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  • CYP46A1 protects against NMDA-mediated excitotoxicity in Huntington's disease: analysis of lipid raft content
    Biochimie (IF 3.188) Pub Date : 2018-08-11
    Lydie Boussicault, Radhia Kacher, Antonin Lamazière, Peter Vanhoutte, Jocelyne Caboche, Sandrine Betuing, Marie-Claude Potier

    Huntington's Disease (HD) is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin (mHtt) protein leading to degeneration of striatal neurons. Excitotoxicity, consecutive to overstimulation of N-methyl D-aspartate receptors (NMDARs) has a pivotal role in many neurological disorders including HD. Mutant Htt causes enhanced NMDA sensitivity, alteration of NMDAR expression and localization in neurons. Excitotoxic events initiate neuronal death in numerous ways, including activation of apoptotic cascades. Among the NMDAR subunits involved in glutamatergic-mediated excitotoxicity, GluN2B has been extensively reported. In addition to excitotoxicity, alteration of cholesterol metabolism has been observed in HD, with a decrease of cholesterol precursor synthesis along with an increase of cholesterol accumulation, which is deleterious for neurons. Expression of Cholesterol Hydroxylase enzyme, CYP46A1, which converts cholesterol into 24 S‐hydroxycholesterol is down-regulated in HD. We found that CYP46A1 overexpression is beneficial in HD neurons and mouse model, but the mechanisms involved still remain unclear. In this study we addressed the effect of CYP46A1 on NMDAR-mediated excitotoxicity in HD primary neurons and its role in modulating cholesterol and localization of GLUN2B in lipid rafts. We showed that CYP46A1 is protective against NMDAR-mediated excitotoxicity in two different HD neuronal cell models. Cholesterol as well as GluN2B level in lipid raft, are significantly increased by mHtt. Despite a clear effect of CYP46A1 in reducing cholesterol content in lipid raft extracts from wild type neurons, CYP46A1 overexpression in HD neurons could not normalize the increased cholesterol levels in lipid rafts. This study highlights the beneficial role of CYP46A1 against NMDAR-mediated excitotoxicity and gives further insights into the cellular mechanisms underlying CYP46A1-mediated neuroprotection.

  • Exploring receptor selectivity of the chimeric relaxin family peptide R3/I5 by incorporating unnatural amino acids
    Biochimie (IF 3.188) Pub Date : 2018-08-10
    Jia-Hui Wang, Meng-Jun Hu, Lei Zhang, Xiao-Xia Shao, Cai-Hong Lv, Ya-Li Liu, Zeng-Guang Xu, Zhan-Yun Guo

    Relaxin family peptides perform a variety of biological functions by activating four G protein-coupled receptors, namely RXFP1−4. Our recent study demonstrated that selectivity of the chimeric relaxin family peptide R3/I5 towards the homologous RXFP3 and RXFP4 can be modulated by replacement of the highly conserved nonchiral B23Gly or B24Gly with some natural L-amino acids. To investigate the mechanism of this modulating effect, in the present study we incorporated unnatural amino acids into the B23 or B24 position of a semi-synthetic R3/I5 that was prepared by a novel sortase-catalysed ligation approach using synthetic relaxin-3 B-chain and recombinant INSL5 A-chain. R3/I5 was a weak agonist for RXFP3 after B23Gly was replaced by D-Ala or D-Ser, but a strong antagonist for this receptor after B23Gly was replaced by corresponding L-amino acids. However, these replacements always resulted in a weak agonist for RXFP4. Thus, configuration of the B23 residue of R3/I5 affected activation of RXFP3 but not RXFP4. For the B24 residue, both size and configuration affected receptor selectivity of R3/I5. L-amino acids with an appropriate size, such as L-Ser and L-Abu, had the greatest effect on increasing the selectivity of R3/I5 towards RXFP3 over the homologous RXFP4. Our present results provided new insights into receptor selectivity of R3/I5, and would facilitate design of novel agonists or antagonists for RXFP3 and RXFP4 in future studies.

  • A chronic LPS-induced low-grade inflammation fails to reproduce in lean mice the impairment of preference for oily solution found in diet-induced obese mice
    Biochimie (IF 3.188) Pub Date : 2018-08-10
    Arnaud Bernard, Déborah Ancel, Patricia Passilly-Degrace, Jean-François Landrier, Laurent Lagrost, Philippe Besnard

    Diet-induced obesity (DIO) is associated with a decreased oral fat detection in rodents. This alteration has been explained by an impairment of the lipid-mediated signaling in taste bud cells (TBC). However, factors responsible for this defect remain elusive. Diet rich in saturated fatty acids is known to elicit a metabolic inflammation by promoting intestinal permeation to lipopolysaccharides (LPS), Gram-negative bacteria-derived endotoxins. To determine whether a local inflammation of the gustatory tissue might explain the obese-induced impairment of the oro-sensory detection of lipids, mice were subjected to a DIO protocol. Using a combination of behavioral tests, transcriptomic analyses of gustatory papillae and biochemical assays, we have found that i) DIO elicits a pro-inflammatory genic profile in the circumvallate papillae (CVP), known to house the highest density of lingual taste buds, ii) NFkB, a key player of inflammatory process, might play a role in this transcriptomic pattern, iii) plasma LPS levels are negatively correlated with the preference for oily solution, and iv) a chronic infusion of LPS at a level similar to that found in DIO mice is not sufficient to alter the spontaneous preference for fat in lean mice. Taken together these data bring the demonstration that a saturated high fat diet elicits an inflammatory response at the level of peripheral gustatory pathway and a LPS-induced low-grade endotoxemia alone does not explain the change in the preference for dietary lipids observed in DIO mice.

  • Effect of a C-end rule Modification on Antitumor Activity of Thymosin α1
    Biochimie (IF 3.188) Pub Date : 2018-08-08
    Fanwen Wang, Caoying Xu, Renhao Peng, Bin Li, Xutong Shen, Heng Zheng, Xingzhen Lao
  • Irradiation by γ-rays reduces the level of H3S10 phosphorylation and weakens the G2 phase-dependent interaction between H3S10 phosphorylation and γH2AX
    Biochimie (IF 3.188) Pub Date : 2018-08-08
    Eva Bártová, Gabriela Lochmanová, Soňa Legartová, Jana Suchánková, Radek Fedr, Jana Krejčí, Zbyněk Zdráhal
  • Potential Effects of Metformin in DNA BER System Based On Oxidative Status in Type 2 Diabetes
    Biochimie (IF 3.188) Pub Date : 2018-08-08
    Irem Dogan Turacli, Tuba Candar, Emine Berrin YUKSEL, Sebnem Kalay, Ali Kemal OGUZ, Selda Demirtas

    Metformin is used to reduce hyperglycemia that induces energetic stress and leads to reduction in gluconeogenesis. Also, metformin inhibits complex I in oxidative phosphorylation, thereby decreasing cellular ATP levels. Activation of AMPK by the reduced ATP levels can induce inhibition of reactive oxygen species (ROS) production and activate p53-mediated DNA repair. DNA polymerase-β and XRCC1 function to repair DNA damages in the BER (base excision repair) system. In type 2 diabetes patients, metformin can enhance AMPK activation therefore suppress oxidative stress. The changes on oxidative stress may alter p53's function and effect many cellular pathways such as; DNA repair. In our project we aim to understand the effects of metformin on p53 and DNA-BER system based on the oxidative status in type 2 diabetes patients. Oxidative and antioxidative capacity, catalase, SOD, GPx activities and, DNA pol beta, XRCC1 and p53 levels were measured in metformin using or non-using type 2 diabetes patients and controls. Metformin enhanced SOD and GPx activities in type 2 diabetes patients but the reflection of this increase to the total antioxidant capacity was not significant. Although the increase in DNA pol beta was not significant, XRCC1 and p53 levels were significantly upregulated with metformin treatment in type 2 diabetes patients. Our study reinforces the potential benefit of metformin in antioxidative capacity to protect cells from diabetic oxidative stress and in regulation of DNA BER system.

  • N-terminal phosphorylation of glutaminase C decreases its enzymatic activity and cancer cell migration
    Biochimie (IF 3.188) Pub Date : 2018-08-06
    Carolline Fernanda Rodrigues Ascenção, Raghavendra Sashi Krishna Nagampalli, Zeyaul Islam, Matheus Pinto Pinheiro, Larissa Menezes dos Reis, Bianca Alves Pauletti, Carolina Aparecida de Guzzi Cassago, Daniela Campos Granato, Adriana Franco Paes Leme, Sandra Martha Gomes Dias
  • The multifaceted functions of lipopolysaccharide in plant-bacteria interactions
    Biochimie (IF 3.188) Pub Date : 2018-08-02
    Alexander Kutschera, Stefanie Ranf

    In Gram-negative bacteria, the cell envelope largely consists of lipopolysaccharide (LPS), a class of heterogeneous glycolipids. As a fundamental component of the outer membrane, LPS provides stability to the bacterial cell and forms a protective cover shielding it from hostile environments. LPS is not only fundamental to bacterial viability, but also makes a substantial contribution both directly and indirectly to multiple aspects of inter-organismic interactions. During infection of animal and plant hosts, LPS promotes bacterial virulence but simultaneously betrays bacteria to the host immune system. Moreover, dynamic remodulation of LPS structures allows bacteria to fine-tune OM properties and quickly adapt to diverse and often hostile environments, such as those encountered in host tissues. Here, we summarize recent insights into the multiple functions of LPS in plant-bacteria interactions and discuss what we can learn from the latest advances in the field of animal immunity. We further pinpoint open questions and future challenges to unravel the different roles of LPS in the dynamic interplay between bacteria and plant hosts at the mechanistic level.

