Effect of pantoprazole on I-R-induced myocardial injury in diabetic rats targeting inflammatory cytokine release and oxidative stress.

OBJECTIVES: To evaluate the pleiotropic potential and underlying mechanism of pantoprazole (PPZ) (common Proton Pump Inhibitors, PPIs) in type 2 diabetes mellitus (T2DM) -associated ischemia/reperfusion (I-R)-induced myocardial infarction which is still uncharted. Whereas some other PPIs have demonstrated their anti-diabetic, antioxidant, and anti-inflammatory potential. MATERIALS AND METHODS: We evaluated the potential of coinciding treatment of PPZ (4 mg/kg/po/day for 8 weeks) in Wistar albino rats against STZ (50 mg/kg/IP) induced T2DM model and I-R provoked cardiac infarction model in diabetic and non-diabetic condition. RESULTS: PPZ significantly inhibited the perturbed deviations in blood glucose concentration, HbA1c, C-peptide, plasma insulin, and ameliorated the lipid profile (dyslipidemia). PPZ protected myocardial tissue against lipid peroxidation by restoring the levels of serum TBARS and reduced NBT. The significant protective effects of PPZ were evident by ameliorating CKMB, LDH, cTnI, and myocardial oxidative stress in PPZ treated animals. Additionally, PPZ prominently reduced various proinflammatory cytokines release including TGF-ß1, TNF-α, and IL-6. PPZ upsurges the bioavailability of nitrite/nitrate concentration which may pacify the impact of myocardial infarction in diabetic I-R injury. CONCLUSION: The consequences indicate that PPZ possesses a potent protective effect against diabetic I-R-induced myocardial infarction via suppressing oxidative stress, inflammation, and dyslipidemia-associated tissue damage.

Minocycline and Doxycycline: More Than Antibiotics.

Minocycline and doxycycline both are second-generation tetracycline antibiotics with similar chemical structures and comparable antibacterial spectrum. Minocycline has also emerged as the tetracycline of choice for multidrug-resistant Acinetobacter baumannii infections, although doxycycline has also shown the activity. Minocycline showed promising results in experimental neurology, which was due to its highly lipophilic nature. It is clinically safe and effective adjunct to antipsychotic medications. The objective of the current review is to provide clinical and preclinical, non-antibiotic uses of minocycline as well as doxycycline. Relevant literature covers antibiotic actions but is more specifically concerned with the non-antibiotic biological aspect of tetracyclines. Non-antibiotic biological effects for both the antibiotics were identified through searching relevant databases including: PubMed, Scopus, and Web of Science up to 2020, using the keywords 'minocycline and doxycycline'. Anti-inflammatory, anti-oxidant, anti-apoptotic neuroprotective, immunomodulatory and the number of other non-antibiotic effects were compiled for minocycline and doxycycline.

Chronic oral administration of low-dose combination of fenofibrate and rosuvastatin protects the rat heart against experimentally induced acute myocardial infarction.

Fenofibrate and rosuvastatin at low doses might have experimental pleiotropic benefits. This study investigated the combined effect of low doses of fenofibrate and rosuvastatin in isoproterenol-induced experimental myocardial infarction. Rats administered isoproterenol (85 mg/kg/day, s.c.) for 2 days (day 29 and day 30) of 30 days experimental protocol developed significant myocardial infarction that was accompanied with high myocardial oxidative stress and lipid peroxidation, elevated serum markers of cardiac injury, lipid abnormalities, and elevated circulatory levels of C-reactive protein. Pretreatment with low doses of fenofibrate (30 mg/kg/day p.o., 30 days) and rosuvastatin (2 mg/kg/day p.o., 30 days) both alone or in combination markedly prevented isoproterenol-induced myocardial infarction and associated abnormalities while the low-dose combination of fenofibrate and rosuvastatin was more effective. Histopathological study in isoproterenol control rat heart showed necrosis with edema and acute inflammation at the margins of necrotic area. The rat heart from low-dose fenofibrate and rosuvastatin pretreated group showed scanty inflammation and no ischemia. In conclusion, fenofibrate and rosuvastatin pretreatment in low doses might have a therapeutic potential to prevent the pathogenesis of myocardial infarction. Moreover, their combined treatment option might offer superior therapeutic benefits via a marked reduction in myocardial infarct size and oxidative stress, suggesting a possibility of their pleiotropic cardioprotective action at low doses.

Nephroprotective effect of catechin on gentamicin-induced experimental nephrotoxicity.

