• Volume 44, Issue 6

      December 2019

    • MiR-506-3p suppresses the proliferation of ovarian cancer cells by negatively regulating the expression of MTMR6

      YUAN WANG XIA LEI CHENGYING GAO YANXIA XUE XIAOLIN LI HAIYING WANG YAN FENG

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      MicroRNAs have been reported to play a crucial role in ovarian cancer (OC) as the most lethal malignancy of the women.Here, we found miR-506-3p was significantly down-regulated in OC tissues compared with corresponding adjacent nontumortissues. Ectopic miR-506-3p expression inhibited OC cell growth and proliferation using MTT and colony formationassay. Additionally, flow cytometry analysis showed that the overexpression of miR-506-3p induced cell cycle G0/G1phase arrest and cell apoptosis in OC cells. A luciferase reporter assay confirmed that the myotubularin-related protein 6(MTMR6) was the target of miR-506-3p. The expression of MTMR6 was increased in OC tissues compared with adjacenttissues using immunohistochemistry. Elevated MTMR6 protein levels were confirmed in OC cells lines compared withimmortalized fallopian tube epithelial cell line FTE187 using western blotting. In addition, knockdown of MTMR6 imitatedthe effects of miR-506-3p on cell proliferation, cell cycle progression and apoptosis in OC cells. Furthermore, rescueexperiments using MTMR6 overexpression further verified that MTMR6 was a functional target of miR-506-3p. Our dataindicate that miR-506-3p might serve as a tumor suppressor gene and propose a new regulatory mechanism of MTMR6 bymiR-506-3p in OC.

    • Sp7/osterix positively regulates dlx2b and bglap to affect tooth development and bone mineralization in zebrafish larvae

      ZHONGJIAN CHEN ZHIYUN SONG JINJING YANG JIAN HUANG HONGBING JIANG

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      Osterix (or Sp7) is an important transcription factor that promotes osteoblast differentiation by modulating the expression ofa range of target genes. Although many studies have focused on Osterix/Sp7 regulatory mechanisms, the detailed functionshave not been fully elucidated. Toward this end, in this study, we used CRISPR/Cas9 technology to knock out the zebrafishsp7 gene, and then analyzed its phenotype and biological function. Two knockout sp7 mutant lines were successfullyobtained. The bone mineralization level was significantly reduced in the zebrafish sp7-/- homozygote, resulting inabnormal tooth development in the larvae. Quantitative real-time polymerase chain reaction showed that loss of sp7 led todown-regulated expression of the dlx2b and bglap genes related to tooth development and bone mineralization, respectively.Moreover, cell transfection experiments demonstrated that Sp7 directly regulates the expression of dlx2b and bglapthrough Sp7-binding sites on the promoter regions of these two genes. Overall, this study provides new insight into the roleof Sp7 in bone mineralization and tooth development.

    • Long non-coding RNA H19 modulates proliferation and apoptosis in osteoarthritis via regulating miR-106a-5p

      XIAOJUN ZHANG XIAOMEI LIU XIAOQIN NI PENG FENG YU WANG

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      Osteoarthritis (OA), a type of joint diseases, could result in breakdown of joint cartilage and underlying bone. Accumulatingevidences suggested that long non-coding RNAs play important roles in OA progression. However, the underlyingmechanism of H19 in OA is still not fully explored. The expression levels of H19 and miR-106a-5p in OA samples frompatients or cultured chondrocytes were examined by quantitative real time polymerase chain reaction. Cell proliferation andapoptosis were analysed by MTT assay and flow cytometry, respectively. Western blotting was employed to detect theexpression levels of PCNA, CyclinD1, Caspase 3 and Cleaved Caspase 3. StarBase database, luciferase assay and RNAimmunoprecipitation were introduced to confirm the relationship between H19 and miR-106a-5p. The correlation of H19and miR-106a-5p was analysed by Spearman rank analysis. H19 expression was upregulated, while miR-106a-5p level wasdownregulated in OA samples and IL-1beta-treated chondrocytes. H19 overexpression inhibited the proliferation and inducedapoptosis in IL-1beta-treated chondrocytes, while H19 knockdown induced the opposite effect. Luciferase and RIP assaydemonstrated that miR-106a-5p was a direct target of H19. miR-106a-5p overexpression led to proliferation promotion andapoptosis inhibition in chondrocytes treated by IL-1beta and it reversed the effect of H19 addition. We conclude that H19could regulate proliferation and apoptosis of chondrocytes treated by IL-1beta in OA via sponging miR-106a-5p.

