miRPreM and tiRPreM: Improved methodologies for the prediction of miRNAs and tRNA-induced small non-coding RNAs for model and non-model organisms.

In recent years, microRNAs (miRNAs) and tRNA-derived RNA fragments (tRFs) have been reported extensively following different approaches of identification and analysis. Comprehensively analyzing the present approaches to overcome the existing variations, we developed a benchmarking methodology each for the identification of miRNAs and tRFs, termed as miRNA Prediction Methodology (miRPreM) and tRNA-induced small non-coding RNA Prediction Methodology (tiRPreM), respectively. We emphasized the use of respective genome of organism under study for mapping reads, sample data with at least two biological replicates, normalized read count support and novel miRNA prediction by two standard tools with multiple runs. The performance of these methodologies was evaluated by using Oryza coarctata, a wild rice species as a case study for model and non-model organisms. With organism-specific reference genome approach, 98 miRNAs and 60 tRFs were exclusively found. We observed high accuracy (13 out of 15) when tested these genome-specific miRNAs in support of analyzing the data with respective organism. Such a strong impact of miRPreM, we have predicted more than double number of miRNAs (186) as compared with the traditional approaches (79) and with tiRPreM, we have predicted all known classes of tRFs within the same small RNA data. Moreover, the methodologies presented here are in standard form in order to extend its applicability to different organisms rather than restricting to plants. Hence, miRPreM and tiRPreM can fulfill the need of a comprehensive methodology for miRNA prediction and tRF identification, respectively, for model and non-model organisms.

Dual role of an essential HtrA2/Omi protease in the human malaria parasite: Maintenance of mitochondrial homeostasis and induction of apoptosis-like cell death under cellular stress.

Members of the HtrA family of serine proteases are known to play roles in mitochondrial homeostasis as well as in programmed cell death. Mitochondrial homeostasis and metabolism are crucial for the survival and propagation of the malaria parasite within the host. Here we have functionally characterized a Plasmodium falciparum HtrA2 (PfHtrA2) protein, which harbours trypsin-like protease activity that can be inhibited by its specific inhibitor, ucf-101. A transgenic parasite line was generated, using the HA-glmS C-terminal tagging approach, for localization as well as for inducible knock-down of PfHtrA2. The PfHtrA2 was localized in the parasite mitochondrion during the asexual life cycle. Genetic ablation of PfHtrA2 caused significant parasite growth inhibition, decreased replication of mtDNA, increased mitochondrial ROS production, caused mitochondrial fission/fragmentation, and hindered parasite development. However, the ucf-101 treatment did not affect the parasite growth, suggesting the non-protease/chaperone role of PfHtrA2 in the parasite. Under cellular stress conditions, inhibition of PfHtrA2 by ucf-101 reduced activation of the caspase-like protease as well as parasite cell death, suggesting the involvement of protease activity of PfHtrA2 in apoptosis-like cell death in the parasite. Under these cellular stress conditions, the PfHtrA2 gets processed but remains localized in the mitochondrion, suggesting that it acts within the mitochondrion by cleaving intra-mitochondrial substrate(s). This was further supported by trans-expression of PfHtrA2 protease domain in the parasite cytosol, which was unable to induce any cell death in the parasite. Overall, we show the specific roles of PfHtrA2 in maintaining mitochondrial homeostasis as well as in regulating stress-induced cell death.

Multicomponent Amorphous Solid Forms of Telmisartan: Insights into Mechanochemical Activation and Physicochemical Attributes.

