Overexpression of Sirt1 in mesenchymal stem cells protects against bone loss in mice by FOXO3a deacetylation and oxidative stress inhibition.

Objective: B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) deficiency (Bmi-1) leads to an osteoporotic phenotype with a significant downregulation of Sirt1 protein expression. Sirtuin 1 (Sirt1) haploinsufficiency results in a bone loss by decreased bone formation; however, it is unclear whether Sirt1 overexpression in mesenchymal stem cells (MSCs) plays an anti-osteoporotic role. The aim of the study is to identify whether the overexpression of Sirt1 in MSCs could restore skeletal growth retardation and osteoporosis in Bmi-1 deficient mice.

EZH2-Mediated Epigenetic Suppression of GDF15 Predicts a Poor Prognosis and Regulates Cell Proliferation in Non-Small-Cell Lung Cancer.

Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily of cytokines, has been reported to exert very heterogeneous functions in various tumors. However, its expression and roles in mediating non-small-cell lung cancer (NSCLC) progression remain unknown. In this study, we found that GDF15 is downregulated in paired NSCLC tissues and correlated with poor clinical outcomes in NSCLC.

MiR-616-3p modulates cell proliferation and migration through targeting tissue factor pathway inhibitor 2 in preeclampsia.

Objectives: Despite improvements in diagnosis and treatment, preeclampsia (PE) continues to pose a significant risk of maternal and foetal morbidity and mortality if not addressed promptly. An increasing number of studies have suggested that tissue factor pathway inhibitor 2 (TFPI2) acts as a suppressor gene, possibly inhibiting multiple serine proteases affecting cell proliferation and migration. It plays an essential role in the occurrence and development of PE, but the pathogenesis remains unclear.

DNA damage checkpoint pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide.

We previously demonstrated that parathyroid hormone-related peptide (PTHrP) 1-84 knockin ( KI) mice, which lacked a PTHrP nuclear localization sequence (NLS) and C-terminus, displayed early senescence, defective osteoblastic bone formation, and skeletal growth retardation. However, the mechanism of action of the PTHrP NLS and C-terminus in regulating development of skeleton is still unclear. In this study, we examined alterations of oxidative stress and DNA damage response-related molecules in KI skeletal tissue.

Deficient Mice Exhibit Male Infertility.

Previous studies have demonstrated that the polycomb repressor is universally expressed in all types of testicular cells and might regulate the spermatogonia proliferation, however, it is unclear whether plays a critical role in maintaining normal male fertility in vivo. To answer this question, we first confirmed that is universally expressed in all types of testicular cells and found that the gene relative expression levels of in testis were the highest relative to other organs. Then we investigated the role of in maintaining normal male fertility using knockout male mouse model.

1,25-Dihydroxy vitamin D prevents tumorigenesis by inhibiting oxidative stress and inducing tumor cellular senescence in mice.

Human epidemiological studies suggest that 1,25(OH) D deficiency might increase cancer incidence, but no spontaneous tumors have been reported in mice lacking 1,25(OH) D or deficient in its receptor. In our study, we detected, for the first time, diverse types of spontaneous tumors in l,25(OH) D deficient mice more than 1 year of age. This was associated with increased oxidative stress, cellular senescence and senescence-associated secretory phenotype molecules, such as hepatocyte growth factor, mediated via its receptor c-Met.

Pyrroloquinoline quinone plays an important role in rescuing Bmi-1 mice induced developmental disorders of teeth and mandible--anti-oxidant effect of pyrroloquinoline quinone.

To investigate whether pyrroloquinoline quinine (PQQ) plays an important role in rescuing Bmi-1 mice induced developmental disorders of teeth and mandible by regulating oxidative stress. We fed Bmi-1 mice a diet supplemented with PQQ (BKO+PQQ), BKO mice with normal diet (BKO) and wild type mice with normal diet (WT) as controls. We compared the differences of dental, mandibular phenotype by means of X-ray photography, micro CT scanning and three-dimensional reconstruction, HE staining, histochemistry, immunoistohemistry, TUNEL staining, Western blot and Flow cytometry in three groups of animals.

Effect and mechanism of pyrroloquinoline quinone on anti-osteoporosis in Bmi-1 knockout mice-Anti-oxidant effect of pyrroloquinoline quinone.

Pyrroloquinoline quinone (PQQ), considered as an ROS scavenger,could protect mitochondrial activity from damage of oxidative stress. To determine the role of PQQ supplement in rescuing long bone osteoporosis in Bmi-1 mice. We fed Bmi-1 knockout mice a diet supplemented with PQQ (BKO+PQQ), BKO mice with normal diet (BKO) and wild type mice with normal diet (WT) as controls.