    • Arabidopsis SIMILAR TO RCD-ONE genes are ubiquitous and respond to multiple abiotic stresses through diverse signaling pathways

      XIAOLIANG ZHAO LIJIE GAO JIAYAN REN FEI PAN

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      The SIMILAR TO RCD-ONE (SROs) have been characterized as a group of plant-specific proteins which play importantfunctions in stress responses and development. Here, we analyze the expression profiles of six SRO genes under differentstress treatments in Arabidopsis. Our results revealed that RCD1 play an essential role in plant responses to variousenvironmental stresses. SRO1 has partially overlapping functions with RCD1 in plant response to HgCl2 and H2O2 stress.Analysis of the transcriptional expression of SROs indicated that both of the RCD1 and SRO1 transcripts were up-regulatedby HgCl2 and light, not by other stresses, and that of SRO5 was induced by salt. Expression of SRO3 and SRO4 were notinfluenced by stresses. The different effects of these stresses on the expression of the SRO genes indicate that the SROfamily is regulated by multiple signaling pathways. Sequence analyses of the SRO proteins implicate a highly preservedprotein structure and are specific to plants, which might have implications for functional conservation. The ubiquitousexpression and nuclear localization of SRO family suggested that their function might be related to transcription factorregulation and complex formation. Taken together, SRO family is critical for proper plant development and multiple stressresponses.

    • Rational design of type-IA receptor-derived cyclic peptides to target human bone morphogenic protein 2

      XIAOHUA FAN HAI XIA XIAOYUN LIU BENYING LI JUN FANG

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      Human bone morphogenetic protein 2 (BMP2) is a bone-growth regulatory factor involved in the formation of bone andcartilage, and has been recognized as an attractive therapeutic target for a variety of bone diseases and defects. Here, wereport successful design of a head-to-tail cyclic peptide based on crystal structure to target BMP2. Computational alaninescanning identifies two hotspot regions at the crystal complex interface of BMP2 with its type-IA receptor; promising one isstripped from the interface to derive a linear self-inhibitory peptide RPS2[r78-94] that covers residues 78–94 of the receptorprotein. Dynamics simulation and energetics analysis reveal that the peptide is highly flexible in isolated state and cannotspontaneously bind to BMP2. The RPS2[r78-94] peptide is further extended from its N- and C-termini until reaching twospatially vicinal residues 74 and 98 in the crystal structure of intact BMP2–receptor complex system, consequently resultingin a longer peptide RPS2[r74-98], which is then cyclized in a head-to-tail manner to obtain its cyclic counterpartcycRPS2[r74-98]. Computational analysis suggests that the cyclic peptide can well maintain in a conformation similar withits active conformation in complex crystal structure, exhibiting a smaller disorder and a larger potency than its linearcounterpart. Further assays confirm that the two linear peptides RPS2[r78-94] and RPS2[r74-98] are nonbinders of BMP2,whereas, as designed, the cyclic peptide cycRPS2[r74-98] can bind to BMP2 with a moderate affinity. The cyclic peptide isexpected as a lead molecular entity to develop new and potent peptide-based drugs for BMP2-targeted therapy.

    • Correction to: Protein-rich extract of Musca domestica larvae alleviated metabolic disorder in STZ-induced type 2 diabetic rat model via hepatoprotective and pancreatic b-cell protective activities

      HANFANG MEI JIANHUA XU YINRU HE XIA YANG WENBIN LIU WEI TIAN YU ZENG JIAYONG ZHU

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      In the December 2018 issue of the Journal of Biosciences, in the article titled ‘‘Protein-rich extract of Musca domestica larvaealleviated metabolic disorder in STZ-induced type 2 diabetic rat model via hepatoprotective and pancreatic b -cell protectiveactivities’’ by Hanfang Mei et al. (DOI: 10.1007/s12038-018-9804-z; Vol. 43, No. 5, pp. 969–983), the affiliations ofHanfang Mei have been incompletely mentioned as:1Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou 510006, Guangdong, China2School of Basic Courses, Guangzhou 510006, Guangdong, China3Department of Biochemistry and Molecular Biology, Guangdong Pharmaceutical University, Guangzhou Higher EducationMega Center, Guangzhou 510006, Guangdong, ChinaThe correct affiliations should read as:1Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University,Guangzhou Higher Education Mega Center, Guangzhou 510006, Guangdong, China2School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou510006, Guangdong, China3Department of Biochemistry and Molecular Biology, Guangdong Pharmaceutical University, Guangzhou Higher EducationMega Center, Guangzhou 510006, Guangdong, China

