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https://www.readbyqxmd.com/read/29453401/endothelial-smoothened-dependent-hedgehog-signaling-is-not-required-for-sonic-hedgehog-induced-angiogenesis-or-ischemic-tissue-repair
#1
Rajesh Gupta, Alexander R Mackie, Sol Misener, Lijun Liu, Douglas W Losordo, Raj Kishore
Sonic Hedgehog (Shh) signaling induces neovascularization and angiogenesis. It is not known whether the hedgehog signaling pathway in endothelial cells is essential to angiogenesis. Smoothened (Smo) transduces hedgehog signaling across the cell membrane. This study assessed whether endothelial Smoothened-dependent Shh signaling is required for Shh-mediated angiogenesis and ischemic tissue repair. Endothelial-specific smoothened knockout mice, eSmo Null were created using Cre-lox recombination system. eSmo Null mice had no observable phenotype at baseline and showed normal cardiac function...
February 16, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29453315/autophagic-flux-is-regulated-by-interaction-between-the-c-terminal-domain-of-patched1-and-atg101
#2
Lucy X Chen, Cintli C Morales-Alcala, Natalia A Riobo-Del Galdo
The Hedgehog (Hh) receptor Patched1 (PTCH1) is a well-known tumor suppressor that in its active form represses Smoothened (SMO) activity, inhibits proliferation, and induces apoptosis. The cytoplasmic C-terminal domain (CTD) regulates PTCH1 turnover and nucleates a pro-apoptotic complex. In this study, it was mechanistically determined that Autophagy Related 10 (ATG101), essential for mammalian autophagy, physically interacts with the CTD of PTCH1 and connects it to the ULK complex, which stimulates the autophagy machinery in response to changes in nutrient availability...
February 16, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29438012/hedgehog-reciprocally-controls-trafficking-of-smo-and-ptc-through-the-smurf-family-of-e3-ubiquitin-ligases
#3
Shuang Li, Shuangxi Li, Bing Wang, Jin Jiang
Hedgehog (Hh) induces signaling by promoting the reciprocal trafficking of its receptor Patched (Ptc) and the signal transducer Smoothened (Smo), which is inhibited by Ptc, at the cell surface. We identified Smurf family E3 ubiquitin ligases as essential for Smo ubiquitylation and cell surface clearance and demonstrated that Smurf family members mediate the reciprocal trafficking of Ptc and Smo in Drosophila melanogaster G protein-coupled receptor kinase 2 (Gprk2)-mediated phosphorylation of Smurf promoted Smo ubiquitylation by increasing the recruitment of Smurf to Smo, whereas protein kinase A (PKA)-mediated phosphorylation of Smo caused Smurf to dissociate from Smo, thereby inhibiting Smo ubiquitylation...
February 6, 2018: Science Signaling
https://www.readbyqxmd.com/read/29435119/a-dual-mechanism-of-activation-of-the-sonic-hedgehog-pathway-in-anaplastic-thyroid-cancer-crosstalk-with-ras-braf-mek-pathway-and-ligand-secretion-by-tumor-stroma
#4
Alessia Parascandolo, Mikko O Laukkanen, Nancy De Rosa, Clara Ugolini, Maria Carmela Cantisani, Anna Maria Cirafici, Fulvio Basolo, Massimo Santoro, Maria Domenica Castellone
Sonic Hedgehog (Shh) pathway regulates embryonic development of different organs including the thyroid gland. The aberrant activation of Shh signaling has been found in several types of cancer and according to recent evidences it represents an important regulator of tumor-stroma interaction. In this study, we have analyzed expression, activation and molecular mechanisms regulating the Shh pathway and its involvement in the modulation of tumor stroma interaction in anaplastic thyroid cancer (ATC) cells. Our results suggest that Shh signaling undergoes a dual mechanism of induction in ATC cells: 1) a basal non-canonical Smo-dependent activation of Gli transcription factor that is partly caused by interaction with the RAS/BRAF/MEK oncogenic pathway and is characterized by the absence of Shh ligand expression in thyroid cancer cells and 2) a paracrine response of cancer cells to Shh ligand secreted by tumor stroma (fibroblasts and mesenchymal stromal cells, MSCs) inducing cancer cell migration and in vitro tumorigenesis...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29429990/non-canonical-activation-of-hedgehog-in-prostate-cancer-cells-mediated-by-the-interaction-of-transcriptionally-active-androgen-receptor-proteins-with-gli3
#5
Na Li, Sarah Truong, Mannan Nouri, Jackson Moore, Nader Al Nakouzi, Amy Anne Lubik, Ralph Buttyan
Hedgehog (Hh) is an oncogenic signaling pathway that regulates the activity of Gli transcription factors. Canonical Hh is a Smoothened- (Smo-) driven process that alters the post-translational processing of Gli2/Gli3 proteins. Though evidence supports a role for Gli action in prostate cancer (PCa) cell growth and progression, there is little indication that Smo is involved. Here we describe a non-canonical means for activation of Gli transcription in PCa cells mediated by the binding of transcriptionally-active androgen receptors (ARs) to Gli3...
