QPGx-CARES: Qatar pharmacogenetics clinical applications and research enhancement strategies.

Pharmacogenetic (PGx)-informed medication prescription is a cutting-edge genomic application in contemporary medicine, offering the potential to overcome the conventional "trial-and-error" approach in drug prescription. The ability to use an individual's genetic profile to predict drug responses allows for personalized drug and dosage selection, thereby enhancing the safety and efficacy of treatments. However, despite significant scientific and clinical advancements in PGx, its integration into routine healthcare practices remains limited. To address this gap, the Qatar Genome Program (QGP) has embarked on an ambitious initiative known as QPGx-CARES (Qatar Pharmacogenetics Clinical Applications and Research Enhancement Strategies), which aims to set a roadmap for optimizing PGx research and clinical implementation on a national scale. The goal of QPGx-CARES initiative is to integrate PGx testing into clinical settings with the aim of improving patient health outcomes. In 2022, QGP initiated several implementation projects in various clinical settings. These projects aimed to evaluate the clinical utility of PGx testing, gather valuable insights into the effective dissemination of PGx data to healthcare professionals and patients, and identify the gaps and the challenges for wider adoption. QPGx-CARES strategy aimed to integrate evidence-based PGx findings into clinical practice, focusing on implementing PGx testing for cardiovascular medications, supported by robust scientific evidence. The current initiative sets a precedent for the nationwide implementation of precision medicine across diverse clinical domains.

Experimental approaches for induction of diabetes mellitus and assessment of antidiabetic activity: An in vitro and in vivo methodological review.

BACKGROUND: Diabetes mellitus poses a global health challenge, driving the need for innovative therapeutic solutions. Experimental methods play a crucial role in evaluating the efficacy of potential antidiabetic drugs, both in vitro and in vivo. Yet concerns about reproducibility persist, necessitating comprehensive reviews. OBJECTIVES: This review aims to outline experimental approaches for inducing diabetes and evaluating antidiabetic activity, synthesizing data from authoritative sources and academic literature. METHODS: We conducted a systematic search of prominent databases, including PubMed, ScienceDirect, and Scopus, to identify relevant articles spanning from 1943 to the present. A total of 132 articles were selected for inclusion in this review, focusing on in vitro and in vivo experimental validations of antidiabetic treatments. RESULTS: Our review highlights the diverse array of experimental methods employed for inducing diabetes mellitus and evaluating antidiabetic interventions. From cell culture assays to animal models, researchers have employed various techniques to study the effectiveness of novel therapeutic agents. CONCLUSION: This review provides a comprehensive guide to experimental approaches for assessing antidiabetic activity. By synthesizing data from a range of sources, we offer valuable insights into the current methodologies used in diabetes research. Standardizing protocols and enhancing reproducibility are critical for advancing effective antidiabetic treatments.

Ghrelin hormone a new molecular modulator between obesity and glomerular damage.

The incidence of glomerular diseases is increasing worldwide due to increased prevalence of obesity which is a major risk factor for type-2 diabetes mellitus and cardiovascular disorders.Ghrelin, an orexigenic peptide hormone, has been implicated in obesity, and its impact on the pathology and function of the kidneys was found to be significant. Ghrelin known to regulate energy homeostasis and growth hormone release, has been shown to modulate critical signaling pathways involved in the health and survival of podocytes. These derangements directly affect glomerular function and manifest as impaired glomerular filtration barrier and leakage of albumin into urine. Although the pathological features of the above-mentioned disorders are different, they interestingly lead to similar clinical features of glomerular damage. The pathological events are majorly initiated by endocrine imbalance leading to abnormal activation of downstream signaling pathways involved in the development of glomerulosclerosis. In fact, obesity increases the risk of developing chronic kidney disease by altering the secretion of pro-inflammatory cytokines and adipokines, activating the renin-angiotensin-aldosterone system (RAAS), promoting lipotoxicity, oxidative stress and fibrosis within the kidneys. Whilst these bioregulators are well described, their direct involvement in renal homeostasis is still mostly elusive. This review summarized previous and recent evidence on the endocrine properties of ghrelin and perivascular adipose tissue involved in modulating kidney physiology.

