bluuebunny/crossref_metadata_2025 huggingface dataset:
Biodegradable polyanhydride‐based nanomedicines for blood to brain drug delivery
Authors: Brenza Timothy M. , Schlichtmann Benjamin W. , Bhargavan Biju , Vela Ramirez Julia E. , Nelson Rainie D. , Panthani Matthew G. , McMillan JoEllyn M. , Kalyanaraman Balaraman , Gendelman Howard E. , Anantharam Vellareddy , Kanthasamy Anumantha G. , Mallapragada Surya K. , Narasimhan Balaji , Kanmogne Georgette D.
Published: October 2018

An urgent need to deliver therapeutics across the blood–brain barrier (BBB) underlies a paucity of effective therapies currently available for treatment of degenerative, infectious, traumatic, chemical, and metabolic disorders of the nervous system. With an eye toward achieving this goal, an in vitro BBB model was employed to simulate biodegradable polyanhydride nanoparticle‐based drug delivery to the brain. Using a combination of confocal microscopy, flow cytometry, and high performance liquid chromatography, we examined the potential of polyanhydride nanoparticles containing the anti‐oxidant, mito‐apocynin, to be internalized and then transferred from monocytes to human brain microvascular endothelial cells. The efficacy of this nanoparticle‐based delivery platform was demonstrated by neuronal protection against oxidative stress. Taken together, this polyanhydride nanoparticle‐based delivery system holds promise for enhancing neuroprotection by facilitating drug transport across the BBB. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2881–2890, 2018.
Tuning microenvironment for multicellular spheroid formation in thermo‐responsive anionic microgel scaffolds
Authors: Cui Xiaolin , Hartanto Yusak , Wu Chengtie , Bi Jingxiu , Dai Sheng , Zhang Hu
Published: October 2018

Tumor spheroids are considered to be effective in drug screening and evaluation. Three‐dimensional scaffold‐based cell culture becomes very promising in producing multicellular spheroids. Different from other approaches, 3D scaffolds mimic in vivo cellular microenvironment which encourages intercellular and extracellular interactions. The properties of the cellular microenvironment include the surface wettability, chemistry, and charge of the scaffolds which may influence cell attachment, proliferation as well as migration and these properties are essential for multicellular spheroids formation. Through co‐polymerization with different carboxylic acids, we demonstrate that the surface charge density and hydrophobicity of the microenvironment have a great impact on the tumor spheroids formation progress and their size distribution. Our results show that a scaffold with a moderate negative charge density and a highly hydrophilic surface promotes cell proliferation, resulting in quicker and larger spheroids formation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2899–2909, 2018.
In vitro cytotoxic and in vivo antitumoral activities of some aminomethyl derivatives of 2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones—Evaluation of their acetylcholinesterase and carbonic anhydrase enzymes inhibition profiles
Authors: Timur İrfan , Kocyigit Ümit M. , Dastan Taner , Sandal Süleyman , Ceribası Ali Osman , Taslimi Parham , Gulcin İlhami , Koparir Metin , Karatepe Mustafa , Çiftçi Mehmet
Published: October 2018

The 1,2,4‐triazole and its derivatives were reported to exhibit various pharmacological activities such as antimicrobial, analgesic, anti‐inflammatory, antitumoural, cytotoxic, and antioxidant properties. In this study, a series of triazole compounds (M1‐M10) were evaluated for some biological activities. In vitro qualifications of these compounds on acetylcholinesterase (AChE) and human carbonic anhydrase enzyme activities were performed. Also, their antitumoral activities in human colon cancer (HT29) cell line cultures were examined. In addition, colon cancer experimentation was induced in rats by an in vivo method, and the in vivo anticancer effects of triazole derivatives were investigated. Also, the effects of these derivatives in levels of antioxidant vitamin A, vitamin E, and MDA were studied in rat liver and blood samples. Most of the compounds were found to exhibit significant antioxidant and antitumoral activities. All the compounds had cytotoxic activities on HT29 cell lines with their IC50 values lower than 10 µM concentrations. The low IC
50 values of the compounds are M1 (3.88 µM), M2 (2.18 µM), M3 (4.2 µM), M4 (2.58 µM), M5 (2.88 µM), M6 (2.37 µM), M7 (3.49 µM), M8 (4.01 µM), M9 (8.90 µM), and M10 (3.12 µM).
A study on the interaction between cadmium and α‐chymotrypsin and the underlying mechanisms
Authors: Wang Jing , Zheng Xiaolin , Wang Weichao , Guo Hongli , Liu Rutao , Zong Wansong
Published: October 2018

Because cadmium might interact with proteins and, thus, exert toxicity in organisms, it is vital to understand the molecular mechanism of the interaction between cadmium and biologically relevant proteins as well as the structural and functional changes in these proteins. In this study, the interaction between α‐chymotrypsin (α‐ChT) and cadmium chloride (CdCl2) was investigated by performing enzyme activity determinations, multispectroscopic measurements, isothermal titration calorimetry, and molecular docking studies. It was demonstrated that CdCl
2 binds to α‐ChT mainly via electrostatic forces with (21.0 ± 0.982) binding sites, leading to the increase of α‐helix and the decrease of β‐sheet. The interaction between CdCl
2 and α‐ChT loosened the protein skeleton and increased the molecular volume of α‐ChT. CdCl
2 first binds to the interface of α‐ChT and then interacts with the key residues His 57 or Asp 102 or both in the active sites, leading to the activity inhibition of α‐ChT under the exposure of high CdCl
2 concentrations.
Sirtuin3 deficiency exacerbates carbon tetrachloride−induced hepatic injury in mice
Authors: Li Xinshuai , Song Shu , Xu Mengting , Hua Yuyun , Ding Yun , Shan Xiaoyu , Meng Guoliang , Wang Yuqin
Published: October 2018

