bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sucrose nonfermenting AMPK‐related kinase (SNARK) regulates exercise‐stimulated and ischemia‐stimulated glucose transport in the heart
Authors: Sun Xiang‐Lan , Lessard Sarah J. , An Ding , Koh Ho‐Jin , Esumi Hiroyasu , Hirshman Michael F. , Goodyear Laurie J. 
Published: September 2018

AbstractThe signaling mechanisms mediating myocardial glucose transport are not fully understood. Sucrose nonfermenting AMP‐activated protein kinase (AMPK)‐related kinase (SNARK) is an AMPK‐related protein kinase that is expressed in the heart and has been implicated in contraction‐stimulated glucose transport in mouse skeletal muscle. We first determined if SNARK is phosphorylated on Thr208, a site critical for SNARK activity. Mice were treated with exercise, ischemia, submaximal insulin, or maximal insulin. Treadmill exercise slightly, but significantly increased SNARK Thr208 phosphorylation. Ischemia also increased SNARK Thr208 phosphorylation, but there was no effect of submaximal or maximal insulin. HL1 cardiomyocytes were used to overexpress wild‐type (WT) SNARK and to knockdown endogenous SNARK. Overexpression of WT SNARK had no effect on ischemia‐stimulated glucose transport; however, SNARK knockdown significantly decreased ischemia‐stimulated glucose transport. SNARK overexpression or knockdown did not alter insulin‐stimulated glucose transport or glycogen concentrations. To study SNARK function in vivo, SNARK heterozygous knockout mice (SNARK+/−) and WT littermates performed treadmill exercise. Exercise‐stimulated glucose transport was decreased by ~50% in hearts from SNARK+/− mice. In summary, exercise and ischemia increase SNARK Thr208 phosphorylation in the heart and SNARK regulates exercise‐stimulated and ischemia‐stimulated glucose transport. SNARK is a novel mediator of insulin‐independent glucose transport in the heart.
Metabolic changes in adipose tissues in response to β3‐adrenergic receptor activation in mice
Authors: Fujimoto Yusuke , Hashimoto Osamu , Shindo Daichi , Sugiyama Makoto , Tomonaga Shozo , Murakami Masaru , Matsui Tohru , Funaba Masayuki 
Published: September 2018

AbstractBrown and beige adipocytes dissipate energy as heat. Thus, the activation of brown adipocytes and the emergence of beige adipocytes in white adipose tissue (WAT) are suggested to be useful for preventing and treating obesity. Although β3‐adrenergic receptor activation is known to stimulate lipolysis and activation of brown and beige adipocytes, fat depot–dependent changes in metabolite concentrations are not fully elucidated. The current study examined the effect of treatment with CL‐316,243, a β3‐adrenergic receptor agonist, on the relative abundance of metabolites in interscapular brown adipose tissue (iBAT), inguinal WAT (ingWAT), and epididymal WAT (epiWAT). Intraperitoneal injection of CL‐316,243 (1 mg/kg) for 3 consecutive days increased the relative abundance of several glycolysis‐related metabolites in all examined fat depots. The cellular concentrations of metabolites involved in the citric acid cycle and of free amino acids were also increased in epiWAT by CL‐316,243. CL‐316,243 increased the expression levels of several enzymes and transporters related to glucose metabolism and amino acid catabolism in ingWAT and iBAT but not in epiWAT. CL‐316,243 also induced the emergence of more beige adipocytes in ingWAT than in epiWAT. Furthermore, adipocytes surrounded by macrophages were detected in the epiWAT of mice given CL‐316,243. The current study reveals the fat depot–dependent modulation of cellular metabolites in CL‐316,243‐treated mice, presumably resulting from differential regulation of cell metabolism in different cell populations.
Effects of calpain inhibitor on the apoptosis of hepatic stellate cells induced by calcium ionophore A23187
Authors: Li Yanan , Yan Yu , Liu Fang , Wang Luguang , Feng Fumin , Xiao Yonghong 
Published: September 2018

