Vitamin D3 affects mitochondrial biogenesis through mitogen-activated protein kinase in polycystic ovary syndrome mouse model.

Polycystic ovarian syndrome (PCOS) is a disorder characterized by oligomenorrhea, anovulation, and hyperandrogenism. Altered mitochondrial biogenesis can result in hyperandrogenism. The goal of this study was to examine the effect of vitamin D3 on mitochondrial biogenesis of the granulosa cells in the PCOS-induced mouse model. Vitamin D3 applies its effect via the mitogen-activated pathway kinase-extracellular signal-regulated kinases (MAPK-ERK1/2) pathway. The PCOS mouse model was induced by the injection of dehydroepiandrosterone (DHEA). Isolated granulosa cells were subsequently treated with vitamin D3, MAPK activator, and MAPK inhibitor. Gene expression levels were measured using real-time polymerase chain reaction. MAPK proteins were investigated by western blot analysis. We also determined reactive oxygen species (ROS) levels with 2', 7'-dichlorofluorescein diacetate. Mitochondrial membrane potential (mtMP) was also measured by TMJC1. Mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator 1-α and nuclear respiratory factor), antioxidant (superoxide dismutase, glutathione peroxidase, and catalase), and antiapoptotic (B-cell lymphoma-2) genes were upregulated in the PCOS mice that treated with vitamin D3 compared with the PCOS mice without any treatment. Vitamin D3 and MAPK activator-treated groups also reduced ROS levels compared with the nontreated PCOS group. In summary, vitamin D3 and MAPK activator increased the levels of mitochondrial biogenesis, MAPK pathway, and mtMP markers, while concomitantly decreased ROS levels in granulosa cells of the PCOS-induced mice. This study suggests that vitamin D3 may improve mitochondrial biogenesis through stimulation of the MAPK pathway in cultured granulosa cells of DHEA-induced PCOS mice which yet to be investigated.

Visfatin stimulates endometrial cancer cell proliferation via activation of PI3K/Akt and MAPK/ERK1/2 signalling pathways.

OBJECTIVE: Endometrial carcinoma is one of the most common malignancies of the female reproductive system, but the aetiology and pathogenesis are not well understood, although adipokines such as visfatin may be involved. Our study provides insight into the mechanism underlying the tumorigenic effects of visfatin in endometrial carcinoma. METHODS: We investigated the effect of visfatin on endometrial carcinoma cell proliferation, cell cycle, and apoptosis using well-differentiated Ishikawa cells and poorly differentiated KLE cells. We also assessed the effect of visfatin on tumour growth in vivo. RESULTS: Visfatin stimulated the proliferation of both Ishikawa and KLE cells, and visfatin treatment promoted G1/S phase progression and inhibited endometrial carcinoma cell apoptosis. Visfatin promoted endometrial carcinoma tumour growth in BALB/c-nu mice. Transplanted tumour tissues from an endometrial carcinoma mouse model were analysed using immunohistochemical staining, which revealed much stronger positive signals for Ki-67 with over-abundant visfatin. Western blot analysis revealed that insulin receptor (IR), insulin receptor substrate (IRS)1/2 and key components of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)1/2 signalling pathways were highly expressed in endometrial carcinoma cells exposed to visfatin. Treated cells showed increased C-MYC and cyclin D1 and reduced caspase-3 expression. The effects of visfatin on proliferation and apoptosis were abrogated by treatment with the PI3K inhibitor LY294002 and MEK inhibitor U0126. CONCLUSIONS: Visfatin promotes the malignant progression of endometrial carcinoma via activation of IR and PI3K/Akt and MAPK/ERK signalling. Visfatin may serve as a therapeutic target in the treatment of endometrial carcinoma.

EIF3D promotes the progression of preeclampsia by inhibiting of MAPK/ERK1/2 pathway.

Preeclampsia (PE) has been recognized as one of the main reasons for neonatal and maternal mortality and morbidity. This study intended to identify certain genes that correlated with the pathogenesis of PE, and disclose the underlying mechanisms. The GSE14776 and GSE65271 datasets were obtained from the Gene Expression Omnibus database. Venn diagram analysis was performed to identify the differently expressed genes. The potential pathways were analyzed by Gene set enrichment analysis software. The expression of eukaryotic translation initiation factor 3 subunit D (EIF3D) in tissues and cells was respectively tested by immunohistochemistry and the quantitative real-time PCR. Cell transfection was utilized to alter the expression of EIF3D. Cell proliferation, invasion and migration were respectively tested by MTT, EdU, transwell and wound healing assays. Tube formation assay was utilized to determine the tube formation capacity of HTR-8/SVneo cells. ELISA was employed for determination of the concentration of Angiotensin (ANG)-1. Moreover, the expression of EIF3D, proliferation-, metastasis-, tube formation- and MAPK/ERK1/2 pathway-related proteins were measured utilizing western blot. EIF3D was selected in this study. EIF3D was upregulated in placentas tissues collected from patients with PE. EIF3D upregulation observably repressed the proliferation, invasion, migration, wound healing and tube formation of HTR-8/SVneo cells, and the expression of their associated proteins. Besides, the concentration of ANG-1, and the ratios of phosphorylated-ERK1/2 and phosphorylated-MEK1/MEK1 were also markedly lowered by EIF3D upregulation. Whereas, EIF3D knockdown exerted the opposite effects, and these effects were distinctly counteracted by ERK1/2 inhibitor SC-221593 treatment. In conclusion, these observations manifested that EIF3D upregulation might have repressed the progression of PE through modulation of MAPK/ERK1/2 pathway.

Neuroprotective effect of ipriflavone against scopolamine-induced memory impairment in rats.

BACKGROUND: Alzheimer's disease is an age-related neurodegenerative disorder characterized clinically by a progressive loss of memory and cognitive functions resulting in severe dementia. Ipriflavone (IPRI) is a non-hormonal, semi-synthetic isoflavone, clinically used in some countries for the treatment and prevention of postmenopausal osteoporosis. Moreover, ipriflavone is a non-peptidomimetic small molecule AChE inhibitor with an improved bioavailability after systemic administration, due to its efficient blood-brain barrier permeability in comparison with peptidomimetic inhibitors. OBJECTIVE: The present study aimed to evaluate the possible enhancing effects of IPRI on memory impairments caused by scopolamine administration. METHODS: Male rats were administered IPRI (50 mg/kg, oral) 2 h before scopolamine injection (2 mg/kg, intraperitoneally injected) daily for 4 weeks. Effects of IPRI on acetylcholinesterase activity, amyloid-ß precursor processing, and neuroplasticity in the rats' hippocampus were investigated. RESULTS: Daily administration of IPRI reverted memory impairment caused by scopolamine as measured by the reduction of the escape latency. IPRI significantly alleviated the oxidative stress and restored the mRNA expression of both cAMP-response element-binding protein and brain-derived neurotrophic factor in the hippocampus. Furthermore, it significantly increased the expression of ADAM10 and ADAM17 (two putative α-secretase enzymes) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) that associated with decreased expression of ß-secretase (BACE) in the hippocampus. Finally, both the amyloid-ß (Aß) and Tau pathologies were reduced. CONCLUSIONS: IPRI showed promising neuroprotective effects against scopolamine-induced memory dysfunction in rats. These findings contributed to the stimulation of α-secretase enzymes, the activation of MAPK/ERK1/2, and the alleviation of oxidative stress.