Sirtuin3 (SIRT3) plays an important role in maintaining normal mitochondrial function and alleviating oxidative stress. After carbon tetrachloride (CCl4) administration, the expression of SIRT3 decreased in the liver of mice, which indicated that the SIRT3 might play a crucial role during chemical‐induced acute hepatic injury. To verify the hypothesis, CCl
4 was given to induce acute hepatic injury in SIRT3 knockout (KO) mice and wild‐type (WT) mice. CCl
4‐induced liver injury was more severe in SIRT3 KO mice compared with the WT mice. In addition, the oxidative stress induced by CCl
4 was enhanced in the SIRT3 KO mice. Furthermore, the increased expression of dynamin‐related protein 1 was also aggravated in SIRT3 KO mice after CCl
4 administration. In conclusion, our study demonstrated that SIRT3 deficiency exacerbated CCl
4‐induced impairment of the liver in mice, and the mechanism might be related to enhanced oxidative stress.
Mechanism‐based inactivation of cytochrome P450 2D6 by chelidonine
Authors: Liu Yuyang , Cui Tiantian , Peng Ying , Ji Mingshan , Zheng Jiang
Published: October 2018

Chelidonine (CHE) is a major bioactive constituent of greater celandine, a plant used in traditional herbal medicines. CHE has widely been used as an analgesic in clinical settings. We evaluated the inhibitory effects of CHE on human cytochrome P450 enzymes. CHE produced time‐, concentration‐, and NADPH‐dependent inhibition of CYP2D6, with K
I and
k
inact values of 20.49 μM and 11.05 min
−1, respectively. Approximately 76% of CYP2D6 activity was suppressed after 9 minute incubation with CHE (50 μM). The loss of enzyme activity was not restored following dialysis. The estimated partition ratio of the inactivation was about 156. Quinidine, a competitive inhibitor of CYP2D6, attenuated the CHE‐mediated enzyme inactivation, while glutathione and catalase/superoxide dismutase did not markedly ameliorate the inhibitory effect. Upon oxidation using potassium ferricyanide, the 15.1% activity of CYP2D6 was restored. These findings indicate that CHE acted as a mechanism‐based inactivator of CYP2D6 and the observed effects may induce potential drug‐drug interactions.
Candesartan and epigallocatechin‐3‐gallate ameliorate gentamicin‐induced renal damage in rats through p38‐MAPK and NF‐κB pathways
Authors: Ahmed Hebatalla I. , Mohamed Eman A.
Published: October 2018

This study pointed to estimate the possible protective impacts of candesartan and/or epigallocatechin‐3‐gallate (EGCG) against gentamicin‐induced nephrotoxicity. The current work revealed that gentamicin significantly elevated relative kidney weight and the serum level of creatinine and urea. Also, renal level of malondialdehyde was significantly increased with a concurrent decrease in renal glutathione‐S‐transferase and superoxide dismutase activities. Moreover, renal levels of nuclear factor‐kappa B (NF‐κB) and p38 mitogen‐activated protein kinase (p38‐MAPK) were increased together with the elevation of tumor necrosis factor‐alpha and interleukin‐1 beta levels after gentamicin treatment. In addition, caspase‐3 expression was elevated, and histological examination revealed extreme alterations enlightening inflammation, degeneration, and necrosis. Pretreatments with candesartan and/or EGCG attenuated gentamicin‐induced nephrotoxicity. Importantly, the altered expression of p38‐MAPK and NF‐κB may play a significant role in the protective mechanisms exerted by candesartan and EGCG. Coadministration of candesartan and EGCG exhibited more profound response compared with the monotherapy.
Characterizing the noncovalent binding behavior of tartrazine to lysozyme: A combined spectroscopic and computational analysis
Authors: Chen Xue , Qin Pengfei , Zheng Xiuwen , Hu Zunfu , Zong Wansong , Zhang Dongsheng , Yang Baochan
Published: October 2018

Tartrazine is a stable water‐soluble azo dye widely used as a food additive, which could pose potential threats to humans and the environment. In this paper, we evaluated the response mechanism between tartrazine and lysozyme under simulated conditions by means of biophysical methods, including multiple spectroscopic techniques, isothermal titration calorimetry (ITC), and molecular docking studies. From the multispectroscopic analysis, we found that tartrazine could effectively quench the intrinsic fluorescence of lysozyme to form a complex and lead to the conformational and microenvironmental changes of the enzyme. The ITC measurements suggested that the electrostatic forces played a major role in the binding of tartrazine to lysozyme with two binding sites. Finally, the molecular docking indicated that tartrazine had specific interactions with the residues of Trp108. The study provides an important insight within the binding mechanism of tartrazine to lysozyme in vitro.
Network of three specific microRNAs influence type 2 diabetes through inducing insulin resistance in muscle cell lines
Authors: Honardoost Maryam , Keramati Farid , Arefian Ehsan , Mohammadi Yeganeh Samira , Soleimani Masoud
Published: October 2018

Insulin resistance has been implicated as one of the best predictors for type 2 diabetes. Growing evidence propose the involvement of microRNAs (miRNAs) as short regulatory molecules in modulating and inducing resistance. In this regard, we have investigated the role of three selected miRNAs in insulin resistance development (miR‐135, miR‐202, and miR‐214), via assessing glucose uptake levels in C2C12 and L6 muscle cell lines. Interestingly, miRNA‐transfected cells demonstrated a significantly different glucose uptake compared to the positive control cells. In addition, we evaluated the expression levels of three putative miRNA target genes (Rho‐associated coiled‐coil containing protein kinase 1, serine/threonine kinase 2, and vesicle‐associated membrane protein 2) in transfected cells, recruiting luciferase assay. Our results indicated the targeting and downregulation of Rho‐associated coiled‐coil containing protein kinase 1 and serine/threonine kinase 2 genes in all miR‐transfected cell lines (
P ≤ 0.05), but not for vesicle‐associated membrane protein 2. MiRNA upregulation led to the poor stimulation of glucose uptake through insulin and developed insulin‐resistant phenotype in both muscle cell lines. Our study showed the role of three miRNAs in the induction of insulin resistance in cell lines and making them prone to type 2 diabetes development.
Downregulation of PTEN by sodium orthovanadate protects the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment
Authors: Cheng Yutong , Sun Tao , Yin Chengqian , Wang Su , Li Zhao , Tao Ying , Zhang Jingmei , Li Zhizhong , Zhang Hongju
Published: October 2018

