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Tuberculosis, one of the leading cause of death from infectious diseases, is caused by Mycobacterium tuberculosis. The genome of M. tuberculosis has been sequenced and nearly 40% of the whole genome sequence was categorized as hypothetical. Rv0774c was annotated as membrane exported hypothetical protein in TB database. In silico analysis revealed that Rv0774c is a paralog of PE-PGRS multi gene family with 100 aa N-terminal domain similar to PE domain of PE-PGRS proteins. Its C-terminal domain is quite different from PGRS domain, having characteristic lipase signature GXSXG & HG and catalytic residues predicted for lipolytic activity. Therefore, DNA coding for Rv0774c (303 aa), its N-terminal (1-100 aa) and C- terminal domain (100-303 aa) were separately cloned from M. tuberculosis and were over expressed in E. coli. Rv0774c gene and its C-terminal lipolytic domain preferably hydrolyzed short chain esters. Though no enzyme activity was observed in N-terminus PE like domain, it was demonstrated to enhance the thermostability of full length Rv0774c. Tetrahydrolipstatin inhibited the enzyme activity and predicted catalytic residues (Ser-185, Asp-255 and His-281) were confirmed by site directed mutagenesis. Rv0774c was secreted out in culture media by M. tuberculosis and was up-regulated in iron limiting conditions. Treatment of THP-1 cells with rRv0774c resulted in a decline in the LPS induced production of NO and expression of iNOS. rRv0774c treated THP-1 cells also showed an enhanced expression of IL-10 and TLR2. On contrary, it suppressed the LPS induced production of IL-12, chemokines MCP-1 and IL-8. Rv0774c inhibited the LPS induced phosphorylation of p38. These observations suggested that Rv0774c could modulate the pro-inflammatory immune response to support intracellular survival of the mycobacterium., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Recently, we reported that treadmill exercise renders survival benefits in a murine tumor model of a transplantable lymphoma of spontaneous origin, designated as Dalton's lymphoma (DL), owing to an augmented apoptosis of tumor cells. However, the underlying the mechanisms of the same remained unclear with respect to the role alterations if any in the components of tumor microenvironment following physical exercise. Therefore, in the present we investigated the role of oxygen, pH, lactate and cytokines of tumor micro-environment associated with physical exercise-dependent alteration in the growth properties of tumor cells to explore their contribution in modulation of tumor. Physical exercise of tumor-bearing host resulted in a decreased angiogenesis in the vicinity of tumor. This was also found to be accompanied by a decrease in erythrocyte count and increase in the level of oxygen while the content of lactate showed a concomitant decrease in the tumor microenvironment along with normalization of pH. Moreover, physical exercise also resulted in an inhibition of VEGF expression which was correlated to an altered expression of cytokines: IL-1, IL-4, IL-10, TGF-beta and IFN-gamma. Ascitic fluid of tumor-bearing host subjected to physical exercise showed an increase in nitric oxide content along with an increase in the expression of inducible nitric oxide synthase (iNOS). The study discusses the possible role of the aforesaid alterations in constituents of tumor microenvironment of tumor-bearing host following physical exercise in retardation of tumor growth.

Objective(s): In the present study, the mechanism of paraneoplastic neurodegeneration associated with progressive in vivo growth of a T-cell lymphoma of spontaneous origin has been investigated., Methods: Histologically, the brain was investigated by hematoxylin-eosin staining of brain sections. Western blotting was performed to detect the expression of cytokines and other proteins. Macrophage-derived interleukin-1 (IL-1) and tumor necrosis factor (TNF) was estimated by immunoassays. Induction of apoptosis in brain and tumor cells was determined by percent specific DNA fragmentation., Results: Tumor growth was associated with the development of multiple lesions in various regions of the brain along with alterations in the structure and alignment of Purkinje cells, and an increase in the water content in the brain. Brain extract and serum of tumor-bearing mice showed higher levels of proinflammatory cytokines. Induction of apoptosis is suggested to be the cause underlying the loss of cellularity of tumor-bearing hosts in the brain owing to an augmentation in the induction of the caspase-dependent pathway of programmed cell death. Further, the study presents investigations to show the role of nitric oxide and proinflammatory cytokines IL-1, TNF, interferon-gamma and alkaline phosphatase in the manifestation of paraneoplastic neurodegeneration., Conclusions: Growth of a T-cell lymphoma is associated with the manifestation of neurodegeneration caused by soluble proinflammatory factors of tumor and/or host origin.

