The role of platelets in non-alcoholic fatty liver disease: From pathophysiology to therapeutics.

Platelets are one of the key mediators in thrombosis as well as in the progression of many diseases. An increase in platelet activation and a decrease in platelet count is associated with a plethora of liver diseases. In non-alcoholic fatty liver disease (NAFLD), platelets are highly activated and participate in the disease progression by enhancing the pro-thrombotic and pro-inflammatory state. Some altered platelet parameters such as mean platelet volume, plateletcrits, and platelet distribution width, aspartate transaminase to platelet ratio index, liver stiffness to platelet ratio and red cell distribution width to platelet ratio were found to be associated with NAFLD disease. Further, platelet contributes to the progression of cardiovascular complications in NAFLD is gaining the researcher's attention. An elevated mean platelet volume is known to enhance the risk of stroke, atherosclerosis, thrombosis, and myocardial infarction in NAFLD. Evidence also suggested that modulation in platelet function using aspirin, ticlopidine, and cilostazol help in controlling the NAFLD progression. Future research should focus on antiplatelet therapy as a treatment strategy that can control platelet activation in NAFLD as well as its cardiovascular risk. In the present review, we have detailed the role of platelets in NAFLD and its cardiovascular complications. We further aimed to highlight the growing need for antiplatelet therapy in NAFLD.

Chloroquine nasal drops in asymptomatic & mild COVID-19: An exploratory randomized clinical trial.

Background & objectives: Chloroquine (CQN) administered as nasal drops has the potential to achieve much greater local tissue levels than with oral/systemic administration. This trial was undertaken to study the efficacy and safety profile of topical nasal administration of CQN drops in reducing viral load and preventing clinical progression in early COVID-19 infection. Methods: This randomized clinical trial was done with a sample size of 60. Reverse transcription-polymerase chain reaction (RT-PCR) confirmed asymptomatic patients or those with mild COVID-19 illness [National Early Warning Score (NEWS) ≤4] were included. Patients were randomized in a 1:1 manner. Control arm (standard supportive treatment, n=30) was compared with intervention arm (n=30) of standard treatment plus CQN eye drops (0.03%) repurposed as nasal drops administered six times daily (0.5 ml/dose) for 10 days. Outcome measures were adverse events and adherence; clinical progression and outcomes were measured by NEWS; sequential RT-PCR cycle threshold (Ct) values were also noted on days 0, 3, 7 and 10. Results: Nasal CQN was associated with local irritation in seven and non-compliance in one of 30 patients. Eleven patients were excluded due to enrolment error (2 - recovered; 9 - false-positive referral), and 49 patients were analyzed as per modified intention-to-treat analysis. Clinical recovery was noted as similar with 100 per cent asymptomatic by day seven in both arms. Virological outcomes also indicated similarly improving Ct values in both arms, and similar proportion of patients transitioning to non-infectivity by day 10 (controls - 19/25; nasal CQN - 15/24). Nine false-positive patients with enrolment error and day 0 RT-PCR negative were initially uninfected but had continuing COVID-19 exposure and treatment as per randomization. Patients receiving nasal CQN (n=5) demonstrated stable Ct values from day 0 to 10, while patients with no nasal CQN (n=4) demonstrated significant dip in Ct value indicating to infection (Ct<35) and infectivity (Ct<33). Interpretation & conclusions: The present study suggests to the potential of topical nasal CQN in the prevention of COVID-19 infection if administered before the infection is established. No significant differences in clinical or virological outcome were however, demonstrated in patients with mild but established illness.

Chloroquine and Hydroxychloroquine for the Treatment of COVID-19: a Systematic Review and Meta-analysis.

