bluuebunny/crossref_metadata_2025_split huggingface dataset:
TLR2 protects cisplatin‐induced acute kidney injury associated with autophagy via PI3K/Akt signaling pathway
Authors: Shen Qing , Zhang Xi , Li Qiuying , Zhang Jing , Lai Heng , Gan Hua , Du Xiaogang , Li Manli 
Published: November 2018

AbstractToll‐like receptors (TLRs), which are essential components of the innate immune response, play an important role in acute kidney injury (AKI). Toll‐like receptor 2 (TLR2) is constitutively expressed in tubular epithelial cells of the kidney and participates in cisplatin‐induced AKI. The autophagy is a dynamic catabolic process that maintains intracellular homeostasis, which is involved in the pathogenesis of AKI. Recent studies demonstrate that PI3K/Akt signaling pathway regulates autophagy in response to various stimuli. Therefore, we propose that cisplatin might activate TLR2, which subsequently phosphorylates PI3K/Akt, leading to enhanced autophagy of renal tubular epithelial cells and protecting cisplatin‐induced AKI. We found that TLR2 expression was significantly increased in the kidney after the cisplatin treatment. TLR2‐deficient mice exacerbated renal injury in cisplatin‐induced AKI, with higher serum creatinine and blood urea nitrogen, more severe morphological injury compared with that of wild‐type mice. In vitro, we found that inhibition of TLR2 reduced tubular epithelial cell autophagy after the cisplatin treatment. Mechanistically, TLR2 inhibited autophagy via activating PI3K/Akt signaling pathway in renal tubular epithelial cells after the cisplatin treatment. Take together, these results suggest that TLR2 may protect cisplatin‐induced AKI by activating autophagy via PI3K/Akt signaling pathway.
P65‐mediated miR‐590 inhibition modulates the chemoresistance of osteosarcoma to doxorubicin through targeting wild‐type p53‐induced phosphatase 1
Authors: Long Xiao , Lin Xiang‐Jin 
Published: November 2018

AbstractOsteosarcoma (OS) is a primary malignant bone tumor with high morbidity. Developing new therapeutic approaches with neoadjuvant is of great interest in OS treatment. Reportedly, ataxia telangiectasia mutated (ATM)/ataxia telangiectasia and radiation resistance gene 3 related (ATR)‐p53 signaling is considered as a critical DNA damage signaling pathway sensitizing cancer cells to chemotherapies; while wild‐type p53‐induced phosphatase 1 (WIP1), an oncogene overexpressed in diverse cancers, has been regarded as a critical inhibitor in the ATM/ATR‐p53 DNA damage signaling pathway. Herein, the expression of WIP1 in OS tissues and cell lines was examined; to investigate the mechanism of WIP1 abnormal upregulation, online tools were used to predict the upstream regulatory microRNAs (miRNAs) targeting WIP1. Among the candidate miRNAs, the expression and detailed function of miR‐590 were validated. Through binding to the 3′‐untranslated region of WIP1, miR‐590 inhibited WIP1 expression and, therefore, enhanced the effect of Dox on OS cell proliferation and apoptosis through downstream ATM‐p53 signaling. Moreover, RELA could bind to the promoter region of miR‐590 to inhibit its expression, thereby affecting downstream WIP1 and ATM‐p53 signaling. The expression of p65 was upregulated in OS tissues, indicating that the effect of p65 inhibition on cell viability, apoptosis, and related mechanisms could be partially restored by miR‐590 inhibition. Taken together, these results showed that p65‐mediated miR‐590/WIP1/ATM‐p53 modulation might be a novel target to enhance the cellular effect of Dox on OS cell lines.
Structural and functional analysis of single‐nucleotide polymorphic variants of purine‐rich element‐binding protein B
Authors: Ferris Lauren A. , Kelm Robert J. 
Published: November 2018

