bluuebunny/crossref_metadata_2025 huggingface dataset:
A Peptide‐Induced Self‐Cleavage Reaction Initiates the Activation of Tyrosinase
Authors: Kampatsikas Ioannis , Bijelic Aleksandar , Pretzler Matthias , Rompel Annette
Published: March 2019

The conversion of inactive pro‐polyphenol oxidases (pro‐PPOs) into the active enzyme results from the proteolytic cleavage of its C‐terminal domain. Herein, a peptide‐mediated cleavage process that activates pro‐MdPPO1 (Malus domestica) is reported. Mass spectrometry, mutagenesis studies, and X‐ray crystal‐structure analysis of pro‐MdPPO1 (1.35 Å) and two separated C‐terminal domains, one obtained upon self‐cleavage of pro‐MdPPO1 and the other one produced independently, were applied to study the observed self‐cleavage. The sequence Lys 355–Val 370 located in the linker between the active and the C‐terminal domain is indispensable for the self‐cleavage. Partial introduction (Lys 352–Ala 360) of this peptide into the sequence of two other PPOs, MdPPO2 and aurone synthase (CgAUS1), triggered self‐cleavage in the resulting mutants. This is the first experimental proof of a self‐cleavage‐inducing peptide in PPOs, unveiling a new mode of activation for this enzyme class that is independent of any external protease.
Preparation and characterization of rice bran protein‐stabilized emulsion by using ultrasound homogenization
Authors: Sun Li‐Hui , Lv Shi‐Wen , Chen Ci‐Hang , Wang Can
Published: March 2019

Background and objectives

The ultrasound homogenization, an emerging technology with cost‐effectiveness, is widely used in food industry. Rice bran protein is a high‐quality protein with hypoallergenic and attracts a growing interesting in exploring its application. In this study, ultrasound homogenization was used to produce rice bran protein‐stabilized emulsions and the effects of ultrasound power and ultrasound time on characterizations of emulsion were then investigated.

Findings

Results indicated that the emulsions prepared by ultrasound homogenization at 20% power for 20 min had a higher interfacial protein concentration and a smaller droplet size, leading to an increase in stability against creaming. Subsequently, the effects of environmental conditions on emulsion stability were explored, and results demonstrated that emulsion exhibited excellent tolerance for high concentration of NaCl (500 mM) and high temperature (90°C). However, emulsion stability was destroyed under acid conditions.

Conclusions

The ultrasound homogenization technique was an effective method to prepare rice bran protein‐stabilized emulsion, and the emulsions prepared by ultrasound homogenization at 20% power for 20 min possessed good stability against creaming.

Significance and novelty

Rice bran protein isolate showed good emulsifying properties. Ultrasound homogenization could produce an emulsion with good stability and tolerance for high concentration of NaCl and high temperature.
Timing of folic acid/vitamin B12 supplementation and hematologic toxicity during first‐line treatment of patients with nonsquamous non–small cell lung cancer using pemetrexed‐based chemotherapy: The PEMVITASTART randomized trial
Authors: Singh Navneet , Baldi Milind , Kaur Jyotdeep , Muthu Valliappan , Prasad Kuruswamy T. , Behera Digambar , Bal Amanjit , Gupta Nalini , Kapoor Rakesh
Published: March 2019

Background

Vitamin B12 and folic acid (FA) supplementation (B12‐FAS) reduces hematologic toxicity with pemetrexed‐based chemotherapy (PEM). However, the basis for recommending 1 week of B12‐FAS before PEM initiation has never been proven in a randomized trial.

Methods

An open‐label, randomized trial (PEMVITASTART; clinicaltrials.gov identifier NCT02679443) was conducted to compare hematologic toxicity between patients with locally advanced/metastatic nonsquamous non–small cell lung cancer who initiated PEM after 5 to 7 days of B12‐FAS (delayed arm [DA]) versus those who received B12‐FAS simultaneously (≤24 hours) with PEM initiation (immediate arm [IA]). Every 3 weeks, all enrolled patients received pemetrexed (500 mg/m2) AND either cisplatin (65 mg/m2) OR carboplatin (area under the curve = 5.0 mg/mL per minute) on day 1 for a maximum of 6 cycles. Supplementation consisted of oral FA 1000 μg daily and intramuscular vitamin B12 1000 μg every 3 weeks. The primary outcome was any grade of hematologic toxicity and secondary outcomes included grade 3/4 hematologic toxicity, the relative dose intensity delivered, and changes in serum levels of B12/FA/homocysteine.

Results

Of 161 patients (IA, n = 81; DA, n = 80) recruited, 150 (IA, n = 77; DA, n = 73) received ≥1 cycle and were included in a modified intention‐to‐treat analysis. Baseline anemia prevalence was 34.7% (IA, 32.5%; DA, 37%; P = .56). The incidence of any grade anemia, leukopenia, neutropenia, and thrombocytopenia was 87% versus 87.7% (P = .90), 37.7% versus 28.8% (P = .25), 20.8% versus 15.1% (P = .36), and 31.2% versus 16.4% (P = .04), respectively, in the IA and DA, respectively. Grade 3/4 cytopenias and median relative dose intensities delivered (pemetrexed, 93.5%; platinum, 91%) were similar in both arms. After cycle 3 (compared with baseline), serum homocysteine levels were lower, whereas FA and B12 levels were higher. In the DA, serum FA and B12 levels on day 1 of cycle 1 (after 5‐7 days of B12‐FAS) were significantly higher than at baseline, but homocysteine levels were similar.

