V. B. Sameer Kumar

Regulation of vascular endothelial growth factor by metabolic context of the cell.

Expression of vascular endothelial growth factor, major endothelial specific glycoprotein growth factor that promotes angiogenesis is regulated at transcriptional, post transcriptional and posttranslational levels. One of the key posttranslational modifications involved in regulating the angiogenic potential of VEGF is covalent modification involving polyADP ribosylation. Major factors contributing to the regulation of VEGF include factors relating to hypoxia, growth factors and cytokines and hormones. Apart from these, the metabolite status of the cell as sensed by various metabolite regulators can influence the angiogenic potential. Changes in the metabolite status of the cell occur during different conditions associated with excessive or insufficient angiogenesis contributing to pathology. Effect of metabolites, as exemplified by certain metabolites such as lactate, citrate, sarcosine, metabolites of arachidonic acid on angiogenesis through the regulation of expression of VEGF as well as its angiogenic potential through polyADP ribosylation is discussed.

Horizontal transfer of miR-106a/b from cisplatin resistant hepatocarcinoma cells can alter the sensitivity of cervical cancer cells to cisplatin

Recent studies indicate that horizontal transfer of genetic material can act as a communication tool between heterogenous populations of tumour cells, thus altering the chemosensitivity of tumour cells. The present study was designed to check whether the horizontal transfer of miRNAs released by cisplatin resistant (Cp-r) Hepatocarcinoma cells can alter the sensitivity of cervical cancer cells. For this exosomes secreted by cisplatin resistant and cisplatin sensitive HepG2 cells (EXres and EXsen) were isolated and characterised. Cytotoxicity analysis showed that EXres can make Hela cells resistant to cisplatin. Analysis of miR-106a/b levels in EXres and EXsen showed that their levels vary. Mechanistic studies showed that miR-106a/b play an important role in EXsen and EXres mediated change in chemosensitivity of Hela cells to cisplatin. Further SIRT1 was identified as a major target of miR-106a/b using in silico tools and this was proved by experimentation. Also the effect of miR-106a/b in chemosensitivity was seen to be dependent on regulation of SIRT1 by miR-106a/b. In brief, this study brings into light, the SIRT1 dependent mechanism of miR-106a/b mediated regulation of chemosensitivity upon the horizontal transfer from one cell type to another.

Angiogenic Profiling of Synthesized Carbon Quantum Dots

A simple method was employed for the synthesis of green luminescent carbon quantum dots (CQDs) from styrene soot. The CQDs were characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared, and Raman spectroscopy. The prepared carbon quantum dots did not show cellular toxicity and could successfully be used for labeling cells. We also evaluated the effects of carbon quantum dots on the process of angiogenesis. Results of a chorioallantoic membrane (CAM) assay revealed the significant decrease in the density of branched vessels after their treatment with CQDs. Further application of CQDs significantly downregulated the expression levels of pro-angiogenic growth factors like VEGF and FGF. Expression of VEGFR2 and levels of hemoglobin were also significantly lower in CAMs treated with CQDs, indicating that the CQDs inhibit angiogenesis. Data presented here also show that CQDs can selectively target cancer cells and therefore hold potential in the field of cancer therapy.

MoS2–ZnO nanocomposites as highly functional agents for anti-angiogenic and anti-cancer theranostics

Due to its excellent properties, 2D-MoS2 finds potential applications in the fields of electronics, optoelectronics, energy storage and conversion, biomedicine, etc. This work deals with the incorporation of ZnO into 2D-MoS2, its structural, morphological, optical, and magnetic studies and its application as an efficient cancer therapeutic agent. The MoS2-ZnO nanocomposite exhibits remarkable excitation wavelength dependent down-conversion and up-conversion photoluminescence. The observation of wasp-waisted magnetism in the MoS2-ZnO nanocomposite indicates the coupling of ZnO and MoS2 materials inducing multimodal population. The MoS2-ZnO nanocomposite showed cytotoxic properties with a safety index reaching up to ∼2. An in ovo xenograft assay revealed that the MoS2-ZnO nanocomposite retards tumor growth by specifically activating caspase-3 and thereby inducing cellular apoptosis. Moreover, the treatment of xenografts with the MoS2-ZnO nanocomposite down regulated the expression of major pro-angiogenic genes such as VEGF, VEGFR2 etc. thereby curtailing vascularization into the tumor intima. Treatment of tumor xenografts with the MoS2-ZnO nanocomposite caused reduced expression of mesenchymal specific genes and elevated expression of epithelial specific genes, implying a role of the MoS2-ZnO nanocomposite in retarding the process of epithelial to mesenchymal transition (EMT). This study highlights that the introduction of ZnO into MoS2 nanostructures offers a unique idea to design efficient MoS2-based multifunctional nanocomposites that provide opportunities in advanced biomedical and optoelectronic applications.