The present work aims to explore the new solid forms of telmisartan (TEL) with alpha-ketoglutaric acid (KGA) and glutamic acid (GA) as potential coformers using mechanochemical approach and their role in augmentation in physicochemical parameters over pure crystalline TEL. Mechanochemical synthesis was performed using 1:1 stoichiometric ratio of TEL and the selected coformers in the presence of catalytic amount of ethanol for 1 h. The ground product was characterized by PXRD, DSC, and FTIR. The new solid forms were evaluated for apparent solubility, intrinsic dissolution, and physical stability. Preliminary characterization revealed the amorphization of the mechanochemical product as an alternate outcome of cocrystallization screening. Mechanistic understanding of the amorphous phase highlights the formation of amorphous-mediated cocrystallization that involves three steps, viz., molecular recognition, intermediate amorphous phase, and product nucleation. The solubility curves of both multicomponent amorphous solid forms (TEL-KGA and TEL-GA) showed the spring-parachute effect and revealed significant augmentation in apparent solubility (8-10-folds), and intrinsic dissolution release (6-9-folds) as compared to the pure drug. Besides, surface anisotropy and differential elemental distributions in intrinsic dissolution compacts of both solid forms were confirmed by FESEM and EDX mapping. Therefore, amorphous phases prepared from mechanochemical synthesis can serve as a potential solid form for the investigation of a cocrystal through amorphous-mediated cocrystallization. This has greater implications in solubility kinetics wherein the rapid precipitation of the amorphous phase can be prevented by the metastable cocrystal phase and contribute to the significant augmentation in the physicochemical parameters.

Genetic polymorphism of fatty acid binding protein-2 in hyperlipidemic Asian Indians in North India.

BACKGROUND: Fatty acid binding protein-2 (FABP-2) is involved in the metabolism of lipids in the intestine. FABP-2 Ala54Thr polymorphism involves a transition of G to A at codon 54 of FABP-2, resulting in an amino acid substitution Ala54 to Thr54 and is associated with elevated fasting triglycerides in some hyperlipidemic populations. In current genome builds and gene databases the variant of the Ala54Thr FABP-2 (rs 1 799 883) is annotated as c.163A>G (p. Thr55Ala). AIM AND OBJECTIVE: The status of this polymorphism in hyperlipidemic Asian Indians from North India has not been investigated. This study was aimed to evaluate the distribution of the polymorphic variants of the Ala54Thr FABP-2 and their association with lipids in hyperlipidemic subjects. METHODS: Ala54Thr FABP-2 polymorphism in both hyperlipidemic (n = 210) and normolipidemic (n = 342) subjects was assessed by PCR-RFLP. RESULTS: Ala54Thr genotypes and alleles distribution did not differ between the hyperlipidemic and normolipidemic groups. The heterozygous genotype FABP-2 Ala/Thr was significantly associated with higher levels of triglycerides and very low-density lipoproteins as compared to the homozygous variant (Thr/Thr) genotype and the wild type homozygous (Ala/Ala) genotype. CONCLUSIONS: The heterozygous genotype FABP-2 Ala54Thr is a risk factor for the development of hypertriglyceridemia and increased levels of VLDL-c in Asian Indians from North India.

Hydrogeochemical and isotopic evolution of groundwater in shallow and deep aquifers of the Kabul Plain, Afghanistan.

Groundwater from shallow and deep aquifers are widely used for drinking, agricultural and industrial use in Kabul, the capital of Afghanistan. However, unplanned urbanization and rapid population growth has led to the installation of numerous unlicensed wells to meet the public demand. This has caused to extraction of huge amounts of groundwater from the subsurface and further deterioration of groundwater quality. Therefore, understanding the hydrogeochemical characteristics of groundwater in shallow aquifers and deep aquifers is imperative for sustainable management of the groundwater resource in Kabul Plain. Thus, in this study, we used a multi-parameter approach, involving hydrochemical and environmental isotopes to understand the geochemical evolution of entire groundwater system of the Kabul Plain including river and dam water. The results of this study show that shallow and deep aquifers are dominantly of Mg-(Ca)-HCO3 and Na-Cl water type, respectively. We observed that (1) water-rock interaction is the major contributing factor to the chemical compositions of groundwater in the Kabul Plain; (2) groundwater in deep aquifer is mainly influenced by silicate weathering, and dissolution of evaporitic and carbonate minerals and reverse cation exchange; (3) dissolution of carbonates and silicate weathering plays a pivotal role in the groundwater chemistry of shallow aquifer; (4) the stable isotopes of groundwater display that the shallow aquifer is principally recharged by river water and local precipitation; (5) the tritium analysis exhibited that groundwater of shallow aquifer was primarily recharged recently, whereas groundwater of deep aquifer is the mixture of pre 1953 with post 1953 groundwater. This study revealed that there are hydraulic interactions between the two aquifers and the deep aquifer is recharged through shallow aquifer. The findings of this study would be useful for Afghanistan's water authorities to develop an effective strategy for sustainable water resources management in the Kabul Basin.