Conclusions

Simultaneous B12‐FAS initiation with a pemetrexed‐platinum doublet chemotherapy regimen is feasible and does not lead to enhanced hematologic toxicity. Serum homocysteine levels are unaffected by 5 to 7 days of B12‐FAS.
A retrospective validation of the FocalPoint GS slide profiler NFR technology by analysis of interval disease outcomes compared with manual cytology
Authors: Nuttall David S. , Hillier Sharon , Clayton Helen R. , Savage Amanda J. , Martin Cara M. , O’Leary John J.
Published: March 2019

Background

To the authors’ knowledge, published studies reporting on the performance of the FocalPoint GS (FPGS) imaging system have yielded conflicting results to date. However, the results of the MAVARIC study indicated that the FPGS “No Further Review” (NFR) aspect of the technology demonstrated potential and warranted further investigation. The current validation study was performed prior to implementing the NFR slide reporting technology within the routine cervical screening program in Wales, United Kingdom.

Methods

A total of 45,317 SurePath liquid‐based cytology cervical screening samples were submitted for FPGS scanning by 4 Welsh laboratories between 2006 and 2011. The current study (Computer Assisted Evaluation, Screening and Reporting [CAESAR]), reports on a comparison between slides categorized as NFR (8130 slides) and slides manually screened as negative (93,473 slides). Both interventions had a subsequent negative quality control screen.

Results

The histological outcome rates of cervical intraepithelial neoplasia 2 (CIN‐2) (high‐grade squamous intraepithelial lesion or worse [HSIL+]) at 2 years and subsequently 3 years after an FPGS NFR result versus a manually screened negative result were compared. Significantly fewer cases were detected in the NFR cohort compared with the manually screened cohort (P = .043 at 2 years and P = .027 at 3 years). When these cases were subcategorized as cancers and precancers, the interval cancer prevalence between NFR and manually screened samples at 2 years and 3 years was similar; however, the interval precancer prevalence for FPGS NFR was significantly lower (P = .023 at 2 years and P = .026 at 3 years) at approximately one‐half that of manual screening.

Conclusions

The negative predictive potential of the FPGS NFR technology is higher than that of manual screening, and the technology has quality/throughput benefits to support and enhance a laboratory cervical screening service.
Conservation of genetic diversity hotspots of the high‐valued relic yellowhorn (Xanthoceras sorbifolium) considering climate change predictions
Authors: Zhu Ren‐Bin , Wang Qing , Guan Wen‐Bin , Mao Yanjia , Tian Bin , Cheng Ji‐Min , El‐Kassaby Yousry A.
Published: March 2019

Genetic structure and major climate factors may contribute to the distribution of genetic diversity of a highly valued oil tree species Xanthoceras sorbifolium (yellowhorn). Long‐term over utilization along with climate change is affecting the viability of yellowhorn wild populations. To preserve the species known and unknown valuable gene pools, the identification of genetic diversity “hotspots” is a prerequisite for their consideration as in situ conservation high priority. Chloroplast DNA (cpDNA) diversity was high among 38 natural populations (Hd = 0.717, K = 4.616, Tajmas’ D = −0.22) and characterized by high genetic divergence (FST = 0.765) and relatively low gene flow (Nm = 0.03), indicating populations isolation reflecting the species’ habitat fragmentation and inbreeding depression. Six out of the studied 38 populations are defined as genetic diversity “hotspots.” The number and geographic direction of cpDNA mutation steps supported the species southwest to northeast migration history. Climatic factors such as extreme minimum temperature over 30 years indicated that the identified genetic “hotspots” are expected to experience 5°C temperature increase in next following 50 years. The results identified vulnerable genetic diversity “hotspots” and provided fundamental information for the species’ future conservation and breeding activities under the anticipated climate change. More specifically, the role of breeding as a component of a gene resource management strategy aimed at fulfilling both utilization and conservation goals.
Seasonal and spatial variations of water use among riparian vegetation in tropical monsoon region of SW China
Authors: Wang Pingyuan , Liu Wenjie , Zhang Jiaolin , Yang Bin , Singh Ashutosh Kumar , Wu Junen , Jiang Xiaojin
Published: March 2019

Riparian vegetation is an important inhabitant of numerous forest ecosystems, although it is vulnerable and affected by the changes in climate or microclimate. Due to the fluctuation in rainfall and surface water availability, riparian plants usually exposed to two different seasons throughout the year: a dry season and a rainy season. However, water use patterns among riparian plants are still poorly understood in the tropical monsoon region. In this study, we used stable isotope techniques (δD and δ18O) coupled with MixSIAR model to identify the water sources for riparian plants in a tropical forest of SW China. The results showed an apparent seasonal variation in water use patterns for most trees, and the spatial variations were less pronounced between the terrace and floodplain sites. Among most riparian trees, deep soil (below 50 cm) was the main water source in the dry season, and shallow soil (above 15 cm) was the primary water source during the rainy season. However, there was no change in water source for herbs and other shallow‐rooted species with the fluctuation in water availability. This result indicates that shallow‐rooted plants (i.e., herbs and seedlings) struggle for their survivability in a riparian ecosystem because of the water scarcity in shallow soil during the dry season. Thus, lower rainfall and/or extended dry period may affect the productivity and sustainability of riparian vegetation under a future climate change scenario.
Validity of the Seattle Heart Failure Model after heart failure hospitalization
Authors: Li Song , Marcus Patrick , Núñez Julio , Núñez Eduardo , Sanchis Juan , Levy Wayne C.
Published: March 2019

Aims

Heart failure hospitalization is a sentinel event associated with increased mortality risk. Whether long‐term heart failure risk models such as the Seattle Heart Failure Model (SHFM) accurately assess risk in the post‐hospital setting is unknown.

Methods and results

The SHFM was applied to a cohort of 2242 consecutive patients (50% women; mean age 73) on discharge after acute heart failure hospitalization and analysed for the primary endpoint of all‐cause mortality. Model discrimination and calibration were assessed. Direct patient‐level comparison between our study cohort and the original SHFM cohorts was also performed to confirm and quantify the degree and extent of increased mortality risk attributable to post‐hospital status. The SHFM demonstrated good overall risk discrimination (area under the receiver operating characteristic curve 0.704) and was well calibrated in patients <65 years old. The SHFM significantly underestimated mortality risk in patients ≥65 years old post‐hospitalization. Direct patient‐level comparison revealed a stepwise increase in adjusted mortality risk attributable to post‐hospital status for each advancing age group ≥65 years old. This heightened mortality risk showed a diminishing trend over 18 months after discharge.

