Artículos de revistas: "G-Hedgehog"

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Gomes-Gonçalves, Sara, Sérgio Santos-Silva, Andreia V. S. Cruz, Clarisse Rodrigues, Vanessa Soeiro, Patrícia Barradas y João R. Mesquita. "A Thorny Tale of Parasites: Screening for Enteric Protozoan Parasites in Hedgehogs from Portugal". Animals 14, n.º 2 (21 de enero de 2024): 326. http://dx.doi.org/10.3390/ani14020326.

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Enteric protozoan parasites, such as Blastocystis sp., Balantioides coli, Cryptosporidium spp., and Giardia duodenalis, may have implications for both animal and human health.Transmitted through the fecal–oral route, these parasites cause symptoms such as diarrhea, abdominal pain, and weight loss. This study investigated the presence of these enteric protozoan parasites and genetically characterized them in hedgehogs from Portugal. A total of 110 hedgehog stool samples were collected. Molecular detection methods showed an overall occurrence of protozoa in 1.82% (2/110 95% CI: 0.22–6.41) of hedgehogs, with Blastocystis being found in one hedgehog and Cryptosporidium being found in another. No evidence for the presence of B. coli or G. duodenalis was found. This study suggests that there is a need to stay aware of hedgehogs as potential hosts of enteric protozoa. Ongoing research and surveillance efforts are recommended to explore practical prevention and control strategies. The results contribute to the limited knowledge of these parasites in Portuguese hedgehog populations and underscore their potential relevance to both veterinary and public health.

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Khera, Himanshi, Anupam Awasthi y Sidharth Mehan. "Sonic Hedgehog Signaling Activation Promotes Cardioprotective Strategies". Current Signal Transduction Therapy 15, n.º 2 (1 de diciembre de 2020): 197–204. http://dx.doi.org/10.2174/1574362413666181113124958.

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Background: Hedgehog pathway plays a crucial role in the neovascularisation and angiogenesis during the embryonic stage in humans. Three genes of hedgehog protein isolated from humans are Sonic hedgehog, Desert hedgehog and Indian hedgehog gene. Two G-protein coupled receptors identified in the sonic hedgehog pathway served as patched receptor and smoothened receptor. Materials and Methods: Particularly, sonic hedgehog gene plays a versatile role in cellular homeostasis and can be a novel therapeutic target in the prevention of cardiovascular disorders. Further various sonic hedgehog modulators have been reported working as futuristic drug molecules in the modulation of cardiovascular dysfunctions. Results: However, there was limited literature availability that has summarized the possible mechanism of targeting Sonic hedgehog signaling pathway. Conclusion: Thus, the present review is aimed at exploring the role of targeting sonic hedgehog protein signaling and modulators as well as to enlighten that how targeting sonic hedgehog protein involves in the amelioration of atherosclerosis, ischemic heart diseases, vascular endothelial dysfunction, heart failure and congenital heart diseases.

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Rasmussen, Sophie Lund, Ane Elise Schrøder, Ronja Mathiesen, Jeppe Lund Nielsen, Cino Pertoldi y David W. Macdonald. "Wildlife Conservation at a Garden Level: The Effect of Robotic Lawn Mowers on European Hedgehogs (Erinaceus europaeus)". Animals 11, n.º 5 (21 de abril de 2021): 1191. http://dx.doi.org/10.3390/ani11051191.

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We tested the effects of 18 models of robotic lawn mowers in collision with dead European hedgehogs and quantified the results into six damage categories. All models were tested on four weight classes of hedgehogs, each placed in three different positions. None of the robotic lawn mowers tested was able to detect the presence of dependent juvenile hedgehogs (<200 g) and all models had to touch the hedgehogs to detect them. Some models caused extensive damage to the hedgehog cadavers, but there were noteworthy differences in the degree of harm inflicted, with some consistently causing no damage. Our results showed that the following technical features significantly increased the safety index of the robotic lawn mowers: pivoting blades, skid plates, and front wheel drive. Based on these findings, we encourage future collaboration with the manufacturers of robotic lawn mowers to improve the safety for hedgehogs and other garden wildlife species.

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Budiono, Novericko Ginger, Nicole Ting Qian Wen, Punithe Raj A/L Rajendran y Annise Proboningrat. "Speedy Recovery of Subcutaneous Abscess and The Presence of Overgrown Nails in A Pygmy Hedgehog: A Case Report". Jurnal Medik Veteriner 6, n.º 3 (31 de diciembre de 2023): 126–35. http://dx.doi.org/10.20473/jmv.vol6.iss3.2023.126-135.

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This study reported that a 15-month-old intact female African pygmy hedgehog (Atelerix albiventris) was presented to IPB University Veterinary Teaching Hospital to evaluate a 1.5 cm × 1.5 cm × 0.5 cm mass on the left ventral thorax, three days after the mass was first discovered by the owner. Overgrown nails were observed on all four toes of each of the four limbs of the hedgehog. The body weight was 150 g, and the axial temperature was 36.5°C. The heart and respiratory rates were 180 per minute and 40 per minute, respectively. After a thorough physical examination, the patient was diagnosed with subcutaneous abscesses and overgrown nails. The abscess was surgically resected using a local anesthetic. The overgrown nails were trimmed to prevent further injury and the recurrence of abscesses. Following surgery, the hedgehog was discharged directly from the hospital and treated using Amoxicillin 15 mg/kg per oral every 12 hours for seven days, daily routine wound cleaning with sodium chloride, and topical powder of neomycin sulfate 5 mg/g and bacitracin 250 IU/g. The patient responded effectively to the systemic treatment, and medical signs and symptoms resolved. The hedgehog fully recovered from the subcutaneous abscess 14 days after the first hospital visit. No recurrence was reported in the subsequent month after resolution.

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Mukhopadhyay, Saikat y Rajat Rohatgi. "G-protein-coupled receptors, Hedgehog signaling and primary cilia". Seminars in Cell & Developmental Biology 33 (septiembre de 2014): 63–72. http://dx.doi.org/10.1016/j.semcdb.2014.05.002.

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Philipp, Melanie y Marc G. Caron. "Hedgehog Signaling: Is Smo a G Protein-Coupled Receptor?" Current Biology 19, n.º 3 (febrero de 2009): R125—R127. http://dx.doi.org/10.1016/j.cub.2008.12.010.

