Platelet-derived serotonin links vascular disease and tissue fibrosis

Vascular damage and platelet activation are associated with tissue remodeling in diseases such as systemic sclerosis, but the molecular mechanisms underlying this association have not been identified. In this study, we show that serotonin (5-hydroxytryptamine [5-HT]) stored in platelets strongly induces extracellular matrix synthesis in interstitial fibroblasts via activation of 5-HT2B receptors (5-HT2B) in a transforming growth factor β (TGF-β)–dependent manner. Dermal fibrosis was reduced in 5-HT2B−/− mice using both inducible and genetic models of fibrosis. Pharmacologic inactivation of 5-HT2B also effectively prevented the onset of experimental fibrosis and ameliorated established fibrosis. Moreover, inhibition of platelet activation prevented fibrosis in different models of skin fibrosis. Consistently, mice deficient for TPH1, the rate-limiting enzyme for 5-HT production outside the central nervous system, showed reduced experimental skin fibrosis. These findings suggest that 5-HT/5-HT2B signaling links vascular damage and platelet activation to tissue remodeling and identify 5-HT2B as a novel therapeutic target to treat fibrotic diseases.

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Notch-ing up knowledge on molecular mechanisms of skin fibrosis: focus on the multifaceted Notch signalling pathway

Journal of Biomedical Science ◽

10.1186/s12929-021-00732-8 ◽

2021 ◽

Vol 28 (1) ◽

Author(s):

Angelo Giuseppe Condorelli ◽

May El Hachem ◽

Giovanna Zambruno ◽

Alexander Nystrom ◽

Eleonora Candi ◽

...

Keyword(s):

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Notch Pathway ◽

Transforming Growth Factor Β1 ◽

Notch Signalling ◽

Skin Fibrosis ◽

Molecular Networks ◽

Dependent Manner ◽

Wide Range ◽

Health And Disease

AbstractFibrosis can be defined as an excessive and deregulated deposition of extracellular matrix proteins, causing loss of physiological architecture and dysfunction of different tissues and organs. In the skin, fibrosis represents the hallmark of several acquired (e.g. systemic sclerosis and hypertrophic scars) and inherited (i.e. dystrophic epidermolysis bullosa) diseases. A complex series of interactions among a variety of cellular types and a wide range of molecular players drive the fibrogenic process, often in a context-dependent manner. However, the pathogenetic mechanisms leading to skin fibrosis are not completely elucidated. In this scenario, an increasing body of evidence has recently disclosed the involvement of Notch signalling cascade in fibrosis of the skin and other organs. Despite its apparent simplicity, Notch represents one of the most multifaceted, strictly regulated and intricate pathways with still unknown features both in health and disease conditions. Starting from the most recent advances in Notch activation and regulation, this review focuses on the pro-fibrotic function of Notch pathway in fibroproliferative skin disorders describing molecular networks, interplay with other pro-fibrotic molecules and pathways, including the transforming growth factor-β1, and therapeutic strategies under development.

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The Role of BMP Signaling in Endothelial Heterogeneity

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.673396 ◽

2021 ◽

Vol 9 ◽

Author(s):

Orjin Han ◽

Boryeong Pak ◽

Suk-Won Jin

Keyword(s):

Bone Morphogenetic Proteins ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Bmp Signaling ◽

Molecular Characteristics ◽

Dependent Manner ◽

Comprehensive Overview ◽

Endothelial Heterogeneity ◽

Context Dependent

Bone morphogenetic proteins (BMPs), which compose the largest group of the transforming growth factor-β (TGF-ß) superfamily, have been implied to play a crucial role in diverse physiological processes. The most intriguing feature of BMP signaling is that it elicits heterogeneous responses from cells with equivalent identity, thus permitting highly context-dependent signaling outcomes. In endothelial cells (ECs), which are increasingly perceived as a highly heterogeneous population of cells with respect to their morphology, function, as well as molecular characteristics, BMP signaling has shown to elicit diverse and often opposite effects, illustrating the innate complexity of signaling responses. In this review, we provide a concise yet comprehensive overview of how outcomes of BMP signaling are modulated in a context-dependent manner with an emphasis on the underlying molecular mechanisms and summarize how these regulations of the BMP signaling promote endothelial heterogeneity.

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Pomalidomide is effective for prevention and treatment of experimental skin fibrosis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2012-201784 ◽

2012 ◽

Vol 71 (11) ◽

pp. 1895-1899 ◽

Cited By ~ 23

Author(s):

Simon Weingärtner ◽

Pawel Zerr ◽

Michal Tomcik ◽

Katrin Palumbo-Zerr ◽

Alfiya Distler ◽

...