Gastro-protective effect of l-arginine against nitric oxide deficiency-related mucosal injury induced by indomethacin: Does age matter?

Gastric ulcer is a common disease with increased prevalence in the aged population. Aged gastric mucosa has increased susceptibility to injury along with nonsteroidal anti-inflammatory drugs use due to impaired mucosal defense and decreased vasodilator release. We investigated whether l-arginine could protect against age-related gastric ulceration induced by indomethacin. Aged and adult male Wistar rats were administered sole and combined treatment of  l-arginine and Nω -nitro-l-arginine methyl ester ( l-NAME) before induction of gastric ulceration by indomethacin. The gastroprotective effect of  l-arginine was displayed only in adult rats with indomethacin-induced gastric ulceration, as evidenced by a significant decrease in ulcer index, oxidative stress parameters, and mucosal myeloperoxidase activity along with increased mucosal PGE2 levels. Interestingly, the mucosal gene expressions of NF-кB, iNOS, and COX-2 were significantly suppressed by  l-arginine pretreatment and aggregated upon pretreatment with  l-NAME in both adult and aged rats treated with indomethacin. In conclusion,  l-arginine protected the rats' gastric mucosa against indomethacin-induced gastric ulceration, possibly, at least in part, by enhancement of mucosal nitric oxide/PGE2 content along with suppressing gastric inflammation and oxidative stress. This study supposed that the gastroprotective effect of  l-arginine depends on aging, and even so, the adoption of a new approach to gastric ulcer treatment for the aged population is warranted.

Paeonol Protects against Methotrexate Hepatotoxicity by Repressing Oxidative Stress, Inflammation, and Apoptosis-The Role of Drug Efflux Transporters.

Methotrexate (MTX) is an effective chemotherapeutic agent against a wide range of tumors and autoimmune diseases; however, hepatotoxicity limits its clinical use. Oxidative stress and inflammation have been implicated in the pathogenesis of MTX-induced hepatotoxicity. Paeonol is a natural phenolic compound reported for its antioxidant and anti-inflammatory properties. The current study aimed to investigate the protective effect of paeonol against MTX-induced hepatotoxicity in rats and various mechanisms that underlie this postulated effect. Paeonol was administered orally in a dose of 100 mg/kg, alone or along with MTX, for 10 days. Hepatotoxicity was induced via a single intraperitoneal dose of MTX (20 mg/kg) on day 5 of the experiment. Concomitant administration of paeonol with MTX significantly ameliorated distorted hepatic function and histological structure, restored hepatic oxidative stress parameters (MDA, NO, and SOD), and combated inflammatory response (iNOS and TNF-α). Additionally, paeonol enhanced cell proliferation and survival, evidenced by upregulating the proliferating cell nuclear antigen (PCNA) and suppressing apoptosis and the disposition of collagen fibers in rat livers treated with MTX. Importantly, paeonol upregulated the drug efflux transporters, namely P-glycoprotein (P-gp) and the multidrug resistance-associated protein 2 (Mrp-2) in MTX-treated rats. In conclusion, paeonol offered a potent protective effect against MTX-induced hepatotoxicity through suppressing oxidative stress, inflammation, fibrosis, and apoptosis pathways, along with P-gp and Mrp-2 upregulation.

Nephroprotective potential of eugenol in a rat experimental model of chronic kidney injury; targeting NOX, TGF-ß, and Akt signaling.

Chronic kidney disease is a crucial health problem associated with high morbidity and mortality. Eugenol is a natural phenolic plant compound with various pharmacological activities including antioxidant and anti-inflammatory properties. This study was designed to evaluate the possible protective effect of different eugenol doses in an experimental model of chronic CCl4-induced renal damage and investigate various mechanisms that underlie this postulated effect. Eugenol treatment (100 mg/kg) ameliorated kidney damage induced by CCl4 and rectified the distorted kidney function parameters and renal histological structure. Additionally, eugenol at a dose of 100 mg/kg suppressed the upregulated oxidative stress, inflammation and apoptosis in CCl4-treated rats as evident by down regulations of NADPH oxidase (NOX2 and NOX4), proinflammatory markers (IL-6 and TNF-α) and proapoptotic markers (cyt c and caspase-3), respectively. Importantly, eugenol co-administration in rats challenged with CCl4 downregulated the renal protein expressions of both TGF-ß as well as pAkt compared with CCl4 group. In conclusion, eugenol showed a potent nephroprotective effect against CCl4-induced renal damage through its antioxidant, anti-inflammatory and anti-fibrotic activities.