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Philipp, Melanie, Gregory B. Fralish, Alison R. Meloni, Wei Chen, Alyson W. MacInnes, Lawrence S. Barak y Marc G. Caron. "Smoothened Signaling in Vertebrates Is Facilitated by a G Protein-coupled Receptor Kinase". Molecular Biology of the Cell 19, n.º 12 (diciembre de 2008): 5478–89. http://dx.doi.org/10.1091/mbc.e08-05-0448.

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Smoothened, a heptahelical membrane protein, functions as the transducer of Hedgehog signaling. The kinases that modulate Smoothened have been thoroughly analyzed in flies. However, little is known about how phosphorylation affects Smoothened in vertebrates, mainly, because the residues, where Smoothened is phosphorylated are not conserved from Drosophila to vertebrates. Given its molecular architecture, Smoothened signaling is likely to be regulated in a manner analogous to G protein–coupled receptors (GPCRs). Previously, it has been shown, that arrestins and GPCR kinases, (GRKs) not only desensitize G protein–dependent receptor signaling but also function as triggers for GPCR trafficking and formation of signaling complexes. Here we describe that a GRK contributes to Smoothened-mediated signaling in vertebrates. Knockdown of the zebrafish homolog of mammalian GRK2/3 results in lowered Hedgehog transcriptional responses, impaired muscle development, and neural patterning. Results obtained in zebrafish are corroborated both in cell culture, where zGRK2/3 phosphorylates Smoothened and promotes Smoothened signal transduction and in mice where deletion of GRK2 interferes with neural tube patterning. Together, these data suggest that a GRK functions as a vertebrate kinase for Smoothened, promoting Hedgehog signal transduction during early development.

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Norris, W., C. Neyt, P. W. Ingham y P. D. Currie. "Slow muscle induction by Hedgehog signalling in vitro". Journal of Cell Science 113, n.º 15 (1 de agosto de 2000): 2695–703. http://dx.doi.org/10.1242/jcs.113.15.2695.

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Muscles are composed of several fibre types, the precise combination of which determines muscle function. Whereas neonatal and adult fibre type is influenced by a number of extrinsic factors, such as neural input and muscle load, there is little knowledge of how muscle cells are initially determined in the early embryo. In the zebrafish, fibres of the slow twitch class arise from precociously specified myoblasts that lie close to the midline whereas the remainder of the myotome differentiates as fast myosin expressing muscle. In vivo evidence has suggested the Sonic Hedgehog glycoprotein, secreted from the notochord, controls the formation of slow twitch and fast twitch muscle fates. Here we describe an in vitro culture system that we have developed to test directly the ability of zebrafish myoblasts to respond to exogenous Sonic Hedgehog peptide. We find that Sonic Hedgehog peptide can control the binary cell fate choice of embryonic zebrafish myoblasts in vitro. We have also used this culture system to assay the relative activities of different Hedgehog-family proteins and to investigate the possible involvement of heterotrimeric G-proteins in Hedgehog signal transduction.

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Meloni, Alison R., Gregory B. Fralish, Patrick Kelly, Ali Salahpour, James K. Chen, Robert J. Wechsler-Reya, Robert J. Lefkowitz y Marc G. Caron. "Smoothened Signal Transduction Is Promoted by G Protein-Coupled Receptor Kinase 2". Molecular and Cellular Biology 26, n.º 20 (14 de agosto de 2006): 7550–60. http://dx.doi.org/10.1128/mcb.00546-06.

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ABSTRACT Deregulation of the Sonic hedgehog pathway has been implicated in an increasing number of human cancers. In this pathway, the seven-transmembrane (7TM) signaling protein Smoothened regulates cellular proliferation and differentiation through activation of the transcription factor Gli. The activity of mammalian Smoothened is controlled by three different hedgehog proteins, Indian, Desert, and Sonic hedgehog, through their interaction with the Smoothened inhibitor Patched. However, the mechanisms of signal transduction from Smoothened are poorly understood. We show that a kinase which regulates signaling by many “conventional” 7TM G-protein-coupled receptors, G protein-coupled receptor kinase 2 (GRK2), participates in Smoothened signaling. Expression of GRK2, but not catalytically inactive GRK2, synergizes with active Smoothened to mediate Gli-dependent transcription. Moreover, knockdown of endogenous GRK2 by short hairpin RNA (shRNA) significantly reduces signaling in response to the Smoothened agonist SAG and also inhibits signaling induced by an oncogenic Smoothened mutant, Smo M2. We find that GRK2 promotes the association between active Smoothened and β-arrestin 2. Indeed, Gli-dependent signaling, mediated by coexpression of Smoothened and GRK2, is diminished by β-arrestin 2 knockdown with shRNA. Together, these data suggest that GRK2 plays a positive role in Smoothened signaling, at least in part, through the promotion of an association between β-arrestin 2 and Smoothened.

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Gvozdenovic-Jeremic, Jelena y Ljiljana Mojovic. "Drug repositioning for a rare genetic disorder progressive osseous heteroplasia (POH)". Genetika 51, n.º 1 (2019): 347–55. http://dx.doi.org/10.2298/gensr1901347g.

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Progressive osseous heteroplasia (POH) is an ultrarare genetic disease of progressive ectopic ossification caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase (Gs?). Extensive ossification of the deep connective tissues can result in ankylosis of affected joints and growth retardation of involved limbs. Inhibition of main molecular signaling, Hedgehog (Hh) pathway, by pharmacological methods may reduce the severity of ectopic bone formation in POH patients. Hh inhibitors currently used or known for other conditions may be potential candidate drugs for treating this debilitating disease. In this study, three potential Hedgehog pathway inhibitors such as arsenic trioxide, statin, and vitamin D and their combinations were tested on subcutaneous mesenchymal progenitor (SMP) cells of G?s f/f mice model for possible therapeutic application for POH. The combination of these three drugs at their significantly reduced concentrations retained anti-osteogenic activity in SMP cells with aberrant Hedgehog activity. In that light, we propose here a potential new approach of the drug combination in order to reduce potential toxicity, the side effect and increase success rate for Hh inhibitors drug repositioning.

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Gounder, Mrinal M., Mark Andrew Dickson, Nian Wu, S. Percy Ivy, Richard D. Carvajal, Sandra P. D'Angelo, Mary Louise Keohan et al. "A first-in-human, phase Ib combination study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a hedgehog inhibitor, GDC-0449, with a Notch inhibitor, RO4929097, in patients with advanced sarcoma." Journal of Clinical Oncology 30, n.º 15_suppl (20 de mayo de 2012): 10004. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10004.

