Biochemical and Biophysical Research Communications (Biochem Biophys Res Comm)

Publications in this journal

• Article: specific interactions between concanavalin A and glycolipids incorporated into planar lipid membranes

  M Deleers, A Poss, JM Ruysschaert
  Biochemical and Biophysical Research Communications 12/2013; 72(1976):709-713.
• Article: Downregulation of miR-497 promotes tumor growth and angiogenesis by targeting HDGF in non-small cell lung cancer.

  Wen-Yan Zhao, Yan Wang, Zhong-Jun An, Chang-Guo Shi, Guang-Ai Zhu, Bin Wang, Ming-Yan Lu, Chang-Kun Pan, Peng Chen
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  ABSTRACT: MicroRNAs (miRNAs) play important roles in the development of various cancers. MiRNA-497 functions as a tumor-suppressor that is downregulated in several malignancies; however, its role in non-small cell lung cancer (NSCLC) has not been examined in detail. Here, we showed that miR-497 is downregulated in NSCLC tumors and cell lines and its ectopic expression significantly inhibits cell proliferation and colony formation. Integrated analysis identified HDGF as a downstream target of miR-497, and the downregulation of HDGF by miR-497 overexpression confirmed their association. Rescue experiments showed that the inhibitory effect of miR-497 on cell proliferation and colony formation is predominantly mediated by the modulation of HDGF levels. Furthermore, tumor samples from NSCLC patients showed an inverse relationship between miR-497 and HDGF levels, and ectopic expression of miR-497 significantly inhibited tumor growth and angiogenesis in a SCID mouse xenograft model. Our results suggest that miR-497 may serve as a biomarker in NSCLC, and the modulation of its activity may represent a novel therapeutic strategy for the treatment of NSCLC patients.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Cancer cachexia decreases specific force and accelerates fatigue in limb muscle.

  B M Roberts, G S Frye, B Ahn, L F Ferreira, A R Judge
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  ABSTRACT: Cancer cachexia is a complex metabolic syndrome that is characterized by the loss of skeletal muscle mass and weakness, which compromises physical function, reduces quality of life, and ultimately can lead to mortality. Experimental models of cancer cachexia have recapitulated this skeletal muscle atrophy and consequent decline in muscle force generating capacity. However, more recently, we provided evidence that during severe cancer cachexia muscle weakness in the diaphragm muscle cannot be entirely accounted for by the muscle atrophy. This indicates that muscle weakness is not just a consequence of muscle atrophy but that there is also significant contractile dysfunction. The current study aimed to determine whether contractile dysfunction is also present in limb muscles during severe Colon-26 (C26) carcinoma cachexia by studying the glycolytic extensor digitorum longus (EDL) muscle and the oxidative soleus muscle, which has an activity pattern that more closely resembles the diaphragm. Severe C-26 cancer cachexia caused significant muscle fiber atrophy and a reduction in maximum absolute force in both the EDL and soleus muscles. However, normalization to muscle cross sectional area further demonstrated a 13% decrease in maximum isometric specific force in the EDL and an even greater decrease (17%) in maximum isometric specific force in the soleus. Time to peak tension and half relaxation time were also significantly slowed in both the EDL and the solei from C-26 mice compared to controls. Since, in addition to postural control, the oxidative soleus is also important for normal locomotion, we further performed a fatigue trial in the soleus and found that the decrease in relative force was greater and more rapid in solei from C-26 mice compared to controls. These data demonstrate that severe cancer cachexia causes profound muscle weakness that is not entirely explained by the muscle atrophy. In addition, cancer cachexia decreases the fatigue resistance of the soleus muscle, a postural muscle typically resistant to fatigue. Thus, specifically targeting contractile dysfunction represents an additional means to counter muscle weakness in cancer cachexia, in addition to targeting the prevention of muscle atrophy.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) regulates CTL activation and memory programming.

