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Due to the global population growth and economic development, energy demand has increased worldwide. Countries take steps to improve their alternative and renewable energy sources. Algae is one of the alternative energy sources and can be used to produce renewable biofuel. In this study, nondestructive, practical, and rapid image processing techniques were applied to determine the algal growth kinetics and biomass potential of four algal strains, including C. minutum, Chlorella sorokiniana, C. vulgaris, and S. obliquus. Laboratory experiments were conducted to determine different aspects of biomass and chlorophyll production of those algal strains. Suitable non-linear growth models, including Logistic, modified Logistic, Gompertz, and modified Gompertz models, were employed to determine the growth pattern of algae. Moreover, the methane potential of harvested biomass was calculated. The algal strains were incubated for 18 days, and the growth kinetics were determined. After the incubation, the biomass was harvested and assessed for its chemical oxygen demand content and biomethane potential. Among the tested strains, C. sorokiniana was the best in biomass productivity (111.97 ± 0.9 mg L−1d−1). The calculated vegetation indices, namely; colorimetric difference, color index vegetation, vegetative, excess green, excess green minus excess red, combination, and brown index values showed a significant correlation with biomass and chlorophyll content. Among the tested growth models, the modified Gompertz shows the best growth pattern. Further, the estimated theoretical CH 4 yield was highest for C. minutum (0.98 mL g−1) compared to other tested strains. The present findings suggest that image analysis can be used as an alternative method to study the growth kinetics and biomass production potential of different algae during cultivation in wastewater. [Display omitted] • Growth of C. sorokiniana , C. vulgaris , C. minutum , and S. obliquus were compared. • C. sorokiniana outperformed in terms of biomass production in municipal wastewater. • Pioneering attempts on algal growth kinetics using image analysis. • Among the tested growth models, modified Gompertz shows the best fit. • Optimal theoretical CH 4 for C. minutum was 0.98 mL g−1 [ABSTRACT FROM AUTHOR]

Background: The genus Xylaria has been reported as a rich source of biologically active secondary metabolites. In the present study, an endophytic fungus Xylaria psidii has been isolated from the leaf sample of Aegle marmelos (L.) Corr., characterized on the basis of its morphological features and sequence data for the ITS region (KU291350) of the nuclear ribosomal DNA. Biological screening of ethyl acetate extract of Xylaria psidii displayed a potential therapeutic effect on pancreatic cancer cells.Hypothesis: This study was designed systematically to explore Xylaria psidii, an endophytic fungus for the identification of biologically active secondary metabolites against pancreatic cancer cells.Methods: While exploring the bioactive secondary metabolites, a sensitive and reliable LC-MS based dereplication approach was applied to identify four compounds A-D from fungal extract. Further bioactivity guided isolation of fungal extract yielded two major metabolites 1 and 2. The structures of 1 and 2 have been determined by detailed spectroscopic analysis including MS, NMR, IR and UV data and similarity with published data. Xylarione A (1) is new whereas (-) 5-methylmellein (2) is reported for the first time from X. psidii. Both the isolated compounds were screened for their effect on the viability and proliferation against a panel of cancer cell lines (MCF-7, MIA-Pa-Ca-2, NCI-H226, HepG2 and DU145) of different tissue origin.Results: Compounds 1 and 2 exhibited cytotoxicity against pancreatic cancer (MIA-Pa-Ca-2) cells with IC50 values of 16.0 and 19.0 µm, respectively. The cell cycle distribution in MIA-Pa-Ca-2 cells, confirmed a cell cycle arrest at the sub-G1 phase. Cell death induced by 1 and 2 displayed features characteristic of apoptosis. Flow cytometry based analysis of 1 and 2 using Rhodamine-123 displayed substantial loss of mitochondrial membrane potential in a concentration dependent manner by both the compounds.Conclusion: Results conclude that the isolated compounds 1 and 2 are responsible for the activity shown by crude ethyl acetate extract and may act as potential leads for medicinal chemists for designing more potent analogs. [ABSTRACT FROM AUTHOR]

