bluuebunny/crossref_metadata_2025 huggingface dataset:
Network pharmacology‐based prediction of the active ingredients, potential targets, and signaling pathways in compound Lian‐Ge granules for treatment of diabetes
Authors: Xue Jintao , Shi Yongli , Li Chunyan , Song Huijie
Published: October 2018

Aims

Compound Lian‐Ge granules (CLGGs) is a traditional Chinese medicine preparation with good hypoglycemic effect and health function. This study was to predict its active ingredients, potential targets, signaling pathways, and investigate its mechanism of “ingredient‐targets‐pathways.”

Methods

Pharmacodynamics studies on diabetic rats showed that CLGGs had an obvious hypoglycemic effect. On this basis, 27 hypoglycemic active ingredients were screened out. Their targets were confirmed by comparing with these hypoglycemic targets in PharmMapper and DrugBank databases via reversed pharmacophore matching approach. The relationships between ingredients and targets were revealed by comparing data in the String database. A network of “ingredient‐target‐passageway” was constructed.

Results

Studies showed that CLGGs had 24 active ingredients, ie, berberine, puerarin, danshinolic acid A, and sinigrin, etc. These ingredients involved nine targets, ie, insulin‐like growth factor 1 receptor, insulin‐degrading enzyme, ɑ‐amylase, and so on, and 111 metabolic pathways, eg, hypoxia‐inducible factor 1 signaling pathway, PI3K‐Akt signaling pathway, mammalian target of rapamycin signaling pathway, and FoxO signaling pathway.

Conclusion

Using network pharmacology methods, this study predicted the hypoglycemic active ingredients in CLGGs and revealed their targets, and provided a clue for further exploration of the hypoglycemic mechanism of CLGGs.
Synergistic effect of extracellularly supplemented osteopontin and osteocalcin on stem cell proliferation, osteogenic differentiation, and angiogenic properties
Authors: Carvalho Marta S , Cabral Joaquim MS , da Silva Cláudia L , Vashishth Deepak
Published: October 2018

A high demand for functional bone grafts is being observed worldwide, especially due to the increased life expectancy. Osteoinductive components should be incorporated into functional bone grafts, accelerating cell recruitment, cell proliferation, angiogenesis, and new bone formation at a defect site. Noncollagenous bone matrix proteins, especially osteopontin (OPN) and osteocalcin (OC), have been reported to regulate some physiological process, such as cell migration and bone mineralization. However, the effects of OPN and OC on cell proliferation, osteogenic differentiation, mineralization, and angiogenesis are still undefined. Therefore, we assessed the exogenous effect of OPN and OC supplementation on human bone marrow mesenchymal stem/stromal cells (hBM MSC) proliferation and osteogenic differentiation. OPN dose‐dependently increased the proliferation of hBM MSC, as well as improved the angiogenic properties of human umbilical vein endothelial cells (HUVEC) by increasing the capillary‐like tube formation in vitro. On the other hand, OC enhanced the differentiation of hBM MSC into osteoblasts and demonstrated an increase in extracellular calcium levels and alkaline phosphatase activity, as well as higher messenger RNA levels of mature osteogenic markers osteopontin and osteocalcin. In vivo assessment of OC/OPN‐enhanced scaffolds in a critical‐sized defect rabbit long‐bone model revealed no infection, while new bone was being formed. Taken together, these results suggest that OC and OPN stimulate bone regeneration by inducing stem cell proliferation, osteogenesis and by enhancing angiogenic properties. The synergistic effect of OC and OPN observed in this study can be applied as an attractive strategy for bone regeneration therapeutics by targeting different vital cellular processes.
A convenient one‐pot method for the synthesis of symmetrical dialkyl trithiocarbonates using NH4OAc under mild neutral conditions
Authors: Arzehgar Zeinab , Ahmadi Hosna
Published: October 2018

A facial, new, one‐pot method for the preparation of symmetrical organic trithiocarbonates from various alkyl halides and carbon disulfide is described. This is a convenient, clean, and mild procedure, which involves the use of the neutral, nontoxic, commercially available, and inexpensive reagent NH4OAc in the preparation of the trithiocarbonate ion from carbon disulfide.
RELA/NEAT1/miR‐302a‐3p/RELA feedback loop modulates pancreatic ductal adenocarcinoma cell proliferation and migration
Authors: Luo Zhen , Yi Zhong‐Jie , Ou Zheng‐Lin , Han Tong , Wan Tao , Tang Yong‐Chang , Wang Zhi‐Chao , Huang Fei‐Zhou
Published: October 2018

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy due to distant metastasis. RELA, a major component of the NF‐κB pathway, could serve as an oncogene through activating proliferation or migration‐related gene expression, including NEAT1, a well‐known oncogenic long noncoding RNA. In the current study, the expression and function of RELA and NEAT1 in PDAC were examined. The potential upstream regulatory microRNAs of RELA were screened and verified for their correlation with RELA and NEAT1. The expression and function of the selected miR‐302a‐3p were evaluated. RELA and NEAT1 expression were upregulated in PDAC tissues, particularly in PDAC tissues with lymph node metastasis, and their expression correlated with clinical parameters. RELA overexpression promoted PDAC cell proliferation and migration, which could be partially attenuated by the NEAT1 knockdown. By binding to RELA, miR‐302a‐3p inhibited RELA expression, as well as PDAC cell proliferation and migration. RELA downstream NEAT1 expression was negatively regulated by miR‐302a‐3p; the suppressive effect of NEAT1 knockdown on PDAC cell proliferation and migration was partially attenuated by miR‐302a‐3p inhibition. Moreover, through direct binding, the expression of miR‐302a‐3p was also negatively regulated by NEAT1. The expression of miR‐302a‐3p was downregulated and negatively correlated with RELA or NEAT1 in tissue samples, indicating that rescuing miR‐302a‐3p expression may inhibit PDAC cell proliferation and migration through RELA/NEAT1. In summary, RELA, NEAT1, and miR‐302a‐3p form a feedback loop in PDAC to modulate PDAC cell proliferation and migration.
A randomized clinical trial on the antitumoral effects of low molecular weight heparin in the treatment of esophageal cancer
Authors: Taghizadeh Kermani Ali , Hosseini Sare , Fanipakdel Azar , Joudi Mashhad Mona , Akhavan Rezayat Kambiz , Zardadi Mahdi , Gholami Arezoo , Javadinia Seyed Alireza , Ferns Gordon A. , Avan Amir
Published: October 2018