On Optimal and Quantum Code Construction from Cyclic Codes over FqPQ with Applications.

The key objective of this paper is to study the cyclic codes over mixed alphabets on the structure of FqPQ, where P=Fq[v]⟨v3-α22v⟩ and Q=Fq[u,v]⟨u2-α12,v3-α22v⟩ are nonchain finite rings and αi is in Fq/{0} for i∈{1,2}, where q=pm with m≥1 is a positive integer and p is an odd prime. Moreover, with the applications, we obtain better and new quantum error-correcting (QEC) codes. For another application over the ring P, we obtain several optimal codes with the help of the Gray image of cyclic codes.

Kinless hubs are potential target genes in prostate cancer network.

Complex disease networks can be studied successfully using network theoretical approach which helps in finding key disease genes and associated disease modules. We studied prostate cancer (PCa) protein-protein interaction (PPI) network constructed from patients' gene expression datasets and found that the network exhibits hierarchical scale free topology which lacks centrality lethality rule. Knockout experiments of the sets of leading hubs from the network leads to transition from hierarchical (HN) to scale free (SF) topology affecting network integration and organization. This transition, HN â†’ SF, due to removal of significant number of the highest degree hubs, leads to relatively decrease in information processing efficiency, cost effectiveness of signal propagation, compactness, clustering of nodes and energy distributions. A systematic transition from a diassortative PCa PPI network to assortative networks after the removal of top 50 hubs then again reverting to disassortativity nature on further removal of the hubs was also observed indicating the dominance of the largest hubs in PCa network intergration. Further, functional classification of the hubs done by using within module degrees and participation coefficients for PCa network, and leading hubs knockout experiments indicated that kinless hubs serve as the basis of establishing links among constituting modules and heterogeneous nodes to maintain network stabilization. We, then, checked the essentiality of the hubs in the knockout experiment by performing Fisher's exact test on the hubs, and showed that removal of kinless hubs corresponded to maximum lethality in the network. However, excess removal of these hubs essentially may cause network breakdown.

Emerging Multi-Drug Eutectics: Opportunities and Challenges.

Complexity and heterogeneous nature of most diseases have posed greater challenges in the modern healthcare system. Fixed-dose combination can offer an ideal way to improve patient compliance and higher therapeutic efficacy. However, biopharmaceutical issues associated with the drug combinations remain unaddressed. Multidrug eutectics (MDE) have demonstrated significant promise in improving the biopharmaceutical attributes with synergistic therapeutic action. Eutectic mixtures are the multicomponent solid forms that possess lesser melting point than the individual components at a fixed composition. Non-covalent linking of drug combinations as MDE is an innovative strategy with enhanced solubility, dissolution, and mechanical and potential therapeutic efficacy. This review provides a comprehensive overview of the design of MDE, rational selection of drugs, characterization tools, and their therapeutic potential. Besides, the futuristic perspective where MDE could make a significant impact on combination therapy is briefly outlined. Graphical Abstract.

(3R, 3'R)-zeaxanthin protects the retina from photo-oxidative damage via modulating the inflammation and visual health molecular markers.

PURPOSE: Zeaxanthin protects the macula from ocular damage due to light or radiation by scavenging harmful reactive oxygen species. In the present study, zeaxanthin product (OmniXan®; OMX), derived from paprika pods (Capsicum annum; Family-Solanaceae), was tested for its efficacy in the rat retina against photooxidation. METHODS: Forty-two male 8-week-old Wistar rats exposed to 12L/12D, 16L/8D and 24L/0D hours of intense light conditions were orally administrated either 0 or 100 mg/kg BW of zeaxanthin concentration. Retinal morphology was analyzed by histopathology, and target gene expressions were detected with real-time polymerase chain reaction methods. RESULTS: OMX treatment significantly increased the serum zeaxanthin concentration (p < 0.001) and ameliorated oxidative damage by increasing the antioxidant enzyme activities in the retina induced by light (p < 0.001). OMX administration significantly upregulated the expression of genes, including Rhodopsin (Rho), Rod arrestin (SAG), Gα Transducin 1 (GNAT-1), neural cell adhesion molecule (NCAM), growth-associated protein 43 (GAP43), nuclear factor-(erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase (HO-1) and decreased the expression of nuclear factor-κB (NF- κB) and GFAP by OMX treatment rats. The histologic findings confirmed the antioxidant and gene expression data. CONCLUSIONS: This study suggests that OMX is a potent substance that can be used to protect photoreceptor cell degeneration in the retina exposed to intense light.