AbstractWe previously showed that changes in calcium concentrations were related to cell apoptosis in vitro. The endoplasmic reticulum (ER) is the main component of calcium storage and signal transduction, and disrupting the balance of intracellular Ca2+ can cause endoplasmic reticulum stress (ERS). In this process, the ER releases stored Ca
2+ into the cytoplasm and activates calpain‐2. To further investigate the effect of calpain in hepatic stellate cells (HSCs), in the current study, we examine the effect of
N‐acetyl‐leu‐leu‐norleucinal (ALLN) on apoptosis resulting from calcium ionophore A23187–induced ERS. Our findings indicate that calpain inhibition reduces calcium ionophore A23187–induced apoptosis of HSCs and decreases the expression of ER stress proteins that may be related to the calpain/caspase signaling pathway.
Bone marrow–derived mesenchymal stem cells–derived exosomes prevent oligodendrocyte apoptosis through exosomal miR‐134 by targeting caspase‐8
Authors: Xiao Yilei , Geng Fengyang , Wang Guifang , Li Xueyuan , Zhu Jianxin , Zhu Weijie 
Published: September 2018

AbstractIschemic stroke causes severe brain damage and remains one of the leading causes of morbidity and mortality worldwide. The microRNA‐134 (miR‐134) is involved in regulating the process of ischemia injury in neural cells and brain with ischemia stroke. The role of miR‐134 in ischemic stroke remains poorly understood. The purpose of the current study was to investigate the effect of bone marrow–derived mesenchymal stem cells (BMSCs)‐derived exosomal miR‐134 on rat oligodendrocytes (OLs) apoptosis and its underlying mechanism of action. The results demonstrated that levels of miR‐134 in BMSCs‐exosome decreased but increased incaspase‐8 after oxygen‐glucose deprivation (OGD) treatment. Exosomal miR‐134 significantly inhibited apoptosis by decreasing caspase‐8 expression and activity in OGD‐treated group cultured with BMSCs‐exosome and OLs. In addition, the miR‐134 mimics decreased caspase‐8 expression in OGD‐treated OLs, whereas miR‐134 inhibitors exacerbated the changes in the expression of the procaspase‐8 and caspase‐8 cleaved product proteins caused by OGD. The caspase‐8 knockdown using caspase‐8 small interfering RNA decreased OLs apoptosis, reversing the improvements that the miR‐134 inhibited cells apoptosis by targeting caspase‐8. Taken together, these results demonstrated that BMSCs‐derived exosomes suppressed OLs apoptosis through exosomal miR‐134 by negatively regulating the caspase‐8‐dependent apoptosis pathway and may, therefore, be a novel potential therapeutic target for ischemic stroke treatment.
Long noncoding RNA H19 competitively binds miR‐93‐5p to regulate STAT3 expression in breast cancer
Authors: Li Jia‐Peng , Xiang Yuan , Fan Li‐Juan , Yao Ao , Li Hui , Liao Xing‐Hua 
Published: September 2018

AbstractThe long noncoding RNA H19 is overexpressed in many cancers and acts as an oncogene. Here, we explored the role of H19 in breast cancer cells, including the effect of H19 on proliferation, migration, and invasion of breast cancer cells. We also investigated the relation of H19 to microRNA miR‐93‐5p and signal transducers and activators of transcription 3 (STAT3), the target gene of miR‐93‐5p. Ectopic expression of H19 in MCF‐7 cells and knockdown of H19 in MDA‐MB‐231 cells showed that overexpression of H19 promoted proliferation, migration, and invasion, whereas knockdown of H19 reduced proliferation, migration, and invasion in vitro. Dual‐luciferase reporter assays and RNA‐binding protein immunoprecipitation assays proved that H19 was a target of miR‐93‐5p. In addition, H19 antagonized the downregulation of miR‐93‐5p on its target STAT3 and antagonized miR‐93‐5p‐mediated cell proliferation. Our study revealed a new network in the expression of STAT3 involving H19 and miR‐93‐5p, which may contribute to a better understanding of breast cancer pathogenesis and provide new insights into the treatment of this disease.
Pharmacophore modeling and molecular dynamics approach to identify putative DNA Gyrase B inhibitors for resistant tuberculosis
Authors: Kashyap Aanchal , Singh Pankaj Kumar , Satpati Suresh , Verma Himanshu , Silakari Om 
Published: September 2018

