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  1. Book ; Online: Novel Therapeutic Targets and Emerging Treatments for Fibrosis

    Hewitson, Timothy D. / Samuel, Chrishan S.

    2018  

    Abstract: For decades we have known that the overgrowth, hardening and scarring of tissues (so-called fibrosis) represents the final common pathway and best histological predictor of disease progression in most organs. Fibrosis is the culmination of both excess ... ...

    Abstract For decades we have known that the overgrowth, hardening and scarring of tissues (so-called fibrosis) represents the final common pathway and best histological predictor of disease progression in most organs. Fibrosis is the culmination of both excess extracellular matrix deposition due to ongoing or severe injury, and a failure to regenerate. An inadequate wound repair process ultimately results in organ failure through a loss of function, and is therefore a major cause of morbidity and mortality in disease affecting both multiple and individual organs.Whilst the pathology of fibrosis and its significance are well understood, until recently we have known little about its molecular regulation. Current therapies are often indirect and non-specific, and only slow progression by a matter of months.-

    The recent identification of novel therapeutic targets, and the development of new treatment strategies based on them, offers the exciting prospect of more efficacious therapies to treat this debilitating disorder.This Research Topic therefore compromises several up-to-date mini-reviews on currently known and emerging therapeutic targets for fibrosis including: the Transforming Growth Factor (TGF)-family; epigenetic factors; Angiotensin II type 2 (AT2) receptors; mineralocorticoid receptors; adenosine receptors; caveolins; and the sphingosine kinase/sphingosine 1-phosphate and notch signaling pathways. In each case, mechanistic insights into how each of these factors contribute to regulating fibrosis progression are described, along with how they can be targeted (by existing drugs, small molecules or other mimetics) to prevent and/or reverse fibrosis and its contribution to tissue dysfunction and failure.-

    Two additional reviews will discuss various anti-fibrotic therapies that have demonstrated efficacy at the experimental level, but are not yet clinically approved; and the therapeutic potential vs limitations of stem cell-based therapies for reducing fibrosis while facilitating tissue repair. Finally, this Research Topic concludes with a clinical perspective of various anti-fibrotic therapies for cardiovascular disease (CVD), outlining limitations of currently used therapies, the pipeline of anti-fibrotics for CVD and why so many anti-fibrotic drugs have failed at the clinical level
    Keywords Science (General) ; Therapeutics. Pharmacology
    Size 1 electronic resource (162 p.)
    Publisher Frontiers Media SA
    Document type Book ; Online
    Note English ; Open Access
    HBZ-ID HT020099568
    ISBN 9782889453726 ; 2889453723
    Database ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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  2. Article ; Online: Targeting angiopoietin-2 as a novel treatment option for kidney fibrosis.

    Samuel, Chrishan S

    Kidney international

    2022  Volume 102, Issue 4, Page(s) 691–694

    Abstract: Kidney fibrosis is a hallmark of chronic kidney disease yet is poorly treated. Chang et al. determined that plasma and kidney levels of the vascular growth factor, angiopoietin-2, were elevated in patients with chronic kidney disease and mice with kidney ...

    Abstract Kidney fibrosis is a hallmark of chronic kidney disease yet is poorly treated. Chang et al. determined that plasma and kidney levels of the vascular growth factor, angiopoietin-2, were elevated in patients with chronic kidney disease and mice with kidney disease. Angiopoietin-2 inhibited the renoprotective effects of angiopoietin-1 and promoted CC chemokine ligand 2-mediated kidney damage, endothelial cell apoptosis, vascular rarefaction, inflammation, fibrosis, and kidney dysfunction. Hence, therapeutically inhibiting angiopoietin-2 may represent a novel means of treating these chronic kidney disease-associated pathologies.
    MeSH term(s) Angiopoietin-1 ; Angiopoietin-2/metabolism ; Animals ; Chemokines, CC/metabolism ; Fibrosis ; Kidney/pathology ; Ligands ; Mice ; Renal Insufficiency, Chronic/pathology
    Chemical Substances Angiopoietin-1 ; Angiopoietin-2 ; Chemokines, CC ; Ligands
    Language English
    Publishing date 2022-09-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 120573-0
    ISSN 1523-1755 ; 0085-2538
    ISSN (online) 1523-1755
    ISSN 0085-2538
    DOI 10.1016/j.kint.2022.07.023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The involvement of the Wnt/β-catenin signaling cascade in fibrosis progression and its therapeutic targeting by relaxin.