AP9-cd, a novel lignan composition from Cedrus deodara has significant anticancer potential, and to further enhance its activity, it was lucratively encumbered into solid lipid nanoparticles (SLNs). These nanoparticles were formulated by micro-emulsion technique with 70% drug trap competence. AP9-cd-SLNs were regular, solid, globular particles in the range of 100–200 nm, which were confirmed by electron microscopic studies. Moreover, AP9-cd-SLNs were found to be stable for up to six months in terms of color, particle size, zeta potential, drug content and entrapment. AP9-cd-SLNs have 30–50% higher cytotoxic and apoptotic potential than the AP9-cd alone. The augmented anticancer potential of AP9-cd-SLNs was observed in cytotoxic IC 50 value, apoptosis signaling cascade and in Ehrlich ascites tumor (EAT) model. AP9-cd-SLNs induce apoptosis in Molt-4 cells via both intrinsic and extrinsic pathway. Moreover, the dummy nanoparticles (SLNs without AP9-cd) did not have any cytotoxic effect in cancer as well as in normal cells. Consequently, SLNs of AP9-cd significantly augment the apoptotic and antitumor potential of AP9-cd. The present study provides a podium for ornamental the remedial latent via novel delivery systems like solid lipid nanoparticles. [ABSTRACT FROM AUTHOR]

Enzymatic pretreatment is emerging as an efficient tool for the extraction of biofuel precursors from algal biomass. However, yardsticks for end-use directed selection of optimal pretreatment conditions are not yet identified. The present study, for the first time, reveals different optimal conditions for algal biomass solubilization and sugar release. Algal biomass pretreatment optimization was carried out using the Taguchi method. Crude enzyme from Aspergillus fischeri was found effective for pretreatment of Chlorella pyrenoidosa. Maximum sugar yield (190 mg g−1 biomass) from algal biomass was observed at a substrate concentration of 4 g L-1, with a 5% enzyme load at temperature 60°C, pH 5.5, and shaking speed of 80 rpm. In contrast, maximum sCOD (1350 mg g−1 biomass) was obtained at 2 g L−1 substrate concentration with enzyme load of 20% v/v, at 60°C, pH 4, and shaking speed of 100 rpm. Hence, the first set of conditions would be more beneficial for bioethanol production. Whereas another set of conditions would improve the biofuel production that requires maximum solubilization of algal biomass, such as fermentative methane production. Overall, the present observations established that process conditions required for enzymatic pretreatment of algal biomass should be selected according to the desired biofuel type. [Display omitted] • Rhizopus oryzae, Aspergillus sp. and Aspergillus fischeri were tested for enzymatic activity. • Maximum enzyme activity of 0.343 FPU ml−1 was seen in A. fischeri. • Key parameters for microalgae pretreatment were optimized using Taguchi Method. • Enzymatic pretreatment conditions are crucial to obtain desired biofuel type. • A mechanism for the recovery of optimal COD/sugar release was proposed. [ABSTRACT FROM AUTHOR]

Abstract: Aim of present study was to investigate the effect of NAC on experimental chronic hepatotoxicity models induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). CCl4 toxicity was induced by administering 200μl CCl4 (diluted 2:3 in coconut oil)/100g body weight, p.o., twice weekly for 8 weeks. TAA toxicity was induced by administering 150mg/kg b. wt. of TAA i.p., twice weekly for 8 weeks. NAC treatment was started along with toxicants (CCl4 and TAA) for 8 weeks and continued for further 4 weeks. Self reversal group was kept without any treatment for 4 weeks after completion of toxicant treatments. Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), Bilirubin were measured in serum. Hydroxyproline (HP), lipid peroxidation (LPO), catalase (CAT), Glutathione peroxidase (GPx) and Glutathione (GSH) were determined in liver samples by colorimetric methods. Cytochrome P450 2E1 (CYP 450 2E1), activity was determined as hydroxylation of aniline in liver microsomes. General examination and histological analysis were also performed. Serum markers of liver damage (AST, ALT, ALP and Bilirubin) were increased by CCl4 and TAA intoxication (p <0.001), whereas co-treatment with NAC reversed such changes (p <0.001). HP was enhanced in toxicant groups (p <0.001 in CCl4 and TAA), but inhibited by NAC (p <0.001). LPO was increased while as GSH, CAT and GPx decreased by the administration of CCl4 and TAA (p <0.001); co-administration of NAC restored these liver markers to normal levels (p <0.001). Biochemical determinations were corroborated by general and histological findings. Keeping in view the biochemical and histopathological studies, it was concluded that CCl4 and TAA are strong hepatotoxic agents that produce liver fibrosis with close proximity to human etiology (micronodular cirrhosis) and NAC has a significant protective activity against CCl4 and TAA. NAC has also been validated as a model against oxidative burden in chronic liver pathology. [Copyright &y& Elsevier]