Conclusions

The SHFM accurately predicts mortality risk in younger patients after acute heart failure hospitalization. However, patients ≥65 years old had increased adjusted mortality risk for up to 18 months after discharge compared with ambulatory heart failure patients, a pattern consistent with the well‐described post‐hospital syndrome.
Punica granatum (Pomegranate) Seed Oil and Momordica charantia (Bitter Melon) Extract Affect the Lipid's Profile and Oxidative Stability of Femoral Muscles of Rats
Authors: Białek Małgorzata , Białek Agnieszka , Lepionka Tomasz , Paśko Paweł , Galanty Agnieszka , Tokarz Andrzej , Czauderna Marian
Published: March 2019

Pomegranate seed oil (PSO) and bitter melon extract (BM), used in folk medicine nowadays are available as dietary supplements, but information about consequences of their simultaneous usage are still scarce. This study aims to evaluate the influence of supplementation of rats’ diet with PSO separately or jointly with BM on the fatty acid (FA), cholesterol, malondialdehyde (MDA), and tocopherols concentrations in femoral muscles. Sprague‐Dawley rats (n = 36) are fed control diet (group C) or experimental diets supplemented only with 0.15 ml PSO/day (group G) or together with BM (group GM). After 21 weeks of supplementation, muscles are subjected to either gas (FA and cholesterol) or liquid (conjugated FA, tocopherols, and MDA) chromatographic analyses. Applied diets do not influence negatively health and welfare of animals. Conjugated linolenic acid (CLnA) isomers, predominating in PSO, are converted into ct/tc conjugated dienes (CD), with rumenic acid being the main CD, and incorporated into muscles. Supplementation of diet with PSO decreases the cholesterol and MDA contents in muscles. Influence of PSO and BM on activity of desaturases results in varied polyunsaturated FA (PUFA) content. Some PUFA may be converted into conjugated FA either exogenously or as a result of enzymatic or non‐enzymatic processes.

Practical Applications: Dietary sources of conjugated linolenic acid isomer, e.g., PSO and BM, are known for their beneficial properties and thus willingly consumed world‐wide. Limited safety information of their simultaneous use is available despite their over‐consumption and may probably cause adverse effects. PSO and BM given to rats improves a lipid profile of femoral muscles, decreases cholesterol, increases polyunsaturated fatty acids and rumenic acid content, and counteracts lipid oxidation. These results may be a starting point for experiments conducted on farm animals considering their supplementation with PSO in order to possible improvement of nutritional value of their meat. After detailed surveys confirming beneficial influence of both supplements on human health and well‐being, these botanicals may be safely introduced into human diet.

This study evaluates the influence of supplementation of rats’ diet with pomegranate seed oil separately or jointly with bitter melon extract on fatty acid, cholesterol, malondialdehyde, and tocopherols concentrations in femoral muscles. After 21 weeks of supplementation, muscles are subjected to either gas or liquid chromatographic analyses. Supplementation of diet with pomegranate seed oil decreases cholesterol and malondialdehyde contents.
Visible‐Light‐Driven Direct Oxidative Coupling Reaction Leading to Alkyl Aryl Ketones, Catalyzed by Nano Pd/ZnO
Authors: Bazyar Zahra , Hosseini‐Sarvari Mona
Published: March 2019

Direct alkyl sp3 C–H activation to form new C–C bonds is one of the major challenges in synthetic chemistry. Herein, for the first time, we represent a new method, using nano Pd/ZnO which plays both as photoredox and transition‐metal catalyst, for C–C bond formations. By using this catalyst, we have accomplished an oxidative coupling reaction between aryl halides and tertiary amines to yield the corresponding naturally occurring alkyl aryl ketones by using visible light irradiation. Furthermore, the carbonylation process was carried out on a 10 gram scale, with visible light and thermal condition, and it was proved to be scalable, efficient, and economical.
Protective Function of Mitogen‐Activated Protein Kinase Phosphatase 5 in Aging‐ and Diet‐Induced Hepatic Steatosis and Steatohepatitis
Authors: Tang Peng , Low Heng Boon , Png Chin Wen , Torta Federico , Kumar Jaspal Kaur , Lim Hwee Ying , Zhou Yi , Yang Henry , Angeli Veronique , Shabbir Asim , Tai E. Shyong , Flavell Richard A. , Dong Chen , Wenk Markus R. , Yang Dan Yock , Zhang Yongliang
Published: March 2019

Nonalcoholic fatty liver disease is currently the most common liver disease and is a leading cause of liver‐related morbidity and mortality. However, its pathogenesis remains largely unclear. We previously showed that mice deficient in mitogen‐activated protein kinase (MAPK) phosphatase 5 (MKP5) spontaneously developed insulin resistance and glucose intolerance, which are associated with visceral obesity and adipose tissue inflammation. In this study, we discovered that mice deficient in MKP5 developed more severe hepatic steatosis and steatohepatitis with age or with feeding on a high‐fat diet (HFD) compared to wild‐type (WT) mice, and this was associated with increased expression of proinflammatory cytokines and collagen genes. Increased p38 activation in MKP5 knockout (KO) liver compared to that in WT liver was detected, which contributed to increased expression of lipid droplet‐associated protein cell death‐inducing DFF45‐like effector A (CIDEA) and CIDEC/fat‐specific protein 27 but not CIDEB through activating transcription factor 2 (ATF2). In addition, MKP5 KO liver had higher peroxisome proliferator‐activated receptor gamma (PPARγ) expression compared with WT liver. On the other hand, overexpression of MKP5 or inhibition of p38 activation in hepatocytes resulted in reduced expression of PPARγ. Inhibition of p38 resulted in alleviation of hepatic steatosis in KO liver in response to HFD feeding, and this was associated with reduced expression of CIDEA, CIDEC, and proinflammatory cytokines. Conclusion: MKP5 prevents the development of nonalcoholic steatohepatitis by suppressing p38–ATF2 and p38–PPARγ to reduce hepatic lipid accumulation, inflammation, and fibrosis.
Molecular profile of ultrastructure changes of the ligamentum flavum related to lumbar spinal canal stenosis
Authors: Sidon Eliezer , Shemesh Shai S. , Mor‐Yossef Moldovan Lisa , Wiesenfeld Yarden , Ohana Nissim , Benayahu Dafna
Published: March 2019