Rho Kinase Inhibitor, Fasudil, Attenuates Contrast-induced Acute Kidney Injury.

In this study, we tested the hypothesis that fasudil, a Rho kinase inhibitor, would protect against contrast-induced acute kidney injury (CI-AKI) in a mouse model and attempted to elucidate the mechanism involved. Mice subjected to unilateral ligation of the left anterior renal pedicle were divided into four groups: (1) control group, (2) CI-AKI induced by contrast media (CM group), (3) CI-AKI plus low-dose fasudil (LD group) and (4) CI-AKI plus high-dose fasudil (HD group). Animals from groups 2-4 received iodixanol (4.

1,25(OH)D deficiency increases TM40D tumor growth in bone and accelerates tumor-induced bone destruction in a breast cancer bone metastasis model.

Breast cancer is one of the most common malignancies and bone is the commonest site of distant metastases. Evidences indicate that adequate supply of vitamin D will decrease the morbidity and mortality of breast cancer. However, the main role of vitamin D deficiency in breast cancer bone metastases remains unclear.

Research on the function and related mechanism of gene in the intervertebral disc degeneration of mice.

This study aims to investigate the function and related mechanism of gene in intervertebral disc (IVD) degeneration of mice. X-ray, immunohistochemical staining, and alkaline phosphatase (ALP) histochemical staining were used to analyze the phenotypic difference of the intervertebral discs of 4-week-old mice with P27 gene knockout (P27) and wild-type (WT) mice in the same brood. Protein in the intervertebral disc was extracted and western blot analysis was employed to detect the changes in the expression of related molecules in the Shh-signal pathways, including Shh, Patched, Smoothened and Gli2.

Comparison of gene expression profiles between dental pulp and periodontal ligament tissues in humans.

There are anatomical and functional differences between human dental pulp (DP) and periodontal ligament (PDL). However, the molecular biological differences and function of these tissues are poorly understood. In the present study, we employed a cDNA microarray array to screen for differentially expressed genes (DEGs) between human DP and PDL tissues, and used the online software WebGestalt to perform the functional analysis of the DEGs.

Absence of PTHrP nuclear localization and C-terminus sequences leads to abnormal development of T cells.

Parathyroid hormone-related protein (PTHrP), a ubiquitously expressed protein, is composed of four functional domains including N-terminus, mid region, nuclear localization signal (NLS) and C-terminus. Under the direction of NLS, PTHrP can enter cell nucleus from cytoplasm and stimulate mitogenesis. Although PTHrP is considered to have important developmental roles, the role of PTHrP NLS and C-terminus in developmental process remains unknown, especially in T-cell development.

Pyrroloquinoline quinone prevents testosterone deficiency-induced osteoporosis by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption.

Accumulating evidences suggest that oxidative stress caused and deteriorated the aging related osteoporosis and pyrroloquinoline quinone (PQQ) is a powerful antioxidant. However, it is unclear whether PQQ can prevent testosterone deficiency-induced osteoporosis. In this study, the orchidectomized (ORX) mice were supplemented in diet with/without PQQ for 48 weeks, and compared with each other and with sham mice.

Pharmacologic Calcitriol Inhibits Osteoclast Lineage Commitment via the BMP-Smad1 and IκB-NF-κB Pathways.

Vitamin D is involved in a range of physiological processes and its active form and analogs have been used to treat diseases such as osteoporosis. Yet how vitamin D executes its function remains unsolved. Here we show that the active form of vitamin D calcitriol increases the peak bone mass in mice by inhibiting osteoclastogenesis and bone resorption.

Radioprotective effects of pyrroloquinoline quinone on parotid glands in C57BL/6J mice.

The aim of the present study was to investigate whether pyrroloquinoline quinine (PQQ) serve a radioprotective role in parotid gland damage induced by total body irradiation (TBI) in C57BL/6J mice. A total of 15 female 8-week-old C57BL/6J mice were randomly assigned into three treatment groups: i) Untreated control (no irradiation); ii) 4 gray (Gy) X-ray irradiation; iii) 4 Gy X-ray irradiation with additional dietary PQQ (4 mg PQQ/kg in normal diet). Each group included five mice.

BMI-1 Mediates Estrogen-Deficiency-Induced Bone Loss by Inhibiting Reactive Oxygen Species Accumulation and T Cell Activation.

