Urmi Chatterji

Abstract: Arsenic, a major pollutant of water as well as soil, is a known endocrine disruptor, and shows adverse effects on the female reproductive physiology. However, the exact molecular events leading to reproductive dysfunctions as a result of arsenic exposure are yet to be ascertained. This report evaluates the effect and mode of action of chronic oral arsenic exposure on the uterine physiology of mature female albino rats. The effect of chronic oral exposure to arsenic at the dose of 4 microg/ml for 28 days was evaluated on adult female albino rats. Hematoxylin-eosin double staining method evaluated the changes in the histological architecture of the uterus. Circulating levels of gonadotropins and estradiol were assayed by enzyme-linked immunosorbent assay. Expression of the estrogen receptor and estrogen-induced genes was studied at the mRNA level by RT-PCR and at the protein level by immunohistochemistry and western blot analysis. Sodium arsenite treatment decreased circulating levels of estradiol in a dose and time-dependent manner, along with decrease in the levels of both LH and FSH. Histological evaluation revealed degeneration of luminal epithelial cells and endometrial glands in response to arsenic treatment, along with reduction in thickness of the longitudinal muscle layer. Concomitantly, downregulation of estrogen receptor (ER alpha), the estrogen-responsive gene - vascular endothelial growth factor (VEGF), and G1 cell cycle proteins, cyclin D1 and CDK4, was also observed. Together, the results indicate that arsenic disrupted the circulating levels of gonadotropins and estradiol, led to degeneration of luminal epithelial, stromal and myometrial cells of the rat uterus and downregulated the downstream components of the estrogen signaling pathway. Since development and functional maintenance of the uterus is under the influence of estradiol, arsenic-induced structural degeneration may be attributed to the reduction in circulating estradiol levels. Downregulation of the estrogen receptor and estrogen-responsive genes in response to arsenic indicates a mechanism of suppression of female reproductive functions by an environmental toxicant that is contra-mechanistic to that of estrogen.

Abstract: Developing safe and effective nanocarriers for multitype of delivery system is advantageous for several kinds of successful biomedicinal therapy with the same carrier. In the present study, we have designed amino acid biomolecules derived hybrid block copolymers which can act as a promising vehicle for both drug delivery and gene transfer. Two representative natural chiral amino acid-containing (l-phenylalanine and l-alanine) vinyl monomers were polymerized via reversible addition–fragmentation chain transfer (RAFT) process in the presence of monomethoxy poly(ethylene glycol) based macro-chain transfer agents (mPEGn-CTA) for the synthesis of well-defined side-chain amino-acid-based amphiphilic block copolymers, monomethoxy poly(ethylene glycol)-b-poly(Boc-amino acid methacryloyloxyethyl ester) (mPEGn-b-P(Boc-AA-EMA)). The self-assembled micellar aggregation of these amphiphilic block copolymers were studied by fluorescence spectroscopy, atomic force microscopy (AFM) and scanning electron microscopy (SEM)....

Abstract: Methacrylate monomers having a chiral tryptophan moiety (L- and D-) in the side chain, Boc-tryptophan methacryloyloxyethyl ester (Boc-L/D-Trp-HEMA), have been polymerized by the reversible addition-fragmentation chain transfer (RAFT) process. The controlled nature of RAFT polymerization was evidenced by the well-defined molecular weight and low polydispersity index of the resulting homopolymers and further confirmed to have retained end-group functionality by using these polymers as macro-chain transfer agents (macro-CTAs) to prepare well-defined block copolymers with methyl methacrylate (MMA). The presence of chiral and fluorescent tryptophan moieties in the side-chain of homo- and block-copolymers rendered chiroptical and fluorescence behaviour in them, which was studied through polarimetric measurements and fluorescence spectroscopy, respectively. Successive Boc group deprotection from the polymers produced pH responsive and cationic primary amine moieties at the side chain, which were respectively confirmed by UV-visible spectroscopy and dynamic light scattering (DLS). The in vitro cytotoxicity study using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction (MTT) assay established the cellular viability of HeLa cells in the presence of the poly(Boc-L-Trp-HEMA) homopolymer. The excellent biocompatibility of these fluorescent pH responsive cationic polymers can make them suitable candidates for siRNA delivery.

