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  • 更新日期:2020-01-23
  • Design and synthesis of N‑(benzylpiperidinyl)‑4‑fluorobenzamide: A haloperidol analog that reduces neuropathic nociception via σ1 receptor antagonism
    Life Sci. (IF 3.448) Pub Date : 2020-01-23
    Myrna Déciga-Campos; Luis Alberto Melo-Hernández; Héctor Torres-Gómez; Bernhard Wünsch; Dirk Schepmann; María Eva González-Trujano; Josué Espinosa-Juárez; Francisco Javier López-Muñoz; Gabriel Navarrete-Vázquez

    Aims Haloperidol is a neuroleptic drug with high affinity towards the σ1 receptor (σ1R), acting as antagonist that decreases neuropathic pain, but has CNS side effects. This work describes the design and synthesis of a novel analog N‑(1‑benzylpiperidin‑4-yl)‑4‑fluorobenzamide (LMH-2), which produced antihyperalgesic and antiallodynic effects in rats with neuropathy induced by chronic constriction injury of the sciatic nerve (CCI), being more active than gabapentin (The most widely used drug for the treatment of neuropathic pain). Main methods LMH-2 was designed as haloperidol analog. Its structure was characterized by spectroscopic (1H and 13C NMR) and spectrometric mass (electronic impact) techniques. Additionally, in silico predictions of pharmacokinetic, pharmacodynamic and toxicological properties were obtained, with promising results. A competitive binding assay using radioligands was employed to evaluate the in vitro affinity for σ1R, whereas in vivo antihyperalgesic and antiallodynic activities were investigated using Wistar rats with CCI. Key findings LMH-2 showed high affinity for σ1R in an in vitro binding assay, with a Ki = 6.0 nM and a high σ1R/σ2R selectivity ratio. Molecular docking studies were carried out to determine the binding energy and to analyze LMH-2-protein interactions. Through an in silico pharmacological consensus analysis, LMH-2 was considered safe for in vivo evaluation. Thus, LMH-2 had dose-dependent antiallodynic and antihyperalgesic activities; its efficacy was comparable to that of gabapentin, but its potency was 2-times higher than this drug. Significance LMH-2 administration produced antihyperalgesic and antiallodynic effects by the antagonism of σ1R, suggesting its potential use as an analgesic drug for neuropathic pain.

    更新日期:2020-01-23
  • PHLDA1 is a new therapeutic target of oxidative stress and ischemia reperfusion-induced myocardial injury
    Life Sci. (IF 3.448) Pub Date : 2020-01-22
    Yuxuan Guo; Pengyu Jia; Yuqiong Chen; Hang Yu; Xin Xin; Yandong Bao; Huimin Yang; Nan Wu; Yingxian Sun; Dalin Jia

    Aim Oxidative stress plays an important role in myocardial ischemia-reperfusion injury. Pleckstrin homology-like domain, family A, member 1 (PHLDA1) was first identified in apoptosis induced by T cell receptor activation, and was shown to play a different role in different cell types and under different stimuli. The role and mechanism of PHLDA1 in oxidative stress-induced cardiomyocyte injury and cardiac ischemia-reperfusion were therefore determined. Main methods Cell viability and apoptotic rate were measured by Cell Counting Kit-8 and flow cytometry, respectively. Mitochondrial membrane potential was measured using JC-1 test kit. Reactive oxygen species (ROS) production was detected using ROS kit. HE staining was used to detect histological morphology, 2,3,5-triphenyltetrazolium chloride staining to detect infarct size, terminal deoxynucleotidyl transferase dUTP nick end labeling staining to detect the apoptotic rate, and immunohistochemistry and western blot analysis to detect protein expression. The binding of PHLDA1 to Bcl-2 associated X (Bax) was detected by immunoprecipitation. Key findings The results indicated that PHLDA1 is highly expressed in oxidative stress-induced cardiomyocyte and myocardial ischemia-reperfusion injuries. PHLDA1 overexpression in cardiomyocytes promoted oxidative stress-induced cardiomyocyte injury. At the same time, PHLDA1 knockdown improved oxidative stress-induced cardiomyocyte and myocardial ischemia-reperfusion injuries. In addition, PHLDA1 binds to Bax and the interaction is enhanced under H2O2 stimulation. Significance The present results indicated that PHLDA1 interacts with Bax to participate in oxidative stress-induced cardiomyocyte injury and myocardial ischemia reperfusion injury.

    更新日期:2020-01-22
  • Expression of Sfrp5/Wnt5a in human epicardial adipose tissue and their relationship with coronary artery disease
    Life Sci. (IF 3.448) Pub Date : 2020-01-22
    Shan Tong; Yu Du; Qingwei Ji; Ran Dong; Jian Cao; Zhijian Wang; Wei Li; Min Zeng; Hongying Chen; Xiaogang Zhu; Yujie Zhou

    Secreted frizzled-related protein 5 (Sfrp5) primarily acts in combination with wingless-type family member 5a (Wnt5a), to inhibits chronic inflammation and repress atherosclerosis and other metabolic disorders. Epicardial adipose tissue (EAT), surrounding the heart and coronary arteries, has been found to be highly related to the progression of coronary artery disease through adipokines production. However, little is known about EAT-derived Sfrp5 and Wnt5a in humans. We aimed to investigate whether the EAT-derived Sfrp5/Wnt5a levels are altered in patients with CAD. Fifty-eight patients with CAD and 29 patients without CAD who underwent cardiac surgery were enrolled. Serum samples and paired adipose biopsies from EAT and subcutaneous adipose tissue (SAT) were collected, and Sfrp5 and Wnt5a levels were detected. Correlation and multivariate regression analyses were performed to determine the relationship between Sfrp5/Wnt5a expression and CAD and other clinical risk factors. According to the results, the CAD group had lower Sfrp5 and higher Wnt5a levels in EAT and serum (all p < 0.05). Serum Sfrp5 levels were significantly lower in CAD patients with impaired myocardial function. EAT Sfrp5 mRNA levels and serum Sfrp5 levels were both negatively associated with the presence of CAD, after adjustment for known biomarkers, EAT mRNA and serum Wnt5a levels correlated positively with the presence of CAD. Thus, we concluded that low Sfrp5 and high Wnt5a levels are associated with the presence of CAD, independent of other conventional risk factors.

    更新日期:2020-01-22
  • Berberine induces dose-dependent quiescence and apoptosis in A549 cancer cells by modulating cell cyclins and inflammation independent of mTOR pathway
    Life Sci. (IF 3.448) Pub Date : 2020-01-22
    Ravi Kumar; Mansi Awasthi; Anamika Sharma; Yogendra Padwad; Rohit Sharma

    Aim Emerging studies have shown that application of low concentration of bioactive phytomolecules can confer anti-proliferative effects on tumour cells by inducing senescence pathways. The alkaloid berberine is recognized for its anti-cancer attributes but its potential to induce senescence in tumour cells is least understood. Materials and methods The present work assessed the mechanisms pertaining to dose-dependent anti-proliferative effects of berberine in the perspective of senescence and inflammation using human non-small cell lung cancer cell line (A549). Key findings Amongst the different tested bioactive phytomolecules, berberine treatment suppressed the proliferation of A549 cells regardless of the concentration applied. Application of low doses of berberine induced a weak SA-β-gal activity and p21WAF1 expression but did not show evidence of SASP activation due to absence of NF-κB activation and expression of proinflammatory genes. However, treatment with higher dose of berberine showed no evidence of SA-β-gal activity or p21WAF1 expression, but instead induced apoptosis and suppressed the expression of cell cyclins. The proliferative capacity of berberine treated cells was at par with control cells and no SA-β-gal activity could be observed in first generation of berberine treated cells. mTOR pathway showed no distinct activation on account of berberine treatment thereby further emphasizing that low dose of berberine induced quiescence and not senescence in A549 cells. Significance Taken together, our observations indicate that despite its strong anti-proliferative effects, low dose berberine treatment may only induce transient changes akin to quiescence that needs to be considered before implying pro-senescence attributes of berberine in cancer therapeutics.

    更新日期:2020-01-22
  • Effect of resveratrol combined with atorvastatin on re-endothelialization after drug-eluting stents implantation and the underlying mechanism
    Life Sci. (IF 3.448) Pub Date : 2020-01-22
    Changzhe Chen; Chenxi Song; Dong Zhang; Dong Yin; Rui Zhang; Jingzhou Chen; Kefei Dou

    Aims To explore whether the combination of atorvastatins and resveratrol is superior to each individual drug alone regarding re-endothelialization after drug-eluting stents (DESs) implantation. Materials and methods Ninety-four rabbits were randomized into control, atorvastatin, resveratrol, and combined medication groups. Abdominal aorta injury was induced via ballooning, followed by DES implantation. Neointimal formation and re-endothelialization after stent implantation were assessed via optical coherence tomography and scanning electron microscopy. The effects of resveratrol and atorvastatin on bone marrow-derived mesenchymal derived stem cells (BMSCs) were assessed. Key findings Compared with the findings in the resveratrol and atorvastatin groups, the neointimal area and mean neointimal thickness were greater in the combined medication group, which also exhibited improved re-endothelialization. Compared with the effects of monotherapy, combined treatment further protected BMSCs against rapamycin-induced apoptosis and improved cell migration. Combined medication significantly upregulated Akt, p-Akt, eNOS, p-eNOS, and CXCR4 expression in BMSCs compared with the effects of monotherapy, and these effects were abolished by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Significance The combination of atorvastatin and resveratrol has the potential of accelerating re-endothelialization after stent implantation, reducing the risk of thrombosis and improving the safety of DESs.

