bluuebunny/crossref_metadata_2025 huggingface dataset:
The dietary flavone luteolin epigenetically activates the Nrf2 pathway and blocks cell transformation in human colorectal cancer HCT116 cells
Authors: Zuo Qian , Wu Renyi , Xiao Xi , Yang Caizhi , Yang Yuqing , Wang Chao , Lin Lizhu , Kong Ah‐Ng
Published: August 2018

Colorectal cancer remains a leading malignancy in humans. The importance of epigenetic modification in the development of this disease is now being recognized. The reversible and dynamic nature of epigenetic modifications provides a promising strategy in colorectal cancer chemoprevention and treatment. Luteolin (LUT), a flavone dietary phytochemical, can modulate various signaling pathways involved in carcinogenesis. Many studies have demonstrated that LUT inhibits colorectal carcinogenesis by activating the Nuclear factor erythroid 2‐related factor 2 (Nrf2)/antioxidant‐responsive element (ARE) pathway. However, the potential epigenetic mechanism underlying Nrf2/ARE pathway activation remains unclear. In this study, we aimed to explore the anticancer potential of LUT in human colon cancer cells and the epigenetic regulation of the Nrf2/ARE pathway. Specifically, our data showed that LUT suppressed cell proliferation and cellular transformation of HCT116 and HT29 cells in a dose‐dependent manner. Additionally, quantitative real‐time polymerase chain reaction and Western blot analysis were performed to determine the mRNA and protein expression of Nrf2 and its downstream genes after LUT treatment. Bisulfite genomic sequencing revealed that methylation of the Nrf2 promoter region was decreased by LUT, corresponding with the increased mRNA expression of Nrf2. Decreased protein levels and enzyme activities of epigenetic modifying enzymes, such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), were also observed in LUT‐treated HCT116 cells. In summary, our findings suggest that LUT may exert its antitumor activity in part via epigenetic modifications of the Nrf2 gene with subsequent induction of its downstream antioxidative stress pathway.
The prognostic value of long noncoding RNA MEG3 expression in the survival of patients with cancer: A meta‐analysis
Authors: Binabaj Maryam Moradi , Bahrami Afsane , Bahreyni Amirhossein , Shafiee Mojtaba , Rahmani Farzad , Khazaei Majid , Soleimanpour Saman , Ghorbani Elnaz , Fiuji Hamid , Ferns Gordon A. , Ryzhikov Mikhail , Avan Amir , Hassanian Seyed Mahdi
Published: August 2018

Long noncoding RNAs (lncRNAs) play an important role in carcinogenesis and cancer progression. lncRNA maternally expressed gene 3 (MEG3) is a tumor suppressor that is downregulated in several cancers. However, its prognostic value in human malignancies remains controversial. We have therefore undertaken a meta‐analysis to explore the relationship between cancer survival and the expression of lncRNA MEG3. A systematic literature search identified 13 potentially eligible investigations comprising 1733 patients in nine different cancer types. In the pooled analysis, a low expression of MEG3 was associated with low overall survival (OS) in patients with cancer having a combined hazard ratio (HR) of 0.830 (HR = 0.83; 95% CI: 0.70‐0.98; p = 0.03; random effect model). However, subgroup analysis according to cancer type revealed that MEG3 expression was not associated with better OS in gastrointestinal cancer (HR = 0.58, 95% CI = 0.33‐1.03; p = 0.06), and patients with breast cancer (HR = 0.85, 95% CI: 0.12‐5.88; p = 0.87). In conclusion, our results demonstrate that only in the pooled analysis, there was a significant relationship between MEG3 expression and cancer survival. Further investigation of other molecular biomarkers involved in tumorigenesis‐related pathways is necessary.
Transcriptome analysis reveals an altered expression profile of zinc transporters in colorectal cancer
Authors: Barresi Vincenza , Valenti Giovanna , Spampinato Giorgia , Musso Nicolò , Castorina Sergio , Rizzarelli Enrico , Condorelli Daniele Filippo
Published: August 2018

Zinc is a transition metal and catalytic cofactor involved in many biological processes including proliferation, development, differentiation, and metabolism. Zinc transporters (ZnTs) play a fundamental role in cellular zinc homeostasis. ZnTs are responsible of zinc efflux and are encoded by 10 genes belonging to solute carrier family 30A (SLC30A1‐10), while zinc‐regulated transporter (ZRT)/iron‐regulated transporter (IRT)‐like protein (ZIP) transporters are responsible for the influx of zinc into the cytoplasm and are encoded by 14 genes belonging to solute carrier family 39A (SLC39A1‐14). In this study, we analyzed, by transcriptome analysis, the microRNA levels of ZnT‐encoding and ZIP‐encoding genes in colorectal cancer (CRC) samples matched to normal colon tissues and in CRC cell lines. Results revealed an upregulation of specific ZnT and ZIP transcripts in CRC. Upregulation of SLC30A5, SLC30A6, SLC30A7 transcripts, encoding zinc efflux transporters ZnT5, ZnT6, ZnT7, localized on endoplasmic reticulum membranes, might be part of a coordinated transcriptional program associated to the increased activity of the early secretory pathway, while transcriptional upregulation of several specific ZIP transporters (SLC39A6, SLC39A7, SLC39A9, SLC39A10, and SLC39A11) could contribute in meeting the increased demand of zinc in cancer cells. Moreover, exon‐level analysis of SLC30A9, a nuclear receptor coactivator involved in the transcriptional regulation of Wnt‐responsive genes, revealed the differential expression of alternative transcripts in CRC and normal colonic mucosa.
Integrative analysis of significant RNA‐binding proteins in colorectal cancer metastasis
Authors: Zhou Bin , Guo Rui
Published: August 2018

