Relaxin Attenuates Organ Fibrosis an Angiotensin Type 2 Receptor Mechanism in Aged Hypertensive Female Rats.

Background: The antifibrotic effects of recombinant human relaxin (RLX) in the kidney are dependent on an interaction between its cognate receptor (RXFP1) and the angiotensin type 2 receptor (ATR) in male models of disease. Whether RLX has therapeutic effects, which are also mediated ATR, in hypertensive adult and aged/reproductively senescent females is unknown. Thus, we determined whether treatment with RLX provides cardiorenal protection an ATR-dependent mechanism in adult and aged female stroke-prone spontaneously hypertensive rats (SHRSPs).

Immune Mechanisms and Related Targets for the Treatment of Fibrosis in Various Organs.

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.

In Aged Females, the Enhanced Pressor Response to Angiotensin II Is Attenuated By Estrogen Replacement via an Angiotensin Type 2 Receptor-Mediated Mechanism.

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Pulmonary myeloid cell uptake of biodegradable nanoparticles conjugated with an anti-fibrotic agent provides a novel strategy for treating chronic allergic airways disease.

Asthma (chronic allergic airways disease, AAD) is characterized by airway inflammation (AI), airway remodeling (AWR) and airway hyperresponsiveness (AHR). Current treatments for AAD mainly focus on targeting AI and its contribution AHR, with the use of corticosteroids. However, there are no therapies for the direct treatment of AWR, which can contribute to airway obstruction, AHR and corticosteroid resistance independently of AI.

Combining mesenchymal stem cells with serelaxin provides enhanced renoprotection against 1K/DOCA/salt-induced hypertension.

Background And Purpose: Fibrosis is a hallmark of chronic kidney disease (CKD) that significantly contributes to renal dysfunction, and impairs the efficacy of stem cell-based therapies. This study determined whether combining bone marrow-derived mesenchymal stem cells (BM-MSCs) with the renoprotective effects of recombinant human relaxin (serelaxin) could therapeutically reduce renal fibrosis in mice with one kidney/deoxycorticosterone acetate/salt (1K/DOCA/salt)-induced hypertension, compared with the effects of the ACE inhibitor, perindopril.

Experimental Approach: Adult male C57BL/6 mice were uni-nephrectomised and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt) for 21 days.

Relaxin Can Mediate Its Anti-Fibrotic Effects by Targeting the Myofibroblast NLRP3 Inflammasome at the Level of Caspase-1.

Introduction: The NLRP3 inflammasome produces interleukin (IL)-1β and IL-18, which when chronically activated by transforming growth factor (TGF)-β1, contribute to fibrosis. The recombinant form of the anti-fibrotic hormone, relaxin (RLX), suppresses the pro-fibrotic influence of TGF-β1 and toll-like receptor (TLR)-4 on NLRP3 inflammasome priming and activity in human cardiac myofibroblasts and mice with cardiomyopathy. However, whether RLX also modulates components of the myofibroblast NLRP3 inflammasome remains unknown.

The anti-fibrotic actions of relaxin are mediated through AT R-associated protein phosphatases via RXFP1-AT R functional crosstalk in human cardiac myofibroblasts.

Fibrosis is a hallmark of several cardiovascular diseases. The relaxin family peptide receptor 1 (RXFP1) agonist, relaxin, has rapidly occurring anti-fibrotic actions which are mediated through RXFP1 and angiotensin II receptor crosstalk on renal and cardiac myofibroblasts. Here, we investigated whether this would allow relaxin to indirectly activate angiotensin II type 2 receptor (AT R)-specific signal transduction in primary human cardiac myofibroblasts (HCMFs).

Targeting the NLRP3 inflammasome to treat cardiovascular fibrosis.

Cardiovascular fibrosis refers to the scar tissue that develops in the injured heart and blood vessels from an aberrant wound healing response to organ injury or insult. Established fibrosis becomes a hallmark of chronic disease progression and a key contributor to tissue stiffness and dysfunction, which ultimately leads to heart failure. As wound healing and fibrotic responses to myocardial injury are multifactorial processes, current therapies that only target specific contributing factors to disease pathogenesis offer limited overall anti-fibrotic efficacy.

Inflammasomes-A Molecular Link for Altered Immunoregulation and Inflammation Mediated Vascular Dysfunction in Preeclampsia.

Preeclampsia (PE) is a pregnancy-specific multisystem disorder and is associated with maladaptation of the maternal cardiovascular system and abnormal placentation. One of the important characteristics in the pathophysiology of PE is a dysfunction of the placenta. Placental insufficiency is associated with poor trophoblast uterine invasion and impaired transformation of the uterine spiral arterioles to high capacity and low impedance vessels and/or abnormalities in the development of chorionic villi.