Objectives: This paper examined whether nebivolol protects the heart via nitric oxide (NO) synthase and NO-dependent signaling in an in vivo model of acute myocardial infarction. Background: Beta3-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. We hypothesized that specific beta3-AR agonists would attenuate myocardial ischemia-reperfusion (MI/R) injury via eNOS activation and increased NO bioavailability. Methods: Mice were subjected to 45 min of myocardial ischemia in vivo followed by 24 h of reperfusion (R). Nebivolol (500 ng/kg), CL 316243 (1 μg/kg), BRL-37344 (1 μg/kg), or vehicle (VEH) was administered at the time of R. Myocardial area-at-risk (AAR) and infarct size (INF)/AAR was measured at 24 h of R. Cardiac tissue and plasma were collected to evaluate eNOS phosphorylation, neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase expression, and nitrite and nitrosothiol levels. Results: Nebivolol (500 ng/kg) reduced INF/AAR by 37% (p < 0.001 vs. VEH) and serum troponin-I levels from 41 ± 4 ng/ml to 25 ± 4 ng/ml (p < 0.05 vs. VEH). CL 316243 and BRL-37344 reduced INF by 39% and 42%, respectively (p < 0.001 vs. VEH). Nebivolol and CL 316243 increased eNOS phosphorylation at Ser-1177 (p < 0.05 vs. VEH) and increased nitrite and total nitrosylated protein levels. Nebivolol and CL 316243 significantly increased myocardial nNOS expression. Nebivolol failed to reduce INF after MI/R in beta3-AR −/−, eNOS−/−, and in nNOS−/− mice. Conclusions: Our results indicate that beta3-AR agonists protect against MI/R injury. Furthermore, the cardioprotective effects of beta3-AR agonists are mediated by rapid eNOS and nNOS activation and increased NO bioavailability. [Copyright &y& Elsevier]

Abstract: This study describes the anti-cancer activity of P19, an analog of parthenin. P19 induced apoptosis in HL-60 cells and inhibited cell proliferation with 48h IC50 of 3.5μM. At 10mg/kg dose, it doubled the median survival time of L1210 leukemic mice and at 25mg/kg it inhibited Ehrlich ascites tumor growth by 60%. Investigation of the mechanism of P19 induced apoptosis in HL-60 cells revealed that N-acetyl-l-cysteine (NAC) and s-methylisothiourea (sMIT) could reverse several molecular events that lead to cell death by inhibiting nitric oxide (NO) formation. It selectively produced massive NO in cells while quenching the basal ROS levels with concurrent elevation of GSH. P19 disrupted mitochondrial integrity leading to cytochrome c release and caspase-9 activation. P19 also caused caspase-8 activation by selectively elevating the expression of DR4 and DR5. All these events lead to the activation of caspase-3 leading to PARP-1 cleavage and DNA fragmentation. However, knocking down of AIF by siRNA also suppressed the apoptosis substantially thus indicating caspase independent apoptosis, too. Further, contrary to enhanced iNOS expression, its transcription factor, NF-κB (p65) was cleaved with a simultaneous increase in cytosolic IκB-alpha. In addition, P19 potently inhibited pro-survival proteins pSTAT3 and survivin. The multi-modal pro-apoptotic activity of P19 raises its potential usefulness as a promising anti-cancer therapeutic. [Copyright &y& Elsevier]

