bluuebunny/crossref_metadata_2025_split huggingface dataset:
Theaflavin and epigallocatechin‐3‐gallate synergistically induce apoptosis through inhibition of PI3K/Akt signaling upon depolymerizing microtubules in HeLa cells
Authors: Chakrabarty Subhendu , Nag Debasish , Ganguli Arnab , Das Amlan , Ghosh Dastidar Debabrata , Chakrabarti Gopal 
Published: November 2018

AbstractTheaflavin (TF) and epigallocatechin‐3‐gallate (EGCG) both have been reported previously as microtubule depolymerizing agents that also have anticancer effects on various cancer cell lines and in animal models. Here, we have applied TF and EGCG in combination on HeLa cells to investigate if they can potentiate each other to improve their anticancer effect in lower doses and the underlying mechanism. We found that TF and EGCG acted synergistically, in lower doses, to inhibit the growth of HeLa cells. We found the combination of 50 µg/mL TF and 20 µg/mL EGCG to be the most effective combination with a combination index of 0.28. The same combination caused larger accumulation of cells in the G
2/M phase of the cell cycle, potent mitochondrial membrane potential loss, and synergistic augmentation of apoptosis. We have shown that synergistic activity might be due to stronger microtubule depolymerization by simultaneous binding of TF and EGCG at different sites on tubulin: TF binds at vinblastine binding site on tubulin, and EGCG binds near colchicines binding site on tubulin. A detailed mechanistic analysis revealed that stronger microtubule depolymerization caused effective downregulation of PI3K/Akt signaling and potently induced mitochondrial apoptotic signals, which ultimately resulted in the apoptotic death of HeLa cells in a synergistic manner.
Molecular mechanism and role of microRNA‐93 in human cancers: A study based on bioinformatics analysis, meta‐analysis, and quantitative polymerase chain reaction validation
Authors: Gao Yun , Deng Kaifeng , Liu Xuexiang , Dai Meiyu , Chen Xiaoli , Chen Jifei , Chen Jianming , Huang Yujie , Dai Shengming , Chen Jingfan 
Published: November 2018

AbstractIntroductionCurrently, studies have shown that microRNA‐93 (miR‐93) can be an oncogene or a tumor suppressor in different kinds of cancers. The role of miR‐93 in human cancers is inconsistent and the underlying mechanism on the aberrant expression of miR‐93 is complicated.MethodsWe first conducted gene enrichment analysis to give insight into the prospective mechanism of miR‐93. Second, we performed a meta‐analysis to evaluate the clinical value of miR‐93. Finally, a validation test based on quantitative polymerase chain reaction (qPCR) was performed to further investigate the role of miR‐93 in pan‐cancer.ResultsGene Ontology (GO) enrichment analysis results showed that the target genes of miR‐93 were closely related to transcription, and MAPK1, RBBP7 and Smad7 became the hub genes. In the diagnostic meta‐analysis, the overall sensitivity, specificity, and area under the curve were 0.76 (0.64‐0.85), 0.82 (0.64‐0.92), and 0.85 (0.82‐0.88), respectively, which suggested that miR‐93 had excellent performance on the diagnosis for human cancers. In the prognostic meta‐analysis, dysregulated miR‐93 was found to be associated with poor OS in cancer patients. In the qPCR validation test, the serum levels of miR‐93 were upregulated in breast cancer, breast hyperplasia, lung cancer, chronic obstructive pulmonary disease, nasopharyngeal cancer, hepatocellular cancer, gastric ulcer, endometrial cancer, esophageal cancer, laryngeal cancer, and prostate cancer compared with healthy controls.ConclusionsmiR‐93 could act as an effective diagnostic and prognostic factor for cancer patients. Its clinical value for cancer early diagnosis and survival prediction is promising.
Activation of mammalian terget of rapamycin kinase and glycogen synthase kinase‐3β accompanies abnormal accumulation of cholesterol in fibroblasts from Niemann‐Pick type C patients
Authors: Wos Marcin , Komiażyk Magdalena , Pikula Slawomir , Tylki‐Szymanska Anna , Bandorowicz‐Pikula Joanna 
Published: November 2018