Assays for Measuring the Role of MIF in NLRP3 Inflammasome Activation.

Hallmarks of NLRP3 inflammasome activation include the cleavage and secretion of the mature forms of caspase-1, IL-1β, and IL-18 and aggregation of ASC into "specks." We have previously shown that macrophage migratory inhibitory factor (MIF) directly regulates activation of the NLRP3 inflammasome, inhibiting the release of interleukin (IL)-1α, IL-1β, and IL-18. Here we present protocols for studying activation of the NLRP3 inflammasome in human and mouse macrophages and peripheral blood mononuclear cells (PBMCs).

Serelaxin inhibits the profibrotic TGF-β1/IL-1β axis by targeting TLR-4 and the NLRP3 inflammasome in cardiac myofibroblasts.

The recombinant form of the peptide hormone relaxin, serelaxin (RLX), mediates its anti-fibrotic actions by impeding the profibrotic activity of cytokines including TGF-β1 and IL-1β. As IL-1β can be produced by the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domains-containing protein 3 (NLRP3) inflammasome, this study determined whether RLX targeted the inflammasome to inhibit the profibrotic TGF-β1/IL-1β axis in primary human cardiac myofibroblasts (HCMFs) and in mice with isoproterenol (ISO)-induced cardiomyopathy . HCMFs stimulated with TGF-β1 (5 ng/ml), LPS (100 ng/ml), and ATP (5 mM) (T+L+A) for 8 h, to induce the NLRP3 inflammasome, demonstrated significantly increased protein expression of markers of NLRP3 priming (NLRP3, apoptosis-associated speck-like protein containing a C-terminal caspase-recruitment domain, procaspase-1) and activity (IL-1β, IL-18).

Macrophage migration inhibitory factor is required for NLRP3 inflammasome activation.

Macrophage migration inhibitory factor (MIF) exerts multiple effects on immune cells, as well as having functions outside the immune system. MIF can promote inflammation through the induction of other cytokines, including TNF, IL-6, and IL-1 family cytokines. Here, we show that inhibition of MIF regulates the release of IL-1α, IL-1β, and IL-18, not by affecting transcription or translation of these cytokines, but via activation of the NLRP3 inflammasome.

PB1-F2 Peptide Derived from Avian Influenza A Virus H7N9 Induces Inflammation via Activation of the NLRP3 Inflammasome.

The emergence of avian H7N9 influenza A virus in humans with associated high mortality has highlighted the threat of a potential pandemic. Fatal H7N9 infections are characterized by hyperinflammation and increased cellular infiltrates in the lung. Currently there are limited therapies to address the pathologies associated with H7N9 infection and the virulence factors that contribute to these pathologies.

The immune modulatory peptide FhHDM-1 secreted by the helminth Fasciola hepatica prevents NLRP3 inflammasome activation by inhibiting endolysosomal acidification in macrophages.

The NLRP3 inflammasome is a multimeric protein complex that controls the production of IL-1β, a cytokine that influences the development of both innate and adaptive immune responses. Helminth parasites secrete molecules that interact with innate immune cells, modulating their activity to ultimately determine the phenotype of differentiated T cells, thus creating an immune environment that is conducive to sustaining chronic infection. We show that one of these molecules, FhHDM-1, a cathelicidin-like peptide secreted by the helminth parasite, Fasciola hepatica, inhibits the activation of the NLRP3 inflammasome resulting in reduced secretion of IL-1β by macrophages.

Activation of the NLRP3 inflammasome by IAV virulence protein PB1-F2 contributes to severe pathophysiology and disease.

The ability for a host to recognize infection is critical for virus clearance and often begins with induction of inflammation. The PB1-F2 of pathogenic influenza A viruses (IAV) contributes to the pathophysiology of infection, although the mechanism for this is unclear. The NLRP3-inflammasome has been implicated in IAV pathogenesis, but whether IAV virulence proteins can be activators of the complex is unknown.

Characterization of forebrain neurons derived from late-onset Huntington's disease human embryonic stem cell lines.

Huntington's disease (HD) is an incurable neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the Huntingtin (HTT) gene. Recently, induced pluripotent stem cell (iPSC) lines carrying atypical and aggressive (CAG60+) HD variants have been generated and exhibit disparate molecular pathologies. Here we investigate two human embryonic stem cell (hESC) lines carrying CAG37 and CAG51 typical late-onset repeat expansions in comparison to wildtype control lines during undifferentiated states and throughout forebrain neuronal differentiation.