Lumbar spinal canal stenosis (LSCS) is a degenerative disease observed by hypertrophy of the ligamentum flavum (LF) that cause compression of the lumbar neural content. Diabetes mellitus (DM) is a risk factor for the disease and we have shown previously that DM increases the fibrosis and elastic fiber loss in patients with LSCS. The purpose of this study was to find the proteins that play a role in the development of this clinical pathogenesis and the effect of DM on protein expression. LF tissue retrieved from patients diagnosed with LSCS, some were also diagnosed with DM, were compared with LF from patients diagnosed with herniated nucleus pulposus (HNP). The tissues were analyzed by mass spectrometry for proteins profile alteration. We found that LF of LSCS/DM patients exhibited significantly higher levels of proteoglycan proteins and latent transforming growth factor β‐binding protein (LTBP2 and LTBP4). Additionally, an increase of HTRA serine protease 1 and insulin‐like growth factor binding protein‐5 were noted. The higher fibrosis was also associated with proteins related to inflammation and slower tissue repair. Collagen 6 and transforming growth factor inhibitor are related to activation of the anti‐inflammatory M2 pathway that is associated with tissue repair. The decrease of these proteins expression in LSCS/DM is associated with increased levels and activation of M1 pro‐inflammatory pathways. Interestingly, C3 and C4b members of the complement complex and mannose receptor‐like protein (CLEC18) paralogous proteins were detectable solely at the LSCS/DM patients’ samples. Histology analysis shows that inflammatory was induced by the hyperglycemic conditions in diabetic patients involve in altering the matrix compositions. Thus, the protein profiles associated with inflammatory pathways affecting the LF suggested increasing susceptibility of developing the degeneration under hyperglycemic conditions.
Induction of cell‐cycle arrest and apoptosis in human cholangiocarcinoma cells by pristimerin
Authors: Sun Jian‐min , Xu Hai‐tao , Zhao Liang , Zhang Yu‐bao , Kang Peng‐cheng , Song Zeng‐fu , Liu Hai‐shi , Cui Yun‐Fu
Published: March 2019

Pristimerin, a triterpenoid isolated from Celastraceae and Hippocrateaceae, is known to induce cytotoxicity in several cancer cell lines. However, whether pristimerin can induce apoptosis in cholangiocarcinoma cells and the underlying mechanism remain unexplored. We assessed the function of human cholangiocarcinoma QBC and RBE cell lines using various experimental methods such as the cell viability assay to elucidate the viability of cells, flow cytometry to detect the death rate of cells, and Western blot analysis to evaluate the expression of cell cycle‐related proteins and autophagy‐related proteins. Human cholangiocarcinoma QBC cells were transplanted to nude mice to establish an animal model, and the effect of pristimerin on tumor growth in this model was observed. QBC and RBE cell lines treated with pristimerin (0, 5, 10, and 20 μmol/L) demonstrated the induction of apoptosis in a dose‐dependent manner. The cell viability assay revealed a reduction in the cell viability with an increase in the pristimerin concentration. Similarly, flow cytometry revealed a gradual increase in the cell death rate with an increase in the pristimerin concentration. In addition, pristimerin significantly lowered the expression of apoptosis‐related proteins (Bcl‐2, Bcl‐xL, and procaspase‐3), but increased the Bax expression. Furthermore, pristimerin resulted in the G0/G1 cell‐cycle arrest, reducing the expression of cell cycle‐related proteins (cyclin E, CDK2, and CDK4), and increased the expression of autophagy‐related proteins (LC3) in QBC cell line. Treatment with pristimerin could inhibit tumor growth in the nude mouse model.

Overall, this study suggests the potential effect of pristimerin on the cell‐cycle arrest and apoptosis in human cholangiocarcinoma cells.
Epigenetic modifications but not genetic polymorphisms regulate KEAP1 expression in colorectal cancer
Authors: Gao Linbo , Yuan Fang , Che Guanglu , Xiao Xiao , Nie Xinwen , Wang Yanyun , Jia Jin , Kong Ah‐Ng , Zhang Lin
Published: March 2019

Kelch‐like ECH‐associated protein 1 (KEAP1), as a negative regulator of nuclear factor erythroid 2 like 2 (
NRF2), plays a pivotal role in
NRF2 signaling pathway and involves in tumorigenesis. Polymorphisms and methylation in gene promoter region may influence its expression and be related to cancer susceptibility. In this study, we examined the effect of the
KEAP1‐NRF2 interaction on the risk of colorectal cancer (CRC). The polymorphisms of
NRF2 and
KEAP1 were genotyped using the improved multiplex ligase detection reaction assay.
KEAP1 promoter methylation and histone modification were analyzed using bisulfite genome sequencing and chromatin immunoprecipitation (ChIP) assay, respectively. The
KEAP1 rs1048290 CC genotype and C allele were associated with increased risks of CRC (CC vs GG: odds ratio [OR] = 1.39; 95% confidence interval [CI], 1.08‐1.78; CC vs GG/GC: OR = 1.29; 95% CI, 1.05‐1.58; C vs G: OR = 1.18; 95% CI, 1.04‐1.34). The rs1048290‐rs11545829 GT haplotype was associated with a reduced risk of CRC.
KEAP1‐NRF2 interaction analysis revealed that the rs6721961, rs35652124, rs1048290, and rs11545829 conferred the susceptibility to CRC. The hypermethylation of
KEAP1 promoter resulted in lower levels of
KEAP1 messenger RNA (mRNA). After treatment with 5‐aza‐2′‐deoxycytidine/trichostatin A,
KEAP1 promoter methylation was decreased and
KEAP1 mRNA levels were increased. ChIP‐quantitative polymerase chain reaction results showed an enhanced enrichment of H3K4Me3 and H3K27Ac to the promoter of
KEAP1. In vitro methylation analysis showed that the methylated plasmid decreased the transcriptional activity by 70%‐84%. These findings suggest that the
KEAP1‐
NRF2 pathway could potentially impact CRC risk and the downregulation of
KEAP1 could be explained in part by epigenetic modifications.
MicroRNA and exosome: Key players in rheumatoid arthritis
Authors: Zakeri Zahra , Salmaninejad Arash , Hosseini Nayyerehalsadat , Shahbakhsh Yas , Fadaee Elyas , Shahrzad Mohammad Karim , Fadaei Sara
Published: March 2019

