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Biomedical subjects

Ramesh Chandra

Publications and source records attributed to Ramesh Chandra.

At least 19 recordsLinked to original sources
PubMed2006

Preparation, characterization and in vitro drug release studies of novel polymeric nanoparticles.

Polymeric nanoparticles of AADG cross-linked with MBA encapsulating water soluble macromolecules such as FITC-Dextran have been prepared in the reverse micellar system. The particles obtained were of >85nm in diameter which were highly monodisperse. An optically clear solution was obtained on redispersing these nanoparticles in aqueous buffer. Size and morphology of the particles remains the same on re-dispersing the lyophilized powder of these nanoparticles in aqueous buffer. The size dependency of the particles on the monomer and surfactant concentration was observed. The average size of the nanoparticles as obtained from DLS studies ranges from 74 to 114nm in case 0.06M AOT and 62-104nm in case of 0.1M AOT concentration. FITC-Dextran was entrapped into nanoparticles with high efficiency (>70%). The pH dependent release of the entrapped molecules from these nanoparticles was also studied. At pH 5.0 solution, approximately 43% of FITC-Dx was released and at pH 7.4 it was about 70%.

Acrylamides↗
PubMed2006

Synthesis and in vitro cytotoxicity of haloderivatives of noscapine.

Three haloderivatives of noscapine 2-4 were synthesized chemoselectively and their in vitro cytotoxicity was assessed by MTT assay on U-87 human glioblastoma cell lines. At 50 microM concentration after 72 h, 9-chloronoscapine 2, 9-bromonoscapine 3 (EM011), and 9-iodonoscapine 4 killed 87.8%, 51.2%, and 56.8% cells, respectively, however noscapine kills only 40% of the cells; revealing 9-chloronoscapine as a potential cytotoxic agent than noscapine and 9-bromonoscapine (EM011). At low concentration (1 microM) 9-bromonoscapine (46.7%) and 9-chloronoscapine (45.7%) did not show any significant difference.

Antineoplastic Agents↗
PubMed2006

Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death.

We have previously identified the naturally occurring non-toxic antitussive phthalideisoquinoline alkaloid, noscapine as a tubulin-binding agent that arrests mitosis and induces apoptosis. Here we present high-yield efficient synthetic methods and an evaluation of anticancer activity of halogenated noscapine analogs. Our results show that all analogs display higher tubulin-binding activity than noscapine and inhibit proliferation of human cancer cells (MCF-7, MDA-MB-231 and CEM). Surprisingly, the bromo-analog is approximately 40-fold more potent than noscapine in inhibiting cellular proliferation of MCF-7 cells. The ability of these analogs to inhibit cellular proliferation is mediated by cell cycle arrest at the G2/M phase, in that all analogs except 9-iodonoscapine, caused selective mitotic arrest with a higher efficiency than noscapine followed by apoptotic cell death as shown by immunofluorescence and quantitative FACS analyses. Furthermore, our results reveal the appearance of numerous fragmented nuclei as evidenced by DAPI staining. Thus, our data indicate a great potential of these compounds for studying microtubule-mediated processes and as chemotherapeutic agents for the management of human cancers.

Antineoplastic Agents↗
PubMed2006

Novel polyallylamine-dextran sulfate-DNA nanoplexes: highly efficient non-viral vector for gene delivery.

Polyallylamine (PAA), a less investigated polycationic polymer along with polyanionic dextran sulfate (DS) has been complexed with DNA into self assembling PAA-DS-DNA complexes with zinc as stabilizing agent. The complexes prepared were characterized by dynamic light scattering and atomic force microscopy and found to have average hydrodynamic diameter of 150nm with polydispersity below 0.2, i.e. nanoplexes with narrow size distribution. As expected, the zeta potential values increased with the increase in the PAA in the nanoplexes. Further, PAA-DS-DNA nanoplexes were investigated for in vitro transfecting efficacy on HEK 293 cells. The nanoplexes were found to have better gene transfer efficacy compared to the DNA-PAA complex and commercially available transfecting agent lipofectin. The cytotoxicity was also decreased considerably as revealed by MTT colorimetric assay. The nanoplexes prepared with PAA to DS ratio of 2 were found to be most efficient transfecting agent.

Cell Line↗
PubMed2006

Plasmodium vinckei: selection of a strain exhibiting stable resistance to arteether.

A strain of rodent malaria parasite Plasmodium vinckei showing >12-fold resistance to arteether has been selected after exposure to sub-curative doses of drug in 44 sequential passages over a period of 700 days. Experimentally induced resistance was found to be stable after drug free maintenance of parasites for 11 serial passages over a period of 100 days. Cross-sensitivity studies have shown that apart form resistance to related derivatives like artemether and artesunic acid, the derived parasites also show resistance to quinine and mefloquine.