  Zhifeng Sun, Zhengguo Xiao
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  ABSTRACT: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the major carcinogens in tobacco. NNK has been associated with various cancers in tobacco users, especially lung cancer. However, the effects of NNK on cytotoxic T lymphocytes (CTLs), the cells responsible for destrcution of maligant and pathogen-infected cells, has not been elucidated. Using transgenic CTLs in vitro and in vivo, we show that NNK can directly affect CTL activation. NNK can enhance the expression of adhesion molecule CD62L in CTLs during their activation in vitro, but has no effects on their expansion and production of effector molecules such as IFN and granzyme B. After transferred into recipient mice, however, the NNK pretreated CTLs suffer an early loss in expansion. The percentage of memory precursors is higher in NNK pretreated CTLs, but the total amount of memory precursors is similar to controls. The final memory CTL population from NNK pretreated CTLs is reduced, but sustains a more central memory phenotype. In conclusion, NNK can affect CTL activation by modulating adhension molecule expression and reducing memory programming.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Probing Insect Odorant Receptors with their Cognate Ligands: Insights into Structural Features.

  Pingxi Xu, Walter S Leal
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  ABSTRACT: Oodorant receptors (ORs) are essential for insect survival in the environment and thus are ideal molecular targets for the design of insect-inspired modern green chemicals to control populations of agricultural pests and insects of medical importance. Although insect ORs are known for more than a decade, their structural biology is still in its infancy. Here, we unravel the first structural features of ORs from the malaria mosquito, the Southern house mosquito and the silkworm moth. The second extracellular loops (ECL-2s) of their predicted structures are much longer than ECL-1s and ECL-3s. The 27 amino-acid-residue-long of the ECL-2s in mosquito and the 43 amino-acid-residue-long ECL2s in moth ORs are well-conserved. About one-third of the residues are identical, including 3-4 Pro residues. Thorough examination of well-conserved residues in these structures, by point mutation and functional assay with the Xenopus oocyte recording system, strongly suggest that these "loops" include three β-turns and some degree of folding. In the Southern house mosquito three Pro residues in ECL-2 are essential for full activation of the receptor, which is finely tuned to the oviposition attractant 3-methylindole. Additionally, the "corner residues" of prolines, including Gly, Tyr, and Leu are functionally important thus suggesting that turns are stabilized not only by backbone hydrogen bonds, but also by side-chain interactions. Examination of ECL-2s from a distant taxonomical group suggests these ECL-2 loops might be functionally important in all insect ORs. Two of the four Pro residues in the predicted ECL-2 of the bombykol receptor in the silkworm moth, BmorOR1, are essential for function. Experimental evidence indicates that these loops may not be specificity determinants, but they may form a cover to the yet-to-be-identified membrane embedded binding cavities of insect ORs.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Exercise training improve leptin sensitivity in peripheral tissue.

  Sunghwun Kang, Kwi Baek Kim, Ki Ok Shin
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  ABSTRACT: The present study examined the change to the effect of the leptin sensitivity by leptin resistance-induced leptin receptor (ObRb) and leptin-related suppressor of cytokine signaling 3 (SOCS3) mRNA levels in hypothalamic, liver, muscle and leptin protein levels in blood after eight weeks of exercise training and/or dietary control of high fat induced obese rats. After two weeks of adaptation maintenance, four-week-old male SD rats (n=42) were randomly divided into control (CO) (n=8) and high-fat diet (HF) (n=32) groups. The HF group randomly divided into HF, HF+exercise training (HFT), changed to normal diet (HFND) and changed to normal diet and exercise training (HFNDT) groups. Thirteen weeks of HF group average body weight significantly increased in comparison to the CO group (p<0.05). Plasma leptin levels of the HFT, HFND and HFNDT group were significantly decreased in comparison to the HF group (p<0.05). The mRNA expression of ObRb and SOCS3 in the liver and muscle of the HF group was significantly decreased comparison to that of the HFT, HFND and HFNDT group after 8 weeks intervention (p<0.05). In addition, the mRNA expression of ObRb and SOCS3 in the hypothalamus of the HF group was significantly increased comparison to that of the HFT, HFND and HFNDT group (p<0.05). HFND group also was significantly reduced comparison to of the HFT and HFNDT group (p<0.05) These findings suggest that the effect of leptin sensitivity in peripheral may primarily the more relate to combined dietary control and exercise training more than effect of dietary control.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: The CC1-FHA dimer is essential for KIF1A-mediated axonal transport of synaptic vesicles in C.elegans.