  • The effect of electronic-cigarettes aerosol on rat brain lipid profile
    Biochimie (IF 3.188) Pub Date : 2018-08-02
    Vladimiro Cardenia, Fabio Vivarelli, Silvia Cirillo, Moreno Paolini, Donatella Canistro, Maria Teresa Rodriguez-Estrada
  • Exploiting the impact of the secretome of MSCs isolated from different tissue sources on neuronal differentiation and axonal growth
    Biochimie (IF 3.188) Pub Date : 2018-08-02
    Rita C. Assunção-Silva, B. Mendes-Pinheiro, P. Patrício, L. Behie, F.G. Teixeira, L. Pinto, A.J. Salgado

    Cell transplantation free-based therapies using Mesenchymal stem cell (MSC) secretome have recently been presented as a possible for CNS related disorders. MSC secretome is rich in several bio-factors that act synergically towards the repair of damaged tissues, thus making it an ideal candidate for regenerative applications. Great effort is currently being made to map the molecules that compose the MSC secretome. Previous proteomic characterization of the secretome (in the form of conditioned media - CM) of MSCs derived from adipose tissue (ASC), bone-marrow (BMSC) and umbilical cord (HUCPVC) was performed by our group, where proteins relevant for neuroprotection, neurogenic, neurodifferentiation, axon guidance and growth functions were identified. Moreover, we have found significant differences among the expression of several molecules, which may indicate that their therapeutic outcome might be distinct. Having this in mind, in the present study, the neuroregulatory potential of ASC, BMSC and HUCPVC CM in promoting neurodifferentiation and axonal outgrowth was tested in vitro, using human telencephalon neuroprogenitor cells and dorsal root ganglion explants, respectively. The CM from the three MSC populations induced neuronal differentiation from human neural progenitor cells, as well as neurite outgrowth from dorsal root ganglion explants. Moreover, all the MSC populations promoted the same extent of neurodifferentiation, while ASC CM demonstrated higher potential in promoting axonal growth.

  • Serotonin in stem cell based-dental repair and bone formation: a review
    Biochimie (IF 3.188) Pub Date : 2018-08-02
    Anne Baudry, Benoit Schneider, Jean-Marie Launay, Odile Kellermann

    Genetic and pharmacological studies provided evidence that serotonin (5-HT) is an important signaling molecule for the development and the maintenance of mineralized tissues. However, how 5-HT takes part to the homeostasis of teeth and bone remains elusive. In the dental field, a major breakthrough comes from the identification of 5-HT but also dopamine (DA) as "damage" signals necessary for stem cell-based tooth repair. Pulpal stem cells express the overall functions of 5-HT and DA neurons including a definite set of functional 5-HT/DA receptors that render cells responsive for circulating bioamines. Upon tooth injury, activated platelets release bulks of 5-HT/DA that mobilize pulpal stem cells for natural dental repair. The contribution of 5-HT to bone metabolism is more documented with description of both anabolic and resorptive effects. By controlling the tissue-non specific alkaline phosphatase (TNAP), 5-HT2B receptors exert an anabolic function and a pivotal role in mineralization processes. Increasing our understanding of the role of 5-HT receptors in bone metabolism may pave the road for the development of therapeutic strategies towards skeletal-associated pathologies and ectopic calcification.

  • FOXD3 acts as a repressor of the mitochondrial S-adenosylmethionine carrier (SLC25A26) gene expression in cancer cells
    Biochimie (IF 3.188) Pub Date : 2018-08-02
    Cianciulli Antonia, Menga Alessio, Palmieri Ferdinando, Iacobazzi Vito

    The mitochondrial S-adenosylmethionine carrier (SAMC), encoded by the SLC25A26 gene, catalyzes the uptake of S-adenosylmethionine (SAM) from the cytosol into mitochondria in exchange for S-adenosylhomocysteine (SAH), produced inside the mitochondria. In the last years we have been functionally characterizing the promoter of SLC25A26 gene. In this study we show that a silencer activity is present in the region from -756 bp to -504 bp, which specifically binds a protein present in Caski cells nuclear extracts. By in silico analysis, EMSA, ChIP, overexpressing and silencing experiments this protein was identified as FOXD3 which acts as a repressor of SLC25A26 expression. Interestingly, the repressor activity of FOXD3 is completely abolished by treating Caski cells with folate via a mechanism that involves methylation of FOXD3 gene promoter. This finding could have important impact in cancer cells where SLC25A26 is downregulated. Finally, the DPE and INR putative sites were also identified.

  • Cysteine mediated disulfide bond formation in RAGE V domain facilitates its functionally relevant dimerization
    Biochimie (IF 3.188) Pub Date : 2018-08-01
    Nitish Jangde, Rashmi Ray, Sunita Sinha, Khokan Rana, Satyendra Kumar Singh, Prashant Khandagale, Narottam Acharya, Vivek Rai
  • MiR-590-3p Inhibits Proliferation and Promotes Apoptosis by Targeting Activating Transcription Factor 3 in Human Breast Cancer Cells
    Biochimie (IF 3.188) Pub Date : 2018-08-01
    M. Rohini, M. Gokulnath, P.J. Miranda, N. Selvamurugan

    We previously reported that ATF3 and Runx2 are involved in breast cancer progression and bone metastasis. The expression of these genes can be controlled by post-transcriptional regulators such as microRNAs (miRNAs). In this study, we identified and validated the functional role of miR-590-3p in human breast cancer cells (MDA-MB231). There was an inverse correlation between the expression of miR-590-3p and its putative target genes, ATF3 and Runx2 in these cells. Overexpression of miR-590-3p decreased the expression of ATF3 and Runx2 at the mRNA and protein levels in MDA-MB231 cells. Luciferase reporter assay identified a direct interaction of 3’ UTRs of ATF3 and Runx2 with miR-590-3p in these cells. Overexpression of miR-590-3p also decreased proliferation and increased apoptosis of breast cancer cells. Based on our results, we suggest that miR-590-3p might have potential clinical applications towards controlling breast cancer progression and bone metastasis.

  • Sphingolipid metabolism in non-alcoholic fatty liver diseases
    Biochimie (IF 3.188) Pub Date : 2018-07-31
    Marion Régnier, Arnaud Polizzi, Hervé Guillou, Nicolas Loiseau

    Non-alcoholic fatty liver disease (NAFLD) involves a panel of pathologies starting with hepatic steatosis and continuing to irreversible and serious conditions like steatohepatitis (NASH) and hepatocarcinoma. NAFLD is multifactorial in origin and corresponds to abnormal fat deposition in liver. Even if triglycerides are mostly associated with these pathologies, other lipid moieties seem to be involved in the development and severity of NAFLD. That is the case with sphingolipids and more particularly ceramides. In this review, we explore the relationship between NAFLD and sphingolipid metabolism. After providing an analysis of complex sphingolipid metabolism, we focus on the potential involvement of sphingolipids in the different pathologies associated with NAFLD. An unbalanced ratio between ceramides and terminal metabolic products in the liver and plasma promotes weight gain, inflammation, and insulin resistance. In the etiology of NAFLD, some sphingolipid species such as ceramides may be potential biomarkers for NAFLD. We review the clinical relevance of sphingolipids in liver diseases.

  • Structure of the monotopic membrane protein (S)-mandelate dehydrogenase at 2.2Å resolution
    Biochimie (IF 3.188) Pub Date : 2018-07-30
    N. Sukumar, S. Liu, W. Li, F.S. Mathews, B. Mitra, P. Kandavelu
  • The mycosporine-like amino acids porphyra-334 and shinorine are antioxidants and direct antagonists of Keap1-Nrf2 binding
    Biochimie (IF 3.188) Pub Date : 2018-07-30
    Ranko Gacesa, Karl P. Lawrence, Nikolaos D. Georgakopoulos, Kazuo Yabe, Walter C. Dunlap, David J. Barlow, Geoffrey Wells, Antony R. Young, Paul F. Long
  • International descriptive and interventional survey for oxycholesterol determination by gas- and liquid-chromatographic methods
    Biochimie (IF 3.188) Pub Date : 2018-07-29
    Dieter Lütjohann, Ingemar Björkhem, Silvia Friedrichs, Anja Kerksiek, Wolf-Jochen Geilenkeuser, Anita Lövgren-Sandblom, Diana Ansorena, Iciar Astiasarán, Lucia Baila-Rueda, Blanca Barriuso, Lionell Bretillon, Richard W. Browne, Claudio Caccia, Ana Cenarro, Peter J. Crick, Günter Fauler, Guadalupe Garcia-LLatas, William J. Griffiths, Hans-Frieder Schött

    Increasing numbers of laboratories develop new methods based on gas-liquid and high-performance liquid chromatography to determine serum concentrations of oxygenated cholesterol metabolites such as 7α-, 24(S)-, and 27-hydroxycholesterol. We initiated a first international descriptive oxycholesterol (OCS) survey in 2013 and a second interventional survey 2014 in order to compare levels of OCS reported by different laboratories and to define possible sources of analytical errors. In 2013 a set of two lyophilized serum pools (A and B) was sent to nine laboratories in different countries for OCS measurement utilizing their own standard stock solutions. In 2014 eleven laboratories were requested to determine OCS concentrations in lyophilized pooled sera (C and D) utilizing the same provided standard stock solutions of OCS. The participating laboratories submitted results obtained after capillary gas-liquid chromatography-mass selective detection with either epicoprostanol or deuterium labelled sterols as internal standards and high-performance liquid chromatography with mass selective detection and deuterated OCS as internal standard. Each participant received a clear overview of the results in form of Youden-Plots and basic statistical evaluation in its used unit. The coefficients of variation of the concentrations obtained by all laboratories using their individual methods were 58.5–73.3% (survey 1), 56.8–60.3% (survey 2); 36.2–35.8% (survey 1), 56.6–59.8, (survey 2); 61.1–197.7% (survey 1), 47.2–74.2% (survey 2) for 24(S)-, 27-, and 7α-hydroxycholesterol, respectively. We are surprised by the very great differences between the laboratories, even under conditions when the same standards were used. The values of OCS's must be evaluated in relation to the analytical technique used, the efficiency of the ample separation and the nature of the internal standard used. Quantification of the calibration solution and inappropriate internal standards could be identified as major causes for the high variance in the reported results from the different laboratories. A harmonisation of analytical standard methods is highly needed.

