bluuebunny/crossref_metadata_2025 huggingface dataset:
Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats
Authors: Shruthi Karnam , Reddy S Sreenivasa , Chitra P Swathi , Reddy G Bhanuprakash
Published: October 2018

The ubiquitin‐proteasome system (UPS) has been implicated in the pathogenesis of many neurodegenerative diseases. Endoplasmic reticulum (ER) stress is shown to play a pathological role in the development of diabetes and its complications. Hence, the current study is aimed to investigate the role of UPS and ER stress in the cerebral cortex of diabetic rats and examine the therapeutic effect of 4‐phenylbutyric acid (4‐PBA), an ER stress inhibitor. Male Sprague‐Dawley rats were divided into three groups: control, diabetes, and diabetes plus 4‐PBA treatment group. Diabetes was induced by single intraperitoneal streptozotocin injection (37 mg/kg body weight [bw]), and 4‐PBA was administered (40 mg/kg bw/d, intraperitoneal) for 2 months, starting from 2 months of diabetes induction. At the end of 4 months, cerebral cortex was collected for analysis. Declined proteasome activity and ubiquitin C‐terminal hydrolase (UCH)‐L1 expression, increased ubiquitinated proteins, and apoptosis were observed in the diabetic rats. The expression of the ubiquitin‐activating enzyme E1, UCHL5, and ER stress markers (ATF6, pPERK, and CHOP) was markedly elevated, whereas the expression of ER‐associated protein degradation (ERAD) components was downregulated in the diabetic rats. 4‐PBA intervention attenuated ER stress, alterations in UPS, and ERAD components in diabetic rats. Importantly, neuronal apoptosis was lowered in 4‐PBA‐treated diabetic rats. Our observations demonstrate that altered UPS could be one of the underlying mechanisms of neuronal apoptosis in diabetes and chemical chaperones such as 4‐PBA could be potential candidates for preventing these alterations under hyperglycemic conditions.
The competing endogenous circular RNA ADAMTS14 suppressed hepatocellular carcinoma progression through regulating microRNA‐572/regulator of calcineurin 1
Authors: Song Changlong , Li Dianqiu , Liu Hongyu , Sun Hongyan , Liu Zhen , Zhang Lirong , Hu Yu
Published: October 2018

Emerging evidence have discovered that circular RNAs (circRNAs) may serve as diagnostic or tumor promising biomarkers. This study aimed to investigate how circular RNA ADAMTS14 (circADAMTS14) regulates microRNA‐572/
regulator of calcineurin 1(miR‐572/
RCAN1) in hepatocellular carcinoma (HCC). The expression profiles of circRNA/microRNA (mRNA) between HCC tissues and paired adjacent tissues were analyzed via microarray analysis. The expressions of circADAMTS14, miR‐572, and
RCAN1 were measured by real‐time polymerase chain reaction (PCR). The protein expression level of
RCAN1 in HCC cells was detected by western blot. The viability and apoptosis levels of HCC cell lines were measured by the cell counting Kit‐8 (CCK‐8) assay and fluorescence‐activated cell sorter. The invasiveness and migration of cells were detected based on the transwell and wound‐healing assay, respectively. The dual‐luciferase reporter assays were used to reveal circADAMTS14 and
RCAN1 as a potential target of miR‐572, which was predicted by TargetScan and miRBase. The effect of circADAMTS14 on HCC cells was demonstrated by tumor formation in nude mice in vivo. CircADAMTS14 and
RCAN1 were lowly expressed in HCC clinical specimens and cell lines using microarrays and qRT‐PCR, but miR‐572 inversely. Our study further verified the direct interaction between circADAMTS14 and
RCAN1 with miR‐572 via the dual‐luciferase reporter gene assay. Overexpressed circADAMTS14 and
RCAN1 induced apoptosis of HCC cells and inhibited cell proliferation and invasion. But overexpressed miR‐572 could decrease apoptosis of HCC cells and promote proliferation and invasion. In vivo, circADAMTS14 inhibited the tumor growth, correlated positively with the protein expression levels of
RCAN1. Our results demonstrated that circADAMTS14 might suppress HCC progression through regulating miR‐572/
RCAN1 as the competing endogenous RNA.
Ovarian cancer stem cell: A potential therapeutic target for overcoming multidrug resistance
Authors: Mihanfar Aynaz , Aghazadeh Attari Javad , Mohebbi Iraj , Majidinia Maryam , Kaviani Mojtaba , Yousefi Mehdi , Yousefi Bahman
Published: October 2018