Abstract: An essential oil from a lemon grass variety of Cymbopogon flexuosus (CFO) and its major chemical constituent sesquiterpene isointermedeol (ISO) were investigated for their ability to induce apoptosis in human leukaemia HL-60 cells because dysregulation of apoptosis is the hallmark of cancer cells. CFO and ISO inhibited cell proliferation with 48h IC50 of ∼30 and 20μg/ml, respectively. Both induced concentration dependent strong and early apoptosis as measured by various end-points, e.g. annexinV binding, DNA laddering, apoptotic bodies formation and an increase in hypo diploid sub-G0 DNA content during the early 6h period of study. This could be because of early surge in ROS formation with concurrent loss of mitochondrial membrane potential observed. Both CFO and ISO activated apical death receptors TNFR1, DR4 and caspase-8 activity. Simultaneously, both increased the expression of mitochondrial cytochrome c protein with its concomitant release to cytosol leading to caspase-9 activation, suggesting thereby the involvement of both the intrinsic and extrinsic pathways of apoptosis. Further, Bax translocation, and decrease in nuclear NF-κB expression predict multi-target effects of the essential oil and ISO while both appeared to follow similar signaling apoptosis pathways. The easy and abundant availability of the oil combined with its suggested mechanism of cytotoxicity make CFO highly useful in the development of anti-cancer therapeutics. [Copyright &y& Elsevier]

Abstract: Polyalthia longifolia is a lofty evergreen tree found in India and Sri Lanka. We are reporting first time the anticancer potential of P. longifolia leaves extract (A001) and its chloroform fraction (F002). Both inhibited cell proliferation of various human cancer cell lines in which colon cancer cells SW-620 showed maximum inhibition with IC50 value 6.1μg/ml. Furthermore, F002 induce apoptosis in human leukemia HL-60 cells as measured by several biological end points. F002 induce apoptotic bodies formation, DNA ladder, enhanced annexin-V-FITC binding of the cells, increased sub-G0 DNA fraction, loss of mitochondrial membrane potential (ΔΨ mt), release of cytochrome c, activation of caspase-9, caspase-3, and cleavage of poly ADP ribose polymerase (PARP) in HL-60 cells. All the above parameters revealed that F002-induced apoptosis through the mitochondrial-dependent pathway in HL-60 cells. [Copyright &y& Elsevier]

Recently we have identified the novel mitochondrial peptidase responsible for degrading presequences and other short unstructured peptides in mitochondria, the presequence peptidase, which we named PreP peptidasome. In the present study we have identified and characterized the human PreP homologue, hPreP, in brain mitochondria, and we show its capacity to degrade the amyloid β-protein (Aβ). PreP belongs to the pitrilysin oligopeptidase family M16C containing an inverted zinc-binding motif. We show that hPreP is localized to the mitochondrial matrix. In situ immuno-inactivation studies in human brain mitochondria using anti-hPreP antibodies showed complete inhibition of proteolytic activity against Aβ. We have cloned, overexpressed, and purified recombinant hPreP and its mutant with catalytic base Glu78 in the inverted zinc-binding motif replaced by GIn. In vitro studies using recombinant hPreP and liquid chromatography nanospray tandem mass spectrometry revealed novel cleavage specificities against Aβ-(1- 42), Aβ-(1- 40), and Aβ Arctic, a protein that causes increased protofibril formation an early onset familial variant of Alzheimer disease. In contrast to insulin degrading enzyme, which is a functional analogue of hPreP, hPreP does not degrade insulin but does degrade insulin B-chain. Molecular modeling of hPreP based on the crystal structure at 2.1 Å resolution of AtPreP allowed us to identify Cys90 and Cys527 that form disulfide bridges under oxidized conditions and might be involved in redox regulation of the enzyme. Degradation of the mitochondrial Aβ by hPreP may potentially be of importance in the pathology of Alzheimer disease. [ABSTRACT FROM AUTHOR]

