Vinit Raj

Antidiabetic effects of isolated sterols from Ficus racemosa leaves

The present study was undertaken to evaluate the antidiabetic, hypolipidemic, and toxic effects of isolated sterols from Ficus racemosa (FR) leaves using streptozotocin induced diabetic rats. Diabetes was induced by the administration of streptozotocin (50 mg kg−1) intraperitoneally to albino rats. Three sterols were administered once a day for a period of seven days at a dose of 100 mg kg−1 body weight. Blood glucose and body weight changes were measured at different (1st, 3rd, 5th, and 7th) days of the experiment. Serum lipid profiles and hepatic biomarker enzymes levels were measured and various antioxidant parameters in the liver and pancreas were also determined at the end of the experiment. Our results collectively suggested that the oral administration of sterols significantly reduced blood glucose level and restored body weight. Sterols also reduced serum lipid parameters and improved HDL (high density lipoprotein) as compared to a diabetic control group, signifying hypolipidemic action. They increased glutathione and various enzyme levels in the pancreas at the same time. Various oxidative stress parameters in the liver were decreased after sterols administration with respect to the diabetic control rats. Three sterols possessed antidiabetic, antioxidant, and hypolipidemic activities in STZ induced diabetic rats, which supported the use of FR as a supplement for future drug design perspectives.

Indole-fused azepines and analogues as anticancer lead molecules: Privileged findings and future directions

The search for new lead compounds of simple structure, displaying highest quality anti-tumor potency with new mechanisms of action and least adverse effects is the major intention of cancer drug discovery now a days. For the time being, indole-fused azepines emerged as a simple class of compounds prolifically designed with strong pharmacological significances in particular of cancer protecting ability. In the recent years from the efforts of our research group, indole-fused heteroazepines, a simple structural class achieved by fusion of indole with oxygen, sulphur and nitrogen containing heteroazepine rings, have known for its superior outcomes in cancer treatment. Surprisingly, the chemistry and biology of these unique families with an amazing role in cancer drug discovery has remained broadly unexplored. This short review is consequently an endeavor to highlight the preliminary ideas over this structural class and to draw the medical attention towards future development of indole-fused azepines and analogues for their promising function in cancer drug discovery.

Ameliorative effects of pyrazinoic acid against oxidative and metabolic stress manifested in rats with dimethylhydrazine induced colonic carcinoma

ABSTRACT Pyrazinoic acid (PA) is structurally similar to nicotinic acid which acts on G-protein-coupled receptor (GPR109A). GPR109A expresses in colonic and intestinal epithelial sites, and involves in DNA methylation and cellular apoptosis. Therefore, it may be assumed that PA has similar action like nicotinic acid and may be effective against colorectal carcinoma (CRC). CRC was produced via subcutaneous injection of dimethylhydrazine (DMH) at 40 mg/kg body weight once in a week for 4 weeks. After that, PA was administered orally at 2 doses of 10 and 25 mg/kg daily for 15 d to observe the antiproliferative effect. Various physiologic, oxidative stress, molecular parameters, histopathology, RT-PCR and NMR based metabolomics were performed to evaluate the antiproliferative potential of PA. Our results collectively suggested that PA reduced body weight, tumor volume and incidence no. to normal. It restored various oxidative stress parameters and normalized IL-2, IL-6, and COX-2 as compared with carcinogen control. In molecular level, overexpressed IL-6 and COX-2 genes became normal after PA administration. Again, normal tissue architecture was prominent after PA administration. Score plots of PLS-DA models exhibited that PA treated groups were significantly different from CRC group. We found that CRC rat sera have increased levels of acetate, glutamine, o-acetyl-glycoprotein, succinate, citrulline, choline, o-acetyl choline, tryptophan, glycerol, creatinine, lactate, citrate and decreased levels of 3-hydroxy butyrate, dimethyl amine, glucose, maltose, myoinositol. Further the PA therapy has ameliorated the CRC-induced metabolic alterations, signifying its antiproliferative properties. In conclusion, our study provided the evidence that PA demonstrated good antiproliferative effect on DMH induced CRC and thus demonstrated the potential of PA as a useful drug for future anticancer therapy.

