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Nucleus pulposus cell (NPC) is the major cell type maintaining the physiological function of intervertebral discs by producing extracellular matrix (ECM). NPC apoptosis and senescence together contribute to NPC loss, finally leading to intervertebral disc degeneration (IDD). Herein, miR-623 showed to be downregulated within IDD tissue samples according to both bioinformatics and experimental analyses. In LPS-injured NPCs, miR-623 overexpression promoted LPS-suppressed cell proliferation; moreover, miR-623 overexpression inhibited cell apoptosis and senescence, increased ECM secretion, and reduced levels of inflammatory factors. In contrast to miR-623, CXCL12 expression was significantly upregulated in IDD tissues; miR-623 directly bound CXCL12 to inhibit its expression. In LPS-stimulated NPCs, CXCL12 silencing also LPS-induced changes in cell proliferation, cell senescence, ECM secretion, and inflammatory factor levels. More importantly, CXCL12 overexpression aggravated LPS-induced changes and significantly reversed the protective effects of miR-623 overexpression. In conclusion, the miR-623/CXCL12 axis could affect NPC apoptosis and senescence, ECM deposition, and inflammatory factor levels under LPS stimulation in vitro. The p65 signaling might be involved., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A properly functioning immune system is dependent on programmed cell death/apoptosis at virtually every stage of lymphocyte development and activity. Carbon monoxide (CO), an enzymatic product of heme oxyenase-1, has been shown to possess anti-apoptotic effects in a number of different model systems. The purpose of the present study was to expand on this knowledge to determine the role of CO in the well established model of Fas/CD95-induced apoptosis in Jurkat cells, and to determine the mechanism by which CO can modulate T-cell apoptosis. Exposure of Jurkat cells to CO resulted in augmentation in Fas/CD95-induced apoptosis, which correlated with CO-induced up-regulation of the pro-apoptotic protein FADD as well as activation of caspase-8, -9, and -3 while simultaneously down-regulating the anti-apoptotic protein BCL-2. These effects of CO were lost with overexpression of the small interfering RNA of FADD. CO, as demonstrated previously in endothelial cells, was also anti-apoptotic in Jurkat cells against tumor necrosis factor and etoposide. We further demonstrate that this pro-apoptotic effect of CO was independent of reactive oxygen species production and involved inhibition in Fas/CD95-induced activation of the pro-survival ERK MAPK. We conclude that in contrast to other studies showing the anti-apoptotic effects of CO, Fas/CD95-induced cell death in Jurkat cells is augmented by exposure to CO and that this occurs in part via inhibition in the activation of ERK MAPK. These data begin to elucidate specific differences with regard to the effects of CO and cell death pathways and provide important and valuable insight into potential mechanisms of action.

Successful lung transplantation has been limited by the high incidence of acute graft rejection. There is mounting evidence that the stress response gene heme oxygenase-1 (HO-1) and/or its catalytic by-product carbon monoxide (CO) confers cytoprotection against tissue and cellular injury. This led us to hypothesize that CO may protect against lung transplant rejection via its anti-inflammatory and antiapoptotic effects. Orthotopic left lung transplantation was performed in Lewis rat recipients from Brown-Norway rat donors. HO-1 mRNA and protein expression were markedly induced in transplanted rat lungs compared to sham-operated control lungs. Transplanted lungs developed severe intraalveolar hemorrhage, marked infiltration of inflammatory cells, and intravascular coagulation. However, in the presence of CO exposure (500 ppm), the gross anatomy and histology of transplanted lungs showed marked preservation. Furthermore, transplanted lungs displayed increased apoptotic cell death compared with the transplanted lungs of CO-exposed recipients, as assessed by TUNEL and caspase-3 immunostaining. CO exposure inhibited the induction of IL-6 mRNA and protein expression in lung and serum, respectively. Gene array analysis revealed that CO also down-regulated other proinflammatory genes, including MIP-1alpha and MIF, and growth factors such as platelet-derived growth factor, which were up-regulated by transplantation. These data suggest that the anti-inflammatory and antiapoptotic properties of CO confer potent cytoprotection in a rat model of lung transplantation.

Our study aimed at validating the effect of WISP1 on osteoarthritis (OA) and the pathway involved in the WISP1-induced protection against OA. The expression of WISP1 was measured by immunohistochemical analyses. We found that WISP1 expression was shown to be upregulated within human OA cartilage compared with controls. WISP1 expression was related to knee OA severity. rhWISP1 inhibited OA chondrocyte senescence and apoptosis in vitro, which was reversed by the αvβ3 antibody and PI3K/Akt inhibitor LY294002. WISP1 overexpression induced by knee injection of LiCI could also prevent the senescence and apoptosis of rat chondrocytes. Safranin-O staining and Mankin score revealed that WISP1 overexpression can protect rat chondrocytes from degeneration. Nearly opposite results were obtained in the treatment of ICG-001 and siRNA-WISP1 in vivo. These data strongly suggest that WISP1 can protect against the senescence and apoptosis of chondrocytes via modulating the αvβ3 receptor and PI3K/Akt signaling pathway within OA. Therefore, the development of specific activators of WISP1 may present the value of an underlying OA treatment. [ABSTRACT FROM AUTHOR]