Showing papers by "Pallu Reddanna published in 2011"
TL;DR: Investigating the inflammatory responses of mouse macrophages exposed to nanoparticles reveals that Ag NPs exhibit higher propensity in inducing inflammation, mediated by ROS and NF-κB signaling pathways and leading to the induction of COX-2, TNF-α and IL-6, however, no such prominent pro-inflammatory responses were observed with Au NPs, suggesting their bio-compatibility.
Abstract: Recent advances in particle-forming chemistries used for developing nanotechnology has not only widened novel applications for nanoscale materials but also has provided significant concern regarding their biological effects. The present study investigates the inflammatory responses of RAW 264.7 mouse macrophages exposed to nanoparticles (NPs, 5 μg/ml) of varied sizes including silver (Ag), aluminum (Al), carbon black (CB), carbon-coated silver (CAg) and gold (Au). A significant increase in IL-6, reactive oxygen species (ROS) generation, nuclear translocation of nuclear factor-kappa B (NF-κB), induction of cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-α) expression was observed in macrophages with maximum response found in cells exposed to Ag NPs followed by Al, CB and CAg. These pro-inflammatory effects of NPs were dependent on size and duration of exposure and comparable to those induced by lipopolysaccharide (LPS), a known inflammatory mediator. Au NPs, on the other hand, induce...
176 citations
TL;DR: The development of a first cationic lipid-conjugated estrogenic derivative (ESC8) that kills breast cancer cells independent of their ER expression status is reported, which is the first example of an estrogen structure–based molecule that coinduces apoptosis and autophagy in Breast cancer cells.
Abstract: It is a challenge to develop a universal single drug that can treat breast cancer at single- or multiple-stage complications, yet remains nontoxic to normal cells. The challenge is even greater when breast cancer-specific, estrogen-based drugs are being developed that cannot act against multistaged breast cancer complications owing to the cells differential estrogen receptor (ER) expression status and their possession of drug-resistant and metastatic phenotypes. We report here the development of a first cationic lipid-conjugated estrogenic derivative (ESC8) that kills breast cancer cells independent of their ER expression status. This ESC8 molecule apparently is nontoxic to normal breast epithelial cells, as well as to other noncancer cells. ESC8 induces apoptosis through an intrinsic pathway in ER-negative MDA-MB-231 cells. In addition, ESC8 treatment induces autophagy in these cells by interfering with the mTOR activity. This is the first example of an estrogen structure-based molecule that coinduces apoptosis and autophagy in breast cancer cells. Further in vivo study confirms the role of this molecule in tumor regression. Together, our results open new perspective of breast cancer chemotherapy through a single agent, which could provide the therapeutic benefit across all stages of breast cancer.
37 citations
TL;DR: Cloned, expressed, and characterized a novel LOX isoform from the model vertebrate Danio rerio (zebrafish) that carries a Gly at this critical position, classifying this enzyme as putative arachidonic acid R-LOX, indicating that the Ala-versus-Gly concept may not always predict the reaction specificity of vertebrate LOXisoforms.
36 citations
Journal Article•
TL;DR: In this paper, the wound healing properties of bioactive fractions from the extract of Butea monosperma (Lam) stem bark were evaluated in excision, incision and dead space wound healing models using Albino wistar rats.
Abstract: The study aims to evaluate the wound healing properties of bioactive fractions from the extract of Butea monosperma (Lam) stem bark. In this study the stem bark powder was extracted with ethanol, further the ethanolic extract was fractionated with different solvents (petroleum ether, benzene, chloroform and acetone) in increasing order of polarity. Thus prepared extracts were subjected to preliminary phytochemical analysis. The wound healing activity of the ethanolic extract and the fractions isolated from the stem bark of B utea monosperma were evaluated in excision, incision and dead space wound healing models using Albino wistar rats. The wound healing activity was assessed by the breaking strength in case of incision wounds, epithelialization and wound contraction in case of excision wound and granulation tissue dry weight, breaking strength and hydroxyproline content in case of dead space wound. The ethanolic extract and the acetone fraction showed the significant wound healing activity on all three wound models. The phytochemical investigations revealed the presence of alkaloids, tannins, flavonoids, phenolic compounds and steroids. The increased rate of wound contraction and hydroxyproline content in the ethanolic extract and the acetone fraction treated animals provides a scientific base to the ethno medicinal use of Butea monosperma , which is largely attributable to the additive or synergistic effect of their constituents. Keywords: Butea monosperma, Dead space wound, Excision wound, Incision wound.