The current treatment approaches for esophageal cancer are associated with poor survival, and there are ongoing efforts to find new and more effective therapeutic strategies. There are several reports on the antitumoral effects of low‐molecular‐weight heparins (LMWHs). We have assessed the possible survival benefit of LMWHs in esophageal malignancies. This was a randomized, single‐blind, multicenter, Phase II clinical trial on nonmetastatic esophageal cancer candidate for neoadjuvant chemoradiotherapy. Patients were randomly assigned to the chemoradiotherapy‐only arm or chemoradiotherapy plus enoxaparin arm using 1:1 allocation. Radiotherapy was delivered in 1.8‐Gy daily fractions to a dose of 50.4 Gy in both groups. Paclitaxel 50 mg/m2 and carboplatin (AUC 2) were administered weekly, concurrent with radiotherapy. In the intervention group, patients received enoxaparin (40 mg) and chemoradiation daily. 4–6 weeks after treatment, all patients underwent esophagectomy. After a median follow up of 7 months, estimated 1 year disease‐free survival (DFS) in the intervention group was 78.9% and was 70% in the control groups (
p = 0.5). Toxicity from the experimental treatment was minimal, and there were no treatment‐related deaths. A pathologically complete response in intervention and control group was 64.8% and 62.5%, respectively (
p = 0.9). There was a nonsignificant trend toward improved survival by the addition of enoxaparin to the concurrent chemoradiotherapy regimen. However, 1 y DFS of both groups were high as expected. A longer follow‐up and a larger sample size are required.
Effect of mesenchymal stem cells‐derived exosomes on tumor microenvironment: Tumor progression versus tumor suppression
Authors: Shojaei Samaneh , Hashemi Seyed Mahmoud , Ghanbarian Hossein , Salehi Mohammad , Mohammadi‐Yeganeh Samira
Published: October 2018

Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into different cell types. Owing to their immunosuppressive and anti‐inflammatory properties, they are widely used in regenerative medicine, but they have a dual effect on cancer progression and exert both growth‐stimulatory or ‐inhibitory effects on different cancer types. It has been proposed that these controversial effects of MSC in tumor microenvironment (TME) are mediated by their polarization to proinflammatory or anti‐inflammatory phenotype. In addition, they can polarize the immune system cells that in turn influence tumor progression. One of the mechanisms involved in the TME communications is extracellular vesicles (EVs). MSCs, as one of cell populations in TME, produce a large amount of EVs that can influence tumor development. Similar to MSC, MSC‐EVs can exert both anti‐ or protumorigenic effects. In the current study, we will investigate the current knowledge related to MSC role in cancer progression with a focus on the MSC‐EV content in limiting tumor growth, angiogenesis, and metastasis. We suppose MSC‐EVs can be used as safe vehicles for delivering antitumor agents to TME.
Identification of LINC01234 and MIR210HG as novel prognostic signature for colorectal adenocarcinoma
Authors: He Zhiyun , Dang Jie , Song Ailin , Cui Xiang , Ma Zhijun , Zhang Zhongtao
Published: October 2018

This study aimed to identify potential biomarkers and the therapeutic targets for colorectal adenocarcinoma by systematically evaluate a large scale of long noncoding RNAs (lncRNAs) expression data from TCGA. The algorithm t‐distributed stochastic neighbor embedding and hierarchical clustering were utilized to group the samples into three clusters that showed a different prognosis. To identify the relationship between the clustered groups and different histoclinical features, different statistical methods were used. The functions of LINC01234 and MIR210HG were investigated with the help of the public database. The results showed that the expression levels of lncRNAs were able to distinguish the tumor samples from the normal tissues and in further they were able to predict the prognosis of the patients. We proposed two potential lncRNAs, which might serve as a biomarker or therapeutic targets. LINC01234 can be a good biomarker. In contrast, MIR210HG participated in the progression of colorectal adenocarcinoma by regulating hypoxia. It might function through an lncRNA–microRNA–messenger RNA regulatory network with MIR210 and RASSF7.
Transcriptional landscape of alternative splicing during peripheral nerve injury
Authors: Zhao Lili , Yi Sheng
Published: October 2018

Abstarct

Alternative splicing (AS) regulates a variety of biological activities in numerous tissues and organs, including the nervous system. However, the existence and specific roles of AS events during peripheral nerve repair and regeneration remain largely undetermined. In the current study, by mapping splice‐crossing sequence reads, we identified AS events and relevant spliced genes in rat sciatic nerve stumps following sciatic nerve crush. AS‐related genes at 1, 4, 7, and 14 days post nerve crush were compared with those at 0 day to discover alternatively spliced genes induced by sciatic nerve crush. These injury‐induced alternatively spliced genes were then categorized to diseases and biological functions, genetic networks, and canonical signaling pathways. Bioinformatic analysis indicated that these alternatively spliced genes were mainly correlated to immune response, cellular growth, and cellular function maintenance. Our study elucidated AS events following peripheral nerve injury and might help deepen our understanding of the molecular mechanisms underlying peripheral nerve regeneration.
Apoptosis in HepaRG and HL‐7702 cells inducted by polyphyllin II through caspases activation and cell‐cycle arrest
Authors: Wang Wenping , Dong Xiaoxv , You Longtai , Sai Na , Leng Xin , Yang Chunjing , Yin Xingbin , Ni Jian
Published: October 2018