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10004 Background: Aberrant Hedgehog and Notch signaling is seen in sarcoma and anti-tumor activity is enhanced by inhibiting both pathways. This first in man Phase Ib study evaluated safety and efficacy of the combination of GDC-0449 (G), a smoothened inhibitor with RO4929097 (R), a gamma-secretase/notch inhibitor. Methods: The study evaluated fixed dose G (150 mg qd) for 21 days followed by G + R at either 10 mg (level 1) or 15 mg (level 2) QD. At MTD pts were evaluated with G + R (without “lead in” G) or single agent R. Pre and post treatment tumor biopsies were obtained to assess notch and hedgehog inhibition. PK was assessed for each drug. Key eligibility: advanced sarcoma, ECOG ≤ 2, age ≥ 18 and prior therapies ≤ 4. RECIST response was assessed Q6 wks. Results: 34 pts had a median age of 53 yrs (23-78), median priors 3 and various histologies [liposarcoma (7), chondrosarcoma (7), leiomyosarcoma (4), osteosarcoma (2), GIST (2) and other (12)]. No DLT was seen. Common (≥10 %) grade ≤3 toxicity was hypophosphatemia (18%). Systemic exposure (AUC0-24 and Cmax) of G was similar to established studies (not shown). AUC0-24 and Cmax of R was significantly lower (~70%) when administered with G (Table). However, measurement of unbound, free drug (Cfree) of R showed comparable levels between single agent R and G + R, but not when G was a “lead in” (Table). Target inhibition of the notch pathway (cleaved notch) and pAkt was observed in matched tumor biopsies with both arms. Durable SD was seen in both arms: myxoid chondrosarcoma (56 wks), liposarcoma (24+ wks), clear cell (21+ wks), desmoid (17+ wks), spindle cell (15+ wks) and chondrosarcoma (13+ wks). Conclusions: The combination of G+R is well tolerated and the RP2D is G 150 mg qd and R 15 mg qd without a “lead in” G. Despite reduction in total levels of R in the combination, free drug was similar and inhibits target. Disease stability was seen with R and R + G. Further clinical development of notch and hedgehog inhibitors in sarcomas is warranted. [Table: see text]

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Moore, Bryn S., Ann N. Stepanchick, Paul H. Tewson, Cassandra M. Hartle, Jin Zhang, Anne Marie Quinn, Thomas E. Hughes y Tooraj Mirshahi. "Cilia have high cAMP levels that are inhibited by Sonic Hedgehog-regulated calcium dynamics". Proceedings of the National Academy of Sciences 113, n.º 46 (31 de octubre de 2016): 13069–74. http://dx.doi.org/10.1073/pnas.1602393113.

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Protein kinase A (PKA) phosphorylates Gli proteins, acting as a negative regulator of the Hedgehog pathway. PKA was recently detected within the cilium, and PKA activity specifically in cilia regulates Gli processing. Using a cilia-targeted genetically encoded sensor, we found significant basal PKA activity. Using another targeted sensor, we measured basal ciliary cAMP that is fivefold higher than whole-cell cAMP. The elevated basal ciliary cAMP level is a result of adenylyl cyclase 5 and 6 activity that depends on ciliary phosphatidylinositol (3,4,5)-trisphosphate (PIP3), not stimulatory G protein (Gαs), signaling. Sonic Hedgehog (SHH) reduces ciliary cAMP levels, inhibits ciliary PKA activity, and increases Gli1. Remarkably, SHH regulation of ciliary cAMP and downstream signals is not dependent on inhibitory G protein (Gαi/o) signaling but rather Ca2+ entry through a Gd3+-sensitive channel. Therefore, PIP3 sustains high basal cAMP that maintains PKA activity in cilia and Gli repression. SHH activates Gli by inhibiting cAMP through a G protein-independent mechanism that requires extracellular Ca2+ entry.

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Igado, O. O., S. F. Braimah y A. A. Obasa. "Gross Morphology of the Brain and Spinal Cord of the African Pygmy Hedgehog (Atelerix albiventris)". Folia Veterinaria 65, n.º 3 (1 de septiembre de 2021): 15–21. http://dx.doi.org/10.2478/fv-2021-0023.

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Abstract The African pygmy hedgehog (Atelerix albiventris) is an insectivorous animal, native to Africa. The central nervous system (CNS) consists of the brain and the spinal cord, protected by the cranium and vertebral column respectively. Assessment of the gross appearance and morphometries of the African pygmy hedgehog CNS were carried out using six adults (3 males and 3 females). The gross examination showed the brains to be lissencephalic, with relatively large olfactory bulbs, similar to that observed in some rodents. The rootlets of the first cervical spinal nerves were observed to emerge before the foramen magnum. Linear measurements were obtained from both the brain and spinal cord. The mean weight of the animals was 199.00 ± 16.09 g, with the males having an average body weight of 183.50 ± 12.02 g and the females 206.80 ± 11.95 g. Although not statistically significant, the males had a higher encephalisation quotient (0.40 ± 0.08) relative to the females 0.36 ± 0.04). The values for the brain weight, length of spinal cord and heights of the telencephalon and diencephalon at different points were higher in the males, while the spinal cord weight, length of brain and cerebellar height were higher in the females. The spinal cord showed slight enlargements at the cervical, thoracic, lumbar and sacral segments. This study aimed to provide baseline data for the study of the gross appearance and neuromorpho-metrics of the hedgehog, with possible application in regional anaesthesiology and comparative wildlife neuroanatomy.

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He, Xuelian y Q. Richard Lu. "G-Protein Gαs controls medulloblastoma initiation by suppressing sonic hedgehog signaling". Molecular & Cellular Oncology 2, n.º 2 (diciembre de 2014): e975070. http://dx.doi.org/10.4161/23723556.2014.975070.

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Ogden, Stacey K., Dennis Liang Fei, Neal S. Schilling, Yashi F. Ahmed, John Hwa y David J. Robbins. "G protein Gαi functions immediately downstream of Smoothened in Hedgehog signalling". Nature 456, n.º 7224 (5 de noviembre de 2008): 967–70. http://dx.doi.org/10.1038/nature07459.