22 citations
TL;DR: The present study shows the efficacy of CA to overcome MDR-1 mediated drug resistance in HepG2 cells through COX-2 dependant modulation of MDR2 and the inactivation of signal transduction pathways involving Akt, ERK, JNK and p38 and the transcription factor NF-κB in the CA induced down regulation of M DR1.
Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) specific inhibitors are anti-inflammatory agents that have also shown to be useful in anticancer therapy. The effects of chebulagic acid (CA), a benzopyran tannin from Terminalia chebula having COX-2/5-LOX dual inhibitory properties, on the sensitivity of doxorubicin (Dox) in human hepatocellular carcinoma cell line HepG2 were studied in the present investigation. CA increased the accumulation of Dox in a concentration dependant manner and also enhanced the cytotoxicity of Dox in HepG2 cells by 20 folds. Quantitation of interaction by calculating Combination Index (CI) showed a strong synergistic interaction between CA and Dox in terms of cell growth inhibition. Calculation of dose reduction index (DRI) for CA-Dox combinations also showed a significant decrease in the dosage of Dox in the presence of CA. The induction of MDR1 expression by PGE(2), a metabolite of COX-2, and its downregulation by COX-2 knockdown or CA implies that the enhanced sensitivity of HepG2 cells to doxorubicin by CA is mediated by the downregulation of MDR1 expression, via COX-2-dependent mechanism. Further studies reveal the inactivation of signal transduction pathways involving Akt, ERK, JNK and p38 and the transcription factor NF-κB in the CA induced down regulation of MDR1. The present study shows the efficacy of CA to overcome MDR-1 mediated drug resistance in HepG2 cells through COX-2 dependant modulation of MDR-1.
21 citations
Journal Article•
TL;DR: In the present study, HTS-compatible assays for COX-1,COX-2 and 5-LOX were developed for screening of compound libraries with the view to identify potential anti-inflammatory drug candidates.
Abstract: High-throughput screening (HTS) involves testing of compound libraries against validated drug targets using quantitative bioassays to identify 'hit' molecules that modulate the activity of target, which forms the starting point of a drug discovery effort. Eicosanoids formed via cyclooxygenase (COX) and lipoxygenase (LOX) pathways are major players in various inflammatory disorders. As the conventional non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit both the constitutive (COX-1) and the inducible (COX-2) isoforms have gastric and renal side effects and the recently developed COX-2 selective anti-inflammatory drugs (COXIBs) have cardiac side effects, efforts are being made to develop more potent and safer antiinflammatory drugs. Current assay methods for these enzymes, such as oxygraphic, radioisotopic, spectrophotometric etc. are not compatible for screening of large number of compounds as in drug discovery programs. In the present study, HTS-compatible assays for COX-1, COX-2 and 5-LOX were developed for screening of compound libraries with the view to identify potential anti-inflammatory drug candidates. A spectrophotometric assay involving co-oxidation of tetramethyl-p-phenylene diamine (TMPD) during the reduction of prostaglandin G2 (PGG2) to PGH2 was adopted and standardized for screening of compounds against COX-1 and COX-2. Similarly, the HTS-compatible FOX (ferrous oxidation-xylenol orange) based spectrophotometric assay involving the formation of Fe3+/xylenol orange complex showing absorption in the visible range was developed for screening of compounds against 5-LOX.
18 citations
TL;DR: The predictive power of the CoMSIA model was higher than the CoMFA model, the high predictive r(2) values of the test set reveals that the models prove to be useful tools for activity prediction of newly designed 5-LOX inhibitors.
17 citations
TL;DR: The results demonstrate that for small perturbations, 1248 ps simulation time could be regarded a reasonable yardstick to achieve convergence of the results and serves a useful benchmark in drug design efforts using FEP methodologies.
Abstract: In an attempt to establish the criteria for the length of simulation to achieve the desired convergence of free energy calculations, two studies were carried out on chosen complexes of FBPase-AMP mimics. Calculations were performed for varied length of simulations and for different starting configurations using both conventional- and QM/MM-FEP methods. The results demonstrate that for small perturbations, 1248 ps simulation time could be regarded a reasonable yardstick to achieve convergence of the results. As the simulation time is extended, the errors associated with free energy calculations also gradually tapers off. Moreover, when starting the simulation from different initial configurations of the systems, the results are not changed significantly, when performed for 1248 ps. This study carried on FBPase-AMP mimics corroborates well with our previous successful demonstration of requirement of simulation time for solvation studies, both by conventional and ab initio FEP. The establishment of aforementioned criteria of simulation length serves a useful benchmark in drug design efforts using FEP methodologies, to draw a meaningful and unequivocal conclusion.
3 citations