February 12, 2018: Oncogene
https://www.readbyqxmd.com/read/29428667/silybum-marianum-oil-attenuates-hepatic-steatosis-and-oxidative-stress-in-high-fat-diet-fed-mice
#6
Shu Yun Zhu, Ning Jiang, Jing Yang, Jie Tu, Yue Zhou, Xiang Xiao, Ying Dong
In the present study, the effects of Silybum marianum oil (SMO) on hepatic steatosis and oxidative stress were investigated during the development of nonalcoholic fatty liver disease (NAFLD) in high fat diet (HFD)-fed mice. The results showed that body weight, fat mass, and serum biochemical parameters such as triglyceride, free fatty acid, glucose and insulin were reduced by SMO treatment. Meanwhile, SMO decreased the histological injury of liver and the levels of hepatic triglyceride, cholesterol and free fatty acid in HFD-fed mice...
February 8, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29428070/max-margin-weight-learning-for-medical-knowledge-network
#7
Jingchi Jiang, Jing Xie, Chao Zhao, Jia Su, Yi Guan, Qiubin Yu
BACKGROUND AND OBJECTIVE: The application of medical knowledge strongly affects the performance of intelligent diagnosis, and method of learning the weights of medical knowledge plays a substantial role in probabilistic graphical models (PGMs). The purpose of this study is to investigate a discriminative weight-learning method based on a medical knowledge network (MKN). METHODS: We propose a training model called the maximum margin medical knowledge network (M3KN), which is strictly derived for calculating the weight of medical knowledge...
March 2018: Computer Methods and Programs in Biomedicine
https://www.readbyqxmd.com/read/29427915/cigarette-cues-capture-attention-of-smokers-and-never-smokers-but-for-different-reasons
#8
Menton M Deweese, Maurizio Codispoti, Jason D Robinson, Paul M Cinciripini, Francesco Versace
BACKGROUND: While the notion that smokers reliably show higher reactivity to cigarette-related versus neutral cues is both theoretically and empirically supported, it is unclear why never-smokers also show enhanced brain responses to cigarette-related cues. METHODS: Using a repetitive picture viewing paradigm, in which responses evoked by affective cues are more resistant to habituation, we assessed the effects of stimulus repetition on event-related potentials (ERPs) evoked by pleasant, unpleasant, cigarette-related, and neutral images in 34 smokers (SMO) and 34 never-smokers (NEV)...
February 5, 2018: Drug and Alcohol Dependence
https://www.readbyqxmd.com/read/29427441/the-utility-of-the-ankle-spect-ct-scan-to-predict-functional-and-clinical-outcomes-in-supramalleolar-osteotomy-patients
#9
Christopher E Gross, William Barfield, Christine Schweizer, Helmut Rasch, Michael T Hirschmann, Beat Hintermann, Markus Knupp
Combined single-photon emission computed tomography and conventional computed tomography (SPECT/CT) is a hybrid imaging modality that shows a combination of metabolic and structural information about the ankle, including arthritis. We hypothesize that uptake in specific locations within the ankle joint can be associated with both clinical outcomes and may help predict which patients will have a successful SMO. Eighty-five pre-operative SMO patients with varus (37), valgus (41), or neutral (7) alignment of the hindfoot were assessed using SPECT/CT...
February 10, 2018: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
https://www.readbyqxmd.com/read/29425683/cynanbungeigenin-c-and-d-a-pair-of-novel-epimers-from-cynanchum-bungei-suppress-hedgehog-pathway-dependent-medulloblastoma-by-blocking-signaling-at-the-level-of-gli
#10
Xiao-Yu Li, Li-Fei Zhou, Li-Juan Gao, Yang Wei, Shi-Fang Xu, Feng-Yang Chen, Wen-Jing Huang, Wen-Fu Tan, Yi-Ping Ye
Uncontrolled excessive activation of Hedgehog (Hh) signaling pathway is linked to a number of human malignant tumorigenesis. To obtain valuable Hh pathway inhibitors from natural product, in present study, a pair of novel epimers, Cynanbungeigenin C (CBC) and D (CBD) from the plant Cynanchum bungei Decne were chemically characterized by multiple spectroscopic data and chemical derivatization, and evaluated for their inhibition on Hh pathway. Mechanistically, CBC and CBD block Hh pathway signaling not through targeting Smo and Sufu, but at the level of Gli...