The present investigation was carried out to investigate gender dimorphism with respect to the progressive in vivo growth a of T cell lymphoma in a murine system. It was observed that in vivo progression of a transplantable T cell lymphoma of spontaneous origin, designated as Dalton's lymphoma (DL), shows differential growth kinetics in male and female mice. DL growth was observed to be faster in female mice as compared to male mice. We demonstrate the involvement of gender specific gonadal hormones, tumor-associated macrophage (TAM)-derived IL-1 and differential level of IL-4, IL-10 and TNF-alpha in the ascitic fluid of DL-bearing male and female mice. The study has a clinical significance, as the results will help in understanding the mechanism of gender dimorphism with respect to the progression of T cell tumors and in the designing of immunotherapy for such tumors.

Abstract: The present investigation was carried out to investigate if soluble mediators present in tumour microenvironment and systemic circulation of a tumour-bearing host can regulate growth properties and response of the cells of a T cell lymphoma to chemotherapeutic drug: cisplatin, depending on the stage of tumour progression. In order to investigate this, tumour cells of a murine T cell lymphoma, designated as Dalton’s lymphoma (DL), were incubated in vitro for 48h in the presence of ascitic fluid and serum obtained from cisplatin treated or untreated tumour hosts at early or late tumour-bearing stages and cell survival was estimated. It was observed that tumour serum and ascitic fluid showed a tumour stage-dependent differential ability to regulate tumour cell survival and susceptibility of the tumour cells to the cytotoxic action of cisplatin. A tumour stage-dependent qualitative and quantitative difference in the profile of cell survival regulating cytokines: IL-1, IL-2, IFN-γ, TNF-α, VEGF and TGF-β in the ascitic fluid and serum of the tumour-bearing host was observed to be associated with a tumour stage-dependent differential regulation of survival of tumour cells by modulation in the expression of growth regulating proteins: IL-2R, p53, CAD, Hsp70 and Bcl-2. Further the result also showed that production of IL-1, TNF-α, and NO by macrophages could be implicated in the differential action of tumour sera on the altered survival responses of tumour cells depending on the stage of tumour growth. Possible mechanisms involved in the tumour stage-dependent differential survival response of tumour cells and evolution of drug resistance are discussed. The finding of this investigation will have clinical implications in designing of therapeutic strategies for T cell lymphoma based on manipulation of tumour growth regulatory mediators present in the tumour microenvironment. [Copyright &y& Elsevier]