The cancer stem cell (CSC) model encompasses an advantageous paradigm that in recent decades provides a better elucidation for many important biological aspects of cancer initiation, progression, metastasis, and, more important, development of multidrug resistance (MDR). Such several other hematological malignancies and solid tumors and the identification and isolation of ovarian cancer stem cells (OV‐CSCs) show that ovarian cancer also follows this hierarchical model. Gaining a better insight into CSC‐mediated resistance holds promise for improving current ovarian cancer therapies and prolonging the survival of recurrent ovarian cancer patients in the future. Therefore, in this review, we will discuss some important mechanisms by which CSCs can escape chemotherapy, and then review the recent and growing body of evidence that supports the contribution of CSCs to MDR in ovarian cancer.
Arsenic trioxide inhibits the differentiation of fibroblasts to myofibroblasts through nuclear factor erythroid 2‐like 2 (NFE2L2) protein and the Smad2/3 pathway
Authors: Zhong Lingzhi , Hao Haojie , Chen Deyun , Hou Qian , Zhu Ziying , He Wenjun , Sun Sujing , Sun Mengli , Li Meirong , Fu Xiaobing
Published: October 2018

Background

Tissue contraction and the extracellular matrix deposition are part of the pathogenesis of hypertrophic scars. The transcriptional factor NFE2L2 inhibits fibroblast differentiation in idiopathic pulmonary fibrosis and promotes myofibroblast dedifferentiation. Our previous study showed that the transcription factor NFE2L2 was strongly induced on treatment with arsenic trioxide (ATO).

Objective

The present study sought to investigate the effect of ATO on myofibroblast formation to determine its potential role in hypertrophic scar treatment.

Methods

Small interfering RNA against NFE2L2 was used on treatment with ATO in human skin myofibroblasts. The expression levels of fibrosis markers were assessed by reverse transcription polymerase chain reaction, western blot, and immunofluorescence staining. The transforming growth factor‐β1 (TGF‐β1)/Smad2/3 signaling was detected by western blot. A rabbit ear model was used to evaluate the antifibrotic role of ATO.

Results

At the cellular level, ATO abolished fibroblast differentiation in response to TGF‐β1. ATO reduced TGF‐β1‐induced reactive oxygen species accumulation through increased expression of the antioxidant gene HO‐1 in fibroblasts. In addition, ATO promoted the nuclear translocation of NFE2L2 and inhibited the phosphorylation of Smad2/3. In the rabbit ear model, ATO prevented the progression of hypertrophic scar formation.

Conclusions

This study provides the first evidence implying that ATO inhibits the formation of myofibroblasts in vivo and in vitro and provides a possible treatment for hypertrophic scars.
Peroxisome proliferator‐activated receptor γ modulates renal crystal retention associated with high oxalate concentration by regulating tubular epithelial cellular transdifferentiation
Authors: Li Shujue , Lan Yu , Wu Wenzheng , Duan Xiaolu , Kong Zhenzhen , Wu Wenqi , Zeng Guohua
Published: October 2018

