- |||||||||| Reasanz (serelaxin) / Novartis
Preclinical, Journal: Potential therapeutic use of relaxin in accelerating closure of cranial bone defects in mice. (Pubmed Central) - Jul 8, 2020
An incidental finding was that relaxin appeared to enhance trabecular bone growth in an uninjured control bone (femur). Although the results of this study were not supportive of a therapeutic benefit for relaxin on calvarial defect closure, future investigation is needed employing different animal species and experimental models of bone fracture.
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[VIRTUAL] Identification and Characterization of a Distal Enhancer in RXFP1 Gene (ATS 2020 Virtual) - Jul 6, 2020 - Abstract #ATSI2020ATS-I_3604;
AP-1 is a transcription activator of RXFP1 and directly binds to a novel distal enhancer element identified from this study. Further characterization of the AP-1-dependent activation in primary lung fibroblasts from IPF patients may provide insight into the reduced expression of RXFP1 in IPF patients and may support efforts to restore the effectiveness of relaxin-based therapy in IPF patients.
- |||||||||| Natrecor (nesiritide) / J&J, digoxin / Generic mfg., Reasanz (serelaxin) / Novartis
Review, Journal: Pharmacological interventions for heart failure in people with chronic kidney disease. (Pubmed Central) - Jun 25, 2020
Study data for treatment outcomes in patients with heart failure and CKD are sparse despite the potential impact of kidney impairment on the benefits and harms of treatment. Future research aimed at analysing existing data in general population HF studies to explore the effect in subgroups of patients with CKD, considering stage of disease, may yield valuable insights for the management of people with HF and CKD.
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Journal: Familial bilateral cryptorchidism is caused by recessive variants in RXFP2. (Pubmed Central) - Jun 19, 2020
This is the first reported genomic analysis of a family with multiple individuals affected with cryptorchidism. It demonstrates that recessive variants in the RXFP2 gene underlie familial cryptorchidism and solidifies the link between this gene and testicular descent in humans.
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Journal: Serelaxin inhibits the profibrotic TGF-β1/IL-1β axis by targeting TLR-4 and the NLRP3 inflammasome in cardiac myofibroblasts. (Pubmed Central) - Jun 18, 2020
Comparatively, the small molecule NLRP3 inhibitor, N-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino]carbonyl}-4-(1-hydroxy-1-methylethyl)-2-furansulfonamide (1 μM in vitro, 10 mg/kg/d in vivo), inhibited components of the NLRP3 inflammasome in vitro and in vivo and ISO-induced interstitial LV fibrosis in vivo but did not affect nNOS, TLR-4, myofibroblast differentiation, or myofibroblast-induced collagen deposition. Hence, RLX can inhibit the TGF-β1/IL-1β axis via a nNOS-TLR-4-NLRP3 inflammasome-dependent mechanism on cardiac myofibroblasts.-Cáceres, F. T., Gaspari, T. A., Samuel, C. S., Pinar, A. A. Serelaxin inhibits the pro-fibrotic TGF-β1/IL-1β axis by targeting TLR-4 and the NLRP3 inflammasome in cardiac myofibroblasts.
- |||||||||| candesartan cilexetil / Generic mfg., ANI Pharma, irbesartan / Generic mfg., Reasanz (serelaxin) / Novartis
Journal: AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts: Impact on the Therapeutic Targeting of Renal and Cardiac Fibrosis. (Pubmed Central) - Jun 4, 2020
An increased penetration distance was obtained by RLX infusion through tumor feeding artery, and better therapeutic effects were achieved by RLX combined with TACE. These findings have significant implications for the concomitant use of RXFP1 or ATR agonists with ATR blockers, and suggest that functional interactions between the three receptors on myofibroblasts may represent new targets for controlling fibrosis progression.
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Preclinical, Journal: Chronic activation of the relaxin-3 receptor on GABA neurons in rat ventral hippocampus promotes anxiety and social avoidance. (Pubmed Central) - May 29, 2020
Chronic RXFP3 activation in vHip increased anxiety-like behavior in the light-dark box and elevated-plus maze, but not the large open-field test, and reduced social interaction with a conspecific stranger. Our data reveal disruptive effects of persistent RXFP3 signaling on hippocampal GABA networks important in anxiety; and identify a potential therapeutic target for anxiety disorders that warrants further investigation in relevant preclinical models.