BACKGROUND: Gentamicin is an effective aminoglycoside antibiotic employed against severe Gram-negative bacterial infections, but induction of nephrotoxicity limits its frequent clinical use. This study was undertaken to investigate the effect of catechin hydrate on gentamicin-induced nephrotoxicity in rats. METHODS: Rats were administered nephrotoxic dose of gentamicin (100 mg/kg/day, i.p.) once daily for 14 days. Gentamicin-administered rats were treated with catechin hydrate (50 mg/kg/day, per os), the treatment was started 3 days before the administration of gentamicin while it was continued for 14 days from the day of gentamicin administration. RESULTS: Two weeks administration of gentamicin significantly increased the serum creatinine and blood urea nitrogen levels. Renal histopathological examination of gentamicin-administered rats revealed degenerative changes in glomeruli and tubules after 2 weeks. These renal structural and functional abnormalities in gentamicin-administered rats were accompanied with renal oxidative stress as assessed in terms of marked decrease in renal-reduced glutathione (GSH). However, catechin hydrate treatment showed considerably nephroprotective action against gentamicin-induced nephrotoxicity in rats by preventing aforementioned renal structural and functional abnormalities and oxidative stress. CONCLUSION: Catechin hydrate has a potential to prevent gentamicin-induced experimental nephrotoxicity. The renoprotective effect of catechin hydrate against gentamicin-induced nephrotoxicity might be mediated through its antioxidant and possible direct nephroprotective actions.

Exploration of pharmacological interventions to prevent isoproterenol-induced myocardial infarction in experimental models.

High incidences of myocardial infarction associated with high morbidity and mortality, are a major concern and economic burden on industrialized nations. Persistent ß-adrenergic receptor stimulation with isoproterenol leads to the development of oxidative stress, myocardial inflammation, thrombosis, platelet aggregation and calcium overload, which ultimately cause myocardial infarction. Therapeutic agents that are presently employed for the prevention and management of myocardial infarction are beta-blockers, antithrombotics, thrombolytics, statins, angiotensin converting enzyme inhibitors, angiotensin II type 1 receptor blockers, calcium channel blockers and nitrovasodilators. In spite of effective available interventions, the mortality rate of myocardial infarction is progressively increasing. Thus, there has been a regular need to develop effective therapies for the prevention and management of this insidious disease. In this review, the authors give an overview of the consequences of isoproterenol in the pathogenesis of cardiac disorders and various therapeutic possibilities to prevent these disorders.

Catechin averts experimental diabetes mellitus-induced vascular endothelial structural and functional abnormalities.

Diabetes mellitus is associated with an induction of vascular endothelial dysfunction (VED), an initial event that could lead to the pathogenesis of atherosclerosis and hypertension. Previous studies showed that catechin, a key component of green tea, possesses vascular beneficial effects. We investigated the effect of catechin hydrate in diabetes mellitus-induced experimental vascular endothelial abnormalities (VEA). Streptozotocin (50 mg/kg, i.p., once) administration to rats produced diabetes mellitus, which subsequently induced VEA in 8 weeks by markedly attenuating acetylcholine-induced endothelium-dependent relaxation in the isolated aortic ring preparation, decreasing aortic and serum nitrite/nitrate concentrations and impairing aortic endothelial integrity. These abnormalities in diabetic rats were accompanied with elevated aortic superoxide anion generation and serum lipid peroxidation in addition to hyperglycemia. Catechin hydrate treatment (50 mg/kg/day p.o., 3 weeks) markedly prevented diabetes mellitus-induced VEA and vascular oxidative stress. Intriguingly, in vitro incubation of L-NAME (100 µM), an inhibitor of nitric oxide synthase, or Wortmannin (100 nM), a selective inhibitor of phosphatidylinositol 3-kinase (PI3K), markedly prevented catechin hydrate-induced improvement in acetylcholine-provoked endothelium-dependent relaxation in the diabetic rat aorta. Moreover, catechin hydrate treatment considerably reduced the elevated level of serum glucose in diabetic rats. In conclusion, catechin hydrate treatment prevents diabetes mellitus-induced VED through the activation of endothelial PI3K signal and subsequent activation of eNOS and generation of nitric oxide. In addition, reduction in high glucose, vascular oxidative stress, and lipid peroxidation might additionally contribute to catechin hydrate-associated prevention of diabetic VEA.

Signalling mechanisms involved in renal pathological changes during cisplatin-induced nephropathy.

CONTEXT: Cisplatin, a coordination platinum complex, is used as a potential anti-neoplastic agent, having well recognized DNA-damaging property that triggers cell-cycle arrest and cell death in cancer therapy. Beneficial chemotherapeutic actions of cisplatin can be detrimental for kidneys. BACKGROUND: Unbound cisplatin gets accumulated in renal tubular cells, leading to cell injury and death. This liable action of cisplatin on kidneys is mediated by altered intracellular signalling pathways such as mitogen-activated protein kinase (MAPK), extracellular regulated kinase (ERK), or C- Jun N terminal kinase/stress-activated protein kinase (JNK/SAPK). Further, these signalling alterations are responsible for release and activation of tumour necrosis factor (TNF-α), mitochondrial dysfunction, and apoptosis, which ultimately cause the renal pathogenic process. Cisplatin itself enhances the generation of reactive oxygen species (ROS) and activation of nuclear factor-κB (NF-κB), inflammation, and mitochondrial dysfunction, which further leads to renal apoptosis. Cisplatin-induced nephropathy is also mediated through the p53 and protein kinase-Cδ (PKCδ) signalling pathways. OBJECTIVE: This review explores these signalling alterations and their possible role in the pathogenesis of cisplatin-induced renal injury.