    更新日期:2020-01-22
  • Zinc promotes functional recovery after spinal cord injury by activating Nrf2/HO-1 defense pathway and inhibiting inflammation of NLRP3 in nerve cells
    Life Sci. (IF 3.448) Pub Date : 2020-01-22
    Daoyong Li; He Tian; Xian Li; Liang Mao; Xiaoguang Zhao; Jiaquan Lin; Sen Lin; Chang Xu; Yuanye Liu; Yue Guo; Xifan Mei

    Aims To study the specific therapeutic effect of zinc on spinal cord injury (SCI) and its specific protective mechanism. Main methods The effects of zinc ions on neuronal cells were examined in a mouse SCI model and in vitro. In vivo, neurological function was assessed by Basso Mouse Scaleat (BMS) at 1, 3, 5, 7, 10, 14, 21, and 28 days after spinal cord injury. The number of neurons and histomorphology were observed by nissl staining and hematoxylin-eosin staining (HE). The chromatin and mitochondrial structure of neurons were detected by transmission electron microscopy (TEM). The expression of nuclear factor erythroid 2 related factor 2 (Nrf2)-related antioxidant protein and nlrp3 inflammation-related protein were detected in vivo and in vitro by western blot (WB) and immunofluorescence (IF), respectively. Key findings Zinc treatment promoted motor function recovery on days 3, 5, 7, 14, 21 and 28 after SCI. In addition, zinc reduces the mitochondrial void rate in spinal neuronal cells and promotes neuronal recovery. At the same time, zinc reduced the levels of reactive oxygen species (ROS) and malondialdehyde in spinal cord tissue after SCI, while increasing superoxide dismutase activity and glutathione peroxidase production. Zinc treatment resulted in up-regulation of nrf2/ho-1 levels and down-regulation of nlrp3 inflammation-associated protein expression in vitro and in vivo. Significance Zinc has a protective effect on spinal cord injury by inhibiting oxidative damage and nlrp3 inflammation. Potential mechanisms may include activation of the Nrf 2/Ho-1 pathway to inhibit nlrp3 inflammation following spinal cord injury. Zinc has the potential to treat SCI.

    更新日期:2020-01-22
  • An update on the potential role of advanced glycation end products in glycolipid metabolism
    Life Sci. (IF 3.448) Pub Date : 2020-01-22
    Xiaolei Wang; Junjun Liu; Ying Yang; Xiandang Zhang
    更新日期:2020-01-22
  • The benefits and mechanisms of exercise training for Parkinson's disease
    Life Sci. (IF 3.448) Pub Date : 2020-01-22
    Ya-Shuo Feng; Si-Dong Yang; Zi-Xuan Tan; Man-Man Wang; Ying Xing; Fang Dong; Feng Zhang
    更新日期:2020-01-22
  • BRCA1 protects cardiac microvascular endothelial cells against irradiation by regulating p21-mediated cell cycle arrest
    Life Sci. (IF 3.448) Pub Date : 2020-01-21
    Zhi-min Zeng; Hai-yang Du; Le Xiong; Xiao-li Zeng; Peng Zhang; Jing Cai; Long Huang; An-wen Liu
    更新日期:2020-01-22
  • Novel ADAM-17 inhibitor ZLDI-8 inhibits the metastasis of hepatocellular carcinoma by reversing epithelial-mesenchymal transition in vitro and in vivo
    Life Sci. (IF 3.448) Pub Date : 2020-01-21
    Hong-Yuan Lu; Hai-Xiao Chu; Yu-Xin Tan; Xiao-Chun Qin; Ming-Yue Liu; Jing-Da Li; Tian-Shu Ren; Ying-Shi Zhang; Qing-Chun Zhao
    更新日期:2020-01-22
  • The role of TFEB in tumor cell autophagy: Diagnostic and therapeutic opportunities
    Life Sci. (IF 3.448) Pub Date : 2020-01-21
    Afsane Bahrami; Vanessa Bianconi; Matteo Pirro; Hossein M. Orafai; Amirhossein Sahebkar
    更新日期:2020-01-21
  • Mitochondrial characteristics contribute to proliferation and migration potency of MDA-MB-231 cancer cells and their response to cisplatin treatment
    Life Sci. (IF 3.448) Pub Date : 2020-01-20
    Mojdeh Kheirandish-Rostami; Mehryar Habibi Roudkenar; Ali Jahanian-Najafabadi; Kazuo Tomita; Yoshikazu Kuwahara; Tomoaki Sato; Amaneh Mohammadi Roushandeh

    Aim Despite recent advances in therapeutic strategies, cancer is still a leading cause of mortality worldwide. Mitochondrial dysfunction is implicated in cancer initiation and metastasis, and even in chemo- and radio-resistance. However, the precise role of mitochondria in cancer is crosstalk and controversial. This study is trying to find out the effect of transferring normal mitochondria into the highly aggressive and proliferative MDA-MB-231 cancer cells, and to evaluate the effect of the transfer with/without a combination therapy with cisplatin. Materials and methods Normal mitochondria were isolated from human umbilical cord derived-mesenchymal stem cells. The mitochondria were transferred into the MDA-MB-231 cells, and also into cells with mitochondrial dysfunction induced by rhodamine red 6 (R6G). Cell proliferation and sensitivity of the cells to cisplatin were measured by cell counting after the mitochondria transfer. Also, apoptosis was evaluated by DAPI staining and in situ cell death detection (TdT-mediated dUTP nickend labeling; TUNEL) methods. Migration capability of the cells was studied by transwell assay. Key findings Transfer of normal mitochondria into MDA-MB-231 cells increased cell proliferation. However, the transfer of mitochondria enhanced cisplatin-induced apoptosis in MDA-MB-231 cells in which mitochondria were already disrupted. Introduction of normal cell-derived mitochondria into the MDA-MB-231 cells increased their invasive, but decreased the migration potency of the cells in the group with mitochondrial dysfunction (MDA + RG6 + Cisplatin). Conclusion The introduction of healthy mitochondria to highly aggressive and proliferative cells would be considered as a new therapeutic modality for some types of cancer.

    更新日期:2020-01-21
  • Hederagenin protects mice against ovariectomy-induced bone loss by inhibiting RANKL-induced osteoclastogenesis and bone resorption
    Life Sci. (IF 3.448) Pub Date : 2020-01-20
    Kun Tian; Yuangang Su; Jiaxin Ding; Dairong Wang; Yunfei Zhan; Yicheng Li; Jiamin Liang; Xixi Lin; Fangming Song; Ziyi Wang; Jiake Xu; Qian Liu; Jinmin Zhao

    Aims Postmenopausal osteoporosis and other osteolytic bone diseases are often caused by the elevation in osteoclastogenesis and/or increased osteoclastic bone resorption, leading to excessive bone loss. Hederagenin (Hed) is a pentacyclic triterpenoid saponin extracted from various natural medicinal plants and exhibits numerous biological activities and may offer benefits against bone-related conditions. We evaluated the effects of Hed on osteoclast formation and bone resorption in vitro and the in vivo therapeutic benefits in the mouse model of ovariectomy (OVX)-induced bone loss. Main methods In vitro, osteoclast formation were determined by TRAP staining assessed; bone resorption were examined using Hydroxyapatite resorption assay and Podosomal actin belt formation assay; Related molecular mechanisms were determined by western blot assay. Construction of ovx mice by bilateral oophorectomy to simulate bone loss in vivo. Key findings In vitro cellular assays showed that Hed inhibited RANKL-induced osteoclast formation and osteoclast bone (hydroxyapatite) resorption as well as marker gene expression from BMM culture. Mechanistically, Hed attenuated RANKL-induced intracellular reactive oxygen species (ROS) production, and MAPK signaling pathway (ERK and p38) activation which curbed the downstream induction of c-Fos and NFATc1. Consistent with the in vitro findings, Hed administration effectively protected OVX mice from bone loss by reducing osteoclast number and activity on bone surface. Significance Our data provided promising evidence for the potential use of Hederagenin in the treatment of osteoclast-mediated osteolytic bone diseases such as postmenopausal osteoporosis.

    更新日期:2020-01-21
  • 更新日期:2020-01-21
  • Ginsenoside Rd attenuates ACTH-induced corticosterone secretion by blocking the MC2R-cAMP/PKA/CREB pathway in Y1 mouse adrenocortical cells
    Life Sci. (IF 3.448) Pub Date : 2020-01-20
    Wenqi Jin; Rui Ma; Lu Zhai; Xiaohao Xu; Tingting Lou; Qingxia Huang; Jing Wang; Daqing Zhao; Xiangyan Li; Liwei Sun

    Background Higher levels of glucocorticoids (GCs), and impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis may cause or exacerbate the occurrence of metabolic and psychiatric disorders. It has been reported that ginseng saponin extract (GSE) has an inhibitory effect on the hyperactivity of the HPA axis induced by stresses and increased corticosterone level induced by intraperitoneal injection of adrenocorticotrophic hormone (ACTH) in mice. However, the molecular mechanisms by which GSE and its active ginsenosides inhibit corticosterone secretion remain elusive. Main methods Y1 mouse adrenocortical cells were treated with ACTH for up to 60 min to establish a cell model of corticosterone secretion. After treatment with different concentrations of GSE or ginsenoside monomers for 24 h prior to the addition of ACTH, analyses of cAMP content, PKA activity, and the levels of steroidogenesis regulators, melanocortin-2 receptor (MC2R), and melanocortin-2 receptor accessory protein (MRAP) in ACTH-induced Y1 cells were performed. Results We demonstrated that GSE inhibits ACTH-stimulated corticosterone production in Y1 cells by inhibiting factors critical for steroid synthesis. Ginsenoside Rd, an active ingredient of GSE, inhibits corticosterone secretion in the cells and impedes ACTH-induced corticosterone biosynthesis through down-regulation of proteins in the cAMP/PKA/CREB signaling pathway. In addition, Western blot and qPCR analyses showed that ginsenoside Rd attenuated the induction of MC2R and MRAP by ACTH. Conclusion Our findings indicate that ginsenoside Rd inhibits ACTH-induced corticosterone production through blockading the MC2R-cAMP/PKA/CREB pathway in adrenocortical cells. Overall, this mechanism may represent an important therapeutic option for the treatment of stress-related disorders, further supporting the pharmacological benefits of ginseng.