Keyword(s):

Target Genes ◽

Transforming Growth Factor ◽

Skin Fibrosis ◽

Dependent Manner ◽

Preclinical Models ◽

Treatment Regimes ◽

Dermal Fibrosis ◽

Tight Skin ◽

Dermal Thickness ◽

First Time

ObjectivesTissue fibrosis is a major hallmark and a leading cause of death in systemic sclerosis (SSc). Here, we investigated the antifibrotic effects of pomalidomide, an analogue of thalidomide with potent immunomodulatory effects, in preclinical models of skin fibrosis.MethodsWe evaluated the antifibrotic effects of pomalidomide in preventive as well as therapeutic treatment regimes using bleomycin-induced dermal fibrosis as a model of early, inflammatory stages of fibrosis and the tight-skin mouse model as a model of later stages of fibrosis with endogenous activation of fibroblasts.ResultsTreatment with pomalidomide in doses from 0.3 to 30 mg/kd/day prevented skin fibrosis in Tsk-1 mice and in bleomycin-induced dermal fibrosis in a dose-dependent manner and reduced the expression of transforming growth factor (TGF) β-target genes such as PAI-1, CTGF and col 1a1. Pomalidomide was also effective in the setting of pre-established fibrosis and reduced dermal thickness, myofibroblast counts and hydroxyproline content below pretreatment levels.ConclusionsWe demonstrate for the first time that pomalidomide exerts potent antifibrotic effects in different preclinical models of skin fibrosis. These findings lend preclinical support for the clinical studies of pomalidomide in SSc.

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Expression and function of Smad7 in autoimmune and inflammatory diseases

Journal of Molecular Medicine ◽

10.1007/s00109-021-02083-1 ◽

2021 ◽

Author(s):

Yiping Hu ◽

Juan He ◽

Lianhua He ◽

Bihua Xu ◽

Qingwen Wang

Keyword(s):

Posttranscriptional Regulation ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Inflammatory Diseases ◽

Kidney Diseases ◽

Critical Role ◽

Transforming Growth Factor Β ◽

Negative Regulator ◽

Signaling Mechanism ◽

And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

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The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies

Gastrointestinal Tumors ◽

10.1159/000514614 ◽

2021 ◽

pp. 1-8

Author(s):

Mahmood Tavakkoli ◽

Saeed Aali ◽

Borzoo Khaledifar ◽

Gordon A. Ferns ◽

Majid Khazaei ◽

...

Keyword(s):

Angiotensin Ii ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Therapeutic Potential ◽

Angiotensin Receptor Blockers ◽

Surgical Techniques ◽

Treatment Strategies ◽

Transforming Growth Factor Β

Background: Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions. Summary: Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem. Key Message: The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.

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The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽

10.3390/biom9090476 ◽

2019 ◽

Vol 9 (9) ◽

pp. 476 ◽

Cited By ~ 4

Author(s):

Chia-Jung Li ◽

Pei-Yi Chu ◽

Giou-Teng Yiang ◽

Meng-Yu Wu

Keyword(s):

Epithelial Cells ◽

Tumor Progression ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Transforming Growth Factor Β ◽

Inhibition Of Proliferation ◽

Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

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Intracisternal administration of transforming growth factor-β evokes fever through the induction of cyclooxygenase-2 in brain endothelial cells

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00181.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. R266-R275 ◽

Cited By ~ 3

Author(s):

Shigenobu Matsumura ◽

Tetsuro Shibakusa ◽

Teppei Fujikawa ◽

Hiroyuki Yamada ◽

Kiyoshi Matsumura ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Growth Factor ◽

Proinflammatory Cytokines ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cyclooxygenase 2 ◽