AbstractOne of the major mechanisms followed by the therapeutic agents to target the causative organism of TB, mycobacterium tuberculosis (Mtb), involves disruption of the replication cycle of the pathogen DNA. The process involves two steps that occur simultaneously, ie, breakage and reunion of DNA at gyrase A (GyrA) domain and ATP hydrolysis at gyrase B (GyrB) domain. Current therapy for multi‐drug resistant TB involves FDA approved, Fluoroquinolone‐based antibiotics, which act by targeting the replication process at GyrA domain. However, resistance against fluoroquinolones due to mutations in the GyrA domain has limited the use of this therapy and shifted the focus of the research community on the GyrB domain. Thus, this study involves in silico designing of chemotherapeutic agents for resistant TB by targeting GyrB domain. In the current study, a pharmacophore model for GyrB domain was generated using reported inhibitors. It was utilized as a query search against three commercial databases to identify GyrB domain inhibitors. Additionally, a qualitative Hip‐Hop pharmacophore model for GyrA was also developed on the basis of some marketed fluoroquinolone‐based GyrA inhibitors, to remove non‐selective gyrase inhibitors obtained in virtual screening. Further, molecular dynamic simulations were carried out to determine the stability of the obtained molecules in complex with both the domains. Finally, Molecular mechanics with generalized Born and surface area solvation score was calculated to determine the binding affinity of obtained molecule with both domains to determine the selectivity of the obtained molecules that resulted in seven putative specific inhibitors of GyrB domain.
Association between rs2278426 (C/T) and rs892066 (C/G) variants of ANGPTL8 (betatrophin) and susceptibility to type2 diabetes mellitus
Authors: Ghasemi Hassan , Karimi Jamshid , Khodadadi Iraj , Saidijam Massoud , Tavilani Heidar 
Published: September 2018

BackgroundAngiopoietin‐like protein 8 (ANGPTL8) is a hormone that mainly secreted from the liver and adipose tissue and plays an important role in the proliferation of pancreatic beta cells and lipid metabolism. Therefore, we studied the association of ANGPTL8 rs2278426 (C/T) and rs892066 (C/G) polymorphisms with the risk of type 2 diabetes mellitus (T2DM) and their association with biochemical parameters.MethodsTwo hundred and eighty‐eight subjects (controls; n = 138 and type 2 diabetic patients; n = 150) were enrolled in this study. Direct haplotyping was performed using amplification‐refractory mutation system (ARMS)‐RFLP‐PCR.ResultsThe CT genotype frequency of rs2278426 (C/T) variant was significantly higher in T2DM patients compared to the controls group (P = 0.02), and there was a significant association between this genotype and increased risk of T2DM (OR: 2.41, CI: 1.26‐4.59, P = 0.007). In addition, there was a significant relationship between CT genotype of this variant and high‐density lipoprotein cholesterol (HDL‐C), fasting blood sugar (FBS), insulin, insulin resistance and glycated hemoglobin (P < 0.05). Furthermore, bioinformatics analysis revealed that arginine (Arg) to tryptophan (Trp) substitution at rs2278426 position causes structural instability of ANGPTL8 protein. Genotype and allele distribution of rs892066 (C/G) was not statistically significant in T2DM patients compared to the control group. The distribution of haplotypes had no significant difference between controls and T2DM patients (P = 0.24).ConclusionOur results suggest that the rs2278426 (C/T) variant is associated with increased risk of T2DM and may cause dyslipidemia due to its effect on decreasing HDL‐C levels.
MicroRNA‐384‐3p inhibits retinal neovascularization through targeting hexokinase 2 in mice with diabetic retinopathy
Authors: Xia Fei , Sun Juan‐Juan , Jiang Ya‐Qin , Li Cheng‐Fang 
Published: September 2018

AbstractDiabetic retinopathy (DR) presents a microvascular complication of diabetes, which may contribute to visual impairment. The treatment of DR is still controversial. Accumulating studies have reported the role of microRNAs (miRs) in DR. This study aims to explore the functions of microRNA‐384‐3p (miR‐384‐3p) in retinal neovascularization by targeting hexokinase 2 (HK2) in mice with DR. A total of 43 C57BL/6 male mice were selected and divided into normal (
n = 16) and DR (
n = 27) groups. Retinal microvascular endothelial cells (RMECs) were collected from the normal and DR mice and mainly treated with a miR‐384‐3p mimic, a miR‐384‐3p inhibitor, small interfering RNA (siRNA) against HK2 and HK2 overexpression plasmids to understand the underlying regulatory mechanisms of miR‐384‐3p. The relationship between miR‐384‐3p and HK2 was determined by dual‐luciferase reporter assay. The miR‐384‐3p expression and the mRNA and the protein expressions of HK2 and CD31 in retinal tissues and cells were evaluated using reverse transcription quantitative polymerase chain reaction (RT‐qPCR) and western blot assay. Cell proliferation was assessed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. Tube formation was observed by conducting a tube formation experiment. HK2 is a target gene of miR‐384‐3p. The DR mice showed higher expression of HK2 and CD31 but lower expression of miR‐384‐3p. The miR‐384‐3p mimic and siRNA‐HK2 reduced the expression of HK2, decreased cell proliferation and tube formation of RMECs, whereas the miR‐384‐3p inhibitor could reverse these trends. Our study demonstrates that overexpression of miR‐384‐3p inhibits retinal neovascularization in DR mice via inhibition of HK2.
DUSP1 recuses diabetic nephropathy via repressing JNK‐Mff‐mitochondrial fission pathways
Authors: Sheng Junqin , Li Hongyan , Dai Qin , Lu Chang , Xu Min , Zhang Jisheng , Feng Jianxun 
Published: September 2018

