CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPδ

Dysregulated lineage commitment of mesenchymal stem cells(MSCs)contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis.The intrinsic cellular mechanism that regulates MSC commitment remains unclear.Here,we identified Cullin 4B(CUL4B)as a critical regulator of MSC commitment.CUL4B is expressed in bone marrow MSCs(BMSCs)and downregulated with aging in mice and humans.Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation.Moreover,depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy.In addition,CUL4B deficiency in MSCs reduced bone strength.Mechanistically,CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδexpression,respectively.The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription.Collectively,this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs,which has therapeutic implications in osteoporosis.

Gut-on-a-chip for exploring the transport mechanism of Hg(II)

Animal models and static cultures of intestinal epithelial cells are commonly used platforms for exploring mercury ion(Hg(II))transport.However,they cannot reliably simulate the human intestinal microenvironment and monitor cellular physiology in situ;thus,the mechanism of Hg(II)transport in the human intestine is still unclear.Here,a gut-on-a-chip integrated with transepithelial electrical resistance(TEER)sensors and electrochemical sensors is proposed for dynamically simulating the formation of the physical intestinal barrier and monitoring the transport and absorption of Hg(II)in situ.The cellular microenvironment was recreated by applying fluid shear stress(0.02 dyne/cm^(2))and cyclic mechanical strain(1%,0.15 Hz).Hg(II)absorption and physical damage to cells were simultaneously monitored by electrochemical and TEER sensors when intestinal epithelial cells were exposed to different concentrations of Hg(II)mixed in culture medium.Hg(II)absorption increased by 23.59%when tensile strain increased from 1%to 5%,and the corresponding expression of Piezo1 and DMT1 on the cell surface was upregulated.

The histone acetyltransferase MOF is required for the cellular stress response

When exposing to environmental stress or internal damage,such as genotoxic stress,oxidative stress,and heat stress,cells produce a series of adaptive responses called cellular stress responses[1].The major proteins involved in cellular stress are heat shock proteins(HSPs).HSPs remain in a low expression level and display a diffused distribution in the nucleoplasm and cytoplasm under basal conditions.In response to various stress conditions。

A benzoxazine derivative specifically inhibits cell cycle progression in p53-wild type pulmonary adenocarcinoma cells

A fundamental aspect of cancer development is cancer cell proliferation.Seeking for chemical agents that can interfere with cancer cell growth has been of great interest over the years.In our study,we found that a benzoxazine derivative,(6-tert-butyl-3,4-dihydro-2Hbenzo[b][1,4]oxazin-3-yl)methanol(TBM),could inhibit cell growth and caused significant cell cycle arrest in pulmonary adenocarcinoma A549 and H460 cells with wild-type p53,while not affecting the cell cycle distribution in p53-deleted H1299 lung adenocarcinoma cells.Since P53 plays an important role in regulating cell cycle progression,we analyzed the protein level of p53 by Western blot,and detected a significant elevation of p53 level after TBM treatment in A549 and H460 cells.The data suggested that TBM might specifically inhibit the proliferation of p53 wild-type lung adenocarcinoma cells through a p53-dependent cell cycle control pathway.More interestingly,results indicated that TBM might serve as a useful tool for studying the molecular mechanisms of lung cancer cell growth and cell cycle control,especially for the biologic process regulated by P53.