Bhavesh C. Variya

Synthesis, anti-inflammatory, analgesic, 5-lipoxygenase (5-LOX) inhibition activities, and molecular docking study of 7-substituted coumarin derivatives

In the present study, 7-subsituted coumarin derivatives were synthesized using various aromatic and heterocyclic amines, and evaluated in vivo for anti-inflammatory and analgesic activity, and for ulcerogenic risk. The most active compounds were evaluated in vitro for 5-lipoxygenase (5-LOX) inhibition. Docking study was performed to predict the binding affinity, and orientation at the active site of the enzyme. In vivo anti-inflammatory and analgesic activity, and in vitro 5-LOX enzyme inhibition study revealed that compound 33 and 35 are the most potent compounds in all the screening methods. In vitro kinetic study of 35 showed mixed or non-competitive type of inhibition with 5-LOX enzyme. Presence of OCH3 group in 35 and Cl in 33 at C6-position of benzothiazole ring were found very important substitutions for potent activity.

Novel targets for paclitaxel nano formulations: Hopes and hypes in triple negative breast cancer.

Triple negative breast cancer is defined as one of the utmost prevailing breast cancers worldwide, possessing an inadequate prognosis and treatment option limited to chemotherapy and radiotherapy, creating a challenge for researchers as far as developing a specific targeted therapy is concerned. The past research era has shown several promising outcomes for TNBC such as nano-formulations of the chemotherapeutic agents already used for the management of the malignant tumor. Taking a glance at paclitaxel nano formulations, it has been proven beneficial in several researches in the past decade; nevertheless its solubility is often a challenge to scientists in achieving success. We have henceforth discussed the basic heterogeneity of triple negative breast cancer along with the current management options as well as a brief outlook on pros and cons of paclitaxel, known as the most widely used chemotherapeutic agent for the treatment of the disease. We further analyzed the need of nanotechnology pertaining to the problems encountered with the current paclitaxel formulations available discussing the strategic progress in various nano-formulations till date taking into account the basic research strategies required in terms of solubility, permeability, physicochemical properties, active and passive targeting. A thorough review in recent advances in active targeting for TNBC was carried out whereby the various ligands which are at present finding its way into TNBC research such as hyaluronic acid, folic acid, transferrin, etc. were discussed. These ligands have specific receptor affinity to TNBC tumor cells hence can be beneficial for novel drug targeting approaches. Conversely, there are currently several novel strategies in the research pipeline whose targeting ligands have not yet been studied. Therefore, we reviewed upon the numerous novel receptor targets along with the respective nano-formulation aspects which have not yet been fully researched upon and could be exemplified as outstanding target strategies for TNBC which is currently an urgent requirement.

Design, synthesis and pharmacological evaluation of novel substituted quinoline-2-carboxamide derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents.

In continuation of our research for novel human dihydroorotate dehydrogenase (hDHODH) inhibitors, herein we reported design, synthesis and pharmacological evaluation of novel substituted quinoline-2-carboxamide derivatives. Human DHODH enzyme inhibition assay was used to screen the synthesized compounds as hDHODH inhibitors. The synthesized compounds were also evaluated for their antiproliferative effects on the cancer cell lines (HEP-3B and A-375) to establish a proof as anticancer agents. The chemical structures of compounds were confirmed by (1)H, (13)C NMR, IR, MS and elemental analysis. The purity of compounds was also checked by HPLC analysis. Compounds with bulky groups (-OCH3, -OCF3 and -CF3) at C6-position of quinoline ring showed good activity.

Emblica officinalis (Amla): A review for its phytochemistry, ethnomedicinal uses and medicinal potentials with respect to molecular mechanisms.

Medicinal plants, having great elementary and therapeutic importance, are the gift to mankind to acquire healthy lifestyle. Emblica officinalis Gaertn. or Phyllanthus emblica Linn. (Euphorbeaceae), commonly known as Indian gooseberry or Amla, has superior value in entirely indigenous traditional system of medicine, including folklore Ayurveda, for medicinal and nutritional purposes to build up lost vitality and vigor. In this article, numerous phytochemicals isolated from E. officinalis and its ethnomedical and pharmacological potentials with molecular mechanisms are briefly deliberated and recapitulated. The information documented in the present review was collected from more than 270 articles, published or accepted in the last five to six decades, and more than 20 e-books using various online database. Additional information was obtained from various botanical books and dissertations. The extracts from various parts of E. officinalis, especially fruit, contain numerous phytoconstituents viz. higher amount of polyphenols like gallic acid, ellagic acid, different tannins, minerals, vitamins, amino acids, fixed oils, and flavonoids like rutin and quercetin. The extract or plant is identified to be efficacious against diversified ailments like inflammation, cancer, osteoporosis, neurological disorders, hypertension together with lifestyle diseases, parasitic and other infectious disorders. These actions are attributed to either regulation of various molecular pathway involved in several pathophysiologies or antioxidant property which prevents the damage of cellular compartments from oxidative stress. However, serious efforts are required in systemic research to identify, isolate and evaluate the chemical constituents for nutritional and therapeutic potentials.