Dependent Manner ◽

Cox 2 ◽

Β Receptor

Transforming growth factor-β (TGF-β), a pleiotropic cytokine, regulates cell proliferation, differentiation, and apoptosis, and plays a key role in development and tissue homeostasis. TGF-β functions as an anti-inflammatory cytokine because it suppresses microglia and B-lymphocyte functions, as well as the production of proinflammatory cytokines. However, we previously demonstrated that the intracisternal administration of TGF-β induces fever like that produced by proinflammatory cytokines. In this study, we investigated the mechanism of TGF-β-induced fever. The intracisternal administration of TGF-β increased body temperature in a dose-dependent manner. Pretreatment with cyclooxygenase-2 (COX-2)-selective inhibitor significantly suppressed TGF-β-induced fever. COX-2 is known as one of the rate-limiting enzymes of the PGE2 synthesis pathway, suggesting that fever induced by TGF-β is COX-2 and PGE2 dependent. TGF-β increased PGE2 levels in cerebrospinal fluid and increased the expression of COX-2 in the brain. Double immunostaining of COX-2 and von Willebrand factor (vWF, an endothelial cell marker) revealed that COX-2-expressing cells were mainly endothelial cells. Although not all COX-2-immunoreactive cells express TGF-β receptor, some COX-2-immunoreactive cells express activin receptor-like kinase-1 (ALK-1, an endothelial cell-specific TGF-β receptor), suggesting that TGF-β directly or indirectly acts on endothelial cells to induce COX-2 expression. These findings suggest a novel function of TGF-β as a proinflammatory cytokine in the central nervous system.

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Gene expression profiling of bovine endometrium during the oestrous cycle: detection of molecular pathways involved in functional changes

Journal of Molecular Endocrinology ◽

10.1677/jme.1.01799 ◽

2005 ◽

Vol 34 (3) ◽

pp. 889-908 ◽

Cited By ~ 92

Author(s):

S Bauersachs ◽

S E Ulbrich ◽

K Gross ◽

S E M Schmidt ◽

H H D Meyer ◽

...

Keyword(s):

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Cdna Array ◽

Transforming Growth Factor Β ◽

Early Embryo ◽

Oestrous Cycle ◽

Cdna Libraries ◽

Functional Changes ◽

Retinoic Acid Signalling ◽

Subtracted Cdna Libraries

The endometrium plays a central role among the reproductive tissues in the context of early embryo–maternal communication and pregnancy. It undergoes typical changes during the sexual/oestrous cycle, which are regulated by the ovarian hormones progesterone and oestrogen. To identify the underlying molecular mechanisms we have performed the first holistic screen of transcriptome changes in bovine intercaruncular endometrium at two stages of the cycle – end of day 0 (late oestrus, low progesterone) and day 12 (dioestrus, high progesterone). A combination of subtracted cDNA libraries and cDNA array hybridisation revealed 133 genes showing at least a 2-fold change of their mRNA abundance, 65 with higher levels at oestrus and 68 at dioestrus. Interestingly, genes were identified which showed differential expression between different uterine sections as well. The most prominent example was the UTMP (uterine milk protein) mRNA, which was markedly upregulated in the cranial part of the ipsilateral uterine horn at oestrus. A Gene Ontology classification of the genes with known function characterised the oestrus time by elevated expression of genes, for example related to cell adhesion, cell motility and extracellular matrix and the dioestrus time by higher expression of mRNAs encoding for a variety of enzymes and transport proteins, in particular ion channels. Searching in pathway databases and literature data-mining revealed physiological processes and signalling cascades, e.g. the transforming growth factor-β signalling pathway and retinoic acid signalling, which are potentially involved in the regulation of changes of the endometrium during the oestrous cycle.

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Dichotomous roles of TGF-β in human cancer

Biochemical Society Transactions ◽

10.1042/bst20160065 ◽

2016 ◽

Vol 44 (5) ◽

pp. 1441-1454 ◽

Cited By ~ 44

Author(s):

Jennifer J. Huang ◽

Gerard C. Blobe

Keyword(s):

Signaling Pathway ◽

Cancer Progression ◽

Transforming Growth Factor ◽

Human Cancer ◽

Transforming Growth Factor Β ◽

Dependent Manner ◽

Biological Processes ◽

Cellular Homeostasis ◽

Angiogenic Therapy ◽

Promising Strategy

Transforming growth factor-β (TGF-β) mediates numerous biological processes, including embryonic development and the maintenance of cellular homeostasis in a context-dependent manner. Consistent with its central role in maintaining cellular homeostasis, inhibition of TGF-β signaling results in disruption of normal homeostatic processes and subsequent carcinogenesis, defining the TGF-β signaling pathway as a tumor suppressor. However, once carcinogenesis is initiated, the TGF-β signaling pathway promotes cancer progression. This dichotomous function of the TGF-β signaling pathway is mediated through altering effects on both the cancer cells, by inducing apoptosis and inhibiting proliferation, and the tumor microenvironment, by promoting angiogenesis and inhibiting immunosurveillance. Current studies support inhibition of TGF-β signaling either alone, or in conjunction with anti-angiogenic therapy or immunotherapy as a promising strategy for the treatment of human cancers.

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