Characterization and biological activity of relaxin in porcine milk

Frankshun, Amy-Lynn; Ho, Teh‐Yuan; Reimer, David; Chen, Joseph; Lasano, Salamia; Steinetz, Bernard G.; Bartol, Frank F.; Bagnell, Carol A.

doi:10.1530/rep-10-0401

Cited by 28 publications

(19 citation statements)

References 51 publications

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“…The increase in endometrial epithelial RXFP1 expression observed for lactocrine-null gilts at PND 2 also agrees with observations reported for whole uteri 48 h after colostrum deprivation from birth [40]. Because colostrum is a source of bioactive RLX [50], ingestion of RLX by nursing gilts may be acting in a negative regulatory manner to decrease RXFP1 expression [9]. Data indicating that RXFP1 expression is predominantly stromal agree with an earlier report [18] in which both RXFP1 mRNA and protein were localized primarily in this endometrial cell compartment at PND 14.…”

Section: Nursing and Uterine Gland Developmentsupporting

confidence: 89%

“…Mechanistically, these observations are consistent with data indicating that endometrial thickness was reduced and uterine gland genesis was inhibited by PND 14 in the absence of lactocrine signaling from birth. Lactocrine effects on patterns of cell proliferation suggest that mitogenic factors in colostrum are important for support of endometrial morphogenesis in the neonate [16,27,50].…”

Section: Discussionmentioning

confidence: 99%

“…A feed-forward, lactocrine-driven mechanism was proposed [39] to explain how MbFs, exemplified by RLX, might support induction of endometrial ESR1 expression and related downstream effectors of estrogen and/or RLX action, including both VEFGA and RXFP1, in the neonatal porcine endometrium. Administered for 2 days from birth, exogenous RLX, a prototypical MbF in the pig [50], induced uterine expression of both ESR1 and VEFGA, and suppressed expression of RXFP1 [9]. Data indicating that uterotrophic effects of RLX can be inhibited with ICI 182,780 in neonatal gilts [9] and rats [51] suggests that ESR1 activation can occur indirectly, via transactivation of this receptor system.…”

Section: Discussionmentioning

confidence: 99%

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Nursing for 48 Hours from Birth Supports Porcine Uterine Gland Development and Endometrial Cell Compartment-Specific Gene Expression1

Miller

Wiley

Chen

et al. 2013

Biology of Reproduction

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The first 2 wk of neonatal life constitute a critical period for estrogen receptor alpha (ESR1)-dependent uterine adenogenesis in the pig. A relaxin receptor (RXFP1)-mediated, lactocrine-driven mechanism was proposed to explain how nursing could regulate endometrial ESR1 and related gene expression events associated with adenogenesis in the porcine neonate during this period. To determine effects of nursing on endometrial morphogenesis and cell compartment-specific gene expression, gilts (n = 6-8/group) were assigned at birth to be either 1) nursed ad libitum for 48 h, 2) gavage fed milk replacer for 48 h, 3) nursed ad libitum to Postnatal Day (PND) 14, or 4) gavage fed milk replacer for 48 h followed by ad libitum nursing to PND 14. Uteri were collected on PND 2 or PND 14. Endometrial histoarchitecture and both ESR1 and proliferating cell nuclear antigen (PCNA) labeling indexes (LIs) were evaluated. Laser microdissection was used to capture epithelium and stroma to evaluate treatment effects on cell compartment-specific ESR1, VEGFA, and RXFP1 expression. Imposition of a lactocrine-null state by milk replacer feeding for 48 h from birth retarded endometrial development and adenogenesis. Effects of replacer feeding, evident by PND 2, were marked by PND 14 when endometrial thickness, glandularity, and gland depth were reduced. Consistently, in lactocrine-null gilts, PCNA LI was reduced in glandular epithelium (GE) and stroma on PND 14, when epithelial ESR1 expression and ESR1 LI in GE were reduced and stromal VEGFA and RXFP1 expression increased. Results establish that lactocrine signaling effects morphogenetic changes in developing uterine tissues that may determine reproductive capacity later in life.