AbstractBackgroundNiemann Pick type C (NPC) lysosomal disorder is linked to the disruption of cholesterol transport. Recent data suggest that the molecular background of this disease is more complex. It was found that accumulation of cholesterol and glycolipids in the late endosomal/lysosomal compartment of NPC1 cells may affect mitochondrial functions.Materials and MethodsIn this study, primary skin fibroblasts derived from skin biopsies of two anonymous patients with NPC‐carrying mutations in the NPC1 gene, characterized by a high total cholesterol content, as well as two healthy donors were used. The presence of signaling proteins in the whole cell lysates and mitochondrial fractions were examined by Western blotting assay.ResultsIn this report, we provide experimental evidence that in NPC1 cells, dysfunction of mitochondria and cellular metabolism, as reported by Wos et al in 2016, coexist with alterations in signal transduction pathways, such as the mammalian target of rapamycin, AKT, phosphoinositide‐dependent protein kinase‐1, glycogen synthase kinase‐3 β, and Jun amino‐terminal kinase, leading to abnormal cholesterol accumulation and distribution.ConclusionDifferences in signal transduction between control and NPC1 cells may suggest that the latter cells experienced significant alterations in the complex molecular mechanisms that control cellular energy metabolism and vesicular transport.
Inhibitor of growth 4 inhibits cell proliferation, migration, and induces apoptosis of renal cell carcinoma cells
Authors: Sun Jiping , Xie Liyi , Lv Jing , Zhang Wenjing , Lv Jia , Liang Yu , Geng Yingzhou , Li Xudong 
Published: November 2018

AbstractThe inhibitor of growth 4 (ING4) is known as a tumor suppressor. The expressions of ING4 were markedly reduced in human renal clear cell carcinoma (ccRCC) tissues. However, the role of ING4 in renal cell carcinoma (RCC) remains unknown. The aim of the current study was to detect the ING4 expression level and its potential role in human RCC cell lines. Our results showed that ING4 was lowly expressed in human RCC cell lines compared with that in proximal tubular cell line. Ectopic overexpression of ING4 inhibited the proliferation, migration, and invasion properties, and as well as prevented epithelial‐mesenchymal transition (EMT) phenotype of RCC cells. In addition, ING4 overexpression induced cell apoptosis and autophagy in RCC cells. Furthermore, ING4 overexpression suppressed the activation of PI3K/Akt pathway in RCC cells. The activator of PI3K/Akt, insulin‐like growth factor 1, abolished the effects of ING4 on RCC cells. These findings indicated that ING4 presented anticancer activity in RCC cells. The effects of ING4 on RCC cells were mediated by regulating the PI3K/Akt pathway. These findings suggested that ING4 could be used for gene therapy of RCC.
A curcumin derivative hydrazinobenzoylcurcumin suppresses stem‐like features of glioblastoma cells by targeting Ca2+/calmodulin‐dependent protein kinase II
Authors: Shin Hee Jeong , Lee Sanghun , Jung Hye Jin 
Published: November 2018

AbstractGlioblastoma multiforme (GBM) is the most aggressive and common type of human primary brain tumor. Glioblastoma stem‐like cells (GSCs) have been proposed to contribute to tumor initiation, progression, recurrence, and therapeutic resistance of GBM. Therefore, targeting GSCs could be a promising strategy to treat this refractory cancer. Calmodulin (CaM), a major regulator of Ca2+‐dependent signaling, controls various cellular functions via interaction with multiple target proteins. Here, we investigated the anticancer effect of hydrazinobenzoylcurcumin (HBC), a Ca
2+/CaM antagonist, against GSCs derived from U87MG and U373MG cells. HBC significantly inhibited not only the self‐renewal capacity, such as cell growth and neurosphere formation but also the metastasis‐promoting ability, such as migration and invasion of GSCs. HBC induced apoptosis of GSCs in a caspase‐dependent manner. Notably, HBC repressed the phosphorylation of Ca
2+/CaM‐dependent protein kinase II (CaMKII), c‐Met, and its downstream signal transduction mediators, thereby reducing the expression levels of GSC markers, such as CD133, Nanog, Sox2, and Oct4. In addition, the knockdown of CaMKIIγ remarkably decreased the cancer stem cell‐like phenotypes as well as the expression of stemness markers by blocking c‐Met signaling pathway in U87MG GSCs. These results suggest that HBC suppresses the stem‐like features of GBM cells via downregulation of CaM/CaMKII/c‐Met axis and therefore CaMKII may be a novel therapeutic target to eliminate GSCs.
Icaritin inhibits glioblastoma cell viability and glycolysis by blocking the IL‐6/Stat3 pathway
Authors: Li Hongchao , Liang Qinghua , Wang Lin 
Published: November 2018