Cisplatin-Induced Reproductive Toxicity and Oxidative Stress: Ameliorative Effect of Kinetin.

Cisplatin is a commonly used chemotherapeutic agent; however, its potential side effects, including gonadotoxicity and infertility, are a critical problem. Oxidative stress has been implicated in the pathogenesis of cisplatin-induced testicular dysfunction. We investigated whether kinetin use at different concentrations could alleviate gonadal injury associated with cisplatin treatment, with an exploration of the involvement of its antioxidant capacity. Kinetin was administered in different doses of 0.25, 0.5, and 1 mg/kg, alone or along with cisplatin for 10 days. Cisplatin toxicity was induced via a single IP dose of 7 mg/kg on day four. In a dose-dependent manner, concomitant administration of kinetin with cisplatin significantly restored testicular oxidative stress parameters, corrected the distorted sperm quality parameters and histopathological changes, enhanced levels of serum testosterone and testicular StAR protein expression, as well as reduced the up-regulation of testicular TNF-α, IL-1ß, Il-6, and caspase-3, caused by cisplatin. It is worth noting that the testicular protective effect of the highest kinetin dose was comparable/more potent and significantly higher than the effects of vitamin C and the lowest kinetin dose, respectively. Overall, these data indicate that kinetin may offer a promising approach for alleviating cisplatin-induced reproductive toxicity and organ damage, via ameliorating oxidative stress and reducing inflammation and apoptosis.

TLRs-JNK/ NF-κB Pathway Underlies the Protective Effect of the Sulfide Salt Against Liver Toxicity.

Hydrogen sulfide (H2S) is an endogenously gas transmitter signaling molecule with known antioxidant, anti-inflammatory, and cytoprotective properties. Although accumulating evidence shows the therapeutic potential of H2S in various hepatic diseases, its role in cyclophosphamide (CP)-induced hepatotoxicity remains elusive. The present study was undertaken to investigate the impact of endogenous and exogenous H2S on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in CP-induced hepatotoxicity. Either an H2S donor (NaHS (100 µM/kg) or an H2S blocker [dl-propargylglycine (PAG) (30 mg/kg, i. p.)], was administered for 10 days before a single ip injection of CP (200 mg/kg). NaHS attenuated conferred hepatoprotection against CP-induced toxicity, significantly decreasing serum hepatic function tests and improving hepatic histopathology. Additionally, NaHS-treated rats exhibited antioxidant activity in liver tissues compared with the CP group. The upregulated hepatic levels of TLR2/4 and their downstream signaling molecules including c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) were also suppressed by NaHS protective treatment. NaHS showed anti-inflammatory and antiapoptotic effects; reducing hepatic level tumor necrosis factor-alpha (TNF-α) and caspase-3 expression. Interestingly, the cytotoxic events induced in CP-treated rats were not significantly altered upon the blocking of endogenous H2S. Taken together, the present study suggested that exogenously applied H2S rather than the endogenously generated H2S, displayed a hepatoprotective effect against CP-induced hepatotoxicity that might be mediated by TLRs-JNK/NF-κB pathways.

A population study of clinically actionable genetic variation affecting drug response from the Middle East.