    Somanader, Deidree V N / Zhao, Peishen / Widdop, Robert E / Samuel, Chrishan S

    Biochemical pharmacology

    2024  Volume 223, Page(s) 116130

    Abstract: Organ scarring, referred to as fibrosis, results from a failed wound-healing response to chronic tissue injury and is characterised by the aberrant accumulation of various extracellular matrix (ECM) components. Once established, fibrosis is recognised as ...

    Abstract Organ scarring, referred to as fibrosis, results from a failed wound-healing response to chronic tissue injury and is characterised by the aberrant accumulation of various extracellular matrix (ECM) components. Once established, fibrosis is recognised as a hallmark of stiffened and dysfunctional tissues, hence, various fibrosis-related diseases collectively contribute to high morbidity and mortality in developed countries. Despite this, these diseases are ineffectively treated by currently-available medications. The pro-fibrotic cytokine, transforming growth factor (TGF)-β
    MeSH term(s) Humans ; Relaxin/therapeutic use ; beta Catenin/metabolism ; Acute Disease ; Wnt Signaling Pathway ; Transforming Growth Factor beta1 ; Fibrosis
    Chemical Substances Relaxin (9002-69-1) ; beta Catenin ; Transforming Growth Factor beta1
    Language English
    Publishing date 2024-03-13
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 208787-x
    ISSN 1873-2968 ; 0006-2952
    ISSN (online) 1873-2968
    ISSN 0006-2952
    DOI 10.1016/j.bcp.2024.116130
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Immune Mechanisms and Related Targets for the Treatment of Fibrosis in Various Organs.

    Pinar, Anita A / Samuel, Chrishan S

    Current molecular medicine

    2022  Volume 22, Issue 3, Page(s) 240–249

    Abstract: Inflammation and fibrosis are two interrelated disease pathologies with several overlapping components. Three specific cell types, namely macrophages, T helper cells, and myofibroblasts, play important roles in regulating both processes. Following tissue ...

    Abstract Inflammation and fibrosis are two interrelated disease pathologies with several overlapping components. Three specific cell types, namely macrophages, T helper cells, and myofibroblasts, play important roles in regulating both processes. Following tissue injury, an inflammatory stimulus is often necessary to initiate tissue repair, where cytokines released from infiltrating and resident immune and inflammatory cells stimulate the proliferation and activation of extracellular matrix-producing myofibroblasts. However, persistent tissue injury drives an inappropriate pro-fibrotic response. Additionally, activated myofibroblasts can take on the role of traditional antigen-presenting cells, secrete pro-inflammatory cytokines, and recruit inflammatory cells to fibrotic foci, amplifying the fibrotic response in a vicious cycle. Moreover, inflammatory cells have been shown to play contradictory roles in the initiation, amplification, and resolution of fibrotic disease processes. The central role of the inflammasome molecular platform in contributing to fibrosis is only beginning to be fully appreciated. In this review, we discuss the immune mechanisms that can lead to fibrosis, the inflammasomes that have been implicated in the fibrotic process in the context of the immune response to injury, and also discuss current and emerging therapies that target inflammasome-induced collagen deposition to treat organ fibrosis.
    MeSH term(s) Cytokines/metabolism ; Fibrosis ; Humans ; Inflammasomes/metabolism ; Macrophages/metabolism ; Myofibroblasts/metabolism ; Myofibroblasts/pathology
    Chemical Substances Cytokines ; Inflammasomes
    Language English
    Publishing date 2022-01-27
    Publishing country Netherlands
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2064873-X
    ISSN 1875-5666 ; 1566-5240
    ISSN (online) 1875-5666
    ISSN 1566-5240
    DOI 10.2174/1566524022666220114122839
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Determination of Interstitial Collagen Deposition and Related Topography Using the Second Harmonic Generation-Based HistoIndex Platform.

    Bhuiyan, Sadman / Widdop, Robert E / Samuel, Chrishan S

    Methods in molecular biology (Clifton, N.J.)

    2023  Volume 2664, Page(s) 173–184

    Abstract: Interstitial fibrosis is characterized by the increased deposition of extracellular matrix (ECM) components within the interstitial space of various organs, such as the kidneys, heart, lungs, liver, and skin. The primary component of interstitial ... ...

