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Transforming Growth Factor-β/Smad Signaling in Myocardial Disease
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Claudio Humeres, Nikolaos G. Frangogiannis
On a functional basis, the Smads are classified into three groups: (1) the receptor-activated Smads (R-Smads: Smad1, Smad2, Smad3, Smad5, and Smad8); (2) the common Smad (Co-Smad: Smad4); and (3) the inhibitory Smads (I-Smads: Smad6 and Smad7)12. Upon TGFβ-induced ALK5 activation, the R-Smads Smad2 and Smad3 are recruited to the TGF-β complex by the auxiliary adaptor protein SARA (SMAD anchor for receptor activation), which facilitates the interaction of the catalytic region of TβRI with the carboxyl MH2 domain of the R-Smads, leading to R-Smad phosphorylation in the C-terminal SXSS motif13. R-Smad phosphorylation induces a conformational change in the MH2 domain, enabling its dissociation from TβRI/SARA and subsequent association with Smad414. Finally, nuclear localization signal (NLS) motifs in the amino-terminal MH1 domain of the R-Smad/Smad4 complex allow its translocation to the nucleus, where it binds to Smad-binding elements or GC-rich sequences in the promoter regions of TGFβ effector genes, regulating the transcription of target genes15. Typically, ALK5 signaling triggers Smad2 and Smad3 activation, whereas ALK1 signaling activates Smad1/5; these two cascades have been suggested to play antagonistic roles in certain cell types16,17.
Ursolic Acid: A Pentacyclic Triterpene from Plants in Nanomedicine
Published in Mahfoozur Rahman, Sarwar Beg, Mazin A. Zamzami, Hani Choudhry, Aftab Ahmad, Khalid S. Alharbi, Biomarkers as Targeted Herbal Drug Discovery, 2022
Monalisha Sen Gupta, Md. Adil Shaharyar, Mahfoozur Rahman, Kumar Anand, Imran Kazmi, Muhammad Afzal, Sanmoy Karmakar
UA is rarely employed for bone tissue regeneration as the few studies were performed in the field of bone tissue repair. Most importantly, osteoblast differentiation also involves the Smad signaling pathway. The release profile of UA from the suitable incornorated dosage form remarkably increased the alkaline phosphatase (ALP) activity, osteogenic differentiation-related gene type I collagen, runt-related transcription factor 2 expression, and osteoblast-associated protein expression. Moreover, the results of micro-CT images, observations from histomornhological data demonstrated that the UA in a suitable dosage form can improve new bone formation ability. Therefore, the UA can be used as novel bone tissue engineering materials by incorporating into a suitable matrix.
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).
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.
Baicalin protects against renal interstitial fibrosis in mice by inhibiting the TGF-β/Smad signalling pathway
Published in Pharmaceutical Biology, 2022
Hui Wang, Qingtao Jiang, Lizhu Zhang
Activation of TGF-β/Smad exerts a vital effect on the progression of RIF (Chen L et al. 2018). Smad proteins act as intracellular signalling mediators of TGF-β. Therefore, the protein expression of Smad2, and Smad3, and the levels of phosphorylation of Smad2 and Smad3, as well as TGF-β, were investigated by western blotting. The results showed that compared with the sham group, the UUO group showed obviously increased levels of phosphorylated Smad2 and Smad3. In addition, the UUO group exhibited higher levels of TGF-β protein expression. Baicalin treatment decreased the activated phosphorylation of Smad2 (79.4% decrease) and Smad3 (75.4% decrease) in a dose-dependent manner. Similarly, the levels of TGF-β protein expression were reduced (66.3% decrease) with baicalin treatment in a dose-dependent manner. These findings indicate that baicalin inhibited the activation of the TGF-β/Smad pathway (Figure 4(A,B)).
Circulating levels of transforming growth factor beta-1, 2 and 3 in HIV associated preeclamptic pregnancies
Published in Journal of Obstetrics and Gynaecology, 2022
Zamahlabangane Mtshali, Nalini Govender, Thajasvarie Naicker
TGF-β signalling occurs via membrane-bound serine and threonine receptor kinases type I (TBRI) and type II (TBRII), which form a heterocomplex (Huang and Chen 2012). The phosphorylation of TBRII activates TBRI (Huang and Chen 2012), which leads to the phosphorylation of R-SMAD 2/3 proteins, enabling TGF-β and activin signalling (Wrighton et al. 2009). Additionally, the phosphorylation of SMADs 1, 7 or 8 enables bone morphogenetic protein signalling whereas SMAD2/4 activates transcription of the target gene (Attisano and Wrana 2002). The SMAD7 protein in contrast antagonises TGF-β signalling by inducing receptor degradation (Park 2005). It is possible that the lack of significant difference in our study may be attributed to the inhibitory effect of receptor-SMAD interaction. Furthermore, receptor-activated SMAD2 proteins are highly expressed early in the 1st-trimester placenta, indicative of active TGF-β signalling; not term as in our study (Xu et al. 2016). Also amplified SMAD-dependent and independent TGF-β signalling in early-onset preeclampsia (EOPE), is characterised by elevated phosphorylated SMAD2 and reduced SMAD7 expression (Xu et al. 2016). The positive correlations between TGF-β isoforms in normotensive and PE pregnancies with/without HIV infection observed in our study may be attributed to SMAD dysregulation/mutation thus affecting signalling.