IR@IIIM - Indian Institute of Integrative Medicine (CSIR)
Not a member yet
200 research outputs found
Sort by
A Novel cyano derivative of 11-Keto-β-Boswellic acid causes apoptotic death by disrupting PI3K/AKT/Hsp-90 cascade, mitochondrial integrity, and other cell survival signaling events in HL-60 cells
No full textIntervention of apoptosis is a promising strategy for discovery of novel anti-cancer therapeutics. In this study, we examined the ability of a novel cyano derivative of 11-keto-b-boswellic acid, that is, butyl 2-cyano-3,11-dioxours-1,12-dien-24-oate (BCDD) to induce apoptosis in cancer cells. BCDD inhibited cell proliferation with 48 h IC50 of 0.67 mM in HL-60, 1 mM in Molt4, and 1.5 mM in THP1 cells. The mechanism of cell death was investigated in HL-60 cells where it caused apoptosis by acting against several potential apoptosis suppressive targets. It inhibited phosphatidylinositol-3-kinase (PI3K)/AKT activity, NF-kB, Hsp-90, and survivin which may enhance the sensitivity of cells to apoptosis.Also, BCDD decreased the activity of Bid and Bax in cytosol, caused DCmt loss, releasing pro-apoptotic cytochrome c, SMAC/DIABLO leading to caspase-9-mediated down stream activation of caspase-3, ICAD, and PARP1 cleavage.Translocation of apoptotis-inducing factor (AIF) from mitochondria to the nucleus indicated some caspases-independent apoptosis. Though it upregulated DR-5 and caspase-8, the caspase inhibitor yet had no effect on apoptosis as against 75% inhibition by caspase-9 inhibitor. Attempts were made to examine any acclaimed role of AIF in the activation of caspase-8 using siRNA where it had no effect on caspase-8 activity while the Bax-siRNA inhibited caspase-3 activation suggesting predominance of intrinsic signaling. Our studies thus demonstrated that BCDD exerts multi-focal action in cancer cells while it required 10-fold higher the concentration to produce cytotoxicity in normal human PBMC and gingival cell line, and therefore, may find usefulness in the management of human leukemia
A novel parthenin analog exhibits anti-cancer activity: Activation of apoptotic signaling events through robust NO formation in human leukemia HL-60 cells
No full textThis study describes the anti-cancer activity of P19, an analog of parthenin. P19 induced apoptosis in HL-60 cells and inhibited cell proliferation with 48 h IC50 of 3.5 lM. At 10 mg/kg dose, it doubled the median survival time of L1210 leukemic mice and at 25 mg/kg it inhibited Ehrlich ascites tumor growth by 60%.Investigation of the mechanism of P19 induced apoptosis in HL-60 cells revealed that N-acetyl-L-cysteine(NAC) and s-methylisothiourea (sMIT) could reverse several molecular events that lead to cell death by inhibiting nitric oxide (NO) formation. It selectively produced massive NO in cells while quenching the
basal ROS levels with concurrent elevation of GSH. P19 disrupted mitochondrial integrity leading to cytochrome
c release and caspase-9 activation. P19 also caused caspase-8 activation by selectively elevating the expression of DR4 and DR5. All these events lead to the activation of caspase-3 leading to PARP-1 cleavage and DNA fragmentation. However, knocking down of AIF by siRNA also suppressed the apoptosis substantially thus indicating caspase independent apoptosis, too. Further, contrary to enhanced iNOS expression, its transcription factor, NF-jB (p65) was cleaved with a simultaneous increase in cytosolic
IjB-alpha. In addition, P19 potently inhibited pro-survival proteins pSTAT3 and survivin. The multimodal pro-apoptotic activity of P19 raises its potential usefulness as a promising anti-cancer therapeutic
A novel sarsasapogenin glycoside from Asparagus racemosus elicits protective immune responses against HBsAg
No full textThe aim of the present investigation was to evaluate the adjuvant potential of a novel sarsasapogenin glycoside (immunoside) isolated from Asparagus racemosus in combination with hepatitis B surface antigen(HBsAg). Various in vitro and animal derived protocols were used to determine the response of immunoside adjuvanted with HBsAg and the results were compared with alum adjuvanted with HBsAg.Several biomarkers such as antibody titre (IgG, IgG1/IgG2a) were measured in mice sera. Cell proliferation,