AbstractPurine‐rich element‐binding protein B (Purβ) inhibits myofibroblast differentiation by repressing the expression of the smooth muscle α‐actin gene (Acta2). Several reports have identified the structural domains in Purβ that enable its characteristic interaction with purine‐rich single‐stranded DNA (ssDNA) sequences in the Acta2 promoter. However, little is known about the physical and functional effects of single‐nucleotide polymorphisms that alter individual amino acid residues in Purβ. This study evaluated seven rare single amino acid variants of human PURB engineered into the homologous mouse Purβ protein. Mapping the location of variant residues on a homology model of the Purβ homodimer suggested that most of the altered residues are remote from the predicted ssDNA‐binding regions of the protein. The repressor activity of each Purβ variant was assessed in transfected fibroblasts and smooth muscle cells via Acta2 promoter‐reporter assays. A Q64* nonsense variant was completely inactive while missense variants exhibited repressor activity that ranged from ~1.5‐fold greater to ~2‐fold less than wild‐type Purβ. Lower activity variants P223L and R297Q were expressed in bacteria and purified to homogeneity. Each variant was physically indistinguishable from wild‐type Purβ in terms of quaternary structure and thermostability. Results of DNA and protein‐binding assays indicated that the P223L and R297Q variants retained high affinity and specificity for purine‐rich ssDNA sequences but differed in their interaction with other Acta2 regulatory proteins. These findings suggest that the presence of certain variant residues affects the Acta2 repressor activity of Purβ by altering its interaction with other transcription factors but not with ssDNA.
Increased CDKL3 expression predicts poor prognosis and enhances malignant phenotypes in esophageal squamous cell carcinoma
Authors: Ye Wenguang , Zhu Jian , He Dongjie , Yu Dequan , Yang Haihua , Wang Wei , Zhang Mingxin , Zhou Suna 
Published: November 2018

AbstractBackgroundCyclin‐dependent kinase‐like 3 (CDKL3) is a putative protein serine kinase and plays an important role in the regulation of cell growth and/or differentiation. However, studies on the function of CDKL3 in esophageal squamous cell carcinoma (ESCC) is limited. In our study, we explored the role and prognosis of CDKL3 in ESCC and underlying mechanism.Materials and methodsThe expression of CDKL3 was investigated by quantitative reverse transcription polymerase chain reaction and immunohistochemical staining. CDKL3 expression was downregulated by the RNAi‐mediated knockdown. The functions of CDKL3 on cell growth were assessed by Celigo image cytometry, MTT assay, cell‐cycle analysis, Annexin V assay, and caspase‐3/7 activity analysis. The effect of CDKL3 on cellular invasive was investigated by the Transwell assay. Pathscan Stress Signaling Antibody Array was used to study the underlying mechanism. Additionally, the association between the survival and CDKL3 expression in ESCC were evaluated based on the TCGA data.ResultsCDKL3 was highly expressed in ESCC tissues and cell lines. TE‐1 cells transfected with CDKL3‐shRNA‐lentivirus significantly decreased CDKL3 expression and resulted in inhibiting cell proliferation, inducing the S‐phase cell‐cycle arrest, attenuating cellular invasive and increasing cell apoptosis. The expression of pERK1/2, p‐Akt, p‐Smad2, p‐p38 mitogen‐activated protein kinase, cleaved caspase‐7, and phospho‐Chk1 were significantly decreased by CDKL3 knockdown. In addition, high expression of CDKL3 was associated with shorter overall survival.ConclusionOur findings suggest that higher expression of CDKL3 is correlated with poor prognosis in patients with ESCC and play a vital role in the malignant phenotype of ESCC cell lines, which indicating that CDKL3 may be as a new therapeutic target in ESCC.
Epigallocatechin‐3‐gallate regulates mitofusin 2 expression through the peroxisome proliferator‐activated receptor‐γ coactivator‐1α and estrogen‐related receptor‐α pathway
Authors: Shu ZhouWu , Zhang XiaoCong , Zheng Li , Zeng GuoNing , Mo You , Yu Min , Zhang Xin , Tan XueRui 
Published: November 2018

