Mrinmoy Sarkar

Pioglitazone, an anti-diabetic drug requires sustained MAPK activation for its anti-tumor activity in MCF7 breast cancer cells, independent of PPAR-γ pathway

BACKGROUND The thiazolidinedione (TZD) class of peroxisome proliferator-activated receptor gamma (PPAR-γ) ligands are known for their ability to induce adipocyte differentiation, to increase insulin sensitivity including anticancer properties. But, whether or not upstream events like MAPK activation or PPAR-γ signaling are involved or associated with this anticancer activity is not well understood in breast cancer cells. The role of MAPK and PPAR pathways during the pioglitazone (Pio) induced PPAR-γ independent anticancer activity in MCF7 cells has been focused here. METHODS The anticancer activity of Pio has been investigated in breast cancer cells in vitro. Anti-tumor effects were assessed by alamar blue assay, Western blot analysis, cell cycle analysis, and annexin V-FITC/PI binding assay by flow cytometry, Hoechst staining and luciferase assay. RESULTS The anticancer activity of Pio is found to be correlating with the up regulation of CDKIs (p21/p27) and down regulation of CDK-4. This study demonstrates that the induction of CDKIs by Pio is due to the sustained activation of MAPK. The Pio-mediated activation of MAPK is transmitted to activate ELK-1 and the related anti-proliferation is blocked by MEK inhibitor (PD-184352). CONCLUSIONS Pio suppresses the proliferation of MCF7 cells, at least partly by a PPAR-γ-independent mechanism involving the induction of p21 which in turn requires sustained activation of MAPK. These findings implicate the utility of Pio in the treatment of PPAR positive or negative human cancers and the development of a new class of compounds to enhance the effectiveness of Pio.

Electroconductive smart polyacrylamide–polypyrrole (PAC–PPY) hydrogel: a device for controlled release of risperidone

Risperidone is a widely used antipsychotic drug for the treatment of schizophrenia and bipolar disorder. This paper discusses the preparation and use of a drug loaded electro-conductive hydrogel based on polyacrylamide and polypyrrole in the form of cylindrical devices to confer electro-actuable properties and also controlled release of the drug risperidone. The variation in the swelling and oxidation state of the material induced physical and chemical changes in the conducting polymer network. The electro-liberation process was optimized by tuning the properties of the composite. The hydrogel was characterized by various microscopic and spectroscopic analyses, swelling kinetics, and also network parameters. In vitro drug release studies were carried out in 0.1 N HCl and a phosphate buffer using dissolution apparatus with stirring. Cytotoxic results on HepG2 and C6 cells supported the biocompatibility of the hydrogel. A model was proposed for an implantable drug delivery device, where the dose could be adjusted by external signaling.

Anti-inflammatory and Anti-tumor Activities of Parthenolide: An Update

Parthenolide (PTL), the secondary metabolite of feverfew plant (Tanaceum parthenium), has been used in various medical purposes globally. Inflammation represents a physiological response to injury and helps to restore tissue homeostasis. Inflammation and cancer both are associated with genotoxicity, invasion, metastasis, and abnormal tissue repair mechanisms. PTL inhibit major cellular inflammatory and proliferation pathways like NFκB, STAT3, and MAPK along with the activity and expression of several inflammatory mediators including COX. NFκB pathway plays a key role in controlling cell cycle progression and apoptosis together with metastasis and cancer of various types. Elevated NFκB, Wnt/β-catenin pathways are crucial factors of tumorogenesis. PTL inhibits NFκB and Wnt/β-catenin pathways, and thereby promotes apoptosis and suppresses cell proliferation. Experimental data showed that PTL protects normal cells from apoptosis; whereas in cancer cells it induces apoptotic cell death. Hence, parthenolide could be useful in controlling inflammatory diseases alone or together with tumorogenesis due to its evident anticancer potency and anti-inflammatory nature.