    更新日期:2020-01-21
  • Curcumin reduces LPS-induced septic acute kidney injury through suppression of lncRNA PVT1 in mice
    Life Sci. (IF 3.448) Pub Date : 2020-01-20
    Wei Huang; Xueting Li; Dawei Wang; Yinghao Sun; Qian Wang; Yue Bu; Fangfang Niu

    Objective To investigate the protective effects of curcumin on LPS-induced septic acute kidney injury and to explore its underlying molecular mechanisms. Methods A mouse model of septic acute kidney injury (AKI) was given an intraperitoneal injection of lipopolysaccharide (LPS), followed by administration of variable levels of curcumin (intragastric). And NRK cells were used as the kidney cell model for all in vitro studies. Results Curcumin significantly decreased the levels of serum Scr, BUN, and Cyc c and reduced kidney injury in LPS-induced AKI mice. Kidney tissues of LPS-induced AKI mice showed an increase in PVT1, ED-1, TNF-α, IL-1β, IL-6, p-IkBα/IkBα, p-p65/p65, p-JNK/JNK, and p-c-JUN/c-JUN expression levels; however, treatment with curcumin significantly reduced this effect. Curcumin increased the survival rate NRK cells exposed to LPS-induced inflammation in vitro. Moreover, NRK cells that overexpressed PVT1 had lower survival rates than WT NRK cells obtained from mice that received curcumin treatment after treating with LPS. Additionally, curcumin reduced the LPS-induced increase in Bax, cleaved-caspase3/caspase 3, p-IkBα/IkBα, p-p65/p65, p-JNK/JNK, and p-c-JUN/c-JUN protein expression, and increased Bcl2 protein expression in NRK cells. However, the extent of these changes was low in NRK cells that overexpressed PVT1. Conclusion Curcumin decreased PVT1 expression in LPS-induced septic acute kidney tissues and reduced LPS-induced septic acute kidney injury in mice. This might be related to the inhibition of the JNK/NF-κB pathway by curcumin through suppression of lncRNA PVT1.

    更新日期:2020-01-21
  • Small interfering RNA targeting alpha7 nicotinic acetylcholine receptor sensitizes hepatocellular carcinoma cells to sorafenib
    Life Sci. (IF 3.448) Pub Date : 2020-01-18
    Khalil Hajiasgharzadeh; Mohammad Hossein Somi; Behzad Mansoori; Vahid Khaze Shahgoli; Afshin Derakhshani; Ahad Mokhtarzadeh; Dariush Shanehbandi; Behzad Baradaran

    Aims It has been demonstrated that reduced expression of alpha7 nicotinic acetylcholine receptor (α7nAChR) led to reduced chemotherapeutic drugs resistance in various cancer cells. However, whether small interfering RNA (siRNA) mediated knockdown of α7nAChR can reduce sorafenib (SOR) resistance in HCC cells remains to be determined. Materials and methods The effects of α7nAChR-siRNA in combination with SOR treatment was analyzed in human (HepG2) and mouse (Hepa 1–6) HCC cell lines. The MTT, DAPI staining and flow cytometry assays were applied to measure the cell viability, apoptosis and cell cycle progression of the cells. Also, the changes in the mRNA and protein levels of the α7nAChR were measured by quantitative real-time PCR and western blot analysis, respectively. Key findings The results revealed that SOR increased both mRNA and protein levels of α7nAChR in HCC cells. Treatment with α7nAChR-siRNA abolished these effects. Also, SOR treatment in combination with α7nAChR-siRNA significantly sensitizes HCC cells to SOR cytotoxicity. This combination therapy significantly induced HCC cells apoptosis compared to SOR alone. Significance These experimental results indicate that knockdown of α7nAChR by siRNA increased the SOR antitumor activity of HCC cells and suggests that this additive combination is a promising drug candidate for HCC therapy.

    更新日期:2020-01-21
  • LncRNA ZEB1-AS1 facilitates ox-LDL-induced damage of HCtAEC cells and the oxidative stress and inflammatory events of THP-1 cells via miR-942/HMGB1 signaling
    Life Sci. (IF 3.448) Pub Date : 2020-01-18
    Zhaohui Hua; Ke Ma; Shirui Liu; Yongqiang Yue; Hui Cao; Zhen Li

    Aims The role of long noncoding RNA ZEB1 antisense 1 (lncRNA ZEB1-AS1) in carotid artery atherosclerosis remains barely explored. Materials and methods The viability and apoptosis of HCtAEC cells were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Caspase-3 activity detection assay and flow cytometry. The oxidative stress status and inflammation of THP-1 cells were detected by oxidative stress indicator detection kit and Enzyme-linked immunosorbent assay (ELISA). The abundance of ZEB1-AS1, miR-942 and high-mobility group box 1 (HMGB1) was measured by quantitative real time polymerase chain reaction (qRT-PCR). The targets of ZEB1-AS1 and miR-942 in HCtAEC and THP-1 cells were predicted by DIANA tool, and the combination was confirmed by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA-pull down assay. Western blot was conducted to examine the protein expression of HMGB1. Key findings ZEB1-AS1 promoted ox-LDL-mediated injury in HCtAEC and THP-1 cells. MiR-942 was a direct target of ZEB1-AS1, and it was negatively modulated by ZEB1-AS1 in HCtAEC and THP-1 cells. HMGB1 could bind to miR-942, and it was regulated by ZEB1-AS1/miR-942 axis in HCtAEC and THP-1 cells. HMGB1 overexpression or miR-942 depletion reversed the inhibitory effects of ZEB1-AS1 intervention on the injury and apoptosis of HCtAEC cells and the oxidative stress and inflammation of THP-1 cells. Significance LncRNA ZEB1-AS1 contributed to ox-LDL-mediated injury and apoptosis of HCtAEC cells and the oxidative stress and inflammation of THP-1 cells through up-regulating HMGB1 via sponging miR-942. ZEB1-AS1/miR-942/HMGB1 axis might provide a new direction to treatment carotid artery atherosclerosis.

    更新日期:2020-01-21
  • Inflammatory cardiac fibroblast phenotype underlies chronic alcohol-induced cardiac atrophy and dysfunction
    Life Sci. (IF 3.448) Pub Date : 2020-01-18
    A.J. Mouton; E.J. El Hajj; V.K. Ninh; R.W. Siggins; J.D. Gardner

    Aims The purpose of this study was to investigate mechanisms of chronic alcohol-induced cardiac remodeling and dysfunction. We also sought to determine the role of cardiac fibroblasts, which play a dynamic role in cardiac remodeling, in mediating these effects. Main methods Adult male Wistar rats were exposed to ethanol (EtOH) vapor inhalation for 16 weeks. Echocardiography was performed to assess terminal cardiac structure and function. Cardiac fibroblasts were isolated from the left ventricle (LV) for both ex vivo and in vitro analysis. Cultured H9C2 cells were also exposed to conditioned media from alcohol-exposed cardiac fibroblasts. Gene expression in whole LV tissue, isolated cardiac fibroblasts, or cultured H9C2 cells was determined by real-time PCR, and protein expression was determined by Western blot. Key findings EtOH led to LV wall thinning and impaired systolic function, and decreased contractile protein mRNA levels. EtOH increased LV inflammatory markers, JNK and Akt activation, and decreased mTOR expression. EtOH induced myofibroblast activation as assessed by flow cytometry, and increased LV collagen III expression. EtOH increased expression of several inflammatory mediators in cardiac fibroblasts both ex vivo and in vitro. Administration of conditioned media from EtOH-treated fibroblasts decreased contractile protein mRNA levels and impaired Akt and mTOR signaling in differentiated H9C2 cardiomyocytes. Significance Our results indicate that EtOH-induced cardiac atrophy and dysfunction is associated with activation of inflammatory pathways. Furthermore, EtOH may induce a pro-inflammatory cardiac fibroblast phenotype, leading to aberrant fibroblast-myocyte cross-talk. Thus, EtOH may promote cardiac muscle wasting in part by activation of pro-inflammatory fibroblasts.

    更新日期:2020-01-21
  • Antiarrhythmic effect of crotonoside by regulating sodium and calcium channels in rabbit ventricular myocytes
    Life Sci. (IF 3.448) Pub Date : 2020-01-18
    Zhipei Liu; Yuzhong Jia; Lv Song; Youjia Tian; Peipei Zhang; Peihua Zhang; Zhenzhen Cao; Jihua Ma

    Aims Detect the antiarrhythmic effect of crotonoside (Cro). Main methods We used whole-cell patch-clamp techniques to detect the effects of Cro on action potentials (APs) and transmembrane ion currents in isolated rabbit left ventricular myocytes. We also verified the effect of Cro on ventricular arrhythmias caused by aconitine in vivo. Key findings Cro reduced the maximum depolarization velocity (Vmax) of APs and shortened the action potential duration (APD) in a concentration-dependent manner, but it had no significant effect on the resting membrane potential (RMP) or action potential amplitude (APA). It also inhibited the peak sodium current (INa) and L-type calcium current (ICaL) in a concentration-dependent manner with half-maximal inhibitory concentrations (IC50) of 192 μmol/L and 159 μmol/L, respectively. However, Cro had no significant effects on the inward rectifier potassium current (IK1) or rapidly activating delayed rectifier potassium current (IKr). Sea anemone toxin II (ATX II) increased the late sodium current (INaL), but Cro abolished this effect. Moreover, Cro significantly abolished ATX II-induced early afterdepolarizations (EADs) and high extracellular Ca2+ concentration (3.6 mmol/L)-induced delayed afterdepolarizations (DADs). We also verified that Cro effectively delayed the onset time and reduced the incidence of ventricular arrhythmias caused by aconitine in vivo. Significance These results revealed that Cro effectively inhibits INa, INaL, and ICaL in ventricular myocytes. Cro has antiarrhythmic potential and thus deserves further study.