AbstractOur previous study showed that epigallocatechin‐3‐gallate (EGCG) inhibition of human aortic smooth muscle cell (HASMC) proliferation might be mediated via upregulation of mitofusin 2 (Mfn‐2). Studies on the mechanism of Mfn‐2 inhibition of cell proliferation have mainly focused on downstream signaling. However, it is still not clear how upstream signaling molecules regulate Mfn‐2. The promoter region of the Mfn‐2 gene contains cis‐acting elements of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) and estrogen‐related receptor‐α (ERR‐α), suggesting a possible link between EGCG, Mfn‐2, and PGC‐1α/ERR‐α. However, the effect of EGCG on PGC‐1α/ERR‐α remains unknown. In this study, we investigated the role of PGC‐1α/ERR‐α in the regulation of Mfn‐2 induced by EGCG and assessed the underlying mechanisms. The effects of EGCG on cell proliferation of cultured HASMCs were observed by a cell counting kit‐8 (CCK8) and 5‐ethynyl‐2‐deoxyuridine (EdU) incorporation assay. Mfn‐2, PGC‐1α, and ERR‐α gene and protein levels were determined by quantitative real‐time polymerase chain reaction (PCR) and Western blot analysis. PGC‐1α gene‐silencing (PGC‐1α small interfering RNA [siRNA]) was achieved by RNA interference and Mfn‐2 promoter and peroxisome proliferator response element (PPRE) functional activity was achieved by a luciferase transfection assay. The results showed that the ERR‐α‐specific antagonist XCT‐790 and PGC‐1α siRNA decreased the expression of Mfn‐2, thus antagonizing the inhibition of HASMC proliferation induced by EGCG. EGCG enhanced Mfn‐2 promoter (−352 to 459) activity, while XCT‐790 and PGC‐1α siRNA abrogated this effect. PGC‐1α stimulating Mfn‐2 expression was dependent on intact ERR‐α binding in the Mfn‐2 promoter. The transcriptional effect of PGC‐1α on the Mfn‐2 promoter required the integrity of the −432 to 459 region and supported that Mfn‐2 was a key target gene of PGC‐1α. These results imply that PGC‐1α/ERR‐α played important physiological roles in inhibiting the proliferation of HASMCs by modulating Mfn‐2 gene expression. Hence, EGCG regulated Mfn‐2 expression likely through the PGC‐1α/ERR‐α pathway.
Diallyl disulfide suppresses FOXM1‐mediated proliferation and invasion in osteosarcoma by upregulating miR‐134
Authors: Li Yonggang , Wang Zhiyong , Li Jianmin , Sang Xiguang 
Published: November 2018

AbstractDiallyl disulfide (DADS), a volatile component of garlic oil, exerts anticancer activity in various types of cancers, while its anticancer effects against osteosarcoma (OS) have not been previously explored. This study aimed to investigate the anticancer potential of DADS in OS and to explore the underlying mechanisms. DADS reduced the cell viability and increased the expression of miR‐134 in OS cell lines, and this effect was in a time‐ and concentration‐dependent manner. Furthermore, in vitro functional assays revealed that DADS significantly inhibited the proliferation and invasion of human OS U2OS and MG‐63 cells, which was partially reversed by miR‐134 inhibitor transfection. DADS exhibited in vivo antitumor activity and upregulated miR‐134 expression in xenograft tumors. Downregulation of miR‐134 attenuated DADS‐induced antitumor capacity. Further bioinformatics prediction analysis revealed that the 3′‐untranslated region (3′‐UTR) of Forkhead Box M1 (FOXM1) harbored miR‐134‐binding sites, and overexpression of miR‐134 repressed the luciferase activity of the reporting vector containing FOXM1 3′‐UTR. Both miR‐134 overexpression and DADS inhibited FOXM1 expression in U2OS cells, while enforced expression of FOXM1 suppressed DADS‐induced antiproliferation and anti‐invasion capacity in U2OS cells. Furthermore, DADS treatment led to significant downregulation of cyclin D1, c‐myc, and lymphoid enhancer‐binding factor 1 expression, but the remarkably upregulated p21 level in U2OS cells. Collectively, DADS could be a promising anticancer agent for OS, and the underlying mechanisms might be associated with the antiproliferation and anti‐invasion properties through upregulating miR‐134 expression.
Rs6265 polymorphism in brain‐derived neurotrophic factor (Val/Val and Val/Met) promotes proliferation of bladder cancer cells by suppressing microRNA‐205 and enhancing expression of cyclin J
Authors: Zhang Jin , Song Ni , Duan Zhongqi 
Published: November 2018