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Ayers, Katie L. y Pascal P. Thérond. "Evaluating Smoothened as a G-protein-coupled receptor for Hedgehog signalling". Trends in Cell Biology 20, n.º 5 (mayo de 2010): 287–98. http://dx.doi.org/10.1016/j.tcb.2010.02.002.

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Bearman-Brown, Lucy E., Philip J. Baker, Dawn Scott, Antonio Uzal, Luke Evans y Richard W. Yarnell. "Over-Winter Survival and Nest Site Selection of the West-European Hedgehog (Erinaceus europaeus) in Arable Dominated Landscapes". Animals 10, n.º 9 (19 de agosto de 2020): 1449. http://dx.doi.org/10.3390/ani10091449.

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The West-European hedgehog (Erinaceus europaeus) has declined markedly in the UK. The winter hibernation period may make hedgehogs vulnerable to anthropogenic habitat and climate changes. Therefore, we studied two contrasting populations in England to examine patterns of winter nest use, body mass changes and survival during hibernation. No between-site differences were evident in body mass prior to hibernation nor the number of winter nests used, but significant differences in overwinter mass change and survival were observed. Mass change did not, however, affect survival rates; all deaths occurred prior to or after the hibernation period, mainly from predation or vehicle collisions. Hedgehogs consistently nested in proximity to hedgerows, roads and woodlands, but avoided pasture fields; differences between sites were evident for the selection for or avoidance of arable fields, amenity grassland and buildings. Collectively, these data indicate that hibernation was not a period of significant mortality for individuals that had attained sufficient weight (>600 g) pre-hibernation. Conversely, habitat composition did significantly affect the positioning of winter nests, such that different land management practices (historic and current) might potentially influence hibernation success. The limitations of this study and suggestions for future research are discussed.

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Potuijt, Jacob W. P., Jeannette Hoogeboom, Esther de Graaff, Christianne A. van Nieuwenhoven y Robert Jan H. Galjaard. "Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes". Journal of Medical Genetics 57, n.º 10 (16 de marzo de 2020): 660–63. http://dx.doi.org/10.1136/jmedgenet-2019-106685.

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BackgroundThe of zone of polarizing activity regulatory sequence (ZRS) is a regulatory element residing in intron 5 of LMBR1 and regulates Sonic Hedgehog expression in the limb bud. Variants in the ZRS are generally fully penetrant and can cause triphalangeal thumb (TPT) and polydactyly in affected families.ObjectiveIn this report, we describe two families with mild phenotypical presentation.MethodsWe performed a field study for clinical evaluation and sequenced the ZRS for variantsusing Sanger sequencing.ResultsIn family I, a novel 165A>G variant in the ZRS (g.156584405A>G, GRCh37/Hg19) was found. In family II, we identified a 295T>C variant in the ZRS (g.156584535T>C, GRCh37/Hg19). Family members of both families who were presumed to be unaffected shared the variant in the ZRS with affected family members, suggesting reduced penetrance of the genotype. However, clinical examination of these unaffected family members revealed minor anomalies like broad thumbs and lack of thumb opposition. As the phenotype in affected patients is remarkably mild, we suggest that these ZRS variants are minimally disruptive for Sonic Hedgehog expression and therefore can result in subclinical phenotypes.ConclusionOur study underlines the importance of accurate clinical examination and appropriate genetic counselling in families with mild cases of TPT.

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Maier, Dominic, Shuofei Cheng y David R. Hipfner. "The complexities of G-protein-coupled receptor kinase function in Hedgehog signaling". Fly 6, n.º 3 (julio de 2012): 135–41. http://dx.doi.org/10.4161/fly.20245.

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Cheng, S., D. Maier y D. R. Hipfner. "Drosophila G-protein-coupled receptor kinase 2 regulates cAMP-dependent Hedgehog signalling". Journal of Cell Science 125, n.º 1 (1 de enero de 2012): e1-e1. http://dx.doi.org/10.1242/jcs.106047.

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Cheng, S., D. Maier y D. R. Hipfner. "Drosophila G-protein-coupled receptor kinase 2 regulates cAMP-dependent Hedgehog signaling". Development 139, n.º 1 (17 de noviembre de 2011): 85–94. http://dx.doi.org/10.1242/dev.068817.

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Zhao, Jia-wen, Feng-yang Chen, Li-juan Gao, Shi-fang Xu, Yi-ping Ye y Xiao-yu Li. "Two New Steroidal Aglycones from Roots of Cynanchun Paniculatum". Natural Product Communications 11, n.º 6 (junio de 2016): 1934578X1601100. http://dx.doi.org/10.1177/1934578x1601100612.

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Two new 13, 14/14, 15-disecopregnane-type skeleton C21 steroidal aglycones, neocynapanogenin G (1) and neocynapanogenin H (2), were isolated from the hydrolyzed extract of the CHC13 soluble extract of the roots of Cynanchun paniculatum. Their structures were determined on the basis of chemical evidence and extensive spectroscopic methods, including ID and 2D NMR spectroscopy. Compound 1 displayed significant inhibition of the Hedgehog signaling pathway in vitro.

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Kasai, Kenji, Masanori Takahashi, Noriko Osumi, Srikumar Sinnarajah, Tomohiro Takeo, Hiroshi Ikeda, John H. Kehrl, Gen Itoh y Heinz Arnheiter. "The G12 family of heterotrimeric G proteins and Rho GTPase mediate Sonic hedgehog signalling". Genes to Cells 9, n.º 1 (enero de 2004): 49–58. http://dx.doi.org/10.1111/j.1356-9597.2004.00701.x.

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Pusapati, Ganesh V., Jennifer H. Kong, Bhaven B. Patel, Mina Gouti, Andreas Sagner, Ria Sircar, Giovanni Luchetti, Philip W. Ingham, James Briscoe y Rajat Rohatgi. "G protein–coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog". Science Signaling 11, n.º 516 (6 de febrero de 2018): eaao5749. http://dx.doi.org/10.1126/scisignal.aao5749.

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Rao, Rohit, Ralph Salloum, Mei Xin y Q. Richard Lu. "The G protein Gαsacts as a tumor suppressor in sonic hedgehog signaling-driven tumorigenesis". Cell Cycle 15, n.º 10 (6 de abril de 2016): 1325–30. http://dx.doi.org/10.1080/15384101.2016.1164371.