Rhizoma Paridis, a traditional Chinese medicine, has shown promise in cancer prevention and therapy. Polyphyllin II is one of the most significant saponins in Rhizoma Paridis and it has toxic effects on kinds of cancer cells. However, our results in this study proved that the polyphyllin II has hepatotoxicity in vitro through caspases activation and cell‐cycle arrest. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide results indicated polyphyllin II inhibited proliferation, induced apoptosis in HepaRG cells and HL‐7702 cells and showed a concentration and time‐dependent. Then, we selected the innovative cell model‐HepaRG cells to explore the mechanism of hepatotoxicity. Our data showed the reactive oxygen species (ROS) increased and the mitochondrial membrane potential decreased in HepaRG cells after administration of polyphyllin II. Besides, with the increase of concentration, the release of lactate dehydrogenase increased and the S phase of the cell cycle was arrested. Nevertheless, when pretreatment with antioxidant N‐acetylcysteine, apoptotic cells decreased significantly, inhibited the production of ROS and improved the decrease of membrane potential in HepaRG cells. Moreover, polyphyllin II treatment increased levels of Fas, Bax, cytochrome
c, activated caspase‐3, ‐8, ‐9, cleaved poly(ADP‐ribose) polymerase and decreased Bcl‐2 expression levels. Finally, we identified two signal pathways of apoptosis induced by polyphyllin II including the death receptor pathway and the mitochondria pathway. This study confirmed the hepatotoxicity of the polyphyllin II in vitro, which has never been discovered and gave a wake‐up call for the clinical application of Rhizoma Paridis.
Tetrandrine, a novel inhibitor of ether‐à‐go‐go‐1 (Eag1), targeted to cervical cancer development
Authors: Wang Xuzhao , Chen Yafei , Li Junwei , Guo Shuai , Lin Xiaoe , Zhang Hailin , Zhan Yong , An Hailong
Published: October 2018

Mortality‐to‐incidence ratios in patients with cancer are extremely high, positioning cancer as a major cause of death worldwide. Ether‐à‐go‐go‐1 (Eag1) is an ion channel that plays important roles in tumour proliferation, malignant transformation, invasion, metastasis, recurrence, and prognosis. Therefore, identifying potent and specific Eag1 channel inhibitors is crucial. In this study, we identified the first natural inhibitor of Eag1, the traditional Chinese medicine agent tetrandrine, and explored the underlying mechanism. Tetrandrine directly interacted with Eag1 and inhibited the currents in a concentration‐dependent manner (IC50 of 69.97 ± 5.2 μM), and the amino acids Ile
550, Thr
552, and Gln
557 in the Eag1 C‐linker domain were critical for tetrandrine’s inhibitory effect. Moreover, tetrandrine reduced the proliferation of HeLa cells and Chinese hamster ovary (CHO) cells stably expressing Eag1 in a concentration‐dependent manner. Finally, tetrandrine (30 mg/kg/day) inhibited tumor growth in mice, demonstrating a 64.21% inhibitory rate of HeLa cell‐transplanted tumors. These results suggest that tetrandrine is a potent and selective Eag1 channel inhibitor, and could act as a leading compound in the development of therapies for Eag1 ion channel dysfunction‐induced diseases.
DNA methylation regulates α‐smooth muscle actin expression during cardiac fibroblast differentiation
Authors: He Yanru , Ling Sunkai , Sun Yuning , Sheng Zulong , Chen Zhongpu , Pan Xiaodong , Ma Genshan
Published: October 2018

Cardiac fibroblast (CF) differentiation to myofibroblasts expressing α‐smooth muscle actin (α‐SMA) plays a key role in cardiac fibrosis. Therefore, a study of the mechanism regulating α‐SMA expression is a means to understanding the mechanism of fibroblast differentiation and cardiac fibrosis. Previous studies have shown that DNA methylation is associated with gene expression and is related to the development of tissue fibrosis. However, the mechanisms by which CF differentiation is regulated by DNA methylation remain unclear. Here, we explored the epigenetic regulation of α‐SMA expression and its relevance in CF differentiation. In this study, we demonstrated that α‐SMA was overexpressed and DNMT1 expression was downregulated in the infarct area after myocardial infarction. Treatment of CFs with transforming growth factor‐β1 (TGF‐β1) in vitro upregulated α‐SMA expression via epigenetic modifications. TGF‐β1 also inhibited DNMT1 expression and activity during CF differentiation. In addition, α‐SMA expression was regulated by DNMT1. Conversely, increasing DNMT1 expression levels rescued the TGF‐β1‐induced upregulation of α‐SMA expression. Finally, TGF‐β1 regulated α‐SMA expression by inhibiting the DNMT1‐mediated DNA methylation of the α‐SMA promoter. Taken together, our research showed that inhibition of the DNMT1‐mediated DNA methylation of the α‐SMA promoter plays an essential role in CF differentiation. In addition, DNMT1 may be a new target for the prevention and treatment of myocardial fibrosis.
LncRNA DANCR promotes cervical cancer progression by upregulating ROCK1 via sponging miR‐335‐5p
Authors: Liang Huiling , Zhang Chunyan , Guan Hongya , Liu Jia , Cui Yuanbo
Published: October 2018

Emerging evidence highlights the key regulatory roles of long noncoding RNAs (lncRNAs) in the initiation and progression of numerous malignancies. The lncRNA identified as differentiation antagonizing nonprotein coding RNA (DANCR) is a novel lncRNA widely involved in the development of multiple human cancers. However, the function of DANCR and its potential molecular mechanism in cervical cancer remain unclear. In this study, we discovered that DANCR was significantly elevated in cervical cancer tissues and cells, and was closely correlated with poor prognosis of cervical cancer patients. In addition, knockdown of DANCR inhibited proliferation, migration, and invasion of cervical cancer cells in vitro, indicating that DANCR functioned as an oncogene in cervical cancer. Moreover, we verified that DANCR could directly bind to miR‐335‐5p, isolating miR‐335‐5p from its target gene Rho‐associated coiled‐coil containing protein kinase 1 (ROCK1). Functional analysis showed that DANCR regulated ROCK1 expression by competitively binding to miR‐335‐5p. Further cellular behavioral experiments revealed that miR‐335‐5p mimics and ROCK1 knockdown reversed the effects of upregulated DANCR on proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT) of cervical cancer cells by rescue assays. In summary, this study demonstrated that DANCR promoted cervical cancer progression by functioning as a competing endogenous RNA (ceRNA) to regulate ROCK1 expression via sponging miR‐335‐5p, suggesting a novel potential therapeutic target for cervical cancer.
Rs217727 polymorphism in H19 promotes cell apoptosis by regulating the expressions of H19 and the activation of its downstream signaling pathway
Authors: Ge Lili , Wang Qinglei , Hu Shengnan , Yang Xiaoang
Published: October 2018