Acute statin treatment has been reported to be critical in protecting the cardiac cells against ischemia/reperfusion injury by activating PI3K/Akt signal pathway. In vitro rat myocardial ischemia/reperfusion model, chronic statin treatment led to upregulation of phosphatase and tensin homolog (PTEN). This has been potentially indicated the correlation in PTEN and protective effect of statin on myocardium. In this current study, we evaluated the role of sodium orthovanadate a nonspecific inhibitor to PTEN and its correlation with atorvastatin on protecting myocardium against ischemia/reperfusion injury. We found a long‐term statin treatment could increase the PTEN level, and this process was counteracted in the presence of sodium orthovanadate. However, the phosphotyrosine level was not affected by this statin. Besides, this process was mediated by Akt signaling since phosphorylated Akt level was altered by statin and sodium orthovanadate treatment. In a conclusion, this study showed a potential mechanism underlying PTEN‐induced attenuation in long‐term statin’s therapeutic effect, which provided the new insight into the synergic role of PTEN and atorvastatin in protecting cardiac cells against ischemia/reperfusion injury.
MAPKs and NF‐κB‐mediated acrylamide‐induced neuropathy in rat striatum and human neuroblastoma cells SY5Y
Authors: Yan Dandan , Pan Xiaoqi , Yao Jianling , Wang Dun , Wu Xu , Chen Xiaoyi , Shi Nian , Yan Hong
Published: October 2018

Acrylamide (ACR) is a potent neurotoxin that can be produced during high‐temperature food processing, but the underlying toxicological mechanism remains unclear. In this study, the detrimental effects of ACR on the striatal dopaminergic neurons and the roles of mitogen‐activated protein kinases (MAPKs) and nuclear factor κB (NF‐κB) in ACR‐induced neuronal apoptosis were investigated. Acute ACR exposure caused dopaminergic neurons loss and apoptosis as revealed by decreased tyrosine hydroxylase (TH)‐positive cells and TH protein level and increased terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL)‐positive cells in the striatum. ACR‐decreased glutathione content, increased levels of malondialdehyde, proinflammatory cytokines tumor necrosis factor α, and interleukin 6. In addition, nuclear NF‐κB and MAPKs signaling pathway with c‐Jun N‐terminal kinase (JNK) and p38 were activated by ACR. Specific inhibitors were used to explore the roles of MAPKs and NF‐κB pathways in ACR‐induced apoptosis in SH‐SY5Y cells. Pretreatment with JNK‐specific inhibitors SP600125 markedly upregulated the reduced B‐cell lymphoma 2 (Bcl‐2) content and downregulated the increased Bcl‐2‐associated X protein (Bax) level and thereby eventually reduced the proportions of early and late apoptotic cells induced by ACR, while p38 suppression by SB202190 only reversed the decrease in Bcl‐2 expression. Inhibition of NF‐κB by BAY 11‐7082 markedly upregulated Bax level and decreased Bcl‐2 expression, and eventually increasing the proportions of neuronal apoptosis compared with that in ACR alone. These results suggested that JNK contributed to ACR‐induced apoptosis, while NF‐κB acted as a protective regulator in response to ACR‐induced neuropathy. This study helps to offer a deeper insight into the mechanism of ACR‐induced neuropathy.
MiR‐542‐3p controls hepatic stellate cell activation and fibrosis via targeting BMP‐7
Authors: Ji Feihong , Wang Kuifeng , Zhang Yu , Mao Xin‐Li , Huang Qin , Wang Jun , Ye Liping , Li Youming
Published: October 2018

There has been an increasing number of studies about microRNAs as key regulators in the development of hepatic fibrosis. Here, we demonstrate that miR‐542‐3p can promote hepatic fibrosis by downregulating the expression of bone morphogenetic protein 7 (BMP‐7), which is known to antagonize transforming growth factor β1 (TGFβ1)‐mediated fibrogenesis effect. The expression of miR‐542‐3p is increased in activated hepatic stellate cells (HSCs). Downregulation of MiR‐542‐3p by antisense inhibitors can inhibit HSCs activation markers, including α‐smooth muscle actin (α‐SMA) and collagen as well as TGFβ signaling pathways. MiR‐542‐3p was significantly upregulated in carbon tetrachloride (CCl4)‐induced hepatic fibrosis in mice, and downregulation of miR‐542‐3p by lentivirus could prevent the development of hepatic fibrosis. In addition, miR‐542‐3p can directly bind to the 3′‐untranslated region of BMP‐7 mRNA, indicating that its profibrotic effect appears to be caused by its inhibition of BMP‐7. Our results suggest that downregulation of miR‐542‐3p prevents liver fibrosis both in vitro and in vivo, highlighting its potential as a novel biomarker or therapeutic target for hepatic fibrosis.
New insight into BIRC3: A novel prognostic indicator and a potential therapeutic target for liver cancer
Authors: Fu Pei‐Yao , Hu Bo , Ma Xiao‐Lu , Yang Zhang‐Fu , Yu Min‐Cheng , Sun Hai‐Xiang , Huang Ao , Zhang Xin , Wang Jian , Hu Zhi‐Qiang , Zhou Chen‐Hao , Tang Wei‐Guo , Ning Ren , Xu Yang , Zhou Jian
Published: October 2018

Background

Prognosis of hepatocellular carcinoma (HCC) remains poor due to high recurrence rate and ineffective treatment options, highlighting the need to better understand the mechanism of recurrence and metastasis in HCC.