    更新日期:2020-01-21
  • Parkin overexpression attenuates Aβ-induced mitochondrial dysfunction in HEK293 cells by restoring impaired mitophagy
    Life Sci. (IF 3.448) Pub Date : 2020-01-17
    Hongmei Wang; Ting Zhang; Xuhua Ge; Jingjiong Chen; Yuwu Zhao; Jianliang Fu
    更新日期:2020-01-17
  • Oleic acid protects against cadmium induced cardiac and hepatic tissue injury in male Wistar rats: A mechanistic study
    Life Sci. (IF 3.448) Pub Date : 2020-01-17
    Bharati Bhattacharjee; Palash Kumar Pal; Aindrila Chattopadhyay; Debasish Bandyopadhyay
    更新日期:2020-01-17
  • MicroRNA-mediated regulation of Nrf2 signaling pathway: Implications in disease therapy and protection against oxidative stress
    Life Sci. (IF 3.448) Pub Date : 2020-01-16
    Milad Ashrafizadeh; Zahra Ahmadi; Saeed Samarghandian; Reza Mohammadinejad; Habib Yaribeygi; Thozhukat Sathyapalan; Amirhossein Sahebkar
    更新日期:2020-01-16
  • Exosomal miR-106b serves as a novel marker for lung cancer and promotes cancer metastasis via targeting PTEN
    Life Sci. (IF 3.448) Pub Date : 2020-01-16
    Shifang Sun; Hailin Chen; Chenlei Xu; Yun Zhang; Qiaoli Zhang; Lei Chen; Qunli Ding; Zaichun Deng

    As novel non-invasive tumor diagnostic biomarkers, exosomal bioactive miRNAs have received increasing attention. Herein, the aim of this study is to explore the clinical values and roles of exosomal miR106b in lung cancer. The exosomal miR-106b level was much higher in the serum of patients with lung cancer than that in healthy volunteers. Also, the exosomal miR-106b level in the lung cancer patient serum was associated with TNM stages and lymph node metastasis. Furthermore, exosomal miR-106b enhanced the migrated and invasive ability of lung cancer cells and increased the MMP-2 and MMP-9 expression. Mechanistically, exosomal miR-106b could target PTEN, and promote lung cancer cell migration and invasion. More importantly, PTEN overexpression reversed the effect of exosomal miR-106b on lung cancer cell migration and invasion. Taken together, these findings indicate that exosomal miR-106b may be a promising diagnostic biomarker and drug target for patients with lung cancer.

    更新日期:2020-01-16
  • Chronic serotonin reuptake inhibition uncouples brown fat mitochondria and induces beiging/browning process of white fat in overfed rats
    Life Sci. (IF 3.448) Pub Date : 2020-01-16
    Glauber Rudá F. Braz; Aline Isabel da Silva; Severina Cássia A. Silva; Anderson Apolonio S. Pedroza; Maria Daniele T.B. de Lemos; Flávia Ariane S. de Lima; Tercya Lúcidi A. Silva; Claudia Jacques Lagranha

    Aim To investigate whether a chronic 5-HT reuptake inhibitor (i.e. Fluoxetine-FLX) exposure in young adult rats overfed during suckling period would modulate interscapular brown adipose tissue (iBAT) mitochondria and browning agents in white adipose tissue (WAT). Methods Male Wistar rats were assigned into either a normofed group (n = 9 per group) or an overfed group (n = 3 per group) induced by litter size reduction at postnatal day 3 (PND3). Pharmacological manipulation was carried out between PND39 and PND59 and groups were assigned accordingly: Normofed + vehicle solution – NaCl 0.9% (NV group), normofed + FLX solution – 10 mg/kg b.w. (NF group), overfed + vehicle (OV group) and overfed + FLX (OF group). We evaluated mitochondrial oxygen consumption and reactive species (RS) production, oxidative stress analyses (MDA concentration, carbonyl content, REDOX state [GSH/GSSG], global oxy score) in the iBAT, gene (leptin, Ucp1, Sirt1, Pgc1α and Prdm16) and protein (UCP1) expression in the iBAT and epididymal WAT (eWAT). Key findings OV group increased body weight gain, Lee index and oxidative stress in the iBAT. Both FLX-treated groups showed less weight gain compared to their controls. OF group showed different leptin expression in the WAT and iBAT; increased functional UCP1 content and mitochondrial activity with less oxidative stress in the iBAT and upregulation of browning genes in eWAT (Pgc1α, Prdm16 and Ucp1). Conclusion Altogether our findings indicated that FLX treatment in young adult overfed animals improved the iBAT mitochondrial function, reduced oxidative stress and induced transcriptional activation of browning agents in white adipose tissue.

    更新日期:2020-01-16
  • Osteopontin induces atrial fibrosis by activating Akt/GSK-3β/β-catenin pathway and suppressing autophagy
    Life Sci. (IF 3.448) Pub Date : 2020-01-15
    Rongjie Lin; Shaohui Wu; Dan Zhu; Mu Qin; Xu Liu

    Aims Atrial fibrosis is a common feature of atrial fibrillation (AF). Recently, it is reported that osteopontin (OPN) can induce fibrosis in lungs, livers and kidneys. However, its role in atrial fibrosis remains unclear. Here, we sought to determine the involvement of OPN in atrial fibrosis and the underlying mechanisms during this pathological remodeling process. Materials and methods Protein expressions were determined by enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining and immunoblotting. mRNA expressions were detected by qRT-PCR. Cell proliferation was assessed by CCK-8. Left atrial electroanatomical voltage maps were created using PentaRay catheters and a 3-dimensional mapping system. Key findings OPN was highly expressed in the circulation of AF patients and was further increased with the progression of AF. In addition, correlation analysis showed that circulating OPN positively related with low-voltage areas (LVAs, a marker of atrial fibrosis) in AF patients. Immunohistological staining and immunoblotting revealed an increased expression of OPN in AF patients who present a higher degree of atrial fibrosis. Furthermore, in vitro studies in cultured human atrial fibroblasts (hAFs) demonstrated that OPN promoted the proliferation of fibroblasts and increased production of collagen I and fibronectin. Mechanistically, the profibrotic effects of OPN on atrial fibroblasts were determined via activating Akt/GSK-3β/β-catenin signaling and suppressing autophagy. Significance This study uncovered a previously unrecognized profibrotic role of OPN in atrial fibrosis, which was achieved through activation of Akt/GSK-3β/β-catenin signaling pathway and suppression of autophagy, implying a promising therapeutic target in atrial fibrosis and AF.

    更新日期:2020-01-15
  • Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) in non-small cell lung cancer
    Life Sci. (IF 3.448) Pub Date : 2020-01-15
    Zhi Zeng; Zi-yao Wang; Yu-kun Li; Dong-mei Ye; Juan Zeng; Jia-li Hu; Pi-feng Chen; Jiao Xiao; Juan Zou; Zhen-hua Li
    更新日期:2020-01-15
  • Syndecan-1 regulates extracellular matrix expression in keloid fibroblasts via TGF-β1/Smad and MAPK signaling pathways
    Life Sci. (IF 3.448) Pub Date : 2020-01-15
    Jing Cui; Shan Jin; Chenglong Jin; Zhehu Jin

    Aims The present study aimed to explore the effect of syndecan-1 on keloid fibroblasts. Main methods Immunohistochemistry and Western blot were employed to assess the expression of syndecan-1. Primary cultured keloid fibroblasts were transfected with syndecan-1 siRNA. The function of syndecan-1 on the proliferation of keloid fibroblasts was investigated through Cell Counting Kit-8 (CCK-8) and flow cytometry. Extracellular matrix, TGF-β1/Smad, and MAPK related proteins were evaluated by Western blot. Key findings Syndecan-1 was significantly overexpressed in both keloid tissues and fibroblasts. Moreover, the knockdown of syndecan-1 remarkably attenuated the proliferation of keloid fibroblasts and reduced the content of the extracellular matrix. Importantly, syndecan-1 regulates the expression of the extracellular matrix in keloid fibroblasts via TGF-β1/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. Significance The current results revealed a crucial function for syndecan-1 in regulating the expression of extracellular matrix and cell proliferation, thereby designating syndecan-1 as a novel target for keloid.

    更新日期:2020-01-15
  • CYP2J2-produced epoxyeicosatrienoic acids attenuate ischemia/reperfusion-induced acute kidney injury by activating the SIRT1-FoxO3a pathway
    Life Sci. (IF 3.448) Pub Date : 2020-01-15
    Ye Zhu; Ao Ding; Dongliang Yang; Tongxia Cui; Hui Yang; Hua Zhang; Cheng Wang

    Cytochrome P450 (CYP) epoxygenases can metabolize arachidonic acids to epoxyeicosatrienoic acids (EETs), which play a protective role in the renal system, but their involvement in ischemia/reperfusion (I/R)-induced acute kidney injury remains unknown. Here, using a rat model, we demonstrated that forced CYP2J2 expression attenuated I/R-induced renal dysfunction and protected histological integrity. We showed that CYP2J2 significantly decreased I/R-induced upregulation of blood urea nitrogen and serum creatinine and enhanced autophagy during I/R treatment. In addition, we determined the protective effect of CYP2J2 against I/R-caused apoptosis. We demonstrated that CYP2J2 overexpression attenuated the downregulation of SIRT1 and FoxO3a by I/R-induced injury. Moreover, exogenous 11,12-EET addition obviously promoted I/R-induced autophagic flux and suppressed I/R-induced apoptosis through SIRT1–FoxO3a signaling activation. Our data indicate that CYP2J2-produced EETs improve I/R-caused kidney injury by activating the SIRT1–FoxO3a signaling pathway, which protects from renal I/R injury.