  • Variability in lung cancer response to ALK inhibitors cannot be explained by the diversity of ALK fusion variants
    Biochimie (IF 3.188) Pub Date : 2018-07-30
    Natalia V. Mitiushkina, Vladislav I. Tiurin, Aglaya G. Iyevleva, Maxim M. Kholmatov, Elena A. Filippova, Fedor V. Moiseyenko, Nikita E. Levchenko, Ivan S. Sardaryan, Svetlana V. Odintsova, Alexandra M. Lozhkina, Nikita M. Volkov, Nina A. Karaseva, Vladimir M. Moiseyenko, Sergey V. Orlov, Evgeny N. Imyanitov

    Multiple laboratory evidences indicate that distinct variants of ALK translocations differ in their biochemical properties and responsiveness to ALK tyrosine kinase inhibitors (TKIs). These data are supported by some clinical studies, which showed improved responses to crizotinib in non-small cell lung cancer (NSCLC) patients carrying particular variants of ALK translocation. We retrospectively considered 64 Russian patients with ALK-rearranged NSCLC, who were treated by crizotinib (n = 23), ceritinib (n = 39) or alectinib (n = 2). ALK fusion variants were genotyped by PCR. Median progression-free survival (PFS) approached to 18 and 21 months in subjects with “short” (v.3a/b, v.5a/b) vs. “long” (TAPE-domain containing) fusion variants (p = 0.783), respectively; similar data were obtained while comparing EML4/ALK variant 1 vs. other ALK translocations (19 and 21 months, respectively; p = 0.604). Objective response rates were also strikingly similar in the above groups (“short”: 88%, “long”: 77%, p = 0.479; variant 1: 76%, other translocations: 81%, p = 0.753). Furthermore, ALK variants did not influence the disease outcomes when patients treated by crizotinib and ceritinib were analyzed separately. Overall, PFS on ALK TKI did not depend on whether the drug was administered upfront or after chemotherapy. Ceritinib produced significantly longer PFS than crizotinib (p = 0.022). In conclusion, this study revealed that distinct ALK translocation variants render similar clinical responsiveness to ALK inhibitors.

  • S-allyl cysteine as potent anti-gout drug: Insight into the xanthine oxidase inhibition and anti-inflammatory activity
    Biochimie (IF 3.188) Pub Date : 2018-07-27
    Johnson Preethi, Loganathan Chitra, Iruthayaraj Ancy, Poomani Kumaradhas, Thayumanavan Palvannan

    S-allyl cysteine (SAC) is known for its various beneficial effects such as neuroprotection and immunomodulation. The beneficial effect of SAC against gout has not been explored. The present study aims to describe the two roles of SAC: (1) inhibitory effect against xanthine oxidase (XO) enzyme activity; and (2) anti-inflammatory property against MSU crystal-induced gouty inflammation in rat. The inhibitory effect of SAC against bovine XO enzyme activity was determined in vitro. In silico analysis was carried out to determine the intermolecular interaction between SAC and bovine XO. MSU crystal was injected in the right paw of the rat to induce gouty inflammation. SAC (40 mg/kg body weight) and colchicine (positive control; 1 mg/kg body weight) was given for 3 days. At the end of the treatment, the oxidative stress, antioxidant parameters and mitochondrial function were determined in the ankle joint tissue. The concentration of inflammatory cytokines such as TNF-α and IL-1β was measured in the serum using ELISA. SAC inhibited (IC50 value, 33 μg/ml) XO enzyme activity in a competitive mode with corresponding Ki value of 4 μg/ml. In silico analysis predicted the interaction of SAC with the amino acids such as Arg880, Phe798, Phe914 and Phe1009 of XO enzyme. The root mean square deviation, root mean square fluctuation and free energy calculation values confirmed the stable SAC-XO interaction. The inhibition of SAC on XO enzyme activity in in vivo was further confirmed by silkworm model. SAC through reducing oxidative stress, enhancing antioxidants, protecting mitochondrial function has shown anti-inflammatory effect against MSU crystal-induced gout which was observed as reduced level of inflammatory markers in the serum. The medicinal potential of SAC as a preventive agent through its XO inhibitory property as well as curative agent through its anti-inflammatory property against gout has been understood from the present study.

  • A stochastic approach to serotonergic fibers in mental disorders
    Biochimie (IF 3.188) Pub Date : 2018-07-26
    Skirmantas Janušonis, Nils Detering

    Virtually all brain circuits are physically embedded in a three-dimensional matrix of fibers that release 5-hydroxytryptamine (5-HT, serotonin). The density of this matrix varies across brain regions and cortical laminae, and it is altered in some mental disorders, including Major Depressive Disorder and Autism Spectrum Disorder. We investigate how the regional structure of the serotonergic matrix depends on the stochastic behavior of individual serotonergic fibers and introduce a new framework for the quantitative analysis of this behavior. In particular, we show that a step-wise random walk, based on the von Mises-Fisher probability distribution, can provide a realistic and mathematically concise description of these fibers. We also consider other stochastic models, including the fractional Brownian motion. The proposed approach seeks to advance the current understanding of the ascending reticular activating system (ARAS) and may also support future theory-guided therapeutic approaches.

  • 27-hydroxycholesterol decreases cell proliferation in colon cancer cell lines
    Biochimie (IF 3.188) Pub Date : 2018-07-24
    Jessica Warns, Gurdeep Marwarha, Natalie Freking, Othman Ghribi

    Colorectal cancer (CRC) is the third most diagnosed cancer in the western world, affecting 1 out of approximately 22 people in their lifetime. Several epidemiological studies suggest a positive association between high plasma cholesterol levels and colorectal cancer. However, the molecular mechanisms by which cholesterol may alter the risk of colorectal cancer (CRC) are ill-defined as the cholesterol lowering drugs statins do not appear to decrease a patient's risk of developing colorectal cancer. Cholesterol is metabolized to active derivatives including cholesterol oxidization products (COP), known as oxysterols, which have been shown to alter cellular proliferation. These metabolites and not cholesterol per se, may therefore affect the risk of developing colorectal cancer. The cholesterol metabolite or the oxysterol 27-hydroxycholesterol (27-OHC) is the most abundant oxysterol in the plasma and has been shown to be involved in the pathogenesis of several cancers including breast and prostate cancer. However, the role of 27-OHC in colorectal cancer has not been investigated. We treated Caco2 and SW620, two well characterized colon cancer cells with low, physiological and high concentrations of 27-OHC, and found that 27-OHC reduces cellular proliferation in these cells. We also found that the effects of 27-OHC on cell proliferation are not due to cellular cytotoxicity or apoptotic cellular death. Additionally, 27-OHC-induced reduction in cell proliferation is independent of actions on its target nuclear receptors, liver-X-receptors (LXR) and estrogen receptors (ER) activation. Instead, our study demonstrates that 27-OHC significantly decreases AKT activation, a major protein kinase involved in the pathogenesis of cancer as it regulates cell cycle progression, protein synthesis, and cellular survival. Our data shows that treatment with 27-OHC substantially decreases the activation of AKT by reducing levels of its active form, p-AKT, in Caco2 cells but not SW620 cells. All-together, our results show for the first time that the cholesterol metabolite 27-OHC reduces cell proliferation in colorectal cancer cells.

  • Biophysical Characterization of a Recombinant Lipase KV1 from Acinetobacter haemolyticus in Relation to pH and Temperature
    Biochimie (IF 3.188) Pub Date : 2018-07-20
    Kalaivani Batumalaie, Elham Khalili, Naji Arafat Mahat, Fahrul Huyop, Roswanira Abdul Wahab

    Spectroscopic and calorimetric methods were employed to assess the stability and the folding aspect of a novel recombinant alkaline-stable lipase KV1 from Acinetobacter haemolyticus under varying pH and temperature. Data on far ultraviolet-circular dichroism of recombinant lipase KV1 under two alkaline conditions (pH 8.0 and 12.0) at 40˚C reveal strong negative ellipticities at 208, 217, 222 nm, implying its secondary structure belonging to a α + β class with 47.3 and 39.0 % ellipticity, respectively. Results demonstrate that lipase KV1 adopts its most stable conformation at pH 8.0 and 40˚C. Conversely, the protein assumes a random coil structure at pH 4.0 and 80˚C, evident from a strong negative peak at ⁓ 200 nm. This blue shift suggests a general decline in enzyme activity in conjunction with the partially or fully unfolded state that invariably exposed more hydrophobic surfaces of the lipase protein. The maximum emission at ∼335 nm for pH 8.0 and 40˚C indicates the adoption of a favorable protein conformation with a high number of buried tryptophan residues, reducing solvent exposure. Appearance of an intense Amide I absorption band at pH 8.0 corroborates an intact secondary structure. A lower enthalpy value for pH 4.0 over pH 8.0 and 12.0 in the differential scanning calorimetric data corroborates the stability of the lipase at alkaline conditions, while a low Km (0.68 ± 0.03 mM) for tributyrin verifies the high affinity of lipase KV1 for the substrate. The data, herein offer useful insights into future structure-based tunable catalytic activity of lipase KV1.

  • Zinc(II) binding on human wild-type ISCU and Met140 variants modulates NFS1 desulfurase activity
    Biochimie (IF 3.188) Pub Date : 2018-07-20
    Nicholas G. Fox, Alain Martelli, Joseph F. Nabhan, Jay Janz, Oktawia Borkowska, Christine Bulawa, Wyatt W. Yue

    Human de novo iron-sulfur (Fe-S) assembly complex consists of cysteine desulfurase NFS1, accessory protein ISD11, acyl carrier protein ACP, scaffold protein ISCU, and allosteric activator frataxin (FXN). FXN binds the NFS1-ISD11-ACP-ISCU complex (SDAU), to activate the desulfurase activity and Fe-S cluster biosynthesis. In the absence of FXN, the NFS1-ISD11-ACP (SDA) complex was reportedly inhibited by binding of recombinant ISCU. Recent studies also reported a substitution at position Met141 on the yeast ISCU orthologue Isu, to Ile, Leu, Val, or Cys, could bypass the requirement of FXN for Fe-S cluster biosynthesis and cell viability. Here, we show that recombinant human ISCU binds zinc(II) ion, as previously demonstrated with the E. coli orthologue IscU. Surprisingly, the relative proportion between zinc-bound and zinc-depleted forms varies among purification batches. Importantly the presence of zinc in ISCU impacts SDAU desulfurase activity. Indeed, removal of zinc(II) ion from ISCU causes a moderate but significant increase in activity compared to SDA alone, and FXN can activate both zinc-depleted and zinc-bound forms of ISCU complexed to SDA. Taking into consideration the inhibition of desulfurase activity by zinc-bound ISCU, we characterized wild type ISCU and the M140I, M140L, and M140V variants under both zinc-bound and zinc-depleted conditions, and did not observe significant differences in the biochemical and biophysical properties between wild-type and variants. Importantly, in the absence of FXN, ISCU variants behaved like wild-type and did not stimulate the desulfurase activity of the SDA complex. This study therefore identifies an important regulatory role for zinc-bound ISCU in modulation of the human Fe-S assembly system in vitro and reports no ‘FXN bypass’ effect on mutations at position Met140 in human ISCU. Furthermore, this study also calls for caution in interpreting studies involving recombinant ISCU by taking into consideration the influence of the bound zinc(II) ion on SDAU complex activity

