Nrf2-Keap1 in Cardiovascular Disease: Which Is the Cart and Which the Horse?

High levels of oxidant stress in the form of reactive oxidant species are prevalent in the circulation and tissues in various types of cardiovascular disease including heart failure, hypertension, peripheral arterial disease, and stroke. Here we review the role of nuclear factor erythroid 2-related factor 2 (Nrf2), an important and widespread antioxidant and anti-inflammatory transcription factor that may contribute to the pathogenesis and maintenance of cardiovascular diseases. We review studies showing that downregulation of Nrf2 exacerbates heart failure, hypertension, and autonomic function. Finally, we discuss the potential for using Nrf2 modulation as a therapeutic strategy for cardiovascular diseases and autonomic dysfunction.

Phenotyping of lymphocyte subsets, Th-1/Th-2 cytokines and other parameters in high-risk contacts of SARS-CoV-2.

Background: The information on the pathophysiology of infection in high-risk contacts of SARS-CoV-2 is limited. Aims: The aim of the present study was to assess the various factors and their elucidation in the protection of SARS- CoV-2 infection in high-risk contacts. Settings and Design: Cross-sectional descriptive clinical study. Materials and Methods: A total of 136 subjects were recruited in the present study including 100 high-risk subjects and 36 control subjects. Out of 100 high-risk subjects, 44 subjects were found positive for SARS-CoV-2 RNA. Further, absolute blood counts of total T-cells (CD3+), T-helper cells (CD4+), T-cytotoxic cells (CD8+), B lymphocytes (CD19+) Natural Killer (NK) Cells (CD16+, CD56+), cytokines, and other parameters were measured in the samples of study subjects. Statistical Analysis Used: The continuous variables were analyzed by unpaired 't' test, analysis of variance and 'Tukey test' for multiple comparisons. Results: A significant reduction of total leukocyte counts and absolute lymphocyte count was found in the acute SARS-CoV-2 positive group as compared to control group (<0.05). Interestingly, IL-4 level was significantly elevated in SARS-CoV-2 negative high-risk subjects as compared to control and acute SARS-CoV-2 positive group (p < 0.05). A significant decrease of T-cytotoxic, B-cells, and NK cells were found in acute SARS-CoV-2 positive subjects as compared to control groups. Conclusion: The findings of this study may augment our knowledge about the pathogenesis of SARS-CoV-2 infection that could help in making future strategies to control its infection.

Cardioprotective Efficacy of Coriandrum sativum (L.) Seed Extract in Heart Failure Rats Through Modulation of Endothelin Receptors and Antioxidant Potential.

The present study aimed to evaluate the therapeutic and prophylactic potential of Coriandrum sativum extract in isoproterenol-induced heart failure (HF) in Wistar rats. Two weeks after the isoproterenol administration, rats developed severe impairment in left ventricular functions, reduced baroreflex sensitivity, and significant alteration in hemodynamic parameters and lipid profile. HF rats also exhibited enhanced lipid peroxidation and increased expression of endothelin receptors (ETA and ETB). Therapeutic and prophylactic treatment with C. sativum extract significantly (p < .05) improved the left ventricular functions and hemodynamic parameters and increased baroreflex sensitivity. It also inhibited lipid peroxidation, improved lipid profile, and downregulated the expression of endothelin receptors. Simvastatin treatment showed a similar cardioprotective effect. Our results suggest that C. sativum extract provides significant protection from heart failure possibly due to its ability to improve left ventricular functions and baroreflex sensitivity, attenuate lipid peroxidation, and modulate the expression of endothelin receptors.

Inhibition of snake venom induced sterile inflammation and PLA2 activity by Titanium dioxide Nanoparticles in experimental animals.