Methods

We first collected messenger RNA (mRNA) expression data from 442 cases of HCC patients from The Cancer Genome Atlas (TCGA) database as well as 251 HCC patients from Zhongshan Hospital during 2009 and 2010 to analyze the expression pattern from tissue microarray (TMA) of baculoviral IAP repeat containing 3 (BIRC3). Then, we used BIRC3 gain‐of‐function (overexpression) and loss‐of‐function (knockdown) studies to examine the effect of BIRC3 on HCC cell proliferation and invasion. In addition, we also investigated the undying mechanism by which BIRC3 contributes to HCC tumor progression. Functionally, we also used a BIRC3‐specific inhibitor AT‐406 in HCC xenograft model to explore the potential therapeutic benefit of targeting BIRC3 in liver cancer.

Results

BIRC3 serves as a novel prognostic indicator for HCC patients undergoing curative resection. BIRC3 promotes HCC epithelial‐mesenchymal transition (EMT), cell migration, and metastasis via upregulating MAP3K7, therefore, inducing ERK1/2 phosphorylation. The specific BIRC3 inhibitor AT‐406 can inhibit HCC cell proliferation and reduce pulmonary metastases.

Conclusion

BIRC3 induces tumor proliferation and metastasis in vitro and in vivo. BIRC3 may serve as a novel therapeutic target for liver cancer.
Retracted: Propranolol suppresses HUVEC viability, migration, VEGF expression, and promotes apoptosis by downregulation of miR‐4295
Authors: Zhao Feng , Yang Xiaoliang , Xu Guangqi , Bi Jianhai , Lv Renrong , Huo Ran
Published: October 2018

Infantile hemangioma (IH) is a common benign tumor. Human umbilical vein endothelial cells (HUVECs) have the potential of stem cells, which has been widely used in vascular endothelial cell experiments. Oral propranolol was first reported to treat hemangioma in 2008. However, the role of propranolol in IH remains unclear. Therefore, in this study, we investigated the effects of propranolol on HUVECs in vitro, to explore the underlying mechanism of propranolol in IH. HUVECs were treated with 0.15, 1.5, and 15 μM of propranolol, and transfected with microRNA‐4295 (miR‐4295) mimic. Cell viability, migration, and apoptosis were examined using Cell Counting Kit‐8, transwell assay, and flow cytometry analysis, respectively. In addition, the expressions and concentrations of miR‐4295, vascular endothelial growth factor (VEGF), VEGF‐A, FLT1, FLT2, and FOXF1 were assessed using real‐time polymerase chain reaction, Western blot assay, and enzyme‐linked immunosorbent assay. We found that 15 μM of propranolol decreased HUVEC viability the most. Then, cell migration and the concentrations of VEGF and VEGF‐A were reduced, and apoptosis was increased when treated with propranolol. Meanwhile, the expressions of VEGF, VEGF‐A, FLT1, FLT2, and FOXF1 were downregulated by propranolol exposure. Further study showed that miR‐4295 expression was upregulated in IH tissues, and propranolol treatment downregulated miR‐4295 expression in HUVECs. MiR‐4295 overexpression alleviated the reductions of viability, migration, and factors expression, as well as the increase of apoptosis. Propranolol suppressed HUVEC viability, migration, the expression of VEGF, VEGF‐A, FLT1/2, FOXF1, and promoted apoptosis via downregulation of miR‐4295. This study lays a foundation for further study of the effect of propranolol on IH.
Facile and greener hydrothermal honey‐based synthesis of Fe3O4/Au core/shell nanoparticles for drug delivery applications
Authors: Rasouli Elisa , Basirun Wan Jeffrey , Johan Mohd Rafie , Rezayi Majid , Darroudi Majid , Shameli Kamyar , Shanavaz Zohreh , Akbarzadeh Omid , Izadiyan Zahra
Published: October 2018

In the present research, we report a greener, faster, and low‐cost synthesis of gold‐coated iron oxide nanoparticles (Fe3O4/Au‐NPs) by different ratios (1:1, 2:1, and 3:1 molar ratio) of iron oxide and gold with natural honey (0.5% w/v) under hydrothermal conditions for 20 minutes. Honey was used as the reducing and stabilizing agent, respectively. The nanoparticles were characterized by X‐ray diffraction (XRD), UV‐visible spectroscopy, field emission scanning electron microscope (FESEM), energy‐dispersive X‐ray spectroscopy (EDXS), transmission electron microscopy (TEM), selected area electron diffraction (SAED), vibrating sample magnetometer (VSM), and fourier transformed infrared spectroscopy (FT‐IR). The XRD analysis indicated the presence of Fe3O4/Au‐NPs, while the TEM images showed the formation of Fe3O4/Au‐NPs with diameter range between 3.49 nm and 4.11 nm. The VSM study demonstrated that the magnetic properties were decreased in the Fe3O4/Au‐NPs compared with the Fe3O4‐NPs. The cytotoxicity threshold of Fe3O4/Au‐NPs in the WEHI164 cells was determined by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. It was demonstrated no significant toxicity in higher concentration up to 140.0 ppm which can become the main candidates for biological and biomedical applications, such as drug delivery.
Association of MCP‐1 promoter polymorphism with susceptibility to nasopharyngeal carcinoma
Authors: Niu Yuguang , Zhou Guangming , Wang Yahui , Qin Jianing , Ping Jie , Zhang Qing , Han Bo‐Wei , Liu Yu‐Xiang , Yang Chenning , Zhai Yun , Zhang Hongxing , He Fuchu , Mai Hai‐Qiang , Bei Jin‐Xin , Li Yuanfeng , Zhou Gangqiao
Published: October 2018