Rheumatoid arthritis (RA) is known as one of important autoimmune disorders which can lead to joint pain and damage throughout body. Given that internal (ie, genetic and epigenetic alterations) and external factors (ie, lifestyle changes, age, hormones, smoking, stress, and obesity) involved in RA pathogenesis. Increasing evidence indicated that cellular and molecular alterations play critical roles in the initiation and progression of RA. Among various targets and molecular signaling pathways, microRNAs (miRNAs) and their regulatory networks have key roles in the RA pathogenesis. It has been showed that deregulation of many miRNAs involved in different stages of RA. Hence, identification of miRNAs and their signaling pathways in RA, could contribute to new knowledge which help to better treatment of patients with RA. Besides miRNAs, exosomes have been emerged as key messengers in RA pathogenesis. Exsosomes are nanocarriers which could be released from various cells and lead to changing of behaviors recipient cells via targeting their cargos (eg, proteins, messenger RNAs, miRNAs, long noncoding RNAs, DNAs). Here, we summarized several miRNAs involved in RA pathogenesis. Moreover, we highlighted the roles of exosomes in RA pathogenesis.
miR‐224‐5p inhibits proliferation, migration, and invasion by targeting PIK3R3/AKT3 in uveal melanoma
Authors: Li Jianchang , Liu Xiuming , Li Chaopeng , Wang Wenqi
Published: March 2019

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Accumulating investigations have identified the aberrant expression of miRNAs (microRNAs) in UM, such as miR‐181, miR‐20a, miR‐144, miR‐146a. The purpose of this study is to investigate the biological function of miR‐224‐5p in UM. The expression of miR‐224‐5p, PIK3R3, and AKT3 in 30 tumor tissues and paired adjacent noncancerous tissues were analyzed using Western blot analysis and quantitative real‐time polymerase chain reaction (qRT‐PCR) assays. Cell proliferation assay, transwell assay, and wound healing assay were used to measure the effects of miR‐224‐5p on the motility of UM in vitro. Western blot analysis and luciferase assays were used to detect the expression of PIK3R3 and AKT3 as miR‐224‐5p downstream targets. The results of Western blot analysis and qRT‐PCR assays indicated that the expression of miR‐224‐5p was lower in UM tissues compared to normal tissue, while the expression of PIK3R3 and AKT3 were simultaneously increased. Upregulation of miR‐224‐5p significantly inhibited capacities of proliferation, invasion, and migration of OCM‐1A cells and decreased expression of PIK3R3 and AKT3. Luciferase assay demonstrated PIK3R3 and AKT3 as downstream targets of miR‐224‐5p. Moreover, upregulating PIK3R3 and AKT3 restrained miR‐224‐5p‐induced inhibition of the motility of OCM‐1A cells. Thus, our study proved that miR‐224‐5p was involved in proliferation, invasion, and migration of UM cells via regulation the expression of PIK3R3 and AKT3. And the results also established a miR‐224‐5p/PIK3R3/PI3K/AKT axis in the regulation of UM progression, providing an experimental basis for further exploring the miR‐224‐5p as a therapeutic and diagnosis target for patients with UM.
Expression profiling of long noncoding RNAs associated with vasculogenic mimicry in osteosarcoma
Authors: Ren Ke , Ni Yicheng , Li Xingjia , Wang Chen , Chang Qing , Li Yonggang , Gao Zengxin , Wu Sujia , Shi Xin , Song Jie , Yao Nan , Zhou Jing
Published: March 2019

Osteosarcoma (OS) is the most common highly malignant bone tumor in teens. Vasculogenic mimicry (VM) is defined as de novo extracellular matrix‐rich vascular‐like networks formed by highly aggressive tumor cells. We previously reported the presence of VM and it is an unfavorable prognostic factor in OS patients. Long noncoding RNAs (lncRNAs) are aberrantly expressed in OS and involved in cancer cell VM. However, lncRNAs in VM formation of OS have not been investigated. We, therefore, profiled the expression of lncRNAs in highly aggressive OS cell line 143B compared with its parental poorly aggressive cell line HOS. The differentially expressed (DE) lncRNAs and messenger RNA (mRNAs) were subjected to constructed lncRNA‐mRNA coexpressed network. The top‐ranked hub gene lncRNA n340532 knockdown 143B cells were used for in vitro and in vivo VM assays. The annotation of DE lncRNAs was performed according to the coexpressed mRNAs by Gene Ontology and pathway analysis. A total of 1360 DE lncRNAs and 1353 DE mRNAs were screened out. lncRNA MALAT1 and FTX, which have known functions related to VM formation and tumorigenesis were identified in our data. The coexpression network composed of 226 lncRNAs and 118 mRNAs in which lncRNA n340532 had the highest degree number. lncRNA n340532 knockdown reduced VM formation in vitro. The suppression of n340532 also exhibited potent anti‐VM and antimetastasis effect in vivo, suggesting its potential role in OS VM and metastasis. Furthermore, n340532 coexpressed with 10 upregulation mRNAs and 3 downregulation mRNAs. The enriched transforming growth factor‐β signaling pathway, angiogenesis and so forth were targeted by those coexpressed mRNAs, implying n340532 may facilitate VM formation in OS through these pathways and gene functions. Our findings provide evidence for the potential role of lncRNAs in VM formation of OS that could be used in the clinic for anti‐VM therapy in OS.
Integrated analysis of gene expression profiles identifies transcription factors potentially involved in psoriasis pathogenesis
Authors: Zeng Fanfan , Liu Hongbo , Lu Di , Liu Qianqian , Chen Huoying , Zheng Fang
Published: March 2019