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Mahoney, William M., Jagadambika Gunaje, Guenter Daum, Xiu Rong Dong y Mark W. Majesky. "Regulator of G-Protein Signaling – 5 (RGS5) Is a Novel Repressor of Hedgehog Signaling". PLoS ONE 8, n.º 4 (18 de abril de 2013): e61421. http://dx.doi.org/10.1371/journal.pone.0061421.

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Molnar, C., H. Holguin, F. Mayor, A. Ruiz-Gomez y J. F. de Celis. "The G protein-coupled receptor regulatory kinase GPRK2 participates in Hedgehog signaling in Drosophila". Proceedings of the National Academy of Sciences 104, n.º 19 (1 de mayo de 2007): 7963–68. http://dx.doi.org/10.1073/pnas.0702374104.

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Del Giovane, Alice y Antonella Ragnini-Wilson. "Targeting Smoothened as a New Frontier in the Functional Recovery of Central Nervous System Demyelinating Pathologies". International Journal of Molecular Sciences 19, n.º 11 (20 de noviembre de 2018): 3677. http://dx.doi.org/10.3390/ijms19113677.

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Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. Recent phenotypical screens have identified agonists of the atypical G protein-coupled receptor Smoothened and inhibitors of the glioma-associated oncogene 1 as being amongst the most potent stimulators of oligodendrocyte precursor cell (OPC) differentiation in vitro and remyelination in the central nervous system (CNS) of mice. Here, we discuss the current state-of-the-art of studies on the role of Sonic Hedgehog reactivation during remyelination, referring readers to other reviews for the role of Hedgehog signaling in cancer and stem cell maintenance.

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Gudrun Kalmbach HE. "Dynamical interaction geometries for physics with models". Magna Scientia Advanced Research and Reviews 1, n.º 2 (28 de febrero de 2021): 031–37. http://dx.doi.org/10.30574/msarr.2021.1.2.0007.

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The MINT-Wigris Tool bag is presented with its models for color charges as a G-compass the hedgehog for the energy exchange of a nucleon system with its environment, an inner quark-gluon flow in it as 6-roll mill, two nucleon tetrahedrons for the gluon exchange between nucleons quarks, a radial contraction/expansion pulsation for deuteron, two fusion states of the tetrahedrons, a neutrino Gleason operator bound geometry and oscillation dynamics.

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Jiang, Weirong, Xia Yao, Zhaoliang Shan, Wenting Li, Yuxue Gao y Qing Zhang. "E3 ligase Herc4 regulates Hedgehog signalling through promoting Smoothened degradation". Journal of Molecular Cell Biology 11, n.º 9 (29 de marzo de 2019): 791–803. http://dx.doi.org/10.1093/jmcb/mjz024.

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Abstract Hedgehog (Hh) signalling plays conserved roles in controlling embryonic development; its dysregulation causes many diseases including cancers. The G protein-coupled receptor Smoothened (Smo) is the key signal transducer of the Hh pathway, whose posttranslational regulation has been shown to be critical for its accumulation and activation. Ubiquitination has been reported an essential posttranslational regulation of Smo. Here, we identify a novel E3 ligase of Smo, Herc4, which binds to Smo, and regulates Hh signalling by controlling Smo ubiquitination and degradation. Interestingly, our data suggest that Herc4-mediated Smo degradation is regulated by Hh in PKA-primed phosphorylation-dependent and independent manners.

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Riobo, Natalia A. y David R. Manning. "Pathways of signal transduction employed by vertebrate Hedgehogs". Biochemical Journal 403, n.º 3 (12 de abril de 2007): 369–79. http://dx.doi.org/10.1042/bj20061723.

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Signalling by Hh (Hedgehog) proteins is among the most actively studied receptor-mediated phenomena relevant to development and post-embryonic homoeostatic events. The impact of signalling by the Hh proteins is profound, and work pertaining to the presentation of these proteins and the pathways engaged by them continues to yield unique insights into basic aspects of morphogenic signalling. We review here the mechanisms of signalling relevant to the actions of Hh proteins in vertebrates. We emphasize findings within the past several years on the recognition of, in particular, Sonic hedgehog by target cells, pathways of transduction employed by the seven-pass transmembrane protein Smoothened and end points of action, as manifest in the regulation of the Gli transcription factors. Topics of extended interest are those regarding the employment of heterotrimeric G-proteins and G-protein-coupled receptor kinases by Smoothened. We also address the pathways, insofar as known, linking Smoothened to the expression and stability of Gli1, Gli2 and Gli3. The mechanisms by which Hh proteins signal have few, if any, parallels. It is becoming clear in vertebrates, however, that several facets of signalling are shared in common with other venues of signalling. The challenge in understanding both the actions of Hh proteins and the overlapping forms of regulation will be in understanding, in molecular terms, both common and divergent signalling events.

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Yamashita, Erika, Shinichi Negishi, Jun Kikuta, Mami Shimizu y Hidenobu Senpuku. "Effects of Improper Mechanical Force on the Production of Sonic Hedgehog, RANKL, and IL-6 in Human Periodontal Ligament Cells In Vitro". Dentistry Journal 12, n.º 4 (15 de abril de 2024): 108. http://dx.doi.org/10.3390/dj12040108.

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Improper mechanical stress may induce side effects during orthodontic treatment. If the roots and alveolar bones are extensively resorbed following excess mechanical stress, unplanned tooth mobility and inflammation can occur. Although multiple factors are believed to contribute to the development of side effects, the cause is still unknown. Sonic hedgehog (Shh), one of the hedgehog signals significantly associated with cell growth and cancer development, promotes osteoclast formation in the jawbone. Shh may be associated with root and bone resorptions during orthodontic treatment. In this study, we investigated the relationships between Shh, RANKL, and IL-6 in human periodontal ligament (hPDL) cells exposed to improper mechanical force. Weights were placed on hPDL cells and human gingival fibroblasts (HGFs) for an optimal orthodontic force group (1.0 g/cm2) and a heavy orthodontic force group (4.0 g/cm2). A group with no orthodontic force was used as a control group. Real-time PCR, SDS-PAGE, and Western blotting were performed to examine the effects of orthodontic forces on the expression of Shh, RANKL, and IL-6 at 2, 4, 6, 8, 12, and 24 h after the addition of pressure. The protein expression of Shh was not clearly induced by orthodontic forces of 1.0 and 4.0 g/cm2 compared with the control in HGFs and hPDL cells. In contrast, RANKL and IL-6 gene and protein expression was significantly induced by 1.0 and 4.0 g/cm2 in hPDL cells for forces lasting 6~24 h. However, neither protein was expressed in HGFs. RANKL and IL-6 expressions in response to orthodontic forces and in the control were clearly inhibited by Shh inhibitor RU-SKI 43. Shh did not directly link to RANKL and IL-6 for root and bone resorptions by orthodontic force but was associated with cell activities to be finally guided by the production of cytokines in hPDL cells.