Structural comparison of Mtb-DHFR and h-DHFR for design, synthesis and evaluation of selective non-pteridine analogues as antitubercular agents.

Tuberculosis is an infectious disease that affects millions of population every year. Mtb-DHFR is a validated target that is vital for nucleic acids biosynthesis and therefore DNA formation and cell replication. This paper report identification and synthesis of novel compounds for selective inhibition of Mtb-DHFR and unleash the selective structural features necessary to inhibit the same. Virtual screening of databases was carried out to identify novel compounds on the basis of difference between the binding pockets of the two proteins. Consensus docking was performed to improve upon the results and best ten hits were selected. Hit 1 was subjected to analogues design and the analogues were docked against Mtb-DHFR. From the docking results 11 compounds were selected for synthesis and biological assay against H37Rv. Most potent compound (IND-07) was tested for selectivity using enzymatic assay against Mtb-DHFR and h-DHFR. The compounds were found to have good inhibitory activity (25-200 µM) against H37Rv and in enzyme assay against Mtb-DHFR and h-DHFR the compound was found selective towards Mtb-DHFR with selectivity index of 6.53. This work helped to identify indole moiety as novel scaffold for development of novel selective Mtb-DHFR inhibitors as antimycobacterial agents.

Eps15 homology domain containing protein of Plasmodium falciparum (PfEHD) associates with endocytosis and vesicular trafficking towards neutral lipid storage site.

The human malaria parasite, Plasmodium falciparum, takes up numerous host cytosolic components and exogenous nutrients through endocytosis during the intra-erythrocytic stages. Eps15 homology domain-containing proteins (EHDs) are conserved NTPases, which are implicated in membrane remodeling and regulation of specific endocytic transport steps in eukaryotic cells. In the present study, we have characterized the dynamin-like C-terminal Eps15 homology domain containing protein of P. falciparum (PfEHD). Using a GFP-targeting approach, we studied localization and trafficking of PfEHD in the parasite. The PfEHD-GFP fusion protein was found to be a membrane bound protein that associates with vesicular network in the parasite. Time-lapse microscopy studies showed that these vesicles originate at parasite plasma membrane, migrate through the parasite cytosol and culminate into a large multi-vesicular like structure near the food-vacuole. Co-staining of food vacuole membrane showed that the multi-vesicular structure is juxtaposed but outside the food vacuole. Labeling of parasites with neutral lipid specific dye, Nile Red, showed that this large structure is neutral lipid storage site in the parasites. Proteomic analysis identified endocytosis modulators as PfEHD associated proteins in the parasites. Treatment of parasites with endocytosis inhibitors obstructed the development of PfEHD-labeled vesicles and blocked their targeting to the lipid storage site. Overall, our data suggests that the PfEHD is involved in endocytosis and plays a role in the generation of endocytic vesicles at the parasite plasma membrane, that are subsequently targeted to the neutral lipid generation/storage site localized near the food vacuole.

Coenzyme Q10 Supplementation Modulates NFκB and Nrf2 Pathways in Exercise Training.

