Comparing prophylactic effect of exercise and metformin on cognitive brain functions in rats with type 3 diabetes mellitus.

Introduction: Type 2 diabetes mellitus (DM) and Alzheimer's disease (AD) are two major medical conditions that constitute a significant financial burden on most healthcare systems. Due to AD sharing "insulin resistance" mechanistic features with DM, some scientists have proposed "type 3 DM" terminology for it. This study aims to compare the prophylactic effect of exercise and metformin on cognitive brain functions in rats with type 3 DM. Material and methods: Two groups of rats were included in the study: the control group (n = 15) and the streptozotocin-induced type 2 diabetic group (n = 45). The diabetic group was subdivided into three equal subgroups: a sedentary non-treated diabetic group, an exercised group, and a metformin-treated group. We estimated step-down avoidance task latency, serum glucose, insulin, free fatty acids (FFA), cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides (TG), brain Aß-42 and glucose, histological changes by toluidine blue, and immunohistochemistry for brain Aß-42 and tau-positive cells. Results: Serum glucose, FFA, TG, cholesterol, LDL, brain Aß-42, brain glucose, the number of hippocampal dark and degenerated cells, and brain Aß-42 and tau-positive cells, were all significantly lower. In contrast, serum insulin and HDL, the number of hippocampal granular cells, and latency of the step-down avoidance task were significantly higher in exercised and metformin-treated groups compared to the diabetic group. There were significantly higher values of serum insulin and brain/plasma glucose ratio and number of brain tau-positive cells in the metformin-treated group than in the exercised group. Conclusions: We can conclude that exercise can be as effective as metformin regarding prophylaxis against the deleterious effects of type 3 DM on cognitive brain functions.

An integrated phytochemical, in silico and in vivo approach to identify the protective effect of Caroxylon salicornicum against cisplatin hepatotoxicity.

Cisplatin (CIS) is a chemotherapeutic medication for the treatment of cancer. However, hepatotoxicity is among the adverse effects limiting its use. Caroxylon salicornicum is traditionally used for treating inflammatory diseases. In this investigation, three flavonoids, four coumarins, and three sterols were detected in the petroleum ether fraction of C. salicornicum (PEFCS). The isolated phytochemicals exhibited binding affinity toward Keap1, NF-κB, and SIRT1 in silico. The hepatoprotective role of PEFCS (100, 200 and 400 mg/kg) was investigated in vivo. Rats received PEFCS for 14 days and CIS on day 15. CIS increased ALT, AST and ALP and caused tissue injury along with increased ROS, MDA, and NO. Hepatic NF-κB p65, pro-inflammatory mediators, Bax and caspase-3 were increased in CIS-treated animals while antioxidants and Bcl-2 were decreased. PEFCS mitigated hepatocyte injury, and ameliorated transaminases, ALP, oxidative stress (OS) and inflammatory markers. PEFCS downregulated pro-apoptosis markers and boosted Bcl-2 and antioxidants. In addition, PEFCS upregulated Nrf2, HO-1, and SIRT1 in CIS-administered rats. In conclusion, PEFCS is rich in beneficial phytoconstituents and conferred protection against liver injury by attenuating OS and inflammation and upregulating Nrf2 and SIRT1.

The protective effect of 7-hydroxycoumarin against cisplatin-induced liver injury is mediated via attenuation of oxidative stress and inflammation and upregulation of Nrf2/HO-1 pathway.

Cisplatin (CIS) is an effective chemotherapy against different solid cancers. However, the adverse effects, including hepatotoxicity, limit its clinical use. 7-hydroxycoumarin (7-HC) possesses antioxidant and hepatoprotective activities, but its protective effect against CIS hepatotoxicity has not been investigated. This study evaluated the effect of 7-HC on liver injury, oxidative stress (OS), and inflammation provoked by CIS. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 2 weeks followed by intraperitoneal injection of CIS (7 mg/kg) at day 15. CIS increased serum transaminases, alkaline phosphatase (ALP), and bilirubin and provoked tissue injury accompanied by elevated reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO). Liver nuclear factor (NF)-κB p65, inducible NO synthase (iNOS), pro-inflammatory cytokines, Bax, and caspase-3 were upregulated, and antioxidant defenses and Bcl-2 were decreased in CIS-treated rats, while 7-HC prevented liver injury and ameliorated OS, inflammatory and apoptosis markers. In addition, 7-HC enhanced nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase (HO)-1 in CIS-administered rats and in silico studies revealed its binding affinity toward HO-1. In conclusion, 7-HC protected against CIS hepatotoxicity by mitigating OS and inflammatory response and modulating Nrf2/HO-1 pathway.