BACKGROUND: There is no effective therapy for COVID-19. Hydroxychloroquine (HCQ) and chloroquine (CQ) have been used for its treatment but their safety and efficacy remain uncertain. OBJECTIVE: We performed a systematic review to synthesize the available data on the efficacy and safety of CQ and HCQ for the treatment of COVID-19. METHODS: Two reviewers searched for published and pre-published relevant articles between December 2019 and 8 June 2020. The data from the selected studies were abstracted and analyzed for efficacy and safety outcomes. Critical appraisal of the evidence was done by Cochrane risk of bias tool and Newcastle Ottawa Scale. The quality of evidence was graded as per the GRADE approach. RESULTS: We reviewed 12 observational and 3 randomized trials which included 10,659 patients of whom 5713 received CQ/HCQ and 4966 received only standard of care. The efficacy of CQ/HCQ for COVID-19 was inconsistent across the studies. Meta-analysis of included studies revealed no significant reduction in mortality with HCQ use [RR 0.98 95% CI 0.66-1.46], time to fever resolution (mean difference - 0.54 days (- 1.19-011)) or clinical deterioration/development of ARDS with HCQ [RR 0.90 95% CI 0.47-1.71]. There was a higher risk of ECG abnormalities/arrhythmia with HCQ/CQ [RR 1.46 95% CI 1.04 to 2.06]. The quality of evidence was graded as very low for these outcomes. AUTHORS' CONCLUSION: The available evidence suggests that CQ or HCQ does not improve clinical outcomes in COVID-19. Well-designed randomized trials are required for assessing the efficacy and safety of HCQ and CQ for COVID-19.

Beneficial effects of fenofibrate in pulmonary hypertension in rats.

Pulmonary hypertension (PH) is a morbid complication of cardiopulmonary as well as several systemic diseases in humans. It is rapidly progressive and fatal if left untreated. In the present study, we investigated the effect of PPARα agonist fenofibrate (FF) on monocrotaline (MCT)-induced PH in rats. FF, because of its pleiotropic property, could be helpful in reducing inflammation, oxidative stress, and reactive oxygen species. On day 1, MCT (50 mg/kg, s.c.) was given to all the rats in MCT, sildenafil, and FF group except normal control rats. After 3 days of giving MCT, sildenafil (175 µg/kg, orally) and FF (120 mg/kg, orally) were given for 25 days. Echocardiography, hemodynamic parameters, fulton's index, histopathology, oxidative stress parameters, inflammatory markers, Bcl2/Bax gene expression ratio in the right ventricle, and protein expression for NOX-1 in lungs were studied in all the groups. FF has shown to prevent decrease in ratio of pulmonary artery acceleration time to ejection time, increase in ratio of right ventricular outflow tract dimension to aortic outflow dimension, rise in right ventricular systolic pressure, right ventricular hypertrophy, increase in the percentage medial wall thickness (%MWT), increase in oxidative stress and inflammation, increase in NADPH oxidase-1 (NOX-1) expression, and decrease in mRNA expression of Bcl2/Bax ratio caused by MCT. To conclude, FF prevented MCT-induced PH in rats by various mechanisms. It might be helpful in preventing PH in patients who are likely to develop PH.

Pharmacogenomic biomarkers in coronary artery disease: a narrative review.

Coronary artery disease (CAD) has a high mortality rate. Despite various therapeutic targets, non-responsiveness to drugs remains a prevalent issue. Pharmacogenomics assesses the way an individual's genetic attributes affect their likely response to drug therapy. Single-nucleotide polymorphisms play a crucial role in determining these outcomes. This review offers an overview of single-nucleotide polymorphisms investigated in clinical studies and their associations with drug response/nonresponse in the treatment of CAD. A total of 104 studies of whole sets of chromosomes and several genes were explored. A total of 161 polymorphisms exhibited associations with drug response/nonresponse in CAD across diverse ethnic populations. This pool can serve as a pharmacogenomic biomarker for predicting response to drug therapy in patients with CAD.

The effect of thymoquinone, an active component of Nigella sativa, on isoproterenol induced myocardial injury.

Myocardial injury constitutes a major cause of morbidity and mortality in humans. Present study aimed to investigate protective role of thymoquinone, which is an active principle of Nigella sativa (N. sativa) seed (Commonly called as black seed), in isoproterenol induced myocardial injury, a classical example of excess catecholamines related coronary insufficiency and stress cardiomyopathy. Thymoquinone, in olive oil, was administered orally (12.5, 25 and 50mg/kg) to three groups of Wistar albino rats for 7 days, while two control groups were given plain olive oil. Thereafter, thymoquinone receiving groups and one control group were injected, subcutaneously, with isoproterenol (125mg/kg) for 2 days. Myocardial injury was assessed by biochemical markers (plasma LDH, TBARS, GR & SOD and myocardial GSH/GSSG ratio) and cardiac histopathology. Plasma LDH, TBARS and GR increased in control groups receiving isoproterenol, while there was a dose related decrease in these markers in thymoquinone treated groups, down to levels in controls given olive oil only. Decrease in plasma SOD and myocardial GSH/GSSG ratio and histological changes produced with isoproternol were also reversed in thymoquinone treated rats. Results of our study revealed that thymoquinone protects the heart from injury induced by isoproterenol.