Poly(N-vinyl-2-pyrrolidone-maleic anhydride-styrene) grafted terpolymer: Synthesis, characterization, and bactericidal property evaluation against E. coli and S. epidermidis

ABSTRACT Poly(N-vinyl-2-pyrrolidone-maleic anhydride-styrene) terpolymer was prepared using AIBN initiator with acetone as solvent. The terpolymer was grafted with anti-bacterial agents para-aminobenzoic acid and 2,4-dichlorophenol to introduce bactericidal activity to the terpolymer. The terpolymer and the grafted polymers were characterized by FTIR, 1H-NMR, and 13C-NMR spectroscopic methods. Thermal properties were determined by differential scanning calorimetric technique and thermogravimetric analysis. The glass transition temperature was found to be 111°C (terpolymer), 150°C (VMS-G-PABA) and 130°C (VMS-G-DCP). Terpolymer starts degradation at 288°C and grafted terpolymers at 104°C (VMS-G-PABA) and 129°C (VMS-G-DCP), respectively. The anti-bacterial activity of grafted terpolymers were evaluated by the shake flask method against gram positive and gram negative bacteria E. coli and S. epidermidis. The grafted terpolymers showed effective inhibition against both the bacteria, the minimum inhibition concentration was observed to be 75 µg/mL and 80 µg/mL for VMS-G-PABA and 50 µg/mL for VMS-G-DCP against E. coli and S. epidermidis, respectively. The new polymers showed 90% bacterial growth inhibition at 200 µg/mL.

Synthesis of heteroannulated cyclopent[b]indoles: Exploration of in vitro cytotoxicity and molecular docking studies

ABSTRACT A series of novel cyclopent[b]indole analogues that hold isoxazolo-, pyrido-templates were designed and synthesized in good yields. The in vitro cytotoxicity was concerned for all the newly synthesized compounds by MTT assay against HeLa (cervix adeno carcinoma) and MCF-7 (breast cancer). These synthesized compounds were further compared with the standard drug ellipticine, 5-fluorouracil, cisplatin, and methotrexate. The synthesized heteroannulated cyclopent[b]indole compounds were found to show better cytotoxic activity against HeLa and MCF-7 with primary structure activity relationship studies. To identify with the nature of interactions of these molecules, we performed molecular docking studies using the protein kinase CK2 inhibitors. The docking results afforded some valuable information for the future design of more potent inhibitors. GRAPHICAL ABSTRACT

Individual and simultaneous electrochemical determination of metanil yellow and curcumin on carbon quantum dots based glassy carbon electrode

Adulteration of medicinally valuable curcumin (CU) with harmful chemicals as metanil yellow (MY) in recent years have demanded for quick detection techniques of the adulterants. The voltammetric behavior of CU and MY on bare glassy carbon electrode (BGCE) and carbon quantum dots modified glassy carbon electrode (CQDs/GCE) was studied by both cyclic voltammetry (CV) and differential pulse voltammetry (DPV) in phosphate buffer solution of pH 5.4. The MY responded to the CQDs/GCE with two anodic peaks at -0.004 V and 0.136 V and two cathodic peaks at -0.112 and -0.048 V. Under similar conditions CU exhibited two anodic peaks at 0.28 V and 0.55 V and one cathodic peak at 0.25 V. The overlapped voltammogram obtained for CU and MY on BGCE was well separated on the CQDs/GCE. The interference studies revealed that the compounds, demethoxycurcumin and bisdemethoxycurcumin, which are commonly associated with CU, did not interfere with the detection of MY. Real sample was analyzed with fabricated electrode and the recovery values >98% were obtained.