February 6, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29424103/alternative-activation-of-hedgehog-pathway-induced-by-ultraviolet-b-radiation-preliminary-study
#11
A Lesiak, D Sobolewska-Sztychny, I A Bednarski, K Wódz, M Sobjanek, A Woźniacka, J Narbutt
BACKGROUND: There is still much ambiguity in studies of Sonic hedgehog (Shh) pathways and its dysregulation. Some studies concerning the role of the Shh pathway in basal cell carcinoma (BCC) have been conducted, but there is a lack of studies about Shh pathway dysregulation under the influence of ultraviolet (UV)B radiation. AIM: To evaluate skin expression of Shh, Ptch1, Ptch2, Smo and Gli1 proteins in BCCs with and without the influence of UVB radiation. METHODS: In total, 34 healthy controls (HCs) and 42 patients with nodular BCC were recruited into the study...
February 9, 2018: Clinical and Experimental Dermatology
https://www.readbyqxmd.com/read/29423837/analysis-of-hedgehog-signaling-in-periocular-sebaceous-carcinoma
#12
John C Bladen, Mariya Moosajee, Dhani Tracey-White, Michèle Beaconsfield, Edel A O'Toole, Michael P Philpott
PURPOSE: Sebaceous carcinoma (SC) is a clinical masquerader of benign conditions resulting in significant eye morbidity, sometimes leading to extensive surgical treatment including exenteration, and even mortality. Little is known about the genetic or molecular basis of SC. This study identifies the involvement of Hedgehog (Hh) signaling in periocular SC. METHODS: Fifteen patients with periocular SC patients were compared to 15 patients with eyelid nodular basal cell carcinoma (nBCC; a known Hh tumor), alongside four normal individuals as a control for physiological Hh expression...
February 8, 2018: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/29400712/noncanonical-hedgehog-pathway-activation-through-srf-mkl1-promotes-drug-resistance-in-basal-cell-carcinomas
#13
Ramon J Whitson, Alex Lee, Nicole M Urman, Amar Mirza, Catherine Y Yao, Alexander S Brown, Jiang R Li, Gautam Shankar, Micah A Fry, Scott X Atwood, Eunice Y Lee, S Tyler Hollmig, Sumaira Z Aasi, Kavita Y Sarin, Matthew P Scott, Ervin H Epstein, Jean Y Tang, Anthony E Oro
Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity...
February 5, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29396625/tsc1-and-tsc2-regulate-cilia-length-and-canonical-hedgehog-signaling-via-different-mechanisms
#14
Thomas Rosengren, Lasse Jonsgaard Larsen, Lotte Bang Pedersen, Søren Tvorup Christensen, Lisbeth Birk Møller
Primary cilia are sensory organelles that coordinate multiple cellular signaling pathways, including Hedgehog (HH), Wingless/Int (WNT) and Transforming Growth Factor-β (TGF-β) signaling. Similarly, primary cilia have been implicated in regulation of mTOR signaling, in which Tuberous Sclerosis Complex proteins 1 and 2 (TSC1/2) negatively regulate protein synthesis by inactivating the mTOR complex 1 (mTORC1) at energy limiting states. Here we report that TSC1 and TSC2 regulate Smoothened (SMO)-dependent HH signaling in mouse embryonic fibroblasts (MEFs)...
February 2, 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29396391/targeted-inhibition-of-hedgehog-gli-signaling-by-novel-acylguanidine-derivatives-inhibits-melanoma-cell-growth-by-inducing-replication-stress-and-mitotic-catastrophe
#15
Silvia Pietrobono, Roberta Santini, Sinforosa Gagliardi, Francesca Dapporto, David Colecchia, Mario Chiariello, Cosima Leone, Massimo Valoti, Fabrizio Manetti, Elena Petricci, Maurizio Taddei, Barbara Stecca
Aberrant activation of the Hedgehog (HH) signaling is a critical driver in tumorigenesis. The Smoothened (SMO) receptor is one of the major upstream transducers of the HH pathway and a target for the development of anticancer agents. The SMO inhibitor Vismodegib (GDC-0449/Erivedge) has been approved for treatment of basal cell carcinoma. However, the emergence of resistance during Vismodegib treatment and the occurrence of numerous side effects limit its use. Our group has recently discovered and developed novel and potent SMO inhibitors based on acylguanidine or acylthiourea scaffolds...