  Yang Yue, Yi Sheng, Hai-Ning Zhang, Yong Yu, Lin Huo, Wei Feng, Tao Xu
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  ABSTRACT: KIF1A, a member of kinesin-3 motors, plays a pivotal role in anterograde axonal transport of synaptic vesicles (SVs). We have shown that the CC1-FHA tandem of KIF1A forms a stable dimer that is crucial for both the dimerization and activation of the motor. However, it remains to be determined whether the CC1-FHA dimer is essential for KIF1A-mediated axonal transport in vivo. Here, we use C. elegans as the model organism to probe the in vivo function of the CC1-FHA dimer. Disruption of the CC1-FHA dimer severely impairs the KIF1A-mediated regulation of the locomotion and pumping behavior of C. elegans and exerts a significant impact on KIF1A-mediated axonal SV transport. Thus, together with previous structural and biochemical studies, the in vivo data presented in this study firmly establish the essential role of the CC1-FHA dimer for KIF1A-mediated neuronal transport.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Involvement of AAT transporters in methylmercury toxicity in Caenorhabditis elegans.

  Samuel W Caito, Yaofang Zhang, Michael Aschner
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  ABSTRACT: Methylmercury (MeHg) is a potent neurotoxin that enters mammalian cells as a conjugate with L-cysteine through L-type large neutral amino acid transporter, LAT1, by a molecular mimicry mechanism by structurally resembling L-methionine. Caenorhabditis elegans (C. elegans) has been increasingly used to study the neurotoxic effects of MeHg, but little is known about uptake and transport of MeHg in the worm. This study examined whether MeHg uptake through LAT1 is evolutionarily conserved in nematodes. MeHg toxicity in C. elegans was blocked by pre-treatment of worms with L-methionine, suggesting a role for amino acid transporters in MeHg transport. Knockdown of aat-1, aat-2, and aat-3, worm homologues to LAT1, increased the survival of C. elegans following MeHg treatment and significantly attenuated MeHg content following exposure. These results indicate that MeHg is transported in the worm by a conserved mechanism dependent on functioning amino acid transporters.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Disruption of polyubiquitin gene Ubc leads to defective proliferation of hepatocytes and bipotent fetal liver epithelial progenitor cells.

  Hyejin Park, Min-Sik Yoon, Kwon-Yul Ryu
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  ABSTRACT: We have previously demonstrated that disruption of polyubiquitin gene Ubc leads to mid-gestation embryonic lethality most likely due to a defect in fetal liver development, which can be partially rescued by ectopic expression of Ub. In a previous study, we assessed the cause of embryonic lethality with respect to the fetal liver hematopoietic system. We confirmed that Ubc(-/-) embryonic lethality could not be attributed to impaired function of hematopoietic stem cells, which raises the question of whether or not FLECs such as hepatocytes and bile duct cells, the most abundant cell types in the liver, are affected by disruption of Ubc and contribute to embryonic lethality. To answer this, we isolated FLCs from E13.5 embryos and cultured them in vitro. We found that proliferation capacity of Ubc(-/-) cells was significantly reduced compared to that of control cells, especially during the early culture period, however we did not observe the increased number of apoptotic cells. Furthermore, levels of Ub conjugate, but not free Ub, decreased upon disruption of Ubc expression in FLCs, and this could not be compensated for by upregulation of other poly- or mono-ubiquitin genes. Intriguingly, the highest Ubc expression levels throughout the entire culture period were observed in bipotent FLEPCs. Hepatocytes and bipotent FLEPCs were most affected by disruption of Ubc, resulting in defective proliferation as well as reduced cell numbers in vitro. These results suggest that defective proliferation of these cell types may contribute to severe reduction of fetal liver size and potentially mid-gestation lethality of Ubc(-/-) embryos.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Preparation of Quercetin and Rutin-Loaded Ceramide Liposomes and Drug-Releasing Effect in Liposome-in-Hydrogel Complex System.