In Vitro Activity Screening of Snake Venom against Multi Drug ResistantTuberculosis

The re-emergence of multidrug-resistant tuberculosis (MDR-TB) events has brought to light the importance of screening effective novel drugs. In the present study, in vitro activities of different snake (Naja naja, Bungarus fasciatus, Daboia russelli russelli, Naja kaouthia) venoms have been investigated against clinical isolate of MDR-TB strains. All the venoms inhibited the mycobacterial growth for at least a week in common and two of them (Naja naja, Naja kaouthia) showed significantly longer inhibition up to two weeks against the MDR-TB strain with single dose and one repetition of those two venoms exhibited inhibition up to more than 4 weeks.

An update on pathogenesis and management of tuberculosis with special reference to drug resistance

Abstract Drug resistance in tuberculosis (TB) is a global problem and both developed as well as under developed parts of the world are predisposed to drug resistant TB. Multiple drug resistant–TB (MDR-TB) designates the very strain of the pathogen which is resistant to at least two primary anti-TB drugs isoniazid and rifampicin. This strain after acquiring a further bacillary resistance to any second line injectable drug and any of the fluoroquinolones is termed as extensively drug resistant TB (XDR-TB). The present review is endeavored to recapitulate the contemporary state of multidrug resistance in TB, the pathophysiology and recent developments for a rapid and reliable detection of the infection and management of MDR-TB. The challenge of MDR-TB management must be embarked on by skilled doctors at operational BCL-3 laboratory facilities where all allied services for the in-vitro sensitivity testing of mycobacteria are available because it includes extended treatment with costly second–line drugs containing meticulous toxicity. Even more dreaded are some newly emerging TB strains namely XDR-TB which is resistant to many more anti-TB agents (such as isonicotinic acid hydrazide and rifampicin plus second line injectable streptomycin, amikacin and kanamycin). Newer discovery of novel anti-TB drugs through recent research regarding the management of drug resistant tuberculosis would help avert and eradicate MDR-TB as well as XDR-TB. For shortening of the TB–treatment regimen, a few drugs, especially gatifloxacin and moxifloxacin, are being tested, while PA-824, OPC-67683 and TMC-207 are also being studied for both drug resistant and drug susceptible disease. Given the past global trends in MDR-TB, if aggressive preventive and management strategies are not implemented against it, XDR-TB would emerge to a larger extent which would severely cripple global control efforts of TB. However, very recently a newly discovered drug bedoquinoline is demonstrating strong promise towards containment of XDR-TB.

Double Edge Effect of DPP4 Inhibitor Sitagliptin, a Type-2 Anti-Diabetic Drug, on Inflammation, Injury and Cancer

Maintaining a healthy glycaemic condition is associated with so many more other protective/precautionary attributes. Recent advancement in the field of drug discovery have led us find more and more options to choose from. DPP-4 inhibitor sitagliptin makes sustained expression of incretins GLP-1 and GIP that in turn establishes glycaemic control. But recent reports claimed pro-inflammatory as well as pro-carcinogenic action of the drug after prolonged use in T2DM patients. Interestingly, in those cases also, the effector molecule responsible is said to be the incretin GLP-1. The same molecule has been hypothesized for being responsible to cause thyroid C-cell carcinomas. In vitro investigations using human cell lines did not show any clues in support of carcinoma formation. Instead, the DPP-4 inhibitory action of sitagliptin serves in other complications associated with T2DM. In any tissue injury due to hypoxic stress in T2DM, sitagliptin serves in the tissue repair mechanisms via its DPP-4 inhibiting property. Consequently, DPP-4, for not being able to be active in presence of sitagliptin, fails to truncate the CXCL-12/SDF-1 and therefore helps in the homing of HPCs/EPCs to repair the injured tissue. In conclusion, it can be said that more research is definitely required to be confirmed about the pre-cancerous activity of the drug, and to make the drug more usable in favour of the other beneficial effects of it.