Flavonoids of Haloxylon salicornicum (Rimth) prevent cisplatin-induced acute kidney injury by modulating oxidative stress, inflammation, Nrf2, and SIRT1.

Cisplatin (CIS) is an effective chemotherapeutic drug used for the treatment of many types of cancers, but its use is associated with adverse effects. Nephrotoxicity is a serious side effect of CIS and limits its therapeutic utility. Haloxylon salicornicum is a desert shrub used traditionally in the treatment of inflammatory disorders, but neither its flavonoid content nor its protective efficacy against CIS nephrotoxicity has been investigated. In this study, seven flavonoids were isolated from H. salicornicum methanolic extract (HSE) and showed in silico binding affinity with NF-κB, Keap1, and SIRT1. The protective effect of HSE against CIS nephrotoxicity was investigated. Rats received HSE (100, 200, and 400 mg/kg) for 14 days followed by a single injection of CIS. The drug increased Kim-1, BUN, and creatinine and caused multiple histopathological changes. CIS-administered rats showed an increase in renal ROS, MDA, NO, TNF-α, IL-1ß, and NF-κB p65. HSE prevented tissue injury, and diminished ROS, NF-κB, and inflammatory mediators. HSE enhanced antioxidants and Bcl-2 and downregulated pro-apoptosis markers. These effects were associated with downregulation of Keap1 and microRNA-34a, and upregulation of SIRT1 and Nrf2/HO-1 signaling. In conclusion, H. salicornicum is rich in flavonoids, and its extract prevented oxidative stress, inflammation, and kidney injury, and modulated Nrf2/HO-1 and SIRT1 signaling in CIS-treated rats.

7-hydroxycoumarin modulates Nrf2/HO-1 and microRNA-34a/SIRT1 signaling and prevents cisplatin-induced oxidative stress, inflammation, and kidney injury in rats.

The kidneys are vulnerable to toxicity and acute kidney injury (AKI) is the main adverse effect associated with the clinical use of the chemotherapeutic agent cisplatin (CIS). Oxidative stress and inflammation are implicated in CIS nephrotoxicity. In this study, the effect of the antioxidant 7-hydroxycoumarin (7-HC) against CIS-induced renal intoxication was evaluated. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 14 days and CIS (7 mg/kg) at day 15, and samples were collected 3 days after CIS administration. CIS increased serum urea, creatinine and kidney injury molecule (Kim)-1, caused multiple histopathological changes and increased renal reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), NF-κB p65, iNOS, and pro-inflammatory cytokines. 7-HC dose-dependently prevented kidney dysfunction and tissue injury and suppressed ROS and inflammatory mediators. 7-HC boosted renal antioxidants and Bcl-2 while decreased Bax and caspase-3 expression in CIS-administered rats. In addition, 7-HC downregulated Keap-1 and microRNA-34a and upregulated Nrf2, NQO-1, HO-1, and SIRT1. Molecular docking revealed the binding affinity of 7-HC towards NF-κB, Keap-1, and SIRT1. In Conclusion, 7-HC prevented CIS nephrotoxicity by attenuating tissue injury, oxidative stress, inflammation, and apoptotic cell death. The protective efficacy of 7-HC was associated with inhibiting NF-κB and Keap-1, and modulating Nrf2/HO-1 and microRNA34a/Sirt1 signaling.

Necrostatin-1 mitigates renal ischaemia-reperfusion injury - time dependent - via aborting the interacting protein kinase (RIPK-1)-induced inflammatory immune response.