Animals↗
PubMed2006

Rational design of the microtubule-targeting anti-breast cancer drug EM015.

We studied in silico docking of noscapine onto tubulin, combined with calculations of surface charge, pi-pi, van der Waals, and hydrogen bonding interactions, to rationally design a new compound, EM015. This tubulin-binding semisynthetic compound is a selective and potent anti-breast cancer agent and displays a 20-fold lower IC(50) against many tumor cells compared with our founding compound, (S)-6,7-dimethoxy-3-((R)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]-dioxolo-[4,5-g]isoquinolin-5-yl)isobenzo-furan-1(3H)-one (noscapine). Furthermore, EM015 is also effective against a variety of drug-resistant cells. Surprisingly, the cell cycle profile of nontumorigenic normal cells is not affected. Many antimicrotubule cancer drugs in clinic today, particularly taxanes and Vincas, face challenges including frequent visits to the hospital for prolonged i.v. infusions, toxicities, and tumor recurrences due to drug resistance. EM015, on the other hand, is orally available, regresses breast tumor xenografts in nude mice models, and increases longevity. Furthermore, we have failed to observe any detectable toxicity in tissues, such as liver, kidney, spleen, lung, heart, and brain, as well as neurons, which are common targets of antimicrotubule drug therapy. Thus, EM015 has a great promise in the clinic.

Animals↗
PubMed2006

Development of a novel nitro-derivative of noscapine for the potential treatment of drug-resistant ovarian cancer and T-cell lymphoma.

We have shown previously that an antitussive plant alkaloid, noscapine, binds tubulin, displays anticancer activity, and has a safe pharmacological profile in humans. Structure-function analyses pointed to a proton at position-9 of the isoquinoline ring that can be modified without compromising tubulin binding activity. Thus, many noscapine analogs with different functional moieties at position-9 were synthesized. Those analogs that kill human cancer cells resistant to other antimicrotubule agents, vincas and taxanes, were screened. Here, we present one such analog, 9-nitro-noscapine (9-nitro-nos), which binds tubulin and induces apoptosis selectively in tumor cells (ovarian and T-cell lymphoma) resistant to paclitaxel, vinblastine, and teniposide. 9-Nitro-nos treatment at doses as high as 100 microM did not affect the cell cycle profile of normal human fibroblasts. This selectivity of 9-nitro-nos for cancer cells represents a unique edge over the other available antimitotics. 9-Nitro-nos perturbs the progression of cell cycle by mitotic arrest, followed by apoptotic cell death associated with increased caspase-3 activation and appearance of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. Thus, we conclude that 9-nitro-nos has great potential to be a novel therapeutic agent for ovarian and T-cell lymphoma cancers, even those that have become drug-resistant to currently available chemotherapeutic drugs.

Antimitotic Agents↗
PubMed2006

Synthesis and antifungal activity of substituted-10-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indoles.

Series of substituted-10-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indoles derivatives have been synthesized and examined for their activity against pathogenic strains of Aspergillus fumigatus (ITCC 4517), Aspergillus flavus (ITCC 5192) Aspergillus niger (ITCC 5405) and Candida albicans (ITCC No 4718). All synthesized compounds showed mild to moderate activity, except for 2-substituted-10-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indoles 6a-d. The most active 1-(4-chlorophenyl)-10-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole 4c exhibited a MIC value of 5.85 microg/disc against A. fumigatus and 11.71 microg/disc against A. flavus and A. niger in disc diffusion assay. Anti-Aspergillus activity of active compound 4c by microbroth dilution assay was found to be 15.62 microg/ml in case of A. fumigatus and 31.25 microg/ml with A. flavus and A. niger. The MIC90 value of the most active compound by percent germination inhibition assay was found to be 15.62 microg/ml against A. fumigatus. The MIC90 values of substituted-10-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indoles against C. albicans ranged from 15.62 to 250 microg/ml. The in vitro toxicity of the most active 1-(4-chlorophenyl)-10-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole 4c was evaluated using haemolytic assay, in which the compound was found to be non-toxic to human erythrocytes up to a concentration of 312.50 microg/ml. The standard drug amphotericin B exhibited 100% lysis at a concentration of 37.5 microg/ml.

Antifungal Agents↗
PubMed2006

Reversal of P-glycoprotein-mediated multidrug resistance in cancer cells by the c-Jun NH2-terminal kinase.