The differentiated phenotype of renal tubular epithelial cell exerts significant effect on crystal adherence. Peroxisome proliferator‐activated receptor γ (PPARγ) has been shown to be critical for the regulation of cell transdifferentiation in many physiological and pathological conditions; however, little is known about its role in kidney stone formation. In the current study, we found that temporarily high oxalate concentration significantly decreased PPARγ expression, induced Madin Darby Canine Kidney cell dedifferentiation, and prompted subsequent calcium oxalate (CaOx) crystal adhesion in vitro. Furthermore, cell redifferentiation after the removal of the high oxalate concentration, along with a decreasing affinity to crystals, was an endogenic PPARγ‐dependent process. In addition, the PPARγ antagonist GW9662, which can depress total‐PPARγ expression and activity, enhanced cell dedifferentiation induced by high oxalate concentration and inhibited cell redifferentiation after removal of the high oxalate concentration. These effects were partially reversed by the PPARγ agonist 15d‐PGJ2. Similar results were observed in animals that suffered from temporary hyperoxaluria followed by a recovery period. The active crystal‐clearing process occurs through the transphenotypical morphology of renal tubular epithelial cells, reflecting cell transdifferentiation during the recovery period. However, GW9662 delayed cell redifferentiation and increased the secondary temporary crystalluria‐induced crystal retention. This detrimental effect was partially reversed by 15d‐PGJ2. Taken together, our results revealed that endogenic PPARγ activity plays a vital regulatory role in crystal clearance, subsequent crystal adherence, and CaOx stone formation via manipulating the transdifferentiation of renal tubular epithelial cells.
LncRNA882 regulates leukemia inhibitory factor (LIF) by sponging miR‐15b in the endometrial epithelium cells of dairy goat
Authors: Zhang Lei , Liu Xiaorui , Cui Jiuzeng , Che Sicheng , Liu Yuexia , An Xiaopeng , Cao Binyun , Song Yuxuan
Published: October 2018

Despite the fact that long noncoding RNAs (lncRNAs) play roles in almost all biological processes, little is known about their biological function in the endometrium during the formation of endometrial receptivity. In this study, a comprehensive analysis of lncRNAs in goat endometrial tissues on Day 5 (prereceptive endometrium, PE) and Day 15 (receptive endometrium, RE) of pregnancy was performed by using RNA‐Seq. As a result, 668 differentially expressed lncRNAs (DELs) were found between the PE and RE. Further study showed that lncRNA882, regulated by estrogen (E2) and progestin (P4), could act as competing endogenous RNAs (ceRNAs) for miR‐15b, which inhibited the expression of transforming growth factor‐b‐activated kinase 1 binding protein 3 (TAB3) and then indirectly regulated the level of leukemia inhibitory factor (LIF). This was helpful for the formation of endometrial receptivity in dairy goats. In conclusion, we elucidated the endometrium lncRNA profiles of PE and RE in dairy goats; lncRNA882 acted as a ceRNA for miR‐15b and then indirectly regulated the level of LIF in goat endometrial epithelium cells. Thus, this study helped us to better understand the molecular regulation of endometrial receptivity in dairy goats.
Protein malnutrition mitigates the effects of a high‐fat diet on glucose homeostasis in mice
Authors: Branco Renato Chaves Souto , Camargo Rafael Ludemann ,  Batista Thiago Martins , Vettorazzi Jean Franciesco , Lubaczeuski Camila , Bomfim Lucas Henrique Montes , Silveira Leonardo Reis , Boschero Antônio Carlos , Zoppi Cláudio Cesar , Carneiro Everardo Magalhães
Published: October 2018

Nutrient malnutrition, during the early stages of development, may facilitate the onset of metabolic diseases later in life. However, the consequences of nutritional insults, such as a high‐fat diet (HFD) after protein restriction, are still controversial. We assessed overall glucose homeostasis and molecular markers of mitochondrial function in the gastrocnemius muscle of protein‐restricted mice fed an HFD until early adulthood. Male C57BL/6 mice were fed a control (14% protein‐control diet) or a protein‐restricted (6% protein‐restricted diet) diet for 6 weeks. Afterward, mice received an HFD or not for 8 weeks (mice fed a control diet and HFD [CH] and mice fed a protein‐restricted diet and HFD [RH]). RH mice showed lower weight gain and fat accumulation and did not show an increase in fasting plasma glucose and insulin levels compared with CH mice. RH mice showed higher energy expenditure, increased citrate synthase, peroxisome‐proliferator‐activated receptor gamma coactivator 1‐alpha protein content, and higher levels of malate and α‐ketoglutarate compared with CH mice. Moreover, RH mice showed increased AMPc‐dependent kinase and acetyl coenzyme‐A (CoA) carboxylase phosphorylation, lower intramuscular triacylglycerol content, and similar malonyl‐CoA levels. In conclusion, protein undernourishment after weaning does not potentiate fat accumulation and insulin resistance in adult young mice fed an HFD. This outcome seems to be associated with increased skeletal muscle mitochondrial oxidative capacity and reduced lipids accumulation.
Resveratrol restores sensitivity of glioma cells to temozolamide through inhibiting the activation of Wnt signaling pathway
Authors: Yang Hua‐Chao , Wang Jun‐Yi , Bu Xing‐Yao , Yang Bin , Wang Bang‐Qing , Hu Sen , Yan Zhao‐Yue , Gao Yu‐Shuai , Han Shuang‐Yin , Qu Ming‐Qi
Published: October 2018