Background

The objective of the current study was to explore the role of H19 rs217727 polymorphism in the control of hepatocellular carcinoma (HCC).

Method

The Student's t test, Cox regression, and Kaplan–Meier analyses were used to clarify whether the H19 rs217727 polymorphism played an important role in the development of HCC. Real‐time polymerase chain reaction (PCR) and western‐blot analysis were carried out to measure the levels of H19, microRNA (miR)‐675, FAS‐associated death domain (FADD), caspase‐8, and caspase‐3 among H19 CC, CT, and TT groups, as well as in cells transfected with H19/si‐H19, or miR‐675 mimic/inhibitor. The MTT assay, colony formation assay, and flow cytometry assay were performed to detect the effect of H19/miR‐675 on cell viability, cell colony formation, and cell apoptosis.

Result

T allele of H19 rs217727 polymorphism apparently increased the survival rate of patients with HCC. Meanwhile, H19 enhanced miR‐675 expression but reduced the mRNA and protein levels of FADD, caspase‐3, and caspase‐8. The T allele of H19 rs217727 polymorphism apparently increased the apoptotic rate of HCC cells. Furthermore, FADD was a virtual target gene of miR‐675 with a potential “hit” located in the 3′‐untranslated region (UTR) of FADD, whereas H19 inhibited FADD expression via increasing the expression of miR‐675. Moreover, H19 upregulated the expression of miR‐675 whereas reducing the expression of FADD, caspase‐3, and caspase‐8. Finally, H19 and miR‐675 promoted cell proliferation and cell colony formation but repressed cell apoptosis.

Conclusion

In summary, the above findings demonstrated that the polymorphism of rs217727 in H19 was associated with HCC via the H19/miR‐675/FADD/caspase‐8/caspase‐3/apoptosis signaling pathway.
Antibodies reacting to mimotopes of Simian virus 40 large T antigen, the viral oncoprotein, in sera from children
Authors: Mazzoni Elisa , Frontini Francesca , Rotondo John Charles , Zanotta Nunzia , Fioravanti Arianna , Minelli Francesca , Torreggiani Elena , Campisciano Giuseppina , Marcuzzi Annalisa , Guerra Giovanni , Tommasini Alberto , Touzé Antoine , Martini Fernanda , Tognon Mauro , Comar Manola
Published: October 2018

Recent data indicate that the Simian virus 40 (SV40) infection appears to be transmitted in humans independently from early SV40‐contaminated antipolio vaccines. Serum antibodies against SV40 large T antigen (Tag) were analyzed in children/adolescents and young adults. To investigate antibodies reacting to SV40 Tag antigens, serum samples (
n = 812) from children and young adults were analyzed by indirect ELISAs using specific SV40 Tag mimotopes. Mimotopes were synthetic peptides corresponding to SV40 Tag epitopes. In sera (
n = 412) from healthy children up to 17 years old, IgG antibodies against SV40 Tag mimotopes reached an overall prevalence of 15%. IgM antibodies against SV40 Tag were detected in sera of children 6–8 months old confirming and extending the knowledge that SV40 seroconversion occurs early in life. In children/adolescents affected by different diseases (
n = 180) SV40 Tag had a prevalence of 18%, being the difference no significant compared to healthy subjects (
n = 220; 16%) of the same age. Our immunological data indicate that SV40 circulates in children and young adults, both in healthy conditions and affected by distinct diseases. The IgM detection in sera from healthy children suggests that the SV40 infection/seroconversion occurs early in life (>6 months). Our immunological data support the hypothesis that SV40, or a closely related still unknown polyomavirus, infects humans. The SV40 seroprevalence is lower than common polyomaviruses, such as BKPyV and JCPyV, and other new human polyomaviruses. In addition, our immunological surveillance indicates a lack of association between different diseases, considered herein, and SV40.
Mitochondrial dysfunction and inhibition of myoblast differentiation in mice with high‐fat‐diet‐induced pre‐diabetes
Authors: Xu Dengqiu , Jiang Zhenzhou , Sun Zeren , Wang Lu , Zhao Guolin , Hassan Hozeifa M. , Fan Sisi , Zhou Wang , Han Shuangshuang , Zhang Luyong , Wang Tao
Published: October 2018