Green tea catechins: defensive role in cardiovascular disorders.

Green tea, Camellia sinensis (Theaceae), a major source of flavonoids such as catechins, has recently shown multiple cardiovascular health benefits through various experimental and clinical studies. These studies suggest that green tea catechins prevent the incidence of detrimental cardiovascular events, and also lower the cardiovascular mortality rate. Catechins present in green tea have the ability to prevent atherosclerosis, hypertension, endothelial dysfunction, ischemic heart diseases, cardiomyopathy, cardiac hypertrophy and congestive heart failure by decreasing oxidative stress, preventing inflammatory events, reducing platelet aggregation and halting the proliferation of vascular smooth muscle cells. Catechins afford an anti-oxidant effect by inducing anti-oxidant enzymes, inhibiting pro-oxidant enzymes and scavenging free radicals. Catechins present anti-inflammatory activity through the inhibition of transcriptional factor NF-κB-mediated production of cytokines and adhesion molecules. Green tea catechins interfere with vascular growth factors and thus inhibit vascular smooth muscle cell proliferation, and also inhibit thrombogenesis by suppressing platelet adhesion. Additionally, catechins could protect vascular endothelial cells and enhance vascular integrity and regulate blood pressure. In this review various experimental and clinical studies suggesting the role of green tea catechins against the markers of cardiovascular disorders and the underlying mechanisms for these actions are discussed.

Pleiotropic antioxidant potential of rosuvastatin in preventing cardiovascular disorders.

Rosuvastatin is a promising synthetic hydrophillic statin which provides potential benefits in reducing cardiovascular risk factors. Rosuvastatin has potent ability to diminish low density lipoprotein, very low density lipoprotein, triglycerides and enhance high density lipoprotein level to manage high cholesterol level and associated cardiovascular diseases. Intriguingly, numerous studies demonstrated that rosuvastatin can reverse the cardiac disorders such as hypertension, atherosclerosis, ischemic heart disease, congestive heart failure and cardiomyopathy by reducing reactive oxygen species mediated oxidative stress. Rosuvastatin maintain the balance between oxidant generation and oxidant scavenging by reducing NADPH (nicotinamide adenine dinucleotide phosphate)-dependent production of reactive oxygen species, suppressing endothelial nitric oxide synthase (eNOS) uncoupling, inducing and upregulating antioxidant defense mechanism. This review, summaries pleiotropic antioxidant evidences of rosuvastatin in favor of cardioprotection.

Diabetes mellitus associated cardiovascular signalling alteration: a need for the revisit.

Diabetes mellitus, a chronic metabolic disorder, is recognized as a root cause of cardiovascular disorders. A long-term and uncontrolled diabetes mellitus coincides with the cardiovascular signalling alteration, resulting in inadequacy of maintaining the cardiovascular physiology. Nitric oxide (NO) is an imperative mediator of cardiovascular physiology as its signalling is known to mediate vasodilatory, anti-platelet, anti-proliferative, and anti-inflammatory actions in vessels. In 1998, Robert Furchgott, Louis Ignarro and Ferid Murad received the Nobel Prize in Medicine or Physiology for their great discoveries concerning the role of NO (originally identified as endothelium-derived relaxing factor, EDRF) as a key signalling molecule in regulating cardiovascular physiology. The activation of phosphatidylinositol 3-kinase (PI3-K) further activates protein kinase B (PKB/Akt), which subsequently enhances eNOS activation and vascular NO generation. However, in recent studies a marked impairment in PI3-K/Akt-eNOS-NO signalling has been demonstrated in the condition of diabetes mellitus. Therefore, the defective PI3-K-Akt-eNOS-NO signalling pathways could make diabetic patients more vulnerable to cardiovascular disease pathology concerning the key functions of NO. Adenosine produced by cardiac cells has abilities to attenuate the proliferation of cardiac fibroblasts, inhibit collagen synthesis, and defend the myocardium against ischemia-reperfusion injury. However, diabetes mellitus is associated with enhanced unidirectional uptake of interstitial adenosine and reduced ability to release adenosine by cardiac cells during ATP deprivation. The reduced myocardial extracellular availability and increased uptake of adenosine could make diabetic subjects more susceptible to myocardial abnormalities. This review throws lights on diabetes mellitus-associated cardiovascular signalling alterations and their possible contribution to cardiovascular disease pathology.