Cardioprotective role of diacerein in diabetic cardiomyopathy via modulation of inflammasome/caspase1/interleukin1ß pathway in juvenile rats.

Diabetes mellitus is a common metabolic disorder affecting different body organs; one of its serious complications is diabetic cardiomyopathy (DCM). Thus, finding more cardiopreserving agents to protect the heart against such illness is a critical task. For the first time, we planned to study the suspected role of diacerein (DIA) in ameliorating DCM in juvenile rats and explore different mechanisms mediating its effect including inflammasome/caspase1/interleukin1ß pathway. Four-week-aged juvenile rats were randomly divided into groups; the control group, diacerein group, diabetic group, and diabetic-treated group. Streptozotocin (45 mg/kg) single intraperitoneal (i.p.) dose was administered for induction of type 1 diabetes on the 1st day which was confirmed by detecting blood glucose level. DIA was given in a dose of 50 mg/kg/day for 6 weeks to diabetic and non-diabetic rats, then we evaluated different inflammatory, apoptotic, and oxidative stress parameters. Induction of DCM succeeded as there were significant increases in cardiac enzymes, heart weights, fasting blood glucose level (FBG), and glycosylated hemoglobin (HbA1c) associated with elevated blood pressure (BP), histopathological changes, and increased caspase 3 immunoexpression. Furthermore, there was an increase of malondialdehyde (MDA), inflammasome, caspase1, angiotensin II, nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNFα), and interleukin 1ß (IL1ß). However, antioxidant parameters such as reduced glutathione (GSH) and total antioxidant capacity (TAC) significantly declined. Fortunately, DIA reversed the diabetic cardiomyopathy changes mostly due to the observed anti-inflammatory, antioxidant, and anti-apoptotic properties with regulation of blood glucose level.DIA has an ability to regulate DCM-associated biochemical and histopathological disturbances.

Molecular mechanisms mediate roflumilast protective effect against isoprenaline-induced myocardial injury.

BACKGROUND: Myocardial necrosis is one of the most common cardiac and pathological diseases. Unfortunately, using the available medical treatment is not sufficient to rescue the myocardium. So that, we aimed in our model to study the possible cardioprotective effect of roflumilast (ROF) in an experimental model of induced myocardial injury using a toxic dose of isoprenaline (ISO) and detecting the role of vascular endothelial growth factor/endothelial nitric oxide synthase (VEGF/eNOS) and cyclic guanosine monophosphate/cyclic adenosine monophosphate/ sirtuin1 (cGMP/cAMP/SIRT1) signaling cascade. MATERIALS AND METHODS: Animals were divided into five groups; control, ISO given group (150 mg/kg) i.p. on the 4th and 5th day, 3 ROF co-administered groups in different doses (0.25, 0.5, 1 mg/kg/day) for 5 days. RESULTS: Our data revealed that ISO could induce cardiac toxicity as manifested by significant increases in troponin I, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), and cleaved caspase-3 with toxic histopathological changes. Meanwhile, there were significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, eNOS, cGMP, cAMP and SIRT1. However, co-administration of ROF showed significant improvement and normalization of ISO induced cardiac damage. CONCLUSION: We concluded that ROF successfully reduced ISO induced myocardial injury and this could be attributed to modulation of PDE4, VEGF/eNOS and cGMP/cAMP/SIRT1 signaling pathways with antioxidant, anti-inflammatory, and anti-apoptotic properties.

Testicular cytoprotective effect of glucagon like peptide-1 in diabetic rats involves inhibition of apoptosis, endoplasmic reticulum stress and activation of autophagy.

This study aimed to explore the possible cytoprotective effects of exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in the testicles of diabetic rats. Exenatide has numerous advantageous properties in addition to its hypoglycemic effect. However, its impact on testicular tissue in diabetes needs more clarification. Therefore, rats were divided into control, exenatide-treated, diabetic and exenatide-treated diabetic groups. Blood glucose and serum levels of insulin, testosterone, pituitary gonadotropins and kisspeptin-1 were measured. Real-time PCR for beclin-1, p62, mammalian target of rapamycin (mTOR), and AMP-activated protein kinase (AMPK), were estimated in testicular tissue in addition to markers of oxidative stress, inflammation, and endoplasmic reticulum stress. Also, immuno-expression of protein P53, nuclear erythroid factor2 (Nrf2) and vimentin was conducted. Exenatide was able to attenuate diabetic toxic changes and enhance autophagy in testicular tissue. These results indicate the protective effect of exenatide against diabetic testicular dysfunction.

Leptin alleviated ovarian ischemia-reperfusion injury in rats via modulation of Sirt-1/Nrf2 and TLR4/NF-kB/caspase-3 signaling pathways.