    • Overcoming randomness does not rule out the importance of inherent randomness for functionality

      YARON ILAN

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      Randomness is intrinsic to many natural processes. It is also clear that, under certain conditions, disorders are not associatedwith functionality. Several examples in which overcoming, suppressing, or combining both randomness and non-randomnessis required are drawn from various fields. However, the need to suppress or overcome randomness does not negateits importance under certain conditions and its significance in valid processes and organ functions. Randomness should beacknowledged rather than ignored or suppressed; it can be viewed, at worst, as a disturbing disorder that may be treated toproduce order, or, at best, as a ‘beneficial disorder’ that can be considered as a higher level of functionality.

    • Rapid burst of ethylene evolution by premature seed: A warning sign for the onset of spongy tissue disorder in Alphonso mango fruit?

      SESHADRI SHIVASHANKAR MANOHARAN SUMATHI

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      Moisture stress induced in premature seeds due to the breakdown of funiculus in Alphonso mango led to the burst ofethylene evolution, which in turn caused a sudden increase of polyphenol oxidase activity in the pulp, resulting in thedevelopment of a black spot near the seed base. Reduced levels of very long chain fatty acids in 70% mature seeds withblack spots were associated with a sudden increase of cytokinins followed by a rapid rise of starch-metabolizing enzymesculminating in the onset of pre-germination events. Concurrently, an overproduction of p-OH benzoic acid inhibitedamylase and polygalacturonase enzymes and led to partial degradation of the stored starch and pectin in the pulp. A paralleldrop in climacteric ethylene production by the pulp led to incomplete ripening coupled with changes in composition, textureand aroma of the pulp, characteristic of spongy tissue. The results have provided strong experimental evidence to supportthe fact that increased competition for resources among developing fruits for the synthesis of seed fat plays a critical role inspongy tissue formation in Alphonso mango. The major highlight of the study is that rapid ethylene evolution by prematureseed is an early warning sign for the initiation of spongy tissue formation in Alphonso mango.

    • A cross-eyed geneticist’s view V. How Sydney Brenner, Leslie Barnett, Eugene Katz, and Francis Crick inferred that UGA is a nonsense codon

      DURGADAS P KASBEKAR

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    • Laser-ablation-synthesized nanoparticles and animal cell lines studies

      MAHADEVAIAH NAWNEET K KURREY G K GOWTHAM R SOMSHEKAR

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      Nanoparticles (NPs) synthesized by laser ablation in distilled water were used to study their biological effect on normal andcancer cells. Parameters such as cell morphology, cell proliferation and viability were examined for treated cell lines, andthe effect was represented in terms of cells cytotoxicity using standard procedures. The study reveals the higher cytotoxiceffect of nanoparticles on cancerous cells of breast, melanoma and colon origin compared to normal fibroblast cells NIH-3T3. Furthermore, DNA fragmentation assay results demonstrated the apoptosis mediated cell death in nanoparticle-treatedcancer cells. The distinct role of nanoparticles in normal and cancer cells of different origin showed that nanoparticles werespecific to cause cytotoxicity in particular cancer cells type. NPs exhibit cytotoxic effects in cancer cells by inducingapoptosis. These studies provide fundamental evidence for the easy, simple and safe mode of nanoparticles synthesis andtheir application in cancer cells death.

    • Involvement of putrescine in osmotic stress-induced ABA signaling in leaves of wheat seedlings