AbstractBackgroundIn this study, we evaluated the effect of rs6265 polymorphism on the expression of brain‐derived neurotrophic factor (BDNF) and relevant downstream targets, as well as the involvement of this polymorphism in bladder cancer.MethodA computational analysis and luciferase assays were used to explore the interaction among BDNF, miR‐205, and cyclin J (CCNJ). Real‐time polymerase chain reaction (RT‐PCR) and Western blot analysis were carried out to determine the effect of rs6265 polymorphism on the expression of BDNF and relevant downstream genes.ResultBDNF directly inhibited miR‐205 expression but enhanced the expression of CCNJ, which was identified as a virtual target gene of miR‐205. Furthermore, the inhibitory effect of BDNF carrying the Val genotype, defined as BDNF (Val), on miR‐205 expression was much stronger than that of BDNF (Met), while the inductive effect of BDNF (Val) on CCNJ expression was much weaker than that of BDNF (Met). miR‐205 and CCNJ small interfering RNA (siRNA) were found to reduce cell proliferation and arrest the cells in G0/G1 phase. In addition, miR‐205 expression in patients carrying BDNF genotyped as Met/Met (defined as Met/Met group) was much higher than patients carrying BDNF genotyped as Val/Val and Val/Met (defined as Val/Val group and Val/Met group). As an inhibitor of CCNJ expression, the inhibitory effect of miR‐205 was much higher in the Met/Met group than that in the Val/Val and Val/Met groups.ConclusionIn summary, we suggested that the rs6265 polymorphism in BDNF upregulates the expression of CCNJ in bladder cancer via the inhibition of miR‐205 expression, which leads to the promoted proliferation of bladder cancer cells.
Stabilization of hypoxia‐inducible factor 1α by cobalt chloride impairs podocyte morphology and slit‐diaphragm function
Authors: Nakuluri Krishnamurthy , Mukhi Dhanunjay , Mungamuri Sathish Kumar , Pasupulati Anil Kumar 
Published: November 2018

AbstractGlomerular podocytes are the major components of the renal filtration barrier, and altered podocyte permselectivity is a key event in the pathogenesis of proteinuric conditions. Clinical conditions such as ischemia and sleep apnea and extreme physiological conditions such as high‐altitude sickness are presented with renal hypoxia and are associated with significant proteinuria. Hypoxia is considered as an etiological factor in the progression of acute renal injury. A sustained increase in hypoxia‐inducible factor 1α (HIF1α) is a major adaptive stimulus to the hypoxic conditions. Although the temporal association between hypoxia and proteinuria is known, the mechanism by which hypoxia elicits proteinuria remains to be investigated. Furthermore, stabilization of HIF1α is being considered as a therapeutic option to treat anemia in patients with chronic kidney disease. Therefore, in this study, we induced stabilization of HIF1α in glomerular regions in vivo and in podocytes in vitro upon exposure to cobalt chloride. The elevated HIF1α expression is concurrence with diminished expression of nephrin and podocin, podocyte foot‐processes effacement, and significant proteinuria. Podocytes exposed to cobalt chloride lost their arborized morphology and cell‐cell connections and also displayed cytoskeletal derangements. Elevation in expression of HIF1α is in concomitance with loss of nephrin and podocin in patients with diabetic nephropathy and chronic kidney disease. In summary, the current study suggests that HIF1α stabilization impairs podocyte function vis‐à‐vis glomerular permselectivity.
The antiproliferative effects of cold atmospheric plasma‐activated media on different cancer cell lines, the implication of ozone as a possible underlying mechanism
Authors: Mokhtari Hesam , Farahmand Leila , Yaserian Kiomars , Jalili Neda , Majidzadeh‐A Keivan 
Published: November 2018