Objective. Ovarian torsion is a gynecological emergency that occurs mostly during the female reproductive years due to ovarian masses or surgical manipulation. This work aims to explore the probable protective effect of leptin on rat ovaries due to ischemia-reperfusion (IR) injury. Methods. Wistar albino rats were divided into four groups: 1) control group; 2) ovarian IR group (OVIR); 3) leptin group I [OVIR + leptin (10 µg/kg body weight, b.w.)]; and 4) leptin group II (OVIR + leptin (100 µg/kg b.w.)]. Serum levels of estradiol and anti-Mullerian hormone (AMH) were measured. Levels of oxidative stress and inflammatory markers in ovarian tissue were determined along with the expression of sirtuin 1 (Sirt1), nuclear erythroid factor-2 (Nrf2), cyclooxygenase-2 (COX-2), nuclear factor kappa (NF-κB), toll like receptor-4 (TLR4), and caspase-3. Results. Serum estradiol and AMH levels were decreased with increased expression of COX-2, TLR4, caspase-3, and NF-κB and decreased expression of Sirt1and Nrf2 in ovary of the OVIR group, which were improved by exogenous administration of both leptin doses. Conclusion. Leptin administration dose-dependently reduced the severity of OVIR injury via modulation of Sirt-1/Nrf2 and TLR4/NF-kB/caspase-3 signaling pathways. Thus, leptin may be used as an adjuvant measure to prevent ovarian damage and improve the outcomes. However, clinical studies are needed to evaluate these results in humans.

Phosphodiesterase inhibitor, Vinpocetine, guards against doxorubicin induced cardiotoxicity via modulation of HIF/VEGF and cGMP/cAMP/SIRT signaling pathways.

METHODS: 50 male Wistar albino rats were subjected to DOX toxicity via administration of single i.p. Dose (15 mg/kg) on the 4th day with or without co-administration of VIN (10, 20, 30 mg/kg/day) orally for 5 days. RESULTS: Our data revealed that VIN succeeded in protecting the heart against DOX induced damage as manifested by significant decrease of cardiac enzymes, hypoxia inducible factor alpha (HIF-1α), vascular endothelial growth factor-A (VEGF-A), tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and caspase3 levels. Furthermore, VIN given group showed marked improvement of the histopathological changes of cardiac injury, total antioxidant capacity (TAC), elevation of reduced glutathione (GSH), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP) and sirtuin-1 (SIRT-1). CONCLUSION: We concluded that VIN could ameliorate DOX induced cardiac damage and this effect may be attributed to modulation of HIF/VEGF signaling pathway, up-regulation of cGMP/cAMP/SIRT pathway, inhibition of phosphodiesterase enzyme, besides its anti-apoptotic, anti-inflammatory, and anti-oxidant properties.

Angiotensin 1-7 mitigates rhabdomyolysis induced renal injury in rats via modulation of TLR-4/NF-kB/iNOS and Nrf-2/heme­oxygenase-1 signaling pathways.

AIMS: Rhabdomyolysis (RM) is a critical condition with a high mortality rate, but effective management is still deficient. Till date, there are no studies that have addressed the effect of angiotensin 1-7 in this condition, hence, the rationale of this study was to evaluate the potential protective effect of Angiotensin 1-7 (Ang1-7), on rhabdomyolysis (RM) induced kidney injury in rats and detecting the underlying mechanistic insights. MAIN METHODS: Forty adult male albino rats were divided into groups; the control group, RM group, RM+Ang1-7 group, and RM+Ang1-7+ A779 group. Sera and urine samples were collected for analysis of renal and muscle injury markers. Kidney tissues were taken for estimation of oxidative, inflammatory, and apoptotic markers as well as angiotensin-II (Ang II) and Ang1-7. Renal histology and expression of inducible nitric oxide synthase-1 (iNOS), real-time PCR for angiotensin-converting enzyme-2 (ACE-2), nuclear erythroid factor-2 (Nrf-2), Toll like receptor 4 (TLR-4) and NF-kB in kidney tissues were also measured. KEY FINDINGS: Induction of RM caused renal oxidative stress injury, inflammation, apoptosis and marked deterioration in kidney functions as well as reduction of Ang1-7 and raised Angiotensin-II level in kidney tissues. Administration of Ang1-7 to the RM group reversed all the affected parameters which were blocked by A779 administration (Mas receptor blocker). SIGNIFICANCE: We concluded that Ang1-7 could be a potential therapeutic agent that could mitigate RM-induced renal injury. The underlying mechanisms may involve Stimulation of the ACE-2/Ang1-7/MasR axis and modulation of TLR-4/NF-kB/iNOS and Nrf-2/heme­oxygenase -1 pathways.