  • Cloning, purification and characterization of nigrelysin, a novel actinoporin from the sea anemone Anthopleura nigrescens
    Biochimie (IF 3.188) Pub Date : 2018-07-21
    Javier Alvarado-Mesén, Frank Solano-Campos, Liem Canet, Lohans Pedrera, Yadira P. Hervis, Carmen Soto, Henry Borbón, María E. Lanio, Bruno Lomonte, Aisel Valle, Carlos Alvarez

    Actinoporins constitute a unique class of pore-forming toxins found in sea anemones that being secreted as soluble monomers are able to bind and permeabilize membranes leading to cell death. The interest in these proteins has risen due to their high cytotoxicity that can be properly used to design immunotoxins against tumor cells and antigen-releasing systems to cell cytosol. In this work we describe a novel actinoporin produced by Anthopleura nigrescens, an anemone found in the Central American Pacific Ocean. Here we report the amino acid sequence of an actinoporin as deduced from cDNA obtained from total body RNA. The synthetic DNA sequence encoding for one cytolysin variant was expressed in BL21 Star (DE3) Escherichia coli and the protein purified by chromatography on CM Sephadex C-25 with more than 97% homogeneity as verified by MS-MS and HPLC analyses. This actinoporin comprises 179 amino acid residues, consistent with its observed isotope-averaged molecular mass of 19661 Da. The toxin lacks Cys and readily permeabilizes erythrocytes, as well as L1210 cells. CD spectroscopy revealed that its secondary structure is dominated by beta structure (58.5%) with 5.5% of α-helix, and 35% of random structure. Moreover, binding experiments to lipidic monolayers and to liposomes, as well as permeabilization studies in vesicles, revealed that the affinity of this toxin for sphingomyelin-containing membranes is quite similar to sticholysin II (StII). Comparison by spectroscopic techniques and modeling the three-dimensional structure of nigrelysin (Ng) showed a high homology with StII but several differences were also detectable. Taken together, these results reinforce the notion that Ng is a novel member of the actinoporin pore-forming toxin (PFT) family with a HA as high as that of StII, the most potent actinoporin so far described, but with peculiar structural characteristics contributing to expand the understanding of the structure-function relationship in this protein family.

  • The impact of Mesenchymal Stem Cells and their secretome as a treatment for gliomas
    Biochimie (IF 3.188) Pub Date : 2018-07-19
    E.D. Gomes, J. Vieira de Castro, B.M. Costa, A.J. Salgado

    In recent years, we have witnessed a significant increase in the amount of studies using Mesenchymal Stem Cells (MSCs) for cancer therapy, mostly as vectors for drug or gene delivery strategies. This is because of their intrinsic capacity of homing into tumor niches. However, the interactions between MSCs themselves and tumor cells is not fully understood, with contradictory results frequently being observed regarding their effects on cancer cell invasion and proliferation. This poses an important question of safety in respect to the application of these cells. The source of the MSC population used, as well as the type of cancer cells under study might strongly influence this interaction. Moreover, differences in isolation protocols, culture media compositions, time of culture and conditioned media collection, or even timing and mode of MSCs administration to in vivo models of cancer may also affect the interaction MSC-tumor cells. In this review, we drive our focus into malignant brain tumors, particularly gliomas, one of the deadliest forms of cancer. Moreover, we look with some detail into different studies using MSCs as a treatment for brain tumors and compare them, highlighting the main deviations and similarities among them.

  • Induction of peroxisomal changes in oligodendrocytes treated with 7-ketocholesterol: Attenuation by α-tocopherol
    Biochimie (IF 3.188) Pub Date : 2018-07-19
    Thomas Nury, Randa Sghaier, Amira Zarrouk, Franck Ménétrier, Tugba Uzun, Valerio Leoni, Claudio Caccia, Wiem Meddeb, Amira Namsi, Khouloud Sassi, Wafa Mihoubi, Jean-Marc Riedinger, Mustapha Cherkaoui-Malki, Thibault Moreau, Anne Vejux, Gérard Lizard

    The involvement of organelles in cell death is well established especially for endoplasmic reticulum, lysosomes and mitochondria. However, the role of the peroxisome is not well known, though peroxisomal dysfunction favors a rupture of redox equilibrium. To study the role of peroxisomes in cell death, 158 N murine oligodendrocytes were treated with 7-ketocholesterol (7 KC: 25–50 μM, 24 h). The highest concentration is known to induce oxiapoptophagy (OXIdative stress + APOPTOsis + autoPHAGY), whereas the lowest concentration does not induce cell death. In those conditions (with 7 KC: 50 μM) morphological, topographical and functional peroxisome alterations associated with modifications of the cytoplasmic distribution of mitochondria, with mitochondrial dysfunction (loss of transmembrane mitochondrial potential, decreased level of cardiolipins) and oxidative stress were observed: presence of peroxisomes with abnormal sizes and shapes similar to those observed in Zellweger fibroblasts, lower cellular level of ABCD3, used as a marker of peroxisomal mass, measured by flow cytometry, lower mRNA and protein levels (measured by RT-qPCR and western blotting) of ABCD1 and ABCD3 (two ATP-dependent peroxisomal transporters), and of ACOX1 and MFP2 enzymes, and lower mRNA level of DHAPAT, involved in peroxisomal β-oxidation and plasmalogen synthesis, respectively, and increased levels of very long chain fatty acids (VLCFA: C24:0, C24:1, C26:0 and C26:1, quantified by gas chromatography coupled with mass spectrometry) metabolized by peroxisomal β-oxidation. In the presence of 7 KC (25 μM), slight mitochondrial dysfunction and oxidative stress were found, and no induction of apoptosis was detected; however, modifications of the cytoplasmic distribution of mitochondria and clusters of mitochondria were detected. The peroxisomal alterations observed with 7 KC (25 μM) were similar to those with 7 KC (50 μM). In addition, data obtained by transmission electron microcopy and immunofluorescence microscopy by dual staining with antibodies raised against p62, involved in autophagy, and ABCD3, a peroxisomal ABC transporter, support that 7 KC (25–50 μM) induces pexophagy. 7 KC (25–50 μM)-induced side effects were attenuated by α-tocopherol but not by α-tocotrienol, whereas the anti-oxidant properties of these molecules determined with the FRAP assay were in the same range. These data provide evidences that 7 KC, at concentrations inducing or not cell death, triggers morphological, topographical and functional peroxisomal alterations associated with minor or major mitochondrial changes.

  • Gerli invited minireview Fatty acids and oxidized lipoproteins contribute to autophagy and innate immunity responses upon the degeneration of retinal pigment epithelium and development of age-related macular degeneration
    Biochimie (IF 3.188) Pub Date : 2018-07-18
    Kai Kaarniranta, Ali Koskela, Szabolcs Felszeghy, Niko Kivinen, Antero Salminen, Anu Kauppinen

    Retinal pigment epithelium (RPE) damage is a primary sign in the development of age-related macular degeneration (AMD) the leading cause of blindness in western countries. RPE cells are exposed to chronic oxidative stress due to constant light exposure, active fatty acid metabolism and high oxygen consumption. RPE cells phagocytosize lipid rich photoreceptor outer segment (POS) which is regulated by circadian rhytmn. Docosahexaenoic acid is present in high quantity in POS and increases oxidative stress, while its metabolites have cytoprotective effects in RPE. During RPE aging, reactive oxygen species and oxidized lipoproteins are considered to be major causes of disturbed autophagy clearance that lead to chronic innate immunity response involved in NOD-Like, Toll-Like, Advanced Glycation End product Receptors (NRLP, TLR, RAGE, respectively), pentraxins and complement systems. We discuss role of fatty acids and lipoproteins in the degeneration of RPE and development of AMD.

  • Dual mechanism of type VII collagen transfer by bone marrow mesenchymal stem cell extracellular vesicles to recessive dystrophic epidermolysis bullosa fibroblasts
    Biochimie (IF 3.188) Pub Date : 2018-04-10
    Jeffrey D. McBride, Luis Rodriguez-Menocal, Ambar Candanedo, Wellington Guzman, Marta Garcia-Contreras, Evangelos V. Badiavas

    Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering disease resulting from a lack of type VII collagen production. Recent clinical trials have shown efficacy of bone marrow-derived mesenchymal stem cells (BM-MSCs) in the treatment of epidermolysis bullosa, including improved basement membrane restructuring and cutaneous wound healing. The mechanism as to how type VII collagen is transferred from donor stem cell to recipient RDEB cells has not been defined. Here, we submit the model that BM-MSC-derived extracellular vesicles serve at least two roles: 1) to help transport type VII collagen within the extracellular space; and 2) to feed RDEB fibroblasts with messenger RNA that codes for type VII collagen, resulting in COL7A1 translation and synthesis of type VII collagen alpha chain proteins by RDEB fibroblasts. Utilizing a chemoselective ligation detection method, we found RDEB cells that were treated simultaneously with BM-MSC EVs and an l-methionine analog, l-homopropargylglycine (HPG), synthesized collagen VII alpha chain protein that contained the alkyne group of HPG to react (i.e. undergo the Click-iT® reaction) with azide-modified Alexa 594, suggesting de novo synthesis of type VII collagen by RDEB fibroblasts. Thus, our results support a model in which BM-MSC EVs help increase type VII collagen levels available to recipient cells by 1) donating BM-MSC type VII collagen protein and 2) inducing RDEB fibroblasts to make their own type VII collagen protein. These findings allow us to hypothesize that the secretome of BM-MSCs could have therapeutic value in the treatment of RDEB-related skin disorders.

