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Journal, PD(L)-1 Biomarker, IO Biomarker: Relaxin gene delivery mitigates liver metastasis and synergizes with check point therapy. (Pubmed Central) - Oct 24, 2019
The combination of the RLN gene therapy with PD-L1 blockade immunotherapy further produces a synergistic anti-metastatic efficacy. Collectively, the targeted RLN gene therapy represents a highly efficient, safe, and versatile anti-metastatic modality, and is promising for clinical translation.
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Journal: Insulin-Like Peptide 3 (INSL3) Serum Concentration During Human Male Fetal Life. (Pubmed Central) - Oct 17, 2019
Testicular fetal INSL3 mRNA relative expression was low from weeks 14-16, rose significantly weeks 17 and 18, and returned to low levels at week 21. These findings further support the role of INSL3 in human testicular descent and could prove relevant in uncovering the pathophysiology of cryptorchidism.
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Journal: Androgen-dependent alternative mRNA isoform expression in prostate cancer cells. (Pubmed Central) - Oct 2, 2019
Importantly, analysis of transcriptome data from 497 tumour samples in the TGCA prostate adenocarcinoma (PRAD) cohort identified 13 mRNA isoforms (including TPD52, TACC2 and NDUFV3) that are differentially regulated in localised prostate cancer relative to normal tissue, and 3 ( OSBPL1A, CLK3 and TSC22D3) which change significantly with Gleason grade and tumour stage. Our findings dramatically increase the number of known androgen regulated isoforms in prostate cancer, and indicate a highly complex response to androgens in prostate cancer cells that could be clinically important.
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Journal: Effect of Relaxin Expression from an Alginate Gel-Encapsulated Adenovirus on Scar Remodeling in a Pig Model. (Pubmed Central) - Oct 2, 2019
Our findings dramatically increase the number of known androgen regulated isoforms in prostate cancer, and indicate a highly complex response to androgens in prostate cancer cells that could be clinically important. These results support a prominent role for RLX in scar remodeling and suggest that gel/Ad-RLX may have therapeutic effects on scar formation.
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SERELAXIN TO LOWER PORTAL PRESSURE (STOPP): A RANDOMIZED PHASE 2 PROOF-OF-CONCEPT STUDY (Hynes Convention Center, Hall B) - Sep 29, 2019 - Abstract #AASLD2019AASLD_1055;
P2
Future studies could evaluate effects in patients with less severe portal hypertension (HVPG 5-10 mmHg), in whom intrahepatic vascular resistance mainly contributes to increased portal pressure. ClinicalTrials.gov Identifier: NCT02669875.
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Journal: Genetic Determinants of Glycated Hemoglobin in Type 1 Diabetes. (Pubmed Central) - Sep 26, 2019
Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA in FinnDiane at genome-wide significance (P < 5 × 10)...A weighted genetic risk score created from 55 HbA associated variants from the literature was associated with HbA in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA may lead to better prevention of diabetic complications.
- |||||||||| Journal: Newer hormonal pharmacotherapies for heart failure. (Pubmed Central) - Sep 22, 2019
However, drugs targeting these novel pathways (aliskiren, tolvaptan, ularitide, serelaxin, bosentan, macitentan) failed to show mortality benefit...If proven to be efficacious in larger outcome trials, finerenone can be a valuable addition baseline HF therapy. More basic, translational, and phenotype specific clinical research is warranted to improve HF pharmacotherapy.
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Integration of Quantitative Proteomics and Metabolomics Reveal Mechanism of Tissue Hypoxia in a Chronic Ischemic-Hypoxic Rat Model (Exhibit Hall 2-3 - Henry B. Gonzalez Convention Center) - Sep 20, 2019 - Abstract #AABB2019AABB_403;
Additionally, other signaling pathways such as complement and coagulation cascades, GnRH signaling, relaxin signaling, protein processing in the endoplasmic reticulum, as well as AGE-RAGE signaling were markedly altered in the ischemic-hypoxic model, implying their involvement in tissue hypoxia... This study provides a view on the molecular networks of ischemic-hypoxic pathology and indicates that the omics strategy is a powerful approach to explore the mechanisms of hypoxia, thus it may serve as a new tool to tackle traditionally-unsolved clinical complications.