Psoriasis is a common inflammatory skin disease mediated by cells and molecules in both the innate and adaptive immune systems. Recently, gene expression profile analysis revealed a large set of immune‐related differentially expressed genes (DEGs) in psoriasis. However, the associations between these DEGs and their transcriptional regulation mechanisms have not been completely elucidated. In this study, several psoriasis Gene Expression Omnibus data sets were systematically analyzed using bioinformatics tools to uncover important transcription factors (TFs) that regulate the expression of immune‐related DEGs and further enhance our understanding of psoriasis pathogenesis. Common DEGs encoding chemokines, cytokines, antimicrobial peptides, and keratins were identified in psoriasis, and extensive correlations existed among these DEGs. Several common TFs that bind the promoters of the DEGs, including the well‐known signal transducer and activator of transcription 1 (STAT1), STAT3, and nuclear factor κ‐light‐chain‐enhancer of activated B cells (NF‐κB) as well as ETS homologous factor (EHF), Fos‐like antigen 1 (FOSL1), and Forkhead box C1 (FOXC1), which are rarely studied in psoriasis, were also identified. STAT1, EHF, FOSL1, STAT3, and NFKB1 were positively correlated with these DEGs in psoriasis lesions, whereas FOXC1 was negatively correlated with most DEGs. The decreased expression of the DEGs was accompanied by the downregulation of STAT1, EHF, FOSL1, STAT3, and NFKB1 and the upregulation of FOXC1 upon blocking interleukin 17 (IL‐17) or tumor necrosis factor α signaling in psoriasis. Additionally, the downregulation of IL37 in psoriasis was negatively correlated with STAT1 and CXCL10, which are associated with Th1 responses. These results suggest that TFs play an important role in the pathogenesis of psoriasis, and interfering with the activity of key TFs may be a promising therapeutic strategy for psoriasis.
Docosahexaenoic acid enhances M2 macrophage polarization via the p38 signaling pathway and autophagy
Authors: Kawano Aki , Ariyoshi Wataru , Yoshioka Yoshie , Hikiji Hisako , Nishihara Tatsuji , Okinaga Toshinori
Published: March 2019

Macrophages, critical modulators of the immune response, polarize into various phenotypes, including M1 and M2. M1 macrophages are typically activated by lipopolysaccharide and produce proinflammatory cytokines. Conversely, M2 macrophages are activated by stimulation with interleukin 4 (IL)−4 and promote tissue remodeling and anti‐inflammatory reactions. Recently, polyunsaturated fatty acids (PUFAs) have been shown to play important roles in the regulation of inflammation. Docosahexaenoic acid (DHA), a PUFA, has anti‐inflammatory effects on chronic inflammatory disease, but its role in macrophage polarization remains unclear. In this study, we clarified the effects of DHA on macrophage polarization using U937 cells. Treatment with DHA resulted in upregulation of M2 macrophage markers and increased secretion of anti‐inflammatory cytokines by U937 cells. IL‐4, but not DHA, triggered phosphorylation of signal transducer and activator of transcription 6 (STAT6). DHA enhanced the expression of krüppel‐like factor‐4 (KLF4), a transcription factor involved in the regulation of macrophage polarization and increased the phosphorylation of p38 mitogen‐activated protein kinase (MAPK). A selective inhibitor of p38 MAPK downregulated the expression of CD206 in DHA‐treated U937 cells. Moreover, inhibitors of autophagy suppressed the phosphorylation of p38 MAPK and the expression of CD206 in DHA‐treated U937 cells. Expression of microtubule‐associated protein light chain 3‐II, which is involved in autophagosome formation, was enhanced in DHA‐treated U937 cells. Taken together, these results indicated that DHA enhanced the expression of M2 macrophage markers through the p38 MAPK signaling pathway and autophagy, suggesting that DHA regulates M2 macrophage polarization and plays an important role in innate immunity.
c‐Myc mediated upregulation of long noncoding RNA SNHG12 regulates proliferation and drug sensitivity in natural killer/T‐cell lymphoma
Authors: Zhu Linan , Zhang Xudong , Fu Xiaorui , Li Zhaoming , Sun Zhenchang , Wu Jingjing , Wang Xinhua , Wang Feng , Li Xiangke , Niu Songtao , Ding Mengjie , Yang Zhenzhen , Yang Wanqiu , Yin Meifeng , Zhang Lei , Zhang Mingzhi
Published: March 2019

