Depletion of intrinsic expression of Interleukin-8 in prostate cancer cells causes cell cycle arrest, spontaneous apoptosis and increases the efficacy of chemotherapeutic drugs

Abstract Background The progression of all cancers is characterized by increased-cell proliferation and decreased-apoptosis. The androgen-independent prostate cancer (AIPC) is the terminal stage of the disease. Many chemokines and cytokines are suspects to cause this increased tumor cell survival that ultimately leads to resistance to therapy and demise of the host. The AIPC cells, but not androgen-responsive cells, constitutively express abundant amount of the pro-inflammatory chemokine, Interleukin-8 (IL-8). The mechanism of IL-8 mediated survival and therapeutic resistance in AIPC cells is unclear at present. The purpose of this report is to show the pervasive role of IL-8 in malignant progression of androgen-independent prostate cancer (AIPC) and to provide a potential new therapeutic avenue, using RNA interference. Results The functional consequence of IL-8 depletion in AIPC cells was investigated by RNA interference in two IL-8 secreting AIPC cell lines, PC-3 and DU145. The non-IL-8 secreting LNCaP and LAPC-4 cells served as controls. Cells were transfected with RISC-free siRNA (control) or validated-pool of IL-8 siRNA. Transfection with 50 nM IL-8 siRNA caused >95% depletion of IL-8 mRNA and >92% decrease in IL-8 protein. This reduction in IL-8 led to cell cycle arrest at G1/S boundary and decreases in cell cycle-regulated proteins: Cyclin D1 and Cyclin B1 (both decreased >50%) and inhibition of ERK1/2 activity by >50%. Further, the spontaneous apoptosis was increased by >43% in IL-8 depleted cells, evidenced by increases in caspase-9 activation and cleaved-PARP. IL-8 depletion caused significant decreases in anti-apoptotic proteins, BCL-2, BCL-xL due to decrease in both mRNA and post-translational stability, and increased levels of pro-apoptotic BAX and BAD proteins. More significantly, depletion of intracellular IL-8 increased the cytotoxic activity of multiple chemotherapeutic drugs. Specifically, the cytotoxicity of Docetaxel, Staurosporine and Rapamycin increased significantly (>40% at IC50 dose) in IL-8 depleted cells as compared to that in C-siRNA transfected cells. Conclusion These results show the pervasive role of IL-8 in promoting tumor cell survival, and resistance to cytotoxic drugs, regardless of the cytotoxic mechanism of antiproliferative drugs, and point to potential therapeutic significance of IL-8 depletion in men with AIPC.</p

ON CONFORMAL QUASI HEMI-SLANT SUBMERSIONS FROM LORENTZIAN PARA SASAKIAN MANIFOLDS ONTP RIEMANNIAN MANIFOLDS

In the present article, our purpose is to define and study conformal quasi hemi-slant submersions (cqhs submersions, in short) from Lorentzian para Sasakian manifolds onto Riemannian manifolds. Its geometric properties are also investigated. Lastly, we give a non-trivial example for this type of submersio

Transformative Role of Photovoltaics in Phasing Out Alternating Current Based Grid by Local DC Power Networks for Sustainable Global Economic Growth

For sustainable global economic growth, eradication of global energy poverty and addressing climate challenges, free fuel based solar and wind energy sources are the only viable solution for electricity generation. Due to inherent advantages, photovoltaics has emerged as the major source of electrical power. Local generation of direct current (DC) power by PV and the use of batteries for storing electrical power have the potential of transforming global electricity infrastructure to address the problems faced by alternating current (AC) based centralized power generation and long haul transmission and distribution

Analysis of Genetic Diversity in Twelve Cultivars of Pea Based on Morphological and Simple Sequence Repeat Markers