    更新日期:2020-01-15
  • Knockdown of circ_0084043 suppresses the development of human melanoma cells through miR-429/tribbles homolog 2 axis and Wnt/β-catenin pathway
    Life Sci. (IF 3.448) Pub Date : 2020-01-15
    Zhibing Chen; Junjie Chen; Qingbiao Wa; Mei He; Xiao Wang; Jianwen Zhou; Ying Cen

    Aims Circular RNAs (circRNAs) have been emerged as novel regulators in multiple tumorigenesis, including melanoma. CircRNA_0084043 was recently demonstrated to be deregulated in human melanoma cells. Nevertheless, its role and mechanism are largely unrevealed in melanoma. Materials and methods Expression of circ_0084043, miRNA (miR)-429 and tribbles homolog 2 (TRIB2) was detected using reverse transcription-quantitative PCR quantitative PCR (RT-qPCR) and western blotting. Cell proliferation, apoptosis, migration and invasion were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry and transwell assays, respectively. The activation of Wnt/β-catenin pathway was evaluated by western blotting. The target binding among circ_0084043, miR-429 and TRIB2 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation. In vivo, mice xenograft model was generated to investigate tumor growth. Key findings Expression of circ_0084043 and TRIB2 was upregulated in human melanoma tissues and cell lines. Both circ_0084043 knockdown and TRIB2 silencing could decrease cell proliferation, migration and invasion, but facilitate apoptosis in A375 and SK-MEL-28 cells. Furthermore, TRIB2 restoration partially abrogated the tumor-suppressive role of circ_0084043 knockdown in melanoma cells in vitro. Then, we verified that circ_0084043 positively and physically controlled TRIB2 expression through sponging miR-429. Besides, expression of β-catenin, c-Myc and cyclinD1 was inhibited in A375 and SK-MEL-28 cells when circ_0084043 was knocked down, accompanied with increased miR-429 and decreased TRIB2. Notably, circ_0084043 downregulation impeded tumor growth of A375 cells in vivo. Significance Knockdown of circ_0084043 suppressed the malignant development of melanoma presumably through modulating miR429/TRIB2 axis and inactivating Wnt/β-catenin signaling pathway.

    更新日期:2020-01-15
  • Repair strategies for injured peripheral nerve: Review
    Life Sci. (IF 3.448) Pub Date : 2020-01-15
    Chand Raza; Hasib Aamir Riaz; Rabia Anjum; Noor ul Ain Shakeel
    更新日期:2020-01-15
  • The molecular mechanisms by which vitamin D improve glucose homeostasis: A mechanistic review
    Life Sci. (IF 3.448) Pub Date : 2020-01-14
    Habib Yaribeygi; Mina Maleki; Thozhukat Sathyapalan; Helia Iranpanah; Hossein M. Orafai; Tannaz Jamialahmadi; Amirhossein Sahebkar

    Diabetes mellitus (DM) is a complex metabolic disorder involving multiple deleterious molecular pathways and cellular defects leading to disturbance in the biologic milieu. It is currently a global health concern with growing incidence, especially among younger adults. There is an unmet need to find new therapeutic targets for the management of diabetes. Vitamin D is a promising target in the pathophysiology of DM, especially since vitamin D deficiency is common in patients with diabetes compared to people without diabetes. Evidence suggests that it can play significant roles in improving peripheral insulin sensitivity and glucose metabolism, however, the exact pathophysiological mechanism is not clarified yet. In this current study, we have reviewed the evidence on the effect of vitamin D in improving insulin resistance via distinct molecular pathways.

    更新日期:2020-01-15
  • Analysis of vismodegib resistance in D473G and W535L mutants of SMO receptor and design of novel drug derivatives using molecular dynamics simulations
    Life Sci. (IF 3.448) Pub Date : 2020-01-14
    Siyan Liao; Cecilia Floyd; Nicholas Verratti; Lauren Leung; Chun Wu

    Aims Vismodegib is an effective antagonist of smoothened receptors for treatment of locally advanced or metastatic basal cell carcinoma. However, it often suffers from drug resistance due to mutations. Two common mutants, D4736.55G and W5357.55L, were found to cause serious drug resistance. Although the reduction of drug binding affinity (~40-fold) was thought to be the major reasons, the detailed structural, energetic and dynamic mechanisms at the molecular level are still unknown. Main methods Molecular dynamics simulations and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations were performed on three complex systems of wild-type (WT) and two mutants with vismodegib. Then, virtual screening was used to select three potential derivatives of vismodegib from the 77 new derivatives designed by modifying the substitutions on the phenylpyridine ring of vismodegib. Key findings The MM-GBSA binding energy data of the two mutants showed a significant reduction in binding affinity. The energy decomposition identified that the key contributing residues were in the binding site. The D4736.55G mutant affected the binding of the ligand by directly changing the conformations of the key residues in TM6, while the W5357.55L mutant mainly depended on long range allosteric effect. More importantly, the methylsulfonyl benzamide moiety was identified to be the pharmacophore of the ligand, and two of the three derivatives from the virtual screening showed much higher MM-GBSA binding affinity to the two mutants than vismodegib did. Significance These results might help to understand resistance mechanisms and the two derivatives can be good candidates for future experiments.

    更新日期:2020-01-15
  • Thymoquinone and pentoxifylline enhance the chemotherapeutic effect of cisplatin by targeting Notch signaling pathway in mice
    Life Sci. (IF 3.448) Pub Date : 2020-01-14
    Esraa M. Mosalam; Abdel-Aziz A. Zidan; Eman T. Mehanna; Noha M. Mesbah; Dina M. Abo-Elmatty
    更新日期:2020-01-15
  • MiR-346-5p promotes colorectal cancer cell proliferation in vitro and in vivo by targeting FBXL2 and activating the β-catenin signaling pathway
    Life Sci. (IF 3.448) Pub Date : 2020-01-14
    Shuang Pan; Wei Wu; Fu Ren; Lei Li; Yao Li; Weihong Li; Aimei Wang; Dahua Liu; Yongyan Dong
    更新日期:2020-01-15
  • Circ_0063517 acts as ceRNA, targeting the miR-31-5p-ETBR axis to regulate angiogenesis of vascular endothelial cells in preeclampsia
    Life Sci. (IF 3.448) Pub Date : 2020-01-14
    Wei Li; Nan Yu; Lei Fan; Su-Hua Chen; Jian-Li Wu

    Aims Accumulated evidence indicates that the dysregulation of circular RNAs (circRNAs) plays pivotal roles in many human diseases including preeclampsia (PE). Circ_0063517 has been verified to be down-regulated in PE. But the role of circ_0063517 in PE is still unclear. This research aims to probe into the effect of circ_0063517 on angiogenesis in PE development. Main methods The expression of circ_0063517, endothelin receptor type B (ETBR) and miR-31-5p was assessed by quantitative reverse transcription polymerase chain reaction (RT-qPCR). MTT assay, colony formation assay, scratch assay, transwell assay, and tube formation assay were performed to detect proliferation, migration, and angiogenesis, respectively. Dual luciferase reporter system and RNA immunoprecipitation (RIP) assay were carried out to determine the interaction between miR-31-5p and circ_0063517(or ETBR). ETBR, VEGFRA, and VEGFR2 levels were detected by western blot analysis. The effect of circ_0063517 and ETBR on angiogenesis was evaluated in N-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced PE in vivo. Key findings The levels of circ_0063517 and ETBR were down-regulated in the placenta tissue of PE patients. Conversely, the level of miR-31-5p was up-regulated in PE. Overexpression of circ_0063517 or knockdown of miR-31-5p facilitated growth, migration, and angiogenesis of vascular endothelial cells. Circ_0063517 knockdown-induced repression of the expression of ETBR, VEGFA, and VEGFR2 was partly counteracted by ETBR overexpression. Mechanistically, circ_0063517 sponged miR-31-5p to regulate ETBR expression. Finally, circ_0063517 promoted angiogenesis via enhancing ETBR expression in PE in vivo. Significance Our findings suggest that circ_0063517-miR-31-5p-ETBR axis regulates angiogenesis during the pathological process of PE.

    更新日期:2020-01-14
  • Decreased secretion of tumor necrosis factor-α attenuates macrophages-induced insulin resistance in skeletal muscle
    Life Sci. (IF 3.448) Pub Date : 2020-01-14
    Lixia Bu; Xiaohong Cao; Zilong Zhang; Huiwen Wu; Renwei Guo; Mingfeng Ma

    Aims Macrophages, as an important member of immune system, engulf and digest pathogens in innate immunity and help initiate adaptive immunity. However, macrophages also involve in occurrence and development of many diseases, such as obesity and type 2 diabetes. Here, we aimed to reveal how activated macrophages cause insulin resistance in skeletal muscle in vitro through simulating body environment. Main methods We established RAW264.7 macrophages and C2C12 myotubes co-incubation model in vitro using Transwell filter to simulate body environment and investigated effects of RAW264.7 cells on insulin-regulated glucose metabolism in C2C12 myotubes. Immunofluorescence, Immunoblot and glucose uptake tests were used to assess metabolic changes in C2C12 myotubes. ELISA test detected secretions of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) from RAW264.7 cells. In addition, RNA interference and inhibitor treatment were used. Key findings Activated RAW264.7 cells attenuated insulin response in C2C12 myotubes. Activated RAW264.7 cells secreted a lot of TNF-α and IL-6. We found that TNFα, but not IL-6, caused insulin resistance of skeletal muscle in a dose-dependent manner. The results further indicated that activation of TNF-α downstream proteins, inhibitor of nuclear factor κ-B kinase (IKK) and the jun-N-terminal kinase 1 (JNK1) led to phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser residues and insulin resistance in C2C12 myotubes. Significance Our research provided further and direct demonstration on activated macrophage-induced insulin resistance in skeletal muscle, suggesting TNF-α might become a therapeutic target to ameliorate and treat type 2 diabetes.

