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Malignant Neoplasms
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Mark Biro, Vesna Petronic-Rosic
Overview: BCC is the most common human cancer. The average age of patients diagnosed with BCC is 60 years old, with a higher incidence in men. Additional risk factors include ultraviolet light exposure, immunosuppression, solid organ transplant, fair skin complexion, xeroderma pigmentosum, albinism, and basal cell nevus syndrome. Tumorigenesis involves mutations that activate the sonic hedgehog protein (SHH) and promote the binding of SHH to the PTCH1 receptor. The binding of SHH to PTCH1 prevents PTCH1 inhibition of both SMO and cyclin proteins. Without inhibition from PTCH1, SMO promotes continuous activation of the SHH pathway. Cyclin proteins enter the cell nucleus and bind to genes to promote constitutive cell growth. The understanding of this pathway has allowed for the development of targeted therapy.
Fetal Alcohol Syndrome
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Margaret P. Adam, H. Eugene Hoyme
Mutations in many different genes have been found to cause holoprosencephaly. Mutations in the gene Sonic Hedgehog (SHH) have been found to account for 3.7% of all cases of holoprosencephaly and about 17% of cases of familial holoprosencephaly (30-32). The Sonic Hedgehog protein is a signaling molecule that initiates a cascade of events that eventually leads to activation and transcription of a group of target genes. The pattern of Shh expression in vertebrates is largest in the developing head region (33). In the mouse, gene expression of Shh has been found, among other places, in the notochord and floorplate of the neural tube. In addition, disruption of the Shh gene expression in the mouse has been found to cause cyclopia with absence of the ventral neural tube cells (30). More recently, in 2002, Ahlgren et al. (33) demonstrated a marked downregulation of Shh in chick embryos exposed to alcohol at embryonic stage 9–10, with resultant cranial neural crest cell death and decreased size of the frontonasal mass. This effect could be rescued by administration of Shh protein. In addition, they found similar craniofacial phenotypes in chick embryos treated with antibodies that block Shh signaling. Therefore, data from Ahlgren et al. (33) support the theory that alcohol causes neural crest cell death, possibly by inhibiting the Sonic Hedgehog pathway, therefore leading to many of the craniofacial and neurodevelopmental abnormalities observed in FAS.
Hedgehog signaling in spermatogenesis and male fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Sandeep Kumar Bansal, Meghali Joshi, Rajender Singh
Sonic hedgehog protein in humans is encoded by the SHH gene. This gene has been found to have the most critical roles in development via patterning many systems, such as limbs, brain, spinal cord, lungs, thalamus and teeth. The expression of this gene has also been linked to some specific cancerous tumors, such as embryonic cerebellar tumors, medulloblastoma and the progression of prostate cancer tumors. A few studies have been conducted on the role of the shh gene in spermatogenesis; however, the significance of the Shh gene in spermatogenesis is not clear. Recently, Zou et al. studied a case report of a cryptorchid man and checked Shh signaling in mice and patient with obstructive azoospermia and a patient with prostate cancer (15). They reported Shh immunostaining in spermatocytes of juvenile and adult mouse testis and in patients with obstructive azoospermia and prostate cancer. Earlier, Turner et al. revealed that Shh signaling genes are expressed and transcribed in adult mouse epididymis (16). From these studies, it is clear that the shh gene is expressed in human and mouse testis; however, their expression and roles at different stages of spermatogenesis remain unclear. Earlier, Yuasa et al. found that sonic hedgehog is involved in osteoblast differentiation by cooperating with BMP-2 (17). Similarly, the expression of Shh in mouse and human spermatocytes may be associated with germ cell differentiation. Moreover, Amankulor et al. revealed that acute brain injury activates sonic hedgehog signaling (18). Chen et al. reported that sonic hedgehog signaling has a protective role in endotoxin-induced acute lung injury in a mouse model (19). Shh signaling has been found in the adult immune system, participating in CD4+ T-lymphocyte activation. Shh expression is also upregulated in acute lung injury (20). These studies indicate that sonic hedgehog may have some crucial roles in the testis, like repairing testicular injuries.
Extracellular vesicles in type 2 diabetes mellitus: key roles in pathogenesis, complications, and therapy
Published in Journal of Extracellular Vesicles, 2019
Yongwei Xiao, Lei Zheng, Xiaofeng Zou, Jigang Wang, Jianing Zhong, Tianyu Zhong
Previously, Deng et al. [59] found that the retinal binding protein 4 (RBP4)-containing EVs derived from adipose tissue of obese mice could stimulate the differentiation of monocytes into M1 macrophages through the TLR4/TRIF pathway. These M1 macrophages could increase the secretion of both TNF-α and IL-6, which might induce insulin resistance in myocytes. Subsequently, it was confirmed that the EVs differentiating monocytes into M1 macrophages came from adipocytes [60]. These adipocyte-derived EVs was found to contain adiponectin, an adipocyte-specific protein, and show clear enrichment of some pro-inflammatory cytokines such as TNF-α and RBP-4. Recently, Zhang et al. [61] observed that adipocyte-derived EVs from obese mice could induce M1 macrophage phenotype and cause insulin resistance in the adipocyte. The EVs secreted by adipocytes were delivered to bone marrow macrophages (BMMs), and the miR-155 in these EVs could effectively induce BMMs polarization toward M1 phenotypes by targeting SOCS1 and regulating the JAK/STAT pathway. Similarly, Song et al. [62] revealed that the sonic hedgehog protein carried by mice adipocyte-EVs could mediate BMMs to M1 macrophage polarization through the Ptch/PI3K pathway, possibly contributing to insulin resistance in adipocytes. Furthermore, high concentration of pro-inflammatory cytokines (including IL-6, MCP-1, RBP-4, and adiponectin) contained in the EVs of adipose tissue from obese patients was found to induce insulin resistance in hepatocytes and myocytes [63].
Emerging therapeutic options for periorbital and orbital cutaneous basal and squamous cell carcinomas
Published in Orbit, 2023
Edward J. Wladis, Stephen H. Wrzesinski, Michael I. Rothschild, Alejandro P. Adam
The patched-1 cell surface receptor (PTCH) typically inhibits the activity of a protein called smoothened (SMO). However, when the sonic hedgehog protein binds to PTCH, SMO is activated, resulting in angiogenesis and cellular proliferation.11 Notably, patients with Gorlin syndrome suffer from a mutation in PTCH that results in disinhibition of SMO, thereby inducing the development of basal cell carcinomas. Moreover, 90% of sporadic basal cell carcinomas are characterized by the loss of function of the PTCH gene.12 Based on these considerations, inhibition of the hedgehog pathway is a meaningful mechanism to address unresectable basal cell carcinomas and three hedgehog inhibitors are currently in use.
Emerging drugs for the treatment of basal cell carcinoma
Published in Expert Opinion on Emerging Drugs, 2021
Florian Herms, Nicole Basset-Seguin
Sonic hedgehog (Shh) pathway activation is a key pathophysiological event in BCC formation. PTCH1 is a transmembrane protein, which negatively regulates SMO, another transmembrane protein of Shh pathway. When PTCH1 binds to its ligand, such as sonic hedgehog protein, SMO is relieved, migrates to the cilium and activate Gli transcription factors (Figure 1). Activation of Shh pathway has been reported in BCNS, due to germline mutations on PTCH1 gene [4,5], and in sporadic BCC, with 90% of the tumors bearing somatic inactivating mutations of PTCH1 and 10% activation of SMO [6].