AbstractGlioblastoma (GBM) is a common and aggressive brain tumor that is associated with significant increase in glycolysis for energy production. Icaritin is a natural compound and exhibits anticancer activity in GBM. However, the effect of icaritin on glycolysis in GBM cells remains unclear. The aim of the current study was to investigate the effect of icaritin on glycolysis in GBM cells. The human GBM cell lines U87 and T98G were treated with icaritin or the inhibitor of Stat3 (S3I‐201) in the presence or absence of recombinant human interleukin (IL)‐6. Cell viability was measured using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5 diphenyltetrazolium bromide (MTT) assay. The glycolysis was analyzed by detecting the glucose consumption and lactate production. The Western blot analysis was conducted to detect the expressions of hexokinase 2 (HK2), signal transducer and activator of transcription 3 (Stat3), p‐Stat3, and B lymphoma Mo‐MLV insertion region 1 (Bmi‐1). Results showed that icaritin inhibited the viability of U87 and T98G cells in a dose‐dependent manner. The decreased glucose consumption and lactate production, accompanied by reduced expressions of HK2, were found in both U87 and T98G cells. Icaritin inhibited the IL‐6/Stat3 pathway, which is evidenced by the decreased expressions of p‐Stat3 and Bmi‐1. IL‐6 treatment induced the phosphorylation of Stat3 and Bmi‐1 expression, increased cell viability, as well as elevated glucose consumption, lactate production, and HK2 expression; however, the effects of IL‐6 were attenuated by icaritin or S3I‐201 treatment. In conclusion, icaritin exerted inhibitory effects on cell viability and glycolysis in GBM cells, which was mediated by the IL‐6/Stat3 pathway.
Predictive values of obesity categories for cardiovascular disease risk factors in Chinese adult population
Authors: Yin Dong , Yan Yongxin , Xu Ning , Hui Yuan , Han Guanjun , Ma Ning , Yang Chuanhui , Wang Guofeng 
Published: November 2018

AbstractObjectiveWhether obesity categories can be used to predict cardiovascular disease (CVD) in Chinese adults remains unclear. This aim of this study was to examine the predictive values of obesity categories for CVD risk factors in Chinese adults.MethodsThis study comprised a sample size of 3480 men and 6364 women aged ≥25 years (age range 25‐89 years), from the medical health check‐up center of Lianyungang First People's Hospital. The following CVD risk factor outcomes were used: hypertension, diabetes, dyslipidemia, insulin resistance, and metabolic syndrome (Mets). Framingham risk scores were used to evaluate the CVD. Four categories of obesity were used, based on body mass index (BMI) and waist circumference: no risk, increased risk, high risk, and very high risk. Predictive abilities were determined by calculating the odds ratios (OR) of CVD risk.ResultsA graded linear relationship between obesity categories and CVD risk was observed across the categories, except for dyslipidemia. The people in the very high‐risk category had the highest OR of having more unfavorable CVD risk factors compared with those in the lower risk category. For example, the OR of diabetes increased with the increase in risk category (OR, 1.13, 1.36, and 1.83, respectively, for increased, high, and very high risk categories in men and OR, 1.52, 1.80, and 2.78, respectively, for increased, high, and very high risk category in women).ConclusionsThese findings suggest that obesity categories provide clinical insights into identifying multiple CVD risk factors in Chinese adults.
Pyrazinamide drug resistance in RpsA mutant (∆438A) of Mycobacterium tuberculosis: Dynamics of essential motions and free‐energy landscape analysis
Authors: Singh Aditi , Somvanshi Pallavi , Grover Abhinav 
Published: November 2018

AbstractPyrazinamide is an essential first‐line antitubercular drug which plays pivotal role in tuberculosis treatment. It is a prodrug that requires amide hydrolysis by mycobacterial pyrazinamidase enzyme for conversion into pyrazinoic acid (POA). POA is known to target ribosomal protein S1 (RpsA), aspartate decarboxylase (PanD), and some other mycobacterial proteins. Spontaneous chromosomal mutations in RpsA have been reported for phenotypic resistance against pyrazinamide. We have constructed and validated 3D models of the native and Δ438A mutant form of RpsA protein. RpsA protein variants were then docked to POA and long range molecular dynamics simulations were carried out. Per residue binding free‐energy calculations, free‐energy landscape analysis, and essential dynamics analysis were performed to outline the mechanism underlying the high‐level PZA resistance conferred by the most frequently occurring deletion mutant of RpsA. Our study revealed the conformational modulation of POA binding site due to the disruptive collective modes of motions and increased conformational flexibility in the mutant than the native form. Residue wise MMPBSA decomposition and protein‐drug interaction pattern revealed the difference of energetically favorable binding site in the wild‐type (WT) protein in comparison with the mutant. Analysis of size and shape of minimal energy landscape area delineated higher stability of the WT complex than the mutant form. Our study provides mechanistic insights into pyrazinamide resistance in Δ438A RpsA mutant, and the results arising out of this study will pave way for design of novel and effective inhibitors targeting the resistant strains of Mycobacterium tuberculosis.
Dysregulation of miR‐125b predicts poor response to therapy in pediatric acute lymphoblastic leukemia
Authors: El‐Khazragy Nashwa , Elshimy Amal Ali , Hassan Safaa Shawky , Matbouly Safa , Safwat Gehan , Zannoun Mohamed , Riad Ramez. A. 
Published: November 2018

