Charu Sharma

Cardioprotective effect of lycopene against isoproterenol-induced myocardial infarction in rats

The present study was designed to evaluate the cardioprotective potential of lycopene (LCP) against isoproterenol (ISP)-induced myocardial infarction (MI), by assessing hemodynamic, biochemical and histopathological parameters. Wistar male albino rats were orally administered with LCP (0.5, 1.0 and 1.5 mg/kg) or with vehicle for 30 days, with concurrent subcutaneous injections of ISP (85 mg/kg) on days 28 and 29. ISP significantly (p < 0.05) decreased systolic, diastolic and mean arterial blood pressure (SAP, DAP and MAP, respectively) and heart rate (HR). ISP also decreased contractility (+LVdP/dt), relaxation (−LVdP/dt) and increased left ventricular end-diastolic pressure (LVEDP). In addition to functional impairment, ISP also caused a significant (p < 0.05) decrease in antioxidants, namely, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx), glutathione (GSH), cardiac injury marker enzymes, creatine phosphokinase-MB (CK-MB) and lactate dehydrogenase (LDH), as well as induced lipid peroxidation, malonaldialdehyde (MDA) and histopathological alterations in heart. However, pretreatment with LCP significantly (p < 0.05) attenuated ISP-induced cardiac dysfunction as evidenced by improved SAP, DAP, MAP, HR, (±)LVdP/dt and reduced LVEDP. Pretreatment with LCP also significantly (p < 0.05) prevented the depletion of antioxidants (SOD, CAT, GSHPx and GSH), myocyte injury marker enzymes (CK-MB and LDH) and inhibited lipid peroxidation and MDA formation in the heart. Furthermore, reduced necrosis, edema and infiltration of inflammatory cells on histopathological examination also depicted the protective effect of LCP against the deleterious effect of ISP. Based on the results, it is suggested that LCP possesses significant cardioprotective potential and may serve as an adjunct in treatment and prophylaxis of MI.

Protective Effects of Cardamom in Isoproterenol-Induced Myocardial Infarction in Rats.

Cardamom is a popular spice that has been commonly used in cuisines for flavor since ancient times. It has copious health benefits such as improving digestion, stimulating metabolism, and exhibits antioxidant and anti-inflammatory effects. The current study investigated the effect of cardamom on hemodynamic, biochemical, histopathological and ultrastructural changes in isoproterenol (ISO)-induced myocardial infarction. Wistar male albino rats were randomly divided and treated with extract of cardamom (100 and 200 mg/kg per oral) or normal saline for 30 days with concomitant administration of ISO (85 mg/kg, subcutaneous) on 29th and 30th days, at 24 h interval. ISO injections to rats caused cardiac dysfunction evidenced by declined arterial pressure indices, heart rate, contractility and relaxation along with increased preload. ISO also caused a significant decrease in endogenous antioxidants, superoxide dismutase, catalase, glutathione peroxidase, depletion of cardiomyocytes enzymes, creatine kinase-MB, lactate dehydrogenase and increase in lipid peroxidation. All these changes in cardiac and left ventricular function as well as endogenous antioxidants, lipid peroxidation and myocyte enzymes were ameliorated when the rats were pretreated with cardamom. Additionally, the protective effects were strengthened by improved histopathology and ultrastructural changes, which specifies the salvage of cardiomyocytes from the deleterious effects of ISO. The present study findings demonstrate that cardamom significantly protects the myocardium and exerts cardioprotective effects by free radical scavenging and antioxidant activities.

Effect of fluoroquinolones on the expression of matrix metalloproteinase in debrided cornea of rats

Matrix metalloproteinases (MMPs) are implicated in regenerative and healing processes in corneal injuries. Based upon reports that topical fluoroquinolones (FQs) may cause perforations during corneal healing by modulating MMPs, this study evaluated the comparative effects of commercially available FQs eye drops on the expression of MMP-2 and MMP-9 in the cornea after ethanol injury. Uniform corneal epithelial defects were created using 70% ethanol in the right eye of the rats (n = 6). The groups studied were (I) sham, (II) normal saline with benzalkonium chloride (NS-BKC), (III) norfloxacin 0.3%, (IV) ciprofloxacin 0.3%, (V) lomefloxacin 0.3%, (VI) sparfloxacin 0.3%, (VII) gatifloxacin 0.3%, and (VIII) moxifloxacin 0.5%. Each treatment was instilled six times/day up to 48 h and rats were sacrificed using excess of anesthesia. The corneas were excised to study the expression of MMP-2 and MMP-9 using gelatin zymography and real-time PCR. All the FQs significantly increased the expression of MMP-2 and MMP-9 as compared to the sham and NS-BKC-treated group. NS-BKC did not show a significant effect on MMPs expression compared to the sham group. Among the studied FQs, ciprofloxacin was observed to exhibit maximal induction of MMP-2 and MMP-9, whereas lomefloxacin exhibited an equivocal effect on both MMP-2 and MMP-9 expression. Findings of the present study demonstrate that topical application of FQs may induce the expression of MMP-2 and MMP-9 in debrided corneal epithelium and, therefore, may delay corneal wound healing. Thus, it can be concluded that selecting a FQ for ophthalmic use having minimal effect on MMPs may impact wound healing in injured or vulnerable cornea.