A significant impediment to the success of cancer chemotherapy is multidrug resistance (MDR). A typical form of MDR is attributable to the overexpression of membrane transport proteins, such as P-glycoprotein, resulting in an increased drug efflux. In this study, we show that adenovirus-mediated enhancement of the c-Jun NH2-terminal kinase (JNK) reduces the level of P-glycoprotein in a dose- and time-dependent manner. Protein turnover assay shows that the decrease of P-glycoprotein is independent of its protein stability. Instead, this occurs primarily at the mRNA level, as revealed by reverse transcription-PCR analysis. We find that P-glycoprotein down-regulation requires the catalytic activity of JNK and is mediated by the c-Jun transcription factor, as either pharmacologic inhibition of JNK activity or dominant-negative suppression of c-Jun remarkably abolishes the ability of JNK to down-regulate P-glycoprotein. In addition, electrophoretic mobility shift assay reveals that adenoviral JNK increases the activator protein binding activity of the mdr1 gene in the MDR cells. We further show that the decrease of P-glycoprotein level is associated with a significant increase in intracellular drug accumulation and dramatically enhances the sensitivity of MDR cancer cells to chemotherapeutic agents. Our study provides the first direct evidence that enhancement of the JNK pathway down-regulates P-glycoprotein and reverses P-glycoprotein-mediated MDR in cancer cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Magnetic field correlation imaging.

A magnetic resonance imaging (MRI) method is presented for estimating the magnetic field correlation (MFC) associated with magnetic field inhomogeneities (MFIs) within biological tissues. The method utilizes asymmetric spin echoes and is based on a detailed theory for the effect of MFIs on nuclear magnetic resonance (NMR) signal decay. The validity of the method is supported with results from phantom experiments at 1.5 and 3 T, and human brain images obtained at 3 T are shown to demonstrate the method's feasibility. The preliminary results suggest that MFC imaging may be useful for the quantitative assessment of iron within the brain.

Algorithms↗
PubMed2006

Hematopoietic stem cell antigen CD34: role in adhesion or homing.

CD34 is highly glycosylated surface antigen of enormous clinical utility in the identification, enumeration, and purification of engraftable lymphohematopoietic progenitors for transplantation. However, recently its importance in the specific marking of most immature hematopoietic stem/progenitor cells have been questioned by addressing long-term reconstitution capability of CD34(-) hematopoietic cellular fractions. These controversies have stimulated a demand for elucidation of the structure, function, and molecular interactions of CD34 to define exactly its biological significance in clinical regimens. There is accumulating data showing the participation of CD34 in adhesion or perhaps homing of lymphohematopoietic progenitors. On the other hand, CD34 has been demonstrated to down-regulate cytokine-induced differentiation and proliferation of CD34(+) cells. Studies in CD34 knockout mice revealed normal hematopoiesis but a profound delay in hematopoietic reconstitution after sublethal irradiation of the mice. In short, CD34 expression is likely to represent a specific state of hematopoietic development that may have altered adhering properties with expanding and differentiating capabilities in both in vitro and in vivo conditions. This article focuses on the adhesive properties of CD34 and its potential role in homing, which are likely to mimic lymphocyte homing to the inflammatory sites.

Animals↗
PubMed2006

PU.1: An ETS family transcription factor that regulates leukemogenesis besides normal hematopoiesis.

The hematopoietic transcription factor PU.1, which is required for lymphomyeloid differentiation of stem cells, was originally identified as an oncogene. In erythroid progenitors, the integration of spleen focus-forming virus (SFFV) into the PU.1 locus causes its overexpression, which blocks their terminal differentiation into erythrocytes and ultimately leads to the development of erythroleukemia. However, in myeloid lineages, PU.1 promotes granulocytic and monocytic differentiation, and graded reduction in its expression blocks their differentiation or maturation and thereby causes myelogenous leukemia. Thus, in addition to normal hematopoietic regulation, PU.1 plays a significant role in leukemogenesis. In the following review, we have consolidated our understanding of the role of transcription factor PU.1 in the development of erythroid as well myeloid leukemia.

Animals↗
PubMed2006

Treatment of hormone-refractory breast cancer: apoptosis and regression of human tumors implanted in mice.

Following surgery, the hormone dependence of breast tumors is exploited for therapy using antagonists such as tamoxifen, although occasional hormone-resistant clones do appear. Another chemotherapeutic strategy uses microtubule inhibitors such as taxanes. Unfortunately, these agents elicit toxicities such as leukocytopenia, diarrhea, alopecia, and peripheral neuropathies and are also associated with the emergence of drug resistance. We have previously described a tubulin-binding, natural compound, noscapine, that was nontoxic and triggered apoptosis in many cancer types albeit at 10 mumol/L or higher concentrations depending on the cell type. We now show that a synthetic analogue of noscapine, 9-bromonoscapine, is approximately 10-fold to 15-fold more potent than noscapine in inhibiting cell proliferation and induces apoptosis following G2-M arrest in hormone-insensitive human breast cancers (MDA-MB-231). Furthermore, a clear loss of mitochondrial membrane potential, release of cytochrome c, activation of the terminal caspase-3, and the cleavage of its substrates such as poly(ADP-ribose) polymerase, suggest an intrinsic apoptotic mechanism. Taken together, these data point to a mitochondrially mediated apoptosis of hormone-insensitive breast cancer cells. Human tumor xenografts in nude mice showed significant tumor volume reduction and a surprising increase in longevity without signs of obvious toxicity. Thus, our data provide compelling evidence that 9-bromonoscapine can be useful for the therapy of hormone-refractory breast cancer.