AbstractExcessive mitochondrial fission has been identified as the pathogenesis of diabetic nephropathy (DN), although the upstream regulatory signal for mitochondrial fission activation in the setting of DN remains unknown. In the current study, we found that dual‐specificity protein phosphatase‐1 (DUSP1) was actually downregulated by chronic hyperglycemia stimulus. Lower DUSP1 expression was associated with glucose metabolism disorder, renal dysfunction, kidney hypertrophy, renal fibrosis, and glomerular apoptosis. At the molecular level, defective DUSP1 expression activated JNK pathway, and the latter selectively opened mitochondrial fission by modulating mitochondrial fission factor (Mff) phosphorylation. Excessive Mff‐related mitochondrial fission evoked mitochondrial oxidative stress, promoted mPTP opening, exacerbated proapoptotic protein leakage into the cytoplasm, and finally initiated mitochondria‐dependent cellular apoptosis in the setting of diabetes. However, overexpression of DUSP1 interrupted Mff‐related mitochondrial fission, reducing hyperglycemia‐mediated mitochondrial damage and thus improving renal function. Overall, we have shown that DUSP1 functions as a novel malefactor in diabetic renal damage that mediates via modifying Mff‐related mitochondrial fission. Thus, finding strategies to regulate the balance of the DUSP1‐JNK‐Mff signaling pathway and mitochondrial homeostasis may be a therapeutic target for treating diabetic nephropathy in clinical practice.
Defective bone repair in diclofenac treated C57Bl6 mice with and without lipopolysaccharide induced systemic inflammation
Authors: Ramirez‐Garcia‐Luna Jose L. , Wong Timothy H. , Chan Daniel , Al‐Saran Yazeed , Awlia Ayman , Abou‐Rjeili Mira , Ouellet Suzie , Akoury Elie , Lemarié Catherine A. , Henderson Janet E. , Martineau Paul A. 
Published: September 2018

AbstractBone repair after trauma or surgical intervention involves a tightly regulated cascade of events that starts with hemostasis and an inflammatory response, which are critical for successful healing. Nonsteroidal anti‐inflammatory drugs (NSAID) are routinely prescribed for pain relief despite their potential inhibitory effect on bone repair. The goal of this study was to determine the impact of administration of the non‐selective NSAID diclofenac in the inflammatory phase of bone repair in mice with or without lipopolysaccharide‐induced systemic inflammation. Repair of femoral window defects was characterized using micro computed tomography imaging and histological analyses at 2 weeks postoperative. The data indicate (a) impaired bone regeneration associated with reduced osteoblast, osteoclast, and macrophage activity; (b) changes in the number, activity, and distribution of mast cells in regenerating bone; and (c) impaired angiogenesis due to a direct toxic effect of diclofenac on vascular endothelial cells. The results of this study provide strong evidence to support the conjecture that administration of NSAIDs in the first 2 weeks after orthopaedic surgery disrupts the healing cascade and exacerbates the negative effects of systemic inflammation on the repair process.
MicroRNA‐10b expression predicts long‐term survival in patients with solid tumor
Authors: Zhang Yi , Wang Li‐Juan , Yang He‐Quan , Wang Rong , Wu Hua‐Jun 
Published: September 2018