Abstract: A general and facile strategy was developed to prepare biocompatible peptide side-chain polymeric materials via reversible addition–fragmentation chain transfer (RAFT) polymerization. Three new dipeptide based monomers, Boc-Phe-Phe-oxyethyl methacrylate (Boc-FF-EMA), Boc-Ile-Phe-oxyethyl methacrylate (Boc-IF-EMA) and Boc-Val-Phe-oxyethyl methacrylate (Boc-VF-EMA), were synthesized and subsequently polymerized by RAFT process to afford well-defined peptide side-chain polymers, P(Boc-dipep-EMA), with controlled molecular weight, narrow polydispersity and precise chain end functionality. Further, a monomethoxy poly(ethylene glycol) (mPEG) based macro-chain transfer agent was employed for RAFT polymerization of these monomers to prepare well defined amphiphilic block copolymers, mPEG-b-P(Boc-dipep-EMA). Subsequent deprotection of side-chain Boc groups produced pH responsive homo- and block copolymers with primary amine moieties at the side chains. The cationic surface charge of various polymeric architectures was studied using dynamic light scattering (DLS) measurements. Atomic force microscopy (AFM) was employed to investigate the self-assembly of block copolymers. The in vitro biocompatibility to HeLa cells was investigated with these polymers to confirm their minimum cytotoxicity. These polymers have great potential for the pH-sensitive delivery of small interfering RNA (siRNA) owing to their interesting phase transition behaviour and biocompatibility.

Abstract: 3,3'-Diindolylmethane (DIM), a natural autolytic product in plants of the Brassica genus, including broccoli, cauliflower, and Brussels sprouts, exhibits promising cancer protective activities, especially against mammary neoplasia in animal models. We observed previously that DIM induced a G(1) cell-cycle arrest and strong induction of cell-cycle inhibitor p21 expression and promoter activity in both estrogen-responsive and -independent breast cancer cell lines. We showed recently that DIM up-regulates the expression of interferon gamma (IFNgamma) in human MCF-7 breast cancer cells. This novel effect may contribute to the anticancer effects of DIM because IFNgamma plays an important role in preventing the development of primary and transplanted tumors. In this study, we observed that DIM activated the IFNgamma signaling pathway in human breast cancer cells. DIM activated the expression of the IFNgamma receptor (IFNGR1) and IFNgamma-responsive genes p56- and p69-oligoadenylate synthase (OAS). In cotreatments with IFNgamma, DIM produced an additive activation of endogenous p69-OAS and of an OAS-Luc reporter and a synergistic activation of a GAS-Luc reporter. DIM synergistically augmented the IFNgamma induced phosphorylation of signal transducer and activator of transcription factor 1, further evidence of DIM activation of the IFNgamma pathway. DIM and IFNgamma produced an additive inhibition of cell proliferation and a synergistic increase in levels of major histocompatibility complex class-1 (MHC-1) expression, accompanied by increased levels of mRNAs of MHC-1-associated proteins and transporters. These results reveal novel immune activating and potentiating activities of DIM in human tumor cells that may contribute to the established effectiveness of this dietary indole against various tumors types.

Abstract: In this paper recent developments in the estimation of frontier functions and the measurement of efficiency are surveyed, and the potential applicability of these methods in agricultural economics is discussed. Frontier production, cost and profit functions are discussed, along with the construction of technical, allocative, scale and overall efficiency measures relative to these estimated frontiers. The two primary methods of frontier estimation, econometric and linear programming, are compared. A survey of recent applications of frontier methods in agriculture is also provided. (This abstract was borrowed from another version of this item.)