The aberrant expression of RNA‐binding proteins (RBPs) plays a crucial role in the occurrence and progression of human cancer. However, the key functions of RBPs in the metastasis of colorectal cancer have not yet been fully elucidated. Here, we integrated multi‐omics data and identified four differentially expressed RBPs (APOBEC3G, EEF1A2, EIF5AL1 and CELF3) in patients with colorectal cancer metastasis. To clarify the underlying molecular mechanisms, we systematically analyzed the genomic features and downstream regulatory relationships of the four RBPs. In a genomic level, the copy number variations of APOBEC3G, EEF1A2, and CELF3 demonstrated significantly differential distributions between metastatic and nonmetastatic patients. Besides that, combining sequence and expression information, we identified 436 putative RNA targets regulated by the four RBPs through strict multistep bioinformatics screening. For the downstream analysis, the evidence from functional enrichment analysis and public literature indicated the roles of these target genes in the carcinogenesis and progression of colorectal cancer. Furthermore, through the machine learning algorithm and statistical analysis, we obtained two gene candidates that had obvious effects on the metastasis and overall survival status of patients with colorectal cancer. In summary, our study comprehensively explored the influence of APOBEC3G, EEF1A2, EIF5AL1, and CELF3 in colorectal cancer metastasis, which may offer favorable perspectives for clinical diagnosis and therapy.
The oncoprotein Myc controls the phosphorylation of S6 kinase and AKT through protein phosphatase 2A
Authors: Chellini Lidia , Monteleone Valentina , Lombari Malinska , Caldarola Sara , Loreni Fabrizio
Published: August 2018

This study focuses on the effects of Myc oncoprotein on the translational apparatus of the cell. Translation is an energy consuming process that involves a large number of accessory factors. The production of components of the protein synthesis machinery can be regulated at the transcriptional level by specific factors. It has been shown that the product of the oncogene Myc, a transcription factor frequently activated in cancer, can control translational activity through an increase in the transcription of the eIF4F complex components (eIF4E, eIF4AI, and eIF4GI). However, additional effects at the posttranslational level have also been described. For instance, it has been shown that Myc upregulation can induce mammalian target of rapamycin (mTOR)–dependent 4E‐binding protein 1 (4E‐BP1) hyperphosphorylation. We induced overexpression or inhibition of Myc through transfection of complementary DNA constructs or specific small interfering RNA in PC3 (prostate carcinoma) and HeLa (cervical carcinoma) cells. We have observed that overexpression of Myc causes an increase in 4E‐BP1 phosphorylation and activation of protein synthesis. Unexpectedly, we detected a parallel decrease in the phosphorylation level of S6 kinase (in PC3 and HeLa) and AKT (in HeLa). We report evidence that these changes are mediated by an increase in protein phosphatase 2A activity.
Exploring the effect of E76K mutation on SHP2 cause gain‐of‐function activity by a molecular dynamics study
Authors: Li Wei‐Ya , Wei Hui‐Yu , Sun Ying‐Zhan , Zhou Hui , Ma Ying , Wang Run‐Ling
Published: August 2018

Juvenile myelomonocytic leukemia (JMML), an invasive myeloproliferative neoplasm, is a childhood disease with very high clinical lethality. Somatic mutation E76K in SHP2 is the most commonly identified mutation found in up to 35% of patients with JMML. To investigate the effect of gain‐of‐function mutation‐E76K on SHP2 activity, molecular dynamic simulations on the wild‐type SHP2 (SHP2‐WT) system and the mutated E76K (SHP2‐E76K) system were performed. The evaluation of stability of these two systems indicated that the simulated trajectories were stable after simulation for 3 nanoseconds. The root mean square fluctuation and the per‐residue root mean square deviation illustrated that there were two regions (residues Tyr 81‐Glu 83 and Glu 258‐Leu 261) in the wild‐type system and the mutated system, which had large differences. The principal component analysis, dynamic cross correlation maps analysis, as well as secondary structure analysis suggested that the mutated E76K impacted the movement of these two regions in SHP2 protein. Furthermore, residue interaction network analysis, hydrogen bond occupancy, and binding free energies analysis were used to explain how the two regions were specifically affected by the mutant. The results indicated that the primary variances between SHP2‐WT and SHP2‐E76K were the different interactions between Glu/Lys 76 and Arg 265, Tyr 80 and Leu 77, Leu 77 and Tyr 81, Thr 73 and Glu 258, Ala 75 and Cys 259, Phe 71 and Tyr 81, Ala 75 and Glu 258, and Tyr 73 and Glu/Lys 76. Consequently, these findings here might provide insights into the increased activity in SHP2‐E76K.
Oxidative damage in glutaric aciduria type I patients and the protective effects of l‐carnitine treatment
Authors: Guerreiro Gilian , Faverzani Jéssica , Jacques Carlos Eduardo Diaz , Marchetti Desirèe P. , Sitta Angela , de Moura Coelho Daniella , Kayser Aline , Kok Fernando , Athayde Larissa , Manfredini Vanusa , Wajner Moacir , Vargas Carmen Regla
Published: August 2018