• The lethal concentration of As in P. hypophthalamus was found to be 28.61 mg/L. • The LC 50 of As and high temperature in P. hypophthalamus was found to be 26.88 mg/L. • Acute As and high temperature exposure causes generation of ROS. • Exposure to arsenic and high temperature causes neurosuppressive of AChE. The water bodies are greatly influenced by heavy metal contamination and global increasing temperature. Arsenic (As) is one of the most dangerous widespread pollutants that pose health threats to human, animals and fishes. Considering the above, the study has been carried out to delineate 96 h median lethal concentration of arsenic alone and in combination with high temperature (As-T, 34 °C) by conducting static non-renewable bio-assay acute toxicity in Pangasianodon hypophthalmus (average weight 6.25 ± 0.69 g, length 5.32 cm). Effect of definitive doses such as 25, 26, 27, 28, 29 and 30 mg/L of As alone and in combination with high temperature (As-T) were evaluated on stress biomarkers and cellular metabolism of P. hypophthalmus. The lethal concentration (96 h LC 50) of As alone and in combination with high temperature was found to be 28.16 mg/L and 26.88 mg/L, respectively. The stress biomarkers in terms of catalase, superoxide dismutase (SOD) and glutathione-s-transferase (GST) in liver, gill, brain and kidney, blood glucose and NBT were remarkable higher (p < 0.01) in comparison to unexposed group (control group). Brain neurotransmitter enzyme, AChE, immunological status (blood glucose and NBT) and cellular metabolic enzymes (lactate dehydrogenase LDH, malate dehydrogenase MDH, aspartate aminotransferase AST, and alanine aminotransferase ALT, glucose-6-phosphate dehydrogenase G6PDH and ATPase) were noticeably (p < 0.01) altered by As and As-T exposure. The histopathological study exhibited devastating changes with exposure to As and As-T such as bile stagnation, hepatocyte with irregular nucleus, eosinophilic granules in the cytoplasm, necrosis, and nuclear hypertrophy in liver and curling of secondary lamellae, hypertrophy of lamellar epithelium, blood congestion, incomplete fusion of secondary lamellae, complete fusion of several lamellae and aneurysm in gill. Overall results clearly indicate that acute exposure of As and high temperature led to pronounced deleterious alterations on stress biomarkers and cellular and metabolic activities of P. hypophthalmus. [ABSTRACT FROM AUTHOR]

Tumor angiogenesis and PI3K/Akt/mTOR pathway are two major molecular objectives for the treatment and management of breast cancer. Here we first time report the molecular mechanism of a marine sponge alkaloid derivative 4-chloro fascapysin (4-CF) for its anticancer and antiangiogenesis potential. It simultaneously targets multiple cancer and angiogenesis dynamics, such as proliferation, chemotaxis cell migration, and invasion, growth factors signaling cascade, autophagy and apoptosis in HUVEC and MDAMB-231 breast cancer cells. It inhibited the VEGF mediated microvessel sprouting and blood vessel formation in the matrigel plug of C57/BL6J mice. It inhibits the tumor growth in ET (solid) mouse tumor model. It significantly inhibited cell survival through PI3K/Akt/mTOR pathway, with attendant effects on key pro-angiogenesis factors like HIF-1α, eNOS and MMP-2/9. The cytotoxicity of 4-CF was reversed by co-treatment with the VEGF and Akt inhibitors sunitinib and perifosine, respectively or by the addition of neutralizing VEGF antibodies. The apoptotic potential of 4-CF was through mitochondrial dependent as illustrated through loss of mitochondrial membrane potential. The safety profile of 4-CF was acceptable as it exhibits five times high cytotoxic IC50 value in normal cells as well as no apparent toxicities in experimental tumor mice at therapeutic doses. [ABSTRACT FROM AUTHOR]

Endophytes as a ubiquitous associate of the plant are considered as a promising candidate for sustainable agriculture. These organisms play a pivotal role in the regulation of the primary and secondary metabolism of their host plant. The direct and long-lasting interaction of endophytes with the host enables them to escape from harsh environmental conditions. Especially, their endophytic nature makes them better candidates over epiphytes and rhizospheric microbes in interaction with plants. Current research findings revealed that the endophytes help plants in making nutrient acquisition from the soil, nitrogen fixation, phosphate availability, phytohormone and antimicrobial production. There is a huge potential for developing novel products like endophytes-based microbial formulations and elicitors to improve plant health, ameliorating stress tolerance in plants and source of therapeutically important secondary metabolites. The present review specifically dealt with attributes such as host-tissue specificity of endophytes, the importance of seed-associated endophytes, endophyte-parasite plant-host plant interaction as well as their applications in plant in-vitro systems and as microbial consortium. In addition, the conserved endophytic microbial communities in different plants are also looked upon possibly to understand the plant-endophytic microbiome on similar lines of the animal-gut microbiome. Primarily, the purpose of this review is to implicate the endophytic flora as probiotics influencing overall plant health and their survival under extreme environmental conditions. [ABSTRACT FROM AUTHOR]