Metabolomics approach discriminates toxicity index of pyrazinamide and its metabolic products, pyrazinoic acid and 5-hydroxy pyrazinoic acid:

Pyrazinamide (PYZ)—an essential component of primary drug regimen used for the treatment and management of multidrug resistant or latent tuberculosis—is well known for its hepatoxicity. However, the mechanism of PYZ-induced hepatotoxicity is still unknown to researchers. Studies have shown that the drug is metabolized in the liver to pyrazinoic acid (PA) and 5-hydroxy pyrazinoic acid (5-OHPA) which individually may cause different degrees of hepatotoxicity. To evaluate this hypothesis, PYZ, PA, and 5-OHPA were administered to albino Wistar rats orally (respectively, at 250, 125, and 125 mg kg−1 for 28 days). Compared to normal rats, PYZ and its metabolic products decreased the weights of dosed rats and induced liver injury and a status of oxidative stress as assessed by combined histopathological and biochemical analysis. Compared to normal controls, the biochemical and morphological changes were more aberrant in PA- and 5-OHPA-dosed rats with respect to those dosed with PYZ. Finally, the serum metabolic profiles of rats dosed with PYZ, PA, and 5-OHPA were measured and compared with those of normal control rats. With respect to normal control rats, the rats dosed with PYZ and 5-OHPA showed most aberrant metabolic perturbations in their sera as compared to those dosed with PA. Altogether, the study suggests that PYZ-induced hepatotoxicity might be associated with its metabolized products, where 5-OHPA contributes to a higher degree in its overall toxicity than PA.

Poly(lactic- co -glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations

Purpose The application of betulinic acid (B), a potent antineoplastic agent, is limited due to poor bioavailability, short plasma half-life and inappropriate tissue distribution. Thus, we aimed to prepare novel 50:50 poly(lactic-co-glycolic acid) (PLGA)-loaded B nanoparticles (BNP) and to compare its anti-hepatocellular carcinoma (HCC) activity with parent B. Methods BNP were synthesized and characterized using different methods such as scanning electron microscopy (SEM), fourier-transform infrared (FTIR) spectrometry and particle size analyses. Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol (PVA). The anti-HCC response was evaluated through in vitro cell line study using Hep-G2 cells, confocal microscopy, in vivo oral pharmacokinetics and animal studies. Further, quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was conducted to observe the changes in the expression of specific genes. Results Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol. Physicochemical characterization exhibited particle size of 257.1 nm with zeta potential −0.170 mV (optimized batch B, BNP). SEM and FTIR analyses of BNP showed that cylindrical particles of B converted to spherical particles in BNP and there were no interaction between B and used polymers. The release study of optimized BNP was highest (≥80%) than any other formulation. Later, in vitro cell culture analysis using Hep-G2 cells and confocal microscopy studies revealed that BNP had the highest inhibition and penetration properties than parent B. Oral pharmacokinetics studies using albino Wistar rats at single 100 mg dose again exhibited BNP had the higher 50% of plasma concentration (t1/2), a higher maximum plasma concentration (Cmax) and took longer to reach the maximum plasma concentration (Tmax) than parent B. Next, our in vivo study using nitrosodiethyl amine (NDEA)-induced HCC model documented BNP decreased in number of nodules, restored body weight, oxidative stress parameters, liver marker enzymes and histological architecture than parent B. Lastly, qRT-PCR studies further demonstrated that anti-HCC properties of BNP may be due to over expression of antiapoptotic caspases i.e., caspase 3 and 8. Conclusion The prepared BNP showed a better therapeutic response against HCC and could be attributed as future candidate molecule for HCC treatment.

Novel 1,3,4-thiadiazoles inhibit colorectal cancer via blockade of IL-6/COX-2 mediated JAK2/STAT3 signals as evidenced through data-based mathematical modeling

We attempted a preclinical study using DMH-induced CRC rat model to evaluate the antitumor potential of our recently synthesized 1,3,4-thiadiazoles. The molecular insights were confirmed through ELISA, qRT-PCR and western blot analyses. The CRC condition was produced in response to COX-2 and IL-6 induced activation of JAK2/STAT3 which, in turn, was due to the enhanced phosphorylation of JAK2 and STAT3. The treatment with 1,3,4-thiadiazole derivatives (VR24 and VR27) caused the significant blockade of this signaling pathway. The behavior of STAT3 populations in response to IL-6 and COX-2 stimulations was further confirmed through data-based mathematical modeling using the quantitative western blot data. Finally, VR24 and VR27 restored the perturbed metabolites associated to DMH-induced CRC as evidenced through 1H NMR based serum metabolomics. The tumor protecting ability of VR24 and VR27 was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.