The deficiency of the enzyme glutaryl‐CoA dehydrogenase, known as glutaric acidemia type I (GA‐I), leads to the accumulation of glutaric acid (GA) and glutarilcarnitine (C5DC) in the tissues and body fluids, unleashing important neurotoxic effects. l‐carnitine (l‐car) is recommended for the treatment of GA‐I, aiming to induce the excretion of toxic metabolites. l‐car has also demonstrated an important role as antioxidant and anti‐inflammatory in some neurometabolic diseases. This study evaluated GA‐I patients at diagnosis moment and treated the oxidative damage to lipids, proteins, and the inflammatory profile, as well as in vivo and in vitro DNA damage, reactive nitrogen species (RNS), and antioxidant capacity, verifying if the actual treatment with l‐car (100 mg kg−1 day−1) is able to protect the organism against these processes. Significant increases of GA and C5DC were observed in GA‐I patients. A deficiency of carnitine in patients before the supplementation was found. GA‐I patients presented significantly increased levels of isoprostanes, di‐tyrosine, urinary oxidized guanine species, and the RNS, as well as a reduced antioxidant capacity. The l‐car supplementation induced beneficial effects reducing these biomarkers levels and increasing the antioxidant capacity. GA, in three different concentrations, significantly induced DNA damage in vitro, and the l‐car was able to prevent this damage. Significant increases of pro‐inflammatory cytokines IL‐6, IL‐8, GM‐CSF, and TNF‐α were shown in patients. Thus, the beneficial effects of l‐car presented in the treatment of GA‐I are due not only by increasing the excretion of accumulated toxic metabolites, but also by preventing oxidative damage.
Licochalcone C induced apoptosis in human oral squamous cell carcinoma cells by regulation of the JAK2/STAT3 signaling pathway
Authors: Oh Ha‐Na , Seo Ji‐Hye , Lee Mee‐Hyun , Kim Cheolhee , Kim Eunae , Yoon Goo , Cho Seung‐Sik , Cho Young Sik , Choi Hyun Woo , Shim Jung‐Hyun , Chae Jung‐Il
Published: August 2018

Oral cancer is of an aggressive malignancy that arises on oral cavity and lip, 90% of cancers histologically originated in the squamous cells. Licochalcone (LC)C has been known as natural phenolic chalconoid substances, and its origin is the root of Glycyrrhiza glabra or Glycyrrhiza inflata. LCC inhibited oral squamous cell carcinoma (OSCC) cell viability, mitochondrial function, and anchorage‐independent growth in a dose‐dependent manner. To investigate the ability of LCC to target Janus kinase 2 (JAK2), we performed pull‐down binding assay, kinase assay, and docking simulation. The molecular docking studies were performed between JAK2 and the potent inhibitor LCC. It was shown that LCC tightly interacted with ATP‐binding site of JAK2. In addition, LCC inhibited the JAK2/signal transducer and activator of transcription 3 pathway, upregulated p21, and downregulated Bcl‐2, Mcl‐1, and Survivin, while it disrupted mitochondrial membrane potential and subsequently caused cytochrome c release with activation of multi‐caspase, eventually leading to apoptosis in HN22 and HSC4 cells. LCC elevated the protein levels of Bax, cleaved Bid and PARP, and increased Apaf‐1, and this effect was reversed by LCC treatment. Our results demonstrated that treatment of OSCC cells with LCC induced the death receptor (DR)4 and DR5 expression level with the generation of reactive oxygen species and the upregulation of CHOP protein expression. Taken together, these results could provide the basis for clinical application as a new therapeutic strategy in the treatment of oral cancer.
Isolation of AccGalectin1 from Apis cerana cerana and its functions in development and adverse stress response
Authors: Wang Lijun , Wang Chen , Li Han , Yang Xinxin , Wang Ying , Guo Xingqi , Xu Baohua
Published: August 2018

The galectins are a family of lectins that play important roles in development, immunity, and the regulation of cellular responses. Much research has focused on the functions of galectins in mammals, though less in insects. Here, we identified the AccGalectin1 gene in Apis cerana cerana for the first time and explored its functions. The open reading frame of AccGalectin1 is 1449 base pairs and encodes a 482‐amino‐acid protein. AccGalectin1 expression was high during the transition between developmental stages and was high in the head, thorax, and epidermis compared with its levels in other tissues. In addition, the expression of AccGalectin1 was induced by several adverse stresses, including both abiotic and biotic stresses. A disk diffusion assay of recombinant AccGalectin1 protein revealed possible roles in protecting cells from oxidative stress. Furthermore, the expression levels of multiple oxidative genes (AccCAT, AccTpx1, AccTrx2, etc) were increased after AccGalectin1 was knocked down in Apis cerana cerana using RNA interference. We also observed that the malondialdehyde content in the AccGalectin1‐silenced bees was higher than that in the control bees, while the antioxidant enzymatic activities of superoxide dismutase and peroxidase were lower. Considering these results, we suggest that AccGalectin1 may be indispensable for protecting honeybees from biotic and abiotic damage by participating in the oxidative resistance response and the immune response. These results may provide insight into the precise functions of galectins in mammals and other insects.
Neutrophil‐to‐C3 ratio and neutrophil‐to‐lymphocyte ratio were associated with disease activity in patients with systemic lupus erythematosus
Authors: Yu Jianlin , Zeng Tingting , Wu Yang , Tian Yongjian , Tan Liming , Duan Xinwang , Wu Qiong , Li Hua , Yu Le
Published: August 2018

Background

Systemic lupus erythematosus is prone to recurrent attacks, and its treatment is related to disease activities. It is important to accurately assess the patient's disease activity. So, the purpose of this study was to investigate the relation between neutrophil‐to‐C3 ratio (NC3R), neutrophil‐to‐lymphocyte ratio (NLR), and disease activity in patients with Systemic lupus erythematosus (SLE).

Methods

This was a retrospective study. One hundred and ninety‐four patients with SLE and 71 healthy controls were included in this study. We divided the patients into two groups according to the SLE disease activity (SLEDAI). Group 1 included patients with a score of >9 (patients with severe disease activity), and Group 2 included patients with a score of 9 and lower (patients with mild disease activity). Correlations between NC3R, NLR, and disease activity were analyzed.