Clinical implementation of pharmacogenomics will help in personalizing drug prescriptions and alleviate the personal and financial burden due to inefficacy and adverse reactions to drugs. However, such implementation is lagging in many parts of the world, including the Middle East, mainly due to the lack of data on the distribution of actionable pharmacogenomic variation in these ethnicities. We analyzed 6,045 whole genomes from the Qatari population for the distribution of allele frequencies of 2,629 variants in 1,026 genes known to affect 559 drugs or classes of drugs. We also performed a focused analysis of genotypes or diplotypes of 15 genes affecting 46 drugs, which have guidelines for clinical implementation and predicted their phenotypic impact. The allele frequencies of 1,320 variants in 703 genes affecting 299 drugs or class of drugs were significantly different between the Qatari population and other world populations. On average, Qataris carry 3.6 actionable genotypes/diplotypes, affecting 13 drugs with guidelines for clinical implementation, and 99.5% of the individuals had at least one clinically actionable genotype/diplotype. Increased risk of simvastatin-induced myopathy could be predicted in ~32% of Qataris from the diplotypes of SLCO1B1, which is higher compared to many other populations, while fewer Qataris may need tacrolimus dosage adjustments for achieving immunosuppression based on the CYP3A5 diplotypes compared to other world populations. Distinct distribution of actionable pharmacogenomic variation was also observed among the Qatari subpopulations. Our comprehensive study of the distribution of actionable genetic variation affecting drugs in a Middle Eastern population has potential implications for preemptive pharmacogenomic implementation in the region and beyond.

Nephroprotective effect of exogenous hydrogen sulfide donor against cyclophosphamide-induced toxicity is mediated by Nrf2/HO-1/NF-κB signaling pathway.

AIM: Cyclophosphamide (CP) is an effective anticancer and immunosuppressive agent. However, it induces nephrotoxicity that limits its use. This study explored the effect of H2S, an important biological signaling molecule with a cytoprotective activity, on CP-induced nephrotoxicity. METHODS: Male Wistar rats were treated with saline or NaHS (100 µM/kg/day, H2S donor) or dl-propargylglycine (PAG) (30 mg/kg/day, H2S blocker) for 10 days before a single i.p injection of CP (200 mg/kg). Then, rats were sacrificed, and renal functions were assessed in serum. Histopathological changes, as well as oxidant defenses, inflammatory and apoptotic markers in the renal tissue, were evaluated. KEY FINDINGS: Pretreatment with NaHS significantly reduced the urea and creatinine levels that were elevated in CP-intoxicated rats. NaHS increased the expression of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2) and its subsequent antioxidant proteins; heme oxygenase-1 (HO-1), NAD(P) H quinone oxidoreductase 1 (NQO1), reduced glutathione (GSH) and superoxide dismutase (SOD). Moreover, NaHS prohibited the histopathological damage induced by CP. The inhibition of caspase-3 and nuclear factor kappa B (NF-κB) supported the protective role of H2S against CP-induced kidney damage. On the other hand, blocking endogenous H2S did not provide a more significant deterioration in CP-induced nephrotoxicity in terms of oxidative stress or inflammatory status. SIGNIFICANCE: Exogenous H2S donors exhibited a protective effect against CP-induced nephrotoxicity, which may be mediated via the Nrf2/HO-1/NF-κB signaling pathway. However, endogenous H2S may be insufficient to protect the cell against the induced oxidative damage. This approach provides a novel target to prevent nephrotoxicity of CP.

Low-dose lixisenatide protects against early-onset nephropathy induced in diabetic rats.

AIM: Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. This study was performed to investigate the possible protective effect of lixisenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, on early diabetic nephropathy induced in diabetic rats and explore the various mechanisms underlie this postulated effect. MAIN METHODS: Early DN was induced after 3 weeks in diabetic rats fed with a high-fat diet (HFD) and treated with low dose STZ. One week after induction of diabetes, diabetic rats were administered lixisenatide at two dose levels (1 and 10 nmole/kg/day, ip) or glimepiride (2 mg/kg/day, p.o.) for 2 weeks. KEY FINDINGS: Lixisenatide, in a low dose regimen, induced a nephroprotective effect evident by significant decreases in serum creatinine and serum urea along with improved renal histology. Low lixisenatide dose showed an antioxidant effect, exhibited by a significant decrease in renal malondialdehyde and total NOx- levels along with a marked rise in total antioxidant capacity. Apart from ameliorating glucose intolerance and insulin resistance, significant down-regulation in renal expressions of iNOS, COX-2, and TGF-B1 were recorded in the diabetic group treated with low dose lixisenatide. Furthermore, low dose lixisenatide was reported to be superior to glimepiride as a nephroprotective. On the contrary, treatment with large dose lixisenatide was founded to be deleterious. SIGNIFICANCE: Low-dose lixisenatide treatment was able to protect against early diabetic nephropathy, which might represent a promising approach in the management of diabetes and its renal complication however, further clinical studies are warranted.