The recently defined necroptosis process participates in the pathophysiology of several tissue injuries. Targeting the necroptosis mediator receptor-interacting protein kinase (RIPK1) by necrostatin-1 in different phases of ischaemia-reperfusion injury (IRI) may provide new insight into the protection against renal IRI. The rat groups included (n = 8 in each group): 1) Sham; 2) Renal IRI; 3) Necrostatin-1 treatment 20 min before ischaemia induction in a dose of 1.65 mg/kg/intravenous; 4) Necrostatin-1 injection just before reperfusion; 5) Necrostatin-1 injection 20 min after reperfusion establishment; and 6) drug injection at both the pre-ischaemia and at reperfusion time in the same dose. Timing dependent, necrostatin-1 diminished RIPK1 (p < 0.001), and aborted the necroptosis-induced renal cell injury. Necrostatin-1 decreased the renal chemokine (CXCL1), interleukin-6, intercellular adhesion molecule (ICAM-1), myeloperoxidase, and the nuclear factor (NFκB), concomitant with reduced inducible nitric oxide synthase (iNOS), inflammatory cell infiltration, and diminished cell death represented by apoptotic cell count and the BAX/Bcl2 protein ratio. In group 6, the cell injury was minimal and the renal functions (creatinine, BUN and creatinine clearance) were almost normalised. The inflammatory markers were diminished (p < 0.001) compared to the IRI group. The results were confirmed by histopathological examination. In conclusion, RIPK1 inhibition ameliorates the inflammatory immune response induced by renal IRI. The use of two doses was more beneficial as the pathophysiology of cell injury is characterised.

Umbelliferone ameliorates oxidative stress and testicular injury, improves steroidogenesis and upregulates peroxisome proliferator-activated receptor gamma in type 2 diabetic rats.

OBJECTIVES: Diabetes mellitus (DM) is a chronic disease associated with serious complications, including male infertility. Umbelliferone (UMB) is a coumarin with promising antioxidant, anti-inflammatory and other beneficial effects. This study investigated the ameliorative effect of UMB against testicular injury, oxidative stress and altered steroidogenesis in rats with type 2 DM. METHODS: Rats received a high fat diet for 4 weeks followed by a single injection of streptozotocin. Diabetic rats were treated with UMB or pioglitazone (PIO) for 6 weeks and samples were collected for analysis. KEY FINDINGS: Diabetic rats exhibited hyperglycemia, insulin resistance and dyslipidemia associated with increased serum pro-inflammatory cytokines, and decreased gonadotropins and testosterone. UMB significantly ameliorated metabolic alterations, decreased pro-inflammatory cytokines, and increased gonadotropins and testosterone levels. UMB prevented testicular injury, suppressed lipid peroxidation and nitric oxide and increased antioxidants in diabetic rats. In addition, UMB upregulated testicular gonadotropins receptors, steroidogenesis markers (steroidogenic acute regulatory protein, cytochrome P450 family 17 subfamily A member 1 [CYP17A1], 3ß-hydroxysteroid dehydrogenase [3ß-HSD] and 17ß-hydroxysteroid dehydrogenase [17ß-HSD]), and peroxisome proliferator-activated receptor gamma (PPARγ) expression. CONCLUSIONS: UMB prevents testicular injury by preventing metabolic alterations, suppressing oxidative damage and inflammation, and boosting antioxidant defenses in diabetic rats. UMB enhanced pituitary-gonadal axis and steroidogenesis and upregulated testicular PPARγ in diabetic rats. Thus, UMB may represent a protective agent against testicular injury and sexual dysfunction associated with chronic hyperglycemia.

Effect of mandarin peel extract on experimentally induced arthritis in male rats.

BACKGROUND: Rheumatoid arthritis (RA) is associated with joint damage. For treatment, non-steroidal anti-inflammatory drugs (NSAIDs), steroidal agents, and immune-suppressants are used. Their side-effects require a safe and effective natural alternative. ANIMALS AND METHODS: Thirty-six male albino rats, half kept under observation for 1 week (group I) and others for 2 weeks (group II) were used. Each group was subdivided into: normal (A), RA (B), and oral mandarin-peel extract (MPE) treated (C). Ankle diameter, serum levels of RF, interleukin (IL)-1ß, TNFα, IL-4, IL-10, liver homogenates malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and nitric oxide (NO) were measured together with the histopathological examination. RESULTS: MPE treatment was associated with increased serum IL-4, IL-10, liver homogenates GSH, and SOD, and decreased ankle diameter, serum RF, IL-1ß, TNFα, liver homogenates MDA, NO, inflammatory cell infiltrate, and necrosis. Two weeks' treatment was better. CONCLUSIONS: MPE has useful effects in alleviating the disturbed ankle diameter, serum pro- and anti-inflammatory mediators, oxidative stress, and ankle joint histopathology in rheumatic rats.