Nasopharyngeal carcinoma (NPC) is prevalent among populations from southern China and is influenced by both genetic and environmental risk factors. The monocyte chemoattractant protein‐1 (MCP‐1), a member of cysteine‐cysteine chemokine family, plays critical roles in cancers. A polymorphism within the MCP‐1 promoter, rs1024611, has been shown to be significantly associated with the risk of several cancers. Our purpose was to assess the role of rs1024611 in NPC susceptibility. By polymerase chain reaction‐restriction fragment length polymorphism method, we genotyped rs1024611 in 593 patients with NPC (cases) and 480 cancer‐free subjects (controls) among Guangxi population from southern China. We observed that the G allele of rs1024611 was significantly associated with the increased risk of NPC in an additive model and dominant model, respectively (P = 0.018 and 0.010, odds ratio = 1.25 and 1.41, respectively). No appreciable variation of the effects was found across the subgroups stratified by age, sex, nationality, smoking and drinking status, and smoking level. In addition, significantly higher messenger RNA (mRNA) expression level of MCP‐1 was observed in NPC tissues than that in normal nasopharyngeal tissues, and the G allele of rs1024611 was significantly associated with elevated mRNA expression level of MCP‐1 in Epstein‐Barr virus‐transformed lymphocytes. In conclusion, our findings suggested that rs1024611 at the MCP‐1 promoter may be a risk factor for NPC. Further studies with larger sample size are necessary to confirm these findings.
SATB1 3′‐UTR and lncRNA‐UCA1 competitively bind to miR‐495‐3p and together regulate the proliferation and invasion of gastric cancer
Authors: Sun Li , Liu Lina , Yang Junshu , Li Hai , Zhang Can
Published: October 2018

High expression of special AT‐rich‐binding protein 1 (SATB1) correlates with the advanced TNM stage and short overall and recurrence‐free survival of gastric cancer (GC). A bioinformatic analysis revealed that SATB1 3′‐untranslated region (3′‐UTR) and long noncoding RNA UCA1 (lncRNA‐UCA1) might competitively bind to microRNA‐495‐3p (miR‐495‐3p). Interestingly, lncRNA‐UCA1 is also an important contributor to GC. The current study aimed to demonstrate the potential interaction among SATB1/miR‐495‐3p/lncRNA‐UCA1 network and their effects on GC proliferation and invasion. The expression in GC and paracancerous normal tissues were assessed using real‐time polymerase chain reaction and Western blot analysis. Luciferase reporter, RNA pull‐down, and transfection assays were performed to determine the interaction among SATB1/miR‐495‐3p/lncRNA‐UCA1 network in GC cells. GC proliferation and invasion were evaluated using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide, transwell invasion, and colony formation assays. Results showed higher expression of SATB1 and lncRNA‐UCA1 but lower miR‐495‐3p expression in GC than in the normal tissues. In luciferase reporter assay, miR‐495‐3p bound to three seed sequences in SATB1 3′‐UTR but only one in lncRNA‐UCA1. SATB1 knockdown increased the combination of miR‐495‐3p with lncRNA‐UCA1 but decreased lncRNA‐UCA1 expression. Decreased lncRNA‐UCA1 was also observed with the mimics increased miR‐495‐3p. These data suggested that SATB1 3′‐UTR functions as a competing endogenous RNA of miR‐495‐3p and positively regulates lncRNA‐UCA1. LncRNA‐UCA1 knockdown only decreased SATB1 expression in MKN‐45 cells but not in BGC‐823 cells, which suggested that the regulatory effect of lncRNA‐UCA1 on SATB1 by sponging miR‐495‐3p is cell‐dependent. This study further identified that SATB1/miR‐495‐3p/lncRNA‐UCA1 network is implicated in GC proliferation and invasion. The current study firstly revealed that SATB1 interacts with miR‐495‐3p/lncRNA‐UCA1 network, whereby enhancing GC proliferation and invasion.
Paeoniflorin attenuated bupivacaine‐induced neurotoxicity in SH‐SY5Y cells via suppression of the p38 MAPK pathway
Authors: Chen Long , Li Qiushi , Wang Hao , Chen Quan , Wu Yuanyuan , Shang You
Published: October 2018

Bupivacain, a common local anesthetic, can cause neurotoxicity and permanent neurological disorders. Paeoniflorin has been widely reported as a potential neuroprotective agent in neural injury models. However, the roles and molecular basis of paeoniflorin in bupivacaine‐induced neurotoxicity are still undefined. In the current study, 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay was performed to detect cell viability. Apoptotic rate was measured through double‐staining of Annexin V‐FITC and propidium iodide on a flow cytometer. Western blot assay was carried out to examine the protein levels of p38 mitogen‐activated protein kinase (p38 MAPK), phosphorylated‐p38 MAPK (p‐p38 MAPK), Bcl‐2, and Bax. caspase‐3 activity was determined using a caspase‐3 activity assay kit. We found that paeoniflorin dose‐dependently attenuated bupivacaine‐induced viability inhibition and apoptosis in SH‐SY5Y cells. Moreover, paeoniflorin inhibited bupivacaine‐induced activation of p38 MAPK pathway in SH‐SY5Y cells. Paeoniflorin alone showed no significant effect on cell viability, apoptosis and p38 MAPK signaling in SH‐SY5Y cells. Inhibition of p38 MAPK signaling by SB203580 or small interfering RNA targeting p38 (si‐p38) abated bupivacaine‐induced viability inhibition and apoptosis in SH‐SY5Y cells. In conclusion, paeoniflorin alleviated bupivacaine‐induced neurotoxicity in SH‐SY5Y cells via suppression of the p38 MAPK pathway, highlighting the potential values of paeoniflorin in relieving bupivacaine‐induced neurotoxicity.
Ameliorative effect of carnosine and N‐acetylcysteine against sodium nitrite induced nephrotoxicity in rats
Authors: Ansari Fariheen Aisha , Khan Aijaz Ahmed , Mahmood Riaz
Published: October 2018