Empagliflozin alleviates neuronal apoptosis induced by cerebral ischemia/reperfusion injury through HIF-1α/VEGF signaling pathway.

Ischemic stroke is a serious condition associated with severe functional disability and high mortality, however; effective therapy remains elusive. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, has been shown to exert additional non-glycemic benefits including anti-apoptotic effects in different disease settings. Thereby, this study was designed to investigate the ameliorative effect of empagliflozin on the neuronal apoptosis exhibited in cerebral ischemia/reperfusion (I/R) in a rat model targeting HIF-1α/VEGF signaling which is involved in this insult. Global cerebral I/R injury was induced in male Wistar rats through occlusion of the bilateral common carotid arteries for 30 min followed by one-hour reperfusion. Empagliflozin doses of 1 and 10 mg/kg were administered 1 and 24 h after reperfusion. In I/R-injured rats, empagliflozin treatments significantly reduced infarct size and enhanced neurobehavioral functions in a dose-dependent manner. The drug alleviated neuronal death and cerebral injury inflicted by global ischemia as it suppressed neuronal caspase-3 protein expression. In parallel, protein expressions of HIF-1α and its downstream mediator VEGF were upregulated in the ischemic brain following empagliflozin treatment. The results indicated that empagliflozin attenuates cerebral I/R-induced neuronal death via the HIF-1α/VEGF cascade.

Combined treatments with metformin and phosphodiesterase inhibitors alleviate nonalcoholic fatty liver disease in high-fat diet fed rats: a comparative study.

Nonalcoholic fatty liver disease (NAFLD) is an excessive accumulation of fats in the liver resulting in hepatic inflammation and fibrous tissue formation along with insulin resistance. This study was designed to investigate the possible protective effects of metformin alone and in combination with different phosphodiesterase inhibitors (PDEIs). Rats were fed a high-fat diet (HFD) for 16 weeks to induce NAFLD. Starting from week 12, rats received metformin alone or in combination with pentoxifylline, cilostazol, or sildenafil. HFD administration resulted in hepatic steatosis and inflammation in rats. In addition, liver index, body composition index, activities of liver enzymes, and serum lipids deviated from normal. Further, significant elevations were recorded compared to control in terms of serum glucose, insulin, and HOMA-IR (homeostasis model assessment index for insulin resistance), oxidative stress parameters, hepatic TNF-α and NF-κB gene expression, and iNOS protein expression. Rats treated with metformin showed a significant improvement in the aforementioned parameters. However, the addition of pentoxifylline to metformin treatment synergized its action and produced a fortified effect against HFD-induced NAFLD better than other PDEIs. Data from this study indicated that combined treatment of metformin and pentoxifylline had the most remarkable ameliorated effects against HFD-induced NAFLD; further clinical investigations are needed to approve PDEIs for NAFLD treatment.

Empagliflozin attenuates transient cerebral ischemia/reperfusion injury in hyperglycemic rats via repressing oxidative-inflammatory-apoptotic pathway.

Hyperglycemia is one of the ischemic neuronal damage triggers that exacerbate the response to oxidative stress, inflammation, and apoptosis induced by cerebral ischemia/reperfusion (I/R) injury. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT 2) inhibitor, was shown to effectively reduce hyperglycemia and glucotoxicity besides improving glycemic control in diabetics. Therefore, the present study was conducted to investigate the neuroprotective effect of empagliflozin against cerebral I/R injury in hyperglycemic rats. Hyperglycemia was induced by streptozotocin (55 mg/kg), and transient cerebral I/R was induced by bilateral common carotid occlusion for 30 min followed by 24-h reperfusion. Either empagliflozin (10 mg/kg; i.p.) or gliclazide (2 mg/kg, p.o.) was administered at 1 and 24 h after reperfusion. Treatment with empagliflozin showed a significant amelioration of behavioral/neurological functions and histopathological changes observed in brain tissues of hyperglycemic rats subjected to cerebral I/R injury. Comparable to gliclazide, empagliflozin decreased cerebral infarct volume along with suppression of cerebral oxidative stress, inflammatory, and apoptotic markers in brain tissues of hyperglycemic I/R-injured rats. These findings suggested that empagliflozin can significantly alleviate neuronal damage resulting from global I/R injury induced in hyperglycemic rats. The proposed neuroprotective effect of empagliflozin may be attributed to its glycemic control effect and related antioxidant, anti-inflammatory, and antiapoptotic effects.