Pre‐diabetes is characterized by impaired glucose tolerance (IGT) and/or impaired fasting glucose. Impairment of skeletal muscle function is closely associated with the progression of diabetes. However, the entire pathological characteristics and mechanisms of pre‐diabetes in skeletal muscle remain fully unknown. Here, we established a mouse model of pre‐diabetes, in which 6‐week‐old male C57BL6/J mice were fed either normal diet or high‐fat diet (HFD) for 8 or 16 weeks. Both non‐fasting and fasting glucose levels and the results of glucose and insulin tolerance tests showed that mice fed an 8‐week HFD developed pre‐diabetes with IGT; whereas mice fed a 16‐week HFD presented with impaired fasting glucose and impaired glucose tolerance (IFG‐IGT). Mice at both stages of pre‐diabetes displayed decreased numbers of mitochondria in skeletal muscle. Moreover, IFG‐IGT mice exhibited decreased mitochondrial membrane potential and ATP production in skeletal muscle and muscle degeneration characterized by a shift in muscle fibers from predominantly oxidative type I to glycolytic type II. Western blotting and histological analysis confirmed that myoblast differentiation was only inhibited in IFG‐IGT mice. For primary skeletal muscle satellite cells, inhibition of differentiation was observed in palmitic acid‐induced insulin resistance model. Moreover, enhanced myoblast differentiation increased glucose uptake and insulin sensitivity. These findings indicate that pre‐diabetes result in mitochondrial dysfunction and inhibition of myoblast differentiation in skeletal muscle. Therefore, interventions that enhance myoblast differentiation may improve insulin resistance of diabetes at the earlier stage.
Retracted: Suppression of microRNA‐342‐3p increases glutamate transporters and prevents dopaminergic neuron loss through activating the Wnt signaling pathway via p21‐activated kinase 1 in mice with Parkinson's disease
Authors: Wu Dong‐Mei , Wang Shan , Wen Xin , Han Xin‐Rui , Wang Yong‐Jian , Shen Min , Fan Shao‐Hua , Zhuang Juan , Zhang Zi‐Feng , Shan Qun , Li Meng‐Qiu , Hu Bin , Sun Chun‐Hui , Lu Jun , Chen Gui‐Quan , Zheng Yuan‐Lin
Published: October 2018

Development of effective therapeutic drugs for Parkinson's disease (PD) is of great importance. Aberrant microRNA (miRNA) expression has been identified in postmortem human PD brain samples, in vitro and in vivo PD models. However, the role of miR‐342‐3p in PD has been understudied. The study explores the effects of miR‐342‐3p on expression of glutamate (Glu) transporter, and dopaminergic neuron apoptosis and proliferation by targeting p21‐activated kinase 1 (PAK1) through the Wnt signaling pathway in PD mice. After establishment of PD mouse models, gain‐ or loss‐of‐function assay was performed to explore the functional role of miR‐342‐3p in PD. Number of apoptotic neurons and Glu concentration was then determined. Subsequently, PC12 cells were treated with miR‐342‐3p mimic, miR‐342‐3p inhibitor, dickkopf‐1 (DKK1), and miR‐342‐3p inhibitor + DKK1. The expression of miR‐342‐3p, PAK1, the Wnt signaling pathway‐related and apoptosis‐related genes, Glutamate transporter subtype 1 (GLT‐1), l‐glutamate/
l‐aspartate transporter (GLAST), tyrosine hydroxylase (TH) was measured. Also, cell viability and apoptosis were evaluated. PD mice exhibited increased miR‐342‐3p, while decreased expression of PAK1, GLT‐1, GLAST, TH, and the Wnt signaling pathway‐related and antiapoptosis genes. miR‐342‐3p downregulation could promote expression of PAK1, the Wnt signaling pathway‐related and antiapoptosis genes. GLT‐1, GLAST, and TH as well as cell viability, but reduce cell apoptosis rate. The results indicated that suppression of miR‐342‐3p improves expression of Glu transporter and promotes dopaminergic neuron proliferation while suppressing apoptosis through the Wnt signaling pathway by targeting PAK1 in mice with PD.
Novel pathways involved in cisplatin resistance identified by a proteomics approach in non‐small‐cell lung cancer cells
Authors: Milone Maria Rita , Lombardi Rita , Roca Maria Serena , Bruzzese Francesca , Addi Laura , Pucci Biagio , Budillon Alfredo
Published: October 2018

Although platinum‐based chemotherapy remains the standard‐of‐care for most patients with advanced non‐small‐cell lung cancer (NSCLC), acquired resistance occurs frequently predicting poor prognosis. To examine the mechanisms underlying platinum resistance, we have generated and characterized by proteomic approach the resistant A549 CDDP‐resistant (CPr‐A549) and their parental A549 cells, identifying 15 proteins differentially expressed (13 upregulated and 2 downregulated in CPr‐A549). In details, we highlighted a coherent network of proteins clustering together and involved in altered protein folding and endoplasmic reticulum stress, correlated with epithelial to mesenchymal transition process and cancer stem cell markers, where vimentin played a hierarchical role, ultimately resulting in increased aggressive features. By using publicly available databases we showed that the modulated proteins could contribute to NSCLC carcinogenesis and correlate with NSCLC patients prognosis and survival probability, suggesting that they can be used as novel potential prognostic/predictive biomarkers or therapeutic targets to overcome platinum‐resistance.
LncRNA–CDC6 promotes breast cancer progression and function as ceRNA to target CDC6 by sponging microRNA‐215
Authors: Kong Xiaoli , Duan Yi , Sang Yuting , Li Yaming , Zhang Hanwen , Liang Yiran , Liu Ying , Zhang Ning , Yang Qifeng
Published: October 2018

Rapid proliferation and metastasis of breast cancers resulted in poor prognosis in clinic. Recent studies have proved that long noncoding RNAs (lncRNAs) were involved in tumor progression. In this study, we aimed to determine the roles and mechanisms of lncRNA–cell division cycle 6 (CDC6) in regulating proliferation and metastasis of breast cancer. Clinically, lncRNA–CDC6 was highly expressed in tumor tissues and was positively correlated with clinical stages of breast cancers. Functionally, the ectopic expression of lncRNA–CDC6 promoted proliferation via regulation of G1 phase checkpoint, and further promoting the migration capability. Moreover, lncRNA–CDC6 could function as competitive endogenous RNA (ceRNA) via directly sponging of microRNA‐215 (miR‐215), which further regulating the expression of CDC6. Taken together, our results proved that lncRNA–CDC6 could function as ceRNA and promote the proliferation and metastasis of breast cancer cells, which provided a novel prognostic marker for breast cancers in clinic.
Autophagic dysfunction in Alzheimer’s disease: Cellular and molecular mechanistic approaches to halt Alzheimer’s pathogenesis
Authors: Uddin Md. Sahab , Mamun Abdullah Al , Labu Zubair Khalid , Hidalgo‐Lanussa Oscar , Barreto George E. , Ashraf Ghulam Md
Published: October 2018

