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      Volume 42, Issue 3

      September 2017,   pages  355-521

    • Amar Klar: A giant among scientists (1947–2017)


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    • What history tells us XLIII Bacteriophage: The contexts in which it was discovered


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    • Amalaki Rasayana improved memory and neuronal metabolic activity in AβPP-PS1 mouse model of Alzheimer’s disease


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      Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by progressive loss of memoryand cognitive function. The cerebral metabolic rate of glucose oxidation has been shown to be reduced in AD. The presentstudy evaluated efficacy of dietary Amalaki Rasayana (AR), an Ayurvedic formulation used in Indian traditional system, inAβPP-PS1 mouse model of AD in ameliorating memory and neurometabolism, and compared with donepezil, a standardFDA approved drug for AD. The memory of mice was measured using Morris Water Maze analysis. The cerebralmetabolism was followed by 13C labelling of brain amino acids in tissue extracts ex vivo using ${}^{1}$H-[${}^{13}$C]-NMR spectroscopytogether with a short time infusion of [1,6-${}^{13}$C2]glucose to mice. The intervention with Amalaki Rasayana showedimproved learning and memory in AbPP-PS1 mice. The ${}^{13}$C labelings of GluC4, GABAC2 and GlnC4 were reduced inAbPP-PS1 mice when compared with wild-type controls. Intervention of AR increased the ${}^{13}$C labelling of amino acidssuggesting a significant enhancement in glutamatergic and GABAergic metabolic activity in AβPP-PS1 mice similar to thatobserved with donepezil treatment. These data suggest that AR has potential to improve memory and cognitive function inAD.

    • Differential reduction of reactive oxygen species by human tissuespecific mesenchymal stem cells from different donors under oxidative stress


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      Clinical trials using human Mesenchymal Stem Cells (MSCs) have shown promising results in the treatment of variousdiseases. Different tissue sources, such as bone marrow, adipose tissue, dental pulp and umbilical cord, are being routinelyused in regenerative medicine. MSCs are known to reduce increased oxidative stress levels in pathophysiological conditions.Differences in the ability of MSCs from different donors and tissues to ameliorate oxidative damage have not beenreported yet. In this study, for the first time, we investigated the differences in the reactive oxygen species (ROS) reductionabilities of tissue-specific MSCs to mitigate cellular damage in oxidative stress. Hepatic Stellate cells (LX-2) and cardiomyocyteswere treated with Antimycin A (AMA) to induce oxidative stress and tissue specific MSCs were co-cultured tostudy the reduction in ROS levels. We found that both donor’s age and source of tissue affected the ability of MSCs toreduce increased ROS levels in damaged cells. In addition, the abilities of same MSCs differed in LX-2 and cardiomyocytesin terms of magnitude of reduction of ROS, suggesting that the type of recipient cells should be kept in consideration whenusing MSCs in regenerative medicine for treatment purposes.

    • Protein complex finding and ranking: An application to Alzheimer’s disease


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      Protein complexes are known to play a major role in controlling cellular activity in a living being. Identifying complexesfrom raw protein–protein interactions (PPIs) is an important area of research. Earlier work has been limited mostly to yeastand a few other model organisms. Such protein complex identification methods, when applied to large human PPIs oftengive poor performance. We introduce a novel method called ComFiR to detect such protein complexes and further rankdiseased complexes based on a query disease. We have shown that it has better performance in identifying proteincomplexes from human PPI data. This method is evaluated in terms of positive predictive value, sensitivity and accuracy.We have introduced a ranking approach and showed its application on Alzheimer’s disease.

    • miR-200a-3p promotes β-Amyloid-induced neuronal apoptosis through down-regulation of SIRT1 in Alzheimer’s disease


