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Abstract Stem cells transplantation has shown considerable promise in intervertebral disc repair and low-back pain release. Cartilage endplate stem cells (CESCs) also showed potential for nucleus pulposus (NP) regeneration in a rabbit disc degeneration model, the precise mechanism was unclear. Here we investigated the effects of CESCs on NP cells (NPCs) proliferation and the mechanism in vitro. CESCs and NPCs were isolated from surgical specimens of degenerative human lumbar disc. NPCs were co-cultured with CESCs at a 1:1 ratio or cultured in CESCs conditioned medium (CESCs-CM). NPCs proliferation was evaluated by Ki-67 staining, CCK-8 assay and cell cycle analysis. Gene expressions were detected by qRT-PCR and activation of Akt and ERK1/2 was detected by western blot. CXCR4 antagonist AMD3100 was used to block SDF-1/CXCR4 axis. ERK1/2 and Akt inhibitors were used to block Akt and ERK1/2 activation. Results showed that NPCs proliferation was promoted by direct-contact co-culturing with CESCs as well as culturing in CESCs-CM. SDF-1 expression level in CESCs was significantly higher than that in NPCs, while CXCR4 was the opposite. Promotion of NPCs proliferation mediated by CESCs-CM could be partially attenuated by AMD3100. CESCs-CM activated both Akt and ERK1/2 in NPCs, while rhSDF-1 scarcely activated Akt but obviously activated ERK1/2. Akt and ERK1/2 inhibitors could partially inhibited CESCs-CM mediated promotion of NPCs proliferation and showed cumulative effect, while ERK1/2 inhibitor and AMD3100 could significantly abrogate SDF-1 mediated promotion of NPCs proliferation. Our results suggested that CESCs might promote NPCs proliferation in a paracrine pathway, which was partially mediated by SDF-1/CXCR4 axis via ERK1/2 signaling transduction pathway. Highlights • NPCs proliferation was promoted by co-cultured CESCs and CESCs-CM in vitro. • SDF-1 and CXCR4 were expressed in a complementary pattern in CESCs and NPCs. • CESCs promoted NPCs proliferation partially via SDF-1/CXCR4 axis. • SDF-1/CXCR4 axis mainly activated ERK1/2 pathway rather than Akt pathway in NPCs. • CESCs upregulated TIMP1 expression in NPCs in a SDF-1/CXCR4 axis independent manner. [ABSTRACT FROM AUTHOR]

Abstract: Nitration of tyrosine residues in proteins is associated with cell response to oxidative/nitrosative stress. Tyrosine nitration is relatively low abundant post-translational modification that may affect protein functions. Little is known about the extent of protein tyrosine nitration in cells during progression through the cell cycle. Here we report identification of proteins enriched for tyrosine nitration in cells synchronized in G0/G1, S or G2/M phases of the cell cycle. We identified 27 proteins in cells synchronized in G0/G1 phase, 37 proteins in S phase synchronized cells, and 12 proteins related to G2/M phase. Nineteen of the identified proteins were previously described as regulators of cell proliferation. Thus, our data indicate which tyrosine nitrated proteins may affect regulation of the cell cycle. [Copyright &y& Elsevier]