The widespread use of sodium nitrite (NaNO2) for various industrial purposes has increased human exposure to alarmingly high levels of nitrate/nitrite. Because NaNO
2 is a strong oxidizing agent, induction of oxidative stress is one of the mechanisms by which it can exert toxicity in humans and animals. We have investigated the possible protection offered by carnosine (CAR) and N‐acetylcysteine (NAC) against NaNO
2‐induced nephrotoxicity in rats. Animals orally received CAR at 100 mg/kg body weight/d for seven days or NAC at 100 mg/kg body weight/d for five days followed by a single oral dose of NaNO
2 at 60 mg/kg body weight. The rats were killed after 24 hours, and the kidneys were removed and processed for various analyses. NaNO
2 induced oxidative stress in kidneys, as shown by the decreased activities of antioxidant defense, brush border membrane, and metabolic enzymes. DNA‐protein crosslinking and DNA fragmentation were also observed. CAR/NAC pretreatment significantly protected the kidney against these biochemical alterations. Histological studies supported these findings, showing kidney damage in NaNO
2‐treated animals and reduced tissue impairment in the combination groups. The protection offered by CAR and NAC against NaNO
2‐induced damage, and their nontoxic nature, makes them potential therapeutic agents against nitrite‐induced nephrotoxicity.
Association between CASP3 polymorphisms and overall cancer risk: A meta‐analysis of case‐control studies
Authors: Hashemi Mohammad , Moazeni‐Roodi Abdolkarim , Ghavami Saeid
Published: October 2018

Several studies inspected the relationship between caspase‐3 (CASP3) polymorphisms and the risk of several human cancers, but the findings remain controversial. We conducted a meta‐analysis aiming to inspect the association between CASP3 rs1049216 T>C, rs12108497 C>T, rs4647603 G>A, rs4647602 C>A, rs6948 T>G, rs2705897 A>C, and rs113420705 G>A polymorphisms and cancer risk. Eligible studies were recognized by searching the Web of Science, PubMed, Scopus, and Google Scholar databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to quantitatively evaluate the association between each polymorphism of CASP3 and cancer risk. The rs4647603 variant significantly increased the risk of cancer in an overdominant (OR, 1.44; 95% CI, 1.03‐2.01; P = 0.03; AG vs AA+GG) inheritance model. Regarding the rs4647602 variant, the findings revealed that this variant was associated with protection against cancer in homozygous codominant (OR, 0.67; 95% CI, 0.56‐0.80;
P < 0.00001; AA vs CC), dominant (OR, 0.84; 95% CI, 0.73‐0.96;
P = 0.009; AC+AA vs CC), recessive (OR, 0.70; 95% CI, 0.61‐0.79;
P < 0.00001; AA vs AC+CC), and allele (OR, 0.81; 95% CI, 0.75‐0.88;
P = 0.00001; A vs C) models. The findings suggested that the rs2705897 variant significantly decreased the risk of cancer in heterozygous codominant (OR, 0.80; 95% CI, 0.67‐0.94;
P = 0.009; AC vs AA), dominant (OR, 0.81; 95% CI, 0.69‐0.95;
P = 0.009; AC+CC vs AA), overdominant (OR, 0.80; 95% CI, 0.68‐0.95;
P = 0.01; AC vs CC+AA), and allele (OR, 0.85; 95% CI, 0.74‐0.97;
P = 0.02; C vs A) models. The results did not support an association between CASP3 rs1049216 and rs6948 polymorphisms and cancer risk. In summary, the findings of this meta‐analysis support an association between CASP3 polymorphisms and cancer risk. Larger and well‐designed studies are desired to evaluate these associations in detail.
Parallelization of CPPTRAJ enables large scale analysis of molecular dynamics trajectory data
Authors: Roe Daniel R. , Cheatham Thomas E.
Published: October 2018

Advances in biomolecular simulation methods and access to large scale computer resources have led to a massive increase in the amount of data generated. The key enablers have been optimization and parallelization of the simulation codes. However, much of the software used to analyze trajectory data from these simulations is still run in serial, or in some cases many threads via shared memory. Here, we describe the addition of multiple levels of parallel trajectory processing to the molecular dynamics simulation analysis software CPPTRAJ. In addition to the existing OpenMP shared‐memory parallelism, CPPTRAJ now has two additional levels of message passing (MPI) parallelism involving both across‐trajectory processing and across‐ensemble processing. All three levels of parallelism can be simultaneously active, leading to significant speed ups in data analysis of large datasets on the NCSA Blue Waters supercomputer by better leveraging the many available nodes and its parallel file system. © 2018 Wiley Periodicals, Inc.
Linear polarizabilities and second hyperpolarizabilities of streptocyanines: Results from broken‐Symmetry DFT and new CCSD(T) benchmarks
Authors: Xu Lihua , Kumar Anshuman , Wong Bryan M.
Published: October 2018

We present a detailed analysis of the linear polarizability (α) and second hyperpolarizability (γ) in a series of streptocyanines, as predicted with various range‐separated functionals and CCSD(T)‐based methods. Contrary to previous work on these systems, we find that the lowest‐energy electronic states for the larger streptocyanine oligomers are not closed‐shell singlets, and improved accuracy can be obtained with certain DFT methods by allowing the system to relax to a lower‐energy broken‐symmetry solution. Our extensive analyses are complemented by new large‐scale CCSD(T) and explicitly correlated CCSD(T)‐F12 calculations that comprise the most complete and accurate benchmarks of α and γ for the streptocyanine systems to date. Taken together, our CCSD(T) and broken‐symmetry DFT calculations (1) show that the MP2 benchmarks used in previous studies still exhibit significant errors (~ 25% for α and ~100% for γ) and, therefore, the MP2 calculations should not be used as reliable benchmarks for polarizabilities or hyperpolarizabilities, and (2) emphasize the importance of testing for a lower‐energy open‐shell configuration when calculating nonlinear optical properties for these systems. © 2018 Wiley Periodicals, Inc.
Molecular enhanced sampling with autoencoders: On‐the‐fly collective variable discovery and accelerated free energy landscape exploration
Authors: Chen Wei , Ferguson Andrew L.
Published: October 2018