Protective effects of red grape (Vitis vinifera) juice through restoration of antioxidant defense, endocrine swing and Hsf1, Hsp72 levels in heat stress induced testicular dysregulation of Wister rat

Ability of red grape juice (RGJ), a known antioxidant, on testis of adult Wister rat to protect from oxidative stress induced damages by heat stress has been investigated in this study. Heat stress was induced maintaining body and testicular temperature at 43°C for 30min/day for 15 days using a hyperthermia induction chamber. Four groups of rats (n=6 per group) comprising of Group-I (control) -kept at 32°C, Group-II -exposed to heat stress alone, Group-III received RGJ (0.8ml/rat/day) alone and Group-IV -exposed to heat stress and received RGJ at same dose. Analysis of blood and testicular tissue exhibited significant reduction in serum testosterone, testicular superoxide dismutase, testicular catalase and testicular glutathione (all p < 0.001); whereas, significant rise in the level of serum corticosteroid, testicular lipid peroxidase and the apoptotic enzyme caspase-3 of testis (all p < 0.001) were observed along with substantial increase in testicular Hsp72 and Hsf-1, and decrease in 17β-HSD3 were noted in heat stressed rats compared to controls. In Group-IV rats, RGJ administration could restore these parameters to normal levels. The signs of retention were clear in Group-IV rats and found to be significantly different as compared to that of the Group-II rats. In testicular histology of rats exposed to heat stress alone revealed remarkable germ cell degeneration and tubular deformations which were prevented by RGJ treatment (Group-IV). The reduced number of sperm level in Group-II also restored in RGJ treatment (Group-IV). The above results indicate that consumption of RGJ may substantially protect testis from heat stress induce dysfunctions.

Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity

Chronic exposure of glucose rich environment creates several physiological and pathophysiological changes. There are several pathways by which hyperglycemia exacerbate its toxic effect on cells, tissues and organ systems. Hyperglycemia can induce oxidative stress, upsurge polyol pathway, activate protein kinase C (PKC), enhance hexosamine biosynthetic pathway (HBP), promote the formation of advanced glycation end-products (AGEs) and finally alters gene expressions. Prolonged hyperglycemic condition leads to severe diabetic condition by damaging the pancreatic β-cell and inducing insulin resistance. Numerous complications have been associated with diabetes, thus it has become a major health issue in the 21st century and has received serious attention. Dysregulation in the cardiovascular and reproductive systems along with nephropathy, retinopathy, neuropathy, diabetic foot ulcer may arise in the advanced stages of diabetes. High glucose level also encourages proliferation of cancer cells, development of osteoarthritis and potentiates a suitable environment for infections. This review culminates how elevated glucose level carries out its toxicity in cells, metabolic distortion along with organ dysfunction and elucidates the complications associated with chronic hyperglycemia.

Molecular modeling of NK-CT1, from Indian monocellate cobra (Naja kaouthia) and its docking interaction with human DNA topoisomerase II alpha.

A 6.76 kDa molecular weight cardio and cytotoxic protein of 60 amino acids in length called NK-CT1, was purified from the venom of Indian monocellate cobra (Naja kaouthia) by ion-exchange chromatography and HPLC as described in our earlier report. Therefore it is of interest to utlize the sequence of NK-CT1 for further functional inference using molecular modeling and docking. Thus homology model of NK-CT1 is described in this report. The anti-proliferative activity of the protein, binding with human DNA topoisomerase-II alpha was demonstrated using docking data with AUTODOCK and AUTODOCK MGL tools. Data shows that M26, V27 and S28 of NK-CT1 is in close contact with the nucleotides of the oligonucleotide, bound with topoisomerase-II alpha complex.

In vitro screening of snake venom against multidrug-resistant tuberculosis

Abstract The re-emergence of multidrug-resistant tuberculosis (MDR-TB) has brought to light the importance of screening effective novel drugs. In the present study, in vitro activities of different snake ( Naja naja , Bungarus fasciatus , Daboia russelli russelli , Naja kaouthia ) venoms have been investigated against clinical isolate of MDR-TB strains. The treatment with all the venoms inhibited the mycobacterial growth for at least a week in common and two of them ( Naja naja and Naja kaouthia ) showed significantly longer inhibition up to two weeks against the MDR-TB strain with single dose and a repetition of those two venoms exhibited inhibition up to more than four weeks.