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Girgiri, I., B. Gambo, B. Ibrahim y A. Bwala. "Morphometric studies of some visceral organs and gastrointestinal tract of four-toed african hedgehog (atelerix albiventris)". Journal of Morphological Sciences 32, n.º 01 (enero de 2015): 029–32. http://dx.doi.org/10.4322/jms.071014.

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Abstract Introductions: Morphometric studies were carried out on some visceral organs and gastrointestinal tract of African four-toed hedgehogs found in Maiduguri, Nigeria. Materials and Methods: Twelve (12) healthy adult hedgehogs, (6 male and 6 females) were used. The overall mean body weight was 239.5±28.3 g, and was statistically not significant (p > 0.05) between the sexes. The absolute (g) and relative (%) values for nearly all the visceral organs measured were consistently higher in the female, but were statistically not significant (p > 0.05) between the sexes. Results: The gastrointestinal tract morphology was simple, and lacks ceca. The overall mean length of the greater curvature of the stomach was 7.42±0.95 cm, with females (8.17±1.14 cm) having significantly higher values (p < 0.05) than (6.67±0.75 cm) observed in the males. Conclusions: The results obtained in this study will be useful in comparative anatomical studies, and as basic research data in varied ield of zoology and veterinary sciences.

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He, Xuelian, Liguo Zhang, Ying Chen, Marc Remke, David Shih, Fanghui Lu, Haibo Wang et al. "The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog−driven medulloblastoma". Nature Medicine 20, n.º 9 (24 de agosto de 2014): 1035–42. http://dx.doi.org/10.1038/nm.3666.

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Liu, Chuanliang, Qiongqiong Hu, Jia Jing, Yun Zhang, Jing Jin, Liulei Zhang, Lili Mu et al. "Regulator of G protein signaling 5 (RGS5) inhibits sonic hedgehog function in mouse cortical neurons". Molecular and Cellular Neuroscience 83 (septiembre de 2017): 65–73. http://dx.doi.org/10.1016/j.mcn.2017.06.005.

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Singh, Jaskirat, Xiaohui Wen y Suzie J. Scales. "The Orphan G Protein-coupled Receptor Gpr175 (Tpra40) Enhances Hedgehog Signaling by Modulating cAMP Levels". Journal of Biological Chemistry 290, n.º 49 (8 de octubre de 2015): 29663–75. http://dx.doi.org/10.1074/jbc.m115.665810.

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37

Zhan, Jing, Liang-liang Shi, Yan Wang, Bai Wei y Sheng-li Yang. "In Vivo Study on the Effects of Xiaoaiping on the Stemness of Hepatocellular Carcinoma Cells". Evidence-Based Complementary and Alternative Medicine 2019 (23 de junio de 2019): 1–10. http://dx.doi.org/10.1155/2019/4738243.

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Aims.The aim of this study was to examine the effects of Xiaoaiping on the stemness of hepatocellular carcinoma (HCC) cellsin vivoand to investigate the underlying molecular mechanism.Methods.A subcutaneous xenograft nude mouse model was established using Hep3B-derived HCC cells. The mice were randomly assigned to the 100 mg/kg Xiaoaiping or 100μL/20 g normal saline (control) groups (n =3/sex/group) for daily intragastric administration for 14 days. The tumor size was closely monitored during the dosing phase. After the treatment period, the tumor tissues were weighed and harvested for mRNA and protein isolation. qPCR and Western blotting were used to evaluate the expression of cancer stemness markers (epithelial cell adhesion molecule [EpCAM], cluster of differentiation [CD13], CD90, aldehyde dehydrogenase 1 [ALDH1], CD44, and CD45), totipotency factors (sex determining region Y-box 2 [Sox2], Nanog, and octamer-binding transcription factor 4 [Oct4]), and genes involved in the Notch, Wnt/β-catenin, Hedgehog, and Hippo signaling pathways.Key Findings.The tumor size and weight were significantly reduced in the nude mice treated with 100 mg/kg Xiaoaiping when compared with the controls. The Xiaoaiping effects on the stemness markers and totipotency factors included decreased expression of EpCAM, CD24, CD47, Sox2, Oct4, and sal-like protein 4 (SALL4), as well as increased expression of CD13 and ALDH1. In addition, Xiaoaiping inhibited the Hippo, Wnt, and Hedgehog signaling pathways.Conclusion.Xiaoaiping significantly inhibited the growth of HCC xenograft in nude mice. These antitumor effects may be mediated by modulating the expression of multiple stemness markers and totipotency factors and inhibition of the Hippo, Wnt, and Hedgehog signaling pathways.

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Pfirrmann, Thorsten, Enrico Jandt, Swantje Ranft, Ashwin Lokapally, Herbert Neuhaus, Muriel Perron y Thomas Hollemann. "Hedgehog-dependent E3-ligase Midline1 regulates ubiquitin-mediated proteasomal degradation of Pax6 during visual system development". Proceedings of the National Academy of Sciences 113, n.º 36 (23 de agosto de 2016): 10103–8. http://dx.doi.org/10.1073/pnas.1600770113.

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Pax6 is a key transcription factor involved in eye, brain, and pancreas development. Although pax6 is expressed in the whole prospective retinal field, subsequently its expression becomes restricted to the optic cup by reciprocal transcriptional repression of pax6 and pax2. However, it remains unclear how Pax6 protein is removed from the eyestalk territory on time. Here, we report that Mid1, a member of the RBCC/TRIM E3 ligase family, which was first identified in patients with the X-chromosome–linked Opitz BBB/G (OS) syndrome, interacts with Pax6. We found that the forming eyestalk is a major domain of mid1 expression, controlled by the morphogen Sonic hedgehog (Shh). Here, Mid1 regulates the ubiquitination and proteasomal degradation of Pax6 protein. Accordantly, when Mid1 levels are knocked down, Pax6 expression is expanded and eyes are enlarged. Our findings indicate that remaining or misaddressed Pax6 protein is cleared from the eyestalk region to properly set the border between the eyestalk territory and the retina via Mid1. Thus, we identified a posttranslational mechanism, regulated by Sonic hedgehog, which is important to suppress Pax6 activity and thus breaks pax6 autoregulation at defined steps during the formation of the visual system.

