-
Signal Transduction and Targeted Therapy Mar 2022Although the treatment of myocardial infarction (MI) has improved considerably, it is still a worldwide disease with high morbidity and high mortality. Whilst there is... (Review)
Review
Although the treatment of myocardial infarction (MI) has improved considerably, it is still a worldwide disease with high morbidity and high mortality. Whilst there is still a long way to go for discovering ideal treatments, therapeutic strategies committed to cardioprotection and cardiac repair following cardiac ischemia are emerging. Evidence of pathological characteristics in MI illustrates cell signaling pathways that participate in the survival, proliferation, apoptosis, autophagy of cardiomyocytes, endothelial cells, fibroblasts, monocytes, and stem cells. These signaling pathways include the key players in inflammation response, e.g., NLRP3/caspase-1 and TLR4/MyD88/NF-κB; the crucial mediators in oxidative stress and apoptosis, for instance, Notch, Hippo/YAP, RhoA/ROCK, Nrf2/HO-1, and Sonic hedgehog; the controller of myocardial fibrosis such as TGF-β/SMADs and Wnt/β-catenin; and the main regulator of angiogenesis, PI3K/Akt, MAPK, JAK/STAT, Sonic hedgehog, etc. Since signaling pathways play an important role in administering the process of MI, aiming at targeting these aberrant signaling pathways and improving the pathological manifestations in MI is indispensable and promising. Hence, drug therapy, gene therapy, protein therapy, cell therapy, and exosome therapy have been emerging and are known as novel therapies. In this review, we summarize the therapeutic strategies for MI by regulating these associated pathways, which contribute to inhibiting cardiomyocytes death, attenuating inflammation, enhancing angiogenesis, etc. so as to repair and re-functionalize damaged hearts.
Topics: Endothelial Cells; Hedgehog Proteins; Humans; Inflammation; Myocardial Infarction; Phosphatidylinositol 3-Kinases; Signal Transduction
PubMed: 35273164
DOI: 10.1038/s41392-022-00925-z -
Cold Spring Harbor Perspectives in... May 2017It has been a decade since it was discovered that primary cilia have an essential role in Hedgehog (Hh) signaling in mammals. This discovery came from screens in the... (Review)
Review
It has been a decade since it was discovered that primary cilia have an essential role in Hedgehog (Hh) signaling in mammals. This discovery came from screens in the mouse that identified a set of genes that are required for both normal Hh signaling and for the formation of primary cilia. Since then, dozens of mouse mutations have been identified that disrupt cilia in a variety of ways and have complex effects on Hedgehog signaling. Here, we summarize the genetic and developmental studies used to deduce how Hedgehog signal transduction is linked to cilia and the complex effects that perturbation of cilia structure can have on Hh signaling. We conclude by describing the current status of our understanding of the cell-type-specific regulation of ciliogenesis and how that determines the ability of cells to respond to Hedgehog ligands.
Topics: Animals; Cilia; Hedgehog Proteins; Mammals; Signal Transduction
PubMed: 27881449
DOI: 10.1101/cshperspect.a028175 -
Seminars in Cancer Biology Oct 2022Cell-cell communication through evolutionarily conserved signaling pathways governs embryonic development and adult tissue homeostasis. Deregulation of these signaling... (Review)
Review
Cell-cell communication through evolutionarily conserved signaling pathways governs embryonic development and adult tissue homeostasis. Deregulation of these signaling pathways has been implicated in a wide range of human diseases including cancer. One such pathway is the Hedgehog (Hh) pathway, which was originally discovered in Drosophila and later found to play a fundamental role in human development and diseases. Abnormal Hh pathway activation is a major driver of basal cell carcinomas (BCC) and medulloblastoma. Hh exerts it biological influence through a largely conserved signal transduction pathway from the activation of the GPCR family transmembrane protein Smoothened (Smo) to the conversion of latent Zn-finger transcription factors Gli/Ci proteins from their repressor (Gli/Ci) to activator (Gli/Ci) forms. Studies from model organisms and human patients have provided deep insight into the Hh signal transduction mechanisms, revealed roles of Hh signaling in a wide range of human cancers, and suggested multiple strategies for targeting this pathway in cancer treatment.
