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Developmental Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James H. Tonsgard, Nikolas Mata-Machado
HHT has an autosomal dominant inheritance. Linkage analysis indicates at least five genes, four of which have been identified. The genes for HHT are located in the transforming growth factor beta (TGF-β) signaling pathway that regulates cell proliferation, differentiation, apoptosis, and migration. Mutations in endoglin or ENG, activin receptor-like kinase or ALK1/ACVRL, and Smad 4, cause JJT1, HHT2, and the combined juvenile polyposis HHT syndrome, respectively. Endoglin and ACVRL1 mutations are seen in roughly 85% of cases. Smad4 mutations are seen in less than 2% of cases. Mutations in bone morphogenetic 9 protein (BMP9 – GDF2 gene) have been reported in some patients. This gene exerts its effects by binding to specific endothelial cell surface receptors, which leads to the association of Smad proteins that regulate gene expression in endothelial cells. Approximately 15% of patients who appear to have HHT clinically do not have identifiable mutations. Additional genes are predicted on chromosome 5 (HHT3) and chromosome 7 (HHT4).
Molecular Pathways Regulating the Geometric Induction of Bone Formation
Published in Ugo Ripamonti, The Geometric Induction of Bone Formation, 2020
Members of the TGF-β superfamily, which includes the BMPs, are responsible for proliferation and differentiation of bone progenitors and the TGF-β isoforms are master regulators of mesenchymal cell fate and are involved in controlling early osteoblast differentiation (reviewed in Grafe et al. 2018). To transduce their signal, TGF-β ligands require two classes of serine/threonine kinase receptors, TGF-β receptor type I (TβRI), or ALK-5, and TGF-β receptor type II (TβRII) (Shi and Massagué 2003). The classical intracellular signalling pathway downstream of the receptors involves the Smad pathway (Feng and Derynck 2005). The Smads are composed of a group of receptor-regulated Smads (R-Smads), Smad1, 2, 3, 5 and 8, the inhibitory Smads (Smad6 and 7), and the common mediator Smad (co-Smad), Smad 4. Intracellular signalling initiates when TβRI phosphorylates R-Smads and the activated R-Smads heterodimerize with Smad-4, followed by translocation of the entire complex to the nucleus to drive transcriptional responses (Ross and Hill 2008).
Familial Pancreatic Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The SMAD4 (SMAD family member 4) gene on chromosome 18q21.2 spans 56.6 kb and encodes a 552 aa, 60 kDa protein (SMAD4) that is a member of the Smad family of signal transduction proteins. SMAD4 forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which, upon phosphorylation and activation by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling, take part in the regulation of target gene transcription. SMAD4 inactivation disrupts TGF-β signaling and results in tumorigenesis and metastatic recurrence of pancreatic cancer (60% of cases) as well as juvenile polyposis syndrome.
Epithelial cell dysfunction in chronic rhinosinusitis: the epithelial–mesenchymal transition
Published in Expert Review of Clinical Immunology, 2023
Jing Yuan, Ming Wang, Chengshuo Wang, Luo Zhang
Several drugs have been shown to be involved in the inhibition of both TGF-β1/Smad and non-Smad pathways. Fidarestat, an Aldose reductase inhibitor, which blocks TGF-β-induced activation of the PI3K/AKT/GSK3β pathway, also blocked Smad2/3 phosphorylation thereby improving EMT progression in asthmatic mice [95]. The herbal medicine Osthole can alleviate the TGF-β1-induced EMT process by inhibiting both MAPK and Smad2/3 pathway activation [104]. Propolis and Dioscin inhibited TGF-β1-induced activation in A549 cells and 16HBECs, respectively. Smad2 and AKT activation, therefore, prevented or treated EMT [105,106]. ICG001, an inhibitor of β-catenin, can increase the expression of E-cadherin and decrease the expression of TGF-β1, Snail, MMP-7, MMP-9, α-SMA, and Fibronectin, reversing the airway remodeling in epithelium with EMT [114].
Glaucoma – ‘A Stiff Eye in a Stiff Body’
Published in Current Eye Research, 2023
Sarah Powell, Mustapha Irnaten, Colm O’Brien
There are a number of pro-fibrotic molecules upregulated in glaucoma, including CTGF,75,82 TGF-ß, the matricellular protein TSP-1 and secreted protein acidic and rich in cysteine.47,75,83 TGFß, a pro-fibrotic cytokine84 is an important regulator of ECM synthesis and propagates ECM remodeling by activating Smad proteins (members of the signal transducer family) following its binding to serine/threonine kinase receptors.84 Smad protein activation results in their translocation to the nucleus where they subsequently function to regulate gene transcription.85,86 TGFß signaling can, of course, also be activated by pathways independent of Smad, in response to the binding of ligands. These non-canonical signaling pathways include MAPK, Rho-like GTPase, phosphatidylinositol-3-kinase and Ak strain transforming pathways.87,88 Several studies89,90 have demonstrated that TGFß plays an important role in wound healing processes in the eye. There is considerable evidence demonstrating that TGFß is overexpressed in the TM and LC regions as well as the aqueous humor of glaucoma patients, thereby suggesting a role for TGFß as a fundamental driver for the pathological deposition of ECM seen in glaucomatous eyes.91,92 TGFß inhibition is an attractive treatment therapy for many diseases such as glaucoma93 and may have implications for the management of glaucoma in the future.
A potential model of systemic sclerosis with pulmonary hypertension induced by monocrotaline plus bleomycin
Published in Clinical and Experimental Hypertension, 2022
Xia Fang, Chao He, Xudong Ni, Tianli Zhang, Qianyu Li, Yi Luo, Wei Long, Rui Wu
In addition to TNF-α, the cytokine TGF-β1 was also found in the serum of the rabbits after injection with MCT plus BLM (Figure 5). Generally, TGF-β1 is produced from injured or diseased tissues where it activates fibroblasts and facilitates extracellular matrix production (27,28). It is recognized by a heterodimeric receptor on the surface of the plasma membrane (the TGF-β type I and type II half-receptor) (29). Once activated, the interaction of the Smad2 and Smad3 transcription factors with the Smad4 transcription factor is triggered via phosphorylation, where together they translocate to the nucleus to induce gene transcription (30). Smads, the intracellular signaling effectors, induce gene expression responses, and the specificity and impressive versatility of Smad signaling depend on crosstalk from other pathways. TGF-β1/Smad signaling plays various biological roles in mammals (31). In this study, the level of serum TGF-β1 significantly increased (Figure 5), suggesting that the characteristics of SSc are due to TGF-β1/Smad2 signaling. However, further clarification of the detailed mechanism is needed.