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Gonzalez-Quevedo, Rosa, Marina Shoffer, Lily Horng y Anthony E. Oro. "Receptor tyrosine phosphatase–dependent cytoskeletal remodeling by the hedgehog-responsive gene MIM/BEG4". Journal of Cell Biology 168, n.º 3 (31 de enero de 2005): 453–63. http://dx.doi.org/10.1083/jcb.200409078.

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During development, dynamic remodeling of the actin cytoskeleton allows the precise placement and morphology of tissues. Morphogens such as Sonic hedgehog (Shh) and local cues such as receptor protein tyrosine phosphatases (RPTPs) mediate this process, but how they regulate the cytoskeleton is poorly understood. We previously identified Basal cell carcinoma–enriched gene 4 (BEG4)/Missing in Metastasis (MIM), a Shh-inducible, Wiskott-Aldrich homology 2 domain–containing protein that potentiates Gli transcription (Callahan, C.A., T. Ofstad, L. Horng, J.K. Wang, H.H. Zhen, P.A. Coulombe, and A.E. Oro. 2004. Genes Dev. 18:2724–2729). Here, we show that endogenous MIM is induced in a patched1-dependent manner and regulates the actin cytoskeleton. MIM functions by bundling F-actin, a process that requires self-association but is independent of G-actin binding. Cytoskeletal remodeling requires an activation domain distinct from sequences required for bundling in vitro. This domain associates with RPTPδ and, in turn, enhances RPTPδ membrane localization. MIM-dependent cytoskeletal changes can be inhibited using a soluble RPTPδ-D2 domain. Our data suggest that the hedgehog-responsive gene MIM cooperates with RPTP to induce cytoskeletal changes.

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40

Mukhopadhyay, Saikat, Xiaohui Wen, Navneet Ratti, Alexander Loktev, Linda Rangell, Suzie J. Scales y Peter K. Jackson. "The Ciliary G-Protein-Coupled Receptor Gpr161 Negatively Regulates the Sonic Hedgehog Pathway via cAMP Signaling". Cell 152, n.º 1-2 (enero de 2013): 210–23. http://dx.doi.org/10.1016/j.cell.2012.12.026.

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Xie, Chen, Pen-Jen Lin y Jijun Hao. "Eggmanone Effectively Overcomes Prostate Cancer Cell Chemoresistance". Biomedicines 9, n.º 5 (12 de mayo de 2021): 538. http://dx.doi.org/10.3390/biomedicines9050538.

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Prostate cancer chemoresistance is a major therapeutic problem, and the underlying mechanism is not well understood and effective therapies to overcome this problem are not available. Phosphodiesterase-4 (PDE4), a main intracellular enzyme for cAMP hydrolysis, has been previously shown to involve in the early chemo-sensitive prostate cancer cell proliferation and progression, but its role in the more-advanced chemo-resistant prostate cancer is completely unknown. Here we found that the expression of PDE4 subtype, PDE4D, is highly elevated in the chemo-resistant prostate cancer cells (DU145-TxR and PC3-TxR) in comparison to the chemo-sensitive prostate cancer cells (DU145 and PC3). Inhibition of PDE4D with a potent and selective PDED4 inhibitor, Eggmanone, effectively decreases the invasion and proliferation as well as induces cell death of the chemo-resistant prostate cancer cells (DU145-TxR and PC3-TxR). These results were confirmed by siRNA knockdown of PDE4D. We and colleagues previously reported that Eggmanone can effectively blocked sonic Hedgehog signaling via PDE4D inhibition, and here our study suggests that that Eggmanone downregulated proliferation of the chemo-resistant prostate cancer cells via sonic Hedgehog signaling. In addition, Eggmanone treatment dose-dependently increases docetaxel cytotoxicity to DU145-TxR and PC3-TxR. As cancer stem cells (CSCs) are known to be implicated in cancer chemoresistance, we further examined Eggmanone impacts on CSC-like properties in the chemo-resistant prostate cancer cells. Our study shows that Eggmanone effectively down-regulates the expression of CSCs’ marker genes Nanog and ABC sub-family G member 2 (ABCG2) and attenuates sphere formation in DU145-TxR and PC3-TxR cells. In summary, our work shows that Eggmanone effectively overcomes the chemoresistance of prostate cancer cells presumably through sonic Hedgehog signaling and targeting CSCs, suggesting that Eggmanone may serve as a novel agent for chemo-resistant prostate cancer.

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42

Heller, Daniel A., Daniel Tylawsky y G. Praveen Raju. "Abstract 1992: P-selectin-targeted delivery of intracranial therapeutics across an intact BBB in Sonic Hedgehog medulloblastoma". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 1992. http://dx.doi.org/10.1158/1538-7445.am2023-1992.

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Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor with ~30% mediated by Sonic hedgehog (SHH) signaling. While SHH effector Smoothened inhibition is promising, therapeutic index is reduced by high systemic doses required for sufficient intracranial drug concentrations. Treatment-related toxicities associated with radiation therapy result in lifelong morbidity, and SHH pathway inhibition in children notably results in permanent bone defects. Here, we found that nanoparticle-mediated P-selectin targeting on tumor vasculature induces caveolin-1-dependent transcellular passage across the blood-brain barrier. A vismodegib nanocarrier that targets P-selectin exhibited striking efficacy and markedly reduced both bone-related toxicities and drug exposure to healthy brain. These findings demonstrate a potent strategy and novel mechanism for targeted intracranial pharmacodelivery that overcomes the restrictive endothelial barrier to achieve enhanced tumor-selective penetration and has therapeutic implications for other diseases within the central nervous system. Citation Format: Daniel A. Heller, Daniel Tylawsky, G. Praveen Raju. P-selectin-targeted delivery of intracranial therapeutics across an intact BBB in Sonic Hedgehog medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1992.