  • Chemistry, biochemistry, metabolic fate and mechanism of action of 6-oxo-cholestan-3β,5α-diol (OCDO), a tumor promoter and cholesterol metabolite
    Biochimie (IF 3.188) Pub Date : 2018-04-12
    Marc Poirot, Regis Soules, Arnaud Mallinger, Florence Dalenc, Sandrine Silvente-Poirot

    Oxygenation products of cholesterol, named oxysterols, were suspected since the 20th century to be involved in carcinogenesis. Among the family of oxysterol molecules, cholesterol-5,6-epoxides (5,6-EC) retained the attention of scientists because they contain a putative alkylating epoxide group. However, studies failed into demonstrating that 5,6-EC were direct carcinogens and revealed a surprising chemical stability and unreactivity towards nucleophiles in standard conditions. Analyses of 5,6-EC metabolism in normal cells showed that they were extensively transformed into cholestane-3β,5α,6β-triol (CT) by the cholesterol-5,6-epoxide hydrolase (ChEH). Studies performed in cancer cells showed that CT was additionally metabolized into an oxysterol identified as the 6-oxo-cholestan-3β,5α-diol (OCDO), by the 11β-hydroxysteroid dehydrogenase of type 2 (HSD2), the enzyme which inactivates cortisol into cortisone. Importantly, OCDO was shown to display tumor promoter properties in breast cancers, by binding to the glucocorticoid receptor, and independently of their estrogen receptor status, revealing the existence of a new tumorigenic pathway centered on 5,6-EC. In breast tumors from patients, OCDO production as well as the expression of the enzymes involved in the pathway producing OCDO, namely ChEH subunits and HSD2, were higher compared to normal tissues, and overexpression of these enzymes correlate with a higher risk of patient death, indicating that this onco-metabolism is of major importance to breast cancer pathology. Herein, we will review the actual knowledge and the future trends in OCDO chemistry, biochemistry, metabolism and mechanism of action and will discuss the impact of OCDO discovery on new anticancer therapeutic strategies.

  • Exposing mesenchymal stem cells to chondroitin sulphated proteoglycans reduces their angiogenic and neuro-adhesive paracrine activity
    Biochimie (IF 3.188) Pub Date : 2018-04-19
    Chelsea R. Wood, Ibtesam R.T. Al Delfi, John F. Innes, Peter Myint, William E.B. Johnson

    The multifactorial complexity of spinal cord injuries includes the formation of a glial scar, of which chondroitin sulphated proteoglycans (CSPG) are an integral component. Previous studies have shown CSPG to have inhibitory effects on endothelial and neuronal cell growth, highlighting the difficulty of spinal cord regeneration. Mesenchymal stem/stromal cells (MSC) are widely used as a cell therapy, and there is mounting evidence for their angiogenic and neurotrophic paracrine properties. However, in vivo studies have observed poor engraftment and survival of MSC when injected into SCI. Currently, it is not known whether increasing CSPG concentrations seen after SCI may affect MSC; therefore we have investigated the effects of CSPG exposure to MSC in vitro. CSPG-mediated inhibition of MSC adhesion was observed when MSC were cultured on substrates of increasing CSPG concentration, however MSC viability was not affected even up to five days of culture. Culture conditioned medium harvested from these cultures (primed MSC CM) was used as both culture substrata and soluble medium for EA.hy926 endothelial cells and SH-SY5Y neuronal cells. MSC CM was angiogenic, promoting endothelial cell adhesion, proliferation and tubule formation. However, exposing MSC to CSPG reduced the effects of CSPG-primed MSC CM on endothelial cell adhesion and proliferation, but did not reduce MSC-induced endothelial tubule formation. Primed MSC CM also promoted neuronal cell adhesion, which was reduced following exposure to CSPG. There were no marked differences in neurite outgrowth in MSC CM from CSPG primed MSC cultures versus control conditions, although non-primed MSC CM from the same donors was found to significantly enhance neurite outgrowth. Taken together, these studies demonstrate that MSC are resilient to CSPG exposure, but that there is a marked effect of CSPG on their paracrine regenerative activity. The findings increase our understanding of how the wound microenvironment after SCI can mitigate the beneficial effects of MSC transplantation.

  • The effect of oxysterols on nerve impulses
    Biochimie (IF 3.188) Pub Date : 2018-04-21
    Maryem Bezine, Amira Namsi, Randa Sghaier, Rym Ben Khalifa, Haithem Hamdouni, Fatiha Brahmi, Iham Badreddine, Wafa Mihoubi, Thomas Nury, Anne Vejux, Amira Zarrouk, Jérôme de Sèze, Thibault Moreau, Boubker Nasser, Gérard Lizard

    The propagation of nerve impulses in myelinated nerve fibers depends on a number of factors involving the myelin and neural axons. In several neurodegenerative diseases, nerve impulses can be affected by the structural and biochemical characteristics of the myelin sheath and the activity of ion channels located in the nodes of Ranvier. Though it is generally accepted that lipid disorders are involved in the development of neurodegenerative diseases, little is known about their impact on nerve impulses. Cholesterol oxide derivatives (also called oxysterols), which are either formed enzymatically or as a result of cholesterol auto-oxidation or both, are often found in abnormal levels in the brain and body fluids of patients with neurodegenerative diseases. This leads to the question of whether these molecules, which can accumulate in the plasma membrane and influence its structure and functions (fluidity, membrane proteins activities, signaling pathways), can have an impact on nerve impulses. It is currently thought that the ability of oxysterols to modulate nerve impulses could be explained by their influence on the characteristics and production of myelin as well as the functionality of Na+ and K+ channels.

  • EBI2 – Sensor for dihydroxycholesterol gradients in neuroinflammation
    Biochimie (IF 3.188) Pub Date : 2018-04-22
    Florian C. Kurschus, Florian Wanke

    Dihydroxycholesterols such as 7α,25-dihydroxysterols (7α,25-OHC) and 7α,27-OHC are generated from cholesterol by the enzymes CH25H, CYP7B1 and CYP27A1 in steady state but also in the context of inflammation. The G-protein coupled receptor (GPCR) Epstein-Barr virus-induced gene 2 (EBI2), also known as GPR183, senses these oxysterols and induces chemotactic migration of immune cells towards higher concentrations of these ligands. We recently showed that these ligands are upregulated in the CNS in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis and that EBI2 enhanced early infiltration of encephalitogenic T cells into the CNS. In this short-review we discuss the role of dihydroxysterol-sensing by immune cells in neuroinflammation.

  • The pericyte secretome: Potential impact on regeneration
    Biochimie (IF 3.188) Pub Date : 2018-04-23
    Abderahim Gaceb, Marco Barbariga, Ilknur Özen, Gesine Paul

    Personalized and regenerative medicine is an emerging therapeutic strategy that is based on cell biology and biomedical engineering used to develop biological substitutes to maintain normal function or restore damaged tissues and organs.The secretory capacities of different cell types are now explored as such possible therapeutic regenerative agents in a variety of diseases. A secretome can comprise chemokines, cytokines, growth factors, but also extracellular matrix components, microvesicles and exosomes as well as genetic material and may differ depending on the tissue and the stimulus applied to the cell. With regard to clinical applications, the secretome of mesenchymal stem cells (MSC) is currently the most widely explored. However, other cell types such as pericytes may have similar properties as MSC and the potential therapeutic possibilities of these cells are only just beginning to emerge.In this review, we will summarize the currently available data describing the secretome of pericytes and its potential implications for tissue regeneration, whereby we especially focus on brain pericytes as potential new target cell for neuroregeneration and brain repair.

  • In vitro oxidized HDL and HDL from type 2 diabetes patients have reduced ability to efflux oxysterols from THP-1 macrophages
    Biochimie (IF 3.188) Pub Date : 2018-04-26
    Yinan Chena, Maud Arnal-Levron, Françoise Hullin-Matsuda, Carole Knibbe, Philippe Moulin, Céline Luquain-Costaz, Isabelle Delton

    Oxidized LDL (OxLDL) that are enriched in products of lipid peroxidation including oxysterols have been shown to induce cellular oxidative stress and cytotoxicity therefore accelerating atheroma plaque formation. Upon oxLDL exposure of THP-1 macrophages, intracellular oxidation of LDL derived-cholesterol as well as endogenous cholesterol was increased. The oxysterols intracellularly produced were efficiently exported to HDL whereas apolipoprotein A1 was inefficient. These findings prompted us to investigate the consequences of modification of HDL by oxidation and glycation as observed in type 2 diabetes with respect to oxysterol and cholesterol efflux. We show that efflux of oxysterols was significantly impaired after in vitro oxidation and glycoxidation of HDL whereas glycation alone had no impact. Cholesterol efflux was only slightly decreased by oxHDL or glycoxidized HDL and not changed with glycated HDL. The defect of HDL towards oxysterol efflux was also observed with HDL isolated from diabetic subjects as compared to healthy controls. These findings support a deleterious cellular retention of oxysterols due to dysfunctional HDL in type 2 diabetes.