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      The aberrantly expressed microRNAs (miRNAs) including miR-200a-3p have been reported in the brains of Alzheimer’sdisease (AD) patients in recent researches. Nevertheless, the role of miR-200a-3p in AD has not been characterized. Thepurpose of this study was to examine whether miR-200a-3p regulated b-Ameyloid (Ab)-induced neuronal apoptosis bytargeting SIRT1, a known anti-apoptotic protein. An increased level of miR-200a-3p and a decreased level of SIRT1 in thehippocampus of APPswe/PSDE9 mice (a model for AD) were observed. To construct an in vitro cell model of AD, PC12cells were cultured in presence of Ab25-35. The results of flow cytometry analysis showed that the apoptosis rate andcleaved-caspase-3 expression in PC12 cells exposed to Ab25-35 were remarkably increased, but the apoptosis rate andcleaved-caspase-3 activity were decreased when cells were transfected with anti-miR-200a-3p. On the other hand, MTTassay showed that the cell survival rate was increased in the Ab25-35 ? anti-miR-200a-3p group compared with the Ab25-35 ? anti-miR-NC group. Dual-luciferase reporter gene assay validated the predicted miR-200a-3p binding sites in the 30-UTR of SIRT1 mRNA. In addition, downregulation of SIRT1 promoted Ab25-35-induced neuronal apoptosis and cleavedcaspase-3 level in PC12 cells, whereas anti-miR-200a-3p reversed these effects. Knockdown of SIRT1 decreased theinhibitory effect of Ab25-35 on cell viability, while anti-miR-200a-3p attenuated this effect. Overall, the results suggest thatsuppression of miR-200a-3p attenuates Ab25-35-induced apoptosis in PC12 cells by targeting SIRT1. Thus, miR-200a-3pmay be a potential therapeutic target for treatment of AD.

    • Knockdown of Cripto-1 inhibits the proliferation, migration, invasion, and angiogenesis in prostate carcinoma cells


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      Cripto-1 (CR-1) is a member of the epidermal growth factor-Cripto-1/FRL1/Cryptic gene family that plays a key role in thevarious malignant cancers. However, the role of CR-1 in prostate carcinoma (PCa) remains limited. The expression of CR-1was down-regulated by small interfering RNA (siRNA). Western blot measured the expression levels of CR-1 and somerelated proteins. We performed Cell Counting Kit-8, 5-ethynyl-2-deoxyuridine (EdU) incorporation assay and flowcytometry to detect the cellular proliferation and cycle. The transwell assay was used to observe cellular migration andinvasion. The ability of angiogenesis was evaluated by tube formation assay. Our results showed that CR-1 knockdownmarkedly inhibited cell proliferation and induced cycle arrest in G1 phase, as p21 and p27 were up-regulated, whereascyclin D1 and cyclin E1 were diminished. Moreover, silencing of CR-1 dramatically inhibited cell migration and invasion,repressed matrix metalloproteinases, and disturbed epithelial-mesenchymal transition. CR-1 siRNA suppressed the secretedlevel of vascular endothelial growth factor, and reduced protein level of Vascular endothelial growth factor receptor 2. Wefurther found that decreased CR-1 expression inhibited FAK/Src/PI3K and Wnt/b-catenin signalling in PCa cells. Theseresults suggested CR-1 might be served as an effective therapeutic target in PCa.

    • Targeting cleavage and polyadenylation specific factor 1 via shRNA inhibits cell proliferation in human ovarian cancer


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      Cleavage and polyadenylation specificity factor 1 (CPSF1), a member of CPSF complex, has been reported to play a keyrole in pre-mRNA 30-end formation, but its possible role in ovarian cancer remains unclear. In the present study, we foundthe mRNA level of CPSF1 was overexpressed in ovarian cancer tissues using Oncomine Cancer Microarray database. Thenthe loss-of-function assays, including CCK-8, colony formation and flow cytometry assays, were performed to determinethe effects of CPSF1 on cell viability, proliferation, cell cycle and apoptosis of human ovarian cancer cell lines (SKOV-3and OVCAR-3). The results indicated that depletion of CPSF1 suppressed cell viability, impaired colony formation ability,induced cell cycle arrest at G0/G1 phase and promoted cell apoptosis in ovarian cancer cells. Furthermore, knockdown ofCPSF1 upregulated the expression of cleaved caspase-3 and PARP and downregulated CDK4/cyclin D1 expression. Thesedata suggested that CPSF1 could promote ovarian cancer cell growth and proliferation in vitro and its depletion might serveas a potential therapeutic target for human ovarian cancer.

