title: 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 ∼147nm 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.
authors.affiliation: Reproductive Biology ResearchCSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Ghungroo
authors.initials: G
authors.lastname: Saraswat
authors.affiliation: Laboratory Animal ScienceCSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Rajdeep
authors.initials: R
authors.lastname: Guha
authors.affiliation: Reproductive Biology ResearchCSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Mondal
authors.affiliation: Reproductive Biology ResearchCSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India Department of Biological Sciences and BioengineeringIndian Institute of Technology, Kanpur, Uttar Pradesh, India.
authors.forename: Piyali
authors.initials: P
authors.lastname: Saha
authors.affiliation: Reproductive Biology ResearchCSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India Department of Biological SciencesOhio University, Ohio, USA.
authors.forename: Sayani
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Reproductive Biology ResearchCSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Prarthana
authors.initials: P
authors.lastname: Chakraborty
authors.affiliation: Laboratory Animal ScienceCSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India.
authors.forename: Aditya
authors.initials: A
authors.lastname: Konar
authors.affiliation: Reproductive Biology ResearchCSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India snkabir@iicb.res.in sdnkabir@gmail.com.
authors.forename: Syed N
authors.initials: SN
authors.lastname: Kabir
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003270:Contraceptive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003656:Decidua / Q000187:drug effects / Q000502:physiology; D010064:Embryo Implantation / Q000187:drug effects*; D005260:Female; D005298:Fertility / Q000187:drug effects*; D007529:Isoflavones / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects; D014599:Uterus / Q000166:cytology / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D003270:Contraceptive Agents; D007529:Isoflavones; D014665:Vasodilator Agents; C033607:puerarin