Results

NC3R and NLR in patients with SLE were obviously higher compared to healthy controls (P < 0.05). There was an obviously significant difference in NC3R and NLR between Group 1 and Group 2 (P < 0.05). SLEDAI scores were positively correlated with NC3R (r = 0.353, P < 0.01) and NLR (r = 0.237, P = 0.01). Receiver operating characteristic (ROC) curve analysis showed that the cutoff value of NC3R to identify SLE with high disease activity was 5.935, with sensitivity and specificity being 75.9% and 67.0%, while that of NLR was 2.293, with sensitivity being 68.9% and specificity being 82.8%.

Conclusion

NC3R and NLR are two useful inflammatory markers for evaluating disease activity in patients with SLE.
Influence of alpha thalassemia on clinical and laboratory parameters among nigerian children with sickle cell anemia
Authors: Olatunya Oladele S. , Albuquerque Dulcineia M. , Adekile Adekunle , Costa Fernando F.
Published: August 2018

Background

There is paucity of data on the influence of alpha thalassemia on the clinical and laboratory parameters among Nigerian sickle cell anemia (SCA) patients. This study aimed to determine the prevalence of alpha thalassemia and the influence of alpha thalassemia on laboratory parameters and clinical manifestations in a group of young NigerianSCApatients.

Methods

This was a cross‐sectional retrospective study conducted on 100 patients withSCAand 63 controls. The diagnosis ofSCAwas confirmed byDNAstudies. Alpha thalassemia genotyping was performed by multiplex gap‐PCRmethod. Laboratory parameters including complete blood count, hemoglobin quantitation, serum lactate dehydrogenase (LDH), and bilirubin were determined with standard techniques.

Results

Alpha thalassemia was found in 41 (41.0%) patients compared to 24 (38.1%) controls (P = 0.744), and all were due to the 3.7 κb α‐globin gene deletions. Alpha thalassemia was associated with more frequent bone pain crisis, higher hemoglobin concentration, red blood cell count, and HbA2level among the patients. On the contrary, patients with alpha thalassemia had lower mean corpuscular volume, mean corpuscular hemoglobin, and white blood cell count (WBC) (P ˂ 0.05). There were 6 (6.0%) patients with leg ulcers, and none of them had alpha thalassemia,P = 0.04.

Conclusion

This study confirms that coexistence of alpha thalassemia withSCAsignificantly influences both the clinical and laboratory manifestations of young NigerianSCApatients. The coexistence of this genetic modifier is associated with increased bone pain crisis and protects against sickle leg ulcers among the patients.
Norepinephrine stimulation downregulates the β2‐adrenergic receptor–nitric oxide pathway in human pulmonary artery endothelial cells
Authors: Yu Wande , Gu Yue , Chen PeiP , Luo Jie , Liu Pengfei , Chao Yuelin , Chen Shao‐Liang , Zhang Hang
Published: August 2018

Background

Norepinephrine (NE)‐mediated vasoconstriction plays an important role in pulmonary hypertension associated with left heart disease (PH‐LHD). However, the role of NE‐mediated endothelial cell dysfunction in the pathogenesis of PH‐LHD remains to be elucidated.

Methods and Results

An enzyme‐linked immunosorbent assay showed that the NE concentration in the plasma of patients with PH‐LHD was higher and the nitrate–nitrite concentration was lower than those in the control group. NE treatment decreased phospho‐Ser633‐eNOS and β2‐adrenergic receptor (β2‐AR) levels in the membrane of human pulmonary artery endothelial cells (HPAECs) analysed by western blot analysis. Consistently, fluorescence microscopy and flow cytometry showed that nitric oxide (NO) production was also decreased in HPAECs. Coimmunoprecipitation confirmed a direct interaction between β2‐AR and endothelial NO synthase (eNOS). Overexpression of β2‐AR attenuated the decline in phospho‐Ser633‐eNOS and NO production. Additionally, the expression of phospho‐Ser633‐eNOS and β2‐AR was decreased in human pulmonary artery endothelium. Finally, our results indicate that NE stimulated HPAEC proliferation, which was blocked by protein kinase A inhibitor or protein kinase B (PKB–AKT) inhibitor.

Conclusions

These data provide a novel mechanism for NE‐decreased endothelium‐derived NO and NE‐induced HPAEC proliferation that leads to PH‐LHD, suggesting a potential therapeutic target for PH‐LHD.
Effect of microRNA‐26a on vascular endothelial cell injury caused by lower extremity ischemia–reperfusion injury through the AMPK pathway by targeting PFKFB3
Authors: Wu Ye , Zhang Min‐Hong , Xue Yan , Zhang Tao , Wu Na , Guo Wei , Du Xin , Xu Yong‐Le
Published: August 2018

Vascular endothelial cell (VEC) dysfunction plays an important role in the ischemia–reperfusion injury (IRI)‐related diseases, and microRNAs (miRNAs) are key factors during this process. We conducted this study to investigate whether miRNA‐26a (miR‐26a) has effect on the IRI‐induced VEC injury via the AMPK pathway by targeting 6‐phosphofructo‐2‐kinase–fructose‐2,6‐biphosphatase 3 (PFKFB3). IRI rat models were successfully constructed by an abdominal incision. Additionally, the cultured VECs were further treated with miR‐26a mimic or inhibitor, and si‐PFKFB3. Both the reverse‐transcription quantitative polymerase chain reaction and the western blot assay method were carried out to examine the expressions of PFKFB3, endothelial nitric oxide synthase (eNOS), and 5’‐adenosine monophosphate‐activated protein kinase (AMPK) α1, as well as the extent of the AMPK α1 phosphorylation levels in vascular tissues. Circulating endothelial cell (CEC), von Willebrand factor (VWF), thrombomodulin (TM), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), and endothelin (ET) were all measured. In the rat model of an IRI, a poorly expressed miR‐26a and contrarily highly expressed PFKFB3 were identified in vascular tissues. In response to an overexpression of miR‐26a or to the PFKFB3 gene silencing, decreased CEC number, TM, VWF, MDA, and ET contents, increased AMPK α1, and eNOS levels, as well as the extent of AMPK α1 phosphorylation coordinate with both increased SOD and NO contents based on the restoration of the AMPK pathway. Overexpression of the miR‐26a or si‐PFKFB3 provides an elevation in cell proliferation. Our study suggests that the miR‐26a RNA alleviates lower extremity IRI‐induced VEC injury in rats through the activation of the AMPK pathway by inhibiting PFKFB3.
Global estimate of gastric cancer in Helicobacter pylori–infected population: A systematic review and meta‐analysis
Authors: Pormohammad Ali , Mohtavinejad Naser , Gholizadeh Pourya , Dabiri Hossein , Salimi Chirani Alireza , Hashemi Ali , Nasiri Mohammad Javad
Published: August 2018