      HY DU GS CHEN JM YU YY BAO GT LIU HP LIU R GUPTA

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      To elucidate one mechanism by which putrescine (Put) functions in plant signaling under osmotic stress, Put and ABAcontents, and plasma membrane-NADPH oxidase (PM-NOX) activity were detected in wheat seedling leaves. Underosmotic stress, ABA and Put contents, PM-NOX activity, and PM-NOX-dependent O2.- production all increased. Theinhibitor tungstate (T) of ABA bio-synthesis reduced the increases in ABA and Put contents under osmotic stress. Theinhibitor D-arginine (D-Arg) of Put bio-synthesis didn’t reduce osmotic-induced increase of ABA, but it inhibited theincreases of PM-NOX activity and O2 . - production, and the inhibitory effects were reversed by exogenous Put. Thesefindings suggested that ABA might regulate Put biosynthesis, and Put might regulate PM-NOX activity. Treatments withthree inhibitors imidazole (I), diphenylene iodonium (DPI) and pyridine (P) of PM-NOX reduced significantly not only O2 . -production, but also the stress-induced increase of Put content, which indicated that O2 . - production might regulate Putbiosynthesis. Treatments with EGTA (Ca2+ chelator), La3+ and verapamil (V) (Ca2+ channel blockers) reduced significantlythe stress-induced increase of Put content, which suggested that Ca2+ might regulate Put biosynthesis. With thesefindings, it could be concluded that Put was involved in ABA signaling induced by osmotic stress via regulating PM-NOXactivity in wheat seedling leaves.

    • Molecular cloning and characterization of genes related to the ethylene signal transduction pathway in pomegranate (Punica granatum L.) under different temperature treatments

      RONG HUANG WEI LI XIAO-WAN GUAN BIAO XIE SHUI-MING ZHANG

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      Low temperature storage is a common method for storing pomegranates post-harvest; however, unsuitable low temperaturescan cause fruit chilling injuries, the molecular mechanism of which is as yet unclear. Ethylene is a major factor affecting thepost-harvest storage quality of pomegranates, and functions mainly through the ethylene signal transduction pathway.ERF1, ERF2 and ETR are key genes in the ethylene signal transduction pathway. Here, we used RACE and homologouscloning techniques to obtain PgERF1 (KU058889), PgERF2 (KU058890) and PgETR (KU058891) from Punica granatumcv. Yushizi. Sequence alignment and functional domain analysis revealed that both PgERF1 and PgERF2 contained aDNA-binding-site at the 120th to 177th amino acids of the N-terminus, which is a typical AP2/ERF center structuredomain. Analysis of changes in expression of PgERF1, PgERF2 and PgETR following storage for different lengths of time(0, 14, 28, 42 and 56 days) at different temperatures (0 deg C, 5 deg C, 10 deg C and 15 deg C) revealed that the expression levels ofPgERF1 and PgERF2 had a significant positive correlation. At the same time, the expression of both PgERF1 and PgERF2increased continuously with time when seeds were stored at 0 deg C. However, there was no obvious linear relationshipbetween time stored and the levels of expression of PgETR. Therefore, we inferred that at 0 deg C, the ethylene signaltransduction pathway might play an important role in fruit chilling injuries during post-harvest storage.

    • Presence of carbohydrate binding modules in extracellular region of class C G-protein coupled receptors (C GPCR): An in silico investigation on sweet taste receptor

      ELAHEH KASHANI-AMIN AMIRHOSSEIN SAKHTEMAN BAGHER LARIJANI AZADEH EBRAHIM-HABIBI

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      Sweet taste receptor (STR) is a C GPCR family member and a suggested drug target for metabolic disorders such asdiabetes. Detailed characteristics of the molecule as well as its ligand interactions mode are yet considerably unclear due toexperimental study limitations of transmembrane proteins. An in silico study was designed to find the putative carbohydratebinding sites on STR. To this end, a-D-glucose and its a-1,4-oligomers (degree of polymerization up to 14) were chosen asprobes and docked into an ensemble of different conformations of the extracellular region of STR monomers (T1R2 andT1R3), using AutoDock Vina. Ensembles had been sampled from an MD simulation experiment. Best poses were furtherenergy-minimized in the presence of water molecules with Amber14 forcefield. For each monomer, four distinct bindingregions consisting of one or two binding pockets could be distinguished. These regions were further investigated withregard to hydrophobicity and hydrophilicity of the residues, as well as residue compositions and non-covalent interactionswith ligands. Popular binding regions showed similar characteristics to carbohydrate binding modules (CBM). Observationof several conserved or semi-conserved residues in these binding regions suggests a possibility to extrapolate the results toother C GPCR family members. In conclusion, presence of CBM in STR and, by extrapolation, in other C GPCR familymembers is suggested, similar to previously proposed sites in gut fungal C GPCRs, through transcriptome analyses. STRmodes of interaction with carbohydrates are also discussed and characteristics of non-covalent interactions in C GPCRfamily are highlighted.