C-peptide corrects hepatocellular dysfunction in a rat model of type 1 diabetes.

C-peptide is gaining much interest recently due to its well-documented beneficial effects on multiple organ dysfunction induced by diabetes. Our study was designed to investigate the effect of C-peptide on hepatocellular dysfunction in diabetic rats. Wistar male rats were separated into four groups: control, diabetic, diabetic + insulin, and diabetic + C-peptide. Serum levels of glucose, insulin, and liver biomarkers were assessed. Liver sections were collected for histopathological examination and immuno-histochemical assessment of tumor necrosis factor alpha (TNF-α). Oxidative stress markers and gene expression of inducible nitric oxide synthase (iNOS), transforming growth factor beta 1 (TGF-ß1), and glucose-6-phosphatase (G6Pase) were also measured in liver tissues. C-peptide administration prevented hepatic dysfunction induced by diabetes to a similar extent as that of insulin which was confirmed microscopically. We concluded that C-peptide could be used as an alternative therapy to insulin to correct hepatocellular dysfunction associated with type 1 diabetes mellitus (T1DM).

The possible protective effect of Nano-Selenium on the endocrine and exocrine pancreatic functions in a rat model of acute pancreatitis.

BACKGROUND: Acute pancreatitis is a serious condition with multi-factorial etiology. The negative impact of acute pancreatitis on the exocrine pancreatic function is well documented; however, its impact on the endocrine function needs more elucidation. Our study aimed to investigate the effect of Nano-Selenium (Nano-Se) on both pancreatic functions in acute pancreatitis. METHODS: l-arginine induced acute pancreatitis in rats was used as a model. Fifty adult male albino rats were separated into groups: 1- control group (C), 2- C+ Nano-Se, 3-acute pancreatitis group (AP) and 4- AP+ Nano-Se. Nano-Se was administered before induction of acute pancreatitis. Serum levels of amylase, lipase, selenium, glucose, insulin and interleukin-1ß (IL-1ß) were measured. Homeostatic model assessment of beta cell function (HOMA-ß) was also calculated. Oxidative stress markers, selenium content and the anti-apoptotic factor, B-cell leukemia/lymphoma-2 (Bcl-2) were assayed in pancreatic tissue along with immuno-expression of nuclear transcription factor-kappa B (NF-κB). RESULTS: Acute pancreatitis negatively affected both pancreatic functions. Nano-Se administration lessened the developed pancreatic injury and improved both pancreatic functions. CONCLUSION: Nano-Se could improve the deteriorated pancreatic functions in acute pancreatitis via its anti-inflammatory, antioxidant and pro-apoptotic actions. Thus, it may be used in prevention of acute pancreatitis and the associated hyperglycemia in vulnerable individuals such as patients undergoing endoscopic retrograde cholangio-pancreatography.

Rupatadine, a dual antagonist of histamine and platelet-activating factor (PAF), attenuates experimentally induced diabetic nephropathy in rats.

The role of histamine and platelet activating factor (PAF) as involved mediators in the pathophysiology of diabetic complications, in particular diabetic nephropathy (DN), has become a new focus of concern. Accordingly, the present study designed to explore the effect of rupatadine (RUP), a dual antagonist of histamine (H1) and PAF, on the progression of experimentally induced DN in rats. Rats were divided into five groups: control, RUP alone, streptozotocin (STZ)-diabetic model, STZ/RUP (3 mg/kg/day), and STZ/RUP (6 mg/kg/day). Treatment has continued for 4 weeks after diabetes confirmation. At the end of the study, serum was collected for measurement of glucose, insulin, urea, creatinine, histamine, and PAF. Renal tissue homogenates were prepared for measuring oxidative stress indices, tumor necrosis factor (TNF-α), cystatin C, and p21. Moreover, immunohistochemical expression of transforming growth factor-ß1 (TGF-ß1) and p53 along with histological pictures was also conducted. Antagonizing H1 and PAF receptors by RUP ameliorated the experimentally induced DN as evident by decreasing all serum parameters augmented by STZ together with improvement of the histopathological picture. RUP administration also improved oxidative-antioxidative agents with reduction in the anti-inflammatory marker, TNF-α. Additionally, the immunohistochemical expression of the fibrosis marker; TGF-ß1, was also decreased. STZ-induced DN showed a p21/p53-dependent induction of premature senescence and RUP administration decreased the expression of p21 and p53 levels in injured renal tissue. RUP represents a novel promising drug to prevent DN complicated diabetes probably via its inhibitory effect on H1 and PAF receptors. The renal protection was also related to the anti-inflammatory and antioxidant roles and PAF-facilitated senescence effect via p21/p53 signaling.