There is information regarding the rates of gastric cancer (GC) in different populations and the important role of Helicobacter pylori in GC development; however, no comprehensive study has yet been performed to investigate the prevalence of GC in H. pylori–infected patients. PubMed, Embase, and Cochrane Library through January 1, 2000 were searched without language restrictions. Quality of included studies was assessed with a critical appraisal checklist recommended by the Joanna Briggs Institute. All of the analyses were conducted using Comprehensive Meta‐Analysis Software Version 2.0 and Stata 14.0. Forty‐four studies from 17 countries were included. The pooled frequency of GC was 17.4% (95% confidence interval: 16.4–18.5) in H. pylori–infected population. The frequency of GC among H. pylori–infected population varied markedly across countries. The highest rate of GC was observed in H. pylori–infected individuals from Asian countries. The frequency of GC was relatively high in H. pylori–infected population in the world. However, the eradication of H. pylori might be a promising strategy for GC prevention, especially in high‐risk populations such as Asian countries.
Insulin promotes macrophage phenotype transition through PI3K/Akt and PPAR‐γ signaling during diabetic wound healing
Authors: Yu Tianyi , Gao Min , Yang Peilang , Liu Dan , Wang Di , Song Fei , Zhang Xiong , Liu Yan
Published: August 2018

Overactivation and persistent chronic inflammation are the major pathogenic characteristics of diabetic‐impaired healing, and diabetic wound healing can be promoted by stimulating the transition of macrophage phenotype from pro‐inflammatory (M1) to anti‐inflammatory (M2). Our previous studies found that the application of insulin induced an advanced initiation and resolution of inflammatory response. To further explore the mechanism, we have investigated the effect of insulin on macrophage phenotype switch utilizing a diabetic rat model and a human monocytic THP‐1 cell. We have utilized the high glucose (HG) and HG plus insulin to stimulate the M1 macrophages derived from lipopolysaccharide‐treated THP‐1 cells. We studied the secretion of inflammatory mediator and related signaling pathways by using western blot test, immunofluorescence, and Rac1 pull‐down assay. We have found that the production of pro‐inflammatory mediators, which thereafter induced macrophage polarization toward M1 phenotype, has been elevated due to consistent HG exposure. HG plus insulin stimulation, on the other hand, promoted anti‐inflammatory effects. Experiments performed on diabetic burn wounds indicated that the insulin modulated macrophages transition from M1 to M2 phenotype. We found that PI3K/Akt/Rac‐1 and PPAR‐γ signaling pathways are involved in the anti‐inflammatory effect of insulin. Insulin inhibited HG‐induced activation of p38, NF‐κB, and STAT1 transcriptional activity by activating Akt‐Rac‐1 signaling. Moreover, insulin performs anti‐inflammatory effects through upregulation of PPAR‐γ expression and induced P38‐mediated dephosphorylation of PPAR‐γ (Ser112). In conclusion, insulin downregulates inflammatory response, regulates M1 macrophage transition in response to HG, and thus improves chronic wound healing.
Emerging role of SIRT3 in endothelial metabolism, angiogenesis, and cardiovascular disease
Authors: He Xiaochen , Zeng Heng , Chen Jian‐Xiong
Published: August 2018

Sirtuin 3 (SIRT3) a mitochondrial enzyme that plays an important role in energy homeostasis, cardiac remodeling, and heart failure (HF). The expression of SIRT3 declines with advanced age, cardiovascular, and metabolic diseases. Accumulating evidence suggests that SIRT3 plays a critical role in protecting the heart from cardiac hypertrophy, cardiac dysfunction associated with HF, and in the protection of cardiac cells from stress‐mediated cell death. Clinical studies have demonstrated that HF with preserved ejection fraction (HFpEF) in patients present with abnormalities in coronary microcirculation related to endothelial dysfunction and coronary microvascular rarefaction. Although SIRT3‐mediated regulation of mitochondrial homeostasis and heart function has been intensively investigated, the effect of SIRT3 on endothelial cell (EC) glycolytic metabolism and microvascular function has not been well studied. ECs utilize glycolysis for generating ATP rather than oxidative phosphorylation to maintain their normal functions and promote angiogenesis and EC–cardiomyocyte interactions. Emerging evidence indicates that SIRT3 is involved in the regulation of endothelial metabolism and angiogenesis and thus affects the development of cardiovascular diseases associated with aging. This review will discuss the current knowledge of SIRT3 and its functional role on endothelial metabolism, cardiac function, and cardiovascular diseases.
The mechanical and pharmacological regulation of glioblastoma cell migration in 3D matrices
Authors: Kaphle Pranita , Li Yongchao , Yao Li
Published: August 2018