  Soo Nam Park, Min Hye Lee, Su Ji Kim, Eun Ryeong Yu
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  ABSTRACT: In this study, we developed a 2-step delivery system to enhance transdermal permeation of quercetin and its glycoside rutin, an antioxidant. Liposome-in-hydrogel complex systems were prepared by incorporating ceramide liposomes, which consist of biocompatible lipid membranes, into cellulose hydrogel. We evaluated the encapsulation efficiency, in vitro release behavior, and skin permeability of formulations that remained stable for over 3 weeks. Rutin had greater encapsulation efficiency and better in vitro release properties than quercetin. However, quercetin demonstrated greater skin permeability than rutin. We also found that liposome-in-hydrogel complex systems (quercetin, 67.42%; rutin 59.82%) improved skin permeability of quercetin and rutin compared to control (phosphate buffer, pH 7.4) (quercetin, 2.48%; rutin, 1.89%) or single systems of hydrogel (quercetin, 31.77%; rutin, 26.35%) or liposome (quercetin, 48.35%; rutin, 37.41%). These results indicate that liposome-in-hydrogel systems can function as potential drug delivery systems to enhance transdermal permeation of the water-insoluble antioxidants quercetin and rutin.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: GnRH Neuron Type-Specific Transcriptome Analysis by Laser Captured Single-Cell Microarray in the Medaka.

  Shogo Moriya, Satoshi Ogawa, Ishwar S Parhar
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  ABSTRACT: Most vertebrates possess at least two gonadotropin-releasing hormone (GnRH) neuron types. To understand the physiological significance of the multiple GnRH systems in the brain, we examined three GnRH neuron type-specific transcriptomes using single-cell microarray analyses in the medaka (Oryzias latipes). A microarray profile of the three GnRH neuron types revealed five genes that are uniquely expressed in specific GnRH neuron types. GnRH1 neurons expressed three genes that are homologous to functionally characterised genes, GnRH2 neurons uniquely expressed one unnamed gene, and GnRH3 neurons uniquely expressed one known gene. These genes may be involved in the modulation or maintenance of each GnRH neuron type.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Rapamycin Targeting mTOR and Hedgehog Signaling Pathways Blocks Human Rhabdomyosarcoma Growth in Xenograft Murine Model.

  Samer Z Kaylani, Jianmin Xu, Ritesh K Srivastava, Levy Kopelovich, Joseph G Pressey, Mohammad Athar
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  ABSTRACT: Rhabdomyosarcomas (RMS) represents the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis. Interestingly, the mechanism by which rapamycin diminished RMS tumor growth involved simultaneous inhibition of mTOR and hedgehog (Hh) pathways. Diminution in these pathways in this model of RMS also inhibited epithelial mesenchymal transition (EMT) which then dampened the invasiveness of these tumors. Our data provide bases for using rapamycin either alone or in combination with traditional chemotherapeutic drugs to block the pathogenesis of high risk RMS.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Picropodophyllin inhibits epithelial ovarian cancer cells in vitro and in vivo.

  Xiaosheng Lu, Ledan Wang, Jie Mei, Xin Wang, Xueqiong Zhu, Qiong Zhang, Jieqiang Lv
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  ABSTRACT: Epithelial ovarian cancer (EOC) is one of the leading causes of gynecological cancer death. Approximately 70% of the patients experience recurrence accompanied by the development of drug resistance 2-3 years after chemotherapy. Picropodophyllin (PPP) is a newly identified insulin-like growth factor-1 receptor (IGF-1R) inhibitor that has been shown to have anticancer properties. In this study, we investigated the effect of PPP on EOC growth in vitro and in vivo. The EOC cell line SKOV-3 was treated with increasing concentrations of PPP or cisplatin, and cell viability and apoptosis were evaluated. To study the effects of PPP on EOC growth, apoptosis, and toxicity in vivo, a BALB/c nude mouse xenograft model was established. Mice were treated with normal saline (controls), PPP, cisplatin, or PPP in combination with cisplatin. In addition, the expression of phosphorylated IGF-1R (pIGF-1R) was examined in vitro and in vivo. PPP induced a dose-dependent decrease in SKOV-3 cell viability in vitro and reduced tumor volume and weight in the in vivo xenograft model. Furthermore, PPP in combination with cisplatin was more effective in inhibiting the growth of SKOV-3 cells and xenografts than either drug alone. PPP-mediated growth inhibition was associated with apoptosis induction in vitro and in vivo. PPP was well tolerated in vivo and exerted its effects with minimal hepatotoxicity and renal toxicity. PPP downregulated the expression of pIGF-1R in vitro and in vivo, an effect that appeared to be associated with its growth inhibitory properties. Our results indicate that PPP may have therapeutic application in the treatment of EOC.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Acetylcholine Receptors Regulate Gene Expression that Is Essential for Primitive Streak Formation in Murine Embryoid Bodies.

