Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1

Cancer therapeutics: Extending a drug's reach A new drug that blocks heat shock proteins (HSPs), helper proteins that are co-opted by cancer cells to promote tumor growth, shows promise for cancer treatment. Several drugs have targeted HSPs, since cancer cells are known to hijack these helper proteins to shield themselves from destruction by the body. However, the drugs have had limited success. Hye-Kyung Park and Byoung Heon Kang at Ulsan National Institutes of Science and Technology in South Korea and coworkers noticed that the drugs were not absorbed into mitochondria, a key cellular compartment, and HSPs in this compartment were therefore not being blocked. They identified a new HSP inhibitor that can reach every cellular compartment and inhibit all HSPs. Testing in mice showed that this inhibitor effectively triggered death of tumor cells, and therefore shows promise for anti-cancer therapy. The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity

Surgical ciliated cyst of the mandible after orthognathic surgery: a case report with review of the literature

Background : Surgical ciliated cysts, also known as postoperative maxillary cysts or implantation cysts, occur mainly in the posterior maxilla after radical maxillary sinus surgery; they rarely develop in the mandible. They are thought to occur when the sinonasal epithelium is infiltrated by a surgical instrument during surgery or as a result of transplantation of bone or cartilage with respiratory epithelium attached. Case presentation : We report a case in which a surgical ciliated cyst developed in the anterior part of the mandible, presumably as a result of bimaxillary orthognathic surgery and genioplasty performed 24 years earlier. We then review the few similar cases reported in the literature. Conclusion : Surgical ciliated cysts in the mandible are extremely rare, but they could occur after simultaneous surgery on the maxilla and mandible, even decades later. To prevent surgical ciliated cysts in the mandible, we recommend that the surgical instruments, especially the saw blade used during bimaxillary surgery, be new or cleaned and that previously placed plates and screws be removed at an appropriate time

Phagosome Escape of Rough Mycobacterium abscessus Strains in Murine Macrophage via Phagosomal Rupture Can Lead to Type I Interferon Production and Their Cell-To-Cell Spread

Mycobacterium abscessus complex (MAB) is a rapidly growing mycobacterium(RGM) whose clinical significance as an emerging human pathogen has been increasing worldwide. It has two types of colony morphology, a smooth (S) type, producing high glycopeptidolipid (GPL) content, and a rough (R) type, which produces low levels of GPLs and is associated with increased virulence. However, the mechanism responsible for their difference in virulence is poorly known. By ultrastructural examination of murine macrophages infected, we found that MAB-R strains could replicate more actively in the macrophage phagosome than the S variants and that they could escape into cytosol via phagosomal rupture. The cytosolic access of MAB-R strains via phagosomal rupture led to enhanced Type I interferon (IFN) production and cell death, which resulted in their cell-to-cell spreading. This behavior can provide an additional niche for the survival of MAB-R strains. In addition, we found that their enhancement of cell death mediated cell spreading are dependent on Type I IFN signaling via comparison of wild-type and IFNAR1 knockout mice. In conclusion, our data indicated that a transition of MAB-S strains into MAB-R variants increased their virulence via enhanced Type I IFN production, which led to enhanced survival in infected macrophage via cell death mediated cell-to-cell spreading. This result provides not only a novel insight into the difference in virulence between MAB-R and -S variants but also hints to their treatment strategy

Metabolic engineering of a reduced-genome strain of Escherichia coli for L-threonine production

© 2009 Lee et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Rough colony morphology of Mycobacterium massiliense Type II genotype is due to the deletion of glycopeptidolipid locus within its genome