Pea(Pisum sativum L.)is the second most important legume crop worldwide after chickpea (Cicer arietinum L.) and valuable resources for their genetic improvement. This study aimed to analyze genetic diversity of pea cultivars through morphological and molecular markers. The present investigation was carried out with 12 pea cultivars using 28 simple sequence repeat markers. A total of 60 polymorphic bands with an average of 2.31 bands per primer were obtained. The polymorphic information content, diversity index and resolving power were ranged from 0.50 to 0.33, 0.61 to 0.86 and 0.44 to 1.0 with an average of 0.46, 0.73 and 0.76, respectively. The 12 pea cultivars were grouped into 3 clusters obtained from cluster analysis with a Jaccardd's similarity coefficient range of 0.47-0.78, indicating the sufficient genetic divergence among these cultivars of pea. The principal component analysis showed that first three principal components explained 86.97% of the total variation, suggesting the contribution of quantitative traits in genetic variability. The contribution of 32.59% for number of seeds per plant, stem circumference, number of pods per plant and number of seeds per pod in the PC1 leads to the conclusion that these traits contribute more to the total variation observed in the 12 pea cultivars and would make a good parental stock material. Overall, this SSR analysis complements morphological characters of initial selection of these pea germplasms for future breeding program

Ionic Liquid-Based Gel Polymer Electrolytes for Application in Rechargeable Lithium Batteries

Depleting fossil fuels has put pressing need for the search of alternative energy resources. Solar and wind energy resources are being considered one of the viable solutions. However, these intermittent sources require efficient energy storage systems in terms of rechargeable Li batteries. In Li batteries, electrolyte is one of the most important components to determine the performance, as it conducts the ions between the electrodes. In battery, mostly liquid electrolyte is used as it shows high ionic conductivity and electrode/electrolyte contact which help to reduce the internal resistance. But these are not electrochemically very stable and raised some major problems such as reactivity with electrode, dissolution of electrode ions, leakage, volatility, fast Li dendrite growth, etc. Therefore, in order to improve its electrochemical performance, selection of electrolyte is an important issue. In the present study, ionic liquid (IL)-based polymer electrolyte is used over liquid electrolyte in which IL acts as a plasticizer and improves ionic conductivity and amorphicity. These electrolytes have high thermal and electrochemical stability, therefore, can be used in high voltage Li battery. Also, their mechanical stability helps to suppress Li dendrites growth. Therefore, polymer electrolytes can open a new way in the progression of battery application

Study of prescribing pattern of drugs used in the treatment of bronchial asthma at tertiary care hospital of northern India

Background: Asthma is a chronic inflammatory disease requiring long term treatment. For an effective control of asthma symptoms background knowledge of the prescribing pattern of anti-asthmatic drugs is a must.Methods: A prospective, observational study was conducted in the Department of Respiratory Medicine OPD, King George's Medical University, Lucknow. 114 patients of asthma were recruited for the study. A case report form was filled from patient’s prescription containing the demographic details of the patients, presenting complaints, investigations and drugs prescribed along with their dose, duration, frequency, route of administration.Results: 114 patients’ prescriptions were assessed which showed average number of drugs per prescription - 3.22. 42.8% and 50% of the drugs were prescribed in accordance with World Health Organization model list of essential medicines and National list of essential medicines. Short acting β2 agonist (salbutamol), 61.4% was the most commonly and frequently prescribed single anti asthmatic drug. Combination of inhaled corticosteroid and long acting β2 agonist, 86.8% was the most commonly prescribed fixed dose combination anti asthmatic drug. Inhalational route (75%) was the most preferred one over oral route (25%).Conclusions: Asthma being a chronic disease requires prolonged treatment which imposes economic burden on the patients. Judicious prescription of drugs not only improves the patient clinically but also removes the unnecessary burden. Data obtained from these studies can be used as a guide to make future decisions regarding standard prescription

Calcineurin signaling and membrane lipid homeostasis regulates iron mediated multidrug resistance mechanisms in Candida albicans