Genistein prevents isoproterenol-induced cardiac hypertrophy in rats.

Genistein, an isoflavone and a rich constituent of soy, possesses important regulatory effects on nitric oxide (NO) synthesis and oxidative stress. Transient and low release of NO by endothelial nitric oxide synthase (eNOS) has been shown to be beneficial, while high and sustained release by inducible nitric oxide synthase (iNOS) may be detrimental in pathological cardiac hypertrophy. The present study was designed to evaluate whether genistein could prevent isoproterenol-induced cardiac hypertrophy in male Wistar rats (150-200 g, 10-12 weeks old) rats. Isoproterenol (5 mg·(kg body weight)(-1)) was injected subcutaneously once daily for 14 days to induced cardiac hypertrophy. Genistein (0.1 and 0.2 mg·kg(-1), subcutaneous injection once daily) was administered along with isoproterenol. Heart tissue was studied for myocyte size and fibrosis. Myocardial thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), catalase levels, and 1-OH proline (collagen content) were also estimated. Genistein significantly prevented any isoproterenol-induced increase in heart weight to body weight ratio, left ventricular mass (echocardiographic), myocardial 1-OH proline, fibrosis, myocyte size and myocardial oxidative stress. These beneficial effects of genistein were blocked by a nonselective NOS inhibitor (L-NAME), but not by a selective iNOS inhibitor (aminoguanidine). Thus, the present study suggests that the salutary effects of genistein on isoproterenol-induced cardiac hypertrophy may be mediated through inhibition of iNOS and potentiation of eNOS activities.

Oxidative stress and cardiac hypertrophy: a review.

Cardiac hypertrophy (CH) is an adaptive response of the heart to pressure overload. It is a common pathological feature in the natural course of some major cardiovascular diseases, like, hypertension and myocardial infarction. Cardiac hypertrophy is strongly associated with an increased risk of heart failure and sudden cardiac death. The complex and dynamic pathophysiological mechanisms of CH has been the focus of intense scientific investigation, in an effort to design preventive and curative strategies. Oxidative stress has been identified as one of the key contributing factors in the development of cardiac hypertrophy. In this review, evidences supporting the oxidative stress as a cause of cardiac hypertrophy with emphasis on mitochondrial oxidative stress and possible options for pharmacological interventions have been discussed. Reactive oxygen species (ROS) also activate a broad variety of hypertrophy signaling kinases and transcription factors, like, MAP kinase, NF K-B, etc. In addition to profound alteration of cellular function, ROS modulate the extracellular matrix function, evidenced by increased interstitial and perivascular fibrosis. Translocator protein (TSPO) present in the outer mitochondrial membrane is known to be involved in oxidative stress and cardiovascular pathology. Recently, its role in cardiac hypertrophy has been reported by us. All these evidences strongly provide support to beneficial role of drugs which selectively interfere with the generation of free radicals or augment endogenous antioxidants in cardiac hypertrophy.

Hepatic drug metabolism and gut microbiome.

This chapter focuses on intestinal microbiota and its effect on drug metabolism. Here, we discussed about different drugs which are metabolized either by some enzymes or gut microbiota and their mechanism. Nowadays, consuming drugs without a doctor's prescription is common. This chapter will make people aware about its negative consequences and how it is related to gut microbiota dysbiosis. Intestinal disorders like inflammatory bowel disease (IBD), colorectal cancer (CRC) and metabolic disorders such as obesity and type 2 diabetes mellitus (T2D) are found to be affected with gut microbiota dysbiosis. To address this issue, we discussed a variety of strategies such as fecal microbiota transplantation (FMT), probiotics and antibiotic stewardship programs which are commonly used to tackle this problem.