This study reports the effects of Q10, coenzyme Q10 or ubiquinone, a component of the electron transport chain in mitochondria, on nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), inhibitors of kappa B (IκB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and hemeoxygenase 1 (HO-1) in rats after chronic exercise training for 6 weeks. 8-week old male Wistar rats were assigned randomly to one of four treatments planned in a 2 x 2 factorial arrangement of two condition (sedentary vs. exercise training), and two coenzyme Q10 levels (0 and 300 mg/kg per day for 6 weeks). The expression levels of the target proteins were determined in the heart, liver and muscle, and biochemical parameters including creatinine, urea, glucose and lipid profile were investigated in plasma. When compared with sedentary group, significant decreases in heart, liver and muscle NFκB levels by 45%, 26% and 44% were observed in Q10 supplemented rats after exercise training, respectively, while the inhibitory protein IκB increased by 179%, 111% and 127% in heart, liver and muscle tissues. Q10 supplementation caused an increase in Nrf2 (167%, 165% and 90%) and HO-1 (107%, 156% and 114%) after exercise training in heart, liver and muscle tissues (p < 0.05). No significant change was observed in any of the parameters associated with protein, carbohydrate and lipid metabolism, except that exercise caused a decrease in plasma triglyceride, which was further decreased by Q10. In conclusion, these results suggest that Q10 modulates the expression of NFκB, IκB, Nrf2 and HO-1 in exercise training, indicating an anti-inflammatory effect of Q10 and emphasizes its role in antioxidant defense. Key pointsCoenzyme Q10 is a component of the electron transport chain in mitochondria which is linked to the generation of energy in the cell.Coenzyme Q10 may inhibit the peroxidation of lipids, thus acting as an antioxidant and protects tissue against oxidative injury.Using of coenzyme Q10 can significantly elevate IκB, Nrf2 and HO-1 and reduce NFκB during exercise training.

Partial Reversal of Obesity-Induced Insulin Resistance Owing to Anti-Inflammatory Immunomodulatory Potential of Flaxseed Oil.

The present study was designed to assess the potential of supplementation of diet with Flaxseed (Linum usitatissimum, L.) oil (FXO), on obesity-related inflammation and reversal of obesity-induced insulin resistance. Swiss Albino mice, C57bl/6 mice and co-culture of 3T3-L1 adipocytes - RAW 264.7 macrophages to mimick obese adipose tissue environment were used for the study. Oral gavage of FXO at concentrations of 4, 8 or 16 mg/kg body weight (bwt) for 4 weeks or high-fat diet (HFD, 60% energy as fat) supplemented with dietary FXO (4, 8 or 16 mg/kg bwt) was given to the mice. FXO was characterised using gas chromatography - mass spectrometry. FXO supplemented HFD-fed mice (4 mg/kg bwt exhibited reduced adiposity index, serum glucose levels and triglycerides (8 and 16 mg/kg bwt) and improvement in insulin sensitisation (4, 8 and 16 mg/kg bwt) when compared with HFD mice. The co-culture showed a dose-dependent shift in cytokines towards anti-inflammatory (IL-4) state, with a decrease in pro-inflammatory TNF-α (p < 0.05). For immunomodulatory studies a dose-dependent increase (p < 0.05) was observed in antigen-specific levels of Th2 (IL-4) cytokine, serum anti-ova IgG1 and IgE levels. Suppression in anti-ova IgG2a, IgG2b, and IgG3 and antigen-specific Th1 cytokines like TNF-α and IFN-γ significantly (p < 0.05) was observed at 16 mg/kg bwt dosage. The results indicate that FXO exhibits an anti-inflammatory immunomodulatory potential and may partially relieve symptoms of obesity-associated insulin resistance.

A monoclonal antibody against 47.2 kDa cell surface antigen prevents adherence and affects biofilm formation of Candida albicans.

Candida albicans is an opportunistic dimorphic pathogen that exists in both planktonic and biofilm phases causing deep-rooted infections in mainly immunocompromised patients. Antibodies are believed to play anti-Candida activity by different mechanisms, like inhibition of adhesion and neutralization of virulence-related antigens. Inhibition of adhesion is one of the important strategies to prevent Candida infections and biofilm formation. In this study, monoclonal antibody (MAb 7D7) against C. albicans biofilm cell surface antigen (47.2 kDa) was generated to determine the changes in adherence and viability of C. albicans. In this regard XTT assay was carried out in 30, 60, 90 min and 48 h (maturation time) time points using MAb 7D7 and it (MAb 7D7) was found to be effective against adhesion and the formation of C. albicans biofilm on polystyrene as well as monolayer of human epithelial cells (HeLa). This result may also prove to be a valuable addition to the reagents available to study C. albicans cell surface dynamics and interaction of the fungus with host cells.

miR-135a targets IRS2 and regulates insulin signaling and glucose uptake in the diabetic gastrocnemius skeletal muscle.