    • Translin: A multifunctional protein involved in nucleic acid metabolism

      ALKA GUPTA VINAYAKI S PILLAI RAJANI KANT CHITTELA

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      Translin, a highly conserved, DNA/RNA binding protein, is abundantly expressed in brain, testis and in certain malignancies.It was discovered initially in the quest to find proteins that bind to alternating polypurines-polypyrimidines repeats.It has been implicated to have a role in RNA metabolism (tRNA processing, RNAi, RNA transport, etc.), transcription,DNA damage response, etc. Studies from human, mice, drosophila and yeast have revealed that it forms an octameric ring,which is important for its function. Translin is a cytoplasmic protein, but under genotoxic stress, it migrates into thenucleus, binds to the break point hot spots and therefore, thought to be involved in chromosomal translocation events aswell as DNA damage related response. Its structure is known and DNA binding regions, GTP binding region and regionsresponsible for homotypic and heterotypic interaction are known. It forms a ball like structure with open central channel foraccommodating the substrate nucleic acids. Besides this, translin protein binds to 30 and 50 UTR of certain mRNAs andprobably regulates their availability for translation. It is also involved in mRNA transport and cell cycle progression. Itforms a heteromeric complex with translin associated factor-X (TRAX) to form C3PO complex which is involved in RNAsilencing process. Recently, it has been shown that translin is upregulated under starvation conditions in Drosophila and isinvolved in the integration of sleep and metabolic rate of the flies. Earlier studies classified translin as a DNA repair protein;however subsequent studies showed that it is a multifunctional protein. With this background, in this review we havesummarized the translin biochemical activities, cellular function as well as structural properties of this important protein.

    • Biophysical methods for quality evaluation of decellularized and recellularized tissue-engineered constructs of organs and tissues

      ELENA ALEXANDROVNA GUBAREVA ELENA VYACHESLAVOVNA KUEVDA ALEXANDER ALEXANDROVICH BASOV ALEKSANDR SERGEEVICH SOTNICHENKO SERGEY NIKOLAEVICH BOLOTIN STEPAN SERGEEVICH DZHIMAK

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      Tissue engineering is rapidly growing now and can become a promising alternative to transplantation of organs and tissues,as it is devoid of major shortcomings of transplantology, such as acute shortage, complexity of selection, delivery andstorage of donor material, lifelong immunosuppressive therapy. One of the most widely known methods of obtainingbiological scaffolds for the subsequent creation of tissue-engineered constructs of organs and tissues is decellularization.The evaluation of the quality of the obtained scaffolds, based on the study of the viability of cell structures in decellularizedand recellularized matrices, is one of the priorities of modern regenerative medicine worldwide. In this investigation, thebiophysical criteria of decellularization and recellularization of tissue-engineered constructs based on the evaluation of thegeneration of free radicals in native, decellularized and recellularized tissues by EPR spectroscopy and chemoluminescencein a complex assessment of the quality of biological matrixes obtained are considered using intrathoracic organs and tissuesof rats. It has been established that the intensity indices of free radical generation in native and recellularized tissues ofanimal organs, as well as in decellularized matrices, can serve as one of the express criteria for quantitative assessment ofcell structures viability.

    • Investigation of the response to salinity of transgenic potato plants overexpressing the transcription factor StERF94

      MARIAM CHARFEDDINE SAFA CHARFEDDINE IMEN GHAZALA DONIA BOUAZIZ RADHIA GARGOURI BOUZID

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      Salinity is one of the most important constraints threatening the cultivation of potato plants (Solanum tuberosum L.). Itaffects plant growth and leads to significant yield loss. Consequently, it is important to improve the tolerance of potatoplants to salinity. In this context, we investigated the involvement of a potato ethylene responsive factor (StERF94) in plantresponse to salinity, since our previous genome-wide analysis showed that it may be related to biotic and abiotic stressresponse. ERF proteins belong to a large family of transcription factors that participate in plant response to abiotic stresses.We have previously identified the StERF94 gene which shows increased expression in potato plants submitted to salttreatment. In this study, transgenic potato plants overexpressing StERF94 were produced and submitted to salt treatment(100 mM NaCl) in vitro and under greenhouse culture conditions. StERF94 transgenic lines showed lower decrease of stemelongation under salt treatment in comparison to non-transgenic wild-type plants. Moreover, these plants showed a lowlevel of H2O2 and Malondialdehyde content, and an increase in catalase and GPX (Gluthation peroxidase) activitiescompared to non-transgenic plants. In a second step, enhanced expression of some target genes for example CuZn-SOD,DHN25 (Dehydrin) and ERD (Early Responsive to Dehydration) was noted in the StERF94 transgenic plants, submitted tosalt treatment. The StERF94 factor was also involved in the activation of osmoprotectant synthesis. Taken together, all thesedata suggest that overexpression of the StERF94 transcription factor increases the tolerance of potato plants to salinity byimproving plant growth, osmoprotectant synthesis and antioxidant activityleading to low oxidative stress damage.

