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Lai Yee Leung, Ying Deng-Bryant, Katherine Cardiff, Megan Winter, Frank Tortella, Deborah Shear
BACKGROUND: Energy metabolic dysfunction is a key determinant of cellular damage following traumatic brain injury and may be worsened by additional insults. This study evaluated the acute/subacute effects of combined hypoxemia (HX) and hemorrhagic shock (HS) on cerebral interstitial levels of glucose, lactate, and pyruvate in a rat model of penetrating ballistic-like brain injury (PBBI). METHODS: Rats were randomly assigned into the sham control, PBBI, and combined injury (P + HH) groups...
November 2016: Journal of Trauma and Acute Care Surgery
Mu He, Stephanie Agbu, Kathryn V Anderson
The mammalian Hedgehog (Hh) signaling pathway is required for development and for maintenance of adult stem cells, and overactivation of the pathway can cause tumorigenesis. All responses to Hh family ligands in mammals require the primary cilium, an ancient microtubule-based organelle that extends from the cell surface. Genetic studies in mice and humans have defined specific functions for cilium-associated microtubule motor proteins: they act in the construction and disassembly of the primary cilium, they control ciliary length and stability, and some have direct roles in mammalian Hh signal transduction...
October 17, 2016: Trends in Cell Biology
Aliye Akcalı, Pınar Gümüş, Özgün Özçaka, Banu Öztürk-Ceyhan, Taina Tervahartiala, Heidi Husu, Anna Maria Heikkinen, Timo Sorsa, Nurcan Buduneli
OBJECTIVES: The study evaluated the levels of matrix metalloproteinase-8 (MMP-8), MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) in biofluids of women with gestational diabetes mellitus (GDM) and systemically healthy counterparts with different status of periodontal health. MATERIALS & METHODS: 71 women with GDM and gingivitis (Gg), 30 women with GDM and healthy periodontium (Gh), 28 systemically and periodontally healthy women (Hh) and 37 systemically healthy women with gingivitis (Hg) were evaluated...
October 20, 2016: Journal of Periodontology
Yan Wang, Jung-Mao Hsu, Ya'an Kang, Yongkun Wei, Pei-Chih Lee, Shing-Jyh Chang, Yi-Hsin Hsu, Jennifer L Hsu, Hung-Ling Wang, Wei-Chao Chang, Chia-Wei Li, Hsin-Wei Liao, Shih-Shin Chang, Weiya Xia, How-Wen Ko, Chao-Kai Chou, Jason B Fleming, Huamin Wang, Rosa F Hwang, Yue Chen, Jun Qin, Mien-Chie Hung
The oncogenic transcription factor Gli1 is a critical effector in the Hedgehog (Hh) pathway which is necessary for the development and progression of pancreatic ductal adenocarcinoma (PDAC). While TGF-β and K-Ras are known regulators of Gli1 gene transcription in this setting, it is not understood how Gli1 functional activity is regulated. Here we report the identification of Gli1 as a substrate for the protein arginine N-methyltransferase PRMT1 in PDAC. We found that PRMT1 methylates Gli1 at R597, promoting its transcriptional activity by enhancing the binding of Gli1 to its target gene promoters...
October 6, 2016: Cancer Research
Meri Kankaanpää, Maria Raitakari, Leila Muukkonen, Siv Gustafsson, Merja Heitto, Ari Palomäki, Kimmo Suojanen, Veli-Pekka Harjola
BACKGROUND: To assess whether the use of point-of-care testing (POCT) and early assessment team (EAT) model shortens emergency department (ED) length of stay (LOS). METHODS: This prospective, observational study with comparison between three study periods was performed in three phases in a metropolitan ED with 57,000 annual visits. Data were collected from adult ambulatory patients who were discharged home. Phase 1 served as a control (n = 1559 in one month)...
October 18, 2016: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine
Jun Yang, Wenjing Huang, Wenfu Tan
The major obstacle limiting the efficacy of current Smoothened (Smo) inhibitors is the primary and acquired resistance mainly caused by Smo mutations and Gli amplification. In this context, developing Hh inhibitors targeting Gli, the final effector of this signaling pathway, may combat the resistance. In this study we found that solasonine, a natural glycoalkaloid compound, significantly inhibited the hedgehog (Hh) pathway activity. Meanwhile, solasonine may obviously inhibit the alkaline phosphatase (ALP) activity in C3H10T1/2 cells, concomitantly with reductions of the mRNA expression of Gli1 and Ptch1...
