Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis

Kaftanovskaya, Elena M.; Ng, Hooi Hooi; Soula, Mariluz; Rivas, Bryan; Myhr, Courtney; Ho, Brian A.; Cervantes, Briana; Shupe, Thomas; Devarasetty, Mahesh; Hu, Xin; Xu, Xin; Patnaik, Samarjit; Wilson, Kenneth J.; Barnaeva, Elena; Ferrer, Marc; Southall, Noel; Marugán, Juan; Bishop, Colin E.; Agoulnik, Irina U.; Agoulnik, Alexander I.

doi:10.1096/fj.201901046r

Cited by 24 publications

(25 citation statements)

References 40 publications

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“…Alternatively, small molecule agonists have proven to be an attractive alternative to therapies with peptide ligands due to improved stability and potential oral bioavailability. A high-throughput screening of small molecules successfully identified the first RXFP1 agonist, compound ML290, which has antifibrotic effects recently demonstrated in a mouse model of liver fibrosis (Kaftanovskaya et al 2019). Due to the structural similarities of RXFP1 and RXFP2, the same approach that was used for the selection and optimization of ML290 can be applied to identify a small molecule agonist that specifically targets RXFP2.…”

Section: Discussionmentioning

confidence: 99%

Diverse functions of insulin-like 3 peptide

Esteban‐Lopez

Agoulnik

2020

Journal of Endocrinology

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Insulin-like 3 peptide (INSL3) is a member of the insulin-like peptide superfamily and is the only known physiological ligand of relaxin family peptide receptor 2 (RXFP2), a G protein-coupled receptor (GPCR). In mammals INSL3 is primarily produced both in testicular Leydig cells and in ovarian theca cells, but circulating levels of the hormone are much higher in males than in females. The INSL3/RXFP2 system has an essential role in the development of the gubernaculum for the initial transabdominal descent of the testis and in maintaining proper reproductive health in men. Although its function in female physiology has been less well-characterized, it was reported that INSL3 deletion affects antral follicle development during the follicular phase of the menstrual cycle and uterus function. Since the discovery of its role in the reproductive system, the study of INSL3/RXFP2 has expanded to others organs such as skeletal muscle, bone, kidney, thyroid, brain, and eye. This review aims to summarize the various advances in understanding the physiological function of this ligand-receptor pair since its first discovery and elucidate its future therapeutic potential in the management of various diseases.

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Section: Discussionmentioning

confidence: 99%

Diverse functions of insulin-like 3 peptide

Esteban‐Lopez

Agoulnik

2020

Journal of Endocrinology

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“…Organoids were constructed using a slight modification of previously published protocols. [ 22‐25 ] Cryopreserved primary human hepatocytes, kupffer cells, and hepatic stellate cells were purchased from TRL/Lonza. Human liver sinusoidal endothelial cells were purchased from ScienCell and expanded for three passages according to the manufacturer's instructions, before being cryopreserved in 5 × 10 5 aliquots.…”

Section: Methodsmentioning

confidence: 99%

“…Liver organoids have been fully characterized as previously published, and they show high viability over at least 28 days, produce urea, albumin and alpha1 antitrypsin, and P450 reductase, and show a primitive bilary system and metabolize diazepam for at least 28 days. [ 22‐25 ]…”

Section: Methodsmentioning

confidence: 99%

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The potential toxic effects of magnesium oxide nanoparticles and valproate on liver tissue

Mekky

Seeds

Diab

et al. 2020

J Biochem & Molecular Tox

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The liver is the main organ responsible for drug and xenobiotic metabolism and detoxification in the body. There are many antiepileptic drugs and nanoparticles that have been reported to cause serious untoward biological responses and hepatotoxicity. The aim of this study is to investigate the potential toxic effect of aspartic acid‐coated magnesium oxide nanoparticles (Mg nano) and valproate (valp) using an in vitro three‐dimensional (3D) human liver organoid model and an in vivo pentylenetetrazole (PTZ)‐induced convulsion model in rats. Here, 3D human liver organoids were treated with valp or valp + Mg nano for 24 h and then incubated with PTZ for an extra 24 h. As the in vivo model, rats were treated with valp, Mg nano, or valp + Mg nano for 4 weeks and then they were treated with PTZ for 24 h. Toxicity in the liver organoids was demonstrated by reduced cell viability, decreased ATP, and increased reactive oxygen species. In the rat convulsion model, results revealed elevated serum alanine aminotransferase and aspartate aminotransferase levels. Both the in vitro and in vivo data demonstrated the potential toxic effects of valp + Mg nano on the liver tissues.

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“…ML290 is a specific agonist for human RXFP1 and does not activate the rodent receptor ( Huang et al, 2015 ). In this study, we utilized a unique strain of mice generated in our laboratory with knock-in of the human RXFP1 ( Kaftanovskaya et al, 2019 ) to test the therapeutic efficacies of ML290 in vivo . A plethora of studies reported the anti-fibrotic role of relaxin ( Samuel et al, 2016 ), and we recently showed that ML290 replicates the protective functions of relaxin in a mouse model of liver fibrosis ( Kaftanovskaya et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Anti-apoptotic and Matrix Remodeling Actions of a Small Molecule Agonist of the Human Relaxin Receptor, ML290 in Mice With Unilateral Ureteral Obstruction

Soula

Rivas

et al. 2021

Front. Physiol.

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Diseases, such as diabetes and hypertension, often lead to chronic kidney failure. The peptide hormone relaxin has been shown to have therapeutic effects in various organs. In the present study, we tested the hypothesis that ML290, a small molecule agonist of the human relaxin receptor (RXFP1), is able to target the kidney to remodel the extracellular matrix and reduce apoptosis induced by unilateral ureteral obstruction (UUO). UUO was performed on the left kidney of humanized RXFP1 mice, where the right kidneys served as contralateral controls. Mice were randomly allocated to receive either vehicle or ML290 (30 mg/kg) via daily intraperitoneal injection, and kidneys were collected for apoptosis, RNA, and protein analyses. UUO significantly increased expression of pro-apoptotic markers in both vehicle- and ML290-treated mice when compared to their contralateral control kidneys. Specifically, Bax expression and Erk1/2 activity were upregulated, accompanied by an increase of TUNEL-positive cells in the UUO kidneys. Additionally, UUO induced marked increase in myofibroblast differentiation and aberrant remodeling on the extracellular matrix. ML290 suppressed these processes by promoting a reduction of pro-apoptotic, fibroblastic, and inflammatory markers in the UUO kidneys. Finally, the potent effects of ML290 to remodel the extracellular matrix were demonstrated by its ability to reduce collagen gene expression in the UUO kidneys. Our data indicate that daily administration of ML290 has renal protective effects in the UUO mouse model, specifically through its anti-apoptotic and extracellular matrix remodeling properties.

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Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis

Cited by 24 publications

References 40 publications

Diverse functions of insulin-like 3 peptide

Diverse functions of insulin-like 3 peptide

The potential toxic effects of magnesium oxide nanoparticles and valproate on liver tissue

Anti-apoptotic and Matrix Remodeling Actions of a Small Molecule Agonist of the Human Relaxin Receptor, ML290 in Mice With Unilateral Ureteral Obstruction

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