Although aberrant miRNA signatures are associated with diabetes, yet, the status and role of altered miRNAs in the diabetic skeletal muscle is currently poorly understood. Here, we report that 41 miRNAs are altered in the diabetic gastrocnemius skeletal muscle and of these, miR-135a that is identified as a critical regulator of myogenesis, is significantly up-regulated. IRS2 is predicted as its potential putative target and its levels are down-regulated in the diabetic gastrocnemius skeletal muscle. In C2C12 cells, while miR-135a levels decreased during differentiation, IRS2 levels were up-regulated. miR-135a significantly reduced IRS2 protein levels and its 3'UTR luciferase reporter activity and these were blunted by the miR-135a inhibitor and mutation in the miR-135a binding site. Knock-down of endogenous miR-135a levels increased IRS2 at the mRNA and protein levels. miR-135a also attenuated insulin stimulated phosphorylation and activation of PI3Kp85α and Akt and glucose uptake. miR-135a levels were also found to be elevated in the human diabetic skeletal muscle. In-vivo silencing of miR-135a alleviated hyperglycemia, improved glucose tolerance and significantly restored the levels of IRS2 and p-Akt in the gastrocnemius skeletal muscle of db/db mice without any effect on their hepatic levels. These suggest that miR-135a targets IRS2 levels by binding to its 3'UTR and this interaction regulates skeletal muscle insulin signaling.

Cell specific apoptosis by RLX is mediated by NFκB in human colon carcinoma HCT-116 cells.

BACKGROUND: Resistance to chemotherapy represents a major obstacle in correcting colorectal carcinomas (CRC). Inspite of recent advances in the treatment of metastatic disease, the prognosis of the patients remains poor. RLX, a vasicinone analogue has been reported to possess potent bronchodilator, anti-asthmatic and anti-inflammatory properties. However, its anti-cancer activity is unknown. RESULTS: Here, we report for the first time that RLX has anti-cancer property against panel of human cancer cell lines and most potent activity was found against HCT-116 cells with IC50 value of 12 µM and have further investigated the involvement of NFκB and caspase-3 in RLX action in CRC apoptosis. Following RLX and BEZ-235 treatment in HCT-116, we observed significant down-regulation of NFκB (1 to 0.1 fold) and up-regulation of caspase-3 (1 to 2 fold) protein expressions. Additionally, morphological studies revealed membrane blebbing, cell shrinkage, chromatin condensation and finally apoptosis in HCT-116 cells. CONCLUSIONS: Overall, these findings indicate that RLX is a potent small molecule which triggers apoptosis, and promising potential candidate to be a chemotherapeutic agent.

Anti-tumour activity of a novel coumarin-chalcone hybrid is mediated through intrinsic apoptotic pathway by inducing PUMA and altering Bax/Bcl-2 ratio.

Coumarins and chalcones are secondary plant metabolites which have shown an array of pharmacological properties including anti-tumour activity. We have previously reported on the synthesis and anti-proliferative activity of a series of novel coumarin-chalcone hybrids. Now we report on the in vivo efficacy as well as mechanism of action of the most potent molecule of the series, S009-131. Oral administration of this molecule resulted in regression of tumours induced by HeLa cell xenografts in nod SCID mice. The molecule inhibited proliferation of cervical cancer cells (HeLa and C33A) by inducing apoptosis and arresting cell cycle at G2/M phase. Apoptosis was induced through induction of caspase-dependent intrinsic pathway and alterations in the cellular levels of Bcl-2 family proteins. The mitochondrial transmembrane potential got highly depleted in S009-131 treated cells due to an increase in Bax/Bcl-2 ratio and intracellular ROS. The molecule induced release of cytochrome c into the cytosol and activation of initiator caspase-9 and executioner caspases-3/7. Tumour suppressor protein p53 and its transcriptional target PUMA were up regulated, suggesting their role in mediating the cell death. These results suggest that S009-131 is a potent candidate for the chemotherapy of cervical carcinoma.

SBSI: an extensible distributed software infrastructure for parameter estimation in systems biology.