Comparative evaluation of HMG CoA reductase inhibitors in experimentally-induced myocardial necrosis: Biochemical, morphological and histological studies

The present study was carried out to evaluate the protective effect of different statins on isoproterenol (ISO) induced myocardial necrosis. Atorvastatin, rosuvastatin, fluvastatin, simvastatin and pravastatin (10 mg/kg/day) were administered for 12 weeks. After pretreatment of 12 weeks myocardial necrosis was induced by subsequent injection of ISO (85 mg/kg/day, s.c.) to wistar rats. Serum biochemical parameters like glucose, lipid profile, cardiac markers and transaminases were evaluated. Animals were killed and heart was excised for histopathology and antioxidant study. Statins pretreated rats showed significant protection against ISO induced elevation in serum biochemical parameters and serum level of cardiac marker enzymes and transaminase level as compared to ISO control group. Mild to moderate protection was observed in different statins treated heart in histopathology and TTC stained sections. Result from our study also revealed that statins could efficiently protect against ISO intoxicated myocardial necrosis by impairing membrane bound enzyme integrity and endogenous antioxidant enzyme levels. Amongst all statins used, rosuvastatin and pravastatin were found to have maximum cardio-protective activity against ISO induced myocardial necrosis as compared to other statins.

DEAE-Dextran coated paclitaxel nanoparticles act as multifunctional nano system for intranuclear delivery to triple negative breast cancer through VEGF and NOTCH1 inhibition

Graphical abstract Figure. No Caption available. Abstract Triple negative breast cancer revolution has identified a plethora of therapeutic targets making it apparent that a single target for its treatment could be rare hence creating an urge to develop robust technologies for combination drug therapy. Paclitaxel, hailed as the most significant advancement in chemotherapy faces several underpinnings due to its low solubility and permeability. Advancing research has demonstrated the role of interferons in cancer. DEAE‐Dextran, an emerging molecule with evidence of interferon induction was utilized in the present study to develop a nanoformulation in conjugation with paclitaxel to target multiple therapeutic pathways, with diminution of paclitaxel adverse effects and develop a specific targeted nano system. Evidently, it was demonstrated that DEAE‐Dextran coated nanoformulation portrays significant synergistic cytotoxicity in the various cell lines. Moreover, overcoming the activation of ROS by paclitaxel, the combination drug therapy more effectively inhibited ROS through &bgr;‐interferon induction. The nanoformulation was further conjugated to FITC for internalization studies which subsequently indicated maximum cellular uptake at 60 min post treatment demonstrated by green fluorescence from FITC lighting up the nuclear membrane. Precisely, the mechanistic approach of nuclear‐targeted nanoformulation was evaluated by in vivo xenograft studies which showed a synergistic release of &bgr;‐interferon at the target organ. Moreover, the combination nanoformulation inculcated multiple mechanistic approaches through VEGF and NOTCH1 inhibition along with dual &bgr; and &ggr;‐interferon overexpression. Overall, the combination therapy may be a promising multifunctional nanomaterial for intranuclear drug delivery in TNBC.

Repeated dose 28-day oral toxicity study of DEAE-Dextran in mice: An advancement in safety chemotherapeutics

ABSTRACT Cancer has emerged as a global threat with challenges for safe chemotherapeutics. Most of the currently available anti‐cancer drugs exhibit significant toxicity. Amongst novel agents, interferons have exhibited anti‐proliferative and cytoprotective roles. However, due to stability drawbacks of interferons, we have identified an interferon inducer DEAE‐Dextran, which resolves the stability issues. Based on the previous history of toxicity pertaining to the current chemotherapeutic agents, it is equally essential to determine the safety of DEAE‐Dextran. In the present study, repeated dose 28 day oral toxicity of DEAE‐Dextran has been evaluated in accordance to OECD‐407. We found absence of any CNS behavioral changes related to self‐mutilation, walking backwards, aggressiveness on handling or tonic‐clonic seizures during the 28 day study. Neither the motor activity nor grip strength was altered during the treatment duration with DEAE‐Dextran implying absence of any effect on the skeletal muscles. Interestingly, we also found that treatment with DEAE‐Dextran did not present any significant cardiac, hepatic, renal, gastrointestinal, lymphatic or reproductive system toxicity or alteration in the bodys normal physiology based upon the various organ function tests. Henceforth, it may be concluded that DEAE‐Dextran is a safe anti‐cancer agent devoid of any sub‐acute toxicity. HIGHLIGHTSBreast cancer treatment faces challenges of safe chemotherapeutic agents since they exhibit toxicity.Interferon inducers could manifest safe drugs since they enhance the natural defense mechanism of the body.DEAE‐Dextran investigated as an anti‐cancer agent, it is adequately important to determine its toxicity profile.Toxicity profile of DEAE‐Dextran indicates no alteration in body system functions declaring it safe for administration.