Problem We previously demonstrated the existence of gender dimorphism in a murine tumor model with respect to the growth of a spontaneous T-cell lymphoma designated as Dalton’s lymphoma and several aspects of host-tumor interaction. We also demonstrated the involvement of macrophages in manifestation of gender-dependent differential tumor growth [ J Reprod Immunol 2005; 65:17, Cancer Invest 2006; 24:1, J Biomed Sci 2007 (in press), J Reprod Immunol 2007; 74:90 ]. Although monocytes/macrophages of tumor-bearing hosts have been used to differentiate into macrophage-derived dendritic cells for various applications in the immunotherapy of cancer, it remains unclear if macrophages show a gender-dependent differential response to the signals of granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for differentiation to cells with dendritic cell morphology (MO-DC) and if these MO-DC have a gender-dependent differential therapeutic efficacy in inhibiting tumor growth. Method of study Peritoneal macrophage obtained from male and female mice were incubated in vitro for a period of 7 days in a medium containing GM-CSF (800 IU/mL) and IL-4 (500 IU/mL) followed by incubation for further 24 hr in medium alone or containing lipopolysaccharide (LPS; 10 ng/mL) to differentiate into cells with DC morphology (MO-DC). The MO-DC thus obtained were used to check a variety of phenotypic and functional parameters related to their gender-dependent anti-tumor activity. Results The MO-DC obtained from male mice showed a better response to GM-CSF and IL-4 treatment and activation by LPS for differentiating into cells with DC phenotype compared with that of female mice. MO-DC of male mice showed a comparatively higher tumoricidal activity, expression of DC markers [chemokine receptor-5 (CCR-5), ICAM-1 (CD-54) and CD-80], MLR, pinocytosis and production of NO, IFN-γ and TNF-α. Adoptive transfer of MO-DC obtained from male mice to tumor-bearing mice resulted in a longer prolongation of survival duration and a better retardation of tumor growth compared with the MO-DC obtained from female mice. Conclusion To the best of our knowledge, this is the first report of its kind to demonstrate the existence of gender dimorphism in the antitumor and other accessory functions of macrophages differentiated in vitro into cells with DC morphology. These observations may have long lasting clinical significance in developing gender-specific protocols regarding the use of MO-DC in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Little information is available regarding the existence of gender dimorphism of tumor growth for most types of tumors. In a previous report we have demonstrated the existence of gender dimorphism in the growth of a murine T cell lymphoma, designated as Dalton''s lymphoma (DL); moreover, tumor-associated macrophages (TAM) were found to play a central role in the manifestation of gender dimorphism observed in the growth of this T cell lymphoma. In view of these observations, the present investigation was undertaken to study if gender dimorphism in the growth of a T cell tumor also could be associated with a gender-dependent differential myelopoiesis of bone marrow cells. We have demonstrated the existence of a gender dimorphism in the proliferation, apoptosis and myeloid differentiation of bone marrow cells obtained from male and female tumor-bearing hosts. Androgen and estrogen were found to alter directly the growth properties of bone marrow cells, as also determined by the use of receptor antagonists of these hormones, flutamide and tamoxifen. Bone marrow cells of male and female tumor-bearing hosts also showed a differential expression of the cell cycle and apoptosis regulatory protein p53 and macrophage-colony stimulating factor (M-CSF) genes. Bone marrow cells of male tumor-bearing hosts showed a predominant differentiation in the macrophage lineage whereas those of female tumor-bearing mice were in the granulocyte lineage. Bone marrow-derived macrophages (BMDM) from male and female tumor-bearing mice also showed the existence of gender dimorphism with respect to their differentiation and activation. These observations are of clinical significance with respect to understanding of the host–tumor relationship at the level of gender dimorphism of myelopoiesis. [Copyright &y& Elsevier]

The present study was conducted to investigate the effect of prolactin (PRL) on the progressive growth of a T cell lymphoma. Using a murine model of a transplantable T cell lymphoma, designated as the Dalton's lymphoma (DL) it is shown that in vivo administration of PRL to tumor bearing mice reduces the survival duration of tumor-bearing host due to an augmentation of tumor growth. In vitro studies demonstrated that PRL directly stimulates the proliferation of DL cells in a dose and time dependent manner. PRL-treated DL cells showed an increase in cell size along with a decrease in cells with apoptotic morphology. Evidence also is presented to show the involvement of tumor and macrophage-derived cytokines: IL-1, IL-2, TGF-β, and M-CSF in PRL-dependent augmentation of tumor growth. Moreover, PRL treatment was found to inhibit Caspase-activated DNase (CAD) expression in DL cells indicating that PRL acts through modulation of caspase dependent pathway of apoptosis. The study is of novel significance as it demonstrates for the first time that PRL can promote growth of a T cell lymphoma involving host and tumor-derived tumor growth promoting cytokines. [ABSTRACT FROM AUTHOR]