  Norie Arima, Yoshimi Uchida, Ruoxing Yu, Koh Nakayama, Hiroshi Nishina
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  ABSTRACT: Muscarinic acetylcholine receptors (mAchRs) are critical components of the cholinergic system, which is the key regulator of both the central and peripheral nervous systems in mammals. Interestingly, several components of the cholinergic system, including mAchRs and choline acetyltransferase (ChAT), have recently been found to be expressed in mouse embryonic stem (ES) cells and human placenta. These results raise the intriguing possibility that mAchRs play physiological roles in the regulation of early embryogenesis. Early embryogenesis can be mimicked in vitro using an ES cell-based culture system in which the cells form a primitive streak-like structure and efficiently develop into mesodermal progenitors. Here we report that chemical inhibitors specifically targeting mAchRs suppressed the expression of genes essential for primitive streak formation, including Wnt3, and thereby blocked mesodermal progenitor differentiation. Interestingly, mAchR inhibitors also reduced the expression of Cyp26a1, an enzyme involved in the catabolism of retinoic acid (RA). RA is an important regulator of Wnt3 signaling. Our study presents evidence indicating that mAchRs influence RA signaling necessary for the induction of the primitive streak. To our knowledge, this is the first report showing that mAchRs have important functions not only in adult mammals but also during early mammalian embryogenesis.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Ubiquitination of the heterotrimeric G protein α subunits Gαi2 and Gαq is prevented by the guanine nucleotide exchange factor Ric-8A.

  Kanako Chishiki, Sachiko Kamakura, Satoru Yuzawa, Junya Hayase, Hideki Sumimoto
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  ABSTRACT: The cytosolic protein Ric-8A acts as a guanine nucleotide exchange factor for Gα subunits of the Gi, Gq, and G12/13 classes of heterotrimeric G protein in vitro, and also increases the amounts of these Gα proteins in vivo. The mechanism whereby Ric-8 regulates Gα content has not been fully understood. Here we show that Ric-8A appears to stabilize Gαi2 and Gαq by preventing their ubiquitination. Ric-8A interacts with and stabilizes Gαi2, Gαq, Gα12, but not Gαs, when expressed in COS-7 cells. The protein levels of Gαi2 and Gαq appear to be controlled via the ubiquitin-proteasome degradation pathway, because these Gα subunits undergo polyubiquitination and are stabilized with the proteasome inhibitor MG132. The ubiquitination of Gαi2 and Gαq is suppressed by expression of Ric-8A. The suppression appears to require Ric-8A interaction with these Gα proteins, because the C-terminal truncation of Gαq and Gαi2 completely abrogates their interaction with Ric-8A, their stabilization by Ric-8A, and Ric-8A-mediated inhibition of Gα ubiquitination.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Gambogic acid induces EGFR degradation and Akt/mTORC1 inhibition through AMPK dependent-LRIG1 upregulation in cultured U87 glioma cells.