Topics: Animals; Humans; Hedgehog Proteins; Receptors, G-Protein-Coupled; Zinc Finger Protein GLI1; Signal Transduction; Transcription Factors; Neoplasms; Drosophila
PubMed: 33836254
DOI: 10.1016/j.semcancer.2021.04.003 -
Advances in Therapy Mar 2022Non-melanoma skin cancers, also known as keratinocyte tumors, have an increasing incidence worldwide, with basal cell carcinoma and squamous cell carcinoma being the... (Review)
Review
Non-melanoma skin cancers, also known as keratinocyte tumors, have an increasing incidence worldwide, with basal cell carcinoma and squamous cell carcinoma being the most represented ones. Although surgery represents the gold-standard treatment for both tumors, some cases can progress to an advanced or a metastatic state and targeted therapy is required. Hedgehog signaling pathway has an important role in the development of basal cell carcinoma, and its inhibition is the key to new treatment options available for the treatment of locally advanced and metastatic basal cell carcinoma. Cutaneous squamous cell carcinoma is the second most frequent malignant skin cancer; when presenting in advanced or metastatic stage, alternative treatments are required; cemiplimab is a human monoclonal antibody directed against programmed cell death-1 receptor that acts by blocking T-cell inactivation and is the first drug approved for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma. Studies evaluating pembrolizumab, ipilimumab and nivolumab as alternative treatments for advanced squamous cell carcinoma are still underway. Objective of this review is to analyze and discuss the novel therapies for advanced basal cell carcinoma and squamous cell carcinoma to obtain a sharper perspective of the available treatment options.
Topics: Adult; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Hedgehog Proteins; Humans; Programmed Cell Death 1 Receptor; Skin Neoplasms
PubMed: 35089534
DOI: 10.1007/s12325-022-02044-1 -
Biomolecules Jun 2022Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called... (Review)
Review
Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called ciliogenesis, which involves several mechanisms including planar cell polarity (PCP) and the Hedgehog (Hh) signaling pathway. Some gene complexes, such as BBSome or CPLANE (ciliogenesis and planar polarity effector), have been linked to ciliogenesis. CPLANE complex is composed of , and , which bind to and for cilia formation. Defects in these genes have been linked to a malfunction of intraflagellar transport and defects in the planar cell polarity, as well as defective activation of the Hedgehog signalling pathway. These faults lead to defective cilium formation, resulting in ciliopathies, including orofacial-digital syndrome (OFDS) and Bardet-Biedl syndrome (BBS). Considering the close relationship, between the CPLANE complex and cilium formation, it can be expected that defects in the genes that encode subunits of the CPLANE complex may be related to other ciliopathies.
Topics: Cell Polarity; Cilia; Ciliopathies; Hedgehog Proteins; Humans; Protein Transport
PubMed: 35740972
DOI: 10.3390/biom12060847 -
American Journal of Respiratory Cell... Aug 2022We previously identified a novel molecular subtype of idiopathic pulmonary fibrosis (IPF) defined by increased expression of cilium-associated genes, airway mucin gene ,...
We previously identified a novel molecular subtype of idiopathic pulmonary fibrosis (IPF) defined by increased expression of cilium-associated genes, airway mucin gene , and marker of basal cell airway progenitors. Here we show the association of and cilia gene expression in human IPF airway epithelial cells, providing further rationale for examining the role of cilium genes in the pathogenesis of IPF. We demonstrate increased multiciliogenesis and changes in motile cilia structure of multiciliated cells both in IPF and bleomycin lung fibrosis models. Importantly, conditional deletion of a cilium gene, Ift88 (intraflagellar transport 88), in Krt5 basal cells reduces Krt5 pod formation and lung fibrosis, whereas no changes are observed in Ift88 conditional deletion in club cell progenitors. Our findings indicate that aberrant injury-activated primary ciliogenesis and Hedgehog signaling may play a causative role in Krt5 pod formation, which leads to aberrant multiciliogenesis and lung fibrosis. This implies that modulating cilium gene expression in Krt5 cell progenitors is a potential therapeutic target for IPF.
Topics: Bleomycin; Cilia; Hedgehog Proteins; Humans; Idiopathic Pulmonary Fibrosis; Signal Transduction
PubMed: 35608953
DOI: 10.1165/rcmb.2021-0554OC -
Nature Communications Jul 2022Th17 cells are key drivers of autoimmune disease. However, the signaling pathways regulating Th17 polarization are poorly understood. Hedgehog signaling regulates cell...