AbstractRecent studies have proven several promising anticancer activities for cold atmospheric plasma (CAP) against a wide range of cancer cells in vitro. Recently, media treated with CAP have also found to effectively eradicate cancer cells similar to the CAP. Based on advantages, many researchers prefer to apply CAP‐activated media (PAM) as an alternative to cap in the treatment of cancer. However, less has been achieved regarding the anticancer effects and anticancer mechanisms of PAM. Investigating the selective anticancerous activities of PAM, the viability of SKBR3, MCF7, ASPC‐1, A‐549, G‐292, and SW742 cancer cell lines, as well as normal human skin fibroblasts (FMGB‐1) and MCF10A cells in relation to the media activation time, and the length of exposure was studied. Also, we examined the concentration of ozone in media as a function to CAP activation time since recent studies have proposed ozone as a pivotal reactive species in the induction of cell death. Based on the result, both increasing the duration of media activation time and the length of exposure to PAM could significantly increase the anticancer activity. Nevertheless, the cytotoxicity on normal cells was either not affected or slightly increased. Among the six tested cancer cell lines, SW742 was the most resistant and SKBR3 the most susceptible cancer cell lines to PAM. Also, increasing duration of treatment with CAP resulted in a significant rise in O3 concentration levels in media. Overall, these results suggest PAM, as a promising tool in the treatment of different cancers and O
3 formation as a probable underlying mechanism.
Knockdown of TRPV4 suppresses osteoclast differentiation and osteoporosis by inhibiting autophagy through Ca2+–calcineurin–NFATc1 pathway
Authors: Cao Boran , Dai Xin , Wang Wenbo 
Published: November 2018

AbstractThe aim of this study is to evaluate the effect of transient receptor potential vanilloid 4 (TRPV4) on osteoclast differentiation and osteoporosis, and to investigate the underlying mechanism. The results showed that TRPV4 expression and intracellular Ca2+ concentration were significantly upregulated in macrophage colony‐stimulating factor (M‐CSF)‐stimulated and receptor activator of nuclear factor κΒ ligand (RANKL)‐stimulated RAW264.7 cells. Furthermore, TRPV4 overexpression further increased the M‐CSF‐ and RANKL‐induced number of tartrate‐resistant acid phosphatase (TRAP)‐positive osteoclasts and expression of osteoclastogenesis‐related genes (TRAP, c‐Fos, and nuclear factor of activated T cells [NFATc1]), activated the Ca
2+–calcineurin–NFATc1 signaling and increased autophagy‐related proteins (light chain [LC] 3II and Beclin‐1) during osteoclast differentiation. In contrast, TRPV4 knockdown exerted the opposite effects. Mechanically, inhibition of Ca
2+–calcineurin–NFATc1 signaling by FK506 or 11R‐VIVIT abrogated the TRPV4 overexpression‐induced osteoclast differentiation and autophagy induction. Moreover, suppression of autophagy by 3‐methyladenine attenuated the TRPV4‐induced osteoclast differentiation. In addition, short hairpin RNA TRPV4‐lentivirus administration significantly diminished the increased levels of several osteoclastogenesis‐related genes (RANKL, TRAP, and tumor necrosis factor‐α), alleviated the disturbed microarchitecture of lumbar vertebrae, restored the decreased bone mineral density, ratio of bone volume to total tissue volume, trabecular thickness, and trabecular number, and diminished the increased trabecular separation, in ovariectomy (OVX)‐induced osteoporosis mice. Consistent with the in vitro data, TRPV4 knockdown significantly decreased the induced number of TRAP‐positive osteoclasts, the increased LC3 and NFATc1 expression in the lumbar vertebrae of OVX mice. In conclusion, TRPV4 knockdown suppresses osteoclast differentiation and osteoporosis by inhibiting autophagy through Ca
2+–calcineurin–NFATc1 pathway.
Laurus nobilis leaf extract controls inflammation by suppressing NLRP3 inflammasome activation
Authors: Lee Eun Hye , Shin Jin Hak , Kim Seon Sook , Lee Hanbyeol , Yang Se‐Ran , Seo Su Ryeon 
Published: November 2018