Animals↗
PubMed2005

Synthesis, antibacterial activity and QSAR studies of 1,2-disubstituted-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines.

Some new substituted-tetrahydroisoquinoline derivatives were synthesized and evaluated for their in vitro antimicrobial activities against the standard Gram positive and Gram negative strains: Staphylococcus aureus (ATCC 25923), S. epidermidis (WHO-6), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 4a-c proved to be effective with MIC 3.5-20 (microg ml(-1)). Quantitative structure activity relationship (QSAR) studies with multiple linear regression analysis were applied to find correlation between different calculated molecular descriptors of the synthesized compounds and biological activity.

Anti-Bacterial Agents↗
PubMed2005

Polyethylenimine nanoparticles as efficient transfecting agents for mammalian cells.

Two cross-linkers based on polyethylene glycol (PEG) (MW=6 and 8 kDa), were synthesized for self-assembling and formation of nanoparticles of branched, high molecular weight polyethylenimine (PEI). Cross-linking was realized in two ways, viz., ionic as well as covalent. Ionic cross-linking was accomplished by using PEG-bis (phosphate) whereas, the covalent one was achieved by using PEG-bis (p-nitrophenylcarbonate). A range of nanoparticles of PEI was prepared by varying the degree of cross-linking (i.e. the amount of cross-linkers used). PEI-PEG nanoparticles were characterized by dynamic light scattering and transmission electron microscopy and found to be in the range of approximately 18-75 nm (hydrodynamic radii) with almost uniform population. Subsequently, these particles were used for DNA binding assay and zeta-potential measurements, taking native PEI-PEG nanoparticles as reference. As expected, the zeta potential values decreased, on increasing the percentage of cross-linking as well as on complexation with DNA. Further, PEI-PEG nanoparticles were investigated for their transfecting efficacy on COS-1 cells. It was found that PEI-PEG nanoparticles were 5- to 16-fold more efficient as transfecting agents compared to lipofectin and PEI itself. The toxicity of PEI-PEG nanoparticles was found to be reduced considerably in comparison to PEI polymer, as determined by MTT colorimetric assay. Out of the various systems prepared, PEI-PEG8000 (5% ionic) nanoparticles were found to be the most efficient transfecting agent for in vitro transfection.

Animals↗
PubMed2005

Drug-resistant T-lymphoid tumors undergo apoptosis selectively in response to an antimicrotubule agent, EM011.

We have shown previously that EM011, a synthetic compound, binds tubulin with a higher affinity than the founding compound, noscapine, without changing total microtubule polymer mass. Now we show that EM011 is potently effective against vinblastine-resistant human lymphoblastoid line CEM/VLB100 and its parental vinblastine-sensitive line CEM. The cytotoxicity is mediated by cell cycle arrest at G2/M phase and subsequent apoptosis, as indicated by altered plasma membrane asymmetry, loss of mitochondrial transmembrane potential, activation of caspase-3, and increased DNA fragmentation. Furthermore, oral EM011 treatment of nude mice bearing human lymphoma xenografts results in pronounced tumor regression by triggering apoptosis and significantly lengthens the survival time of mice. EM011 treatment does not have obvious side effects in tissues with frequently dividing cells, such as the spleen and duodenum. In addition, EM011 does not show any toxicity in the liver, lung, heart, brain, and sciatic nerve. More importantly, EM011 does not affect hematopoiesis as determined by complete blood count profiles. These findings suggest that EM011 may be a safe and effective chemotherapeutic agent for oral treatment of drug-resistant human lymphomas.

Animals↗
PubMed2005

Synthesis and antimicrobial activity of N-alkyl and N-aryl piperazine derivatives.

A series of substituted piperazine derivatives have been synthesized and tested for antimicrobial activity. The antibacterial activity was tested against Staphylococcus aureus (MTCCB 737), Pseudomonas aeruginosa (MTCCB 741), Streptomyces epidermidis (MTCCB 1824) and Escherichia coli (MTCCB 1652), and antifungal activity against Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger. All synthesized compounds showed significant activity against bacterial strains but were found to be less active against tested fungi. In vitro toxicity tests demonstrated that compounds 4d and 6a showed very less toxicity against human erythrocytes.

Anti-Infective Agents↗