    更新日期:2020-01-14
  • Bio-tactics for neuroprotection of retinal ganglion cells in the treatment of glaucoma
    Life Sci. (IF 3.448) Pub Date : 2020-01-14
    Khushwant S. Yadav; Sushmita Sharma; Vaishali Y. Londhe
    更新日期:2020-01-14
  • Long non-coding RNA ASMTL-AS1 inhibits tumor growth and glycolysis by regulating the miR-93-3p/miR-660/FOXO1 axis in papillary thyroid carcinoma
    Life Sci. (IF 3.448) Pub Date : 2020-01-14
    Zhiyi Feng; Rong Chen; Nanqi Huang; Chaoyuan Luo

    Long non-coding RNA (lncRNA) is emerging as an essential player in cancer progression. However, its biological function and clinical implication in papillary thyroid carcinoma (PTC) remain poorly understood. In the current study, we found that a novel lncRNA, ASMTL antisense RNA 1 (ASMTL-AS1), was significantly downregulated in PTC. And its downregulation was positively linked to larger tumor size, advanced clinical stage and unfavorable outcome. Overexpression of ASMTL-AS1 evidently inhibited PTC cell proliferation and glycolysis, while knockdown of ASMTL-AS1 resulted in the opposite effect. Regarding the mechanism, ASMTL-AS1 was capable of sponging miR-93-3p and miR-660 to elevate FOXO1 expression, leading to repressing glycolysis and tumorigenesis. In turn, FOXO1 could also increase ASMTL-AS1 expression via directly binding to ASMTL-AS1 promoter, which formed a positive feedback regulation loop. Importantly, the regulatory axis of ASMTL-AS1/miR-93-3p/miR-660/FOXO1 was also identified in vivo. Collectively, our data clearly indicate that ASMTL-AS1 functions as a novel tumor suppressor in PTC through regulation of miR-93-3p/miR-660/FOXO1 pathway. Targeting ASMTL-AS1 and its downstream pathway may be an effective therapeutic approach for patients with PTC.

    更新日期:2020-01-14
  • Nicotine promotes activation of human pancreatic stellate cells through inducing autophagy via α7nAChR-mediated JAK2/STAT3 signaling pathway
    Life Sci. (IF 3.448) Pub Date : 2020-01-14
    Zhiren Li; Xiaoyun Zhang; Tong Jin; Jianyu Hao

    Aim Pancreatic stellate cells (PSCs) are the main functional cells leading to pancreatic fibrosis. Nicotine is widely considered as an independent risk factor of pancreatic fibrosis, but the mechanism is still unclear. Our study was aimed to explore the effects of nicotine on human pancreatic stellate cells (hPSCs) and involved pathways. Materials and methods Primary human PSCs were cultured and treated with nicotine (0.1 μM and 1 μM). The proliferation, apoptosis, α-SMA expression, extracellular matrix metabolism and autophagy of hPSCs were detected by CCK-8 assay, flow cytometry, real-time PCR and Western blotting analysis. The α7nAChR-mediated JAK2/STAT3 signaling pathway was also examined, and an α7nAChR antagonist α-bungarotoxin (α-BTX) was used to perform inhibition experiments. Key findings The proliferation, α-SMA expression and autophagy of hPSCs were significantly promoted by 1 μM nicotine. Meanwhile, the apoptosis of hPSCs was significantly reduced. The extracellular matrix metabolism of hPSCs was also regulated by nicotine. Moreover, the α7nAChR-mediated JAK2/STAT3 signaling pathway was activated by nicotine, this pathway and effects of nicotine can be blocked by α-BTX. Significance Our finding suggests that nicotine can promote activation of human pancreatic stellate cells (hPSCs) through inducing autophagy via α7nAChR-mediated JAK2/STAT3 signaling pathway, providing a new insight into the mechanisms by which nicotine affects pancreatic fibrosis.

    更新日期:2020-01-14
  • HOTAIRM1 suppresses cell proliferation and invasion in ovarian cancer through facilitating ARHGAP24 expression by sponging miR-106a-5p
    Life Sci. (IF 3.448) Pub Date : 2020-01-11
    Hongtu Chao; Mengli Zhang; Hongyi Hou; Zhenzhong Zhang; Nan Li

    Aims Ovarian cancer (OC) is the most lethal gynecologic malignant tumors all over the world. HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) has been reported as an important regulator in multiple tumors. However, the functions of HOTAIRM1 in OC and its possible molecular mechanisms remain unclear. Main methods qRT-PCR analysis was performed to detect the expression levels of HOTAIRM1, miR-106a-5p and ARHGAP24 mRNA in OC tissues and cells. The functional effects of HOTAIRM1, miR-106a-5p and ARHGAP24 on OC cells were determined by MTT, colony formation, flow cytometry and Transwell assays. Luciferase reporter, RIP and RNA pull-down assays were used to examine the interaction between miR-106a-5p and HOTAIRM1 or ARHGAP24. Tumor xenografts were constructed in nude mice to confirm the roles of HOTAIRM1 in OC in vivo. Key findings HOTAIRM1 expression was lowered in OC tumor tissues and cells. Decreased HOTAIRM1 expression was associated with advanced FIGO stages and lymphatic metastasis. Up-regulation of HOTAIRM1 suppressed OC cell proliferation and invasion, and promoted apoptosis. Also, HOTAIRM1 slowed OC tumor growth in vivo. Moreover, HOTAIRM1 could serve as a competing endogenous RNA (ceRNA) of miR-106a-5p to derepress ARHGAP24 expression. HOTAIRM1-mediated inhibitory effect on OC progression was partly reversed following the restoration of miR-106a-5p expression. Furthermore, ARHGAP24 overexpression repressed OC progression in vitro. Significance In conclusion, our study showed that HOTAIRM1 suppressed OC progression through derepression of ARHGAP24 by sponging miR-106a-5p. This finding provides novel insights into the mechanisms of HOTAIRM1 in OC and highlights a potential therapeutic strategy for the treatment of OC.

    更新日期:2020-01-13
  • Acid sphingomyelinase/ceramide mediates structural remodeling of cerebral artery and small mesenteric artery in simulated weightless rats
    Life Sci. (IF 3.448) Pub Date : 2020-01-10
    Yu-Ting Su; Yao-Ping Cheng; Xi-Zhang; Xiao-Ping Xie; Yao-Ming Chang; Jun-Xiang Bao

    Aims Weightlessness exposure conduces to substantial vascular remodeling, mechanisms behind which remain unclear. Acid sphingomyelinase (ASM) catalyzed ceramide (Cer) generation accounts for multiple vascular disorders, so the role of it in adjustment of cerebral artery (CA) and small mesenteric artery (MA) was investigated in simulated weightless rats. Main methods Rats were hindlimb unloaded tail suspended (HU) to simulate the effect of weightlessness. Arterial morphology was examined by hematoxylin-eosin staining. Cer abundance was measured by immunohistochemistry. Western blotting was used to detect protein content. Apoptosis was detected by transferase-mediated dUTP nick end labeling. Key findings During 4 weeks of tail suspension, intima-media thickness (IMT) and media cross section area (CSA) were increased gradually in CA but decreased gradually in MA (P < .05). Correspondingly, the apoptosis and proliferation of vascular smooth muscle cells were reduced and enhanced respectively in CA (P < .05), while promoted and restrained in MA (P < .05). As compared to control, both ASM protein expression and Cer content were lowered in CA and elevated in MA of HU rats (P < .05). Permeable Cer incubation reversed the change of apoptosis and proliferation in CA of HU rats, while ASM inhibition recapitulated it in control rats. On the contrary, ASM inhibitors restored the alteration of apoptosis and proliferation in MA of HU. Significance The results suggest that by controlling the balance between apoptosis and proliferation, ASM/Cer exerts an important role in structural adaptation of CA and MA to simulated weightlessness.

    更新日期:2020-01-11
  • Involvement of p75NTR in the effects of Aβ on L-type Ca2+ channel in cultured neuronal networks
    Life Sci. (IF 3.448) Pub Date : 2020-01-10
    Yifan Wang; Haidan Tang; Chengmin Yang; Hucheng Zhao; Chongdong Jian

    Ca2+ overload in neurons has been implicated in Alzheimer's Disease (AD). Upregulation of Ca2+ through L-type Ca2+ channels was known to be involved in the neurodegeneration induced by amyloid-β (Aβ) peptides in AD. However, little is known about the mechanism by which upregulation of L-type Ca2+ channel currents is linked to Aβ-induced neuronal toxicity. In the present study, we found that the L-type Ca2+ current in transgenic AD mice (Tg2576) neurons is greater than in wild-type (WT) neurons, and this Ca2+ channel current change were rescued in Tg2576/p75NTR+/− (p75 neurotrophin receptor) neurons. We further examined the changes in the gating of L-type Ca2+ channels following Aβ42 treatment, and the results showed that the L-type Ca2+ channel current was significantly increased by Aβ42 treatment in WT hippocampal neurons. Blocking or decreasing the expression of p75NTR eliminated the influence of Aβ42 on the L-type Ca2+ channel current in WT hippocampal neurons. We also evaluated how Aβ42 affected the voltage-dependent activation and inactivation of L-type Ca2+ channels in cultured WT neurons. The results indicated that the half-maximal activation voltage (V1/2) was left shifted, and the half-inactivation voltage (V1/2) displayed a right shift in neuron treated by Aβ42. Decreasing the expression of p75NTR eliminated the effect of Aβ42 on voltage-dependent activation and inactivation of the L-type Ca2+ channel. These results indicate that Aβ42 changes L-type Ca2+ channel currents by modulating the channel's activation and inactivation dynamics, while decreasing p75NTR expression can remove this effect.

    更新日期:2020-01-11
  • Nifedipine inhibits oxidative stress and ameliorates osteoarthritis by activating the nuclear factor erythroid-2-related factor 2 pathway
    Life Sci. (IF 3.448) Pub Date : 2020-01-09
    Jun Yao; Huiping Long; Jianping Zhao; Gang Zhong; Jia Li

    Nifedipine is a voltage-gated calcium channel inhibitor widely used in the treatment of hypertension. Nifedipine has been reported to have antioxidant and anti-apoptotic effects and promotes cell proliferation. However, the effects of nifedipine on oxidative stress and apoptosis in osteoarthritic (OA) chondrocytes are still unclear. In this study, we sought to investigate whether nifedipine alleviates oxidative stress and apoptosis in OA through nuclear factor erythroid-2-related factor 2 (Nrf2) activation. The cytotoxicity of nifedipine against human chondrocytes was detected using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) kit, whereas mRNA and protein expression levels were measured using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. The oxidative stress level was analyzed by measuring reactive oxygen species (ROS), glutathione peroxidase (GSH-px), catalase (CAT) and superoxide dismutase (SOD) activities. The role of Nrf2 in the effect of nifedipine on OA was analyzed using an Nrf2 inhibitor brusatol (BR). The result showed that nifedipine inhibited the expression of matrix metalloprotein(MMP)-13, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, inducible nitric oxide (NO) synthase (iNOS), and prostaglandin E2 (PGE2), as well as reduced ROS production in human OA chondrocytes, which was partially reversed by BR. Nifedipine prevented cartilage degeneration and contributed to the expression of Nrf-2 in chondrocytes. These results indicate that nifedipine inhibited inflammation and oxidative stress in chondrocytes via activation of Nrf-2/HO-1 signaling.