Cardiac fibrosis will increase wall stiffness and diastolic dysfunction, which will eventually lead to heart failure. Asenapine maleate (AM) is widely used in the treatment of schizophrenia. In the current study, we explored the potential mechanism underlying the role of AM in angiotensin II (Ang II)-induced cardiac fibrosis. Cardiac fibroblasts (CFs) were stimulated using Ang II with or without AM. Cell proliferation was measured using the cell counting kit-8 assay and the Cell-Light EdU Apollo567 In Vitro Kit. The expression levels of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) were detected using immunofluorescence or western blotting. At the protein level, the expression levels of the components of the transforming growth factor beta 1 (TGFβ1)/mitogen-activated protein kinase (MAPK) signaling pathway were also detected. After Ang II stimulation, TGFβ1, TGFβ1 receptor, α-SMA, fibronectin (Fn), collagen type I (Col1), and collagen type III (Col3) mRNA levels increased; the TGFβ1/MAPK signaling pathway was activated in CFs. After AM pretreatment, cell proliferation was inhibited, the numbers of PCNA -positive cells and the levels of cardiac fibrosis markers decreased. The activity of the TGFβ1/MAPK signaling pathway was also inhibited. Therefore, AM can inhibit cardiac fibrosis by blocking the Ang II-induced activation through TGFβ1/MAPK signaling pathway. This is the first report to demonstrate that AM can inhibit Ang II-induced cardiac fibrosis by down-regulating the TGFβ1/MAPK signaling pathway. In this process, AM inhibited the proliferation and activation of CFs and reduced the levels of cardiac fibrosis markers. Thus, AM represents a potential treatment strategy for cardiac fibrosis. • Asenapine maleate (AM): new cardiac uses for an old drug. • AM, as a drug for the treatment of schizophrenia, could inhibit cardiac fibrosis. • AM acts through ROS/TGFβ1/MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) have obtained growing attention due to their potential effects as novel regulators in various tumors. This study aimed to investigate the expression and roles of lncRNA LINC01139 (LINC01139) in the progression of hepatocellular carcinoma (HCC). We found that LINC01139 was over-expressed in HCC specimens and cell lines, and its upregulation was observed to be associated with advanced TNM stage, lymph node metastasis and poor clinical prognosis of HCC patients. Multivariate analyses confirmed that LINC01139 expression was an independent poor prognostic factor for HCC patients. Functionally, the knockdown of LINC01139 suppressed cell proliferation, clone formation and metastasis of HCC cells. Moreover, luciferase assays and rescue experiments revealed that LINC01139/miR-30/MYBL2 established the ceRNA network involved in the modulation of cell proliferation and metastasis of HCC cells. Overall, LINC01139 may exhibit an oncogenic function in HCC via acting as a sponge for miR-30 to upregulate MYBL2, and may serve as a potential therapeutic target and a prognostic biomarker for HCC patients. • The levels of lncRNA LINC01139 was up-regulated in HCC. • Overexpression of lncRNA LINC01139 was associated with advanced clinical features and poor prognosis in HCC patients. • LncRNA LINC01139 promoted HCC cells proliferation and metastasis through miR-30 family/MYBL2 axis. [ABSTRACT FROM AUTHOR]

Stroke ranks as the second leading cause of disability and death globally. Trigger receptors expressed on myeloid cells (TREM) −1 are responsible for the activation of the innate immune response and also play a critical role in inflammation. In this study, we reported the contribution of TREM-1 after ischemic damage in a rat middle cerebral artery occlusion (MCAO) model. This study also demonstrated that TREM-1 expression was upregulated following cerebral infarction in rats. TREM-1 inhibition was determined using its selective inhibitor, LP17, which indicated a neuroprotective effect on cerebral infarction damage. The findings revealed that inhibition of TREM-1 by administering LP17 improved cerebral damage and decreased ischemic areas and brain water contents. Moreover, LP17 decreased MCAO-induced microglial activation and neurodegeneration, evidenced by a reduction in the expression of microglial Iba-1 and FJ-B positive cells, and reversed neuronal loss. Besides, the contribution of LP17 to ischemic neuronal damage may be associated with a decrease in the production of pro-inflammatory cytokines, and enhanced production of anti-inflammatory cytokine IL-10. Both in vivo and in vitro studies showed that inhibiting TREM-1 attenuated ROS accumulation, lipid per-oxidation (LPO) contents such as malondialdehyde (MDA) and enhanced the superoxide dismutase (SOD) activity after ischemia. Inhibiting TREM-1 alleviated inflammation and pyroptosis found in MCAO rats. This was achieved through the inhibition of the levels of NLRP3, caspase-1, ASC (an apoptosis-associated speck-like protein containing a CARD) and gasdermin D. These results confirmed that inhibiting TREM-1 protects against ischemia-induced neuronal damage and alleviates microglial mediated neuro-inflammation by reducing oxidative stress and pyroptosis. Therefore, blocking TREM-1 expression provides an effective intervention for improving ischemic stroke. • TREM-1-targeting LP-17 alleviates ischemic neuronal damage and microglial activation in MCAO rats. • TREM-1-targeting LP-17 attenuates inflammation, oxidative stress and pyroptosis in MCAO rats. • Suppressing TREM-1 inhibits oxidative stress and pyroptosis in OGDR-treated co-culture cells. [ABSTRACT FROM AUTHOR]

