase, aspartate transaminase, and alkaline phosphatase activities as well as total bilirubin, triglycerides and total cholesterol levels. This is in addition to the disrupted histological architecture in the CCl4 group. Rats receiving CCl4 and co-treated with TLM (3 and 10 mg kg-1 , orally) showed ameliorated serum biochemical and histological changes almost to the control level. Nevertheless, rats treated with TLM (1 mg kg-1 ) didn't show any significant changes compared to CCl4 intoxicated group. In addition, TLM rectified oxidative status disrupted by CCl4 intoxication. Interestingly, TLM protected against CCl4 -induced expressions of nuclear factor-κB, inducible nitric oxide synthase and cyclooxygenase-II, in a dose related manner. Moreover, TLM (3 and 10 mg kg-1 ) significantly modified CCl4 -induced elevation in tumor necrosis factor-α and nitric oxide levels. Furthermore, TLM showed a marked decline in CD68+ cells stained areas and reduced activity of myeloperoxidase enzyme compared to CCl4 -intoxicated group. In conclusion, both doses of TLM (3 and 10 mg kg-1 ) showed significant hepato-protective effects. However, TLM at a dose of 10 mg kg-1 didn't show significant efficacy above 3 mg kg-1 which is nearly equivalent to the human anti-hypertensive dose of 40 mg. Thus, may be effective in guarding against several hepatic complications due to its antioxidant and anti-inflammatory activities. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 359-370, 2017.

A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens.

The study aim was to assess the inductive properties of artemisinin antimalarials using mephenytoin as a probe for CYP2B6 and CYP2C19 enzymatic activity. The population pharmacokinetics of S-mephenytoin and its metabolites S-nirvanol and S-4'-hydroxymephenytoin, including enzyme turn-over models for induction, were described by nonlinear mixed effects modeling. Rich data (8-16 samples/occasion/subject) were collected from 14 healthy volunteers who received mephenytoin before and during ten days of artemisinin administration. Sparse data (3 samples/occasion/subject) were collected from 74 healthy volunteers who received mephenytoin before, during and after five days administration of artemisinin, dihydroartemisinin, arteether, artemether or artesunate. The production rate of CYP2B6 was increased 79.7% by artemisinin, 61.5% by arteether, 76.1% by artemether, 19.9% by dihydroartemisinin and 16.9% by artesunate. The production rate of CYP2C19 increased 51.2% by artemisinin, 14.8% by arteether and 24.9% by artemether. In conclusion, all studied artemisinin derivatives induced CYP2B6. CYP2C19 induction by arteether and artemether as well as CYP2B6 and CYP2C19 induction by artemisinin was confirmed. The inductive capacity is different among the artemisinin drugs, which is of importance when selecting drugs to be used in antimalarial combination therapy such that the potential for drug-drug interactions is minimized.