Abstract: Pyruvate dehydrogenase kinase (PDK) inhibits pyruvate dehydrogenase (PDH) activity and thus promotes energetic switch from mitochondrial glucose oxidation to cytoplasmic glycolysis in cancerous cells (a phenomenon known as the ‘Warburg effect’) for their energy need, which facilitates the cancer progression by resisting induction of apoptosis and promoting tumor metastasis. Thus, in the present investigation, we explored the molecular mechanisms of the tumoricidal action of dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, on cells of a murine T cell lymphoma, designated as Dalton’s lymphoma (DL). In vitro treatment of tumor cells with DCA inhibited their survival accompanied by a modulation of the biophysical composition of tumor-conditioned medium with respect to pH, glucose and lactate. DCA treatment also altered expression of HIF1-α and pH regulators: VATPase and MCT1 and production of cytokines: IL-10, IL-6 and IFN-γ. Moreover, we also observed an alteration in the expression of other apoptosis and cell survival regulatory molecules: PUMA, GLUT1, Bcl2, p53, CAD, caspase-3 and HSP70. The study discusses the role of novel molecular mechanisms underlying DCA-dependent inhibition of tumor cell survival. This study shows for the first time that DCA-dependent alteration of tumor cell survival involves altered pH homeostasis and glucose metabolism. Thus, these findings will provide a new insight for therapeutic applications of DCA as a novel antineoplastic agent against T cell lymphoma. [Copyright &y& Elsevier]

Abstract: The present investigation was undertaken to study if curcumin, which is recognized for its potential as an antineoplastic and immunopotentiating agent, can also influence the process of myelopoiesis in a tumor-bearing host. Administration of curcumin to tumor-bearing host augmented count of bone marrow cell (BMC) accompanied by an up-regulated BMC survival and a declined induction of apoptosis. Curcumin administration modulated expression of cell survival regulatory molecules: Bcl2, p53, caspase-activated DNase (CAD) and p53-upregulated modulator of apoptosis (PUMA) along with enhanced expression of genes of receptors for M-CSF and GM-CSF in BMC. The BMC harvested from curcumin-administered hosts showed an up-regulated colony forming ability with predominant differentiation into bone marrow-derived macrophages (BMDM), responsive for activation to tumoricidal state. The number of F4/80 positive bone marrow resident macrophages (BMM), showing an augmented expression of M-CSF, was also augmented in the bone marrow of curcumin-administered host. In vitro reconstitution experiments indicated that only BMM of curcumin-administered hosts, but not in vitro curcumin-exposed BMM, augmented BMC survival. It suggests that curcumin-dependent modulation of BMM is of indirect nature. Such prosurvival action of curcumin is associated with altered TH1/TH2 cytokine balance in serum. Augmented level of serum-borne IFN-γ was found to mediate modulation of BMM to produce enhanced amount of monokines (IL-1, IL-6, TNF-α), which are suggested to augment the BMC survival. Taken together the present investigation indicates that curcumin can potentiate myelopoiesis in a tumor-bearing host, which may have implications in its therapeutic utility. [Copyright &y& Elsevier]

Abstract: Aspirin is an anti-inflammatory drug demonstrated to possess a tremendous anticancer potential. As progression of some tumors is influenced by sex hormones, we investigated if the antineoplastic action of aspirin shows gender dependence. Using a murine model of T-cell lymphoma, the present investigation was undertaken to study if the antitumor actions of aspirin against lymphoma cells display gender dimorphism. The findings of the present investigation indicate that aspirin administration to male and female tumor-bearing hosts resulted in gender dependent differential tumor growth retardation. Such gender dichotomy of aspirin''s antitumor action was associated with a differential impact on cell cycle progression and expression of cell survival regulatory molecules. Aspirin administration was also found to modulate crucial parameters of tumor microenvironment, including contents of glucose, lactate and cell growth regulatory cytokines, in a gender specific manner. Aspirin was found to reverse estrogen-dependent augmentation of tumor cell survival in vitro. Taken together the results of the present study suggest that the antineoplastic action of aspirin is gender-dependent and should be considered in designing of gender-specific therapeutic applications of aspirin. [Copyright &y& Elsevier]