October 14, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Qian Sun, Jing Bai, Renrong Lv
Since hedgehog (HH)/Gli1 that contributes to cancer proliferation and metastasis has been masked for decades, the signaling pathway was investigated about its exact role in proliferation and metastasis of cutaneous squamous cell carcinoma (SCC). Sonic hedgehog homolog (Shh), GLI family zinc finger 1 (Gli1), and vascular endothelial growth factor (VEGF) expressions in cutaneous SCC tissues were analyzed with immunohistochemistry, and their correlations with cutaneous SCC patients' prognosis were conducted with Kaplan-Meier curve...
October 17, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Grégoire P Millet, Franck Brocherie, Raphael Faiss, Olivier Girard
The authors report that many LHTL studies in normobaric hypoxia (NH) "failed to show a positive outcome", which in our view is only partially true. In a cross-over design, we (Saugy et al. 2016) recently tested if LHTL in hypobaric hypoxia (HH) would lead to larger performance enhancement than in NH. Our hypothesis was that HH (i.e. natural altitude) would lead to larger enhancement than NH but the results were contrary to this hypothesis. So we cannot support the affirmation by Lundby & Robach that "natural altitude remains the best approach"...
October 17, 2016: Experimental Physiology
Elissaveta Petrova, Arne Scholz, Juliane Paul, Andrea Sturz, Katja Haike, Franziska Siegel, Dominik Mumberg, Ningshu Liu
Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in de novo fatty acid synthesis, and its ACC1 isoform is overexpressed in pancreatic and various other cancers. The activity of many oncogenic signaling molecules, including WNT and Hedgehog (HH), is post-translationally modified by lipidation. Here, we report that inhibition of ACC by a small molecule inhibitor, BAY ACC002, blocked WNT3A lipidation, secretion, and signaling. In pancreatic cancer cells, where WNT and HH are key oncogenic drivers, ACC inhibition simultaneously suppressed WNT and HH signaling, and led to anti-proliferative effects...
October 13, 2016: Oncotarget
Daniel Konstantinou, Nina Bertaux-Skeirik, Yana Zavros
The Hedgehog (Hh) signaling pathway not only plays a key part in controlling embryonic development, but in the adult stomach governs important cellular events such as epithelial cell differentiation, proliferation, gastric disease, and regeneration. In particular, Sonic Hedgehog (Shh) signaling has been well studied for its role in gastric physiology and pathophysiology. Shh is secreted from the gastric parietal cells and contributes to the regeneration of the epithelium in response to injury, or the development of gastritis during Helicobacter pylori infection...
October 14, 2016: Current Opinion in Pharmacology
F Faião-Flores, D K Alves-Fernandes, P C Pennacchi, S Sandri, A L S A Vicente, C Scapulatempo-Neto, V L Vazquez, R M Reis, J Chauhan, C R Goding, K S Smalley, S S Maria-Engler
BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naïve cells...
October 17, 2016: Oncogene
David M Dror, Arpita Chakraborty, Atanu Majumdar, Pradeep Panda, Ruth Koren
BACKGROUND & OBJECTIVES: The evidence-base of the impact of community-based health insurance (CBHI) on access to healthcare and financial protection in India is weak. We investigated the impact of CBHI in rural Uttar Pradesh and Bihar s0 tates of India on insured households' self-medication and financial position. METHODS: Data originated from (i) household surveys, and (ii) the Management Information System of each CBHI. Study design was "staggered implementation" cluster randomized controlled trial with enrollment of one-third of the treatment group in each of the years 2011, 2012 and 2013...
June 2016: Indian Journal of Medical Research
Lotte Skøt, Tina Jeppesen, Angelina Isabella Mellentin, Ask Elklit
PURPOSE: This descriptive study sought to explore barriers faced by Deaf and hard-of-hearing (D/HH) individuals in Denmark when accessing medical and psychosocial services following large-scale disasters and individual traumatic experiences. METHODS: Semi-structured interviews were conducted with nine D/HH individuals who had experienced at least one disaster or other traumatic event. RESULTS: Difficulties were encountered during interactions with first response and healthcare services, which centered on: (1) lack of Deaf awareness among professionals, (2) problems accessing interpreter services, (3) professionals relying on hearing relatives to disseminate information, and (4) professionals who were unwilling to adjust their speech or try different forms of communication...
October 17, 2016: Disability and Rehabilitation
Guoqiang Ma, Shuang Li, Yuhong Han, Shuangxi Li, Tao Yue, Bing Wang, Jin Jiang
Hedgehog (Hh) signaling plays a central role in development and diseases. Hh activates its signal transducer and GPCR-family protein Smoothened (Smo) by inducing Smo phosphorylation, but whether Smo is activated through other post-translational modifications remains unexplored. Here we show that sumoylation acts in parallel with phosphorylation to promote Smo cell-surface expression and Hh signaling. We find that Hh stimulates Smo sumoylation by dissociating it from a desumoylation enzyme Ulp1. Sumoylation of Smo in turn recruits a deubiquitinase UBPY/USP8 to antagonize Smo ubiquitination and degradation, leading to its cell-surface accumulation and elevated Hh pathway activity...