  • Ophiopogonin D improves osteointegration of titanium alloy implants under diabetic conditions by inhibition of ROS overproduction via Wnt/β-catenin signaling pathway
    Biochimie (IF 3.188) Pub Date : 2018-04-26
    Xiang-Yu Ma, Xin-Xin Wen, Xiao-Jiang Yang, Da-Peng Zhou, Qiong Wu, Ya-Fei Feng, Hai-Jiao Ding, Wei Lei, Hai-Long Yu, Bing Liu, Liang-Bi Xiang, Tian-Sheng Wang

    A high failure rate of titanium implants in diabetic patients has been indicated in clinical evidences. Excessive oxidative stress at the bone-implant interface plays an important role in the impaired osteointegration under diabetic conditions. While the underlying mechanisms remain unknown and the targeted treatments are urgently needed. Ophiopogonin D (OP-D), isolated from Chinese herbal Radix Ophiopogon japonicus, is generally reported to be a potent antioxidant agent. In the present study, we hypothesized that OP-D exerted promotive effects on osteointegration against oxidative stress, and investigated the underlying mechanisms associated with alteration of Wnt/β-catenin signaling pathway. Rabbit osteoblasts incubated on titanium alloy implant were co-cultured with normal serum (NS), diabetic serum (DS), DS + OP-D, DS + NAC (a potent ROS inhibitor) and DS + OP-D + Dkk1 (a Wnt inhibitor) for examinations of osteoblast behaviors. For in vivo study, titanium alloy implants were implanted into the femoral condyle defects on diabetic rabbits. Results demonstrated that diabetes-induced oxidative stress resulted in osteoblast dysfunctions and apoptotic injury at the bone-implant interface, concomitant with the inactivation of Wnt/β-catenin signaling. Importantly, OP-D administration attenuated oxidative stress, directly reactivating Wnt/β-catenin signaling. Osteoblast dysfunctions were thus reversed as evidenced by improved osteoblast adhesion, proliferation and differentiation, and ameliorated apoptotic injury, exerting similar effects to NAC treatment. In addition, the positive effects afforded by OP-D were confirmed by improved osteointegration and oetogenesis within the titanium alloy implants in vivo by Micro-CT and histological analyses. Furthermore, the pro-osteogenic effects of OP-D were almost completely abolished by the Wnt inhibitor Dkk1. These results demonstrated, for the first time, OP-D administration alleviated the damaged osteointegration of titanium alloy implants under diabetic conditions by means of inhibiting oxidative stress via a Wnt/β-catenin-dependent mechanism. The OP-D administration would become a reliable treatment strategy for implant failure therapy in diabetics due to the optimal anti-oxidative and pro-osteogenic properties.

  • Fishing Wild-type Sparing Inhibitors of Proto-oncogene c-Met Variants in Renal Cell Carcinoma from a Curated Tyrosine Kinase Inhibitor Pool using Analog-sensitive Kinase Technology
    Biochimie (IF 3.188) Pub Date : 2018-07-11
    Zhenfan Wang, Minjun Jiang, Ninghan Feng, Chen Li

    A variety of missense mutations in proto-oncogene protein tyrosine kinase c-Met have been clinically observed in the patients and families of papillary renal cell carcinoma (pRCC), imparting that the kinase mutations can be exploited as a new and potential therapeutic target for pRCC. Here, a systematic inhibitor response-to-kinase mutation profile for ATP-competitive tyrosine kinase inhibitors (TKIs) against pRCC-related c-Met mutations is created using a rigorous thermodynamic cycle scheme, from which we are able to identify a number of representative inhibitor/mutation pairs with passivation and sensitization. It is revealed that passivation is commonly caused by steric hindrance between the mutated residue and inhibitor ligand, while sensitization usually results from the formation of favorable nonbonded interactions upon the mutation. The type II inhibitor Nintedanib possesses a high selectivity (7.2-fold) for c-MetY1248H variant over wild type. Structural and energetic analysis revealed that the Y1248H mutation is located in kinase's activation loop which can directly contact the extended moiety of type II inhibitor. The titratable variant residue His1248 is protonated with stabilization by its vicinal negatively charged residue Asp1246, which can form a geometrically satisfactory hydrogen bond and a weak cation-π interaction with the inhibitor ligand, thus conferring variant selectivity to the Nintedanib/Y1248H sensitization.

  • 7β-hydroxycholesterol-induced cell death, oxidative stress, and fatty acid metabolism dysfunctions attenuated with sea urchin egg oil
    Biochimie (IF 3.188) Pub Date : 2018-07-09
    Amira Zarrouk, Yosra Ben Salem, Jawhar Hafsa, Randa Sghaier, Bassem Charfeddine, Khalifa Limem, Mohamed Hammami, Hatem Majdoub

    Some oxysterols resulting either from enzymatic oxidation or autoxidation of cholesterol are associated with age-related diseases including neurodegenerative diseases. Among these oxysterols, 7β-hydroxycholesterol (7β-OHC) is often found at increased levels in patients. It is therefore important to identify molecules or mixtures of molecules to prevent 7β-OHC-induced side effects. Consequently, murine oligodendrocytes (158 N) were cultured in the absence or presence of 7β-OHC (20 μg/mL, 24 h) with or without a natural oil extracted from sea urchin (Paracentrotus lividus) eggs known for its biological activity. Firstly, the chemical composition of this oil was determined using 31P NMR and GC-MS. Secondly, this oil was used to reduce 7β-OHC-induced side effects. To this end, the oil (160 μg/mL) was added to the culture medium of 158 N cells 2 h before 7β-OHC. The effects of 7β-OHC with or without the oil on cell viability were studied with the MTT test. Photometric methods were used to analyze antioxidant enzyme activities, superoxide dismutase (SOD) and glutathione peroxidase (GPx), as well as the generation of lipid peroxidation products (malondialdehyde (MDA), conjugated dienes (CDs)) and protein oxidation product (carbonylated proteins (CPs)). Gas chromatography was used to determine the fatty acid profile. With 7β-OHC, an induction of cell death associated with oxidative stress (alteration of GPx and SOD activities) was observed; an overproduction of lipid peroxidation products (MDA and CDs) and CPs was also revealed. Sea urchin egg oil attenuated 7β-OHC-induced cytotoxicity: 7β-OHC-induced cell death was reduced, GPx and SOD activities were normalized, and lower levels of MDA, CDs and CPs were produced. In addition, whereas a disturbed fatty acid profile was observed with 7β-OHC, similar fatty acid profiles were found in control cells and in cells cultured with 7β-OHC associated with sea urchin egg oil. These data demonstrate the protective activities of sea urchin egg oil against 7β-OHC-induced side effects on 158 N cells, supporting the concept that this oil may have benefits in the prevention of neurodegenerative diseases.

  • Contribution of microRNAs to the immunosuppressive function of mesenchymal stem cells
    Biochimie (IF 3.188) Pub Date : 2018-07-06
    Yves-Marie Pers, Marie Maumus, Claire Bony, Christian Jorgensen, Danièle Noël

    Mesenchymal stem/stromal cells (MSCs) are progenitor cells identified in many adult tissues, in particular in bone marrow or adipose tissue and, in placental tissues. MSCs exert pleiotropic functions that render them attractive for many clinical applications, both in degenerative and inflammatory diseases. Their main mode of action is through the secretion of trophic factors that can be released in the extracellular milieu or packaged within extracellular vesicles. These factors can be proteins, lipids, mRNA or miRNA that possess diverse effects, notably pro-angiogenic, anti-fibrotic, anti-apoptotic or anti-inflammatory effects. The anti-inflammatory role of a number of miRNAs has been demonstrated in different types of immune cells but few have been associated with the immunomodulatory function of MSCs. In this review, we summarize the data on the miRNAs that have been validated as participating to the anti-inflammatory role of MSCs.

  • In vitro and in silico studies of naphthoquinones and peptidomimetics toward Plasmodium falciparum plasmepsin V
    Biochimie (IF 3.188) Pub Date : 2018-07-06
    Pichamon Sittikul, Napat Songtawee, Ngampong Kongkathip, Nonlawat Boonyalai

    Plasmodium proteases play both regulatory and effector roles in essential biological processes in this important pathogen and have long been investigated as drug targets. Plasmepsin V from P. falciparum (PfPMV) is an essential protease that processes proteins for export into the host erythrocyte and is a focus of ongoing drug development efforts. In the present study, recombinant protein production, inhibition assays, binding studies as well as molecular docking and molecular dynamics simulation studies were used to investigate the mode of binding of a PEXEL-based peptidomimetic and naphthoquinone compounds to PfPMV. Consistent with our previous study, refolded PfPMVs were produced with functional characteristics similar to the soluble counterpart. Naphthoquinone compounds inhibited PfPMV activity by 50% at 50 μM but did not affect pepsin activity. The IC50 values of compounds 31 and 37 against PfPMV were 22.25 and 68.94 μM, respectively. Molecular dynamics simulations revealed that PEXEL peptide interacted with PfPMV active site residues via electrostatic interactions while naphthoquinone binding preferred van der Waal interactions. P1′-Ser of the PfEMP2 substrate formed an additional H-bond with Asp365 promoting the catalytic efficiency. Additionally, the effect of metal ions on the secondary structure of PfPMV was examined. Our results confirmed that Hg2+ ions reversibly induced the changes in secondary structure of the protein whereas Fe3+ ions induced irreversibly. No change was observed in the presence of Ca2+ ions. Overall, the results here suggested that naphthoquinone derivatives may represent another source of antimalarial inhibitors targeting aspartic proteases but further chemical modifications are required.

  • Tocopherol suppresses 24(S)-hydroxycholesterol-induced cell death via inhibition of CaMKII phosphorylation
    Biochimie (IF 3.188) Pub Date : 2018-07-07
    Yuki Kimura, Minori Asa, Yasuomi Urano, Yoshiro Saito, Kiyotaka Nishikawa, Noriko Noguchi

    Although 24(S)-hydroxycholesterol (24 S-OHC) plays an important role to maintain homeostasis of cholesterol in the brain, it induces neuronal cell death at high concentrations. 24 S-OHC-induced cell death was suppressed by γ-tocopherol (γ-Toc) but not by γ-tocotrienol (γ-Toc3) in a similar way to α-tocopherol (α-Toc) and α-tocotrienol (α-Toc3) in human neuroblastoma SH-SY5Y cells. Both γ-Toc and γ-Toc3 significantly inhibited cumene hydroperoxide-induced cell death, as previously shown in the case of α-Toc and α-Toc3. Lipid droplet-like structure formation induced by 24 S-OHC was suppressed by neither γ-Toc nor γ-Toc3. The phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) was induced by 24 S-OHC, which was suppressed by CaMKII phosphorylation-site inhibitor mM3 but not by calmodulin-binding-site inhibitor KN62. A calcium chelator, BAPTA-AM, inhibited calcium ionophore A23187-induced CaMKII phosphorylation but not 24 S-OHC-induced CaMKII phosphorylation. Receptor-interacting protein kinase 1 (RIPK1) phosphorylation induced by 24S-OHC was not inhibited by either mM3 or KN62, suggesting that CaMKII activation does not affect RIPK1 phosphorylation. Knockdown of RIPK1 using siRNA induced not only inhibition of CaMKII phosphorylation but also reduction of total CaMKII protein levels, suggesting that RIPK1 may regulate CaMKII signalling. 24 S-OHC-induced RIPK1 phosphorylation was inhibited by neither α-Toc nor α-Toc3. In contrast, CaMKII phosphorylation induced by 24 S-OHC was significantly suppressed by α-Toc but not by α-Toc3. These results suggest that CaMKII activation is involved in the mechanism of 24 S-OHC-induced cell death and that Toc inhibits the cell death via inhibition of CaMKII activation through a RIPK1 phosphorylation-independent pathway.