The invasion of glioblastoma is a complex process based on the interactions of tumor cells and the extracellular matrix. Tumors that are engineered using biomaterials are more physiologically relevant than a two‐dimensional (2D) cell culture system. Matrix metalloproteinases and the plasminogen activator generated by tumor cells regulate a tumor’s invasive behavior. In this study, microtumors were fabricated by encapsulating U87 glioma cells in Type I collagen and then glioma cell migration in the collagen hydrogels was investigated. Crosslinking of collagen with 8S‐StarPEG increased the hydrogel viscosity and reduced the tumor cell migration speed in the hydrogels. The higher migration speed corresponded to the increased gene expression of MMP‐2, MMP‐9, urokinase plasminogen activator (uPA), and tissue plasminogen activator (tPA) in glioma cells grown in non‐crosslinked collagen hydrogels. Inhibitors of these molecules hindered U87 and A172 cell migration in collagen hydrogels. Aprotinin and tranexamic acid did not inhibit U87 and A172 migration on the culture dish. This study demonstrated the differential effect of pharmacologic molecules on tumor cell motility in either a 2D or three‐dimensional culture environment.
Prevalence of rheumatoid cachexia in rheumatoid arthritis: a systematic review and meta‐analysis
Authors: Santo Rafaela C.E. , Fernandes Kevin Z. , Lora Priscila S. , Filippin Lidiane I. , Xavier Ricardo M.
Published: August 2018

Background

Low muscle mass occurs in patients with rheumatoid arthritis without weight loss; this condition is referred as rheumatoid cachexia. The aim of the current study was to perform a systematic review with meta‐analysis to determine the rheumatoid cachexia prevalence.

Methods

A systematic review with meta‐analysis of observational studies published in English, between 1994 and 2016, was conducted using MEDLINE (via PubMed) and other relevant sources. Search strategies were based on pre‐defined keywords and medical subject headings. The methodological quality of included studies was assessed using the Newcastle‐Ottawa Scale. Meta‐analysis was used to estimate the prevalence, and because studies reported different methods and criteria to estimate body composition and prevalence of rheumatoid cachexia, subgroup analyses were performed. Meta‐regression adjusted for the 28‐joint disease activity score and disease duration (years) was performed (significance level at P ≤ 0.05).

Results

Of 136 full articles (one duplicate publication) screened for inclusion in the study, eight were included. The estimated overall prevalence of rheumatoid cachexia was 19% [95% confidence interval (CI) 07–33%]. This prevalence was 29% (95% CI 15–46%) when body composition was measured by dual‐energy X‐ray absorptiometry. When the diagnostic criteria were fat‐free mass index below the 10th percentile and fat mass index above the 25th percentile, rheumatoid cachexia prevalence was 32% (95% CI 14–52%). The 28‐joint disease activity score and disease duration had no influence on the estimated prevalence of rheumatoid cachexia (P > 0.05). Most studies were rated as having moderate methodological quality.

Conclusions

Meta‐analysis showed a prevalence of rheumatoid cachexia of 15‐32%, according to different criteria, demonstrating that this condition is a frequent comorbidity of rheumatoid arthritis. To better understand its clinical impact, more studies using standardized definitions and prospective evaluations are urgently needed.
Spleen and liver stiffness for noninvasive assessment of portal hypertension in cirrhotic patients with large esophageal varices
Authors: Tseng Yujen , Li Feng , Wang Jian , Chen Shiyao , Jiang Wei , Shen Xizhong , Wu Shengdi
Published: August 2018

Purpose

Noninvasive evaluation of portal hypertension is needed for cirrhotic patients with large esophageal varices. This study was aimed at assessing the diagnostic value of liver/spleen stiffness in predicting hepatic vein pressure gradient (HVPG) in this special population.

Methods

In the present prospective cohort study, liver/spleen stiffness was measured by transient elastography. Patients also underwent HVPG assessment, upper gastrointestinal endoscopy, and other noninvasive serum models.

Results

Ninety‐nine cirrhotic patients with large esophageal varices were enrolled. Liver/spleen stiffness strongly correlated with HVPG. In regards to significant portal hypertension, area under receiver operating characteristic curves (AUROCs) for liver/spleen stiffness were 0.74 and 0.91. Accuracy for detecting significant portal hypertension was 79% for spleen stiffness of 48.9 kPa (sensitivity: 76%, specificity: 100%, positive predictive value: 100%, negative predictive value: 38%) and 75% for liver stiffness of 16.0 kPa (sensitivity: 78%, specificity: 54%, positive predictive value: 92%, negative predictive value: 27%). Similarly, spleen stiffness had significant higher AUROCs for predicting HVPG ≥16 and ≥20 mm Hg than that of liver stiffness and other noninvasive serum models.

Conclusion

In cirrhotic patients with large esophageal varices, liver stiffness and spleen stiffness correlate with HVPG, and spleen stiffness is superior to liver stiffness in predicting portal hypertension.
A Highly Efficient Catalyst for the Suzuki‐Miyaura Cross‐Coupling Reaction of 5‐(5‐chloropyridin‐3‐yl)‐3‐methyl‐1,3,4‐oxadiazol‐2(3H)‐one
Authors: Savitha Bhaskaran , Koti Reddy Eeda , Parthasarathi D. , Pakkath Rajeesh , Sajith Ayyiliath M. , Ananda kumar C. S. , Haridas Karickal R. , Syed Ali Padusha M.
Published: August 2018

A highly efficient protocol for the synthesis of diverse aryl (heteroaryl) substituted pyridyl oxadiazol‐2(3H)‐one analogues using Suzuki‐Miyaura cross‐coupling strategy under microwave enhanced conditions is developed. The method is found to be compatible with a wide range of aryl (heteroaryl) boronic acids.
Synthesis of deuterium‐labeled 2‐quinoxalinecarboxylic acid and 3‐methylquinoxaline‐2‐carboxylic acid from deuterium aniline
Authors: Chen Wulian , Zhao Chaomin , Deng Xiaojun
Published: August 2018