Background: Recently, we introduced the complete genome sequence of Mycobacterium massiliense clinical isolates, Asan 50594 belonging to Type II genotype with rough colony morphology. Here, to address the issue of whether the rough colony morphotype of M. massiliense Type II genotype is genetically determined or not, we compared polymorphisms of the glycopeptidolipid (GPL) gene locus between M. massiliense Type II Asan 50594 and other rapidly growing mycobacteria (RGM) strains via analysis of genome databases.Results: We found deletions of 10 genes (24.8 kb), in the GPL biosynthesis related gene cluster of Asan 50594 genome, but no deletions in those of other smooth RGMs. To check the presence of deletions of GPL biosynthesis related genes in Mycobacterium abscessus - complex strains, PCRs targeting 12 different GPL genes (10 genes deleted in Asan 50594 genome as well as 2 conserved genes) were applied into 76 clinical strains of the M. abscessus complex strains [54 strains (Type I: 33, and Type II: 21) of M. massiliense and 22 strains (rough morphoype: 11 and smooth morphotype: 11) of M. abscessus]. No strains of the Type II genotype produced PCR amplicons in a total of 10 deleted GPL genes, suggesting loss of GPL biosynthesis genes in the genome of M. massiliense type II genotype strains.Conclusions: Our data suggested that the rough colony morphotype of the M. massiliense Type II genotype may be acquired via deletion events at the GPL gene locus for evolutionary adaptation between the host and pathogen.OAIID:oai:osos.snu.ac.kr:snu2013-01/102/0000006653/7SEQ:7PERF_CD:SNU2013-01EVAL_ITEM_CD:102USER_ID:0000006653ADJUST_YN:YEMP_ID:A077651DEPT_CD:806CITE_RATE:4.397FILENAME:rough colony morphology of mycobacterium.pdfDEPT_NM:의과학과SCOPUS_YN:YCONFIRM:

Predicting the Interactome of Xanthomonas oryzae pathovar oryzae for target selection and DB service

<p>Abstract</p> <p>Background</p> <p>Protein-protein interactions (PPIs) play key roles in various cellular functions. In addition, some critical inter-species interactions such as host-pathogen interactions and pathogenicity occur through PPIs. Phytopathogenic bacteria infect hosts through attachment to host tissue, enzyme secretion, exopolysaccharides production, toxins release, iron acquisition, and effector proteins secretion. Many such mechanisms involve some kind of protein-protein interaction in hosts. Our first aim was to predict the whole protein interaction pairs (interactome) of <it>Xanthomonas oryzae </it>pathovar oryzae (Xoo) that is an important pathogenic bacterium that causes bacterial blight (BB) in rice. We developed a detection protocol to find possibly interacting proteins in its host using whole genome PPI prediction algorithms. The second aim was to build a DB server and a bioinformatic procedure for finding target proteins in Xoo for developing pesticides that block host-pathogen protein interactions within critical biochemical pathways.</p> <p>Description</p> <p>A PPI network in Xoo proteome was predicted by bioinformatics algorithms: PSIMAP, PEIMAP, and iPfam. We present the resultant species specific interaction network and host-pathogen interaction, XooNET. It is a comprehensive predicted initial PPI data for Xoo. XooNET can be used by experimentalists to pick up protein targets for blocking pathological interactions. XooNET uses most of the major types of PPI algorithms. They are: 1) Protein Structural Interactome MAP (PSIMAP), a method using structural domain of SCOP, 2) Protein Experimental Interactome MAP (PEIMAP), a common method using public resources of experimental protein interaction information such as HPRD, BIND, DIP, MINT, IntAct, and BioGrid, and 3) Domain-domain interactions, a method using Pfam domains such as iPfam. Additionally, XooNET provides information on network properties of the Xoo interactome.</p> <p>Conclusion</p> <p>XooNET is an open and free public database server for protein interaction information for Xoo. It contains 4,538 proteins and 26,932 possible interactions consisting of 18,503 (PSIMAP), 3,118 (PEIMAP), and 8,938 (iPfam) pairs. In addition, XooNET provides 3,407 possible interaction pairs between two sets of proteins; 141 Xoo proteins that are predicted as membrane proteins and rice proteomes. The resultant interacting partners of a query protein can be easily retrieved by users as well as the interaction networks in graphical web interfaces. XooNET is freely available from <url>http://bioportal.kobic.kr/XooNET/</url>.</p