Malignant gliomas are aggressive primary neoplasms that originate in the glial cells of the brain or the spine with notable resistance to standard treatment options. We carried out the study with the aim to shed light on the sensitization of resveratrol to temozolomide (TMZ) against glioma through the Wnt signaling pathway. Initially, glioma cell lines with strong resistance to TMZ were selected by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Then, the glioma cells were subjected to resveratrol, TMZ, Wnt signaling pathway inhibitors, and activators. Cell survival rate and inhibitory concentration at half maximum value were detected by MTT, apoptosis by flow cytometry, and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling staining, in vitro proliferation by hanging drop method and β‐catenin translocation into nuclei by TOP/FOP‐FLASH assay. The expressions of the Wnt signaling pathway‐related and apoptosis‐related factors were determined by western blot analysis. Nude mice with glioma xenograft were established to detect tumorigenic ability. Glioma cell lines T98G and U138 which were highly resistant to TMZ were selected for subsequent experiments. Resveratrol increased the efficacy of TMZ by restraining cell proliferation, tumor growth, and promoting cell apoptosis in glioma cells. Resveratrol inhibited Wnt2 and β‐catenin expressions yet elevated GSK‐3β expression. Moreover, the Wnt signaling pathway participates in the sensitivity enhancing of resveratrol to TMZ via regulating
O
6‐methylguanine‐DNA methyltransferase (MGMT) expression. Resveratrol sensitized TMZ‐induced glioma cell apoptosis by repressing the activation of the Wnt signaling pathway and downregulating MGMT expression, which may confer new thoughts to the chemotherapy of glioma.
Chromatin‐regulatory genes served as potential therapeutic targets for patients with urothelial bladder carcinoma
Authors: Qiu Jian‐Guo , Shi Da‐Yan , Liu Xin , Zheng Xi‐Xia , Wang Lei , Li Qian
Published: October 2018

Urothelial bladder carcinoma is the ninth most common cancer in the world, with an estimated 150,000 deaths per year. Two comprehensive analysis based on The Cancer Genome Atlas urothelial bladder carcinoma reported that chromatin modifier gene mutations were common in bladder cancer. We aimed to find how the mutations and transcriptional profiles of the genes involving in chromatin modification affected the prognosis of patients. The data were retrieved from the Genomic Data Commons data portal and the gene list in pathway Chromatin Modifying Enzymes were obtained from Reactome. The expression levels and mutational profiles of the genes involving in the chromatin were utilized altogether to construct a fusion patient similarity network by similarity network fusion. The genes that were differentially expressed in one clustered group or two were identified. Fifty chromatin‐regulating genes had nonsilent mutations in at least 10 patients. KMT2D, KDM6A, CREBBP, ARID1A, and ARID2 had enriched inactivating mutations. Among 399 cases where both the single‐nucleotide polymorphism information and the messenger RNA expression profiles were available, 326, 23, and 50 patients were clustered into Groups 1, 2, and 3, respectively. The survival analysis suggested that the patients in these three groups had a different prognosis. Thity‐one genes were identified as differentially expressed in any group. The Gene Ontology term enrichment showed that the differentially expressed genes were enriched in the immune response especially in the complement activation. Altogether, chromatin‐regulatory genes were key in bladder cancer and can serve, with the differentially expressed genes, as potential therapeutic targets.
Retracted: Effects of microRNA‐370 on mesangial cell proliferation and extracellular matrix accumulation by binding to canopy 1 in a rat model of diabetic nephropathy
Authors: Yu Feng‐Na , Hu Ming‐Lan , Wang Xin‐Fang , Li Xiang‐Ping , Zhang Bei‐Hao , Lu Xiao‐Qing , Wang Rui‐Qiang
Published: October 2018

