Identification of Inhibitors of Thrombospondin 1 Activation of TGF-β

Suto, Mark J.; Gupta, Vandana V.; Mathew, Biji; Zhang, Wei; Pallero, Manuel A.; Murphy-Ullrich, Joanne E.

doi:10.1021/acsmedchemlett.9b00540

Cited by 14 publications

(4 citation statements)

References 13 publications

(28 reference statements)

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“…Antibodies to TGF-β ligand (both to individual and to all TGFβ isoforms) also exist, as do ligand traps (124,(129)(130)(131). Agents targeted at preventing L-TGF-β activation such as integrin inhibitors have already entered clinical trials of inflammatory diseases (125), and antibodies and small molecules blocking L-TGF-β are in preclinical development (132,133). Angiotensin converting enzyme inhibitors and angiotensin-II receptor blockers such as losartan has been evaluated in clinical trials of COVID-19 (NCT04312009 and NCT04312009) given their low cost, worldwide availability as approved drugs for hypertension and heart failure, and their potential modulation of surface expression of the ACE2 receptor where the SARS-CoV-2 spike protein binds for its cellular uptake route.…”

Section: Tgf-β Pathway Inhibitors May Ameliorate Tgf-β Driven Thrombo...mentioning

confidence: 99%

Microvascular significance of TGF-β axis activation in COVID-19

Arguinchona

Zagona-Prizio

Joyce

et al. 2023

Front. Cardiovasc. Med.

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As 2023 approaches, the COVID-19 pandemic has killed millions. While vaccines have been a crucial intervention, only a few effective medications exist for prevention and treatment of COVID-19 in breakthrough cases or in unvaccinated or immunocompromised patients. SARS-CoV-2 displays early and unusual features of micro-thrombosis and immune dysregulation that target endothelial beds of the lungs, skin, and other organs. Notably, anticoagulation improves outcomes in some COVID-19 patients. The protein transforming growth factor-beta (TGF-β1) has constitutive roles in maintaining a healthy microvasculature through its roles in regulating inflammation, clotting, and wound healing. However, after infection (including viral infection) TGF-β1 activation may augment coagulation, cause immune dysregulation, and direct a path toward tissue fibrosis. Dysregulation of TGF-β signaling in immune cells and its localization in areas of microvascular injury are now well-described in COVID-19, and such events may contribute to the acute respiratory distress syndrome and skin micro-thrombosis outcomes frequently seen in severe COVID-19. The high concentration of TGF-β in platelets and in other cells within microvascular thrombi, its ability to activate the clotting cascade and dysregulate immune pathways, and its pro-fibrotic properties all contribute to a unique milieu in the COVID-19 microvasculature. This unique environment allows for propagation of microvascular clotting and immune dysregulation. In this review we summarize the physiological functions of TGF-β and detail the evidence for its effects on the microvasculature in COVID-19. In addition, we explore the potential role of existing TGF-β inhibitors for the prevention and treatment of COVID-19 associated microvascular thrombosis and immune dysregulation.

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Section: Tgf-β Pathway Inhibitors May Ameliorate Tgf-β Driven Thrombo...mentioning

confidence: 99%

Microvascular significance of TGF-β axis activation in COVID-19

Arguinchona

Zagona-Prizio

Joyce

et al. 2023

Front. Cardiovasc. Med.

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“…Hypertrophic scars involve many types of prefibrotic cytokines, particularly the important regulatory factor TGF- β 1 which was found to be regulated by the matricellular protein THBS1 [ 20 , 21 ]. Although THBS1 is mainly released by activated platelets, it is also produced by other cells, such as fibroblasts, endothelial cells, and macrophages, during inflammation or stress [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of THBS1 on the Biological Function of Hypertrophic Scar Fibroblasts

Jiang

Guo

Lin

et al. 2020

BioMed Research International

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Hypertrophic scarring is a skin collagen disease that can occur following skin damage and is unlikely to heal or subside naturally. Since surgical treatment often worsens scarring, it is important to investigate the pathogenesis and prevention of hypertrophic scarring. Thrombospondin-1 (THBS1) is a matrix glycoprotein that can affect fibrosis by activating TGF-β1, which plays a key role in wound repair and tissue regeneration; therefore, we investigated the effects of THBS1 on the biological function of hypertrophic scar fibroblasts. THBS1 expression was measured in hypertrophic scars and adjacent tissues as well as normal fibroblasts, normal scar fibroblasts, and hypertrophic scar fibroblasts. In addition, THBS1 was overexpressed or silenced in hypertrophic scar fibroblasts to determine the effects of THBS1 on cell proliferation, apoptosis, and migration, as well as TGF-β1 expression. Finally, the role of THBS1 in hypertrophic scarring was confirmed in vivo using a mouse model. We found that THBS1 expression was increased in hypertrophic scar tissues and fibroblasts and promoted the growth and migration of hypertrophic scar fibroblasts as well as TGF-β1 expression. Interestingly, we found that si-THBS1 inhibited the occurrence and development of bleomycin-induced hypertrophic scars in vivo and downregulated TGF-β1 expression. Together, our findings suggest that THBS1 is abnormally expressed in hypertrophic scars and can induce the growth of hypertrophic scar fibroblasts by regulating TGF-β1. Consequently, THBS1 could be an ideal target for treating hypertrophic scarring.

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“…[42] Similarly, the half-life of LSKL is only 15 minutes, which greatly limits its clinical application. In order to improve the retention time of LSKL in vivo, researchers have structurally modified the LSKL peptide to obtain the small molecule SRI-35241, which has a half-life of 1.8 h. [43] However, it still struggles to meet clinical needs and new strategies have yet to be developed.…”

Section: Antifibrotic Peptides For the Treatment Of Liver Fibrosismentioning

confidence: 99%

Peptide‐Based Nanoarchitectonics for the Treatment of Liver Fibrosis

Huang

Zou

2023

ChemBioChem

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Liver fibrosis is a process of excessive accumulation of extracellular matrix caused by liver injury. Liver fibrosis can progress to cirrhosis or even liver cancer without proper intervention. Until now, no effective therapeutic drugs have been clinically approved for treating liver fibrosis. Hence, the development of safe and effective antifibrotic drugs is particularly important. As a representative biomaterial, peptides have been investigated as key components for constructing antifibrotic nanomaterials given their advantages of biological origination, synthetic availability, and good biocompatibility. Peptides serve as multifunctional motifs in antifibrotic nanomaterials, such as liver‐targeting molecules, antifibrotic molecules, and self‐assembling building blocks for the formation of the nanomaterials. In this review, we focus on peptide‐based nanoarchitectonics for treating liver fibrosis, including nanomaterials modified with liver‐targeting peptides, nanomaterials for the efficient delivery of antifibrotic peptides, and self‐assembled peptide nanomaterials for the delivery of antifibrotic drugs. The design rules of these peptide‐based nanomaterials are described. The antifibrotic mechanisms and effects of these peptide‐based nanomaterials in treating liver fibrosis and related diseases are highlighted. The challenges and future perspectives of using peptide‐based nanoarchitectonics for the treatment of liver fibrosis are discussed. These results are expected to accelerate the rational design and clinical translation of antifibrotic nanomaterials.

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Identification of Inhibitors of Thrombospondin 1 Activation of TGF-β

Cited by 14 publications

References 13 publications

Microvascular significance of TGF-β axis activation in COVID-19

Microvascular significance of TGF-β axis activation in COVID-19

Effect of THBS1 on the Biological Function of Hypertrophic Scar Fibroblasts

Peptide‐Based Nanoarchitectonics for the Treatment of Liver Fibrosis

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