We previously demonstrated that iron deprivation enhances drug susceptibility of Candida albicans by increasing membrane fluidity which correlated with the lower expression of ERG11 transcript and ergosterol levels. The iron restriction dependent membrane perturbations led to an increase in passive diffusion and drug susceptibility. The mechanisms underlying iron homeostasis and multidrug resistance (MDR), however, are not yet resolved. To evaluate the potential mechanisms, we used whole genome transcriptome and electrospray ionization tandem mass spectrometry (ESI-MS/MS) based lipidome analyses of iron deprived Candida cells to examine the new cellular circuitry of the MDR of this pathogen. Our transcriptome data revealed a link between calcineurin signaling and iron homeostasis. Among the several categories of iron deprivation responsive genes, the down regulation of calcineurin signaling genes including HSP90, CMP1 and CRZ1 was noteworthy. Interestingly, iron deprived Candida cells as well as iron acquisition defective mutants phenocopied molecular chaperone HSP90 and calcineurin mutants and thus were sensitive to alkaline pH, salinity and membrane perturbations. In contrast, sensitivity to above stresses did not change in iron deprived DSY2146 strain with a hyperactive allele of calcineurin. Although, iron deprivation phenocopied compromised HSP90 and calcineurin, it was independent of protein kinase C signaling cascade. Notably, the phenotypes associated with iron deprivation in genetically impaired calcineurin and HSP90 could be reversed with iron supplementation. The observed down regulation of ergosterol (ERG1, ERG2, ERG11 and ERG25) and sphingolipid biosynthesis (AUR1 and SCS7) genes followed by lipidome analysis confirmed that iron deprivation not only disrupted ergosterol biosynthesis, but it also affected sphingolipid homeostasis in Candida cells. These lipid compositional changes suggested extensive remodeling of the membranes in iron deprived Candida cells. Taken together, our data provide the first novel insight into the intricate relationship between cellular iron, calcineurin signaling, membrane lipid homeostasis and drug susceptibility of Candida cells

Therapeutic effect of hydroethanolic extract of Trianthema portulacastrum L. against N-Nitroso-N-Methylurea-induced mammary tumors in Wistar rats

This study evaluated the therapeutic action of hydroethanolic extract of Trianthema portulacastrum L. (TPE) on N-nitroso-N-methylurea (NMU)-induced mammary tumors in Wistar rats. A hydroethanolic was prepared and subjected to qualitative and quantitative phytochemical screening. After acclimatization, Wistar rats were divided into 4 groups of 6 rats each: Group A (vehicle control), Group B (TPE control), Group C (TPE treatment) and group D (NMU control). NMU (50 mg/kg body weight) was injected intraperitoneally at 50, 80 and 110 days of age. After the induction of palpable tumors,the rats were administered 200 mg/kg bw of TPE by oral gavage for 2 months. The treatment with TPE significantly (p&lt;0.05) decreased tumor incidence, frequency, size and malignancy in comparison to the tumor-bearing rats that were not administered TPE. Immunohistochemical analysis revealed that TPE treatment significantly reduced the expression of PCNA, VEGF, ER-α and ER-β, and caused non-significant reductions in matrix metallopeptidase-9 (MMP-9). Caspase-3 expression significantly increased in TPE-treated rats in comparison with NMU-treated controls. The qRT-PCR resultsshowed PCNA and ER-β expression was down regulated and caspase-3 expression was up regulated in the TPE-treated group. The present study showed the in vivo therapeutic action of TPE extract on NMU-induced mammary tumors. TPE exhibited antitumor activity through its antiproliferative, antiangiogenic, pro-apoptotic, and estrogen receptor-modulatory properties

Therapeutic effect of hydroethanolic extract of Trianthema portulacastrum L. against N-Nitroso-N-Methylurea-induced mammary tumors in Wistar rats

406-415This study evaluated the therapeutic action of hydroethanolic extract of Trianthema portulacastrum L. (TPE) on N-nitroso-N-methylurea (NMU)-induced mammary tumors in Wistar rats. A hydroethanolic was prepared and subjected to qualitative and quantitative phytochemical screening. After acclimatization, Wistar rats were divided into 4 groups of 6 rats each: Group A (vehicle control), Group B (TPE control), Group C (TPE treatment) and group D (NMU control). NMU (50 mg/kg body weight) was injected intraperitoneally at 50, 80 and 110 days of age. After the induction of palpable tumors, the rats were administered 200 mg/kg bw of TPE by oral gavage for 2 months. The treatment with TPE significantly (pin vivo therapeutic action of TPE extract on NMU-induced mammary tumors. TPE exhibited antitumor activity through its antiproliferative, antiangiogenic, pro-apoptotic, and estrogen receptor-modulatory properties