Sterile inflammation (SI) is an essential process in response to snakebite and injury. The venom induced pathophysiological response to sterile inflammation results into many harmful and deleterious effects that ultimately leads to death. The available treatment for snakebite is antiserum which does not provide enough protection against venom-induced pathophysiological changes like haemorrhage, necrosis, nephrotoxicity and often develop hypersensitive reactions. In order to overcome these hindrances, scientists around the globe are searching for an alternative therapy to provide better treatment to the snake envenomation patients. In the present study TiO2 (Titanium dioxide)-NPs (Nanoparticles) has been assessed for antisnake venom activity and its potential to be used as an antidote. In this study, the synthesis of TiO2-NPs arrays has been demonstrated on p-type Silicon Si < 100 > substrate (∼30 ohm-cm) and the surface topography has been detected by Field-emission scanning electron microscopy (FESEM). The TiO2-NPs successfully neutralized the Daboia russelii venom (DRV) and Naja kaouthia venom (NKV)-induced lethal activity. Viper venom induced haemorrhagic, coagulant and anticoagulant activities were effectively neutralized both in in-vitro and in vivo studies. The cobra and viper venoms-induced sterile inflammatory molecules (IL-6, HMGB1, HSP70, HSP90, S100B and vWF) were effectively neutralised by the TiO2-NPs in experimental animals.

Ameliorative Effect of Beraprost Sodium on Celecoxib Induced Cardiotoxicity in Rats.

Selective COX-2 inhibitors are most widely used analgesic and anti-inflammatory drugs; however, its maximal use is highly associated with various serious abnormal cardiovascular events. Beraprost sodium (BPS), prostacyclin analogue has been shown to vasodilatory, antiplatelates, anti-inflmmatory, and antioxidant activity. The objective of the present study was to evaluate the effect of BPS on celecoxib cardiotoxicity in rats. Toxicity was induced in male Albino rats (250-280 g) by celecoxib (100 mg/kg/day). BPS (30 µg/kg/day) was administered alone and in combination with celecoxib for 14 days and various biochemicals, hemodynamic, left ventricular, biochemical, and histopathological parameters were studied. Cardiotoxicity of celecoxib was revealed by a significant increase in serum lactate dehydrogenase (LDH), troponin-T (Tn-T), tumor necrosis factor-α (TNF- α), creatine kinase-MB (CK-MB) and systolic blood pressure (SBP), left ventricular end diastolic pressure (LVEDP), LV (dp/dt)max, and LV (dp/dt)min as well as tissue thiobarbituric acid reactive substance (TBARS) and a significant decrease in tissue reduced glutathione (GSH). However, treatment with BPS reversed these alteration in LDH, Tn-T, TNF-α, CK-MB, SBP, LVEDP, LV (dp/dt)max, LV (dp/dt)min, TBARS and GSH levels. The histopathological study in cardiac left ventricle revealed protection of myocardium as manifested reduction of fibrosis by abolition of collagen deposition when celecoxib was combined with beraprost sodium. It could be concluded that beraprost sodium may prove a useful adjunct in patients being prescribed celecoxib.

Levosimendan reduces myocardial damage and improves cardiodynamics in streptozotocin induced diabetic cardiomyopathy via SERCA2a/NCX1 pathway.

AIMS: Diabetic cardiomyopathy (DCM) is one of the most common causes of mortality. Its pathophysiology is not fully understood and involve number of factors including, cardiovascular and metabolic disorders. The present study was designed to study the pathogenesis of DCM and to explore the effects of levosimendan along with either ramipril or insulin in the long term management of DCM. MATERIALS AND METHODS: Streptozotocin (STZ) was used to develop DCM in Wistar rats at the dose of 25mg/kg body weight for three consecutive days. Rats were randomly divided into 9 groups and treatments were started after 2weeks of STZ administration. KEY FINDINGS: Persistent hyperglycemia was observed in STZ treated rats, leading to significant contractile dysfunction as evidenced by decreased left ventricular pressure (LVP), +LV (dp/dt), -LV (dp/dt) as well as elevated Tau and LVEDP. Marked myocardial damage such as fibrosis, increased wall tension, depletion of contractile proteins were observed as evidenced by increased levels of TGF-ß, BNP, cTroponin-I, as well as decreased expression of SERCA2a and NCX1 proteins in diabetic rats. The levosimendan alone and also in combination with either ramipril or insulin significantly normalized the myocardial dysfunctions developed during the course of persistent hyperglycemia. SIGNIFICANCE: The study suggests that levosimendan treatment improves cardiac dysfunction significantly. Its combined use with ramipril proves better than with insulin in correcting myocardial performance as well as reduction in myocardial damage.