A Review on the Modification of Polysaccharide Through Graft Copolymerization for Various Potential Applications

Introduction: Graft copolymerization is one of the most promising technique uses to modify the properties of naturally available polymers with a minimum loss in their native characteristics. Methods and Materials: Graft copolymerization is a very significant technique to add hybrid properties in backbone of polymers. The grafting generally initiated through the formation of free radical centers on the polymer backbone as well as monomer. Results: Grafted polysaccharides have various applications in different important scientific areas such as drug delivery, pharmaceutical field, plastic industry, waste water treatment, tannery effluent treatment, textile industry, agriculture area, etc. all of this fascinated us to summarize the major research articles over the last two decades outlining different methods of grafting, surface modification, graft copolymerization of synthetic and natural polymers. Conclusion: Various redox initiator systems viz. Ceric ammonium nitrate, per sulfate, Irradiation, FAS-H2O2 etc. is also explored for grafting of vinyl through conventional and non-conventional techniques.

Indole-fused benzooxazepines: a new structural class of anticancer agents.

Aim: A new series of compounds (1a–16a) bearing indole-fused benzooxazepine was synthesized, characterized and evaluated for anticancer activity. Materials & methods: In this study, all the synthesized compounds were screened via in vitro anticancer testing on Hep-G2 cancer cell line. A computational study was carried out on cancer-related targets including IL-2, IL-6, COX-2 Caspase-3 and Caspase-8. Results: Some of the synthesized compounds effectively controlled the growth of cancerous cells. Conclusion: The most active compounds – 6a, 10a, 13a, 14a and 15a – exemplify notable anticancer profile with GI50 <10 μg/ml. Preliminary structure–activity relationship among the tested compounds can produce an assumption that the electronegative groups at phenyl ring attached with indole-fused benzooxazepine are instrumental for the activity. Molecular docking study showed crucial hydrogen bond and π–π stacking interactions, with good ADMET profiling and molecular dynamic simulation.

Discovery of Novel 2-Amino-5-(Substituted)-1,3,4-Thiadiazole Derivatives: New Utilities for Colon Cancer Treatment

BACKGROUND Colon cancer is one of the most widespread disease, the mortality rate is high due to cancer metastasis and the development of drug resistance. In this regards, new chemotherapeutic agents with specific mechanisms of action and significant effect on patients survival are the new era for the colon cancer drug development. OBJECTIVE The main objective of present study was to design, synthesize of a novel series of 1,3,4-thiadiazole derivatives (VR1 to VR35) and screen them against HT-29 human colon cancer cell line. METHOD Newly 1,3,4-thiadiazole scaffold were designed, synthesized and further, characterized by FTIR, NMR (1H and 13C), MS and elemental analyses. Before the synthesis, molecular dynamic simulation and ADME studies were performed to find out the most potent lead compounds. Later, SRB assay using HT-29 cells and ELISA assays were performed to explore activity and molecular targets of VR24 and VR27 and find out whether in silico data had a similar pattern in the molecular level. RESULTS The results of docking study revealed that both VR24 and VR27 had interaction energy >-5 kcal/mol with various assigned molecular targets and the ligand-protein complexes were found to be stable with IL-6. The computational analysis of molecules showed good ADMET profiling. Later, the in vitro anticancer study was conducted where VR24 and VR27 were found to be active against HT-29 cells (GI50<10 µM). Finally, ELISA assays revealed that both the compounds had higher inhibition properties to various biomarker of colon cancer like IL-6 and COX-2. CONCLUSION Collectively, these result suggested that VR24 and VR27 inhibited the assigned molecular targets, imparting their ameliorative effects against colon cancer. Due to these encouraging results, we concluded that both VR24 and VR27 may be effective against colon cancer therapy in future.

Modern Extraction Techniques for Drugs and Medicinal Agents

Abstract In this chapter, we have tried to include various physicochemical methods of extraction that comprise microwave-assisted extraction, pressurized liquid extraction, supercritical fluid extraction, liquid phase microextraction, solid phase extraction, ultrasound-assisted extraction, cloud-point extraction, enzyme-assisted extraction, membrane-based microextraction, and cooling-assisted microextraction. These are the commonly used techniques nowadays in terms of isolation and separation of ingredients from both chemical and biological mixtures. The description is based on principle, method, and comparison of various techniques. Their commercial applications both in analytical and industrial point of view are also included in this chapter. We also include few special biological extraction techniques at the end of this chapter. Finally, the conclusion is drawn based on the application of different techniques, target molecules, and sample types. This chapter will serve as a valuable tool and key milestone to researchers in a future application.