Pharmacological Properties and Therapeutic Potential of Naringenin: A Citrus Flavonoid of Pharmaceutical Promise

Naringenin chemically known as 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one is a common dietary polyphenolic constituent of the citrus fruits. It has received considerable attention for pharmaceutical and nutritional development due to potent pharmacological activities and therapeutic potential. Accruing evidence from both in vitro and in vivo studies have unraveled numerous biological targets along with complex underlying mechanisms suggesting possible therapeutic applications of naringenin in various neurological, cardiovascular, gastrointestinal, rheumatological, metabolic and malignant disorders. Functionally, this ameliorative effect of naringenin is primarily attributed to its antiinflammatory (via inhibiting recruitment of cytokines and inflammatory transcription factors) and anti-oxidant (via scavenging of free radicals, bolstering of endogenous antioxidant defense system and metal ion chelation) effects. The present article provides a comprehensive review of the various studies that have evaluated the therapeutic potential of naringenin and its actions at the molecular level. It also summarizes the pharmacokinetic data and issues and challenges involved in pharmaceutical development and suggest that it may be a potential agent for further exploration as well as may be useful as a dietary adjunct in treatment of various human ailments.

Thymoquinone Protects against Myocardial Ischemic Injury by Mitigating Oxidative Stress and Inflammation

The present study was aimed at investigating the cardioprotective activity of thymoquinone (TMQ), an active principle of the herb, Nigella sativa, which is used for the management of various diseases. The present study examined the cardioprotective effect of TMQ in isoproterenol- (ISP-) induced myocardial infarction in rats. Myocardial infarction was induced by two subcutaneous injections of ISP (85 mg/kg) at an interval of 24 hr. TMQ (20 mg/kg) was administered orally for 21 days. ISP-treated rats showed depletion of antioxidants and marker enzymes from myocardium along with lipid peroxidation and enhanced levels of proinflammatory cytokines. ISP also induced histopathological alterations in myocardium. Treatment with TMQ prevented the depletion of endogenous antioxidants and myocyte injury marker enzymes and inhibited lipid peroxidation as well as reducing the levels of proinflammatory cytokines. TMQ pretreatment also reduced myonecrosis, edema, and infiltration of inflammatory cells and showed preservation of cardiomyocytes histoarchitecture. The present study results demonstrate that TMQ exerts cardioprotective effect by mitigating oxidative stress, augmenting endogenous antioxidants, and maintaining structural integrity. The results of the present study indicate that TMQ may serve as an excellent agent alone or as adjuvant to prevent the onset and progression of myocardial injury.

Insight into the mechanism of polyphenols on the activity of HMGR by molecular docking

Statins are hypolipidemic drugs that are effective in the treatment of hypercholesterolemia by attenuating cholesterol synthesis in the liver via competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Recently, dietary changes associated with drug therapy have garnered attention as novel drugs to mitigate or ameliorate hypercholesterolemia. The present study was undertaken to observe different dietary polyphenols that can bind to the active site of HMGR and inhibit it. Results from the 12 dietary polyphenols tested reveal that polyphenols can bind to HMGR and block the binding of nicotinamide adenine dinucleotide phosphate (NADP+). We observed that the rigidity of phenolic rings prevents the polyphenols from docking to the enzyme activity site. The presence of an ester linkage between the phenolic rings in (–)-epigallocatechin-3-gallate (EGCG) and the alkyl chain in curcumin allows them to orient in the active site of the HMGR and bind to the catalytic residues. EGCG and curcumin showed binding to the active site residues with a low GRID score, which may be a potential inhibitor of HMGR. Kaempferol showed binding to HMG-CoA, but with low binding affinity. These observations provide a rationale for the consistent hypolipidemic effect of EGCG and curcumin, which has been previously reported in several epidemiological and animal studies. Therefore, this study substantiates the mechanism of polyphenols on the activity of HMGR by molecular docking and provides the impetus for drug design involving further structure–function relationship studies.

Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ9-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.

Licorice treatment prevents oxidative stress, restores cardiac function, and salvages myocardium in rat model of myocardial injury.

The present study examined the effects of licorice on antioxidant defense, functional impairment, histopathology, and ultrastructural alterations in isoproterenol (ISP)-induced myocardial injury in rats. Myocardial necrosis was induced by two subcutaneous injection of ISP (85 mg/kg) at an interval of 24 h. Licorice was administered orally for 30 days in the doses of 100, 200, 400, or 800 mg/kg. ISP-treated rats showed impaired hemodynamics, left ventricular dysfunction, and caused depletion of antioxidants and marker enzymes along with lipid peroxidation from myocardium. ISP also induced histopathological and ultrastructural alterations in myocardium. Pretreatment with licorice prevented the depletion of endogenous antioxidants and myocyte injury marker enzymes, inhibited lipid peroxidation, and showed recovery of hemodynamic and ventricular functions. Licorice treatment also reduced myonecrosis, edema, and infiltration of inflammatory cells and showed preservation of subcellular and ultrastructural components. Our results demonstrate that licorice exerts cardioprotection by reducing oxidative stress, augmenting endogenous antioxidants, and restoring functional parameters as well as maintaining structural integrity.

Development of Novel In Silico Model to Predict Corneal Permeability for Congeneric Drugs: A QSPR Approach

This study was undertaken to determine in vivo permeability coefficients for fluoroquinolones and to assess its correlation with the permeability derived using reported models in the literature. Further, the aim was to develop novel QSPR model to predict corneal permeability for fluoroquinolones and test its suitability on other training sets. The in vivo permeability coefficient was determined using cassette dosing (N-in-One) approach for nine fluoroquinolones (norfloxacin, ciprofloxacin, lomefloxacin, ofloxacin, levofloxacin, sparfloxacin, pefloxacin, gatifloxacin, and moxifloxacin) in rabbits. The correlation between corneal permeability derived using in vivo studies with that derived from reported models was determined. Novel QSPR-based model was developed using in vivo corneal permeability along with other molecular descriptors. The suitability of developed model was tested on β-blockers (n = 15). The model showed better prediction of corneal permeability for fluoroquinolones (r2 > 0.9) as well as β-blockers (r2 > 0.6). The newly developed QSPR model based upon in vivo generated data was found suitable to predict corneal permeability for fluoroquinolones as well as other sets of compounds.

Therapeutic Potential and Pharmaceutical Development of Thymoquinone: A Multitargeted Molecule of Natural Origin

Thymoquinone, a monoterpene molecule is chemically known as 2-methyl-5-isopropyl-1, 4-benzoquinone. It is abundantly present in seeds of Nigella sativa L. that is popularly known as black cumin or black seed and belongs to the family Ranunculaceae. A large number of studies have revealed that thymoquinone is the major active constituent in N. sativa oil this constituent is responsible for the majority of the pharmacological properties. The beneficial organoprotective activities of thymoquinone in experimental animal models of different human diseases are attributed to the potent anti-oxidant and anti-inflammatory properties. Thymoquinone has also been shown to alter numerous molecular and signaling pathways in many inflammatory and degenerative diseases including cancer. Thymoquinone has been reported to possess potent lipophilicity and limited bioavailability and exhibits light and heat sensitivity. Altogether, these physiochemical properties encumber the successful formulation for the delivery of drug in oral dosages form and restrict the pharmaceutical development. In recent past, many efforts were undertaken to improve the bioavailability for clinical usage by manipulating the physiochemical parameters. The present review aimed to provide insights regarding the physicochemical characteristics, pharmacokinetics and the methods to promote pharmaceutical development and endorse the clinical usage of TQ in future by overcoming the associated physiochemical obstacles. It also enumerates briefly the pharmacological and molecular targets of thymoquinone as well as the pharmacological properties in various diseases and the underlying molecular mechanism. Though, a convincing number of experimental studies are available but human studies are not available with thymoquinone despite of the long history of use of black cumin in different diseases. Thus, the clinical studies including pharmacokinetic studies and regulatory toxicity studies are required to encourage the clinical development of thymoquinone.