    • Iris yellow spot virus–induced chloroplast malformation results in male sterility

      AHMED ABDELKHALEK SAMEER H QARI ELSAYED HAFEZ

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      Iris yellow spot virus (IYSV) is one of the most devastating viral pathogens, which causes high economic losses in theonion yield. Physiological and genetic changes are associated with the appearance of chlorotic symptom in the infectedplants. IYSV-N gene sequence analysis revealed that it shared sequence identity of 99% with other Egyptian isolates, atboth genomic and proteomic levels. In addition, N protein sequence with computational examination indicated many motifsinvolved and played different roles in the virus activity and its regulation and stability were detected. In the DifferentialDisplay-Polymerase Chain Reaction (DD-PCR) study, a highly up-regulated gene at 15 days post-biological IYSV inoculation(dpi) was selected for sequencing. Based on the sequencing results that showed the identified gene was coding for achloroplast-related gene, degenerate specific primers were designed for Real-Time PCR analysis. A significant change inthe transcription level of the chloroplast-related gene after 15 dpi suggested that some IYSV proteins interact and/orregulate with chloroplast proteins and this finding supports the DD-PCR results. At 20 dpi, the ultrathin sections showedthat IYSV infection caused many dramatic chloroplasts malformations. The malformation appeared as chloroplast brokenenvelope with the presence of numerous spherical particles inside it and chloroplasts with long stromule. Our findingsindicated that IYSV interrupts normal chloroplast functions, as a part of the onion defence response, however many crucialfactors remain to be elucidated and further studies are needed at both biological and molecular levels.

    • A review of computational algorithms for CpG islands detection

      RANA ADNAN TAHIR DA ZHENG AMINA NAZIR HONG QING

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      CpG islands are generally known as the epigenetic regulatory regions in accordance with histone modifications, methylation,and promoter activity. There is a significant need for the exact mapping of DNA methylation in CpG islands tounderstand the diverse biological functions. However, the precise identification of CpG islands from the whole genomethrough experimental and computational approaches is still challenging. Numerous computational methods are beingdeveloped to detect the CpG-enriched regions, effectively, to reduce the time and cost of the experiments. Here, we reviewsome of the latest computational CpG detection methods that utilize clustering, patterns and physical-distance likeparameters for CpG island detection. The comparative analyses of the methods relying on different principles andparameters allow prioritizing the algorithms for specific CpG associated datasets to achieve higher accuracy and sensitivity.A number of computational tools based on the window, Hidden Markov Model, density and distance-/length-basedalgorithms are being applied on human or mammalian genomes for accurate CpG detection. Comparative analyses of CpGisland detection algorithms facilitate to prefer the method according to the target genome and required parameters to attainhigher accuracy, specificity, and performance. There is still a need for efficient computational CpG detection methods withlower false-positive results. This review provides a better understanding about the principles of tools that will assist toprioritize and develop the algorithms for accurate CpG islands detection.

    • Isoflurane preconditioning protects hepatocytes from oxygen glucose deprivation injury by regulating FoxO6

      YONGHUI ZHONG XUEFANG HU LIANGSHENG MIAO

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      The forkhead protein (FoxO) family plays a crucial role in regulating oxidative stress, cell proliferation, and apoptosis.FoxO6, a member of the FoxO family, helps regulate oxidative stress in gastric cancer and hepatocellular carcinoma.However, it is unclear whether FoxO6 participates in the protective effect of isoflurane preconditioning in liver injurycaused by oxidative stress in ischemia. In this study, we explored the role and mechanism of FoxO6 in the protective effectof isoflurane preconditioning during hepatocyte injury caused by oxygen-glucose deprivation (OGD). Cells from the humanfetal hepatocyte (LO2) line were incubated with 0%, 1%, 2%, 2.5%, 3%, 3.5%, 4%, or 5% isoflurane for 3 h and thenexposed to OGD. Data showed that 3% isoflurane preconditioning inhibited FoxO6 expression, caspase-3 activity, andreactive oxygen species production and promoted cell viability. FoxO6 overexpression abolished the effects of 3%isoflurane preconditioning on caspase-3 activity, reactive oxygen species production, and cell viability in these cells.Moreover, FoxO6 regulated nuclear factor erythroid 2-related factor (Nrf2) expression via c-Myc after 3% isofluranepreconditioning and OGD exposure. Thus, isoflurane preconditioning prevented OGD-induced injury in LO2 cells bymodulating FoxO6, c-Myc, and Nrf2 signaling.