cytokines (IL-2, IFN-� and IL-4), and lymphocyte sub-populations (CD4/CD8, CD3 and CD19)were determined in splenocytes from mice administered subcutaneously with test substances. In these cells CD4/CD8 derived IFN-� release was also determined. Macrophage preparations were used for the determination of IL-12, IFN-� and nitrite content. Seroconversion potential was compared with a standard
vaccine. Acute safety evaluation of immunoside was done in mice. Effect of immunoside on red blood cell haemolysis was determined. The results have suggested that immunoside potentially enhanced anti-HBsAg immune response via augmenting Th1/Th2 response in a dose dependent manner
Synthesis of new fluorescently labeled glycosylphosphatidylinositol (GPI) anchors
No full textThe borondipyrromethene (BODIPY) labeled new glycosylphosphatidylinositol (GPI) molecules were synthesized as cellular probes to study the chemical basis of microdomain organization of GPI-anchored proteins and cholesterol in plasma membrane. The synthesis enabled by a new stereo-selective glycosylation of myo-D-inositol acceptor led to the preparation of optically pure glucosaminyl-(1-6)-a-phosphatidylmyo-D-inositol and its unnatural stereoisomer
Utility of a multidisciplinary approach for genome diagnostics of cultivated and wild germplasm resources of medicinal Withania somnifera, and the status of new species, W. ashwagandha, in the cultivated taxon
No full textRealizing the inconsistencies that exist in the extent and nature of differentiation in the Withania somnifera
genetic resources in India, the 21 cultivated and wild
accessions, and the two hybrids (cultivated 9 wild accessions and vice versa) were investigated for morphological,cytogenetical, chemical profiling, and crossability features.Their nuclear and chloroplast genomes were also assayed at the nucleotide sequence level, and by use of DNA markers. Chloroplast DNA diversity and somatic chromosome number (2n = 48) were not helpful in identifying the differences. Other approaches, on the other hand, especially restriction endonuclease digests, types and sequence length composition of ITS 1 and ITS 2 of nuclear ribosomal DNA, AFLP fingerprinting, and crossability barriers unambiguously provided startling discrete differences between the cultivated and wild accessions, indicating a clear division of W. somnifera into two distinct lineages.These data, therefore, are indicative of the fact that because of the unique characteristics of its nuclear genome, and strong crossability barriers vis-a`-vis wild accessions of W. somnifera, the cultivated accessions should be relegated to the rank of the separate species, W. ashwagandha
Antistaphylococcal and biofilm inhibitory activities of acetyl-11-keto-β-boswellic acid from Boswellia serrata
No full textBoswellic acids are pentacyclic triterpenes, which are produced in plants belonging to the genus Boswellia. Boswellic acids appear in the resin exudates of the plant and it makes up 25-35% of the resin. β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid have been implicated in apoptosis of cancer cells, particularly that of brain tumors and cells affected by leukemia or colon cancer. These molecules are also associated with potent antimicrobial activities. The present study describes the antimicrobial activities of boswellic acid molecules against 112 pathogenic bacterial isolates including ATCC strains. Acetyl-11-keto-β-
boswellic acid (AKBA), which exhibited the most potent antibacterial activity, was further evaluated in time kill studies, postantibiotic effect (PAE) and biofilm susceptibility assay. The mechanism of action of AKBA was investigated by propidium iodide uptake, leakage of 260 and
280 nm absorbing material assays
Antitumor efficacy and apoptotic activity of substituted chloroalkyl 1H-benz[de]isoquinoline-1,3-diones: a new class of potential antineoplastic agents
No full textA series of ten chloroalkyl 1H-benz[de]isoquinoline-1,3-diones (naphthalimides) were synthesized and evaluated for antitumor activity. Amongst them, new compounds 2d and 2i carrying a 6-NO2 substituent in the aromatic portion of the molecule possessed significant antineoplastic activity. The most active compound 2i had elicited significant cytotoxicity in 15 human tumor cell lines namely Leukemia: MOLT-4, HL-60; Lymphoma: U-937; Colon: 502713, HT-29, SW-620,HCT-15, COLO-205; Liver: Hep-2; Prostate DU-145, PC-3;Breast: MCF-7; Neuroblastoma: IMR-32, SK-N-SH and
Ovary: OVCAR-5 out of the 17 cell lines screened. Flow
cytometric analysis performed to study the effect of