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Journal: Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis. (Pubmed Central) - May 27, 2020
In mice expressing human RXFP1 gene treated with carbon tetrachloride, ML290 significantly reduced collagen content, α-smooth muscle actin expression, and cell proliferation around portal ducts. In conclusion, ML290 demonstrated antifibrotic effects in liver fibrosis.-Kaftanovskaya, E. M., Ng, H. H., Soula, M., Rivas, B., Myhr, C., Ho, B. A., Cervantes, B. A., Shupe, T. D., Devarasetty, M., Hu, X., Xu, X., Patnaik, S., Wilson, K. J., Barnaeva, E., Ferrer, M., Southall, N. T., Marugan, J. J., Bishop, C. E., Agoulnik, I. U., Agoulnik, A. I. Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis.
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Review, Journal: The future of bronchodilation: looking for new classes of bronchodilators. (Pubmed Central) - May 27, 2020
Therefore, there is interest in developing new classes that could help to overcome the limits that characterise the existing classes.At least nine potential new classes of bronchodilators have been identified: 1) selective phosphodiesterase inhibitors; 2) bitter-taste receptor agonists; 3) E-prostanoid receptor 4 agonists; 4) Rho kinase inhibitors; 5) calcilytics; 6) agonists of peroxisome proliferator-activated receptor-γ; 7) agonists of relaxin receptor 1; 8) soluble guanylyl cyclase activators; and 9) pepducins. They are under consideration, but they are mostly in a preclinical phase and, consequently, we still do not know which classes will actually be developed for clinical use and whether it will be proven that a possible clinical benefit outweighs the impact of any adverse effect.It is likely that if developed, these new classes may be a useful addition to, rather than a substitution of, the bronchodilator therapy currently used, in order to achieve further optimisation of bronchodilation.
- |||||||||| Reasanz (serelaxin) / Novartis
Review, Journal: Recent developments in relaxin mimetics as therapeutics for cardiovascular diseases. (Pubmed Central) - May 27, 2020
However, relaxin has several limitations of peptide-based drugs such as poor oral bioavailability, laborious, and expensive to synthesize. This review will focus on recent developments in relaxin mimetics, their pharmacology, associated signalling mechanisms, and their therapeutic potential for the management and treatment of cardiovascular disease.
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Journal: The Active Compounds of Yixin Ningshen Tablet and Their Potential Action Mechanism in Treating Coronary Heart Disease- A Network Pharmacology and Proteomics Approach. (Pubmed Central) - May 19, 2020
Through further enrichment analysis and literature study, EGFR, ERBB2, VGFR2, FGF1, ESR1, LOX15, PGH2, HMDH, ADRB1, and ADRB2 were selected and then validated to be the target proteins of Yixin Ningshen tablet by molecular docking, which indicated that Yixin Ningshen tablet might treat CHD mainly through promoting heart regeneration, new vessels' formation, and the blood supply of the myocardial region and reducing cardiac output, oxygen demand, and inflammation as well as arteriosclerosis (promoting vasodilation and intraplaque neoangiogenesis, lowering blood lipid). This study is expected to benefit the clinical application of Yixin Ningshen tablet for the treatment of CHD.
- |||||||||| digoxin / Generic mfg., Reasanz (serelaxin) / Novartis
Journal: Exploring Molecular Mechanism of Huangqi in Treating Heart Failure Using Network Pharmacology. (Pubmed Central) - May 10, 2020
Finally, molecular docking showed that top 10 compounds of Huangqi also had good binding activities to important targets compared with digoxin, which was carried out in CB-Dock molecular docking server. In conclusion, Huangqi has potential effect on regulating overlapping targets and GE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, HIF-1 signaling pathway, and so on to be a latent multitarget, multipathway treatment for HF.
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Journal: Using the novel HiBiT tag to label cell surface relaxin receptors for BRET proximity analysis. (Pubmed Central) - Apr 30, 2020
The fact that there is also no relaxin-mediated change in RXFP1-RXFP1 proximity at the cell surface further supports these conclusions. This work provides a basis by which cell surface GPCR proximity and expression levels can be specifically studied using a facile and homogeneous labeling technique such as HiBiT.