Macromolecular and biomolecular folding landscapes typically contain high free energy barriers that impede efficient sampling of configurational space by standard molecular dynamics simulation. Biased sampling can artificially drive the simulation along prespecified collective variables (CVs), but success depends critically on the availability of good CVs associated with the important collective dynamical motions. Nonlinear machine learning techniques can identify such CVs but typically do not furnish an explicit relationship with the atomic coordinates necessary to perform biased sampling. In this work, we employ auto‐associative artificial neural networks (“autoencoders”) to learn nonlinear CVs that are explicit and differentiable functions of the atomic coordinates. Our approach offers substantial speedups in exploration of configurational space, and is distinguished from existing approaches by its capacity to simultaneously discover and directly accelerate along data‐driven CVs. We demonstrate the approach in simulations of alanine dipeptide and Trp‐cage, and have developed an open‐source and freely available implementation within OpenMM. © 2018 Wiley Periodicals, Inc.
OSPREY 3.0: Open‐source protein redesign for you, with powerful new features
Authors: Hallen Mark A. , Martin Jeffrey W. , Ojewole Adegoke , Jou Jonathan D. , Lowegard Anna U. , Frenkel Marcel S. , Gainza Pablo , Nisonoff Hunter M. , Mukund Aditya , Wang Siyu , Holt Graham T. , Zhou David , Dowd Elizabeth , Donald Bruce R.
Published: October 2018

We present osprey 3.0, a new and greatly improved release of the osprey protein design software. Osprey 3.0 features a convenient new Python interface, which greatly improves its ease of use. It is over two orders of magnitude faster than previous versions of osprey when running the same algorithms on the same hardware. Moreover, osprey 3.0 includes several new algorithms, which introduce substantial speedups as well as improved biophysical modeling. It also includes GPU support, which provides an additional speedup of over an order of magnitude. Like previous versions of osprey, osprey 3.0 offers a unique package of advantages over other design software, including provable design algorithms that account for continuous flexibility during design and model conformational entropy. Finally, we show here empirically that osprey 3.0 accurately predicts the effect of mutations on protein–protein binding. Osprey 3.0 is available at http://www.cs.duke.edu/donaldlab/osprey.php as free and open‐source software. © 2018 Wiley Periodicals, Inc.
Double‐buffered, heterogeneous CPU + GPU integral digestion algorithm for single‐excitation calculations involving a large number of excited states
Authors: Morrison Adrian F. , Epifanovsky Evgeny , Herbert John M.
Published: October 2018

The most widely used quantum‐chemical models for excited states are single‐excitation theories, a category that includes configuration interaction with single substitutions, time‐dependent density functional theory, and also a recently developed ab initio exciton model. When a large number of excited states are desired, these calculations incur a significant bottleneck in the “digestion” step in which two‐electron integrals are contracted with density or density‐like matrices. We present an implementation that moves this step onto graphical processing units (GPUs), and introduce a double‐buffer scheme that minimizes latency by computing integrals on the central processing units (CPUs) concurrently with their digestion on the GPUs. An automatic code generation scheme simplifies the implementation of high‐performance GPU kernels. For the exciton model, which requires separate excited‐state calculations on each electronically coupled chromophore, the heterogeneous implementation described here results in speedups of 2–6× versus a CPU‐only implementation. For traditional time‐dependent density functional theory calculations, we obtain speedups of up to 5× when a large number of excited states is computed. © 2018 Wiley Periodicals, Inc.
Single‐sequence‐based prediction of protein secondary structures and solvent accessibility by deep whole‐sequence learning
Authors: Heffernan Rhys , Paliwal Kuldip , Lyons James , Singh Jaswinder , Yang Yuedong , Zhou Yaoqi
Published: October 2018

Predicting protein structure from sequence alone is challenging. Thus, the majority of methods for protein structure prediction rely on evolutionary information from multiple sequence alignments. In previous work we showed that Long Short‐Term Bidirectional Recurrent Neural Networks (LSTM‐BRNNs) improved over regular neural networks by better capturing intra‐sequence dependencies. Here we show a single‐sequence‐based prediction method employing LSTM‐BRNNs (SPIDER3‐Single), that consistently achieves Q3 accuracy of 72.5%, and correlation coefficient of 0.67 between predicted and actual solvent accessible surface area. Moreover, it yields reasonably accurate prediction of eight‐state secondary structure, main‐chain angles (backbone
ϕ and
ψ torsion angles and C
α‐atom‐based
θ and
τ angles), half‐sphere exposure, and contact number. The method is more accurate than the corresponding evolutionary‐based method for proteins with few sequence homologs, and computationally efficient for large‐scale screening of protein‐structural properties. It is available as an option in the SPIDER3 server, and a standalone version for download, at http://sparks-lab.org. © 2018 Wiley Periodicals, Inc.
MDockPeP: An ab‐initio protein–peptide docking server
Authors: Xu Xianjin , Yan Chengfei , Zou Xiaoqin
Published: October 2018

Protein–peptide interactions play a crucial role in a variety of cellular processes. The protein–peptide complex structure is a key to understand the mechanisms underlying protein–peptide interactions and is critical for peptide therapeutic development. We present a user‐friendly protein–peptide docking server, MDockPeP. Starting from a peptide sequence and a protein receptor structure, the MDockPeP Server globally docks the all‐atom, flexible peptide to the protein receptor. The produced modes are then evaluated with a statistical potential‐based scoring function, ITScorePeP. This method was systematically validated using the peptiDB benchmarking database. At least one near‐native peptide binding mode was ranked among top 10 (or top 500) in 59% (85%) of the bound cases, and in 40.6% (71.9%) of the challenging unbound cases. The server can be used for both protein–peptide complex structure prediction and initial‐stage sampling of the protein–peptide binding modes for other docking or simulation methods. MDockPeP Server is freely available at http://zougrouptoolkit.missouri.edu/mdockpep. © 2018 Wiley Periodicals, Inc.
Rapid estimation of activation energy in heterogeneous catalytic reactions via machine learning
Authors: Takahashi Keisuke , Miyazato Itsuki
Published: October 2018