Nasal‐type natural killer/T‐cell lymphoma (NKTCL) is an aggressive malignancy with poor outcomes. The treatment of NKTCL requires intensive chemotherapy. Long noncoding RNAs (lncRNAs) have been implicated in many cancers, including NKTCL. The elucidation of the multidrug resistance (MDR) may greatly contribute to explore novel therapeutic strategies. Herein, we explored the roles and potential regulatory mechanism of lncRNAs small nucleolar RNA host gene 12 (SNHG12) in MDR of NKTCL. We found that SNHG12 was upregulated in NKTCL tissue sections, and its high expression was positively correlated with clinical grade of malignancy of NKTCL. c‐Myc and SNHG12 expression was upregulated in NKTCL cell lines. c‐Myc‐ and SNHG12 overexpression promoted proliferation and inhibited sensitivity to cisplatin (CDDP) in NK/T‐cell lymphoma cell line YTS cells, and c‐Myc and SNHG12‐downregulation inhibited proliferation and enhanced sensitivity to CDDP in SNK‐6 cells. Moreover, c‐Myc‐ and SNHG12 overexpression increased Ki67 and P‐gp expression in YTS cells, whereas c‐Myc and SNHG12‐downregulation reduced the Ki67 and P‐gp expression in SNK‐6 cells. Correlational analyses revealed that c‐Myc expression was positively correlated with SNHG12 expression in NKTCL tissues. Mechanism research showed that SNHG12 was a direct transcriptional target of c‐Myc and c‐Myc promoted SNHG12 expression in NKTCL cell lines. Further research showed that SNHG12 overexpression reversed the effects of c‐Myc downregulation on proliferation and sensitivity to CDDP in NKTCL cell lines. Taken together, our findings first report that c‐Myc mediated upregulation of SNHG12 promotes proliferation and inhibits drug sensitivity in NKTCL, which provides new insights into the therapeutic target for NKTCL.
Angiotensin‐converting enzyme inhibitors attenuated advanced glycation end products‐induced renal tubular hypertrophy via enhancing nitric oxide signaling
Authors: Hwang Jean‐Yu , Kan Wei‐Chih , Liu Yao‐Bin , Chuang Lea‐Yea , Guh Jinn‐Yuh , Yang Yu‐Lin , Huang Jau‐Shyang
Published: March 2019

Advanced glycation end products (AGE) and angiotensin II were closely correlated with the progression of diabetic nephopathy (DN). Nitric oxide (NO) is a protective mediator of renal tubular hypertrophy in DN. Here, we examined the molecular mechanisms of angiotensin‐converting enzyme inhibitor (ACEI) and NO signaling responsible for diminishing AGE‐induced renal tubular hypertrophy. In human renal proximal tubular cells, AGE decreased NO production, inducible NOS activity, guanosine 3′,5′‐cyclic monophosphate (cGMP) synthesis, and cGMP‐dependent protein kinase (PKG) activation. All theses effects of AGE were reversed by treatment with ACEIs (captopril and enalapril), the NO donor S‐nitroso‐N‐acetylpenicillamine (SNAP), and the PKG activator 8‐para‐chlorophenylthio‐cGMPs (8‐pCPT‐cGMPs). In addition, AGE‐enhanced activation of extracellular signal‐regulated kinase (ERK), c‐Jun N‐terminal kinase (JNK), and p38 mitogen‐activated protein kinase (MAPK) were clearly reduced by captopril, enalapril, SNAP, and 8‐pCPT‐cGMPs. The abilities of ACEIs and NO/PKG activation to inhibit AGE‐induced hypertrophic growth were verified by the observation that captopril, enalapril, SNAP, and 8‐pCPT‐cGMPs decreased protein levels of fibronectin, p21
Waf1/Cip1, and receptor for AGE. The results of the present study suggest that ACEIs significantly reduced AGE‐increased ERK/JNK/p38 MAPK activation and renal tubular hypertrophy partly through enhancement of the NO/PKG pathway.
Small regulatory polypeptide of amino acid response negatively relates to poor prognosis and controls hepatocellular carcinoma progression via regulating microRNA‐5581‐3p/human cardiolipin synthase 1
Authors: Yin Jian , Liu Qian , Chen Chao , Liu Wenxiang
Published: March 2019

Hepatocellular carcinoma (HCC) is one of the most common malignancies with extremely high rates of occurrence and death. Long noncoding RNAs (lncRNAs) have been increasingly revealed to participate in tumorigenesis and development of multiple human cancers, including HCC. LINC00961 is a novel lncRNA which has been uncovered as a tumor suppressor in lung cancer and glioma. However, the role of LINC00961 in HCC has never been probed yet. Herein, we revealed a marked downregulation of LINC00961 in HCC tissues and cell lines. Correlation of low LINC00961 expression with poor outcomes in patients with HCC suggested LINC00961 as an independent predictor for HCC prognosis. Functionally, LINC00961 overexpression obviously inhibited cell proliferation, migration, and invasion in HCC cells. Mechanistically, LINC00961 regulated cardiolipin synthase 1 (CRLS1) expression via sponging miR‐5581‐3p. Importantly, both miR‐5581‐3p upregulation and CRLS1 inhibition led to an acceleration in cellular processes in HCC cells. At length, the rescue assays suggested that LINC00961 functioned in HCC through the miR‐5581‐3p/CRLS1 axis. On the whole, our findings disclosed that LINC00961 played a suppressive role in HCC progression via modulating miR‐5581‐3p/CRLS1, thus providing a potentially effective target for the prognosis and treatment of patients with HCC.
Long‐chain noncoding RNA GAS5 mediates oxidative stress in cardiac microvascular endothelial cells injury
Authors: Diao Liwei , Bai Long , Jiang Xingpei , Li Jianjun , Zhang Qinghua
Published: March 2019

This study is performed to figure out the role of long‐chain noncoding RNA growth‐arrest specific transcript 5 (GAS5) in homocysteine (HCY)‐induced cardiac microvascular endothelial cells (CMECs) injury. CMECs were cultured and the model of CMECs injury was established by coincubation with HCY. To construct stable overexpression of GAS5 cells, the expression of GAS5, microRNA‐33a‐5p (miR‐33a‐5p) and ATP‐binding cassette transporter A1 (ABCA1), and biological characteristics of cells were determined. The messenger RNA (mRNA) level and secretion of vascular endothelial growth factor (VEGF), activity of reactive oxygen species (ROS) and superoxide dismutase (SOD), and the content of malondialdehyde (MDA) were measured. The binding site between GAS5 and miR‐33a‐5p and between miR‐33a‐5p and ABCA1 was verified. CMECs were successfully cultured. Reduction of GAS5 expression and ABCA1 expression together with increased expression of miR‐33a‐5p was found in CMECs induced by HCY. After overexpression of GAS5, there showed increased proliferative activity, decreased cell apoptosis rate and apoptosis index, enhanced cell migration ability, increased number of lumen formation, increased mRNA expression of VEGF in cells and the secretion in the supernatant, decreased activity of ROS and SOD in cells, and decreased content of ROS in cells. miR‐33a‐5p could promote the enrichment of GAS5 and ABCA1 was the direct target gene of miR‐33a‐5p. Our study suggests that the low expression of GAS5 was observed in HCY‐induced CMECs injury, and the upregulation of GAS5 could attenuate HCY‐induced CMECs injury by mediating oxidative stress, and its mechanism is related to the upregulation of ABCA1 expression by competitively binding with miR‐33a‐5p.
Characterization of metabolic profiles and lipopolysaccharide effects on porcine vascular wall mesenchymal stem cells
Authors: Nesci Salvatore , Bernardini Chiara , Salaroli Roberta , Zannoni Augusta , Trombetti Fabiana , Ventrella Vittoria , Pagliarani Alessandra , Forni Monica
Published: March 2019