Elongation factor 4 (EF4) is a member of the family of ribosome- dependent translational GTPase factors, along with elongation factor G and BPI-inducible protein A. Although EF4 is highly conserved in bacterial, mitochondrial, and chloroplast genomes, its exact biological function remains controversial. Here we present the cryo-EM reconstitution of the GTP form of EF4 bound to the ribosome with P and E site tRNAs at 3.8-Å resolution. Interestingly, our structure reveals an unrotated ribosome rather than a clockwise-rotated ribosome, as observed in the presence of EF4-GDP andPsite tRNA. In addition, we also observed a counterclockwise-rotated form of the above complex at 5.7-Å resolution. Taken together, our results shed light on the interactions formed between EF4, the ribosome, and the P site tRNA and illuminate the GTPase activation mechanism at previously unresolved detail. [ABSTRACT FROM AUTHOR]

Many eukaryotic organisms encode more than one RNA-dependent RNA polymerase (RdRP) that probably emerged as a result of gene duplication. Such RdRP paralogs often participate in distinctRNAsilencing pathways and show characteristic repertoires of enzymatic activities in vitro. However, to what extent members of individual paralogous groups can undergo functional changes during speciation remains an open question. We show that orthologs of QDE-1, an RdRP component of the quelling pathway in Neurospora crassa, have rapidly diverged in evolution at the amino acid sequence level. Analyses of purified QDE-1 polymerases from N. crassa (QDE-1Ncr) and related fungi, Thielavia terrestris (QDE-1Tte) and Myceliophthora thermophila (QDE-1Mth), show that all three enzymes can synthesize RNA, but the precise modes of their action differ considerably. Unlike their QDE-1Ncr counterpart favoring processive RNA synthesis, QDE-1Tte and QDE-1Mth produce predominantly short RNA copies via primer-independent initiation. Surprisingly, a 3.19 Å resolution crystal structure of QDE-1Tte reveals a quasisymmetric dimer similar to QDE-1Ncr. Further electron microscopy analyses confirm that QDE-1Tte occurs as a dimer in solution and retains this status upon interaction with a template. We conclude that divergence of orthologous RdRPs can result in functional innovation while retaining overall protein fold and quaternary structure. [ABSTRACT FROM AUTHOR]

A 1 A O ATP synthases couple ion-transport of the A O sector and ATP synthesis/hydrolysis of the A 3 B 3 -headpiece via their stalk subunits D and F. Here, we produced and purified stable A 3 B 3 D- and A 3 B 3 DF-complexes of the Methanosarcina mazei Gö1 A-ATP synthase as confirmed by electron microscopy. Enzymatic studies with these complexes showed that the M. mazei Gö1 A-ATP synthase subunit F is an ATPase activating subunit. The maximum ATP hydrolysis rates ( V max ) of A 3 B 3 D and A 3 B 3 DF were determined by substrate-dependent ATP hydrolysis experiments resulting in a V max of 7.9 s − 1 and 30.4 s − 1 , respectively, while the K M is the same for both. Deletions of the N- or C-termini of subunit F abolished the effect of ATP hydrolysis activation. We generated subunit F mutant proteins with single amino acid substitutions and demonstrated that the subunit F residues S84 and R88 are important in stimulating ATP hydrolysis. Hybrid formation of the A 3 B 3 D-complex with subunit F of the related eukaryotic V-ATPase of Saccharomyces cerevisiae or subunit ε of the F-ATP synthase from Mycobacterium tuberculosis showed that subunit F of the archaea and eukaryotic enzymes are important in ATP hydrolysis. [ABSTRACT FROM AUTHOR]