Estimation of activation energies within heterogeneous catalytic reactions is performed using machine learning and catalysts dataset. In particular, descriptors for determining activation energy are revealed within the 788 activation energy dataset. With the implementation of machine learning and chosen descriptors, activation energy can be instantly predicted with over 90% accuracy during cross‐validation. Thus, rapid estimation of activation energies within heterogeneous catalytic reactions can be made achievable via machine learning, leading toward the acceleration of catalysts design and characterization. © 2018 Wiley Periodicals, Inc.
Controlling the strong field fragmentation of ClCHO+ using two laser pulses –an ab initio molecular dynamics simulation
Authors: Shi Xuetao , Schlegel H. Bernhard
Published: October 2018

For a single, intense 7 μm linearly polarized laser pulse, we found that the branching ratio for the fragmentation of ClCHO+ → Cl + HCO+, H + ClCO+, HCl++CO depended strongly on the orientation of the molecule (J. Phys. Chem. Lett. 2012, 3 2541). The present study explores the possibility of controlling the branching ratio for fragmentation by using two independent pulses with different frequencies, alignment and delay. Born‐Oppenheimer molecular dynamics simulations in the laser field were carried out with the B3LYP/6‐311G(d,p) level of theory using combinations of 3.5, 7 and 10.5 μm sine squared pulses with field strengths of 0.03 au (peak intensity of 3.15×1013 W/cm2) and lengths of 560 fs. A 3.5 μm pulse aligned with the C‐H bond and a 10.5 μm pulse perpendicular to the C‐H bond produced a larger branching ratio for HCl++CO than a comparable single 7 μm pulse. When the 10.5 μm pulse was delayed by one quarter of the pulse envelope, the branching ratio for the high energy product, (HCl++CO 73%) was a factor of three larger than the low energy product (Cl + HCO+, 25%). By contrast, when the 3.5 μm pulse was delayed by one quarter of the pulse envelope, the branching ratio was reversed (HCl++CO 38%; Cl + HCO+, 60%). Continuous wavelet analysis was used to follow the interaction of the laser with the various vibrational modes as a function of time. © 2018 Wiley Periodicals, Inc.
Examination of the structures, energetics, and vibrational frequencies of small sulfur‐containing prototypical dimers, (H2S)2 and H2O/H2S
Authors: Dreux Katelyn M. , Tschumper Gregory S.
Published: October 2018

The optimized geometries, vibrational frequencies, and dissociation energies from MP2 and CCSD(T) computations with large correlation consistent basis sets are reported for (H2S)2 and H2O/H2S. Anharmonic vibrational frequencies have also been computed with second‐order vibrational perturbation theory (VPT2). As such, the fundamental frequencies, overtones, and combination bands reported in this study should also provide a useful road map for future spectroscopic studies of the simple but important heterogeneous H2O/H2S dimer in which the hydrogen bond donor and acceptor can interchange, leading to two unique minima with very similar energies. Near the CCSD(T) complete basis set limit, the HOH⋯SH2 configuration (H2O donor) lies only 0.2 kcal mol−1 below the HSH⋯OH2 structure (H2S donor). When the zero‐point vibrational energy is included, however, the latter configuration becomes slightly lower in energy than the former by <0.1 kcal mol−1. © 2018 Wiley Periodicals, Inc.
A systematic study of minima in alanine dipeptide
Authors: Mironov Vladimir , Alexeev Yuri , Mulligan Vikram Khipple , Fedorov Dmitri G.
Published: October 2018

The alanine dipeptide is a standard system to model dihedral angles in proteins. It is shown that obtaining the Ramachandran plot accurately is a hard problem because of many local minima; depending on the details of geometry optimizations, different Ramachandran plots can be obtained. To locate all energy minima, starting from geometries from MD simulations, 250,000 geometry optimizations were performed at the level of RHF/6‐31G*, followed by re‐optimizations of the located 827 minima at the level of MP2/6–311++G**, yielding 30 unique minima, most of which were not previously reported in literature. Both in vacuo and solvated structures are discussed. The minima are systematically categorized based on four backbone dihedral angles. The Gibbs energies are evaluated and the structural factors determining the relative stabilities of conformers are discussed. © 2018 Wiley Periodicals, Inc.
A computational foray into the mechanism and catalysis of the adduct formation reaction of guanine with crotonaldehyde
Authors: Kroeger Asja A. , Karton Amir
Published: October 2018

Crotonaldehyde, a common environmental pollutant and product of endogenous lipid peroxidation, reacts with guanine to form DNA adducts with pronounced genotoxicity and mutagenicity. Here, we explore the molecular mechanism of this adduct formation using double‐hybrid density functional theory methods. The reaction can be envisaged to occur in a two‐step fashion via an aza‐Michael addition leading to an intermediate ring‐open adduct followed by a cyclization reaction giving the mutagenic ring‐closed adduct. We find that (i) a 1,2‐type addition is favored over a 1,4‐type addition for the aza‐Michael addition, and (ii) an initial tautomerization of the guanine moiety in the resulting ring‐open adduct significantly reduces the barrier toward cyclization compared to the direct cyclization of the ring‐open adduct in its keto‐form. Overall, the aza‐Michael addition is found to be rate‐determining. We further find that participation of a catalytic water molecule significantly reduces the energy barriers of both the addition and cyclization reaction. © 2018 Wiley Periodicals, Inc.