Mechanisms of Chronic Glomerular Injury
Robin S. Goldstein in Mechanisms of Injury in Renal Disease and Toxicity, 2020
Both paracrine and autocrine mechanisms govern mesangial cell proliferation. The list of mitogenic growth factors and inhibitors continues to lengthen. Mitogenic agents include: PDGF, insulin, IGF-1, EGF, TGF-α, TGF-β (low concentration), bFGF, endothelin, serotonin, arginine vasopressin, thrombin, fibronectin, and PGF2α. Potential inhibitors include TGF-β (high concentration), IFN-α, cAMP, heparin, atrial natriuretic peptide, PGI2, and PGE2. After having demonstrated in vitro the potential reaction patterns of mesangial cells, sometimes with contradictory results, a main goal of future investigation will be to elucidate which of these mechanisms is of importance in the in vivo situation. Platelets and macrophages (vide supra) with their array of mediators are likely candidates to become key cells in these investigations, with the initial data of depletion studies supporting this assumption.133–135
Endothelins in the Lung
Sami I. Said in Proinflammatory and Antiinflammatory Peptides, 2020
ET-1 can act as a mitogen in human and animal airway smooth muscle cells, since it stimulated [3H]-thymidine incorporation into DNA, stimulated protein synthesis, enhanced the transient expression of protoocogenes such as c-fos, and increased cell number (196–200). This effect is relatively weak compared with those of other mitogens such as epidermal growth factor (EGF) (198). However, recent evidence indicates that ET-1 acts as a potent co-mitogen (200), an effect also described in other cell systems (201). In human airway smooth muscle cells, this action was mediated via ETa receptors, since mitogenic activity was inhibited by BQ-123 (200) and not induced by ET-3 (202). This is consistent with the presence of ETA receptors detected on human isolated airway smooth muscle (70,99). In rabbit cultured airway smooth muscle cells, ET-1-induced mitogenesis was associated with the activation of a pertussis-sensitive G protein coupled to the stimulation of phospholipase A2, and the generation of thromboxane A2 (196). Pertussis toxin-sensitive mitogen-activated protein (MAP) kinase has been linked to ET-1-induced DNA synthesis in bovine airway smooth muscle cells (203).
Regulation of Growth of Airway Smooth Muscle by Second Messenger Systems
Alastair G. Stewart in AIRWAY WALL REMODELLING in ASTHMA, 2020
Compelling evidence suggests a role for PtdIns 3-kinase and its lipid products in regulating various cellular functions that include mitogenesis.29 PtdIns 3-kinase, which consists of an 85-kDa regulatory subunit (p85) and a 110-kDa catalytic subunit (p110), is required for DNA synthesis induced by some, but not all, growth factors.56 In 3T3 fibroblasts, microinjection of cells with a neutralizing antibody to the p110 catalytic subunit of PtdIns 3-kinase completely inhibited PDGF- and EGF-induced mitogenesis.56 The role of PtdIns 3-kinase activation in modulating cell proliferation is cell-type specific. In some cells, bombesin and LPA, which induce cell proliferation by activating receptors coupled to G proteins, stimulated cell growth in the absence of PtdIns 3-kinase activity.29,56 Taken together, these studies suggest that mitogens may activate different intracellular signaling pathways in a cell-specific manner.
A patent review of pharmaceutical and therapeutic applications of oxadiazole derivatives for the treatment of chronic diseases (2013–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Abbas Hassan, Abid Hussain Khan, Faiza Saleem, Haseen Ahmad, Khalid Mohammed Khan
Many growth factors like mitogens and chemotactic agents play a vital role in cell growth, migration, proliferation, and invasion. In tissue culture, the medium for growing cells generally contains serum (e.g. fetal bovine serum). The serum also stimulates the migration and invasion of cancer cells and fibroblasts. Robust activation in gene transcription occurs by the treatment of cells with serum through serum response factor (SRF). Cirrhosis, diabetic nephropathy, and heart failure are characterized by the excess deposition of cellular matrix or fibrosis. Tissue fibrosis causes systematic sclerosis and idiopathic pulmonary fibrosis. The inhibitors of Rho- and myocardin-related transcription factors and serum response factor (Rho/MRTF/SRF)-mediated gene transcription can be used for the treatment of cancer and fibrotic disease. Recently, novel 2,5-disubstituted 1,3,4-oxadiazole derivatives have been reported to inhibit Rho/MRTF/SRF-mediated gene transcription. The biological activity of the 1,3,4-oxadiazole derivatives was estimated in the SRE.L luciferase reporter assay. Compounds 21, 22, and 23 showed excellent potent activity having IC50 values 0.0012 nM, 0.019 nM, and 0.02 nM, respectively (Figure 9) [29].
Endostatin in fibrosis and as a potential candidate of anti-fibrotic therapy
Published in Drug Delivery, 2021
Zequn Zhang, Xi Liu, Zhaolong Shen, Jun Quan, Changwei Lin, Xiaorong Li, Gui Hu
Platelet-derived growth factor (PDGF) is a major mitogenic agent. There are five PDGF subtypes: PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and PDGF-DD. PDGF receptor (PDGFR) is a transmembrane glycoprotein with tyrosine-protein kinase activity, including three kinds of dimers, αα, αβ, and ββ, which are composed of PDGF-α and PDGFR-β subunits in a certain way. PDGF-A and PDGF-C predominantly bind to PDGFR-α chain, PDGF-B binds to both -α and -β chains, and PDGF-D binds to the β chain only. PDGF functions depend not just on the concentration of the ligand but also on ligand binding to specific receptors. Mesenchymal cells are the principal site of PDGFRs expression. Once bound by ligands, PDGFRs are phosphorylated to activate transcription factors and diverse cytoplasmic signaling cascades, like Janus kinase, mitogen-activated protein kinase, p38, phospholipase C, and Ras GTPase activating protein, driving downstream gene expression and exerting biological effects (De Donatis et al. 2008; Klinkhammer et al. 2018; Papadopoulos & Lennartsson 2018; Sil et al. 2018).
Palbociclib and beyond for the treatment of HR + HER2- metastatic breast cancer: an Asian-Pacific perspective and practical management guide on the use of CDK4/6 inhibitors
Published in Current Medical Research and Opinion, 2020
Shaheenah Dawood, Joanne Wing-yan Chiu, Chiun-Sheng Huang, Shona Nag, Aumkhae Sookprasert, Yoon-Sim Yap, Mastura Md Yusof
Endocrine therapies targeting the estrogen receptor (ER) signaling pathway – the established first-line treatment for most patients – provide a median progression-free survival (mPFS) or time to progression of 6–15 months in ER + HER2- mBC7–12. However, the eventual development of resistance to antiestrogens, through deregulation of downstream or alternate mitogenic pathways, has spurred the development of new therapeutic targets with novel mechanisms of action and the use of combination strategies to overcome resistance. Recently, the co-targeting of pathways associated with endocrine resistance has proven promising. Combination endocrine therapies targeting the mammalian target of rapamycin (mTOR)13,14, cyclin-dependent kinases 4 and 6 (CDK4/6) pathways15–17 or PIK3CA-mutated breast cancer18 have all demonstrated efficacy in overcoming endocrine resistance. Here we will focus on the use of palbociclib, and other CDK4/6 inhibitors, in the management of patients with HR + HER2- mBC.
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