An efficient and simple synthetic route of deuterium‐labeled 2‐quinoxalinecarboxylic acid‐d4 (QCA‐d4) and 3‐methylquinoxaline‐2‐carboxylic acid‐d4 (MQCA‐d4) is presented with 99.9% and 99.6% isotopic enrichment using aniline‐d5 as labeled starting material. Their chemical structures were confirmed by 1H NMR, and their isotopic abundance was determined by mass spectrometry analysis.
Comparison of the Diagnostic Performance of Synthetic Versus Acquired High b‐Value (1500 s/mm2) Diffusion‐Weighted MRI in Women With Breast Cancers
Authors: Park Jung Hyun , Yun Bo La , Jang Mijung , Ahn Hye Shin , Kim Sun Mi , Lee Soo Hyun , Kang Eunyoung , Kim Eun‐Kyu , Park So Yeon
Published: August 2018

Background

Acquired high b‐value (>1000 s/mm2) diffusion‐weighted imaging (DWI) has its strength in lesion detection. However, it is not easily used, due to a lower signal‐to‐noise ratio, eddy current distortions, and prolonged acquisition times. Synthetic DWI does not have these disadvantages because it is based on indirect acquisition, calculated in a voxel‐wise manner.

Purpose

To compare the diagnostic performance of synthetic and acquired high b‐value (1500 s/mm2) DWI in women with breast cancer.

Study Type

Retrospective.

Population

A total of 108 patients (median age 49 years [range 32–77]) with 133 breast cancers.

Field Strength/Sequence

3T, echo‐planar imaging.

Assessment

Three radiologists independently reviewed image sets of both synthetic (S‐b1500) and acquired (A‐b1500) high b‐value DWI. Malignancy confidence of the lesion was scored using a 6‐point Likert‐type scale.

Statistical Test

Jack‐knife alternative free‐response receiver‐operating characteristic 1 (JAFROC1) analysis was used. Sensitivity and positive predictive value (PPV) were compared using generalized estimating equations. An independent t‐test was used to compare the confidence. An intraclass correlation coefficient was calculated to compare interobserver agreement.

Results

The JAFROC1 figures of merit values were 0.816 and 0.808 in S‐b1500 and A‐b1500, respectively, with no statistically significant difference (P = 0.637). Sensitivity was higher in synthetic than in A‐b1500 for readers 2 (P = 0.015) and 3 (P = 0.037). Although sensitivity was higher in S‐b1500 than in A‐b1500 for reader 1, the difference was not significant (P = 0.487). The PPV of S‐b1500 was not significantly different from that of A‐b1500 (P = 0.397). The malignancy confidence of true‐positive tumors was higher in S‐b1500 than in A‐b1500 (P = 0.013). Interobserver agreement was good for both sequences.

Data Conclusions

The synthetic high b‐value DWI may improve the diagnostic sensitivity for breast cancer detection without affecting PPV compared with acquired high b‐value DWI.

Level of Evidence: 3

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2019;49:857–863.
Role of phenol red in the stabilization of the Sabin type 2 inactivated polio vaccine at various pH values
Authors: Huijuan Yang , Xiaohu Dai , Ze Liu , Wei Cai , Jian Zhou , Lei Ma , Shaohui Song , Weidong Li , Guoyang Liao
Published: August 2018

To analyze the effects of phenol red at various pH values on the Sabin type 2 inactivated polio vaccine (sIPV2), several biophysical techniques were used to evaluate the particle size and capsid protein for conformation. sIPV2’s size was assessed via transmission electron microscopy and dynamic light scattering. The effects of various pH values (from 4.0 to 7.0) on the biophysical characters of sIPV2 particles in solution were determined by dynamic light scattering and zeta potential. The results clearly indicated that aggregation and instability occurred in the solution of sIPV2 particles at a pH of 6.0. Under similar conditions, by dynamic light scattering and zeta potential, the virus particles in solution showed more dispersion and were stable with the addition of 0.05 mM phenol red. According to circular dichroism and intrinsic tryptophan fluorescence data, it was observed that the secondary and tertiary structures of the sIPV2 particles were more stable with the protection of phenol red. At a pH below 6.0, the sIPV2 solution with phenol red had more D‐antigen content, which was confirmed by enzyme‐linked immunosorbent assay and rat experiments. These results strongly suggested that phenol red improved the pH stability of the sIPV2. The study indicated the potential of phenol red in preserving vaccine potency of the sIPV2 at various pH values.
Predictors of appropriate ICD therapy in Japanese patients with structural heart diseases: A major role of prior sustained ventricular tachycardia in secondary prevention
Authors: Nagahara Daigo , Fujito Takefumi , Mochizuki Atsushi , Shimoshige Shinya , Hashimoto Akiyoshi , Miura Tetsuji
Published: August 2018

Background

Implantable cardioverter defibrillator (ICD) and cardiac resynchronization with a defibrillator (CRT‐D) are established therapies for secondary prevention of sudden cardiac death (SCD) in patients with structural heart disease (SHD), but the rates of subsequent ICD/CRT‐D therapy widely differ among patients with SHD. The aim of this study was to determine clinical factors associated with appropriate therapy for preventing SCD in patients with SHD.

Methods

We enrolled 147 patients with SHD (mean age, 59 ± 15 years; mean ejection fraction [EF], 45 ± 15%) who underwent ICD/CRT‐D implantation for secondary prevention of SCD (ischemic heart disease, n = 50; nonischemic heart disease, n = 97). ICD/CRT‐D was implanted for aborted cardiopulmonary arrest (CPA, n = 65) or sustained ventricular tachycardia (VT, n = 82).