We have synthesized a novel quinazolinone chalcone derivative (QC) and first time reported its in-vitro and in-vivo anticancer potential. It inhibited the cell proliferation of different cancer cell lines like PC-3, Panc-1, Mia-Paca-2, A549, MCF-7 and HCT-116. It induces apoptosis as measured by several biological endpoints such as apoptotic body formation, evident by Hoechst and scanning electron microscopy, enhanced annexinV-FITC binding of the cells, increased sub-G0 cell fraction, loss of mitochondrial membrane potential (Δψm), reduction of Bcl-2/Bax ratio, activation of caspase-9, caspase-3 and PARP-1 (poly-ADP Ribose polymerase) cleavage in HCT-116 cells. In spite of apoptosis, QC significantly hammers the downstream and upstream signaling cascade of PI3K/Akt/mTOR pathway and cell cycle regulator Skp-2, p21 and p27. Interestingly, QC induces the S and G2/M phase of HCT-116 cells at experimental doses. QC inhibits the tumor growth of Ehrlich ascites carcinoma (EAC), Ehrlich tumor (ET, solid) and sarcoma-180(solid) mice models. Furthermore, it was found to be non-toxic as no animal mortality (0/7) occurred during experimental doses. The present study provides an insight of anticancer potential of QC, which may be useful in managing and treating cancer. [ABSTRACT FROM AUTHOR]

Leukemia is one of the deadliest types of cancer. Lack of effective treatment strategies has resulted in an extensive quest for new therapeutic molecules against it. This study explores the molecular mechanism of anticancer activity of P16, a semisynthetic analog of parthenin, against the human acute lymphoblastic leukemia MOLT-4 cells. P16 displayed antiproliferative activity in different cancer cell lines; however, MOLT-4 cells showed highest sensitivity for P16 with IC50 value of 0.6 μM. Further studies revealed that P16 induced cell death by apoptosis. It caused mitochondrial stress, which was mediated by the translocation of Bax from cytosol to mitochondria and release of cytochrome c into the cytosol and consequent activation of caspase-9. However, P16 was also able to activate caspase-8, thus involving both extrinsic and intrinsic pathways of apoptosis. Further, activation of caspase-3 led to cleavage of its target proteins PARP-1 and ICAD, which resulted in apoptotic DNA damage. P16 induced apoptosis was accompanied by the down-regulation of important leukemic cell survival proteins like pAKT (S473), pAKT (T308), pP70S6K, pCRAF, and pERK1/2. However, inhibition of caspases by Z-VAD-FMK reversed the down-regulatory effect of P16 on pAKT (S473) and pP70S6K, as evident by the cell viability assay and flow cytometric analysis but this inhibition did not completely reverse the antiproliferative effect of P16, thereby indicating the role of additional factors apart from caspases in P16 induced apoptosis in MOLT-4 cells. Owing to its antiproliferative potential against leukemia cells, P16 can further be explored as an effective therapeutics against leukemia. [ABSTRACT FROM AUTHOR]

SecA is an ATP-dependent molecular motor pumping secretory and outer membrane proteins across the cytoplasmic membrane in bacteria. SecA associates with the protein-conducting channel, the heterotrimeric SecYEG complex, in a so-called posttranslational manner. A recent study further showed binding of a monomeric state of SecA to the ribosome. However, the true oligomeric state of SecA remains controversial because SecA can also form functional dimers, and high-resolution crystal structures exist for both the monomer and the dimer. Here we present the cryo-electron microscopy structures of Escherichia coli SecA bound to the ribosome. We show that not only a monomeric SecA binds to the ribosome but also that two copies of SecA can be observed that form an elongated dimer. Two copies of SecA completely surround the tunnel exit, providing a unique environment to the nascent polypeptides emerging from the ribosome. We identified the N-terminal helix of SecA required for a stable association with the ribosome. The structures indicate a possible function of the dimeric form of SecA at the ribosome. [ABSTRACT FROM AUTHOR]

Highlights: [•] Five of six fractions tested showed cytotoxicity effects on PC-3 and HL-60 cells with IC50 varied between 12 and 88μg/ml. [•] Ethyl acetate fraction of G. epunctata was the most active on HL-60 cells (IC50: 12μg/ml). [•] After 24h this fraction induced an increase of cells population in a sub-G1 phase in a dose-dependent. [•] EtOAc fraction induces apoptosis of HL-60 cells through G0/G1 phase arrest and loss of membrane mitochondrial potential. [ABSTRACT FROM AUTHOR]