Proadrenomedullin N-terminal 20 peptide (PAMP) is elevated in sepsis, but the function and possible mechanism of PAMP in bacterial infection is elusive. This study is aim to evaluate the role of PAMP in the interaction between the Enterohemorrhagic E. coli (EHEC) and the host barrier. Our results showed that PAMP alleviated the EHEC-induced disruption of goblet cells and mucosal damage in the intestine, increased the expression of occludin in the colon of EHEC-infected mice, and reduced the proinflammatory cytokines level in serum significantly compared with the control group. Meanwhile, lipopolysaccharide (LPS) stimulation could dose-dependently induce the expression of preproADM, the precursor of PAMP, in human intestinal epithelial cell (HIEC) and human umbilical vein endothelial cell (HUVEC). In addition, PAMP inhibited the growth of EHEC O157:H7 and destroyed the inner and outer membrane. At low concentration, PAMP attenuated the EHEC virulence genes including hlyA and eaeA, which was also confirmed from reduced hemolysis to red cells and adhesion to HIEC. These results indicated that EHEC infection would modulate the expression of PAMP in intestinal epithelium or vascular endothelium, and in turn exerted a protective effect in EHEC induced infection by rupturing the bacterial cell membrane and attenuating the bacterial virulence. • The protective activity of PAMP to the colon from Enterohemorrhagic E. coli infection. • The mechanism explains the anti-bacterial activity of PAMP. • Lipopolysaccharide induces the expression of PAMP precursor in intestinal epithelial cells. • The role of PAMP in interaction between E. coli infection and intestinal epithelium is proposed. [ABSTRACT FROM AUTHOR]

Ghrelin is a gastric acyl-peptide that plays an important role in cell proliferation. In the present study, we explored the role of ghrelin in A549 cell proliferation and the possible molecular mechanisms. We found that ghrelin promotes A549 cell proliferation, knockdown of the growth hormone secretagogue receptor (GHSR) attenuated A549 cell proliferation caused by ghrelin. Ghrelin induced the rapid phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, ERK, mammalian target of rapamycin (mTOR) and P70S6K. PI3K inhibitor (LY 294002), ERK inhibitor (PD98059) and mTOR inhibitor (Rapamycin) inhibited ghrelin-induced A549 cell proliferation. Moreover, GHSR siRNA inhibited phosphorylation of PI3K, Akt, ERK, mTOR and P70S6K induced by ghrelin. Akt and mTOR/P70S6K phosphorylation was inhibited by LY 294002 but not by PD98059. These results indicate that ghrelin promotes A549 cell proliferation via GHSR-dependent PI3K/Akt/mTOR/P70S6K and ERK signaling pathways. [ABSTRACT FROM AUTHOR]

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein with multi-functions and plays an important role in tumorigenesis and metastasis in various human cancers. In the present study, we found that HMGB1 induced migration of in human non-small cell lung cancer (NSCLC) cells by up-regulating integrin αvβ3 expression. Further investigation evidenced that HMGB1 activated Toll-like receptor 4 (TLR4) and NF-κB, which was responsible for αvβ3 up-regulation. Furthermore, HMGB1-induced integrin αvβ3 expression led to focal adhesion kinase (FAK) phosphorylation and increased paxillin and talin mRNA expression. Knockdown HMGB1 inhibited xenograft tumor metastasis in athymic mice. Taken together, our findings suggested that HMGB1 enhances tumor cell migration ability by activating αvβ3/FAK through TLR4/NF-κB signaling, leading to metastasis of NSCLC. [ABSTRACT FROM AUTHOR]

Highlights: [•] Metabolic syndrome exacerbated MI/R induced injury accompanied by decreased Nur77. [•] ROS led to Nur77 translocation in metabolic syndrome. [•] Inhibiting relocation of Nur77 to mitochondria reduced ROS-induced cardiomyocyte injury in metabolic syndrome. [Copyright &y& Elsevier]