Molecular cues to the anti-implantation effect of nano-puerarin in rats

Abstract

Puerarin, a selective oestrogen receptor modulator, intercepts implantation in rats, albeit at unacceptably higher doses. We developed poly lactic-co-glycolic acid-encapsulated nano-puerarin (PN) and mapped the molecular pathway underlying its anti-implantation effects. Smooth-surfaced and spherical PN having a mean diameter of ~147 nm was obtained with good yield, efficient encapsulation, and optimum drug loading. In culture, PN slowly and steadily released puerarin, which was readily taken up by the decidual cells. PN exerted a dose-dependent anti-implantation effect. As marked by attenuated expression of stromal cell desmin, alkaline phosphatase, IGFBP1, and decidual prolactin-related protein, the anti-implantation effect of PN seemed secondary to compromised decidualization. Using in vivo (pregnant and pseudopregnant rats) and in vitro (endometrial stromal cell culture) treatment models, we document that PN enforced inhibition of uterine expression of Hbegf and Hoxa10 and their downstream signalling molecules, Cyclin D3 (CCND3)/CDK4. PN also efficiently ablated the Ihh-Nr2f2-Bmp2 signalling pathway and invited the loss of uterine potential for decidualization. There was a dose-dependent up-regulation of RHOA and its effector protein kinase, ROCK1, leading to the promotion of MLC phosphorylation and actin-myosin interaction. PN also down-regulated the stromal cell activation of ERK½ and expression of MMP9. These effects acting together stabilized the stroma and inhibited the stromal cell migration. Central to this array of events was the adversely altered endometrial expression of oestrogen receptor subtypes and repression of progesterone receptor that indulged endless proliferation of luminal epithelia and distorted the precisely choreographed stroma-epithelia crosstalk. Thus, PN dismantles the endometrial bed preparation and prevents implantation.Reproduction (2016) 151 693-707

Quercetin interferes with the fluid volume and receptivity development of the uterus in rats during the peri-implantation period

“…It was documented that expression of FGF-1 in women with implantation failure was lesser than in fertile women, indicating that FGF-1 is a critical maternal factor needed for implantation [48]. Ihh signaling pathway has also been found to be essential for implantation and decidualization [49]. Its expression is under the control of progesterone [50].…”

Endocrine Pharmacology Research in India: Scientific Progress in Last Five Years

“…It is reported as selectiveoestrogen receptor modulator that adversely modulates the endometrial expression of oestrogen receptor-α and β resulting in anti-implantation (Saha et al, 2012). This group recently developed poly lactic-co-glycolic acid-encapsulated nano-puerarin and further studied the molecular pathway underlying its anti-implantation effects (Saraswat et al, 2016). The administration of ethanol extract of P. oleracea L. (Portulacea) blocked ovulation by inhibiting cyclooxygenase activity, altered estrous cycle with a prolonged diestrous, increased the uterine muscle weight and ovary weight suggesting its anti-ovulation effect in rats (Londonkar and Nayaka 2013).…”

“…Excess iodine when administered above its tolerable ranges (100 and 500 times more than recommended doses) for prolonged duration acts on thyroid itself developing a state of biochemical hypothyroidism (as evident by low T3) that induces oxidative stress in testis and reduces circulating testosterone level resulting in structural and functional changes of male gonads (Chakraborty et al, 2016). Where as in females, iodine in excess exerts biphasic mode of action depending on the dose (100 and 500 times) in female reproductive physiology and both the doses used in this study affected fertility equally in adult rats (Mahapatra and Chandra 2017).…”