Synthesis, characterization, microstructure determination, thermal studies of poly (N-vinyl pyrrolidone-maleic anhydride-methyl methacrylate)

ABSTRACT Synthesis of Poly (N-vinyl pyrrolidone-maleic anhydride-methyl methacrylate) terpolymer using azobisisobutyronitrile in 1,4-dioxan is described. The polymers with different composition were synthesized and characterized using FTIR, 1HNMR, 13NMR, TGA and DSC techniques. The monomer-monomer interactions were studied using Finemann-Ross and Kelen-Tudos methods by calculating the reactivity ratio. The reactivity ratio r1 and r2 with respect to methyl methacrylate and N-vinylpyrrolidone-maleic anhydride complexomer are found to be 6.05 and 0.06 respectively. The study showed methyl methacrylate have higher reactivity than N-vinyl-2-pyrrolidone-maleic anhydride complex, i.e., the terpolymer contained methyl methacrylate in higher ratio. The thermal stability of poly (N-vinyl pyrrolidone-maleic anhydride-methyl methacrylate) was 165°C and the glass transition temperature was found to increase from 153°C to 182°C as MMA concentration increase. The studies indicate the activity of the polymer to inhibit bacterial growth is very poor.

Curcumin and its synthetic analogue dimethoxycurcumin differentially modulates antioxidant status of normal human peripheral blood mononuclear cells

Abstract Curcumin is a polyphenol derived from the herb Curcuma longa, which has been extensively studied in terms of its antitumour, antioxidant, and chemopreventive activity as well as various other effects. In the present work we compared curcumin with its synthetic analogue dimethoxycurcumin (dimc) in terms of its antioxidant enzyme-modulating effects in human peripheral blood mononuclear cells (PBMC). We found that these compounds modulate antioxidant enzymes differentially. Both curcumin and dimethoxycurcumin effected a decrease in lipid peroxidation status in PBMC, however, curcumin had better activity in this regard. An increase in the activity of catalase was seen in the case of curcumin-treated PBMC, whereas dimc increased catalase activity significantly to almost twofold level. Real time-polymerase chain reaction (RT-PCR) analysis revealed significant up-regulation of catalase at mRNA level post treatment with curcumin as well as dimc, however, dimc had better activity in this regard. Glutathione reductase (GR) activity and reduced glutathione levels increased in the case of peripheral blood mononuclear cells (PBMC) treated with curcumin, however, the trend was reversed with dimethoxycurcumin where, both glutathione reductase activity and reduced glutathione levels were significantly reduced. RT-PCR analysis of glutathione reductase mRNA levels showed decrease in mRNA levels post treatment with dimethoxycurcumin (dimc) further corroborating GR enzyme assay results, however, we could not obtain significant result post curcumin treatment. NFkB reporter assay and western blot analysis of nuclear as well as cytosolic fractions of NFkB revealed that curcumin inhibits NFkB activation whereas inhibition was much less with dimc. It has been reported that curcumin and dimc exerts differential cytotoxicity in normal and tumour cells and the reason for this had been attributed to the differential uptake of these compounds by normal cells and tumour cells. Based on our results we propose that differential modulation of antioxidant enzymes via NFkB pathway could be the reason behind differential cytotoxicity of dimc as well as curcumin in normal cells and tumour cells in addition to differential uptake of these compounds as reported previously.

2-Deoxy Glucose Reduces Angiogenic and Metastatic Potency of Tumor Cells

Tumor growth and metastasis has become a major cause of mortality and morbidity worldwide [1,2]. Several strategies to stop or ratherslow down the growth of tumor havebeen under rigorous investigation for past few decades [3]. Blocking angiogenic process (The process of formation of new blood vessels from preexisting ones) has been one of them [4]. Angiogenesis is critical in the process of tumor growth and metastasis owing to the fact that (1) tumors are not viable beyond 2 mm diameter and induction on neo vessel formation is waranted for further tumor survival [5]. Further (2) the neo vessels, so formed are leaky in nature, which significantly contribute to the escape of tumor cells into the circulation leading to metastasis [6]. Considering the importance of metabolic shift in tumor cells from aerobic respiration to aerobic glycolysis, several studies have been undertaken to check if blocking glycolysis can contribute to retarded tumor growth [7]. Of the many reports available few of them have proved the cytotoxic nature of several glycolytic inhibitors [7]. The major glycolytics inhibitors reported to be anti tumor in nature include a) 3-Bromo pyruvate which has been suggested to act by inhibiting hexokinase [8,9]. b) Lonidamine,which act by inhibiting mitochondrially bound hexokinase [10] and 2 deoxy glucose (2-DG).