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Journal: Review: Mammary gland development in swine: embryo to early lactation. (Pubmed Central) - Sep 20, 2019
This growth is in response to estrogen, progesterone, prolactin and relaxin...Attempts to enhance milk production by manipulation of mammary development at stages before lactation generally have met with limited success. A more in depth understanding of the processes regulating porcine mammary gland morphogenesis at all stages of development is needed to make further progress.
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Clinical, Journal: Effects of Serelaxin in Patients with Acute Heart Failure. (Pubmed Central) - Aug 30, 2019
P3
In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).
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Biased Relaxin-RXFP1 Agonist ML290 Attenuates the Development of Pulmonary Hypertension (Zone 2, Science and Technology Hall) - Aug 21, 2019 - Abstract #AHA2019AHA_3984;
ML290, an allosteric activator of RXFP1 signaling, inhibits TGFβ-induced phenotypic modulation and demonstrates efficacy in experimental pulmonary hypertension. Biased small molecule RXFP1 agonism may be a promising approach for treating cardiopulmonary disease.
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Review, Journal: Effect of the peptides Relaxin, Neuregulin, Ghrelin and Glucagon-like peptide-1, on cardiomyocyte factors involved in the molecular mechanisms leading to diastolic dysfunction and/or heart failure with preserved ejection fraction. (Pubmed Central) - Aug 11, 2019
Ghrelin also reduces cardiac fibrosis. In summary, Glucagon-like peptide-1, Relaxin-2, Neuregulin-1, and Ghrelin each modify calcium dynamics, collagen expression, and myocardial fibrosis through attenuation of deleterious signaling cascades, and induction of adaptive pathways, representing potential therapeutic targets for HFpEF.
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Biomarker, Journal: Serum relaxin-2 as a novel biomarker for prostate cancer. (Pubmed Central) - Aug 3, 2019
In summary, Glucagon-like peptide-1, Relaxin-2, Neuregulin-1, and Ghrelin each modify calcium dynamics, collagen expression, and myocardial fibrosis through attenuation of deleterious signaling cascades, and induction of adaptive pathways, representing potential therapeutic targets for HFpEF. No abstract available
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Journal: Functionality of an absolutely conserved glycine residue in the chimeric relaxin family peptide R3/I5. (Pubmed Central) - Aug 3, 2019
In contrast to the effect on insulin family activity, D-Ala or D-Ser replacement had no detrimental effect on the binding and activation potencies of the mature R3/I5 towards both RXFP3 and RXFP4, suggesting that the conserved Gly residue is irrelevant to the relaxin family's activity. The present study revealed functionality of the conserved B-chain Gly residue for a relaxin family peptide for the first time, providing an overview of its contribution to foldability and activity of the insulin superfamily.
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Journal: Evidence for the role of INSL3 on sperm production in boars by passive immunisation. (Pubmed Central) - Jul 26, 2019
Insulin-like factor 3 (INSL3), previously called relaxin-like factor, is essential for foetal testis descent and has been implicated in sperm production in adult males...Antibody administration reduced testis weight and caused a fourfold increase in the frequency of apoptotic germ cells, which was associated with upregulation of the pro-apoptotic caspase 3 and BAX, and downregulation of the anti-apoptotic XIAP and BCL2, and a substantial marked reduction in sperm concentration. Neutralising INSL3 delivered by passive immunisation reduced testis weight and sperm concentration by inducing germ cell apoptosis, suggesting that INSL3 acts as a germ cell survival/anti-apoptotic factor in the maintenance of sperm production.