    • Cholesterol-lowering drug, in combination with chromium chloride, induces early apoptotic signals in intracellular L. donovani amastigotes, leading to death


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      Leishmania establishes a successful parasitism by evading both oxidative and non-oxidative killing pathways, and its drugresistance against the currently available therapeutics demands for a safe and cheap drug. Since the parasite synthesizesergosterol instead of cholesterol, using the same biochemical pathway and enzymes, an inhibitor of HMG-CoA-Reductase,Lovastatin, has been tried for its anti-Leishmanial effect. Lovastatin, being an inhibitor of HMG-CoA-Reductase, inhibitsinfection by cholesterol depletion, while chromium chloride complexes, at their higher concentrations, are reported toexhibit cytotoxicity. In intracellular amastigotes, cytotoxicity has been checked by assessing various manifestation of celldeath, viz. DNA fragmentation, AnnexinV-FITC binding and JC-1 fluorescence ratio. Release of hydrogen peroxide (HPO)and nitric oxide (NO) has been assessed in live cell. Lovastatin and CrCl3.6H2O in combination has appeared to beineffective on promastigotes but has induced cytotoxic effect on the intracellular amastigotes through up-regulation ofcellular signalling mechanisms. CrCl3.6H2O stimulates generation of NO, leading to reduction of the number of intracellularamastigote, while Lovastatin shows HPO-mediated killing of the same, keeping the host cell unaffected. This noveltherapeutic approach, involving two known safe compounds in suboptimal doses, may resolve human visceralLeishmaniasis.

    • Cinnamomum osmophloeum Kanehira ethanol extracts prevents human liver-derived HepG2 cell death from oxidation stress by induction of ghrelin gene expression


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      Diabetes patients associated with liver disease carry a significant risk of morbidity and mortality. Cinnamon has beenreported to reduce fructose-induced oxidative stress in the rat liver. However, the mechanism by which cinnamon protectsthe liver in a high-saccharide environment remains to be investigated. HepG2 cells were cultured with 30 mM D-ribose tomimic the high-oxidative-stress environment, typical of a liver in a diabetic patient. Three different chemical types of C.osmophloeum ethanol extracts (CEEs) were added in HepG2 culture media and the administration of all three CEEsprotected HepG2 cells from D-ribose damage and increased cell survival by approximately 20%. Exclusively, the transcriptvariant 1 of the ghrelin gene, but not variant 3, was 2–3 times induced by the addition of these CEEs. Moreover, themRNAs of ghrelin processing enzyme, furin, and mboat4 were detected in HepG2 cells. The ghrelin hormones in theculture media were increased 4–9 times by the addition of CEEs. The protective effects of ghrelin on HepG2 cells inD-ribose environment were further confirmed by recombinant ghrelin transfection. We conclude that the CEEs induceghrelin gene expression and protect HepG2 cells from D-ribose-induced oxidative damage through ghrelin signalling.

    • High temperatures influence sexual development differentially in male and female tadpoles of the Indian skipper frog, Euphlyctis cyanophlyctis


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      Although sex determination in amphibians is believed to be a genetic process, environmental factors such as temperatureare known to influence the sex differentiation and development. Extremely low and high temperatures influence gonadaldevelopment and sex ratio in amphibians but the mechanism of action is not known. In the present study, effect of differenttemperatures on gonadal development, sex ratio and metamorphosis was studied in the Indian skipper frog, Euphlyctiscyanophlyctis. The embryos of Gosner stage 7 were exposed to 20, 22, 24, 26, 28, 30 and 32 deg C up to tadpole stage 42. Theembryos (stage 7) were also exposed to 20 and 32 deg C up to tadpole stage 25 (non-feeding stages). Tadpoles of stage 25 werereared at 20 and 32 deg C up to stage 42 (feeding stages). The results show that exposure to higher temperatures (28, 30 and32 deg C) during stages 7–42 produced male-biased sex ratio. Rearing of tadpoles at 32 deg C during stages 25–42 produced malebiasedsex ratio, while exposure during stages 7–25 did not affect sex ratio. Embryos and tadpoles exposed to lower temperatures (20 and 22 deg C) died during the early stages. High temperatures stimulated testis development, and disturbedovary development. Exposure to high temperatures resulted in the early metamorphosis of tadpoles with reduced body size.These results demonstrated that high temperatures influence gonadal development differently in male and female tadpoles,leading to male-biased sex ratio. These results suggest that high temperature probably acts through stress hormones andfavours the small-sized sex.

    • Can embryonic skipper frogs (Euphlyctis cyanophlyctis) learn to recognise kairomones in the absence of a nervous system?