Abstract: Indole-3-carbinol (I3C) is produced by members of the family Cruciferae, and particularly members of the genus Brassica (e.g., cabbage, radishes, cauliflower, broccoli, Brussels sprouts, and daikon). Under acidic conditions, 13C is converted to a series of oligomeric products (among which 3,3'-diindolylmethane is a major component) thought to be responsible for its biological effects in vivo. In vitro, 13C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer, and leukemic cells; induce G1/S arrest of the cell cycle, and induce apoptosis. The cell cycle arrest involves downregulation of cyclin D1, cyclin E, cyclin- dependent kinase (CDK)2, CDK4, and CDK6 and upregulation of p15, p21, and p27. Apoptosis by I3C involves downregulation antiapoptotic gene products, including Bcl-2, Bcl-xL, survivin, inhibitor-of-apoptosis protein (IAP), X chromosome-linked IAP (XIAP), and Fas-associated death domain protein-like interleukin-1-beta-converting enzyme inhibitory protein (FLIP); upregulation of proapoptotic protein Bax; release of micochondrial cytochrome C; and activation of caspase-9 and caspase-3. This agent inhibits the activation of various transcription factors including nuclear factor-kappaB, SP1, estrogen receptor, androgen receptor and nuclear factor-E2-related factor 2 (Nrf2). This indole potentiates the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through induction of death receptors and synergises with chemotherapeutic agents through downregulation of P-glycoprotein (P-gp). In vivo, I3C was found to be a potent chemopreventive agent for hormonal-dependent cancers such as breast and cervical cancer. These effects are mediated through its ability to induce apoptosis, inhibit DNA-carcinogen adduct formation, and suppress free-radical production, stimulate 2-hydroxylation of estradiol, inhibit invasion and angiogenesis. Numerous studies have indicated that I3C also has a strong hepatoprotective activity against various carcinogens. Initial clinical trials in women have shown that I3C is a promising agent against breast and cervical cancers.

Abstract: The herb Artemisia annua has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. In 1971, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This compound, called qinghaosu (QHS, artemisinin), is a sesquiterpene lactone that bears a peroxide grouping and, unlike most other antimalarials, lacks a nitrogen-containing heterocyclic ring system. The compound has been used successfully in several thousand malaria patients in China, including those with both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate, appear to be more potent than QHS itself. Sodium artesunate acts rapidly in restoring to consciousness comatose patients with cerebral malaria. Thus QHS and its derivatives offer promise as a totally new class of antimalarials.

Abstract: In recent decades many advances have occurred in the understanding of the role of cytokines in breast cancer. New signalling pathways of interleukin (IL)-1 family, IL-6, IL-11, IL-18, interferons (IFNs) and interferon regulatory factors 1 (IRF-1) and 2 (IRF-2) have been found within tumour microenvironments and in metastatic sites. Some cytokines (IL-1, IL-6, IL-11, TGFbeta) stimulate while others (IL-12, IL-18, IFNs) inhibit breast cancer proliferation and/or invasion. Similarly, high circulating levels of some cytokines seem to be favourable (soluble IL-2R) while others are unfavourable (IL-1beta, IL-6, IL-8, IL-10, IL-18, gp130) prognostic indicators. So far IL-2, IFNalpha, IFNbeta and occasionally IFNgamma, IL-6, IL-12 have been the cytokines used for anti tumour treatment of advanced breast cancer either to induce or increase hormone sensitivity and/or to stimulate cellular immunity. Disappointing results occurred in most trials; however, two long-term pilot studies suggest that IL-2 and IFNbeta, when used appropriately can have a positive effect on clinical benefit and overall survival of patients with minimal residual disease after chemotherapy or with disseminated disease controlled by conventional endocrine therapy.

Abstract: Artemisia annua L. is used throughout Asia and Africa as tea and press juice to treat malaria and related symptomes (fever, chills). Its active ingredient, artemisinin (ARS), has been developed as antimalarial drug and is used worldwide. Interestingly, the bioactivity is not restricted to malaria treatment. We and others found that ARS-type drugs also reveal anticancer in vitro and in vivo. In this review, we give a systematic overview of the literature published over the past two decades until the end of 2016. Like other natural products, ARS acts in a multi-specific manner against tumors. The cellular response of ARS and its derivatives (dihydroartemisinin, artesunate, artemether, arteether) towards cancer cells include oxidative stress response by reactive oxygen species and nitric oxide, DNA damage and repair (base excision repair, homologous recombination, non-homologous end-joining), various cell death modes (apoptosis, autophagy, ferroptosis, necrosis, necroptosis, oncosis), inhibition of angiogenesis and tumor-related signal transduction pathways (e.g. Wnt/β-catenin pathway, AMPK pathway, metastatic pathways, and others) and signal transducers (NF-κB, MYC/MAX, AP-1, CREBP, mTOR etc). ARS-type drugs are at the stairways to the clinics. Several published case reports and pilot phase I/II trials indicate clinical anticancer activity of these compounds. Because of unexpected cases of hepatotoxicity, combinations of ARS-type drugs with complementary and alternative medicines are not recommended, until controlled clinical trials will prove the safety of non-approved combination treatments.