Comparative effectiveness of phosphodiesterase 3, 4, and 5 inhibitors in amelioration of high-fat diet-induced nonalcoholic fatty liver in rats.

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease linked to insulin resistance, oxidative stress, and cytokine imbalance. Phosphodiesterase (PDE) inhibitors have shown remarkable antioxidant and anti-inflammatory potential in different disease sets including liver diseases. This study aimed to compare the ameliorative effect of different PDE inhibitors on a high-fat diet (HFD)-induced NAFLD. Male Wistar rats were fed a HFD for 16 weeks to induce NAFLD, and then, oral treatments of a vehicle or different PDE inhibitors (pentoxifylline (50 mg/kg), cilostazol (20 mg/kg), or sildenafil (5 mg/kg)) were started in the last four weeks and given on a daily basis. Rats' body composition and liver indices were recorded. Serum levels of liver enzymes, glucose, insulin, bilirubin, total cholesterol, triglycerides, and nitric oxide were measured. Liver tissues were used for histopathological examination and detecting oxidative stress and inflammatory markers. Results showed that different PDE inhibitors exhibited different efficacy against liver injury and metabolic disorders associated with HFD-induced NAFLD in rodents evident by different strength-ameliorated effects on the aforementioned parameters. Compared to cilostazol and sildenafil, insulin resistance, hepatic oxidative stress, and inflammatory markers were significantly reduced by pentoxifylline treatment. Furthermore, pentoxifylline nearly completely reversed hepatocyte steatosis and exhibited superior rectifying effect on the rats' liver status compared with other PDE inhibitors. This investigation highlighted the potential role of PDE inhibitors in NAFLD treatment. Pentoxifylline had the most remarkable ameliorative effects against NAFLD, while sildenafil was the least effective.

Preparation and Evaluation of Atorvastatin-Loaded Nanoemulgel on Wound-Healing Efficacy.

Tissue repair and wound healing are complex processes that involve inflammation, granulation, and remodeling of the tissue. The potential of various statins including atorvastatin (ATR) to improve the wound healing effect was established. The aim of this study was to formulate and evaluate the efficacy of topical application of ATR-based nanoemulgel on wound healing. The prepared formulations (ATR gel, ATR emulgel, and ATR nanoemulgel) were evaluated for their physical appearance, rheological behavior, in vitro drug release and ex vivo drug permeation. The in vivo wound healing effect was evaluated in wound-induced rats. The prepared ATR gel formulations showed good physical properties and were comparable. The release profiles of drugs from gel, emulgel, and nanoemulgel were distinct. Skin permeation potential of ATR was significantly (p < 0.05) enhanced when formulated into nanoemulgel. In vivo wound healing studies showed that ATR nanoemulgel exhibited the highest percent wound contraction. Histopathological assessment showed marked improvement in the skin histological architecture after 21 days of ATR nanoemulgel treatment. In conclusion, the data demonstrated here signify the prospective of ATR nanoemulgel as an innovative therapeutic approach in wound healing.

Modulation of eNOS/iNOS by nebivolol protects against cyclosporine A-mediated nephrotoxicity through targeting inflammatory and apoptotic pathways.

The aim of this study was to investigate effect of nitric oxide (NO) modulation on possible nephroprotective mechanisms of nebivolol (NEB) in cyclosporine A (CsA)-induced nephrotoxicity. Rats were treated with 20 mg/kg/day s.c. of CsA for 21 days, with NEB alone (10 mg/kg/day orally) or together with a NOS inhibitor, L-NAME (10 mg/kg/day i.p.). NEB conferred nephroprotection against CsA-induced toxicity, significantly decreasing serum kidney function tests and improving renal histopathology. NEB showed antioxidant effects, by significantly decreasing renal malondialdehyde levels, while increasing reduced glutathione levels and catalase activity. NEB showed anti-inflammatory and anti-apoptotic effects; reducing renal expression NF-κB and fas ligand. NEB also reversed CsA-induced effects on NO system; increasing renal NO level, with up-regulation of eNOS and down-regulation of iNOS expression. Administering L-NAME with NEB reversed all beneficial effects of NEB. Thus, NEB's modulation of NO system in CsA-induced nephrotoxicity might be the triggering mechanism controlling NEB's nephroprotective effect.