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      In this study, we used larval Euphlyctis cyanophlyctis to determine the predator recognition mechanism. We conducted aseries of experiments to determine if larval E. cyanophlyctis have the innate ability to recognise predatory odour (kairomones)as a threat or if they learn to do so during ontogeny. In the case of learning, we wanted to determine thedevelopmental window during which learning is accomplished. Further, we tested the antipredator response of predatornaı

      ¨ve as well as predator-experienced tadpoles to chemical cues of different origins in order to assess if they exhibitdifferential responses. Our results clearly indicate that predator-naı¨ve tadpoles of E. cyanophlyctis do not reduce theiractivity against predatory cues of dragonfly nymphs, suggesting that they lack the innate ability to recognise kairomones.However, they could learn to do so when trained to perceive kairomones simultaneously along with alarm cues. Surprisingly,larval E. cyanophlyctis could learn to recognise kairomones through association during embryonic stages evenbefore the development of a nervous system. Although larval E. cyanophlyctis lack the innate ability to recognise kairomones,they were able to recognise conspecific alarm cues on the first encounter, indicating that they have the innateability to recognise alarm cues as a potential threat.

    • Modulation of chaperone-like and membranolytic activities of major horse seminal plasma protein HSP-1/2 by L-carnitine


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      The major protein of horse seminal plasma, HSP-1/2, exhibits membranolytic and chaperone-like activities and plays acrucial role in regulating sperm capacitation. L-Carnitine is a small polar molecule present in high concentrations inmammalian seminal plasma. The present results demonstrate that L-carnitine binds to HSP-1/2 and increases its thermalstability, enhances cooperativity of its chemical unfolding and decreases both chaperone-like and membranolytic activitiesof this protein. The HSP-1/2–L-carnitine complex exhibits anti-oxidative behaviour by inhibiting the production ofhydroxyl radicals, suggesting that it can protect other constituents of seminal plasma from damage by hydroxyl radicals. AsHSP-1/2 and L-carnitine share the same spatiotemporal location in the horse reproductive tract, this interaction is physiologicallysignificant and may prevent premature interaction of HSP-1/2 with sperm, which in turn regulates the spermcapacitation.

    • Promoter polymorphism MMP-1 (-1607 2G/1G) and MMP-3 (-1612 5A/6A) in development of HAND and modulation of pathogenesis of HAND


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      The pathogenesis of HIV-associated neurocognitive disorder (HAND) is modulated by host genetic susceptibility factorssuch as Matrix metalloproteinases (MMPs). Promoter polymorphism of MMP-1 and MMP-3 may modify the expression ofthe gene. Hence, we evaluated the association of MMP-1-16072G/1G and MMP-3-1612 5A/6A polymorphisms withdevelopment of HAND and the modulation of pathogenesis of HAND. We enrolled a total of 180 individuals, 50 HIVinfectedindividuals with HAND, 130 without HAND, and 150 healthy controls. Polymorphism of MMP-1 and MMP-3were genotyped by PCR-RFLP. MMP-1-1607 2G1G, -16071G/2G-1G/1G genotypes and -1607 1G allele were associatedwith the development of HAND (OR = 1.64, P = 0.05; OR = 1.45, P = 0.04; OR = 1.69, P = 0.05). MMP-1-16071G1G, MMP-3-16125A5A genotypes increased the risk for the development of HAND (OR = 1.78, P = 0.25;OR = 2.39, P = 0.13). MMP-3-1612 5A5A, -1612 6A/5A-5A/5A genotypes and -1612 5A allele were associated with thereduced risk of HAND (OR = 0.40, P = 0.05; OR = 0.53, P = 0.04; OR = 0.40, P = 0.01). Haplotype 5A1G increasedthe risk of development of HAND (OR = 1.93, P = 0.05). As observed in advanced HIV disease stage, MMP-1-16071G1G genotype enhance the risk for advancement of HIV disease (OR = 1.69, P = 0.89). MMP-3-1612 6A5A genotypeshowed higher risk for development of HAND in alcohol users (0R = 1.65, P = 0.44). MMP-1 genotype may have aninfluence on development of HAND whereas MMP3-1612 5A5A genotype may reduce risk for pathogenesis of HAND.