Molecular docking, synthesis and biological screening of mefenamic acid derivatives as anti-inflammatory agents

ABSTRACT Drug induced gastrointestinal ulceration, renal side effects and hepatotoxicity are the main causes of numerous Non‐Steroidal Anti‐inflammatory Drugs (NSAIDs). Cyclooxygenase‐2 (COX‐2) inhibitors discovered to decrease the gastrointestinal issues, but unfortunately, most of them are associated with major cardiovascular adverse effects. Along these lines, various new strategies and frameworks were developed wherein basic alterations of the present medications were accounted for. The aim of the study was to prepare derivatives of mefenamic acid to evaluate anti‐inflammatory activity with fewer adverse reactions. In this study, molecular docking investigations of outlined derivatives were done utilizing Protein Data Bank (PDB ID‐4PH9). Synthesis of heterocyclic compounds was carried out utilizing Dicyclohexylcarbodiimide/4‐Dimethylaminopyridine (DCC/DMAP) coupling. Acute toxicity prediction was performed using free online GUSAR (General Unrestricted Structure‐Activity Relationships) software. The study indicated most of the compounds under safe category. In‐vitro pharmacological assessment of heterocyclic compounds was done for COX‐1 and COX‐2 enzymes for the determination of selectivity. In vivo pharmacological screening for anti‐inflammatory activity and ED50 value were determined utilizing carrageenan induced rat paw edema. Gastro intestinal safety study was carried out on selected compounds and found to be devoid of any gastric ulcer toxicity. Most of the compounds indicated high scores as compared to standard during molecular modelling, analysis and displayed interactions with active amino acids of a COX‐2 enzyme. The pharmacological screening uncovered that compound substituted with p‐bromophenyl indicated maximum potency. Graphical abstract Anti‐inflammatory activity with IC50=2.13 &mgr;M. Figure. No Caption available.

Insights from diversified anti-angiogenic models: Role of β-interferon inducer DEAE-Dextran

BACKGROUND Angiogenesis, the physiological process involving growth of new blood vessels from preexisting vessels, is essential for organ growth and repair. However, the imbalance in angiogenesis contributes to copious pathologies including cancer. Preceding the development of anti-angiogenic or proangiogenic agents, its evaluation is equally imperative; hence, precise and adequate models required. Valid mammalian models are expensive, time-consuming and not easy to set up, instigating legal and ethical aspects making it necessary to establish models with satisfactory activity and limited drawbacks. METHODS We investigated the activity of DEAE-Dextran on diversified models viz. in vitro cell migration assay, ex vivo aortic ring assay, in vitro chick yolk sac membrane assay and in vivo matrigel plug xenograft model corroborating its anti-angiogenic potential and establishing the best means of evaluation. RESULTS Assorted models were reproducible and correlative to one another. DEAE-Dextran exhibited excellent anti-angiogenic effect in cell migration assay over a duration of 24h compared to the vehicle control fibroblast cell line and aortic ring possessed an alleviated rate of sprouting when treated with DEAE-Dextran with contrast to vehicle control aorta. Similarly, decreased vascular density was observed in DEAE-Dextran treated chick embryos implicating potency of the β-interferon inducer. Augmenting to these results, the matrigel plugs also mitigated vascular net as well as reduced levels of angiogenic marker CD31. CONCLUSION Substantially, DEAE-Dextran leads to anti-tumor activity through anti-angiogenic action and a combination of in vitro and in vivo model is vital for the judgement of anti-angiogenic potential since an in vitro model exempts mammalian-culture considerations.

Suppression of abdominal fat and anti-hyperlipidemic potential of Emblica officinalis: Upregulation of PPARs and identification of active moiety

Since ancient time, Emblica officinalis (E. officinalis) is being used for the management of various ailments. Phytochemical analysis proves that fruit juice of E. officinalis contains high amount gallic acid, which could be responsible for medicinal potentials. Hence in this study, gallic acid and fruit juice of E. officinalis were evaluated for anti-hyperlipidemic potential in various experimental animal models. Experimentally, hyperlipidemia was induced through administration of poloxamer-407, tyloxapol and high-fat-diet supplement in rats. Treatment with gallic acid as well as fruit juice of E. officinalis decreased plasma cholesterol and reduced oil infiltration in liver and aorta. Mechanistically, E. officinalis increased peroxisome proliferator-activated receptors-α (PPARα) expression and increased activity of lipid oxidation through carnitine palmitoyl transferase (CPT) along with decreased activity of hepatic lipogenic enzymes i.e. glucose-6-phosphate dehydrogenase (G6PD), fatty acid synthase (FAS) and malic enzyme (ME). Additionally, E. officinalis increased cholesterol uptake through increased LDL-receptor expressions on hepatocytes and decreased LDL-receptor degradation due to decreased proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. Simultaneously, E. officinalis showed ability to restore glucose homeostasis through increased Glut4 and PPARγ protein expression in adipose tissue. These findings exposed central role of gallic acid in E. officinalis arbitrated anti-hyperlipidemic action through upregulation of PPARs, Glut4 and lipogenic enzymes, and decreased expression of PCSK9 and lipogenic enzymes. Findings from this experiment demonstrated that E. officinalis is a potential therapy for management of hyperlipidemia and gallic acid could be a potential lead candidate.