AbstractLaurus nobilis Linn. (Lauraceae), commonly known as Bay, has been used as a traditional medicine in the Mediterranean and Europe to treat diverse immunological disorders. Although the effects of L. nobilis on immunosuppression have been reported, the detailed underlying mechanism remains unclear. In this study, to elucidate the anti‐inflammatory mechanism of L. nobilis, we examined the effect of L. nobilis leaf extract on inflammasome activation in mouse bone marrow‐derived macrophages. L. nobilis leaf extract inhibited NOD‐like receptor pyrin domain‐containing 3 (NLRP3) inflammasome activation, which was associated with caspase‐1 activation, interleukin‐1β secretion, and apoptosis‐associated speck‐like protein containing a CARD (ASC) pyroptosome complex formation. We also observed that 1,8‐cineole, the major component of L. nobilis extract, consistently suppressed NLRP3 inflammasome activation. Furthermore, L. nobilis leaf extract attenuated the in vivo expression of proinflammatory cytokines in an acute lung injury mouse model. Our results provide the first evidence that L. nobilis leaf extract modulates inflammatory signaling by suppressing inflammasome activation.
Repression of TXNIP–NLRP3 axis restores intestinal barrier function via inhibition of myeloperoxidase activity and oxidative stress in nonalcoholic steatohepatitis
Authors: Bai Ru‐Xue , Xu Ying‐Ying , Qin Geng , Chen Yan‐Ming , Wang Hui‐Fen , Wang Miao , Du Shi‐Yu 
Published: November 2018

AbstractDysfunction of the intestinal barrier function occurs in hepatic injury, but the specific mechanisms responsible are largely unknown. Recently, NOD‐like receptor 3 (NLRP3) inflammasome functions in impairing endothelial barrier function. In this study, we test the hypothesis that TXNIP–NLRP3 axis repression prevents against intestinal barrier function disruption in nonalcoholic steatohepatitis (NASH). First, lipopolysaccharide (LPS)‐induced alterations in expression of ZO‐1 and occludin, myeloperoxidase (MPO) activity, reactive oxygen species (ROS) level, and transepithelial electric resistance (TEER) in intestinal epithelial cells (IECs) isolated from C57BL/6 wild‐type (WT) and TXNIP−/− mice were evaluated. The underlying regulatory mechanisms of TXNIP knockout in vivo were investigated with the detection of expressions of TXNIP, NLRP3 and ZO‐1, and occludin, the interaction of TXNIP–NLRP3, MPO activity, ROS level, permeability of intestinal mucosa, levels of inflammatory factors in serum, and LPS concentration. We identified that TXNIP knockout promoted ZO‐1 and occludin expression, yet reduced MPO activity, ROS level, and cell permeability in IECs, indicating restored the intestinal barrier function. However, LPS upregulated TXNIP and NLRP3 expression, as well as contributed to the interaction between TXNIP and NLRP3 in vitro. Furthermore, TXNIP was significantly upregulated in the intestinal mucosa of NASH mice and its knockout repaired the intestinal barrier disrupt, inhibited expression of inflammatory factors, and reduced LPS concentration as well as hepatic injury in vivo. Taken together, our findings demonstrated that inhibited the activation of the TXNIP–NLRP3 axis reduced MPO activity and oxidative stress and thus restoring the intestinal barrier function in NASH. TXNIP–NLRP3 axis may be a promising therapeutic strategy for the NASH treatment.