Th17 cells are key drivers of autoimmune disease. However, the signaling pathways regulating Th17 polarization are poorly understood. Hedgehog signaling regulates cell fate decisions during embryogenesis and adult tissue patterning. Here we find that cell-autonomous Hedgehog signaling, independent of exogenous ligands, selectively drives the polarization of Th17 cells but not other T helper cell subsets. We show that endogenous Hedgehog ligand, Ihh, signals to activate both canonical and non-canonical Hedgehog pathways through Gli3 and AMPK. We demonstrate that Hedgehog pathway inhibition with either the clinically-approved small molecule inhibitor vismodegib or genetic ablation of Ihh in CD4T cells greatly diminishes disease severity in two mouse models of intestinal inflammation. We confirm that Hedgehog pathway expression is upregulated in tissue from human ulcerative colitis patients and correlates with Th17 marker expression. This work implicates Hedgehog signaling in Th17 polarization and intestinal immunopathology and indicates the potential therapeutic use of Hedgehog inhibitors in the treatment of inflammatory bowel disease.
Topics: Adult; Animals; Colitis, Ulcerative; Hedgehog Proteins; Humans; Mice; Signal Transduction; Th17 Cells; Virulence
PubMed: 35835905
DOI: 10.1038/s41467-022-31722-5 -
Open Biology Mar 2021Hedgehog acyltransferase (Hhat), a member of the membrane-bound -acyltransferase (MBOAT) family, catalyses the covalent attachment of palmitate to the N-terminus of... (Review)
Review
Hedgehog acyltransferase (Hhat), a member of the membrane-bound -acyltransferase (MBOAT) family, catalyses the covalent attachment of palmitate to the N-terminus of Hedgehog proteins. Palmitoylation is a post-translational modification essential for Hedgehog signalling. This review explores the mechanisms involved in Hhat acyltransferase enzymatic activity, similarities and differences between Hhat and other MBOAT enzymes, and the role of palmitoylation in Hedgehog signalling. and cell-based assays for Hhat activity have been developed, and residues within Hhat and Hedgehog essential for palmitoylation have been identified. In cells, Hhat promotes the transfer of palmitoyl-CoA from the cytoplasmic to the luminal side of the endoplasmic reticulum membrane, where Shh palmitoylation occurs. Palmitoylation is required for efficient delivery of secreted Hedgehog to its receptor Patched1, as well as for the deactivation of Patched1, which initiates the downstream Hedgehog signalling pathway. While Hhat loss is lethal during embryogenesis, mutations in Hhat have been linked to disease states or abnormalities in mice and humans. In adults, aberrant re-expression of Hedgehog ligands promotes tumorigenesis in an Hhat-dependent manner in a variety of different cancers, including pancreatic, breast and lung. Targeting hedgehog palmitoylation by inhibition of Hhat is thus a promising, potential intervention in human disease.
Topics: Acyltransferases; Animals; Hedgehog Proteins; Humans; Lipoylation; Neoplasms; Protein Processing, Post-Translational; Signal Transduction
PubMed: 33653085
DOI: 10.1098/rsob.200414 -
Actas Dermo-sifiliograficas Oct 2014In January 2012, vismodegib (Erivedge, manufactured by Genentech) became the first selective inhibitor of the Hedgehog signaling pathway to be approved by the US Food... (Review)
Review
In January 2012, vismodegib (Erivedge, manufactured by Genentech) became the first selective inhibitor of the Hedgehog signaling pathway to be approved by the US Food and Drug Administration for the treatment of locally advanced and metastatic basal cell carcinoma. The drug selectively binds to Smoothened, a 7-helix transmembrane receptor, thereby inhibiting activation of transcription factors of the glioma-associated oncogene family and suppressing tumor proliferation and growth. Studies published to date have assessed the efficacy of vismodegib according to clinical and radiologic outcomes but little information is available on the molecular mechanisms underpinning the proven clinical efficacy of the drug. This review will cover recent data on the Hedgehog signaling pathway and data from clinical trials with vismodegib in the treatment of basal cell carcinoma, and will consider its use in other types of tumor.
Topics: Anilides; Carcinoma, Basal Cell; Clinical Trials as Topic; Hedgehog Proteins; Humans; Pyridines; Signal Transduction; Skin Neoplasms
PubMed: 24359667
DOI: 10.1016/j.ad.2013.09.012 -
Cold Spring Harbor Perspectives in... Jun 2012Hedgehog proteins are intercellular signaling molecules that play a central role in animal development. In response to the signal, Gli zinc finger proteins are shuttled...
Hedgehog proteins are intercellular signaling molecules that play a central role in animal development. In response to the signal, Gli zinc finger proteins are shuttled along the primary cilium to the nucleus to activate target genes.
Topics: Animals; Hedgehog Proteins; Mice; Signal Transduction
PubMed: 22661636
DOI: 10.1101/cshperspect.a011221