Serum Uric Acid Level as a Predictive Biomarker of Gestational Hypertension Severity; A Prospective Observational Case-Control Study.

BACKGROUND: Pre-eclampsia poses a significant potential risk of hypertensive disorders during pregnancy, a leading cause of maternal deaths. Hyperuricemia is associated with adverse effects on endothelial function, normal cellular metabolism, and platelet aggregation and adhesion. This study was designed to compare serum urate levels in normotensive pregnant women to those with pregnancy-induced hypertension, and to evaluate its value as a potential predictive marker of hypertension severity during pregnancy. METHODS: A prospective, observational, case-control study conducted on 100 pregnant women in their third trimester. Pregnant women were classified into two groups (n=50) according to arterial blood pressure measurements: group I had normal blood pressure, and group II had a blood pressure of ≥ 140/90, which was further subdivided according to hypertension severity into IIa (pregnancy- induced hypertension, IIb (mild pre-eclampsia), and IIc (severe pre-eclampsia). Blood samples were obtained on admission. Serum urate, high sensitive C-reactive protein, and interleukin-1ß levels, and lipid profile were compared among the groups. RESULTS: A significant increase in the mean values of serum urate, C-reactive protein, and interleukin- 1ß levels was detected in gestational hypertensives. In addition, there was a positive correlation between serum urate levels and C-reactive protein and interleukin-1ß, as well as between serum urate levels and hypertension severity. CONCLUSION: Hyperuricemia and increased C-reactive protein and interleukin-1ß serum levels correlate with the severity of pregnancy-induced hypertension, and these biomarkers may play a role in the pathogenesis of pre-eclampsia. Serum urate measurement is sensitive, reliable markers that correlate well with the severity of hypertension in pregnant females with pre-eclampsia.

Induction of labor with prostaglandin e2 in women with previous cesarean section and unfavorable cervix.

BACKGROUND: Induction of labor is common in obstetric practice. According to the most current studies, the rate varies from 9.5 to 33.7 percent of all pregnancies annually. In the absence of a ripe or favorable cervix, a successful vaginal birth is less likely. Therefore, cervical ripening or preparedness for induction should be assessed before a regimen is selected. To objective is to study the pregnancy outcome of induction of labor with prostaglandin E2 (PGE2) in women with one previous lower segment cesarean section. METHODS: A prospective study was conducted at Maternity & Children Hospital, Buraidah (Qassim), Saudi Arabia. The sample included 153 consecutive women with one previous cesarean section, of whom 75 underwent induction of labor (study group) and 78 were admitted with spontaneous onset of labor (control group). Vaginal tablets of PGE2 were used for cervical ripening in the study group. Mode of delivery, neonatal outcome, indications for cesarean section, and rate of uterine rupture were compared between the groups. RESULTS: There were no significant differences between the study and control groups in mean (_S.D.) maternal age (30:9 _ 4:7 years versus 31:2 _ 4:8 years, P » 0:6), gestational age at delivery (39:2 _ 1:8 weeks versus 39:3 _ 1:6 weeks, P » 0:36), overall rate of cesarean section (24% versus 20.5%, P » 0:8), rates of low 5-min Apgar score (3.1% versus 3.7%, P » 0:67) or cesarean section performed for non-reassuring fetal heart rate (9.3% versus 7.69%, P » 0:1). There were no cases of uterine rupture, in both groups. CONCLUSION: The findings suggest that induction of labor in women with one previous cesarean section does not increase the risk of cesarean section rate and does not adversely affect immediate neonatal outcome. We cautiously suggest that when there is no absolute indication for repeated cesarean section, induction of labor may be considered.