    Abstract Interstitial fibrosis is characterized by the increased deposition of extracellular matrix (ECM) components within the interstitial space of various organs, such as the kidneys, heart, lungs, liver, and skin. The primary component of interstitial fibrosis-related scarring is interstitial collagen. Therefore, the therapeutic application of anti-fibrotic medication hinges on the accurate measurement of interstitial collagen levels within tissue samples. Current histological measurement techniques for interstitial collagen are generally semi-quantitative in nature and only provide a ratio of collagen levels within tissues. However, the Genesis™ 200 imaging system and supplemental image analysis software, FibroIndex™, from HistoIndex™, is a novel, automated platform for imaging and characterizing interstitial collagen deposition and related topographical properties of the collagen structures within an organ, in the absence of any staining. This is achieved by using a property of light known as second harmonic generation (SHG). Using a rigorous optimization protocol, collagen structures in tissue sections can be imaged with a high degree of reproducibility and ensures homogeneity across all samples while minimizing the introduction of any imaging artefacts or photobleaching (decreased tissue fluorescence due to prolonged exposure to the laser). This chapter outlines the protocol that should be undertaken to optimize HistoIndex scanning of tissue sections, and the outputs that can be measured and analyzed using the FibroIndex™ software.
    MeSH term(s) Collagen/analysis ; Collagen/metabolism ; Second Harmonic Generation Microscopy/methods ; Fibrosis/metabolism ; Fibrosis/pathology ; Software ; Microtomy ; Reproducibility of Results ; Photobleaching ; Artifacts ; Lasers ; Paraffin ; Animals ; Mice ; Kidney/metabolism ; Kidney/pathology
    Chemical Substances Collagen (9007-34-5) ; Paraffin (8002-74-2)
    Language English
    Publishing date 2023-07-07
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-3179-9_13
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Relaxin as an anti-fibrotic treatment: Perspectives, challenges and future directions.

    Samuel, Chrishan S / Bennett, Robert G

    Biochemical pharmacology

    2021  Volume 197, Page(s) 114884

    Abstract: Fibrosis refers to the scarring and hardening of tissues, which results from a failed immune system-coordinated wound healing response to chronic organ injury and which manifests from the aberrant accumulation of various extracellular matrix components ( ... ...

    Abstract Fibrosis refers to the scarring and hardening of tissues, which results from a failed immune system-coordinated wound healing response to chronic organ injury and which manifests from the aberrant accumulation of various extracellular matrix components (ECM), primarily collagen. Despite being a hallmark of prolonged tissue damage and related dysfunction, and commonly associated with high morbidity and mortality, there are currently no effective cures for its regression. An emerging therapy that meets several criteria of an effective anti-fibrotic treatment, is the recombinant drug-based form of the human hormone, relaxin (also referred to as serelaxin, which is bioactive in several other species). This review outlines the broad anti-fibrotic and related organ-protective roles of relaxin, mainly from studies conducted in preclinical models of ageing and fibrotic disease, including its ability to ameliorate several aspects of fibrosis progression and maturation, from immune cell infiltration, pro-inflammatory and pro-fibrotic cytokine secretion, oxidative stress, organ hypertrophy, cell apoptosis, myofibroblast differentiation and ECM production, to its ability to facilitate established ECM degradation. Studies that have compared and/or combined these therapeutic effects of relaxin with current standard of care medication have also been discussed, along with the main challenges that have hindered the translation of the anti-fibrotic efficacy of relaxin to the clinic. The review then outlines the future directions as to where scientists and several pharmaceutical companies that have recognized the therapeutic potential of relaxin are working towards, to progress its development as a treatment for human patients suffering from various fibrotic diseases.
    MeSH term(s) Animals ; Antifibrotic Agents/metabolism ; Antifibrotic Agents/pharmacology ; Antifibrotic Agents/therapeutic use ; Cell Differentiation/drug effects ; Cell Differentiation/physiology ; Fibrosis ; Forecasting ; Humans ; Oxidative Stress/drug effects ; Oxidative Stress/physiology ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Peptide/metabolism ; Relaxin/metabolism ; Relaxin/pharmacology ; Relaxin/therapeutic use
    Chemical Substances Antifibrotic Agents ; Receptors, G-Protein-Coupled ; Receptors, Peptide ; relaxin receptors ; Relaxin (9002-69-1)
    Language English
    Publishing date 2021-12-27
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 208787-x
    ISSN 1873-2968 ; 0006-2952
    ISSN (online) 1873-2968
    ISSN 0006-2952
    DOI 10.1016/j.bcp.2021.114884
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Anti-inflammatory and anti-fibrotic effects of berberine-loaded liquid crystalline nanoparticles.

