Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair.

Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts.

A humanized monoclonal antibody targeting an ectonucleotidase rescues cardiac metabolism and heart function after myocardial infarction.

Myocardial infarction (MI) results in aberrant cardiac metabolism, but no therapeutics have been designed to target cardiac metabolism to enhance heart repair. We engineer a humanized monoclonal antibody against the ectonucleotidase ENPP1 (hENPP1mAb) that targets metabolic crosstalk in the infarcted heart. In mice expressing human ENPP1, systemic administration of hENPP1mAb metabolically reprograms myocytes and non-myocytes and leads to a significant rescue of post-MI heart dysfunction.

Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis.

After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated.

Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury.

Renal ischemia/reperfusion (I/R) injury contributes to the development of acute kidney injury (AKI). Kidney is the second organ rich in mitochondrial content next to the heart. Mitochondrial damage substantially contributes for AKI development.

Author Correction: KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Carbon monoxide sensitizes cisplatin-resistant ovarian cancer cell lines toward cisplatin via attenuation of levels of glutathione and nuclear metallothionein.

Cisplatin resistance remains a major impediment to effective treatment of ovarian cancer. Despite initial platinum responsiveness, thiol-containing peptides and proteins, glutathione (GSH) and metallothionein (MT), bind and inactivate cisplatin in cancer cells. Indeed, high levels of GSH and MT in ovarian cancers impart cisplatin resistance and are predictive of poor prognosis.

Pregnancy Outcomes in Women of Advanced Maternal Age: a Retrospective Cohort Study from China.

This retrospective cohort study attempts to investigate pregnancy complications and adverse pregnancy outcomes in women of advanced maternal age (AMA). Data were extracted from electronic medical records system at West China Second University Hospital of Sichuan University from January 2013 to July 2016. The study cohort consisted 8 subgroups of women on 4 different age levels (20-29 years, 30-34 years, 35-39 years and ≥40 years) and 2 different parities (primiparity and multiparity).

KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling.

Human colorectal cancer stem cells (CSCs) are tumour initiating cells that can self-renew and are highly tumorigenic and chemoresistant. While genetic mutations associated with human colorectal cancer development are well-known, little is known about how and whether epigenetic factors specifically contribute to the functional properties of human colorectal CSCs. Here we report that the KDM3 family of histone demethylases plays an important role in tumorigenic potential and survival of human colorectal CSCs by epigenetically activating Wnt target gene transcription.

Targeting BMI1 Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma.

Squamous cell carcinoma in the head and neck (HNSCC) is a common yet poorly understood cancer, with adverse clinical outcomes due to treatment resistance, recurrence, and metastasis. Putative cancer stem cells (CSCs) have been identified in HNSCC, and BMI1 expression has been linked to these phenotypes, but optimal treatment strategies to overcome chemotherapeutic resistance and eliminate metastases have not yet been identified. Here we show through lineage tracing and genetic ablation that BMI1 CSCs mediate invasive growth and cervical lymph node metastasis in a mouse model of HNSCC.

γ-Aminobutyric Acid Is Synthesized and Released by the Endothelium: Potential Implications.

Rationale: Gamma aminobutyric acid (GABA), a neurotransmitter of the central nervous system, is found in the systemic circulation of humans at a concentration between 0.5 and 3 μmol/L. However, the potential source of circulating GABA and its significance on the vascular system remains unknown.

Branched-Chain Amino Acid-Rich Supplements Containing Microelements Have Antioxidant Effects on Nonalcoholic Steatohepatitis in Mice.

Background: The aim of the present study was to elucidate whether the administration of antioxidant-rich nutrients, including branched-chain amino acids (BCAAs), microelements, and vitamins, both alone and in combination, has a positive impact on liver function in a nonalcoholic steatohepatitis (NASH) mouse model and identify the mechanisms underlying these effects.

Methods: Seven-week-old male KKAy mice fed a methionine- and choline-deficient diet (MCD) for 4 weeks were divided into 7 groups and fed the following planned diets for another 4 weeks: group A (normal diet), group B (MCD; control), group C (MCD with rich microelements), group D (MCD with rich BCAAs), group E (MCD with rich microelements and BCAAs), and group F (MCD with rich microelements, BCAAs, and vitamins). We then conducted biochemical assays, histological analyses, immunohistochemistry for 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2'-nonenal (4-HNE), and Western blotting for insulin glucose signaling, lipid metabolism, and endoplasmic reticulum (ER) stress-related signaling in liver specimens obtained from mice in each group.

Gestational diabetes, preeclampsia and cytokine release: similarities and differences in endothelial cell function.

Gestational diabetes, pre-eclampsia as well as intra-uterine infection during pregnancy affects the function of the endothelium both in the mother and the fetus leading to endothelial dysfunction. Gestational diabetes is also associated with an increased incidence of pre-eclampsia and it is likely that both the hyperglycemia as well as the release of cytokines especially TNFα during hyperglycemia may play an important role in the pathogenesis of endothelial dysfunction leading to preeclampsia. Similarly, some but not all studies have suggested that infection of the mother under certain circumstances can also lead to preeclampsia as women with either a bacterial or viral infection were at a higher risk of developing preeclampsia, compared to women without infection and infection also leads to a release in TNFα.

