BackgroundHepatocellular carcinoma (HCC) remains a major public health problem worldwide. The identification of effective chemotherapeutic targets for advanced HCC patients is urgently required. In this study, we investigated the role of protein phosphatase 2A-B55δ subunit (PP2A-B55δ, encoded by the PPP2R2D gene) and related mechanisms affecting chemotherapy sensitivity of HCC.MethodsExperimental approaches for measuring the levels of PPP2R2D mRNA and B55δ protein in HCC included bioinformatics analyses, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB), immunofluorescence and immunohistochemistry assays. Cell cycle, migration, colony formation, apoptosis, and cell proliferation assays in stable PPP2R2D-knockdown and -overexpression cell lines in vitro, and tumorigenicity assays in vivo, were performed to explore the function of B55δ in cisplatin (cDDP) chemotherapy of HCC. Bioinformatics prediction, luciferase reporter assays, qRT-PCR, WB, and cell cycle analyses were used to reveal the regulatory relationship between microRNA-133b (miR-133b) and PPP2R2D expression. miR-133b mimic and inhibitor were used to elucidate the regulatory mechanism.ResultsOur studies showed that PPP2R2D expression was down-regulated in both HCC tumors and HCC cell lines. Treatment with cDDP increased the amount of B55δ protein. Artificially increasing the expression of B55δ counteracted cyclin-dependent kinase 1 activation, modulated transitions of the cell cycle, and increased the suppressive effect of cDDP on cell migration, colony formation, apoptosis, and proliferation in vitro and tumor growth in vivo, thus enhancing therapeutic efficiency. In contrast, knockdown of B55δ partially inhibited the effect of cDDP chemotherapy. miR-133b was shown to regulate PPP2R2D expression by binding to the 3’-untranslated region of PPP2R2D mRNA. The miR-133b/PPP2R2D signaling pathway affects the effectiveness of cDDP chemotherapy.ConclusionsPP2A-B55δ, regulated by miR-133b, enhances the sensitivity of HCC to cDDP chemotherapy. Our data indicate that PP2A-B55δ might be a novel and attractive target for increasing chemotherapy sensitivity of HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0341-z) contains supplementary material, which is available to authorized users.
Mitochondrial quality control (MQC) is implicated in cell death induced by heavy metal pollutants. Dynamin-related protein 1 (Drp1) regulates mitochondrial fission, which is an important part of MQC. Retinoblastoma (RB) protein can regulate MQC in a transcription-independent manner. Necroptosis plays a critical role in hepatic pathologies such as inflammatory, infectious, and xenobiotics-induced injury and diseases. We aimed to explore the role and mechanism of Drp1 interaction with RB in hepatocyte’s necroptosis caused by cadmium (Cd). CdCl 2 was employed to expose to Institute of Cancer Research (ICR) mice and human hepatic L02 cells. CdCl 2 exposure induced necroptosis and hepatic injury both in vivo and in vitro. Moreover, Drp1 and RB protein were up-regulated and translocated to mitochondria in CdCl 2 -exposed hepatocytes. Inhibition of Drp1 with siRNA (si DNM1L ) or inhibitors not only suppressed the RB expression and its mitochondrial translocation, but also alleviated MQC disorder, necroptosis, and hepatotoxicity caused by CdCl 2 . Moreover, blocking Drp1 with metformin rescued necroptosis and hepatic injury triggered by CdCl 2 . RB was proved to directly interact with Drp1 at mitochondria to form a complex which then bound to receptor interaction protein kinase (RIPK3) and enhanced the formation of necrosome after CdCl 2 exposure. In summary, we found a new molecular mechanism of regulated cell death that Drp1 interacted with RB and promoted them mitochondrial translocation to mediate necroptosis and hepatic injury in hepatocytes induced by Cd-exposure. The mitochondrial Drp1-RB axis would be a novel target for the protection cells from xenobiotics triggering hepatic injury and diseases involved in necroptosis.
IntroductionAtherosclerosis is the main pathological change in diabetic angiopathy, and vascular inflammation plays an important role in early atherosclerosis. Extracellular heat shock protein 90 (eHsp90) is secreted into the serum and is involved in various physiological and pathophysiological processes. However, the specific mechanism of eHsp90 in early atherosclerosis remains unclear. This study explored the relationship between Hsp90 and diabetic lower extremity arterial disease and investigated the expression of eHsp90 in vascular endothelial cells under environmental stimulation and the function and mechanism of eHsp90α involved in diabetic atherosclerosis.Research design and methodsOne hundred and three selected patients were divided into three groups: the diabetes mellitus group (n=27), the diabetic lower extremity arterial disease group (n=46), and the diabetic critical limb ischemia group (n=30). The relationships among serum Hsp90, oxidative stress indexes, and patient outcomes and the correlations among the indexes were analyzed. H&E staining and immunohistochemistry were used to observe the vasculature of amputated feet from patients with diabetic foot. An oxidative stress endothelial injury model was established under high glucose in vitro to explore the role of eHsp90 release in atherosclerosis progression.ResultsThe level of serum Hsp90 was upregulated with aggravation of diabetic vascular disease. Hsp90α was correlated with malondialdehyde to some extent and was an independent risk factor in the progression of diabetic vascular disease, with predictive ability. The expression area of Hsp90α was consistent with the area of inflammatory infiltration in the vessel lumen. Vascular endothelial cells were found to increase eHsp90α secretion under stress. Then inhibition of eHsp90α can reduce the degree of cellular inflammation and damage. Endothelial cell-conditioned medium and recombinant human Hsp90α increased monocyte migration via the low-denisity lipoprotein receptor-related protein 1 (LRP1) receptor to promote disease progression.ConclusionseHsp90α plays a critical role in the early inflammatory injury stage of atherosclerosis.Trial registration numberNCT04787770.
Macrophages, the main immune cells in the skin, form an innate immune barrier. Under physiological conditions, skin maintains immune barrier function through macrophage phagocytosis and antigen presentation. Parenchymal and stromal cell regeneration plays an important role in skin injury repair and uses macrophage plasticity to influence and stabilize the skin microenvironment. Diabetic skin lesions are the most common diabetes complication and are involved in the early pathophysiology of diabetic foot. Therefore, studying the initial link in diabetic skin lesions is a research hot spot in the early pathogenesis of diabetic foot. Skin inflammation caused by hyperglycaemia, oxidative stress and other injuries is an important feature, but the specific mechanism is unknown. Recent studies have suggested that chronic inflammatory injury is widely involved in a variety of skin diseases, and whether it plays an important role in diabetic skin lesions is unclear. In this review, current research hotspots were combined with the pathogenesis of diabetic skin lesions and analysed from the perspectives of the physiological function of skin macrophages, the impairment of skin macrophages in diabetes, and the mechanism of chronic inflammatory injury in macrophages to provide a theoretical basis for early screening and evaluation of diabetic foot.
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