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Journal: Recent progress in the therapeutic role of serelaxin in vascular dysfunction. (Pubmed Central) - Jul 11, 2019
Subsequently, vascular effects of serelaxin and the underlying modes of action in comparison to other vasodilators are discussed. Finally, the usefulness of treatment with serelaxin in vascular dysfunction in different CV diseases, particularly due to oxidative stress, is explained.
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Journal: Cholesterol modulates the binding properties of human relaxin family peptide receptor 3 with its ligands. (Pubmed Central) - Jun 26, 2019
Thereafter, we demonstrated that two B-chain residues, B5Tyr and B12Arg, were primarily responsible for the increased binding potency of these antagonists with human RXFP3 under the cholesterol depletion condition. Our results suggest that cell membrane cholesterol interacts with human RXFP3 and modulates its ligand-binding properties, providing new insights into the influence of membrane lipids on RXFP3 function.
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Biomarker, Journal: Circulating Relaxin-1 Level Is a Surrogate Marker of Myocardial Fibrosis in HFrEF. (Pubmed Central) - Jun 25, 2019
RLN1 can have a biomarker role in ventricular fibrosis; furthermore, it may influence hemodynamic and vasomotor activity via neurohormonal mechanisms of action. Given these valuable findings, RLN1 may be targeted in anti-fibrotic therapeutics and in perioperative care of heart transplantation.
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Review, Journal: Systemic signalling and local effectors in developmental stability, body symmetry, and size. (Pubmed Central) - Jun 23, 2019
...Indeed, recent discoveries in the fruit fly have uncovered a conserved hormone of the insulin/IGF/relaxin family, Dilp8, that is responsible for stabilizing body size and symmetry in the face of growth perturbations...Loss of Dilp8-Lgr3 signaling renders flies incapable of detecting growth perturbations and thus maintaining a stable size and symmetry. These findings help to understand how size and symmetry of somatic tissues remain undeterred in noisy environments, after injury or illnesses, and in the presence of accumulated somatic mutations.
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Journal: Relaxin: reproductive safeguard turned cardiac? (Pubmed Central) - Jun 15, 2019
This assay can also be applied to some other plasma membrane receptors for pharmacological characterization of ligands in future studies. No abstract available
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Journal: Genome-Wide Scan Identifies Selection Signatures in Chinese Wagyu Cattle Using a High-Density SNP Array. (Pubmed Central) - Jun 4, 2019
...In addition, we identified several genes that are associated with body size and weight, including Bos taurus sorting nexin 29 (SNX29), Bos taurus zinc finger imprinted 2 (ZIM2), Bos taurus family with sequence similarity 110 member A (FAM110A), immune system, including Bos taurus toll like receptor 9 (TLR9), Bos taurus TAFA chemokine like family member 1 (TAFA1), Bos taurus glutathione peroxidase 8 (putative) (GPX8), Bos taurus interleukin 5 (IL5), Bos taurus PR domain containing 9 (PRDM9), Bos taurus glutamate ionotropic receptor kainate type subunit 2 (GRIK2) and feed intake efficiency, Bos taurus sodium voltage-gated channel alpha subunit 9 (SCN9A), Bos taurus relaxin family peptide/INSL5 receptor 4 (RXFP4), Bos taurus RNA polymerase II associated protein 3 (RPAP3)...Our findings imply that many genes were selected for important traits in Chinese Wagyu cattle. Moreover, these results can contribute to the understanding of the genetic basis of the studied traits during the formation of this population.
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Review, Journal: Modulation of forebrain function by nucleus incertus and relaxin-3/RXFP3 signaling. (Pubmed Central) - May 30, 2019
This review will focus on the key physiological process of oscillatory theta rhythm and the neural circuits that promote it during behavioral activation, highlighting the ability of NI and relaxin-3/RXFP3 signaling systems to modulate these circuits. A better understanding of these mechanisms may provide a way to therapeutically adjust malfunction of forebrain activity present in several pathological conditions.