  • FasL on the surface of Tag7 (PGRP-S)-activated lymphocytes induces necroptosis in HLA-negative tumor cells with the involvement of lysosomes and mitochondria
    Biochimie (IF 3.188) Pub Date : 2018-07-07
    Tatiana N. Sharapova, Elena A. Romanova, Lidia P. Sashchenko, Denis V. Yashin

    Recently we have found that cytokine IL-2 and innate immunity protein Tag7 activate cytotoxic lymphocytes that kill HLA-negative tumor cells, inducing both apoptosis and necroptosis. Here we decrypt the processes, taking part in necroptosis execution after FasL-Fas interaction. Necroptosis begins with RIPK1 activation and necrosome formation. Subsequent activation of MLKL results in the increase of Ca2+ level in the cell and activation of Ca2+-dependent enzymes causing lysosomal membrane permeabilization and the release of cathepsins to the cytosol. STAT3 translocation to the mitochondria and binding to a component of the respiratory chain complex I causes ROS accumulation. We have shown that transduction of necroptotic signal via TNFR1 and Fas has many common points. It is known that apoptosis plays a major role in physiological cell death; however, under pathological conditions necroptosis is very common. That is why the detailed mechanisms of FasL-Fas necroptosis can help in understanding the processes of elimination of tumor cells that have blocked apoptosis signal transduction.

  • HAMSCs/HBMSCs coculture system ameliorates osteogenesis and angiogenesis against glucolipotoxicity
    Biochimie (IF 3.188) Pub Date : 2018-07-03
    Chunli Zhang, Yifei Du, Hua Yuan, Fei Jiang, Ming Shen, Yuli Wang, Ruixia Wang

    Osteoporosis and vascular lesions induced by glucolipotoxicity are common complications of diabetes mellitus (DM). In order to deal with these complications, we designed a new therapeutic strategy, i.e. coculture system containing human amnion-derived mesenchymal stem cells (HAMSCs) and human bone marrow mesenchymal stem cells (HBMSCs). Two in vitro coculture models, transwell and mixed cocultures, were proposed for 7 days with variable HAMSCs: HBMSCs ratios. Then, supernatant from each coculture was used to reverse the deficiency of HBMSCs and human umbilical vein endothelial cells (HUVECs) impaired by high glucose and palmitic acid (GP). We found that glucolipotoxicity caused by GP remarkably inhibited cell proliferation, osteogenic differentiation and superoxide dismutase (SOD) activity, as well as induced the reactive oxygen species (ROS) level in HBMSCs. Meanwhile, glucolipotoxicity suppressed cell proliferation, tube formation capacity and angiogenic potential of HUVECs. Though, HAMSCs/HBMSCs coculture system reduced HBMSCs dysfunction by antioxidant properties and promoted angiogenesis in HUVECs. The mixed HAMSCs/HBMSCs coculture at the optimal ratio of 3/1 showed significantly greater cell proliferation, antioxidant properties, osteogenic and angiogenic differentiation than HBMSCs or HUVECs alone. In conclusion, the current coculture system of HAMSCs/HBMSCs can be a potential therapeutic material for advancing bone and vascular regeneration against DM-induced glucolipotoxicity.

  • Glucagon-Like peptide-1: A new therapeutic target to treat abdominal aortic aneurysm?
    Biochimie (IF 3.188) Pub Date : 2018-07-03
    Juliette Raffort, Giulia Chinetti, Fabien Lareyre

    Recent antidiabetic drugs including GLP-1 receptor agonists and DPP-IV inhibitors have demonstrated protective effects in several cardiovascular diseases but their effect in abdominal aortic aneurysm (AAA) is far less known. AAA can be associated with extremely high rates of mortality and pharmacological treatments are still lacking underlining the real need to identify new therapeutic targets. The aim of this review was to summarize current knowledge on the role of GLP-1 pathway in AAA. A systematic literature review was performed and 6 relevant studies (2 clinical and 4 experimental) were included. Experimental studies demonstrated a protective effect of both GLP-1 receptor agonists and DPP-IV inhibitors through targeting the main pathophysiological mechanisms underlying AAA formation. The effects of these drugs in human AAA are still poorly known. In the limelight of clinical and experimental studies, we discuss current limits and future directions.

  • The hypothalamic neuropeptide orexin A– a possible regulator in glucose homeostasis and germ cell kinetics in adult mice testes
    Biochimie (IF 3.188) Pub Date : 2018-06-30
    Deepanshu Joshi, Debarshi Sarkar, Shio Kumar Singh

    Orexin A (OXA), a hypothalamic neuropeptide, regulates food intake, sleep-wake cycle and energy balance by binding to its receptor (OX1R). Apart from brain, OXA and OX1R are also present in peripheral organs including reproductive tissues. Mammalian reproduction depends on uptake and proper utilization of glucose in the testes. This study, therefore, examined role of OXA/OX1R system in regulation of glucose homeostasis in adult mouse testis under in vivo and ex vivo conditions. Binding of OXA to OX1R was blocked using an OX1R antagonist, SB-334867. Mice were given a single bilateral intratesticular injection of the antagonist at doses of 4 and 12μg/mouse and sacrificed 24 h post-injection. In order to understand the direct role of OXA in testes of adult mice, an ex vivo experiment was performed where binding of OXA to OX1R in the testis was blocked by using the same OX1R antagonist. The antagonist treatment affected testicular glucose and lactate concentration with concomitant down-regulation in the expression of glucose transporters 3 and 8. A decreased activity in lactate dehydrogenase enzyme and imbalance between germ cell survival and proliferation were also noted in testes in treated mice. The results of ex vivo study supported the results obtained from in vivo study. The findings thus suggest involvement of OXA/OX1R system in regulation of testicular glucose homeostasis and germ cell kinetics in adult mice.

  • G-quadruplex Virtual Drug Screening: A Review
    Biochimie (IF 3.188) Pub Date : 2018-06-30
    Robert C. Monsen, John O. Trent

    Over the past two decades biologists and bioinformaticians have unearthed substantial evidence supporting a role for G-quadruplexes as important mediators of biological processes. This includes telomere damage signaling, transcriptional activity, and splicing. Both their structural heterogeneity and their abundance in oncogene promoters makes them ideal targets for drug discovery. Currently, there are hundreds of deposited DNA and RNA quadruplex atomic structures which have allowed researchers to begin using in silico drug screening approaches to develop novel stabilizing ligands. Here we provide a review of the past decade of G-quadruplex virtual drug discovery approaches and campaigns. With this we introduce relevant virtual screening platforms followed by a discussion of best practices to assist future G4 VS campaigns.

  • Oleanolic acid improves diet-induced obesity by modulating fat preference and inflammation in mice
    Biochimie (IF 3.188) Pub Date : 2018-06-30
    Fatima Zohra Djeziri, Meriem Belarbi, Babar Murtaza, Aziz Hichami, Chahid Benammar, Naim Akhtar Khan

    Obesity, triggered by high-fat diet (HFD), is associated to altered gustatory perception of dietary lipids. Oleanolic acid (OLA), a triterpene, has been reported to exert anti-obesity effects in animal models. Hence, we investigated the role of OLA in the modulation of oro-sensory perception of lipids in control and HFD-induced obese mice. As expected, OLA-treated obese mice exhibited a decrease in body, liver, and visceral adipose tissue weights. OLA treatment improved glucose tolerance, insulin level, plasma lipopolysaccharide (LPS), and hepatic cholesterol and triglyceride concentrations. OLA-treated obese mice exhibited higher fat preference compared to untreated obese mice, probably due to the increase in mRNA encoding CD36, a fat taste receptor, in mouse taste bud cells (mTBC). This phenomenon was associated with fatty-acid induced increases in free intracellular calcium concentrations, [Ca2+]i, induced in mTBC from OLA-treated obese mice. OLA also influenced the expression of mRNA encoding pro-inflammatory cytokines (IL-1β and IL-6) and some lipogenic genes (PPARα, SREBP1, FAS, ChREBP, and G6Pase) in liver and adipose tissue. These findings reveal that OLA improves gustatory perception of lipids and exerts protective effects in obesity.

  • From the Ca2+-activated F1FO-ATPase to the mitochondrial permeability transition pore: an overview
    Biochimie (IF 3.188) Pub Date : 2018-06-28
    Salvatore Nesci, Fabiana Trombetti, Vittoria Ventrella, Alessandra Pagliarani

    Based on recent advances on the Ca2+-activated F1FO-ATPase features, a novel multistep mechanism involving the mitochondrial F1FO complex in the formation and opening of the still enigmatic mitochondrial permeability transition pore (MPTP), is proposed. MPTP opening makes the inner mitochondrial membrane (IMM) permeable to ions and solutes and, through cascade events, addresses cell fate to death. Since MPTP forms when matrix Ca2+ concentration rises and ATP is hydrolyzed by the F1FO-ATPase, conformational changes, triggered by Ca2+ insertion in F1, may be transmitted to FO and locally modify the IMM curvature. These events would cause F1FO-ATPase dimer dissociation and MPTP opening.