    更新日期:2020-01-11
  • Inhibition of lysyl oxidase ameliorates renal injury by inhibiting CD44-mediated pericyte detachment and loss of peritubular capillaries
    Life Sci. (IF 3.448) Pub Date : 2020-01-09
    Mohd Aslam Saifi; Chandraiah Godugu

    Renal fibrosis is a common pathological manifestation of almost all forms of kidney disease irrespective of the etiological cause. Microvascular rarefaction represents itself as an important phenomenon associated with renal fibrosis and shows strong correlation with decline in renal functions. Lysyl oxidase (LOX) catalyzes crosslinking of extracellular matrix (ECM) proteins including collagens, plays an important role in stabilization of degradation resistant matrix. Since, there seems to be a causal link between deposition of excessive ECM and microvascular rarefaction, we investigated the effects of reduction in renal fibrosis on microvascular rarefaction in acute as well as end stage kidney. We used a well-established unilateral ureteral obstruction (UUO)-induced renal fibrosis model to produce renal fibrosis in animals. We treated animals with a LOX inhibitor, β-aminopropionitrile (BAPN, 100 mg/kg, i.p.) and investigated effects on renal fibrosis and microvascular rarefaction. We observed that LOX inhibition was associated with reduction in collagen deposition in UUO-induced renal fibrosis animal model. Further, ECM normalization by LOX inhibition decreased the loss of peritubular capillaries (PTCs) in fibrotic kidney in acute study while the LOX inhibition failed to inhibit PTCs loss in end stage kidney. The results of present study suggested that inhibition of LOX reduces collagen deposition and renal fibrosis. Further, the reduction in fibrosis fails to protect from PTCs loss in chronic study suggesting the absence of strong link between reduction in fibrosis and improvement in PTCs in an end stage kidney.

    更新日期:2020-01-11
  • LncRNA PCAT1 promotes metastasis of endometrial carcinoma through epigenetical downregulation of E-cadherin associated with methyltransferase EZH2
    Life Sci. (IF 3.448) Pub Date : 2020-01-09
    Chunhua Zhang; Shasha Shao; Yujian Zhang; Liyang Wang; Jianzhong Liu; Fang Fang; Peiquan Li; Bo Wang
    更新日期:2020-01-11
  • Allyl isothiocyanate treatment alleviates chronic obstructive pulmonary disease through the Nrf2-Notch1 signaling and upregulation of MRP1
    Life Sci. (IF 3.448) Pub Date : 2020-01-09
    Yuanyuan Zhou; Xiaoya Xu; Jie Wu; Lingling Xu; Min Zhang; Zegeng Li; Dianlei Wang

    Aims Chronic obstructive pulmonary disease (COPD) is a disease with high morbidity and mortality worldwide, which can cause serious social and economic burdens. Allyl isothiocyanate (AITC) is one of the most common natural isothiocyanates and has been shown to have anti-inflammatory and antioxidant biological activities. The purpose of this study was to investigate whether AITC regulated Multidrug resistance-associated protein 1 (MRP1), reactive oxide species (ROS) and reduced glutathione (GSH) levels via Nrf2 and Notch1 signaling pathways to treat COPD and whether there was an interaction between these two pathways. Main methods Lung function indexes and histopathological changes in mice were determined by lung function instrument and HE staining, respectively. The protein expression was analyzed using immunohistochemistry and Western blotting. The mRNA expression was measured by RT-PCR in human bronchial epithelial cell line 16HBE. The contents of ROS, GSH and GSSG were detected by kits in 16HBE cells. Key findings The protein expression of Notch1, Hes1, MRP1, Nrf2, and HO-1 in lung tissues of WT mice and untransfected cells were significantly down-regulated in COPD, then significantly ameliorated in treatment groups. The protein expression of MRP1, Notch1 and Hes1 in lung tissues of Nrf2−/− mice were markedly reduced. There was a significant reduction in expression of Nrf2, HO-1 and MRP1 in si-Notch1 transfected cells. Pretreatment with AITC markedly improved oxidative stress and GSH-redox disorder in COPD. Significance Our study demonstrates that there is a potential interaction between Nrf2 and Notch1 signaling pathways during treatment of COPD.

    更新日期:2020-01-11
  • 2,3,5,4′-Tetrahydroxystilbene-2-O-β-d-glucoside alleviated the acute hepatotoxicity and DNA damage in diethylnitrosamine-contaminated mice
    Life Sci. (IF 3.448) Pub Date : 2020-01-09
    Weihua Yu; Jiuzhou Zhao; Wenli Li; Yipeng Zheng; Jingpu Zhu; Jiangzheng Liu; Rui Liu; Zhao Wang; Xin Wang; Chunxu Hai
    更新日期:2020-01-09
  • Anti-metastatic properties of a potent herbal combination in cell and mice models of triple negative breast cancer
    Life Sci. (IF 3.448) Pub Date : 2020-01-08
    Laleh Arzi; Reyhane Hoshyar; Nazli Jafarzadeh; Gholamhossein Riazi; Majid Sadeghizadeh
    更新日期:2020-01-09
  • The potential effect of imatinib against hypercholesterolemia induced atherosclerosis, endothelial dysfunction and hepatic injury in rabbits
    Life Sci. (IF 3.448) Pub Date : 2020-01-08
    Nora A. Ashry; Rania R. Abdеlaziz; Ghada M. Suddеk

    Aims Imatinib is an effective tyrosine kinase inhibitor which has different therapeutic actions. The recent work demonstrated the possible beneficial effects of imatinib on the progression of atherosclerosis, endothelial dysfunction, and hypercholesterolemia-associated liver damage in rabbits. Main methods Animals had been distributed in 4 groups: group 1 (non-treated): animals fed regular diet; group 2 high cholesterol [HC]: animals fed 1% cholesterol supplemented diet for 30 days; group 3 (HC-Imatinib): animals fed 1% cholesterol supplemented diet+imatinib (0.01 g/kg daily, p.o) for 30 days; group 4 (Imatinib): animals fed regular diet with imatinib (0.01 g/kg daily, p.o). After thirty days, tissue samples and blood were isolated to be detected biochemically, histologically, and for in vitro analysis. Key findings HC exhibited significant elevations in serum lipid parameters, CRP, ALT, AST and ALP. Additionally, HC induced significant increases for aortic and hepatic MDA, aortic NO and hepatic PDGFR-β, while significantly exhibited reductions in aortic and hepatic GSH, SOD and hepatic PPARγ1. Moreover, HC produced impairment in ACh-enhanced aortic relaxation and aortic pathological changes. Histopathological examination of HC-fed rabbits revealed hepatic steatosis compared with non-treated group. Imatinib administration exhibited significant decreases in serum lipid parameters, CRP, ALT, AST and ALP. Additionally, imatinib induced significant decreases for aortic and hepatic MDA, aortic NO and hepatic PDGFR-β, while significantly exhibited elevations in aortic and hepatic GSH, SOD and hepatic PPARγ1 compared with HC animals. Furthermore, imatinib significantly protected against HC produced attenuation in ACh-induced aortic relaxation and pathological changes in aortic and hepatic tissues. Interestingly, imatinib could return serum CRP, ALP, hepatic SOD and PDGFR-β to basal values. Significance The recent observation reports that imatinib could have beneficial effect against atherosclerosis progression, vascular malfunction, and liver damage in high cholesterol diet (HCD)-fed rabbits.

    更新日期:2020-01-09
  • miR-24-3p induces human intervertebral disc degeneration by targeting insulin-like growth factor binding protein 5 and the ERK signaling pathway
    Life Sci. (IF 3.448) Pub Date : 2020-01-08
    Zhonghui Chen; Ming Liu; Weibing Zhang; Ming Deng; Yan Zhou; Yaming Li

    Aims Intervertebral disc degeneration (IDD) was associated with microRNA (miRNA) dysregulation. Therefore, we verified the hypothesis that miRNAs modulated IDD by affecting the insulin-like growth factor-binding protein 5 (IGFBP5)/extracellular signal-regulated kinase (ERK) signaling pathway. Materials and methods The miRNA expression profiles in nucleus pulposus (NP) cells were compared between patients with IDD and controls, and miRNA microarray and quantitative real-time PCR (RT-qPCR) assays were utilized. Luciferase reporter and Western blotting assays were performed to detect the miRNA targets. Key findings RT-qPCR confirmed that the expression level of miR-24-3p was significantly increased in degenerative NP cells. Moreover, the miR-24-3p level was positively correlated with the disc degeneration grade, and miR-24-3p significantly induced NP cell apoptosis. IGFBP5 was determined as a target of miR-24-3p, and IGFBP5 knockdown induced effects on NP cells similar to those induced by miR-24-3p. Compared with control cells, NP cells presented with miR-24-3p overexpression or IGFBP5 downregulation via shRNAs had significantly increased p-ERK and Bax expression levels. Furthermore, in vivo analysis on IDD rat model showed that the downregulation of miR-24-3p could effectively suspend IDD. Significance These results demonstrated that miR-24-3p upregulation could promote IDD through IGFBP5 and the ERK signaling pathway.