Previous studies have shown that estrogen regulates bone homeostasis through regulatory effects on oxidative stress. However, it is unclear how estrogen deficiency triggers reactive oxygen species (ROS) accumulation. Recent studies provide evidence that the B lymphoma Mo-MLV insertion region 1 (BMI-1) plays a critical role in protection against oxidative stress and that this gene is directly regulated by estrogen via estrogen receptor (ER) at the transcriptional level.

Copy number gain of VCX, X-linked multi-copy gene, leads to cell proliferation and apoptosis during spermatogenesis.

Male factor infertility affects one-sixth of couples worldwide, and non-obstructive azoospermia (NOA) is one of the most severe forms. In recent years there has been increasing evidence to implicate the participation of X chromosome in the process of spermatogenesis. To uncover the roles of X-linked multi-copy genes in spermatogenesis, we performed systematic analysis of X-linked gene copy number variations (CNVs) and Y chromosome haplogrouping in 447 idiopathic NOA patients and 485 healthy controls.

Overexpression of Bmi1 in Lymphocytes Stimulates Skeletogenesis by Improving the Osteogenic Microenvironment.

To investigate whether overexpression of Bmi1 in lymphocytes can stimulate skeletogenesis by improving the osteogenic microenvironment, we examined the skeletal phenotype of EμBmi1 transgenic mice with overexpression of Bmi1 in lymphocytes. The size of the skeleton, trabecular bone volume and osteoblast number, indices of proliferation and differentiation of bone marrow mesenchymal stem cells (BM-MSCs) were increased significantly, ROS levels were reduced and antioxidative capacity was enhanced in EμBmi1 mice compared to WT mice. In PTHrP1-84 knockin (Pthrp(KI/KI)) mice, the expression levels of Bmi1 are reduced and potentially can mediate the premature osteoporosis observed.

Use of Hes1-GFP reporter mice to assess activity of the Hes1 promoter in bone cells under chronic inflammation.

Notch signaling plays a critical role in maintaining bone homeostasis partially by controlling the formation of osteoblasts from mesenchymal stem cells (MSCs). We reported that TNF activates Notch signaling in MSCs which inhibits osteoblast differentiation in TNF transgenic (TNF-Tg) mice, a mouse model of chronic inflammatory arthritis. In the current study, we used Hes1-GFP and Hes1-GFP/TNF-Tg mice to study the distribution and dynamic change of Notch active cells in normal and inflammatory bone loss and mechanisms mediating their enhanced proliferation.

PTHrP Nuclear Localization and Carboxyl Terminus Sequences Modulate Dental and Mandibular Development in Part via the Action of p27.

To determine whether the action of the PTHrP nuclear localization sequence and C terminus is mediated through p27 in modulating dental and mandibular development, compound mutant mice, which are homozygous for both p27 deletion and the PTHrP1-84 knock-in mutation (p27(-/-)Pthrp(KI/KI)), were generated. Their teeth and mandibular phenotypes were compared with those of p27(-/-), Pthrp(KI/KI), and wild-type mice. At 2 weeks of age, the mandibular mineral density, alveolar bone volume, osteoblast numbers, and dental volume, dentin sialoprotein-immunopositive areas in the first molar were increased significantly in p27(-/-) mice and decreased dramatically in both Pthrp(KI/KI) and p27(-/-) Pthrp(KI/KI) mice compared with wild-type mice; however, these parameters were partly rescued in p27(-/-) Pthrp(KI/KI) mice compared with Pthrp(KI/KI) mice.

Bmi1 Regulates the Proliferation of Cochlear Supporting Cells Via the Canonical Wnt Signaling Pathway.

Cochlear supporting cells (SCs), which include the cochlear progenitor cells, have been shown to be a promising resource for hair cell (HC) regeneration, but the mechanisms underlying the initiation and regulation of postnatal cochlear SC proliferation are not yet fully understood. Bmi1 is a member of the Polycomb protein family and has been reported to regulate the proliferation of stem cells and progenitor cells in multiple organs. In this study, we investigated the role of Bmi1 in regulating SC and progenitor cell proliferation in neonatal mice cochleae.

The Chromatin Regulator BRPF3 Preferentially Activates the HBO1 Acetyltransferase but Is Dispensable for Mouse Development and Survival.

To interpret epigenetic information, chromatin readers utilize various protein domains for recognition of DNA and histone modifications. Some readers possess multidomains for modification recognition and are thus multivalent. Bromodomain- and plant homeodomain-linked finger-containing protein 3 (BRPF3) is such a chromatin reader, containing two plant homeodomain-linked fingers, one bromodomain and a PWWP domain.