    Chakraborty, Amlan / Paudel, Keshav Raj / Wang, Chao / De Rubis, Gabriele / Chellappan, Dinesh Kumar / Hansbro, Philip Michael / Samuel, Chrishan S / Dua, Kamal

    EXCLI journal

    2023  Volume 22, Page(s) 1104–1108

    Language English
    Publishing date 2023-10-26
    Publishing country Germany
    Document type Journal Article
    ISSN 1611-2156
    ISSN 1611-2156
    DOI 10.17179/excli2023-6467
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Enhancing the Therapeutic Potential of Mesenchymal Stromal Cell-Based Therapies with an Anti-Fibrotic Agent for the Treatment of Chronic Kidney Disease

    Yifang Li / Sharon D. Ricardo / Chrishan S. Samuel

    International Journal of Molecular Sciences, Vol 23, Iss 6035, p

    2022  Volume 6035

    Abstract: Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that ... ...

    Abstract Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that reverse or even halt its progression. In recent years, human bone-marrow-derived mesenchymal stromal cells (BM-MSCs) have been recognised as a novel therapy for CKDs, owing to their well-established immunomodulatory and tissue-reparative properties in preclinical settings, and their promising safety profile that has been demonstrated in patients with CKDs from several clinical trials. However, renal fibrosis (scarring), a hallmark of CKD, has been shown to impair the viability and functionality of BM-MSCs post-transplantation. This has suggested that BM-MSCs might require a pre-treatment or adjunct therapy that can enhance the viability and therapeutic efficacy of these stromal cells in chronic disease settings. To address this, recent studies that have combined BM-MSCs with the anti-fibrotic drug serelaxin (RLX), have demonstrated the enhanced therapeutic potential of this combination therapy in normotensive and hypertensive preclinical models of CKD. In this review, a critical appraisal of the preclinical data available on the anti-fibrotic and renoprotective actions of BM-MSCs or RLX alone and when combined, as a treatment option for normotensive vs. hypertensive CKD, is discussed.
    Keywords chronic kidney disease ; fibrosis ; bone-marrow-derived mesenchymal stromal cells ; relaxin ; wound repair ; angiogenesis ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Enhancing the Therapeutic Potential of Mesenchymal Stromal Cell-Based Therapies with an Anti-Fibrotic Agent for the Treatment of Chronic Kidney Disease.

    Li, Yifang / Ricardo, Sharon D / Samuel, Chrishan S

    International journal of molecular sciences

    2022  Volume 23, Issue 11

    Abstract: Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that ... ...

    Abstract Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that reverse or even halt its progression. In recent years, human bone-marrow-derived mesenchymal stromal cells (BM-MSCs) have been recognised as a novel therapy for CKDs, owing to their well-established immunomodulatory and tissue-reparative properties in preclinical settings, and their promising safety profile that has been demonstrated in patients with CKDs from several clinical trials. However, renal fibrosis (scarring), a hallmark of CKD, has been shown to impair the viability and functionality of BM-MSCs post-transplantation. This has suggested that BM-MSCs might require a pre-treatment or adjunct therapy that can enhance the viability and therapeutic efficacy of these stromal cells in chronic disease settings. To address this, recent studies that have combined BM-MSCs with the anti-fibrotic drug serelaxin (RLX), have demonstrated the enhanced therapeutic potential of this combination therapy in normotensive and hypertensive preclinical models of CKD. In this review, a critical appraisal of the preclinical data available on the anti-fibrotic and renoprotective actions of BM-MSCs or RLX alone and when combined, as a treatment option for normotensive vs. hypertensive CKD, is discussed.
    MeSH term(s) Antifibrotic Agents ; Fibrosis ; Humans ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells ; Renal Insufficiency, Chronic/drug therapy
    Chemical Substances Antifibrotic Agents
    Language English
    Publishing date 2022-05-27
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms23116035
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Functional crosstalk between angiotensin receptors (types 1 and 2) and relaxin family peptide receptor 1 (RXFP1): Implications for the therapeutic targeting of fibrosis.

    Samuel, Chrishan S / Li, Yifang / Wang, Yan / Widdop, Robert E

    British journal of pharmacology

    2022  

    Abstract: Class A, rhodopsin-like, G-protein-coupled receptors (GPCRs) are by far the largest class of GPCRs and are integral membrane proteins used by various cells to convert extracellular signals into intracellular responses. Initially, class A GPCRs were ... ...

    Abstract Class A, rhodopsin-like, G-protein-coupled receptors (GPCRs) are by far the largest class of GPCRs and are integral membrane proteins used by various cells to convert extracellular signals into intracellular responses. Initially, class A GPCRs were believed to function as monomers, but a growing body of evidence has emerged to suggest that these receptors can function as homodimers and heterodimers and can undergo functional crosstalk to influence the actions of agonists or antagonists acting at each receptor. This review will focus on the angiotensin type 1 (AT
    Language English
    Publishing date 2022-12-22
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1111/bph.16019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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