Histone demethylase KDM6B promotes epithelial-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) is a critical event that occurs in embryonic development, tissue repair control, organ fibrosis, and carcinoma invasion and metastasis. Although significant progress has been made in understanding the molecular regulation of EMT, little is known about how chromatin is modified in EMT. Chromatin modifications through histone acetylation and methylation determine the precise control of gene expression.

In vitro mechanisms involved in the regulation of cell survival by lithium chloride and IGF-1 in human hormone-dependent breast cancer cells (MCF-7).

Lithium, the lightest of all solid elements, has been used for the treatment of bipolar disorder since 1970s and prescribed to millions of women worldwide. Lithium chloride (LiCl) has been considered to be a potent inhibitor of glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase that is involved in the control of cell proliferation, differentiation, and apoptosis. In addition, GSK-3β has been found to be inhibited endogenously by insulin-like growth factor-1 (IGF-1), a potent mitogen that plays an important role in the survival, growth, and differentiation of normal and neoplastic cells.

PPARγ potentiates anticancer effects of gemcitabine on human pancreatic cancer cells.

In order to improve the prognosis of patients with unresectable pancreatic cancer, there is an urgent need for enhancement of the anticancer effect of gemcitabine (Gem), a first-line drug for the disease. Here, we demonstrated that ligands for peroxisome proliferator-activated receptor γ (PPARγ) such as pioglitazone (Pio) and rosiglitazone potentiated the cytotoxic action of Gem on human pancreatic cancer cells in a dosage-dependent manner. Notably, the synergistic effect was PPARγ-dependent, since the effect was augmented by PPARγ overexpression and was attenuated by both a PPARγ inhibitor (GW9662) and PPARγ-specific siRNA.

Transducin β-like protein 1 recruits nuclear factor κB to the target gene promoter for transcriptional activation.

Nuclear factor κB (NF-κB) signaling controls a wide range of cellular functions such as tumor progression and invasion by inducing gene expression. Upon stimulation, NF-κB is translocated to the nucleus and binds to its target gene promoters to activate transcription by recruiting transcription coactivators. Although significant progress has been made in understanding NF-κB-mediated transactivation, little is known about how NF-κB is recruited to its target gene promoters.

Dihydrotestosterone is a determinant of calcaneal bone mineral density in men.

Male osteoporosis is an increasingly important health problem worldwide. Though androgen deficiency leads to bone loss in men, information on the relative contribution of aromatizable and non-aromatizable androgens in maintaining bone mineral density (BMD) and the mechanisms involved are unclear. This cross-sectional study was designed to explore the same.

Epigallocatechin-3-gallate improves nonalcoholic steatohepatitis model mice expressing nuclear sterol regulatory element binding protein-1c in adipose tissue.

We examined whether or not epigallocatechin-3-gallate (EGCG) improves liver injury of nonalcoholic steatohepatitis (NASH) model mice expressing nuclear sterol regulatory element-binding protein 1c (nSREBP-1c) in adipose tissue. nSREBP-1c transgenic C57BL6 mice aged 30 weeks were divided into group 1 (no treatment), group 2 (ascorbic acid alone), group 3 (ascorbic acid and 0.05% EGCG), and group 4 (ascorbic acid and 0.

Autocrine loop for IGF-I receptor signaling in SLUG-mediated epithelial-mesenchymal transition.

Akt, a downstream effector kinase of insulin receptor and insulin-like growth factor-I receptor (IGF-IR), is critically involved in epithelial-mesenchymal transition (EMT). The aim of this study was to assess the impact of SLUG in the IGF/IGF-IR/Akt axis. The SLUG-overexpressing MDCK (SLUG-MDCK) cell clones were used as the EMT model.

Radiation exposure impairs luteinizing hormone signal transduction and steroidogenesis in cultured human leydig cells.

Therapeutic, accidental, and experimental radiation exposures decreased serum testosterone in males, leading to various sexual problems. Since testicular Leydig cells are the predominant source of circulating testosterone, findings on the direct effects of radiation on Leydig cell steroidogenesis and the mechanism behind such effects would be of greater importance to the use of safer radiation doses in cancer therapy and to adopt preventive or therapeutic measures to alleviate postirradiation lesions, respectively. Therefore, this study was undertaken to explore the same using cultured human Leydig cells.

Metyrapone-induced corticosterone deficiency impairs glucose oxidation and steroidogenesis in Leydig cells of adult albino rats.

The present study was designed to identify the effects of metyrapone-induced corticosterone deficiency on Leydig cell steroidogenesis in adult male rats. Adult Wistar rats (200-250 g body weight) were treated with metyrapone, an inhibitor of corticosterone synthesis (10 mg/100 g body weight, s.c.