Results

During a follow‐up period of 3.2 ± 3.6 years, 79 of the 147 patients had appropriate ICD/CRT‐D therapies. A Kaplan‐Meier survival curve showed that the rate of appropriate therapy was 54% at 5‐year follow‐up. Prior sustained VT, lower EF, and use of a class I antiarrhythmic drug were significantly more frequent in patients with appropriate therapy. In multivariate analysis, prior sustained VT (hazard ratio, 2.8; 95% CI, 1.60‐4.46; P = .001) was the only independent predictor for appropriate ICD/CRT‐D therapy. Kaplan‐Meier survival curves showed that rates of appropriate therapy during a 5‐year follow‐up period were 70% and 34% in patients with sustained VT and those with CPA, respectively (P = .001).

Conclusions

In SHD patients implanted with an ICD/CRT‐D, prior sustained VT as an indication of ICD/CRT‐D implantation, but not EF or an antiarrhythmic drug, predicts a high rate of appropriate therapy.
Enhancement of the relationship between boreal summer precipitation over eastern China and Australia since the early 1980s
Authors: Ming Jing , Sun Jianqi
Published: August 2018

The relationship between the boreal summer (June–August, JJA) precipitation over eastern China and Australia is investigated in this study. The relationship exhibits a decadal enhancement with correlation coefficients increasing from 0.07 before the early 1980s to 0.60 thereafter. A mechanistic analysis suggests that the variability in sea surface temperature (SST) over the central tropical Pacific could play an important role in enhancing the precipitation relationship between the two regions. Over the past half century, the central Pacific SST has shown a warming trend with a significant decadal change that occurred around the early 1980s. Such changes in the central Pacific SST have resulted in stronger convective activity over the tropics, as well as eastern China and Australia since the early 1980s. In addition, since the early 1980s, the central Pacific SST stimulated anomalous twin anticyclones located on opposite sides of the equator, which changed the transportation of water vapour to eastern China and Australia. These changes in the atmospheric circulation related to central tropical Pacific SST have enhanced the impact on the precipitation variability over eastern China and Australia. Consequently, this has contributed to the covariability in the boreal summer precipitation over the two regions since the early 1980s. The result indicates that concurrent climate anomalies can provide simultaneously occurring natural disasters over Asia and Australia, which creates a challenge for international disaster prevention and mitigation.
Abnormal loading of the hip and knee joints in unilateral hip osteoarthritis persists two years after total hip replacement
Authors: Stief Felix , Schmidt André , van Drongelen Stefan , Lenarz Katharina , Froemel Dara , Tarhan Timur , Lutz Frederick , Meurer Andrea
Published: August 2018

A total hip replacement (THR) is a common and routine procedure to reduce pain and restore normal activity. Gait analysis can provide insights into functional characteristics and dynamic joint loading situation not identifiable by clinical examination or static radiographic measures. The present prospective longitudinal study tested whether 2 years after surgery a THR would restore dynamic loading of the knee and hip joints in the frontal plane to normal. Instrumented gait analysis was performed shortly before surgery and approximately 2 years after THR on 15 unilateral hip osteoarthritis (OA) patients. 15 asymptomatic matched individuals were recruited as healthy controls. Results showed that abnormal joint loading persisted 2 years after THR. The 2nd external knee adduction moment in terminal stance in the affected (−34%, p = 0.002, d = 1.22) and non‐affected limb (−25%, p = 0.035, d = 0.81) was lower compared to controls and thus indicated a shift in the knee joint load distribution from medial to lateral. A correlation analysis revealed that a smaller hip range of motion explained 46% of 2nd knee adduction moment alterations. In contrast, the 2nd external hip adduction moment in terminal stance was postoperatively higher in the affected (+22%, p = 0.007, d = 1.04) and non‐affected limb (+22%, p = 0.005, d = 1.05). Here, 51% of 2nd hip adduction moment alterations can be explained with a greater hip adduction angle. Patients with a THR may therefore be at higher risk for abnormal joint loading and thus for the development of OA in other joints of the lower extremities. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2167–2177, 2018.
Macrophage‐derived inflammatory cytokines regulate growth factors and pain‐related molecules in mice with intervertebral disc injury
Authors: Miyagi Masayuki , Uchida Kentaro , Takano Shotaro , Fujimaki Hisako , Aikawa Jun , Sekiguchi Hiroyuki , Nagura Naoshige , Ohtori Seiji , Inoue Gen , Takaso Masashi
Published: August 2018

Upregulation of inflammatory cytokines and various growth factors is a significant contributor to discogenic low back pain. The aim of this study was to investigate possible regulation of pain‐related molecules by macrophages and the role of macrophage‐derived molecules in injured intervertebral disc (IVD)s. C57BL/6J mice were used in this study. We characterized the expression profiles of genes for tumor necrosis factor (TNF)‐alpha, interleukin (IL)‐1beta, nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) in both intact and injured IVDs. We examined whether macrophage depletion, induced by systemic injection of clodronate‐laden liposomes, affected the expression of these molecules in injured IVDs. The effect of TNF‐alpha on cultured F4/80‐CD11b‐cells in injured IVDs was investigated. Expression of TNF‐alpha and IL‐1beta was significantly increased in injured IVDs, but decreased by macrophage depletion. Expression of NGF and VEGF was also significantly increased, but by contrast was not decreased by macrophage depletion. TNF‐alpha treatment of F4/80‐cells from injured IVDs upregulated NGF, VEGF, cyclooxygenase (COX)‐2, and microsomal prostaglandin E synthase‐1 (mPGES1). IVD injury upregulated inflammatory cytokines and various growth factors. Macrophages in the injured IVDs produced inflammatory cytokines, but not growth factors. Macrophage‐derived inflammatory cytokines regulate growth factors and pain‐related molecules. These findings demonstrate further complexity in the pathogenesis of discogenic pain. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2274–2279, 2018.