Autophagy is a preserved cytoplasmic self‐degradation process and endorses recycling of intracellular constituents into bioenergetics for the controlling of cellular homeostasis. Functional autophagy process is essential in eliminating cytoplasmic waste components and helps in the recycling of some of its constituents. Studies have revealed that neurodegenerative disorders may be caused by mutations in autophagy‐related genes and alterations of autophagic flux. Alzheimer’s disease (AD) is an irrevocable deleterious neurodegenerative disorder characterized by the formation of senile plaques and neurofibrillary tangles (NFTs) in the hippocampus and cortex. In the central nervous system of healthy people, there is no accretion of amyloid β (Aβ) peptides due to the balance between generation and degradation of Aβ. However, for AD patients, the generation of Aβ peptides is higher than lysis that causes accretion of Aβ. Likewise, the maturation of autophagolysosomes and inhibition of their retrograde transport creates favorable conditions for Aβ accumulation. Furthermore, increasing mammalian target of rapamycin (mTOR) signaling raises tau levels as well as phosphorylation. Alteration of mTOR activity occurs in the early stage of AD. In addition, copious evidence links autophagic/lysosomal dysfunction in AD. Compromised mitophagy is also accountable for dysfunctional mitochondria that raises Alzheimer’s pathology. Therefore, autophagic dysfunction might lead to the deposit of atypical proteins in the AD brain and manipulation of autophagy could be considered as an emerging therapeutic target. This review highlights the critical linkage of autophagy in the pathogenesis of AD, and avows a new insight to search for therapeutic target for blocking Alzheimer’s pathogenesis.
Construction and functional characterization of a fully human anti‐CD19 chimeric antigen receptor (huCAR)‐expressing primary human T cells
Authors: Mirzaei Hamid Reza , Jamali Arezoo , Jafarzadeh Leila , Masoumi Elham , Alishah Khadijeh , Fallah Mehrjardi Keyvan , Emami Seyed Amir Hossein , Noorbakhsh Farshid , Till Brian G. , Hadjati Jamshid
Published: October 2018

Although remarkable results have been attained by adoptively transferring T cells expressing fully murine and/or humanized anti‐CD19 chimeric antigen receptors (CARs) to treat B cell malignancies, evidence of human anti‐mouse immune responses against CARs provides a rationale for the development of less immunogenic CARs. By developing a fully human CAR (huCAR), these human anti‐mouse immune responses are likely eliminated. This, perhaps, not only increases the persistence of anti‐CD19 CAR T cells—thereby reducing the risk of tumor relapse—but also facilitates administration of multiple, temporally separated doses of CAR T cells to the same recipient. To these ends, we have designed and constructed a second‐generation fully human anti‐CD19 CAR (or huCAR19) containing a fully human single‐chain variable fragment (ScFv) fused with a CD8a hinge, a 4‐1BB transmembrane domain and intracellular T cell signaling domains of 4‐1BB and CD3z. T cells expressing this CAR specifically recognized and lysed CD19+ target cells produced cytokines and proliferated in vitro. Moreover, cell volume data revealed that our huCAR construct cannot induce antigen‐independent tonic signaling in the absence of cognate antigen. Considering our results, our anti‐CD19 huCAR may overcome issues of transgene immunogenicity that plague trials utilizing CARs containing mouse‐derived ScFvs. These results suggest that this huCAR19 be safely and effectively applied for adaptive T cell immunotherapy in clinical practice.
Generation of functional human pancreatic organoids by transplants of embryonic stem cell derivatives in a 3D‐printed tissue trapper
Authors: Soltanian Anahita , Ghezelayagh Zahra , Mazidi Zahra , Halvaei Majid , Mardpour Soura , Ashtiani Mohammad Kazemi , Hajizadeh‐Saffar Ensiyeh , Tahamtani Yaser , Baharvand Hossein
Published: October 2018

Organoids can be regarded as a beneficial tool for discovery of new therapeutics for diabetes and/or maturation of pancreatic progenitors (PP) towards β cells. Here, we devised a strategy to enhance maturation of PP by assembly of three‐dimensional (3D) pancreatic organoids (PO) containing human embryonic stem (ES) cell derivatives including ES‐derived pancreatic duodenal homeobox 1 (PDX1)
+ early PP, mesenchymal stem cells, and endothelial cells at an optimized cell ratio, on Matrigel. The PO was placed in a 3D‐printed tissue trapper and heterotopically implanted into the peritoneal cavity of immunodeficient mice where it remained for 90 days. Our results indicated that, in contrast to corresponding early PP transplants, 3D PO developed more vascularization as indicated by greater area and number of vessels, a higher number of insulin‐positive cells and improvement of human C‐peptide secretions. Based on our findings, PO‐derived β cells could be considered a novel strategy to study human β‐cell development, novel therapeutics, and regenerative medicine for diabetes.
Loss of HACE1 promotes colorectal cancer cell migration via upregulation of YAP1
Authors: Zhou Zhen , Zhang Hong‐Sheng , Zhang Zhong‐Guo , Sun Hong‐Liang , Liu Hui‐Yun , Gou Xiao‐Meng , Yu Xiao‐Ying , Huang Ying‐Hui
Published: October 2018

