Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis

Earlier we have established a carbazole alkaloid (mahanine) isolated from an Indian edible medicinal plant as an anticancer agent with minimal effect on normal cells. Here we report for the first time that mahanine-treated drug resistant and sensitive virulent Leishmania donovani promastigotes underwent apoptosis through phosphatidylserine externalization, DNA fragmentation and cell cycle arrest. An early induction of reactive oxygen species (ROS) suggests that the mahanine-induced apoptosis was mediated by oxidative stress. Additionally, mahanine-treated Leishmania-infected macrophages exhibited anti-amastigote activity by nitric oxide (NO)/ROS generation along with suppression of uncoupling protein 2 and Th1-biased cytokines response through modulating STAT pathway. Moreover, we have demonstrated the interaction of a few antioxidant enzymes present in parasite with mahanine through molecular modeling. Reduced genetic and protein level expression of one such enzyme namely ascorbate peroxidase was also observed in mahanine-treated promastigotes. Furthermore, oral administration of mahanine in acute murine model exhibited almost complete reduction of parasite burden, upregulation of NO/iNOS/ROS/IL-12 and T cell proliferation. Taken together, we have established a new function of mahanine as a potent antileishmanial molecule, capable of inducing ROS and exploit antioxidant enzymes in parasite along with modulation of host’s immune response which could be developed as an inexpensive and nontoxic therapeutics either alone or in combination

Clone-specific expression, transcriptional regulation, and action of interleukin-6 in human colon carcinoma cells

<p>Abstract</p> <p>Background</p> <p>Many cancer cells produce interleukin-6 (IL-6), a cytokine that plays a role in growth stimulation, metastasis, and angiogenesis of secondary tumours in a variety of malignancies, including colorectal cancer. Effectiveness of IL-6 in this respect may depend on the quantity of basal and inducible IL-6 expressed as the tumour progresses through stages of malignancy. We therefore have evaluated the effect of <it>IL-6 </it>modulators, i.e. IL-1β, prostaglandin E₂, 17β-estradiol, and 1,25-dihydroxyvitamin D₃, on expression and synthesis of the cytokine at different stages of tumour progression.</p> <p>Methods</p> <p>We utilized cultures of the human colon carcinoma cell clones Caco-2/AQ, COGA-1A and COGA-13, all of which expressed differentiation and proliferation markers typical of distinct stages of tumour progression. IL-6 mRNA and protein levels were assayed by RT-PCR and ELISA, respectively. DNA sequencing was utilized to detect polymorphisms in the <it>IL-6 </it>gene promoter.</p> <p>Results</p> <p><it>IL-6 </it>mRNA and protein concentrations were low in well and moderately differentiated Caco-2/AQ and COGA-1A cells, but were high in poorly differentiated COGA-13 cells. Addition of IL-1β (5 ng/ml) to a COGA-13 culture raised IL-6 production approximately thousandfold via a prostaglandin-independent mechanism. Addition of 17β-estradiol (10^-7M) reduced basal IL-6 production by one-third, but IL-1β-inducible IL-6 was unaffected. Search for polymorphisms in the <it>IL-6 </it>promoter revealed the presence of a single haplotype, i.e., -597A/-572G/-174C, in COGA-13 cells, which is associated with a high degree of transcriptional activity of the <it>IL-6 </it>gene. IL-6 blocked differentiation only in Caco-2/AQ cells and stimulated mitosis through up-regulation of c-<it>myc </it>proto-oncogene expression. These effects were inhibited by 10^-8M 1,25-dihydroxyvitamin D₃.</p> <p>Conclusion</p> <p>In human colon carcinoma cells derived from well and moderately differentiated tumours, IL-6 expression is low and only marginally affected, if at all, by PGE₂, 1,25-dihydroxyvitamin D₃, and 17β-estradiol. However, IL-6 is highly abundant in undifferentiated tumour cells and is effectively stimulated by IL-1β. In case of overexpression of an <it>IL-6 </it>gene variant with extreme sensitivity to IL-1β, massive release of the cytokine from undifferentiated tumour cells may accelerate progression towards malignancy by paracrine action on more differentiated tumour cells with a still functioning proliferative IL-6 signalling pathway.</p

The Application of NCaRBS to the Trendelenburg Test and Total Hip Arthroplasty Outcome

This paper compares the frontal plane hip func- tion of subject’s known to have had hip arthroplasty via either the lateral (LA) or posterior (PA) surgical approaches and a group of subjects associated with no pathology (NP). This is investigated through the Trendelenburg test using 3D motion analysis and classification. Here, a recent develop- ment on the Classification and Ranking Belief Simplex (CaRBS) technique, able to undertake n-state classification, so termed NCaRBS is employed. The relationship between post-operative hip function measured during a Trendelen- burg Test using three patient characteristics (pelvic obliquity, frontal plane hip moment and frontal plane hip power) of LA, PA and NP subjects are modelled together. Using these characteristics, the classification accuracy was 93.75% for NP, 57.14% for LA, 38.46% for PA. There was a clear distinction between NP and post-surgical function. 3/6 LA subjects and 6/8 PA subjects were misclassified as having NP function, implying that greater function is restored following the PA to surgery. NCaRBS achieved a higher accuracy (65.116%) than through a linear discriminant analysis (48.837%). A Neural Network with two-nodes achieved the same accuracy (65.116%) and as expected was further improved with three-nodes (69.767%). A valuable benefit to the employment of the NCaRBS technique is the graphical exposition of the contribution of patient characteristics to the classification analysis

25th Annual Computational Neuroscience Meeting: CNS-2016

Abstracts of the 25th Annual Computational Neuroscience Meeting: CNS-2016 Seogwipo City, Jeju-do, South Korea. 2–7 July 201

Preoperative Rehabilitation in Lung Cancer Patients: Yoga Approach

: Lung cancer is one of the leading causes of cancer death worldwide. Surgical removal remains the best option for most tumors of this type. Reduction of cigarette consumption in patients with lung cancer candidates for the surgery could limit the impact of tobacco on postsurgical outcomes. Breathing exercises appear to help combat cigarette cravings. Yoga exercise benefits have been studied in lung cancer survivors, rather than in the preoperative setting. In this study, we have recruited 32 active smokers affected by lung cancer and being candidates for pulmonary surgery. The patients were randomly assigned to two groups: one treated by standard breathing and the other treated by yoga breathing (YB). The groups were evaluated at times T0 (baseline) and T1 (after 7 days of treatment) to compare the effects of the two breathing treatments on pulmonary performance in a presurgery setting. Pulmonary and cardiocirculatory functions have been tested using a self-calibrating computerized spirometer and a portable pulse oximetry device. The findings demonstrate appreciable short-term improvement in lung function assessed by spirometry. We conclude that yoga breathing can be a beneficial preoperative support for thoracic surgery