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Introduction Heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90) chaperones are indispensable to lung cancer cells for their survival and proliferation. In this study we evaluated and compared anticancer potential of methylene blue (MB) as an Hsp70 inhibitor, novobiocin (NB) a well-known Hsp90 inhibitor and their combination. Methods In vitro evaluation was done by cell viability assays, fluorescent staining, and flow cytometry analysis using A549 non-small cell lung cancer cells. In vivo anticancer activity was investigated by evaluating oxidative stress, tumor biomarkers, weight, lung microarchitecture, and Hsp70 and Hsp90 inhibitions via immunoblotting in benzo[a]pyrene induced lung carcinogenesis mice model. Results Using A549 NSCLC cells, we found MB demonstrated lower cell viability versus NB. Together, MB + NB resulted in further decrease in cell viability. SRB assay revealed significantly superior and similar potency for MB versus NB and MB + NB (1:1) versus MB, respectively. Fluorescent staining and flow cytometry analysis displayed early apoptosis by MB (11.4%); early and late apoptosis by MB + NB (13.8%). In vivo, MB significantly inhibited Hsp70. Furthermore, MB significantly alleviated tumor biomarkers (ADA and LDH) and improved lung histopathological features more than NB. Additionally, MB significantly improved SOD, not more than MB + NB or NB and improved LPO. Conclusion MB demonstrated potent anticancer activity in vitro and in vivo via inhibition of Hsp70 in benzo[a]pyrene induced lung carcinogenesis in mice.

Enicostema littorale blume (A. Raynal) is a traditional Indian plant belongs to the Gentianaceae family. A lot of research has been done on this plant for its antidiabetic activity. However, there are no reports on flavonoids from E. littorale for its antidiabetic activity and their mechanism of action. Thus, the aim of this study is to evaluate the antidiabetic activity of Swertisin rich flavonoid fraction (SRF) from Enicostema littorale blume and their mechanism of action.Type 2 Diabetes Mellitus rat model was established by inducing insulin resistance using high fat diet and low dose of streptozotacin injection and was authenticated by HOMA index. The antidiabetic effect of SRF was evaluated on diabetic rats to investigate its long term effects on fasting blood glucose, OGTT, weight of rats, insulin, liver profile, lipid profile, kidney profile, histopathology of liver and pancreas. In addition, antioxidant activity by lipid peroxidation and catalase assay, ex vivo assays and hepatic glycogen content were performed to determine its effect on glycogenesis and hepatic glucose production. Furthermore, the mechanism of action of SRF was evaluated by Real time PCR and the mRNA expression was quantified for Glucokinase (GCK), Insulin receptor substrate (IRS-1), Glucose transporter-2 (GLUT-2) and Glucose transporter-4 (GLUT-4) genes.Treatment of diabetic rats with SRF demonstrated significant (p0.0001) dose dependant hypoglycemic activity as compared to positive control metformin group. A decrease in liver, lipid and kidney function tests was seen as compared to diabetic control indicating normalization of organ function tests. Also, antioxidant activity showed significant decrease in malondialdehyde (MDA) content in liver (p0.001) as compared to pancreas and increased catalytic activity in liver, kidney, spleen and pancreas. The hepatic glycogen content was significantly (p0.001) increased in SRF treated rats indicating its inhibition of hepatic glucose production. Furthermore, ex vivo assays showed the significant (p0.05) increase in glucose uptake by diaphragm. The mRNA expression for GCK, IRS-1, GLUT-2 and GLUT-4 genes showed significant up regulation as compared to diabetic control indicating its mechanism via insulin signalling pathway.The studies suggest that SRF ameliorates the insulin resistance by increasing glucose uptake and sensitizing cells towards insulin via IRS1/PI3K/Akt2 pathway.

Seizures are serious neurological disorders affecting nearly 50 million people worldwide. Seizures are characterized by abnormal, repetitive and synchronised firing of the neurons which is produced as a result of imbalance in the levels of the excitatory and inhibitory neurotransmitters. Neuropeptides are found to regulate seizures by rectifying this imbalance. These neuropeptides are stored in the dense core synaptic vesicles, and are released on excitation. This review focuses on certain neuropeptides which can alleviate both, the effects of seizures as well as epileptogenesis. Thus making it an attractive target for the management of seizures.

Alzheimer's disease (AD) is one of the most frequently encountered diseases in adults with progressive loss of memory and behavioral changes. Inspite of there being an intense research in the field of AD, only a few chemical entities exhibiting anti-AD activity make it through the clinical trials and it is thus need of an hour to develop new drugs or repurpose the existing ones for better management of Alzheimer's disease. Novel therapeutic targets can influence drug discovery in the field of AD. Cyclin Dependent Kinase 5 (Cdk5) which is a serine/threonine kinase can prove to be an upcoming beneficial target to be studied for treating AD. Cdk5 is important for development of CNS and neuron movements, however in AD pathological stimuli cause Cdk5 hyperactivation which eventually results in hyperphosphorylation of various substrates such as amyloid precursor protein, tau and many more. This review provides an insight on Cdk5 as a target for treatment of AD and discuss therapeutic candidates for targeting it.