compound 2i on the progression of cell cycle of MOLT-4
cells, revealed rise in sub-G1 fraction and concomitant
accumulation of cells in S and G2/M phases, indicating
apoptosis, mitotic arrest and/or delay in exit of daughter cells from mitotic cycle respectively. It also induced caspasemediated apoptosis of MOLT-4 cells in a dose dependant manner. Light and electron microscopic studies revealed characteristic morphology of apoptotic MOLT-4 cells after in vitro treatment with 10 μM concentration of the compound.Apoptosis induction was also observed in HL-60 cells by compounds 2d and 2i to an extent much greater than
camptothecin and cis-platin at 10 μM concentration. Both the
compounds have shown minimal suppressive effect on human
PBMC having high IC50 values of 3,582 and 1,536 μM respectively. These compounds inhibited DNA and RNA synthesis in murine ascites Sarcoma-180 tumor cells in vitro at 8 μM concentration. Above results indicate promising chemotherapeutic potential of the key compound 2i
Design and synthesis of spiro derivatives of parthenin as novel anti-cancer agents
No full textSeveral novel spiro derivatives of parthenin (1) have been synthesized by the dipolar cycloaddition using various dipoles viz; benzonitrile oxides, nitrones and azides with exocyclic double bond of C ring(a-methylene-g-butyrolactone). Majority of the compounds exhibited improved anti-cancer activity compared to the parthenin, when screened for their in vitro cytotoxicity against three human cancer cell lines viz., SW-620, DU-145 and PC-3. In vivo screening of select analog revealed improved anti-cancer activity with low mammalian toxicity as compared to parthenin. The results of the cytotoxicity pattern of these derivatives reveals the SAR of these sesquiterpinoid lactones and possible role of a,b-unsaturated ketone of parthenin in inhibiting NF-kB. A mechanistic correlation of anti-cancer activity along with
in vivo and western blotting experiments has been described
Novel thermostable lipase from Bacillus circulans IIIB153: comparison with the mesostable homologue at sequence and structure level
No full textThermophilic Bacillus circulans IIIB153 isolated from hot springs of North West Himalayas, India, produced an extracellular lipase, which exhibited significant
biofilm disruption property on the static biofilm disruption
model with a single species of Actinomyces viscosous. The
gene encoding the lipase was cloned and overexpressed in
Escherichia coli. Recombinant Bacillus circulans lipase
(BCL), a monomer with molecular mass of 43 kDa also
exhibited significant biofilm disruption activity. The enzyme was optimally active at 60�C, pH 8.5 and retained[70% of its original activity after 1 h incubation at 60�C. 3D structure of BCL developed by homology modeling showed a typical a/b hydrolase fold, a characteristic feature of lipolytic enzymes. Comparison of thermostable BCL with mesostable lipase from Chromobacterium viscosum at the sequence and structure level showed distinct variations in the structural features, with the presence of a high content of proline residues, aromatic amino acids and salt bridges. These features along with the presence of zinc-binding site observed in BCL structure could have a potential role in thermal stability of the enzyme
Phylogenetic Characterization of Archaea in Saltpan Sediments
No full textA study was undertaken to investigate the presence of archaeal diversity in saltpan sediments of Goa,
India by 16S rDNA-dependent molecular phylogeny. Small
subunit rRNA (16S rDNA) from saltpan sediment metagenome were amplified by polymerase chain reaction(PCR) using primers specific to the domain archaea. 10 unique phylotypes were obtained by PCR based RFLP of 16S rRNA genes using endonuclease Msp 1, which was most suitable to score the genetic diversity. These phylotypes spanned a wide range within the domain archaea including both crenarchaeota and euryarcheaota. None of the retrieved crenarchaeota sequences could be grouped with previously cultured crenarchaeota however; two sequences were related with haloarchaea. Most of the sequences determined were closely related to the sequences that had been previously obtained from metagenome of a variety of marine environments. The phylogenetic study of a site investigated for the first time revealed the presence of low archaeal population but showed yet unclassified species, may specially adapted to the salt pan sediment of Goa