    • Investigation of axonal regeneration of Triturus ivanbureschi by using physiological and proteomic strategies

      SEÇIL KARAHISAR TURAN MEHMET ALI ONUR FATMA DUYGU ÖZEL DEMIRALP

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      Peripheral nerve injuries are frequently observed and successful treatment depends mainly on the injury type, location of thedamage, and the elapsed time prior to treatment. The regenerative capacity is limited only to the embryonic period in manymammalian tissues, but urodele amphibians do not lose this feature during adulthood. The main purpose of this study is todefine the recovery period after serious sciatic nerve damage of a urodele amphibian, Triturus ivanbureschi. Experimentaltransection damage was performed on the sciatic nerves of T. ivanbureschi specimens. The recovery period of sciatic nerveswere investigated by walking track analysis, electrophysiological recordings, and bottom-up proteomic strategies at differenttime points during a 35-day period. A total of 34 proteins were identified related to the nerve regeneration process.This study showed that the expression levels of certain proteins differ between distal and proximal nerve endings during theregeneration period. In distal nerve stumps, transport proteins, growth factors, signal, and regulatory molecules are highlyexpressed, whereas in proximal nerve stumps, neurite elongation proteins, and cytoskeletal proteins are highly expressed.

    • MiR-195 inhibits migration, invasion and epithelial-mesenchymal transition (EMT) of endometrial carcinoma cells by targeting SOX4

      XIAOMENG ZHAO LILI DAI QIFANG YUE HUA WANG XU WANG YUAN LI RAN CHEN

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      MicroRNAs (miRNAs) have been identified as potential biomarkers for endometrial carcinoma (EC) diagnosis, prognosisand therapy. The purpose of the present study was to investigate the detailed role and molecular mechanism of miR-195 inEC metastasis. qRT-PCR assay was performed to assess the expression of miR-195 and SRY-related high-mobility groupbox 4 (SOX4) mRNA in EC tissues and cells. The levels of N-cadherin, Vimentin, E-cadherin and SOX4 protein weredetermined by western blot. SOX4 protein expression in EC tissues was also determined by Immunohistochemistry (IHC)experiment. Transwell assay was used to analyze cell migration and invasion abilities. Dual-luciferase reporter assay andRNA Immunoprecipitation (RIP) assay were performed to confirm the targeted interaction between miR-195 and SOX4.Our data supported that miR-195 was downregulated and SOX4 was upregulated in EC tissues and cell lines. Upregulationof miR-195 inhibited migration, invasion and epithelial-mesenchymal transition (EMT) of EC cells. Moreover, SOX4 was adirect target of miR-195. MiR-195 overexpression-mediated anti-migration, anti-invasion and anti-EMT effects wereantagonized by SOX4 restoration in EC cells. In conclusion, our study suggested that miR-195 inhibited the migration,invasion and epithelial mesenchymal transition (EMT) of EC cells at least partly by targeting SOX4. Our study provided anovel underlying mechanism for EC metastasis and a promising therapeutic target for EC management.

    • Haploinsufficient tumor suppressor Tip60 negatively regulates oncogenic Aurora B kinase

      ARNAB BOSE SURABHI SUDEVAN VINAY J RAO HIROKI SHIMA ARUN KUMAR TRIVEDI KAZUHIKO IGARASHI TAPAS K KUNDU

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      The Aurora kinases represent a group of serine/threonine kinases which are crucial regulators of mitosis. DysregulatedAurora kinase B (AurkB) expression, stemming from genomic amplification, increased gene transcription or overexpressionof its allosteric activators, is capable of initiating and sustaining malignant phenotypes. Although AurkB level in cells iswell-orchestrated, studies that relate to its stability or activity, independent of mitosis, are lacking. We report that AurkBundergoes acetylation in vitro by lysine acetyltransferases (KATs) belonging to different families, namely by p300 andTip60. The haploinsufficient tumor suppressor Tip60 acetylates two highly conserved lysine residues within the kinasedomain of AurkB which not only impinges the protein stability but also its kinase activity. These results signify a probableoutcome on the increase in ‘‘overall activity’’ of AurkB upon Tip60 downregulation, as observed under cancerous conditions.The present work, therefore, uncovers an important functional interplay between AurkB and Tip60, frailty of whichmay be an initial event in carcinogenesis.