Evidence to support that spontaneous preterm labor is adaptive in nature: neonatal RDS is more common in "indicated`` than in "spontaneous`` preterm birth

Objectives: The onset of preterm labor has been proposed to have survival value and to be adaptive in nature. This hypothesis would predict that induced preterm birth may be associated with higher rates of complications than spontaneous preterm birth. The purpose of this study was to determine if there is a difference in the frequency of neonatal respiratory distress syndrome (RDS), the most common neonatal complication, according to the etiology of preterm birth (e. g., preterm labor [PTL], preterm PROM, or pregnancies which ended because of maternal-fetal indications). Study design: The relationship between the occurrence of RDS and the obstetrical circumstances leading to preterm birth was examined in 257 consecutive singleton preterm births (gestational age: 24-32 weeks). Cases with major congenital anomalies were excluded. The study population was divided into two groups according to the cause of preterm birth: 1) preterm birth due to PTL with intact membranes or preterm PROM (spontaneous preterm birth group); and 2) preterm birth due to maternal or fetal indications (indicated preterm birth group). Results: 1) RDS was diagnosed in 47% of cases; 2) RDS was more common in patients with indicated preterm birth than in those with spontaneous preterm birth group (58.1% vs. 38.4%, P = 0.002); 3) Patients with indicated preterm birth had a significantly higher mean gestational age at birth, but lower mean birth weight, lower rate of histological chorioamnionitis and higher rates of cesarean delivery, 5 min Apgar score of <7, and umbilical arterial blood pH of <7.15 than those with spontaneous preterm birth (P<0.05 for each); 4) Antenatal corticosteroids were used in 73.4% of cases with indicated preterm birth and in 76.9% of those with spontaneous preterm birth; 5) Multivariate analysis demonstrated that indicated preterm birth was associated with an increased risk of RDS after adjusting for confounding variables (OR = 2.29, 95% CI 1.22-4.29). Conclusions: 1) The rate of RDS is greater following "indicated`` rather than spontaneous preterm birth; 2) This observation supports the view that spontaneous preterm labor is adaptive in nature.Goldenberg RL, 2008, LANCET, V371, P75, DOI 10.1016/S0140-6736(08)60074-4Morken NH, 2007, PAEDIATR PERINAT EP, V21, P458Costa S, 2007, EUR J OBSTET GYN R B, V131, P154, DOI 10.1016/j.ejogrb.2006.05.006Ananth CV, 2006, J MATERN-FETAL NEO M, V19, P773, DOI 10.1080/14767050600965882ROBERTS D, 2006, COCHRANE DB SYST REV, V3, P4454, DOI DOI 10.1002/14651858.CD004454.PUB2Ananth CV, 2005, OBSTET GYNECOL, V105, P1084, DOI 10.1097/01.AOG.0000158124.96300.c7JOBE AH, 2005, J PERINATOL S2, V25, pS31Chang EY, 2004, AM J OBSTET GYNECOL, V191, P1414, DOI 10.1016/j.ajog.2004.06.097SHINWELL ES, 2004, ARCH DIS CHILD-FETAL, V89, pF145Elimian A, 2003, OBSTET GYNECOL, V102, P352, DOI 10.1016/S0029-7844(03)00485-XMoutquin JM, 2003, BJOG-INT J OBSTET GY, V110, P30, DOI 10.1016/S1470-0328(03)00021-1Moss TJM, 2002, AM J OBSTET GYNECOL, V187, P1059, DOI 10.1067/mob.2002.126296Kramer BW, 2002, AM J PHYSIOL-LUNG C, V283, pL452, DOI 10.1152/ajplung.00407.2001Kallapur SG, 2001, AM J PHYSIOL-LUNG C, V280, pL527Hacking D, 2001, ARCH DIS CHILD, V84, pF117Bry K, 2001, ACTA PAEDIATR, V90, P74Jobe AH, 2000, AM J RESP CRIT CARE, V162, P1656Shimoya K, 2000, HUM REPROD, V15, P2234Winn HN, 2000, J PERINAT MED, V28, P210Carvalho MA, 1997, INT J GYNECOL OBSTET, V58, P197Bry K, 1997, J CLIN INVEST, V99, P2992YOON BH, 1995, AM J OBSTET GYNECOL, V172, P960SHAH DM, 1995, J PERINATOL, V15, P264SCHIFF E, 1993, AM J OBSTET GYNECOL, V169, P1096SAVITZ DA, 1991, AM J OBSTET GYNECOL, V164, P467HJALMARSON O, 1981, ACTA PAEDIATR SCAND, V70, P773BUSTOS R, 1979, AM J OBSTET GYNECOL, V133, P899