Colorectal cancer (CRC) is the third‐leading cause of cancer mortality worldwide. HACE1 function as a tumor‐suppressor gene and is downregulated in several kinds of cancers. However, the distribution and clinical significance of HACE1 in CRC is still not clarified. In this study, we found that the HACE1 expression is greatly downregulated in CRC tissues and cell lines. Moreover, the HACE1 expression was significantly associated with inhibition of CRC cell proliferation, metastasis, and invasion. HACE1 inhibited epithelial–mesenchymal transition in CRC cells. Furthermore, we found that
HACE1 altered the protein expression of the Hippo pathway by downregulation of YAP1. HACE1 suppresses the invasive ability of CRC cells by negatively regulating the YAP1 pathway. Our data indicates that HACE1 directly targets YAP1 and induces downregulation of YAP1, thereby increasing the activity of the Hippo pathway. In summary, these findings demonstrated that HACE1–YAP1 axis had an important part in the CRC development and progression.
H19/miR‐148a/USP4 axis facilitates liver fibrosis by enhancing TGF‐β signaling in both hepatic stellate cells and hepatocytes
Authors: Zhu Jie , Luo Zhongguang , Pan Yida , Zheng Wanwei , Li Wenshuai , Zhang Ziqiang , Xiong Panpan , Xu Diannan , Du Meiling , Wang Bangting , Yu Jianghong , Zhang Jun , Liu Jie
Published: October 2018

Liver fibrosis is a wound‐healing response represented by excessive extracellular matrix deposition. Activation of hepatic stellate cell (HSC) is the critical cellular basis for hepatic fibrogenesis, whereas hepatocyte undergoes epithelial‐mesenchymal transition (EMT) which is also involved in chronic liver injury. Long noncoding RNA H19 has been found to be associated with cholestatic liver fibrosis lately. However, the role of H19 in liver fibrosis remains largely to be elucidated. In this study, we found that the expression of H19 was significantly upregulated in the liver tissue of CCl4‐induced mice, a toxicant‐induced liver fibrogenesis model. Overexpression of H19 significantly aggravated activation of HSC and EMT of hepatocyte both by stimulating transforming growth factor‐β (TGF‐β) pathway. In terms of mechanism, H19 functioned as a competing endogenous RNA to sponge miR‐148a and subsequently sustained the level of ubiquitin‐specific protease 4 (USP4), which was an identified target of miR‐148a and was able to stabilize TGF‐β receptor I. In conclusion, our findings revealed a novel H19/miR‐148a/USP4 axis which promoted liver fibrosis via TGF‐β pathway in both HSC and hepatocyte, indicating that H19 could become a promising target for the treatment of liver fibrosis.
miR‐15a‐5p suppresses inflammation and fibrosis of peritoneal mesothelial cells induced by peritoneal dialysis via targeting VEGFA
Authors: Shang Jin , He Qianxin , Chen Ying , Yu Dahai , Sun Lulu , Cheng Genyang , Liu Dong , Xiao Jing , Zhao Zhanzheng
Published: October 2018

Long‐term peritoneal dialysis (PD) often ends up with ultrafiltration failure (UFF) which is partially caused by persistent inflammation and fibrosis of peritoneal tissues. However, the mechanism is still unclear. In the current study, the peritoneum from UFF patients demonstrated inflammation and fibrosis which were positively related to the expression of vascular endothelial growth factor A (VEGFA). The in vitro model using human peritoneal mesothelial cells (HPMCs) stimulated by high glucose or advanced glycation end (AGE) product showed consistent changes of inflammation, fibrosis, and VEGFA. What's more, we showed that VEGFA was an instigator of inflammation and fibrosis. Several microRNAs (miRNAs) have been reported to regulate expression of VEGFA elsewhere. Five of them were selected to test the expression in the peritoneum of patients with PD. Results suggested that miR‐15a‐5p was the most significantly downregulated one. Also, in high glucose or AGE product‐stimulated HPMCs, miR‐15a‐5p decreased. When miRNA mimic was used to restore the expression of miR‐15a‐5p, high glucose‐induced VEGFA was repressed. The predicted binding site between these two molecules was confirmed by the dual‐luciferase assay. Restoration of miR‐15a‐5p restrained inflammation and fibrosis of HPMCs. TGF‐β1/Smad2 was shown to be the downstream signaling pathway and their activity was regulated by miR‐15a‐5p/VEGFA. In conclusion, our current study demonstrates that miR‐15a‐5p acts as a regulator of VEGFA mRNA and the following inflammation and fibrosis in peritoneal mesothelial cells. The miR‐15a‐5p/VEGFA pathway may be a potential target for preventing ultrafiltration failure in patients with PD.
The transcriptome profiles and methylation status revealed the potential cancer‐related lncRNAs in patients with cervical cancer
Authors: Yuan Li‐Yun , Qin Xiaomin , Li Lin , Zhou Jinting , Zhou Min , Li Xianxian , Xu Ying , Wang Xiao‐Jun , Xing Hui
Published: October 2018

Cervical cancer continues to be a major public health problem. Although long noncoding RNAs (lncRNAs) were involved in the initiation and progression of cancer, few studies focus on the lncRNAs in the cervical cancer. Here, we systematically studied the clinical information, transcriptome profiling, and methylation array data of cervical squamous cell carcinoma and endocervical adenocarcinoma that retrieved from genomic data commons (GDC). Compared with protein‐coding genes, the expression levels of pseudogenes and lncRNAs were much lower. A total of 190 differentially expressed lncRNAs and 2,326 protein‐coding genes were identified. Meanwhile, 269 differentially methylation regions (DMRs), where 16 lncRNAs were located, were figured out. Only one lncRNA, LINC00592, which was located in the DMRs, was also found differentially expressed. Several transcriptional regulation genes, such as ZNF20, ZNF441, ZNF573, and TMF1, were highly correlated with the expression of LINC00592, which illustrated its possible function on the transcription. Two microRNAs, which were both associated with tumor progression, can bind to LINC00592. Moreover, LINC00592 were also differentially expressed in other tumors. We proposed, with the help of various databases, that LINC00592 is a potential cancer‐related lncRNA in cervical cancer and might activate the cancer progression through the regulation of transcription or structural integrity.
Cell survival controlled by lens‐derived Sema3A–Nrp1 is vital on caffeine‐suppressed corneal innervation during chick organogenesis
Authors: Wang Guang , Jiang Ling‐Min , Tan Bao‐Yi , Li Pei‐Zhi , Zhang Pei‐Ling , Zhang Yu , Cheng Xin , Ma Zheng‐Lai , Li Zhi‐Jie , Brand‐Saberi Beate , Yang Xuesong
Published: October 2018