October 7, 2016: Developmental Cell
Karen Hodgson, Russell A Poldrack, Joanne E Curran, Emma E Knowles, Samuel Mathias, Harald Hh Göring, Nailin Yao, Rene L Olvera, Peter T Fox, Laura Almasy, Ravi Duggirala, Deanna M Barch, John Blangero, David C Glahn
Head movements are typically viewed as a nuisance to functional magnetic resonance imaging (fMRI) analysis, and are particularly problematic for resting state fMRI. However, there is growing evidence that head motion is a behavioral trait with neural and genetic underpinnings. Using data from a large randomly ascertained extended pedigree sample of Mexican Americans (n = 689), we modeled the genetic structure of head motion during resting state fMRI and its relation to 48 other demographic and behavioral phenotypes...
October 15, 2016: Cerebral Cortex
Xu Zhang, Qianni Cheng, Yixiang Wang, Po Sing Leung, Kinglun Kingston Mak
Bone plays a role in energy metabolism, but the interplay between bone and other organs in this process is not completely understood. Here, we show that upregulated Hh signaling in bones results in increased whole-body energy expenditure, white adipose tissue (WAT) browning, hypoglycemia and skeletal muscle atrophy. We found that Hh signaling induces PTHrP secretion from bones and causes WAT browning. Injection of PTHrP-neutralizing antibody attenuates WAT browning and improves the circulating blood glucose level while high-fat diet treatment only rescues hypoglycemia...
October 14, 2016: Cell Death and Differentiation
Gang Liu, Jun Yang, Juan Wang, Xiaohua Liu, Wenjing Huang, Jie Li, Wenfu Tan, Ao Zhang
A series of novel Smo antagonists were developed either by directly incorporating the basic skeleton of the natural product artemisinin or by first breaking artemisinin into structurally simpler and stable intermediates and then reconstructing into diversified heterocyclic derivatives, equipped with a Smo-targeting bullet. 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-arylpropanamide 65 was identified as the most potent with an IC50 value of 9.53 nM against the Hh signaling pathway. Complementary mechanism studies confirmed that 65 inhibits Hh signaling pathway by targeting Smo and shares the same binding site as that of the tool drug cyclopamine...
October 13, 2016: Journal of Medicinal Chemistry
Laura Llull, Steffen Thiel, Sergio Amaro, Álvaro Cervera, Anna M Planas, Ángel Chamorro
Activation of the inflammatory generating complement system might play a pathogenic role in spontaneous subarachnoid hemorrhage (SAH). We studied whether plasma and cerebrospinal fluid (CSF) levels of complement proteins were associated with angiographic vasospasm and cerebral ischemic lesions after SAH. Ficolin-1 (M-ficolin), ficolin-3 (H-ficolin), mannose-binding lectin (MBL), MBL-associated serine protease 2 (MASP-2), MASP-3, and MAp44 were analyzed in plasma of 45 SAH patients at 24 h after bleeding. Additionally, ficolin-1 levels were measured in cerebrospinal fluid (CSF) samples obtained 24 h after bleeding in 19 patients with external ventricular drainage placement...
October 12, 2016: Molecular Neurobiology
Thomas S Voss, Mikkel H Vendelbo, Ulla Kampmann, Steen B Pedersen, Thomas S Nielsen, Mogens Johannsen, Mads V Svart, Niels Jessen, Niels Møller
AIMS/HYPOTHESIS: The aims of this study were to determine the role of lipolysis in hypoglycaemia and define the underlying intracellular mechanisms. METHODS: Nine healthy volunteers were randomised to treatment order of three different treatments (crossover design). Treatments were: (1) saline control; (2) hyperinsulinaemic hypoglycaemia (HH; i.v. bolus of 0.1 U/kg insulin); and (3) hyperinsulinaemic euglycaemia (HE; i.v. bolus of 0.1 U/kg insulin and 20% glucose)...
October 12, 2016: Diabetologia
Annick Vanclooster, Hub Wollersheim, Kris Vanhaecht, Dorine Swinkels, Bert Aertgeerts, David Cassiman
BACKGROUND: HFE-related hereditary haemochromatosis (HH) is a common autosomal recessive disorder with clinical manifestations ranging from asymptomatic disease to possible life-threatening complications. Cirrhosis, hepatocellular carcinoma, diabetes mellitus or osteoporosis can develop in HH patients not treated or monitored optimally. The purpose of this study was to develop key-interventions (KI's) to measure and improve the quality of care delivered to patients diagnosed with HH. METHODS: A RAND-Modified Delphi method was used to develop KI's...
October 13, 2016: BMC Health Services Research
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