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Preclinical, Journal: Leydig cell tumorigenesis - implication of G-protein coupled membrane estrogen receptor, peroxisome proliferator-activated receptor and xenoestrogen exposure. In vivo and in vitro appraisal. (Pubmed Central) - Apr 17, 2020
Considering the above, herein we analyzed the relation between G-protein coupled membrane estrogen receptor, peroxisome proliferator-activated receptor and insulin-like family peptides (insulin-like 3 peptide; INSL3 and relaxin; RLN) expressions as well as estrogen level with impact of xenoestrogen (bisphenol A; BPA, tetrabromobisphenol A; TBBPA, and tetrachlorobisphenol A; TCBPA)...Estrogen/xenoestrogen may play a role in tumor Leydig cell proliferation and biochemical nature but this issue requires further studies. Experimentally-induced LCT in mouse testis and MA-10 cells after BPA exposure seem to be additional models for understanding some aspects of human LCT biology.
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Journal: Coatings releasing the relaxin peptide analogue B7-33 reduce fibrotic encapsulation. (Pubmed Central) - Apr 14, 2020
Subcutaneous implantation of PLGA coated polypropylene samples in mice with and without the peptide demonstrated a marked reduction in capsule thickness (49.2 %) over a 6-week period. It is expected that this novel approach will open the door to a range of new and improved implantable medical devices.
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Journal: Serelaxin alleviates cardiac fibrosis through inhibiting endothelial-to-mesenchymal transition via RXFP1. (Pubmed Central) - Apr 1, 2020
We further demonstrate that Serelaxin administration is able to increase its own receptor expression (RXFP1) through epigenetic regulation in form of histone modifications by attenuating TGFβ-pSMAD2/3 signaling in endothelial cells. This study is the first to identify that Serelaxin increases the expression of its own receptor RXFP1 and that this mediates the inhibition of EndMT and cardiac fibrosis, suggesting that Serelaxin may have a beneficial effect as anti-fibrotic therapy in chronic heart failure.
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Journal: Intraarticular injection of relaxin-2 alleviates shoulder arthrofibrosis. (Pubmed Central) - Mar 29, 2020
The histological hallmarks of contracture (e.g., fibrotic adhesions and reduced joint space) are absent in the animals treated with multiple IA injections of relaxin-2 compared with the untreated control and the sIA- and mIV-treated animals. As these findings show, local delivery of relaxin-2 is an innovative treatment of shoulder arthrofibrosis.
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Clinical, Journal: Potential Influence of the Corpus Luteum on Circulating Reproductive and Volume Regulatory Hormones, Angiogenic and Immunoregulatory Factors in Pregnant Women. (Pubmed Central) - Mar 24, 2020
(1) relaxin was undetectable throughout pregnancy (including late gestation) in the 0 CL cohort, but markedly elevated in ~50% of women in the >1 CL cohort; (2) progesterone, plasma renin activity, and aldosterone transiently surged at 5-6 gestational weeks in the >1 CL group; (3) soluble vascular endothelial growth factor-1 (sFLT-1) abruptly increased between 5-6 and 7-9 gestational weeks in all 3 participant cohorts producing a marked elevation in sFLT-1/PLGF (placental growth factor) ratio exceeding any other time-point during pregnancy; (4) sFLT-1 was higher throughout most of gestation in both IVF cohorts with or without abnormal obstetrical outcomes; (5) during pregnancy, C-reactive protein (CRP) increased in 0 and 1 CL, but not >1 CL cohorts; and (6) plasma protein, but not hemoglobin was lower in the >1 CL group throughout gestation. The findings highlight that, when compared to spontaneously conceived pregnancy, the maternal milieu of IVF pregnancy is not physiologic, and the specific perturbations vary according to IVF protocol and CL status.
- |||||||||| Reasanz (serelaxin) / Novartis
Journal: The Relationship between Serum Relaxin Concentrations and Knee Valgus. (Pubmed Central) - Mar 17, 2020
These findings suggest that serum relaxin concentrations and knee valgus are not independent of each other and more holistic approaches may be necessary to truly map out the risk for injury and ultimately reduce the rate of anterior cruciate ligament injuries. Thus, concluding that knee valgus, a highly utilized modifiable biomechanical risk factor, and relaxin, a hormone that has been associated with anterior cruciate ligament injury in female athletes, are related to each other.