In this study, we investigated the effect of caffeine overexposure on corneal innervation in the early chicken embryo. Caffeine administration restricted corneal innervation by affecting trigeminal nerve development. Immunohistochemistry for phospho‐Histone3 (pHIS3) and C‐caspase3 revealed that cell survival was repressed by caffeine administration. Whole‐mount in situ hybridization against semaphorin 3A (Sema3A) and neuropilin‐1 (Nrp1) showed that both caffeine and 2,2′‐azobis(2‐methylpropionamidine) dihydrochloride (AAPH, a free radical generator) administration upregulates the expression of both Sema3A and Nrp1. Next, we demonstrated that lens ablation in the developing chicken embryos significantly affected NF‐labeled periocular nerve fascicles and innervation to the central eye region. Subsequently, we used a neuroblastoma cell line to investigate in vitro whether or not Sema3A–Nrp1 signaling exerts a key role on the caffeine‐suppressed neuron survival. Knocking‐down Sema3A through transfection with Sema3A‐siRNA dramatically decreased the responsiveness of cells to caffeine administration, as well as cell apoptosis. We suggest that Sema3A–Nrp1 signaling regulates Trp53 and Cdkn1a through Slit2–Robo1 and Ephb2. Taken together, we speculate here that caffeine‐enhanced reactive oxygen species upregulates Sema3A–Nrp1 expression in the lens and periocular tissues, resulting in corneal cell apoptosis, accompanied by its chemorepellent role on the invasion of the developing cornea by trigeminal sensory fibers.
Cancer cachexia impairs neural respiratory drive in hypoxia but not hypercapnia
Authors: Fields Daryl P. , Roberts Brandon M. , Simon Alec K. , Judge Andrew R. , Fuller David D. , Mitchell Gordon S.
Published: October 2018

Background

Cancer cachexia is an insidious process characterized by muscle atrophy with associated motor deficits, including diaphragm weakness and respiratory insufficiency. Although neuropathology contributes to muscle wasting and motor deficits in many clinical disorders, neural involvement in cachexia‐linked respiratory insufficiency has not been explored.

Methods

We first used whole‐body plethysmography to assess ventilatory responses to hypoxic and hypercapnic chemoreflex activation in mice inoculated with the C26 colon adenocarcinoma cell line. Mice were exposed to a sequence of inspired gas mixtures consisting of (i) air, (ii) hypoxia (11% O2) with normocapnia, (iii) hypercapnia (7% CO2) with normoxia, and (iv) combined hypercapnia with hypoxia (i.e. maximal chemoreflex response). We also tested the respiratory neural network directly by recording inspiratory burst output from ligated phrenic nerves, thereby bypassing influences from changes in diaphragm muscle strength, respiratory mechanics, or compensation through recruitment of accessory motor pools.

Results

Cachectic mice demonstrated a significant attenuation of the hypoxic tidal volume (0.26mL±0.01mL vs 0.30mL±0.01mL; p<0.05), breathing frequency (317±10bpm vs 344±6bpm; p<0.05) and phrenic nerve (29.5±2.6% vs 78.8±11.8%; p<0.05) responses. On the other hand, the much larger hypercapnic tidal volume (0.46±0.01mL vs 0.46±0.01mL; p>0.05), breathing frequency (392±5bpm vs 408±5bpm; p>0.05) and phrenic nerve (93.1±8.8% vs 111.1±13.2%; p>0.05) responses were not affected. Further, the concurrent hypercapnia/hypoxia tidal volume (0.45±0.01mL vs 0.45±0.01mL; p>0.05), breathing frequency (395±7bpm vs 400±3bpm; p>0.05), and phrenic nerve (106.8±7.1% vs 147.5±38.8%; p>0.05) responses were not different between C26 cachectic and control mice.

Conclusions

Breathing deficits associated with cancer cachexia are specific to the hypoxic ventilatory response and, thus, reflect disruptions in the hypoxic chemoafferent neural network. Diagnostic techniques that detect decompensation and therapeutic approaches that support the failing hypoxic respiratory response may benefit patients at risk for cancer cachectic‐associated respiratory failure.
Scaling of major organs in hatchling female American alligators (Alligator mississippiensis)
Authors: Eme John , Cooper Cassidy J. , Alvo Andrew , Vasquez Juan , Muhtaseb Sara , Rayman Susan , Schmoyer Thomas , Elsey Ruth M.
Published: October 2018

Allometric equations represent relationships between morphological/physiological traits and body mass Y = aMb, where Y is the trait, a is elevation, b is the exponent describing the shape of the line, and M is body mass. We measured visceral organ masses in hatchling alligators (Alligator mississippiensis) from five clutches from approximately 45 to 500 g wet body mass. The interaction between initial egg mass and clutch identity was significant for initial hatchling mass, but only egg mass, not clutch, had a significant effect on initial snout–vent and head length. Kidney and liver mass showed biphasic scaling with body mass, as determined by “breakpoint” analyses, with the breakpoint at 120 g wet body mass. Kidney and liver wet mass showed slopes b > 1.0 as animals increased approximately 45–120 g, with significantly lower b approximately 0.8–0.9 for alligators 120–500 g. Within kidney and liver mass, below and above the breakpoint, organ mass slopes tended to be similar across clutches. Lung and heart wet mass did not show biphasic scaling, with b approximately 0.8–0.9. Within lung and heart mass, clutches had statistically identical slopes. Combined clutch data for wet mass showed distinct regressions with b > 1.4 for approximately 45–120 g alligators’ kidney and liver mass, compared with approximately 120–500 g alligators’ kidney, liver, lung, and heart mass b < 1.0. Alligators show rapid kidney and liver growth following hatching, with higher rates than lung or heart tissue. Clutch, egg mass, and hatchling size influence organ size, and each factor should be accounted for in future studies exploring reptile morphology and physiology to assess environmental versus clutch contributions.