  Xin-Yao He, Xian-Jin Liu, Xiao Chen, Liu-Guan Bian, Wei-Guo Zhao, Jian-Kang Shen, Qing-Fang Sun
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  ABSTRACT: Glioblastoma multiforme (GBM) is the most common malignant tumor in adults' central nervous system (CNS). The development of novel anti-cancer agents for GBM is urgent. In the current study, we found that gambogic acid induced growth inhibition and apoptosis in cultured U87 glioma cells, which was associated with Akt/ mTORC1 (mTOR complex 1) signaling in-activation. To restore Akt activation by introducing a constitutively active (CA) Akt attenuated gambogic acid-induced cytotoxicity against U87 cells. For mechanism study, we found that gambogic acid induced LRIG1 (leucine-rich repeat and Ig-like domain-containing-1)upregulation, which was responsible for EGFR (epidermal growth factor receptor) degradation and its downstream Akt/mTORC1 inhibition. Further, we provided evidence to support that AMPK (AMP-activated protein kinase)activation mediated gambogic acid-induced LRIG1 upregulation, U87 cell apoptosis and growth inhibition, while AMPK inhibition by shRNA or compound C reduced gambogic acid-induced EGFR/Akt inhibition and cytotoxicity in U87 cells. We here proposed novel signaling mechanism mediating gambogic acid-induced cytotoxic effects in glioma cells.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Heme oxygenase-1 induction alters chemokine regulation and ameliorates human immunodeficiency virus-type-1 infection in lipopolysaccharide-stimulated macrophages.

  Zhao-Hua Zhou, Namita Kumari, Sergei Nekhai, Kathleen A Clouse, Larry M Wahl, Kenneth M Yamada, Subhash Dhawan
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  ABSTRACT: We have elucidated a putative mechanism for the host resistance against HIV-1 infection of primary human monocyte-derived macrophages (MDM) stimulated with lipopolysaccharide (LPS). We show that LPS-activated MDM both inhibited HIV-1 entry into the cells and were refractory to post-entry productive viral replication. LPS-treated cells were virtually negative for mature virions as revealed by transmission electron microscopy. LPS activation of MDM markedly enhanced the expression of heme oxygenase-1 (HO-1), a potent inducible cytoprotective enzyme. Increased HO-1 expression was accompanied by elevated production of macrophage inflammatory chemokines (MIP1α and MIP1β) by LPS-activated MDM, significantly decreased surface chemokine receptor-5 (CCR-5) expression, and substantially reduced virus replication. Treatment of cells with HO-1 inhibitor SnPP IX (tin protoporphyrin IX) attenuated the LPS-mediated responses, HIV-1 replication and secretion of MIP1α, MIP1β, and LD78β chemokines with little change in surface CCR-5 expression. These results identify a novel role for HO-1 in the modulation of host immune response against HIV infection of MDM.
  Biochemical and Biophysical Research Communications 05/2013;
• Article: Importance of muscle biopsy in diagnosis of muscle diseases.

  Bulent Kurt, Yasemin Gulcan Kurt, Emin Ozgur Akgul
  Biochemical and Biophysical Research Communications 05/2013;
• Article: NEK9 depletion induces catastrophic mitosis by impairment of mitotic checkpoint control and spindle dynamics.

  Yasuyuki Kaneta, Axel Ullrich
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  ABSTRACT: NEK9 is known to play a role in spindle assembly and in the control of centrosome separation, but the consequences of NEK9 targeting in cancer cells remain to be elucidated. In this study, we used siRNA to investigate the consequences of targeting NEK9 in glioblastoma and kidney cancer cells as a first step in assessing its potential as an anti-cancer therapeutic target. Live cell imaging revealed that NEK9 depletion of U1242 glioblastoma and Caki2 kidney carcinoma cells resulted in failure of cytokinesis. Interestingly, NEK9-depleted Caki2 cells overrode mitosis under incorrect chromosome alignment and were converted to a micronucleated phenotype, leading to cell death. Whereas, the RPE1 normal epithelium cell line was refractory to abnormal mitosis upon NEK9 knockdown. Nocodazole-induced mitotic arrest was compromised after NEK9 depletion, indicating that NEK9 has an important role in mitotic checkpoint system. Taken together, we propose that NEK9 inhibition represents a novel anti-cancer strategy by induction of mitotic catastrophe via impairment of spindle dynamics, cytokinesis and mitotic checkpoint control.
  Biochemical and Biophysical Research Communications 05/2013;