    更新日期:2020-01-09
  • 1,8-Cineole promotes G0/G1 cell cycle arrest and oxidative stress-induced senescence in HepG2 cells and sensitizes cells to anti-senescence drugs
    Life Sci. (IF 3.448) Pub Date : 2020-01-08
    Boris Rodenak-Kladniew; Agustina Castro; Peter Stärkel; Marianela Galle; Rosana Crespo
    更新日期:2020-01-09
  • Inhibition of mTORC1/P70S6K pathway by Metformin synergistically sensitizes Acute Myeloid Leukemia to Ara-C
    Life Sci. (IF 3.448) Pub Date : 2020-01-08
    Fang Yuan; Cong Cheng; Feiyan Xiao; Hongcai Liu; Shan Cao; Gan Zhou

    Aims Chemo-resistance still was the main obstacle for AML patients, more effective and less toxic forms of therapies were desperately needed. Metformin, a classic hypoglycemic drug for diabetes recently delivered us a new identity that it exerted anti-tumor activity through suppressing mTOR in various tumors. But the anti-tumor effect of metformin in AML was not clear. Methods In this study, we used CCK8 assay and apoptosis assay to determine the anti-leukemia activity of metformin combined with AraC, and explore the mechanism of the joint role of Ara-C/metformin in AML. We finally used xenograft experiment in mice to determine the anti-leukemia effect of Ara-C/metformin in vivo. Key findings We found that metformin could synergistically sensitize AML cells to Ara-C via inhibiting mTORC1/P70S6K pathway. In vivo experiment also verified metformin in aid of Ara-C caused an obviously synergistic anti-tumor effect. Significance We firstly found the synergistic anti-tumor effect of Ara-C/metformin in AML through inhibiting mTORC1/P70S6K pathway.

    更新日期:2020-01-09
  • Pharmacological intervention of histone deacetylase enzymes in the neurodegenerative disorders
    Life Sci. (IF 3.448) Pub Date : 2020-01-08
    Rohan Gupta; Rashmi K. Ambasta; Pravir Kumar
    更新日期:2020-01-09
  • Bioinformatic identification of renal cell carcinoma microenvironment-associated biomarkers with therapeutic and prognostic value
    Life Sci. (IF 3.448) Pub Date : 2020-01-08
    Qingquan Zeng; Weiyi Zhang; Xiaoling Li; Jianqiang Lai; Zuwei Li

    Renal cell carcinoma (RCC) is the ninth most prevalent form of malignancy worldwide. The tumor microenvironment significantly affects gene expression in tumor tissues, which subsequently impacts the prognosis of RCC patients. Available datasets such as The Cancer Genome Atlas (TCGA) can be utilized to improve diagnostic methods and search for novel tumor therapeutic targets and prognostic biomarkers. The current study used the ESTIMATE algorithm to explore the immune and stromal components in RCC. Differentially expressed genes (DEGs) were identified by comparing the gene expression patterns in groups with high and low immune/stromal scores. Functional enrichment analysis was conducted and Kaplan-Meier survival curves were plotted to explore the functions of the DEGs in the tumorigenesis, progression, and prognosis of RCC. Our results revealed that immune and stromal scores are associated with specific clinicopathologic variables in RCC. These variables include gender, tumor grade, tumor stage, tumor size, distant metastasis and prognosis. A total of 48 upregulated and 47 downregulated genes were obtained. Functional enrichment analysis demonstrated a correlation between DEGs and the tumor microenvironment, tumor immune response and RCC tumorigenesis. Kaplan-Meier survival curves showed that 43 out of the 48 identified tumor microenvironment related genes are involved in the prognosis of RCC. Three genes, IL10, IGLL5 and POU2AF1, were selected as the hub genes, and their kinase targets were identified as MAPK1 and PPKCA. A positive correlation was obtained between the expression of IL/POU2AF1 and the abundance of six immune cells. Our study provides potential biomarkers for the therapy and prognosis of RCC.

    更新日期:2020-01-09
  • Benzbromarone mitigates cisplatin nephrotoxicity involving enhanced peroxisome proliferator-activated receptor-alpha (PPAR-α) expression
    Life Sci. (IF 3.448) Pub Date : 2020-01-08
    Esraa Abdel-Nassir Abdel-Razek; Amira M. Abo-Youssef; Amany A. Azouz
    更新日期:2020-01-09
  • Antitumor effects of rafoxanide in diffuse large B cell lymphoma via the PTEN/PI3K/Akt and JNK/c-Jun pathways
    Life Sci. (IF 3.448) Pub Date : 2020-01-08
    Wan He; Zhijian Xu; Dongliang Song; Hui Zhang; Bo Li; Lu Gao; Yong Zhang; Qilin Feng; Dandan Yu; Liangning Hu; Gege Chen; Tao Yi; Xiaosong Wu; Jumei Shi; Weiliang Zhu

    Aims Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive lymphoid malignancies, which remains incurable, thus warranting the development of new therapies. Our previous study determined that rafoxanide is very effective in treating multiple myeloma (MM). In the present study, we tried to evaluate the effects of rafoxanide on DLBCL, as well as the potential underlying molecular mechanisms. Main methods We used CCK-8 assay and flow cytometry to assess cell viability and apoptosis. The proteins and pathways associated with apoptosis and proliferation were evaluated through western blot, and xenograft mice were used as the experimental animal model. We also used the TUNEL assay and immunofluorescence for further analyses. Key findings Treatment with different doses of rafoxanide significantly inhibited cell viability and apoptosis. Additionally, the compound induced cell cycle arrest, reduced mitochondrial membrane potential (Δψm), and stimulated reactive oxygen species (ROS) generation without the influence of normal peripheral blood monocytes (PBMCs). As expected, rafoxanide played a role in regulating these proteins and the PTEN/PI3K/AKT and JNK/c-Jun pathways. Furthermore, immunofluorescence and western blot results showed that rafoxanide upregulated H2AX phosphorylation and then inhibited DNA repair in DLBCL. In the xenograft mouse model, tumor volumes were reduced after intraperitoneal injection with rafoxanide. We also observed that TUNEL positive cells were remarkably increased in rafoxanide-treated tumor tissues. Significance These results collectively provide a novel choice to regular treatment for DLBCL patients with poor prognosis.

    更新日期:2020-01-09
  • Propofol facilitates cisplatin sensitivity via lncRNA MALAT1/miR-30e/ATG5 axis through suppressing autophagy in gastric cancer
    Life Sci. (IF 3.448) Pub Date : 2020-01-08
    Yun-Fei Zhang; Chang-Sheng Li; Yi Zhou; Xi-Hua Lu

    Aims Recently, chemoresistance has been recognized as an obstacle in the treatment of gastric cancer (GC). The aim of this study was to investigate the biological functions and underlying mechanisms of propofol in GC chemoresistance. Main methods CCK-8 assay, flow cytometry and immunofluorescent staining were performed to assess the IC50 concentration, cell apoptosis and autophagy activity of cisplatin in both GC chemosensitive cells (SGC7901) and chemoresistant cells (SGC7901/CDDP). The expression pattern of MALAT1 in GC cells was detected by qRT-PCR. The shRNAs and overexpressing plasmids were employed for the loss or gain-of-function. Dual-luciferase reporter assay was subjected to verify the binding relationship between MALAT1 and miR-30e. Besides, ATG5 mRNA and protein levels were determined using qRT-PCR and western blot analysis. Furthermore, GC xenograft mice model was established to validate the in vitro findings. Key findings Chemoresistant GC cells presented higher IC50 of cisplatin, increased autophagy activity and stronger expression of MALAT1. The application of propofol promoted cell apoptosis and reduced the activity of autophagy through downregulating MALAT1. Silencing of MALAT1 inhibited chemo-induced autophagy, whereas MALAT1 overexpression promoted autophagy in GC cells. Mechanistic researches demonstrated that MALAT1 could bind with miR-30e to regulate ATG5 expression, thus causing the suppression of autophagy. In vivo GC xenograft model treated with both propofol and cisplatin also showed significantly decreased tumor size and weight, which was enhanced by knockdown of MALAT1. Significance Altogether, our study revealed a novel mechanism of propofol of lncRNA MALAT1/miR-30e/ATG5 mediated autophagy-related chemoresistance in GC, casting new lights on the understanding of propofol.

    更新日期:2020-01-08
  • Human amniotic mesenchymal stem cells alleviate paraquat-induced pulmonary fibrosis in rats by inhibiting the inflammatory response
    Life Sci. (IF 3.448) Pub Date : 2020-01-08
    Fang He; Limei Yu

    Aims To investigate the therapeutic effects of human amniotic mesenchymal stem cells (hAMSCs) on paraquat (PQ)-induced pulmonary fibrosis in rats and investigate the inflammatory mechanisms. Main methods hAMSCs were identified by morphological, flow cytometry and immunocytochemistry. A pulmonary fibrosis model was induced by administering PQ to rats. The hAMSC group was treated with hAMSCs after 6 h of PQ poisoning. At 21 days after hAMSC transplantation, lungs were harvested for H&E, Masson and immunohistochemical staining to evaluate pulmonary histopathology, collagen deposition, CD3+ cell infiltration and hAMSC colonization. Arterial blood was used for lactic acid analysis and venous blood was used to detect TNF-α, IL-6, and TGF-β1 by ELISA. Key findings hAMSC can improve the lung structure and decrease collagen deposition induced by PQ. The membranes of CD3+ T cell in the PQ group were round and complete, while that in the hAMSC group rats exhibited punctate or diffuse staining. In addition, the CD3+ cell was decreased by hAMSC administration, and MAB1281-positive cells were detected in lung of hAMSC group rats. The survival rate of the hAMSC group was significantly higher than that of the PQ group at 21 days after injection. TNF-α, IL-6, TGF-β1 and lactic acid were significantly decreased by hAMSCs administration. Significance hAMSCs have a significant therapeutic effect on pulmonary fibrosis induced by acute PQ poisoning and can improve survival rate in rats. Furthermore, hAMSCs administration can improve lung histopathology and reduce collagen deposition by reducing inflammatory CD3+ T cell infiltration, inflammatory cytokine expression and lactic acid levels.

    更新日期:2020-01-08
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