    • A critical analysis of state-of-the-art metagenomics OTU clustering algorithms

      ASHAQ HUSSAIN BHAT PUNIETHAA PRABHU KALPANA BALAKRISHNAN

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      Taxonomic profiling, using hyper-variable regions of 16S rRNA, is one of the important goals in metagenomics analysis.Operational taxonomic unit (OTU) clustering algorithms are the important tools to perform taxonomic profiling by grouping16S rRNA sequence reads into OTU clusters. Presently various OTU clustering algorithms are available within differentpipelines, even some pipelines have implemented more than one clustering algorithms, but there is less literature available forthe relative performance and features of these algorithms. This makes the choice of using these methods unclear. In this studyfive current state-of-the-art OTU clustering algorithms (CDHIT, Mothur’s Average Neighbour, SUMACLUST, Swarm, andUCLUST) have been comprehensively evaluated on the metagenomics sequencing data. It was found that in all the datasets,Mothur’s average neighbour and Swarm created more number of OTU clusters. Based on normalized mutual information(NMI) and normalized information difference (NID), Swarm and Mothur’s average neighbour showed better clusteringqualities than others. But in terms of time complexity the greedy algorithms (SUMACLUST, CDHIT, and UCLUST) performedwell. So there is a trade-off between quality and time, and it is necessary while analysing large size of 16S rRNA genesequencing data.

    • Effect of FIGF overexpression on liver cells transforming to insulin-producing cells

      YAQIN HE XIAOLIANG XIE XIAOYAN LI SHIKUO RONG YUKUI LI ZHENHUI LU

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      Limitation in the number of insulin-producing pancreatic beta-cells is a typical feature of diabetes. It has been indicated thatactivating pancreatic transcription factors can promote the transformation of hepatocytes into insulin-secreting beta-like cells,indicating that direct hepatocyte differentiation seems promising as a treatment for diabetes. Nevertheless, the reprogrammingefficiency still remains low. Our previous study found that the expression of c-fos-induced growth factor (FIGF)was increased in the pancreatic tissues in partial pancreatectomy mice compared to that in normal mice. Here, we observedthat treatment with Ad-FIGF was found to enhance MafA and Ngn3-induced reprogramming of BNL CL.2 cells to b-likecells with the ability of secreting insulin. And FIGF overexpression increased the levels of histone H3/H4 acetylation atMafA and Ngn3 promoter regions in BNL CL.2 cells. Importantly, in vivo study further confirmed that forced expression ofFIGF facilitated the insulin expression and decreased the blood glucose levels in STZ mice. These results strengthen thepossibility of developing cell-based therapies for diabetes through utilizing beta-like cells derived from non-insulin-secretingcells.

    • Type II diabetes mellitus and obesity: Common links, existing therapeutics and future developments

      SUBHADEEP BANERJEE INDRANI TALUKDAR ARNAB BANERJEE ARNAV GUPTA ADVAIT BALAJI RAVIPRASAD ADURI

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      Type II diabetes mellitus (T2DM) and obesity are two common pathophysiological conditions of metabolic syndrome(MetS), a collection of similar metabolic dysfunctions due to sedentary lifestyle and overnutrition. Obesity arises fromimproper adipogenesis which otherwise has a crucial role in maintaining proper metabolic functions. Downstream eventsarising from obesity have been linked to T2DM. The nuclear receptor peroxisome proliferator activator gamma (PPAR-gamma),responsible for maintaining lipid and glucose homeostasis, is down-regulated under obesity leading to a weakened insulinsensitivity of the human body. In course of our review we will outline details of the down-regulation mechanism, provide anoverview of the current clinical therapeutics and their shortcomings. Toxicity studies on the seminal drug troglitazone,belonging to the most effective glitazone anti-diabetic category, is also discussed. This will lead to an overview aboutstructural adaptations on the existing glitazones to alleviate their side effects and toxicity. Finally, we forward a concept ofnovel therapeutics mimicking the glitazone framework, based on some design concepts and preliminary in silico studies.These could be later developed into dual acting drugs towards alleviating the deleterious effects of obesity on normalglucose metabolism, and address obesity in itself.

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