February 2, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29396292/dynarrestin-a-novel-inhibitor-of-cytoplasmic-dynein
#16
Susanne Höing, Ting-Yu Yeh, Matthias Baumann, Nancy E Martinez, Peter Habenberger, Lea Kremer, Hannes C A Drexler, Philipp Küchler, Peter Reinhardt, Axel Choidas, Mia-Lisa Zischinsky, Gunther Zischinsky, Swaran Nandini, Aaron P Ledray, Stephanie A Ketcham, Lydia Reinhardt, Masin Abo-Rady, Michael Glatza, Stephen J King, Peter Nussbaumer, Slava Ziegler, Bert Klebl, Trina A Schroer, Hans R Schöler, Herbert Waldmann, Jared Sterneckert
Aberrant hedgehog (Hh) signaling contributes to the pathogenesis of multiple cancers. Available inhibitors target Smoothened (Smo), which can acquire mutations causing drug resistance. Thus, compounds that inhibit Hh signaling downstream of Smo are urgently needed. We identified dynarrestin, a novel inhibitor of cytoplasmic dyneins 1 and 2. Dynarrestin acts reversibly to inhibit cytoplasmic dynein 1-dependent microtubule binding and motility in vitro without affecting ATP hydrolysis. It rapidly and reversibly inhibits endosome movement in living cells and perturbs mitosis by inducing spindle misorientation and pseudoprometaphase delay...
January 26, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29388014/the-landscape-of-genetic-alterations-in-ameloblastomas-relates-to-clinical-features
#17
Sibel Elif Gültekin, Reem Aziz, Carina Heydt, Burcu Sengüven, Joachim Zöller, Ali Farid Safi, Matthias Kreppel, Reinhard Buettner
Ameloblastoma is a mostly benign, but locally invasive odontogenic tumor eliciting frequent relapses and significant morbidity. Recently, mutually exclusive mutations in BRAF and SMO were identified causing constitutive activation of MAPK and hedgehog signaling pathways. To explore further such clinically relevant genotype-phenotype correlations, we here comprehensively analyzed a large series of ameloblastomas (98 paraffin block of 76 patients) with respect to genomic alterations, clinical presentation, and histological features collected from the archives of three different pathology centers in France, Germany, and Turkey...
February 1, 2018: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29385801/profiling-of-sialylated-oligosaccharides-in-mammalian-milk-using-on-line-solid-phase-extraction-hydrophilic-interaction-chromatography-coupled-with-negative-ion-electrospray-mass-spectrometry
#18
Jingyu Yan, Junjie Ding, Gaowa Jin, Dongping Yu, Long Yu, Zhen Long, Zhimou Guo, Wengang Chai, Xinmiao Liang
Sialylated oligosaccharides are important components in mammalian milk. They play a key role in the health and growth of infants by helping to shape up infant's gastrointestinal microbiota and defense against infection by various pathogenic agents. A detailed knowledge of the structures, compositions, and quantities of the sialylated milk oligosaccharides (SMOs) is a prerequisite for understanding their biological roles. However, due to the presence of very large amounts of lactose and neutral oligosaccharides, accurate analysis of SMOs is difficult...
January 31, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29378965/disruption-of-the-ciliary-gtpase-arl13b-suppresses-sonic-hedgehog-overactivation-and-inhibits-medulloblastoma-formation
#19
Sarah N Bay, Alyssa B Long, Tamara Caspary
Medulloblastoma (MB) is the most common malignant pediatric brain tumor, and overactivation of the Sonic Hedgehog (Shh) signaling pathway, which requires the primary cilium, causes 30% of MBs. Current treatments have known negative side effects or resistance mechanisms, so new treatments are necessary. Shh signaling mutations, like those that remove Patched1 (Ptch1) or activate Smoothened (Smo), cause tumors dependent on the presence of cilia. Genetic ablation of cilia prevents these tumors by removing Gli activator, but cilia are a poor therapeutic target since they support many biological processes...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29378090/chimeric-styrene-monooxygenase-with-increased-efficiency-in-asymmetric-biocatalytic-epoxidation
#20
Maria Luisa Corrado, Tanja Knaus, Francesco Mutti
The styrene monooxygenase (SMO) system from Pseudomonas sp. is constituted by two enzymes (StyA and StyB). StyB catalyses the reduction of FAD at the expense of NADH. After the transfer of FADH2 from StyB to StyA, reaction with O2 generates FAD-OOH that is the epoxidising agent. The waste of redox equivalents due to a partial diffusive transfer of FADH2, the insolubility of recombinant StyB and the impossibility to express StyA and StyB in a 1:1 molar ratio reduce the catalytic efficiency of the natural system...
January 29, 2018: Chembiochem: a European Journal of Chemical Biology
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