Highlights: [•] We have isolated four metabolites from stem bark of Erythrina suberosa. [•] α-Hydroxyerysotrine, 4-Methoxy licoflavanone, Alpinumisoflavone and Wighteone. [•] They inhibit NF-κB and STAT signaling pathway. [•] They induce apoptosis through extrinsic and intrinsic pathways. [ABSTRACT FROM AUTHOR]

Objectives: This paper examined whether nebivolol protects the heart via nitric oxide (NO) synthase and NO-dependent signaling in an in vivo model of acute myocardial infarction.Background: Beta(3)-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. We hypothesized that specific beta(3)-AR agonists would attenuate myocardial ischemia-reperfusion (MI/R) injury via eNOS activation and increased NO bioavailability.Methods: Mice were subjected to 45 min of myocardial ischemia in vivo followed by 24 h of reperfusion (R). Nebivolol (500 ng/kg), CL 316243 (1 μg/kg), BRL-37344 (1 μg/kg), or vehicle (VEH) was administered at the time of R. Myocardial area-at-risk (AAR) and infarct size (INF)/AAR was measured at 24 h of R. Cardiac tissue and plasma were collected to evaluate eNOS phosphorylation, neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase expression, and nitrite and nitrosothiol levels.Results: Nebivolol (500 ng/kg) reduced INF/AAR by 37% (p < 0.001 vs. VEH) and serum troponin-I levels from 41 ± 4 ng/ml to 25 ± 4 ng/ml (p < 0.05 vs. VEH). CL 316243 and BRL-37344 reduced INF by 39% and 42%, respectively (p < 0.001 vs. VEH). Nebivolol and CL 316243 increased eNOS phosphorylation at Ser-1177 (p < 0.05 vs. VEH) and increased nitrite and total nitrosylated protein levels. Nebivolol and CL 316243 significantly increased myocardial nNOS expression. Nebivolol failed to reduce INF after MI/R in beta(3)-AR (-/-), eNOS(-/-), and in nNOS(-/-) mice.Conclusions: Our results indicate that beta(3)-AR agonists protect against MI/R injury. Furthermore, the cardioprotective effects of beta(3)-AR agonists are mediated by rapid eNOS and nNOS activation and increased NO bioavailability. [ABSTRACT FROM AUTHOR]

Abstract: Antioxidants have been used as adjuvant with anticancer therapy to synergize the potential of the anti-neoplastic therapeutics. Based on the fact, we have studied the effect of three natural antioxidants curcumin, silymarin and acteoside on AP9-cd (standardized lignan composition from Cedrus deodara) induced cytotoxicity in human leukemia HL-60 cells. The antioxidant potential of individual test compounds was first evaluated with ferric reducing antioxidant power (FRAP) test, which revealed that all four molecules behave as antioxidants. The apoptotic potential of AP9-cd was significantly enhanced in HL-60 cells in the presence of curcumin, silymarin and acteoside. It was confirmed by using various models like MTT assay, DNA fragmentation, nuclei condensation, sub-Go DNA population, Annexin-V-FITC binding, ROS depletion and immunoblotting in HL-60 cells. AP9-cd and individual antioxidants alone at low doses (10μg and 10μM, respectively) have meager or no cytotoxicity in HL-60 cells, whereas in mutual combinations, there were 2–3 times enhancement in Annexin-V-FITC and sub-Go DNA population. Moreover, prominent DNA ladders were observed at low doses of AP9-cd in combinations with various antioxidants. The Hoechst staining of the nucleus also revealed the same results for the HL-60 cells treated with AP9-cd and different antioxidants. The molecular diagnostics revealed that the combinations induced a strong antioxidant effect which was correlated with the downregulation of NF-κB expression in the nucleus. Out of the three antioxidants, curcumin was found to be more potent than acteoside and silymarin in terms of enhancing the apoptotic potential of AP9-cd. These results propose an important role of natural antioxidant as adjuvant to enhance the anticancer potential of AP9-cd and more likely other anti-neoplastic therapeutics. [Copyright &y& Elsevier]