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Identification and Characterization of a Distal Enhancer in RXFP1 Gene (PENNSYLVANIA CONVENTION CENTER, Hall D-E (200 Level), Area A) - Mar 15, 2020 - Abstract #ATS2020ATS_5984;
AP-1 is a transcription activator of RXFP1 and directly binds to a novel distal enhancer element identified from this study. Further characterization of the AP-1-dependent activation in primary lung fibroblasts from IPF patients may provide insight into the reduced expression of RXFP1 in IPF patients and may support efforts to restore the effectiveness of relaxin-based therapy in IPF patients.
- |||||||||| cisplatin / Generic mfg., Reasanz (serelaxin) / Novartis
Clinical, Journal, IO Biomarker: Efficacy of relaxin for cisplatin-induced testicular dysfunction and epididymal spermatotoxicity. (Pubmed Central) - Mar 14, 2020
This study clearly indicates that RLN exerts a protective effect against CP-induced testicular damage through attenuation of oxidative stress and suppression of apoptosis. Our findings suggest RLN as a potentially efficacious drug for use with cisplatin chemotherapy in order to ameliorate CP-induced side effects and testicular injury adversely affecting spermatogenesis, sperm quality, and oxidative-stress parameters.
- |||||||||| Reasanz (serelaxin) / Novartis
Journal: Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds. (Pubmed Central) - Mar 7, 2020
VhTI grafted peptides showed poor binding and low potency at RXFP3, on the other hand, apamin variants retained significant activity. These variants also showed improved half-life in serum from ~5 min to >6 h, and thus are promising RXFP3 specific pharmacological tools and drug leads for neuropharmacological diseases.
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Journal: The Role of Relaxin-2 in Tissue Remodeling of Chronic Rhinosinusitis With Nasal Polyps. (Pubmed Central) - Feb 22, 2020
These variants also showed improved half-life in serum from ~5 min to >6 h, and thus are promising RXFP3 specific pharmacological tools and drug leads for neuropharmacological diseases. The antifibrotic effects of relaxin-2 may play a role in tissue remodeling in CRSwNP, but the detailed mechanism deserves further study.
- |||||||||| Biomarker, Journal: Update on the diagnosis and management of acute heart failure. (Pubmed Central) - Feb 20, 2020
The antifibrotic effects of relaxin-2 may play a role in tissue remodeling in CRSwNP, but the detailed mechanism deserves further study. Despite many advances in understanding the pathophysiology of AHF, there is currently insufficient evidence to suggest changes to standards of care.
- |||||||||| Reasanz (serelaxin) / Novartis
Journal: Review: Maternal programming of development in the pig and the lactocrine hypothesis. (Pubmed Central) - Feb 15, 2020
Milk-borne bioactive factors (MbFs), exemplified by relaxin, communicated from lactating dam to nursing offspring via a lactocrine mechanism, represent an important source of extraovarian uterotrophic support in the neonatal pig...In this context, reproductive management strategies and husbandry guidelines should be refined to ensure that such practices promote environmental conditions that will optimize uterine capacity and fecundity. This will entail careful consideration of factors affecting lactation, the quality and abundance of colostrum/milk, and practices that will afford neonatal pigs with the opportunity to nurse and consume adequate amounts of colostrum.
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Journal: Genome-wide DNA methylation profiling in ectopic and eutopic of endometrial tissues. (Pubmed Central) - Feb 14, 2020
Our results confirmed the role of DNA methylation alternations in endometriosis development and pathogenesis. Our finding suggests aberrant DNA methylation can activate several signaling pathways including PI3k-AKT signaling, relaxin, and oxytocin which are associated with the pathogenesis of endometriosis.
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Tuning macromolecular fate through site-selective chemical conjugation of a novel half-life extender (Freedom Ballroom E/F, Philadelphia 201 Hotel) - Feb 13, 2020 - Abstract #ACSSp2020ACS_Sp_18261;
In applying these technologies to the extremely short acting serelaxin peptide, we show that this long acting conjugate analog extends the exposure and shows dose responsive target engagement towards a goal for improved treatment for heart failure. Utilizing our newly developed toolbox of technologies, we have prolonged the pharmacokinetic and pharmacodynamic profile of a diverse set of macromolecules and provided a potential path forward toward developable biotherapeutics of the future.
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