AbstractBackgroundNumerous studies have evaluated the significance of the microRNA‐10b (miR‐10b) in the development and progression of many cancers. Their findings revealed that increased expression of miR‐10b is associated with unfavorable prognosis in patients with cancer.ResultsA total of 1,834 patients from 19 studies were included in this study. A significantly shorter overall survival was observed in patients with increased expression of miR‐10b (hazard ratio [HR] = 1.99, 95% confidence interval [CI]: 1.51–2.61). Statistical significance was also observed in subgroup meta‐analysis stratified by the cancer type, cutoff value, analysis type, and sample size. Also, patients with a high expression level of miR‐10b had a poorer disease‐free survival rate (HR = 1.18, 95% CI: 1.05–1.33). In addition, the pooled odds ratios (ORs) showed that increased miR‐10b was also associated with positive lymph node metastasis (OR = 2.09, 95% CI: 1.45–3.03), distant metastasis (OR = 2.40, 95% CI: 1.57–3.67), tumor size (OR = 3.86, 95% CI: 2.25–6.64), and poor clinical stage (OR = 5.02, 95% CI: 3.37–7.47).Materials and MethodsA systematic literature search was conducted on a number of electronic databases, including PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Springer, Google Scholar, and Gene expression omnibus. We retrieved the relevant articles to examine the association between the miR‐10b expression levels and patients’ prognosis. The meta‐analysis was conducted using the RevMan 5.2 software and Stata SE12.0 software.ConclusionsHigh miR‐10b expression was correlated with poor clinical outcome, which indicated the potential clinical use of miR‐10b as a molecular biomarker for cancer, particularly in assessing prognosis for patients with cancers. Further studies should be performed to verify the clinical utility of miR‐10b in human solid tumors.
Proteomic identification of hippocalcin and its protective role in heatstroke‐induced hypothalamic injury in mice
Authors: Ji Jingjing , Hong Xinxin , Su Lei , Liu Zhifeng 
Published: September 2018

AbstractHeatstroke is a devastating condition that is characterized by severe hyperthermia and central nervous system dysfunction. However, the mechanism of thermoregulatory center dysfunction of the hypothalamus in heatstroke is unclear. In this study, we established a heatstroke mouse model and a heat‐stressed neuronal cellular model on the pheochromocytoma‐12 (PC12) cell line. These models revealed that HS promoted obvious neuronal injury in the hypothalamus, with high pathological scores. In addition, PC12 cell apoptosis was evident by decreased cell viability, increased caspase‐3 activity, and high apoptosis rates. Furthermore, 14 differentially expressed proteins in the hypothalamus were analyzed by fluorescence two‐dimensional difference gel electrophoresis and identified by matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry. Expression changes in hippocalcin (HPAC), a downregulated neuron‐specific calcium‐binding protein, were confirmed in the hypothalamus of the heatstroke mice and heat‐stressed PC12 cells by immunochemistry and western blot. Moreover, HPAC overexpression and HPAC‐targeted small interfering RNA experiments revealed that HPAC functioned as an antiapoptotic protein in heat‐stressed PC12 cells and hypothalamic injury. Lastly, ulinastatin (UTI), a cell‐protective drug that is clinically used to treat patients with heatstroke, was used in vitro and in vivo to confirm the role of HPAC; UTI inhibited heat stress (HS)‐induced downregulation of HPAC expression, protected hypothalamic neurons and PC12 cells from HS‐induced apoptosis and increased heat tolerance in the heatstroke animals. In summary, our study has uncovered and demonstrated the protective role of HPAC in heatstroke‐induced hypothalamic injury in mice.
The potential prognostic and therapeutic application of tissue and circulating microRNAs in cervical cancer
Authors: Hasanzadeh Malihe , Movahedi Mehraneh , Rejali Marzieh , Maleki Faezeh , Moetamani‐Ahmadi Mehrdad , Seifi Sima , Hosseini Zeinab , Khazaei Majid , Amerizadeh Forouzan , Ferns Gordon A. , Rezayi Majid , Avan Amir 
Published: September 2018

AbstractCervical cancer (CC) is a common malignancy in women and a major cause of cancer‐related mortality globally. Some novel biomarkers may enable the early diagnosis and monitoring of CC. MicroRNAs (miRNAs) are small noncoding RNAs that control gene translation at a posttranscriptional level. Hence the deregulation of these molecules can cause many diseases. There appears to be an association between aberrant miRNA expression and CC, but the molecular mechanisms involved in the development of CC remain unknown. The upregulation of some circulating miRNAs, for example, miRNA‐20a, miRNA‐203, miRNA‐21, miRNA‐205, miRNA‐218, and miR‐485‐5, as well as tissue‐specific miRNAs, for example, miR‐7, miR‐10a, miR‐17‐5p, miR‐135b, miR‐149, and miR‐203 have been found in patients with CC. There is also growing evidence for the importance of miRNAs in the development of drug resistance. This review therefore highlights recently published preclinical and clinical investigation performed on tissue specific and circulating miRNAs, as potential biomarkers for the detection of patients at early stages of CC, in the prediction of prognosis, and monitoring of their response to therapy.