AbstractBackgroundAcute lymphoblastic leukemia (ALL) is the most well‐known sort of leukemia in children. In spite of favorable survival rates, some patients relapse and achieve a poor outcome.MethodsWe analyzed miR‐125b and Bcl‐2 expressions in pediatric patients with ALL and evaluated their clinical utility as molecular markers for the prediction of disease outcomes.ResultsDownregulation of miR‐125b and increased Bcl‐2 expression levels in pediatric patients with ALL were associated with poor prognosis at diagnosis. At day 28 of induction, miR‐125b was significantly increased, whereas Bcl‐2 was downregulated. Loss of miR‐125b during diagnosis and its elevation after therapy are strongly correlated with short leukemia‐free survival and worse survival. Moreover, the combination of miR‐125b with Bcl‐2 markers can clearly enhance the prediction of the disease outcome. Finally, a univariate analysis highlighted the independent prognostic value of miR‐125 in a pediatric patient with ALL.ConclusionsmiR‐125b and Bcl‐2 together are potent predictors for the prognosis and, therefore, can be used as therapeutic targets in childhood ALL.
Targeting anti‐aging protein sirtuin (Sirt) in the diagnosis of idiopathic pulmonary fibrosis
Authors: Shaikh Sadiya Bi , Prabhu Ashwini , Bhandary Yashodhar Prabhakar 
Published: November 2018

AbstractIdiopathic pulmonary fibrosis (IPF) is a severe, incurable, age‐associated respiratory disorder that has gained significance because of its unknown etiology and lack of therapeutic approaches. IPF causes maximum damage to the alveolar epithelial cells, thereby leading to lung remodeling and initiating epithelial to mesenchymal transition (EMT). The actual molecular mechanisms underlying IPF still remain unclear, and knowledge about these mechanisms would be helpful in its diagnosis. Sirtuins (Sirt) are class of NAD+‐dependent proteins, widely known to exert positive and protective effects on age‐related diseases such as diabetes, cancer, and so on, and are also involved in regulating IPF. The sirtuin family comprises of seven members (Sirt1 to Sirt7), out of which Sirt1, Sirt3, Sirt6, and Sirt7 exert positive effects on IPF. Sirt1 is associated with aging and inhibits cellular senescence and fibrosis. Sirt1 is well recognized in controlling pulmonary fibrosis and is also considered as a prime positive mediator of EMT. The expressions of Sirt3 protein tend to decline in IPF patients; hence it is known as an anti‐fibrotic protein. Sirt6 indeed has been proven to reduce EMT during IPF. Decreased levels of Sirt7 during IPF regulate lung fibroblasts. Hence, active levels of Sirt1, Sirt3, Sirt6, and Sirt7 can be attractive target models to elucidate a novel potential therapeutic approach for IPF. In this prospect, we have discussed the role of Sirtuins in pulmonary fibrosis by exploring the recent research evidence that highlight the role of sirtuins and also describes their protective effects.
D224V and S128Y mutation in FSHRED influence thumb movement differentially: An intricate insight gained by short‐term molecular dynamics simulation
Authors: Gharemirshamlu Fatemeh Rahimi , Afsar Maliha , Mokhdomi Taseem A. , Amin Asif , Bukhari Shoiab , Krishnan Anbarasu , Kumar Chundi Vinay , Bamdad Kourosh , Patel Trupti N. , Qadri Raies A. , Chikan Naveed Anjum , Shabir Nadeem 
Published: November 2018