Lixisenatide ameliorates cerebral ischemia-reperfusion injury via GLP-1 receptor dependent/independent pathways.

Ischemic stroke is a major cause of neurological damage and brain dysfunction with consequent strong cerebral oxidative imbalance, inflammatory and apoptotic responses. Lixisenatide is a new potent glucagon-like peptide -1 (GLP-1) analogue that has been used clinically in the treatment of type II diabetes. Recent studies suggested the beneficial central effects of GLP-1-based therapies on different neurodegenerative diseases. This study aimed to investigate the ameliorative effect of lixisenatide in global cerebral ischemia-reperfusion (I/R) rat model and elaborate the underline mechanisms that could mediate the proposed activity. Adult male Wistar rats were subjected to sham operation or global cerebral I/R injury. Rats were administered the following drugs in two scheduled doses at 1 h and 24 h after reperfusion: lixisenatide (1 and 10 nmole/kg), lixisenatide plus GLP-1 receptor (GLP-1R) antagonist (exendin(9-39)), and pentoxiphylline. Comparable to pentoxiphylline; both doses of lixisenatide produced a significant reduction in infarct volume and amelioration of neurobehavioural functions along with suppression of oxidative stress parameters (catalase, reduced glutathione, malondialdehyde and NO), inflammatory marker (tumor necrosis factor-alpha) and apoptotic marker (caspase-3) in ischemic rat brains. However, these effects weren'tinhibited by GLP-1R antagonist, exendin(9-39), indicating that they are independent on GLP-1R mediation. Also, lixisenatide upregulated protein expression of cerebral endothelial nitric oxide synthase and the angiogenic marker, vascular endothelial growth factor. It's worth noting that this effect was blocked by exendin(9-39). Overall, these data indicated that lixisenatide may offer a promising approach for alleviating cerebral I/R injury via different mechanisms that could be mediated, in part, through GLP-1R.

Lixisenatide, a novel GLP-1 analog, protects against cerebral ischemia/reperfusion injury in diabetic rats.

Type 2 diabetes mellitus (T2DM) is a major risk factor for ischemic stroke accompanied by vascular dysfunction and poor cerebrovascular outcome. Lixisenatide is a glucagon like peptide-1 (GLP-1) analog that is recently used for T2DM treatment with established neuroprotective properties. This study investigated and compared the neuroprotective effect of lixisenatide against glimepiride on diabetic rats subjected to global cerebral ischemia/reperfusion (I/R) injury. T2DM-induced adult male Wistar rats were administered lixisenatide or glimepiride prior to induction of global cerebral I/R-induced injury. Results showed a disturbance in oxidative stress parameters (catalase, reduced glutathione, and malondialdehyde) along with increasing in caspase-3 and tumor necrosis factor-alpha protein expressions in ischemic diabetic brain tissues. An upregulation of protein level of inducible nitric oxide (iNOS) synthase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit, NOX2 gene expression associated with significant suppression of endothelial nitric oxide synthase (eNOS) protein expression are recorded in carotid arteries of diabetic I/R-injured rats. Apart from ameliorating glucose intolerance and insulin resistance, lixisenatide was found to be superior to glimepiride as protective treatment in terms of enhancing behavioral/neurological functions and suppressing cerebral oxidative stress, inflammation, and apoptosis in cerebral I/R-injured diabetic rats. Unlike glimepiride, lixisenatide relieved carotid endothelial dysfunction by increasing eNOS expression. It also dampened vascular nitrosative/oxidative stress via suppression of iNOS and NADPH oxidase expressions. This study supposed that lixisenatide represents a more suitable anti-diabetic therapy for patients who are at risk of ischemic stroke, and even so, the mechanisms of lixisenatide-mediated vascular protection warrant further experimental and clinical investigations.