  • Dihydrodipicolinate synthase is absent in fungi
    Biochimie (IF 3.188) Pub Date : 2018-06-27
    Sebastien Desbois, Ulrik P. John, Matthew A. Perugini
  • Identification of 7α,24-Dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-Dihydroxy-3-oxocholest-4-en-26-oic Acids in Human Cerebrospinal Fluid and Plasma
    Biochimie (IF 3.188) Pub Date : 2018-06-28
    Jonas Abdel-Khalik, Peter J. Crick, Eylan Yutuc, Andrea E. DeBarber, P. Barton Duell, Robert D. Steiner, Ioanna Laina, Yuqin Wang, William J. Griffiths
  • The role of the retinal pigment epithelium and Müller cells secretome in neovascular retinal pathologies
    Biochimie (IF 3.188) Pub Date : 2018-06-28
    Rute S. Araújo, Daniela F. Santos, Gabriela A. Silva

    Secreted trophic factors are key to maintain the structural and functional integrity of the retina, as they regulate cellular pathways responsible for survival, function, and response to injury. Nevertheless, these same factors can also be involved in retinal pathologies, as a consequence of the impairment of the secretory function of cells. The cells considered as major contributors to the retinal secretome are the retinal pigmented epithelium (RPE) and Müller cells. Their role in the pathophysiology of the most common neovascular pathologies in the retina - Age-related Macular Degeneration (AMD), Diabetic Retinopathy (DR), and Retinopathy of Prematurity (ROP) - is highlighted in this short review, together with current trophic factor-based therapies, which are mainly focused on controlling inflammation, cell survival, and angiogenesis.

  • A new xanthatin analogue 1β-hydroxyl-5α-chloro-8-epi-xanthatin induces apoptosis through ROS-mediated ERK/p38 MAPK activation and JAK2/STAT3 inhibition in human hepatocellular carcinoma
    Biochimie (IF 3.188) Pub Date : 2018-06-28
    Xin-Yi Fang, Hai Zhang, Lin Zhao, Shuai Tan, Qing-Cuo Ren, Lun Wang, Xiao-Fei Shen

    1β-hydroxyl-5α-chloro-8-epi-xanthatin (XTT), a sesquiterpene lactone isolated from Xanthium sibiricum, possessed potent cytotoxicity on cancer cells in vitro. The objective of this study was to investigate the anti-tumor effect and underlying mechanisms of XTT on human hepatocellular carcinoma (HCC). Firstly, XTT inhibited the cell growth and induced apoptosis in human HCC cells, which was associated with the induction of Bax and cleaved-caspase-3, inhibition of Bcl-2 and survivin expression. Importantly, XTT induced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), and depletion of glutathione (GSH) in HCC cells through covalently modification of GSH. Furthermore, XTT caused obvious activation of extracellular regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) and inactivation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) in HCC cells. ROS scavenger N-acetyl cysteine abrogated the effects of XTT on ERK/p38 MAPK activation and JAK2/STAT3 inhibition, and rescued HCC cells from XTT-induced apoptosis. Additionally, inhibitors of ERK/p38 MAPKs or activator of JAK2/STAT3 partially abolished XTT-mediated effect. In summary, XTT inhibited cell growth and induced apoptosis in HCC cells through ROS-mediated ERK/p38 MAPK activation and JAK2/STAT3 inhibition by GSH depletion. These findings also show the therapeutic potential of XTT in HCC.

  • LncRNA THOR attenuates cisplatin sensitivity of nasopharyngeal carcinoma cells via enhancing cells stemness
    Biochimie (IF 3.188) Pub Date : 2018-06-26
    G.A.O. Ling, C.H.E.N.G. Xiu-lian, C.A.O. Hua

    The roles and mechanisms of long non-coding RNAs (lncRNA) in nasopharyngeal carcinoma (NPC) cells stemness and chemotherapeutic sensitivity are unclear. Here, Quantitative real-time PCR (qRT-PCR) was performed to detect the lncRNA THOR expression in NPC and normal adjacent tissues, adherent NPC cells and non-adherent NPC spheres, and we found that THOR was significantly increased in NPC tissues and non-adherent NPC spheres. Further in vitro and in vivo experiments were carried out and identified that knockdown of THOR attenuated NPC cells stemness, characterized as the decrease of spheres formation ability, cell proliferation, migration, invasion, stemness markers expression and tumor initiation, and enhanced cisplatin sensitivity of NPC cells. Mechanistically, RNA immunoprecipitation (RIP), immunofluorescence and luciferase reporter analysis indicated that THOR could enhance YAP transcriptional activity via directly binding to YAP and suppressing its translocation from nuclear to cytoplasm. Notably, overexpression of YAP rescued the inhibition of THOR knockdown on NPC cells and spheres stemness and promotion on cisplatin sensitivity. Thus, our results demonstrate that lncRNA THOR could attenuate cisplatin sensitivity of NPC cells by enhancing cells stemness through promoting YAP transcriptional activity.

  • Apurinic/apyrimidinic endonuclease Apn1 from Saccharomyces cerevisiae is recruited to the nucleotide incision repair pathway: kinetic and structural features
    Biochimie (IF 3.188) Pub Date : 2018-06-26
    Elena S. Dyakonova, Vladimir V. Koval, Alexander A. Lomzov, Alexander A. Ishchenko, Olga S. Fedorova
  • Corticoids modulate liposome membrane fluidity and permeability depending on membrane composition and experimental protocol design
    Biochimie (IF 3.188) Pub Date : 2018-06-20
    Samar Kaddah, Nathalie Khreich, Fouad Kaddah, Lhoussain Khrouz, Catherine Charcosset, Hélène Greige-Gerges
  • Serotonin and human cancer: a critical view
    Biochimie (IF 3.188) Pub Date : 2018-06-21
    Denis Sarrouilhe, Marc Mesnil

    Besides its classical functions as a neurotransmitter in the central nervous system, local mediator in the gastrointestinal tract and vasoactive agent in the blood, serotonin has more recently emerged as a growth factor for human tumor cell lines of different origins (carcinomas, glioma and carcinoids). Several data are also available on serotonin involvement in cancer cell migration, metastatic dissemination and tumor angiogenesis. The serotonin-induced signaling pathways that promote tumor progression are complex and only partly understood in some cancer types. The results of several studies showed that serotonin levels in the tumor played a crucial role in cancer progression. A serotonin production and secretion by neuroendocrine cells have been shown in the progression of several solid tumors and the involvement of a serotoninergic autocrine loop was proposed. Specific receptor subtypes are associated with different fundamental stages of tumor progression and the pattern of receptors expression becomes dysregulated in several human tumors when compared with normal cells or tissues. Serotonin receptors, selective serotonin transporter and serotonin synthesis pathways are potential chemotherapeutic targets for the treatment of several cancers in which therapeutic approaches are limited. Through several asked questions, this critical mini-review discusses the relevance of the involvement of serotonin in human cancer progression.

  • Screening and characterization of a Annenix A2 binding aptamer that inhibits the proliferation of myeloma cells
    Biochimie (IF 3.188) Pub Date : 2018-06-15
    Weihua Zhou, Yibin Zhang, Yayue Zeng, Minyuan Peng, Hui Li, Shuming Sun, Bianying Ma, Yanpeng Wang, Mao Ye, Jing Liu

    Multiple myeloma (MM) is a malignant plasma cell disease and is considered incurable. Annexin A2 (ANXA2) is closely related to the proliferation and adhesion of MM. Using protein-SELEX, we performed a screen for aptamers that bind GST-ANXA2 from a library, and GST protein was used for negative selection. The enrichment of the ssDNA pool was monitored by filter-binding assay during selection. After nine rounds of screening and high-throughput sequencing, we obtained six candidate aptamers that bind to the ANXA2 protein. The affinities of the candidate aptamers for ANXA2 were determined by ELONA. Binding of aptamer wh6 to the ANXA2 protein and to the MM cell was verified by aptamer pulldown experiment and flow cytometry, respectively. Aptamer wh6 binds the ANXA2 protein with good stability and has a dissociation constant in the nanomolar range. The binding specificity of aptamer wh6 was confirmed in vivo in nude mouse xenografts with MM cells and with MM bone marrow aspirates. Furthermore, aptamer wh6 can block MM cell adhesion to ANXA2 and block the proliferation of MM cells induced by ANXA2. In summary, wh6 can be considered a promising candidate tool for MM diagnosis and treatment.

  • Predictive metabolic signatures of end-stage renal disease: a multivariate analysis of population-based data
    Biochimie (IF 3.188) Pub Date : 2018-06-15
    Robson E. Silva, João L. Baldim, Daniela A. Chagas-Paula, Marisi G. Soares, João H.G. Lago, Reggiani V. Gonçalves, Rômulo D. Novaes
  • Serotonin in the gut: Blessing or a curse
    Biochimie (IF 3.188) Pub Date : 2018-06-14
    Suhrid Banskota, Jean-Eric Ghia, Waliul I. Khan

    Serotonin (5-hydroxytryptamine or 5-HT) once most extensively studied as a neurotransmitter of the central nervous system, is seen to be predominantly secreted in the gut. About 95% of 5-HT is estimated to be found in gut mainly within the enterochromaffin cells whereas about 5% is found in the brain. 5-HT is an important enteric signaling molecule and is well known for playing a key role in sensory-motor and secretory functions in the gut. In recent times studies uncovering various new functions of gut-derived 5-HT indicate that many more are yet to be discovered in coming days. Recent studies revealed that 5-HT plays a pivotal role in immune cell activation and generation/perpetuation of inflammation in the gut. In addition to its various roles in the gut, there are now emerging evidences that suggest an important role of gut-derived 5-HT in other biological processes beyond the gut, such as bone remodeling and metabolic homeostasis. This review focuses to briefly summarize the accumulated and newly updated role of 5-HT in the maintenance of normal gut physiology and in the pathogenesis of inflammation in the gut. The collected information about this multifaceted signaling molecule may aid in distinguishing its good and bad effects which may lead to the development of novel strategies to overcome the unwanted effect, such as in inflammatory bowel disease.

  • Implication of oxysterols in chronic inflammatory human diseases
    Biochimie (IF 3.188) Pub Date : 2018-06-09
    Gabriella Testa, Daniela Rossin, Giuseppe Poli, Fiorella Biasi, Gabriella Leonarduzzi

    A growing bulk of evidence suggests that cholesterol oxidation products, known as oxysterols, are potentially involved in the pathogenesis of major chronic diseases, including atherosclerosis, Alzheimer's disease, and inflammatory bowel disease. Oxysterols are involved in various key steps of these complex processes, mainly thanks to their ability to act through up-regulation of oxidative stress, inflammation, and cell toxicity. This review summarizes the current knowledge of the effects induced by these compounds on cells, after their accumulation in the arterial wall, brain, and intestine. This evidence might help to develop innovative strategies to counteract the progression of these chronic inflammatory human diseases.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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