AbstractFollicle‐stimulating hormone‐follicle‐stimulating hormone receptor (FSH‐FSHR) interaction is one of the most thoroughly studied signaling pathways primarily because of being implicated in sexual reproduction in mammals by way of maintaining gonadal function and sexual fertility. Despite material advances in understanding the role of point mutations, their mechanistic basis in FSH‐FSHR signaling is still confined to mystically altered behavior of sTYS335 (sulfated tyrosine) yet lacking a substantial theory. To understand the structural basis of receptor modulation, we choose two behaviorally contradicting mutations, namely S128Y (activating) and D224Y (inactivating), found in FSH receptor responsible for ovarian hyperstimulation syndrome and
ovarian dysgenesis, respectively. Using short‐term molecular dynamics simulations, the atomic scale investigations reveal that the binding pattern of sTYS with FSH and movement of the thumb region of FSHR show distinct contrasting patterns in the two mutants, which supposedly could be a critical factor for differential FSHR behavior in activating and inactivating mutations.
Comparison between DiaPlexQ™ STI6 and GeneFinder™ STD I/STD II multiplex Real‐time PCR Kits in the detection of six sexually transmitted disease pathogens
Authors: Huh Hee Jae , Ki Chang‐Seok , Yun Sun Ae , Lee Jungsoo , Oh Gwi Young , Lee Nam‐Sihk , Yoon Young Ho , Lee Nam Yong 
Published: November 2018

BackgroundThe DiaPlexQ™ STI6 Detection Kit (DiaPlexQ; Solgent Co., Ltd., Daejeon, South Korea) is a multiplex real‐time PCR assay for the detection of the following sexually transmitted disease (STD) pathogens: Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma hominis, Trichomonas vaginalis, Ureaplasma urealyticum, and Mycoplasma genitalium. We compared the performance of the DiaPlexQ assay with the GeneFinder™ STD I (CT/NG/UU) and STD II (MG/MH/TV) Multiplex Real‐time PCR Kits (GeneFinder; Infopia Co., Ltd., Anyang, South Korea).MethodsWe evaluated the performance of the DiaPlexQ assay in comparison to that of GeneFinder using 1106 clinical specimens (542 genital swabs and 564 urine samples). The analytical performance of the DiaPlexQ assay, including the limit of detection (LOD) and analytical specificity, was evaluated using reference strains.ResultsThe positive percent agreement, negative percent agreement, and kappa value between the two assays were 96.6%‐99.4%, 98.2%‐99.8%, and 0.93%‐0.99%, respectively. No cross‐reactivity was observed in a collection of 41 different microorganisms and the LOD of the DiaPlexQ assay ranged from 1 to 10 copies/reaction for each microorganism.ConclusionThe DiaPlexQ assay showed comparable performance to that of the GeneFinder assay so that it can be used for the screening and diagnosis of non‐viral curable STD pathogens.
Expression of novel proteins by polyomaviruses and recent advances in the structural and functional features of agnoprotein of JC virus, BK virus, and simian virus 40
Authors: Saribas A. Sami , Coric Pascale , Bouaziz Serge , Safak Mahmut 
Published: November 2018

AbstractPolyomavirus family consists of a highly diverse group of small DNA viruses. The founding family member (MPyV) was first discovered in the newborn mouse in the late 1950s, which induces solid tumors in a wide variety of tissue types that are the epithelial and mesenchymal origin. Later, other family members were also isolated from a number of mammalian, avian and fish species. Some of these viruses significantly contributed to our current understanding of the fundamentals of modern biology such as transcription, replication, splicing, RNA editing, and cell transformation. After the discovery of first two human polyomaviruses (JC virus [JCV] and BK virus [BKV]) in the early 1970s, there has been a rapid expansion in the number of human polyomaviruses in recent years due to the availability of the new technologies and brought the present number to 14. Some of the human polyomaviruses cause considerably serious human diseases, including progressive multifocal leukoencephalopathy, polyomavirus‐associated nephropathy, Merkel cell carcinoma, and trichodysplasia spinulosa. Emerging evidence suggests that the expression of the polyomavirus genome is more complex than previously thought. In addition to encoding universally expressed regulatory and structural proteins (LT‐Ag, Sm t‐Ag, VP1, VP2, and VP3), some polyomaviruses express additional virus‐specific regulatory proteins and microRNAs. This review summarizes the recent advances in polyomavirus genome expression with respect to the new viral proteins and microRNAs other than the universally expressed ones. In addition, a special emphasis is devoted to the recent structural and functional discoveries in the field of polyomavirus agnoprotein which is expressed only by JCV, BKV, and simian virus 40 genomes.