SUMMARY: Complex computational experiments in Systems Biology, such as fitting model parameters to experimental data, can be challenging to perform. Not only do they frequently require a high level of computational power, but the software needed to run the experiment needs to be usable by scientists with varying levels of computational expertise, and modellers need to be able to obtain up-to-date experimental data resources easily. We have developed a software suite, the Systems Biology Software Infrastructure (SBSI), to facilitate the parameter-fitting process. SBSI is a modular software suite composed of three major components: SBSINumerics, a high-performance library containing parallelized algorithms for performing parameter fitting; SBSIDispatcher, a middleware application to track experiments and submit jobs to back-end servers; and SBSIVisual, an extensible client application used to configure optimization experiments and view results. Furthermore, we have created a plugin infrastructure to enable project-specific modules to be easily installed. Plugin developers can take advantage of the existing user-interface and application framework to customize SBSI for their own uses, facilitated by SBSI's use of standard data formats. AVAILABILITY AND IMPLEMENTATION: All SBSI binaries and source-code are freely available from http://sourceforge.net/projects/sbsi under an Apache 2 open-source license. The server-side SBSINumerics runs on any Unix-based operating system; both SBSIVisual and SBSIDispatcher are written in Java and are platform independent, allowing use on Windows, Linux and Mac OS X. The SBSI project website at http://www.sbsi.ed.ac.uk provides documentation and tutorials.

Attenuated neuroprotective effect of riboflavin under UV-B irradiation via miR-203/c-Jun signaling pathway in vivo and in vitro.

BACKGROUND: Riboflavin (RF) or vitamin B2 is known to have neuroprotective effects. In the present study, we report the attenuation of the neuroprotective effects of RF under UV-B irradiation. Preconditioning of UV-B irradiated riboflavin (UV-B-RF) showed attenuated neuroprotective effects compared to that of RF in SH-SY5Y neuroblostoma cell line and primary cortical neurons in vitro and a rat model of cerebral ischemia in vivo. RESULTS: Results indicated that RF pretreatment significantly inhibited cell death and reduced LDH secretion compared to that of the UV-B-RF pretreatment in primary cortical neuron cultures subjected to oxygen glucose deprivation in vitro and cortical brain tissue subjected to ischemic injury in vivo. Further mechanistic studies using cortical neuron cultures revealed that RF treatment induced increased miR-203 expression which in turn inhibited c-Jun expression and increased neuronal cell survival. Functional assays clearly demonstrated that the UV-B-RF preconditioning failed to sustain the increased expression of miR-203 and the decreased levels of c-Jun, mediating the neuroprotective effects of RF. UV-B irradiation attenuated the neuroprotective effects of RF through modulation of the miR-203/c-Jun signaling pathway. CONCLUSION: Thus, the ability of UV-B to serve as a modulator of this neuroprotective signaling pathway warrants further studies into its role as a regulator of other cytoprotective/neuroprotective signaling pathways.

Orally administered lycopene attenuates diethylnitrosamine-induced hepatocarcinogenesis in rats by modulating Nrf-2/HO-1 and Akt/mTOR pathways.

Hepatocarcinogenesis is one of the most prevalent and lethal cancers. We studied the mechanisms underlying the inhibition of diethylnitrosamine (DEN)-induced hepatocarcinogenesis by lycopene in rats. Hepatocarcinogenesis was induced by an intraperitoneal injection of DEN followed by promotion with phenobarbital for 24 successive wk. The rats were given lycopene (20 mg/kg body weight) 3 times a week orally for 4 wk prior to initiation, and the treatment was continued for 24 consecutive wk. Lycopene reduced incidence, number, size, and volume of hepatic nodules. Serum alanine transaminase, aspartate aminotransferase, total bilirubin, and malondialdehyde (MDA) considerably increased and hepatic antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) and glutathione decreased in DEN-treated rats when compared with the control group. Lycopene significantly reversed these biochemical changes and increased the expression of NF-E-2-related factor-2)/heme oxygenase-1, and it decreased NF-κB/cyclooxygenase-2, inhibiting the inflammatory cascade and activating antioxidant signaling (P < 0.05). Lycopene also decreased DEN-induced increases in phosphorylated mammalian target of rapamycin (p-mTOR), phosphorylated p70 ribosomal protein S6 kinase 1, phosphorylated 4E-binding protein 1, and protein kinase B (P < 0.05). Lycopene is an active chemopreventive agent that offers protection against DEN-induced hepatocarcinogenesis by inhibiting NF-κB and mTOR pathways.