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Section: Nursing and Uterine Gland Developmentsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nursing for 48 Hours from Birth Supports Porcine Uterine Gland Development and Endometrial Cell Compartment-Specific Gene Expression1

Miller

Wiley

Chen

et al. 2013

Biology of Reproduction

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“…Colostrum (first milk) contains bioactive factors including relaxin, a prototypical MbF (Frankshun et al 2011), detected in the circulation of nursed pigs by 12 h postnatal (Yan et al 2006). Insulin-like growth factor 1 (IGF1; 7.6 kDa), another member of the insulin family of hormones, is found in porcine colostrum at high concentrations (Simmen et al 1990a, which decline within the first 24-36 h of lactation during the transition from colostrum to mature milk (Klobasa et al 1987, Nguyen et al 2001.…”

Section: Introductionmentioning

confidence: 99%

Effects of age, nursing, and oral IGF1 supplementation on neonatal porcine cervical development

Camp¹,

Wiley²,

Boulos³

et al. 2014

Reproduction

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Nursing supports neonatal porcine uterine and testicular development, however, lactocrine effects on cervical development are undefined. Studies were conducted to determine the effects of i) age and the imposition of the lactocrine-null state from birth (postnatal day 0 (PND0)) by milk replacer feeding on cervical histology; ii) imposition of the lactocrine-null state for 2 days from birth on cervical cell proliferation, as reflected by proliferating cell nuclear antigen immunostaining; and iii) a single feeding of colostrum or milk replacer, administered at birth, with or without oral IGF1, on cervical cell proliferation and phosphorylated AKT (pAKT) and B-cell lymphoma 2 (BCL2) protein levels at 12 h postnatal. Cervical crypt depth and height of luminal epithelium (LE) increased with age by PND14, when both responses were reduced in replacer-fed gilts. Cell proliferation was reduced in LE at PND2, and in crypt epithelium and stroma by PND14 in replacer-fed gilts. Returning replacer-fed gilts to nursing on PND2 did not rescue the cervical phenotype by PND14. A single feeding of colostrum, but not milk replacer, was sufficient to support cervical cell proliferation at 12 h postnatal. IGF1 supplementation induced cell proliferation in replacer-fed gilts, and increased cervical pAKT and BCL2 levels in colostrum-fed gilts and replacer-fed gilts at 12 h postnatal. Results indicate that age and nursing support porcine cervical development, support is initiated at first ingestion of colostrum, IGF1 may be lactocrine-active, and identification of lactocrine-active factors can be accomplished by 12 h postnatal using this bioassay system.

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“…Purified RLX, extracted from porcine ovaries, was obtained from IBSA, Lugano, Switzerland [14]. RLX amount was assessed by an in house developed ELISA with a detection limit of 0.4ng/ml and high specificity due to a double antibody anti RLX detection strategy.…”

Section: Methodsmentioning

confidence: 99%

Effect of Orally Administered Relaxin in Experimental Nash <strong> </strong>

Colucci¹

2020

Preprint

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BACKGROUND Relaxin (RLX), a hormone-like molecule with pleiotropic effects, has been found to reduce matrix deposition and mediate collagen degradation in animal models of chronic liver injuries and might be considered as an adjuvant therapeutic agent for progressive liver diseases. AIMS In the present study, we evaluated whether RLX affects the development of liver fibrosis in an experimental mouse model of NASH in C57BL6 male mice fed with a methionine-choline deficient diet (MCD). Methods Mice were treated per os as we intended to assess the enteric absorption and bioavailability of orally administered RLX (RLX purified from pig ovaries, IBSA SA, Lugano, Switzerland). Mice were fed the MCD diet for 6 weeks. After the initial 3 weeks, one group received drinking water supplemented with RLX (25 mcg/ml) whereas the other continued to receive regular water. A third group of mice fed a regular diet served as control. After 3 additional weeks mice were anesthetized and sacrificed. Results A significant, reduced expression of the pro-inflammatory cytokines TNF-α and of relevant markers of active fibrogenesis and extracellular matrix deposition, Col1A1 and α-SMA, was observed in mice treated with RLX vs controls. RLX also induced a significant decrease of TIMP1 and an increase of both MMP 2 and 9 when evaluated by zymographic analysis in liver extracts. Conclusions Although preliminary pharmacokinetics experiments showed barely detectable amounts of RLX in the blood of mice treated per os, these data support the absorption of orally administered RLX and confirm its potential therapeutic use in the management of liver fibrosis.

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Characterization and biological activity of relaxin in porcine milk

Cited by 28 publications

References 51 publications

Nursing for 48 Hours from Birth Supports Porcine Uterine Gland Development and Endometrial Cell Compartment-Specific Gene Expression1

Nursing for 48 Hours from Birth Supports Porcine Uterine Gland Development and Endometrial Cell Compartment-Specific Gene Expression1

Effects of age, nursing, and oral IGF1 supplementation on neonatal porcine cervical development

Effect of Orally Administered Relaxin in Experimental Nash <strong> </strong>

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