    • Hypoxia stimulates invasion and migration of human cervical cancer cell lines HeLa/SiHa through the Rab11 trafficking of integrin αvβ3/FAK/PI3K pathway-mediated Rac1 activation


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      Hypoxia plays a key role in tumour cell survival, invasion, and metastasis. An increasing number of studies have attemptedto characterize the tumour response to hypoxia and to identify predictive markers of disease. Here we show that hypoxiaincreases tumour cell invasion and migration by the modulation of Rab11, an important molecule for vesicular trafficking.In our study, we found that Rab11, together with the activation of Rac1, could stimulate invasion and migration of cervicalcancer cell lines HeLa/SiHa in hypoxia. Activation of Rac1 activity by hypoxia seems to be central to carcinoma invasion.We also found that these effects could be related to the integrin αvβ3. In addition, we studied the molecular pathway for thisprocess. Our results showed that in cervical cancer cell lines HeLa/SiHa, Rac1 activation in hypoxia could stimulateinvasion and migration, and this process was mediated by integrin αvβ3-mediated FAK and PI3K phosphorylation.Furthermore, hypoxia induced a dramatic increase in αvβ3 integrin surface expression, and this increase is dependent onRab11. In conclusion, our study might provide a new mechanism for the effect of hypoxia on stimulating cervicalcarcinoma invasion.

    • Rice MYC2 (OsMYC2) modulates light-dependent seedling phenotype, disease defence but not ABA signalling


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      Arabidopsis MYC2 (AtMYC2) is a bHLH class transcription factor that mediates light-dependent seedling development,disease defence, JA and ABA signalling. AtMYC2 gene modulates hypocotyl elongation and expression of chlorophyll A/Bbinding protein 1 (CAB1) and rubisco small subunit protein1 (RBCS1) under blue light. The atmyc2 mutants are resistantagainst virulent bacterial pathogens. MYC2 orthologues from several crop plants have been characterized. The rice geneOs10g42430 has been referred earlier as OsMYC2 and has been shown to promote expression of JA-inducible genes.However, the role of OsMYC2 in seedling development under ABA, dark or light of specific wavelengths was not known.It was also not known whether OsMYC2 complements AtMYC2 function in Arabidopsis. We show here that expression ofOsMYC2 in the atmyc2 mutant of Arabidopsis complements the blue-light-mediated defects in hypocotyl elongation andexpression of CAB1 and RBCS1. We generated multiple transgenic rice lines for over-expression and RNAi-mediatedsuppression of OsMYC2. In agreement with AtMYC2 function, OsMYC2 over-expression and RNAi lines showedenhanced and suppressed seedling growth compared to WT plants respectively under blue light, and showed little effectunder white light or dark. In agreement with the negative regulatory role of AtMYC2 in disease defence, the RNAi linesshowed enhanced resistance against bacterial pathogen Xanthomonas oryzae pv oryzae. However, in contrast to AtMYC2function, OsMYC2 influences seedling development under red light and show no effect in ABA-mediated seed germination.Thus, the results suggest evolutionarily conserved as well as the distinct role of OsMYC2 in comparison with AtMYC2.

    • Polymorphisms in the hepatitis C virus core and its association with development of hepatocellular carcinoma


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      Little is known about the mechanisms underlying hepatocellular carcinoma (HCC). Some studies have focused on the roleof HCV viral proteins in hepatocyte transformation. In this work we have compiled and analysed current articles regardingthe impact of polymorphisms in the HCV core gene and protein on the development of HCC. An exhaustive search for fulltextarticles until November 2016 in PubMed database was performed using the MeSH keywords: ‘hepatitis C’, ‘polymorphisms’,

      ‘core’, ‘hepatocellular cancer’ and ‘hepatocarcinogenesis’. Nineteen full-text articles published between 2000and 2016 were considered. Different articles associate not only the HCC development with polymorphisms at residues 70and 91 in the core protein, but more with mortality and treatment response. Also, different polymorphisms were found incore and other viral proteins related to HCC development. Eleven articles reported that HCC development is significantlyassociated with Gln/His70, four associated it with Leu91 and two more associated it with both markers together. Additionalstudies are necessary, including those in different types of populations worldwide, to validate the possibility of the usabilityand influence in chronically HCV-infected patients as well as to observe their interaction with other risk factors or prognosisand genetic markers of the host.

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