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Journal: Central relaxin-3 receptor (RXFP3) activation impairs social recognition and modulates ERK-phosphorylation in specific GABAergic amygdala neurons. (Pubmed Central) - May 29, 2019
In parallel, we used immunoblotting to profile ERK phosphorylation dynamics in whole amygdala after RXFP3-A2 treatment; and multiplex histochemical labelling techniques to reveal that after RXFP3-A2 infusion and social interaction, pERK-immunopositive neurons in amygdala expressed vesicular GABA-transporter mRNA and displayed differential profiles of RXFP3 and oxytocin receptor mRNA. Overall, these findings demonstrate that central relaxin-3/RXFP3 signalling can modulate social recognition in rats via effects within the amygdala and likely interactions with GABA and oxytocin signalling.
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Journal: In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis. (Pubmed Central) - May 22, 2019
As an alternative approach, we generated novel ML290 analogues and tested their activity in the HEK293-RXFP1 cAMP assay and the human hepatic cell line LX-2. Differences in activity of compounds on cAMP activation compared with changes in expression of fibrotic markers indicate the need to better understand cell- and tissue-specific signaling mechanisms and their disease-relevant phenotypes in order to enable drug discovery.
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Review, Journal: Ischemic stroke and select adipose-derived and sex hormones: a review. (Pubmed Central) - May 22, 2019
This review aims to summarize some of the preclinical and clinical studies investigating the principle sex hormones, as well as select adipose-derived hormones, as risk factors or potential treatments for ischemic stroke. In addition, the potential for relaxin, a lesser studied sex hormone, as a novel treatment option for ischemic stroke is explored.
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Review, Journal: The biology and evolution of the Dilp8-Lgr3 pathway: A relaxin-like pathway coupling tissue growth and developmental timing control. (Pubmed Central) - May 17, 2019
The strong conservation of the relaxin pathway throughout animal evolution contrasts with instances of its complete loss in some clades, such as lepidopterans, which must coordinate growth and developmental timing using another mechanism. Research into these areas should generate exciting new insights into the biology of growth coordination, the evolution of the relaxin signaling pathway, and likely reveal unforeseen functions in other developmental stages.
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Journal: Relaxin induces up-regulation of ADAM10 metalloprotease in RXFP1-expressing cells by PI3K/AKT signaling. (Pubmed Central) - Apr 26, 2019
...H9c2 cardiomyocytes and NIH3T3 fibroblasts were incubated with human RLX-2 (17 nmol/l, 24 h) in presence or absence of the PI3K or Akt inhibitors wortmannin (WT, 100 nmol/l) and triciribine (TCN, 1 μmol/l)...RLX significantly increased Akt phosphorylation, ADAM10 and NICD expression, which were abolished by WT or TCN and did not occur with iRLX. These findings highlight a new receptor-specific signal transduction pathway of RLX.
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Journal: Loss of RXFP2 and INSL3 genes in Afrotheria shows that testicular descent is the ancestral condition in placental mammals. (Pubmed Central) - Apr 24, 2019
Furthermore, the absence of shared gene-inactivating mutations and our estimates that the loss of RXFP2 happened at different time points strongly suggest that testicular descent was lost independently in Afrotheria. Our results provide a molecular mechanism that explains the loss of testicular descent in afrotherians and, more generally, highlight how molecular vestiges can provide insights into the evolution of soft-tissue characters.
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Journal: Binding conformation and determinants of a single chain peptide antagonist at the relaxin-3 receptor RXFP3. (Pubmed Central) - Apr 24, 2019
We show that R3 B1-22R has a propensity to form a helical structure and modifications that support a helical conformation are functionally well tolerated while helix breakers such as proline residues disrupt binding. These data suggest the peptide adopts a helical conformation, like relaxin-3, upon binding to RXFP3 but that its smaller size allows it to penetrate deeper into the orthosteric binding site creating more extensive contacts with the receptor.
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