The link between metabolic remodeling and stem cell fate is still unclear. To explore this topic, the metabolic profile of porcine vascular wall mesenchymal stem cells (pVW‐MSCs) was investigated. At the first and second cell passages, pVW‐MSCs exploit both glycolysis and cellular respiration to synthesize adenosine triphosphate (ATP), but in the subsequent (third to eighth) passages they do not show any mitochondrial ATP turnover. Interestingly, when the first passage pVW‐MSCs are exposed to 0.1 or 10 μg/ml lipopolysaccharides (LPSs) for 4 hr, even if ATP synthesis is prevented, the spare respiratory capacity is retained and the glycolytic capacity is unaffected. In contrast, the exposure of pVW‐MSCs at the fifth passage to 10 μg/ml LPS stimulates mitochondrial ATP synthesis. Flow cytometry rules out any reactive oxygen species (ROS) involvement in the LPS effects, thus suggesting that the pVW‐MSC metabolic pattern is modulated by culture conditions via ROS‐independent mechanisms.
Histone demethylase KDM6B regulates 1,25‐dihydroxyvitamin D3‐induced senescence in glioma cells
Authors: Sui Aixia , Xu Yongbing , Pan Baogen , Guo Tao , Wu Jiang , Shen Yongqing , Yang Junjie , Guo Xiaoqiang
Published: March 2019

Vitamin D is a fat‐soluble vitamin and plays an important role in calcium absorption and bone development, whose lack can cause a variety of diseases, including cancer. Human epidemiological studies suggested that vitamin D3 deficiency might increase glioma incidence, but molecular mechanism is less understood. In this study, we show that 1,25‐dihydroxyvitamin D3 (the active form of vitamin D3) induces senescence of glioma cells and increases the expression of senescence markers, INK4A and cyclin‐dependent kinase inhibitor 1A (CDKN1A). 1,25‐Dihydroxyvitamin D3 also upregulates the expression of histone demethylase, KDM6B. Knockdown of KDM6B attenuates 1,25‐dihydroxyvitamin D3‐induced senescence and upregulation of INK4A and CDKN1A. KDM6B promotes the transcription of INK4A by eliminating the trimethylation of repressive marker H3K27me3 near its promoter. This study reveals a new regulatory mechanism involved in vitamin D3 inhibition on gliomas, which is beneficial to prevention and adjuvant therapy of glioma.
Influence of mandibular third molar surgical extraction on the periodontal status of adjacent second molars
Authors: Passarelli Pier Carmine , Lajolo Carlo , Pasquantonio Guido , D'Amato Giuseppe , Docimo Raffaella , Verdugo Fernando , D'Addona Antonio
Published: March 2019

Background

The periodontal health distal of second molars (M2) is often compromised because of third molar (M3) impactions. The aim of this study was to evaluate healing and periodontal status of mandibular M2 after M3 surgical extraction.

Methods

Eighty‐nine consecutive patients with 89 asymptomatic M3 who needed surgical extraction of one fully‐ or semi‐impacted M3 entered this study. Clinical measurements, probing pocket depth (PPD), clinical attachment level (CAL), plaque index (PI), gingival index (GI), and bleeding on probing (BOP), were compared for M2 at baseline (T0) and 6‐months (T1) postsurgical extraction. Multiple logistic regression analysis assessed different risk factors for postoperative changes of periodontal parameters.

Results

Six‐month M2 PPD improved at disto‐vestibular (T0‐5.2/T1‐3.0 mm) and disto‐lingual (T0‐5.4/T1‐3.2 mm) sites. The average attachment gains at T1 were 1.9 and 2 mm, respectively (P < 0.05). BOP, PI, and GI showed significant clinical improvements after extractions. Fifty‐three out of 72 (73.6%) M2 presenting a PPD ≥ 4mm at baseline healed at 6 months recall without periodontal pockets. Older age (mean 55 years, SD 16.7; range 26 to 81) and mean distal PPD at baseline of 7 mm was more likely to be associated with PPD ≥ 4 mm 6 months postextraction (P < 0.05). Past history of periodontitis patients were 41 times more likely to present PPD ≥ 4 mm after healing (OR = 41.4; 95% CI = 10.9 to 156.5, P < 0.05).

Conclusion

Mandibular M3 extractions seem to improve overall periodontal health distal of M2. History of periodontitis, preoperative deep pockets and older age are independent risk factors for poorer healing and residual pockets after M3 surgical extraction.
Dealing with an insufficient future liver remnant: Portal vein embolization and two‐stage hepatectomy
Authors: Kawaguchi Yoshikuni , Lillemoe Heather A. , Vauthey Jean‐Nicolas
Published: March 2019

Colorectal liver metastases (CLM) are not always resectable at the time of diagnosis. An insufficient future liver remnant is a factor excluding patients from curative intent resection. To deal with this issue, two‐stage hepatectomy was introduced approximately 20 years ago. It is a sequential treatment strategy for bilateral CLM, which consists of preoperative chemotherapy, portal vein embolization, and planned first and second liver resections. This study reviews current evidence supporting use of two‐stage hepatectomy.