Pig-to-Nonhuman Primate (NHP) Naked Islet Xenotransplantation

Islet transplantation is an established therapy for selected type 1 diabetes (T1D) patients with severe hypoglycemic unawareness and glycemic liability despite of insulin treatment. However, the donor organ is limited. Porcine islets are the best alternative source to overcome this limitation, and pig-to-nonhuman primate (NHP) naked islet xenotransplantation studies are being performed worldwide. Several studies including our own have presented successful proof-of-concept results based on immunosuppression regimen including the anti-CD154 monoclonal antibody. Particularly, long-term control of diabetes by adult porcine islet transplantation has been demonstrated in five consecutive monkeys, and the longest survival was ~1000 days after transplantation. Currently, pig-to-NHP islet xenotransplantation based on clinically applicable immunosuppression regimen is being pursued. In this chapter, we will describe all the procedures of pig-to-NHP naked islet xenotransplantation: (1) the porcine islet isolation from designated pathogen-free (DPF) miniature pigs, (2) diabetes induction in monkeys, (3) transplantation procedure via the portal vein, (4) immune monitoring comprising humoral and cellular immunity after porcine islet transplantation, and finally (5) liver biopsy and subsequent immunohistochemical procedure in detail

The Effects of Glyburide on Apoptosis and Endoplasmic Reticulum Stress in INS-1 Cells in a Glucolipotoxic Condition

Backgroundβ-cell death due to endoplasmic reticulum (ER) stress has been regarded as an important pathogenic component of type 2 diabetes. The possibility has been suggested that sulfonylurea, currently being used as one of the main oral hypoglycemic agents of type 2 diabetes, increases ER stress, which could lead to sulfonylurea failure. The authors of the present study examined ER stress of β-cells in a glucolipotoxic condition using glyburide (GB) in an environment mimicking type 2 diabetes.MethodsApoptosis was induced by adding various concentrations of GB (0.001 to 200 µM) to a glucolipotoxic condition using 33 mM glucose, and the effects of varied concentrations of palmitate were evaluated via annexin V staining. The markers of ER stress and pro-apoptotic markers were assessed by Western blotting and semi-quantitative reverse transcription-polymerase chain reaction. Additionally, the anti-apoptotic markers were evaluated.ResultsAddition of any concentration of GB in 150 µM palmitate and 33 mM glucose did not increase apoptosis. The expression of phosphorylated eukaryotic initiation factor (eIF-2α) was increased and cleaved caspase 3 was decreased by adding GB to a glucolipotoxic condition. However, other ER stress-associated markers such as Bip-1, X-box binding protein-1, ATF-4 and C/EBP-homologous protein transcription factor and anti-apoptotic markers phosphor-p85 phosphatidylinositol 3-kinase and phosphorylation of Akt did not change significantly.ConclusionGB did not show further deleterious effects on the degree of apoptosis or ER stress of INS-1 cells in a glucolipotoxic condition. Increased phosphorylation of eIF-2α may attenuate ER stress for adaptation to increased ER protein load