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43

Zakharova, Galina, Alexander Modestov, Polina Pugacheva, Rijalda Mekic, Ekaterina Savina, Anastasia Guryanova, Anastasia Rachkova et al. "Distinct Traits of Structural and Regulatory Evolutional Conservation of Human Genes with Specific Focus on Major Cancer Molecular Pathways". Cells 12, n.º 9 (2 de mayo de 2023): 1299. http://dx.doi.org/10.3390/cells12091299.

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The evolution of protein-coding genes has both structural and regulatory components. The first can be assessed by measuring the ratio of non-synonymous to synonymous nucleotide substitutions. The second component can be measured as the normalized proportion of transposable elements that are used as regulatory elements. For the first time, we characterized in parallel the regulatory and structural evolutionary profiles for 10,890 human genes and 2972 molecular pathways. We observed a ~0.1 correlation between the structural and regulatory metrics at the gene level, which appeared much higher (~0.4) at the pathway level. We deposited the data in the publicly available database RetroSpect. We also analyzed the evolutionary dynamics of six cancer pathways of two major axes: Notch/WNT/Hedgehog and AKT/mTOR/EGFR. The Hedgehog pathway had both components slower, whereas the Akt pathway had clearly accelerated structural evolution. In particular, the major hub nodes Akt and beta-catenin showed both components strongly decreased, whereas two major regulators of Akt TCL1 and CTMP had outstandingly high evolutionary rates. We also noticed structural conservation of serine/threonine kinases and the genes related to guanosine metabolism in cancer signaling: GPCRs, G proteins, and small regulatory GTPases (Src, Rac, Ras); however, this was compensated by the accelerated regulatory evolution.

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Shimada, Issei S., Sun-Hee Hwang, Bandarigoda N. Somatilaka, Xin Wang, Patryk Skowron, Jiwoong Kim, Min Kim et al. "Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis". Cell Reports 22, n.º 5 (enero de 2018): 1169–84. http://dx.doi.org/10.1016/j.celrep.2018.01.018.

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Amin, A., Y. Li y R. Finkelstein. "Hedgehog activates the EGF receptor pathway during Drosophila head development". Development 126, n.º 12 (15 de junio de 1999): 2623–30. http://dx.doi.org/10.1242/dev.126.12.2623.

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The Hedgehog (Hh) and Epidermal growth factor receptor (EGFR) signaling pathways play critical roles in pattern formation and cell proliferation in invertebrates and vertebrates. In this study, we demonstrate a direct link between these two pathways in Drosophila melanogaster. Hh and EGFR signaling are each required for the formation of a specific region of the head of the adult fruitfly. We show that hh and vein (vn), which encodes a ligand of the Drosophila EGFR (Schnepp, B., Grumbling, G., Donaldson, T. and Simcox, A. (1996) Genes Dev. 10, 2302–13), are expressed in adjacent domains within the imaginal primordium of this region. Using loss- and gain-of-function approaches, we demonstrate that Hh activates vn expression. We also show that Hh activation of vn is mediated through the gene cubitus interruptus (ci) and that this activation requires the C-terminal region of the Ci protein. Finally, we demonstrate that wingless (wg) represses vn expression, thereby limiting the domain of EGFR signaling.

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46

Shyamala, Baragur V. y Krishna Moorthi Bhat. "A positive role for Patched-Smoothened signaling in promoting cell proliferation during normal head development in Drosophila". Development 129, n.º 8 (15 de abril de 2002): 1839–47. http://dx.doi.org/10.1242/dev.129.8.1839.

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The transmembrane receptor Patched regulates several developmental processes in both invertebrates and vertebrates. In vertebrates, Patched also acts as a tumor suppressor. The Patched pathway normally operates by negatively regulating Smoothened, a G-protein-coupled receptor; binding of Hedgehog ligand to Patched relieves this negative interaction and allows signaling by Smoothened. We show that Ptc regulates Drosophila head development by promoting cell proliferation in the eye-antennal disc. During head morphogenesis, Patched positively interacts with Smoothened, which leads to the activation of Activin type I receptor Baboon and stimulation of cell proliferation in the eye-antennal disc. Thus, loss of Ptc or Smoothened activity affects cell proliferation in the eye-antennal disc and results in adult head capsule defects. Similarly, reducing the dose of smoothened in a patched background enhances the head defects. Consistent with these results, gain-of-function Hedgehog interferes with the activation of Baboon by Patched and Smoothened, leading to a similar head capsule defect. Expression of an activated form of Baboon in the patched domain in a patched mutant background completely rescues the head defects. These results provide insight into head morphogenesis, a process we know very little about, and reveal an unexpected non-canonical positive signaling pathway in which Patched and Smoothened function to promote cell proliferation as opposed to repressing it.

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Doheny, Daniel, Sara G. Manore, Grace L. Wong y Hui-Wen Lo. "Hedgehog Signaling and Truncated GLI1 in Cancer". Cells 9, n.º 9 (17 de septiembre de 2020): 2114. http://dx.doi.org/10.3390/cells9092114.

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The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.

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Li, Fenghe, Molly Duman-Scheel, Dong Yang, Wei Du, Jian Zhang, Chenchao Zhao, Lingfeng Qin y Shijie Xin. "Sonic Hedgehog Signaling Induces Vascular Smooth Muscle Cell Proliferation via Induction of the G 1 Cyclin-Retinoblastoma Axis". Arteriosclerosis, Thrombosis, and Vascular Biology 30, n.º 9 (septiembre de 2010): 1787–94. http://dx.doi.org/10.1161/atvbaha.110.208520.

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Hammerschmidt, Matthias y Andrew P. McMahon. "The Effect of Pertussis Toxin on Zebrafish Development: A Possible Role for Inhibitory G-Proteins in Hedgehog Signaling". Developmental Biology 194, n.º 2 (febrero de 1998): 166–71. http://dx.doi.org/10.1006/dbio.1997.8796.

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Arveseth, Corvin D., John T. Happ, Danielle S. Hedeen, Ju-Fen Zhu, Jacob L. Capener, Dana Klatt Shaw, Ishan Deshpande et al. "Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits". PLOS Biology 19, n.º 4 (22 de abril de 2021): e3001191. http://dx.doi.org/10.1371/journal.pbio.3001191.

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The Hedgehog (Hh) pathway is essential for organ development, homeostasis, and regeneration. Dysfunction of this cascade drives several cancers. To control expression of pathway target genes, the G protein–coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here, we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase (GRK)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus. This process is more fundamentally similar between species than prevailing hypotheses suggest. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology.

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