Rheumatoid Arthritis (RA) affects approximately 1% of the total world population. Despite incessant research and development of new therapeutic agents, management of RA is still a troublesome affair. Histone Deacetylase 1 (HDAC1) is an epigenetic regulator which play important role in pathogenesis of RA. In present study, we hypothesized that Phenethyl isothiocyanate (PEITC), a potent inhibitor of HDAC1, may ameliorate RA. Efficacy of PEITC was evaluated in Complete Freund's Adjuvant (CFA) induced arthritis model in rats. CFA (0.1 ml) was injected subplantarly in the left hind paw on day 0 to all the groups except normal control. The administration of test drug PEITC (10, 24 & 50 mg/kg) and standard drug Ibuprofen started simultaneously and was continued for 21 days. Paw edema, total arthritic index, mobility score, stair climbing ability, behavioral parameters, and bone erosion were evaluated. Further, radiographic studies, TNF-alpha as well as HDAC1 levels in synovial tissue homogenate and histological analysis were performed. Prophylactic treatment of PEITC attenuated paw edema, total arthritic index, mobility score, stair climbing ability, behavioral parameters, and bone erosion in dose dependent manner. Furthermore, there was significant decrease in TNF-alpha as well as HDAC1 levels in synovial tissue homogenate. Histological analysis revealed no cartilage damage, bone erosion, hyperplasia at synovial lining as well as infiltration of inflammatory cells in treatment group. Results of this study suggest potent anti-rheumatoid arthritis activity of Phenethyl isothiocyanate in CFA induced RA model in rats.

Background and Aims Diabetes is a risk factor for exacerbated outcome after acute myocardial infarction (AMI) and doubles the risk of mortality after MI. Increased levels of MMP-2 and MMP-9 in diabetes cause vascular remodelling, which leads to cardiovascular complications of diabetes. We hypothesized that inhibition of MMP-2 and MMP-9 can reduce worsening of myocardial ischemia in diabetic patients. Further, we hypothesized that minocycline induced MMP-2 and MMP-9 inhibition will be potentiated by aspirin and the combination of both drugs will prevent worsening of MI in diabetic patients. In the present study, efficacy of combination of minocycline and aspirin to attenuate exacerbation of myocardial ischemia/reperfusion (I/R) injury in diabetic rats was evaluated. Methods Diabetes was induced in male Wistar rats by streptozotocin (55 mg/kg i.p.). Three weeks after diabetes induction, rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of 3 weeks. At the end of week 6, I/R injury was induced by ligating the left anterior descending coronary artery for 30 min followed by 2 h reperfusion. Results Percentage infarct volume, arrhythmias, mortality, collagen level and MMP-2 and MMP-9 level were significantly increased in vehicle-treated diabetic group when compared with normoglycemic rats. Treatment with a combination of minocycline and aspirin decreased percentage infarct volume, arrhythmias, mortality and collagen level when compared with vehicle-treated diabetic controls and showed reduced levels of MMP-2 and MMP-9. Conclusions Results of the present study suggest that the combination of minocycline and aspirin prevent worsening of AMI in diabetic rats.

Despite an incessant advancement in the treatment of Colorectal Cancer (CRC), 40% of individuals suffer from disease relapse which marks the need for new treatment options. In this study we report synergistic antitumor activity of Laccaic acid (LA) and Phenethyl isothiocyanate (PEITC) combination in colorectal cancer via dual inhibition of DNA methyltransferase-1 and Histone deacetylase-1. Efficacy of combination was evaluated in both in-vitro and in-vivo experiments using human colon carcinoma cell line HT29 and 1,2-dimethyl hydrazine induced colon cancer rat model, respectively. In the cell line studies treatment with combination showed reduced cell viability with apoptotic cell death compared to individual treatment groups which showed necrotic cell death. IC50 value for combination (0.478 μM) was much lower than LA (6.08 μM), PEITC (11.88 μM) and 5-Fluorouracil (9.88 μM). In the in-vivo study combination group significantly attenuated number of aberrant crypt foci, fecal consistency score, IL-6, TNF-α, DNMT1 and HDAC1 levels, histological findings and mortality as compared to negative control. Further, toxic effects produced by combination were significantly less. Results suggest potent synergistic efficacy of Laccaic acid and Phenethyl isothiocyanate combination in colorectal cancer.

Mutual azo prodrug of 5-aminosalicylic acid with L-tryptophan was synthesized by coupling L-tryptophan with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure of synthesized prodrug was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in HCl buffer (pH 1.2) showed negligible release of 5-aminosalicylic acid, whereas in phosphate buffer (pH 7.4) 18% release was observed over a period of 7 h. In rat fecal matter, 87.9% of 5-aminosalicylic acid was released with a half-life of 143.6 min, following first order kinetics. The azo conjugate was evaluated for its ulcerogenic potential by Rainsford's cold stress method. The ameliorating effect of the azo conjugate and therapeutic efficacy of the carrier system was evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. The synthesized prodrug was found to be equally effective in mitigating the colitis in rats as that of sulfasalazine without the ulcerogenicity of 5-amino-salicylic acid.

Mutual azo prodrug of 5-aminosalicylic acid with d-phenylalanine was synthesized by coupling D-phenylalanine with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure of synthesized prodrug was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in HCl buffer (pH 1.2) showed negligible release of 5-aminosalicylic acid, whereas in phosphate buffer (pH 7.4) only 15% release was observed over a period of 7h. In rat fecal matter the release of 5-aminosalicylic acid was almost complete (85%), with a half-life of 160.1 min, following first order kinetics. The azo conjugate was evaluated for its ulcerogenic potential by Rainsford's cold stress method. Therapeutic efficacy of the carrier system and the mitigating effect of the azo conjugate were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. The synthesized prodrug was found to be equally effective in mitigating the colitis in rats as that of sulfasalazine without the ulcerogenicity of 5-aminosalicylic acid.