Central Drug Research Institute

About: Central Drug Research Institute is a facility organization based out in Lucknow, Uttar Pradesh, India. It is known for research contribution in the topics: Catalysis & Leishmania donovani. The organization has 4357 authors who have published 7257 publications receiving 143871 citations. The organization is also known as: Central Drug Research Institute, Lucknow & CDRI.

Angiotensin Receptor Blockade Modulates NFκB and STAT3 Signaling and Inhibits Glial Activation and Neuroinflammation Better than Angiotensin-Converting Enzyme Inhibition

Abstract: Neuroinflammation, sustained by astroglial and microglial activation, is the preceding event in neurodegeneration. Various clinical reports showed better neuroprotection by AT1 receptor blockade (ARB) than angiotensin-converting enzyme inhibition (ACEi), but experimental evidences and associated mechanism for this observation are lacking. Therefore, we investigated the effect of ARB, using Candesartan, and ACEi, using Perindopril, in equimolar concentrations in astroglial (C6) and microglial (BV2) cells employing lipopolysaccharide (LPS) to induce neuroinflammation. Further, Candesartan (0.1 mg/kg) and Perindopril (0.1 mg/kg) were orally administered in male SD rats for five consecutive days, and on the fifth day, rats were challenged with LPS (i.p.; 250 μg/kg) and sacrificed after 24 h. LPS-induced neuroinflammation (increased astroglial and microglial activation, IκBα degradation, NFкB nuclear translocation, STAT3 activation, and TNF-α release) was more efficiently prevented by Candesartan (even at lower concentration of 1 nM) than by Perindopril (1 μM) in both the cell types and in rat model of neuroinflammation. In addition, increased AT1 receptor (AT1R) and decreased AT2 receptor (AT2R) expression was observed in LPS-induced neuroinflammation in both in vitro and in vivo studies. Candesartan, as compared to Perindopril, increased the expression of AT2R in both the experimental conditions. Interestingly, concomitant blockade of AT2R by PD123319 significantly reversed the beneficial effects of Candesartan in both the cell types and in rat model of neuroinflammation. Finally, our data emphasize that superiority of Candesartan as compared to Perindopril is due to better activation of AT2R which results in PP2A activation, IκBα stabilization, and suppression of NFкB and STAT3 inflammatory signaling.

Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-Gingerol in cervical cancer cells

Abstract: Human papilloma virus (HPV) expressing E6 and E7 oncoproteins, is known to inactivate the tumor suppressor p53 through proteasomal degradation in cervical cancers. Therefore, use of small molecules for inhibition of proteasome function and induction of p53 reactivation is a promising strategy for induction of apoptosis in cervical cancer cells. The polyphenolic alkanone, 6-Gingerol (6G), present in the pungent extracts of ginger (Zingiber officinale Roscoe) has shown potent anti-tumorigenic and pro-apoptotic activities against a variety of cancers. In this study we explored the molecular mechanism of action of 6G in human cervical cancer cells in vitro and in vivo. 6G potently inhibited proliferation of the HPV positive cervical cancer cells. 6G was found to: (i) inhibit the chymotrypsin activity of proteasomes, (ii) induce reactivation of p53, (iii) increase levels of p21, (iv) induce DNA damage and G2/M cell cycle arrest, (v) alter expression levels of p53-associated apoptotic markers like, cleaved caspase-3 and PARP, and (vi) potentiate the cytotoxicity of cisplatin. 6G treatment induced significant reduction of tumor volume, tumor weight, proteasome inhibition and p53 accumulation in HeLa xenograft tumor cells in vivo. The 6G treatment was devoid of toxic effects as it did not affect body weights, hematological and osteogenic parameters. Taken together, our data underscores the therapeutic and chemosensitizing effects of 6G in the management and treatment of cervical cancer.

Molecular iodine promoted divergent synthesis of benzimidazoles, benzothiazoles, and 2-benzyl-3-phenyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazines.

Abstract: An unprecedented formation of a new class of 2-benzyl-3-phenyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazines has been discovered during the course of benzimidazole and benzothiazole synthesis, through the molecular iodine-mediated oxidative cyclization with a new C-N and S-N bond formation at ambient temperature.

Dihydrofolate reductase as a therapeutic target for infectious diseases: opportunities and challenges

Abstract: Infectious diseases caused by parasites continue to take a massive toll on human health in the poor regions of the world. Filling the anti-infective drug-discovery pipeline has never been as challenging as it is now. The organisms responsible for these diseases have interesting biology with many potential biochemical targets. Inhibition of metabolic enzymes has been established as an attractive strategy for anti-infectious drug development. In this field, dihydrofolate reductase (DHFR) is an important enzyme in nucleic and amino acid synthesis and an extensively studied drug target over the past 50 years. The challenges for novel DHFR inhibition-based chemotherapeutics for the treatment of infectious diseases are now focused on overcoming the resistance problem as well as cost–effectiveness. Each year, the large number of literature citations attest the continued popularity of DHFR. It becomes truly the ‘enzyme of choice for all seasons and almost all reasons’. Herein, we summarize the opportunities and c...