As one major diabetic complication, diabetic nephropathy (DN) has been reported to be associated with various kinds of microRNA (miRNA). Thus, we conducted this study to explore the potential of miR‐370 in a rat model of DN through investigation of mesangial cell proliferation and extracellular matrix (ECM). A total of 40 healthy adult male Sprague–Dawley rats were enrolled and assigned into normal (n = 10) and DN (
n = 30, DN rat model) groups. Dual‐luciferase reporter assay was performed for the targeting relationship between miR‐370 and canopy 1 (CNPY1). Mesangial cells were collected and transfected with prepared mimic, inhibitor or small interfering RNA (siRNA) for analyzing the effect of miR‐370 on DN mice with the help of expression and cell biological processes detection. CNPY1 was confirmed as a target gene of miR‐370. DN mice had increased expression of miR‐370, fibronectin, type I collagen (Col I), type IV collagen (Col IV), and plasminogen activator inhibitor‐1 (PAI‐1) but reduced CNPY1 expression. Cells transfected with miR‐370 mimic and siRNA–CNPY1 had increased expression of fibronectin, Col I, Col IV, and PAI‐1 but decreased CNPY1 expression. The miR‐370 mimic and siRNA–CNPY1 groups showed increased cell proliferation, as well as elevated ECM accumulation and declined cell apoptosis rate as compared with the blank and negative control groups, with reverse trends observed in the miR‐370 inhibitor group. Our study concludes that overexpression of miR‐370 promotes mesangial cell proliferation and ECM accumulation by suppressing CNPY1 in a rat model of DN.
LINC00707 promotes hepatocellular carcinoma progression through activating ERK/JNK/AKT pathway signaling pathway
Authors: Wang Jianchu , Luo Zongjiang , Yao Tianwei , Li Wenchuan , Pu Jian
Published: October 2018

Increasing evidence has demonstrated that abnormal expression of lncRNA is correlated with various malignant tumors, including hepatocellular carcinoma (HCC). Our current study was aimed to investigate the role of LINC00707 in HCC development. We observed that LINC00707 was upregulated in HCC cell lines compared with normal liver cell lines. Then, Hep3B cells and SNU449 cells were infected with LV‐shLINC00707 and LV‐LINC00707. LINC00707 silencing could greatly repress the proliferation and colony formation of HCC cells in vitro. On the contrary, overexpression of LINC00707 induced HCC cell proliferation and colony formation. In addition, HCC cell apoptosis was significantly enhanced and HCC cell cycle was blocked in G1 phase by LV‐shLINC00707. Hep3B cells and SNU449 cell invasion capacity was restrained by the knockdown of LINC00707, whereas upregulation of LINC00707 exhibited an opposite phenomenon. Accumulating evidence has reported that ERK/JNK/AKT signaling is involved in multiple cancers, including HCC. Here, in our study, we identified that ERK/JNK/AKT signaling was dramatically restrained by silencing of LINC00707 while activated by LV‐LINC00707 in HCC cells. Subsequently, an in vivo experiment was conducted, and it demonstrated that LINC00707 could modulate HCC development through activating ERK/JNK/AKT signaling. Taking the above results together, it was implied in our study that LINC00707 contributed to HCC progression through modulating the ERK/JNK/AKT pathway.
RNA‐binding protein, human antigen R regulates hypoxia‐induced autophagy by targeting ATG7/ATG16L1 expressions and autophagosome formation
Authors: Palanisamy Kalaiselvi , Tsai Tsung‐Hsun , Yu Tung‐Min , Sun Kuo‐Ting , Yu Shao‐Hua , Lin Feng‐Yen , Wang I‐Kuan , Li Chi‐Yuan
Published: October 2018

Autophagy, a prosurvival mechanism offers a protective role during acute kidney injury. We show novel findings on the functional role of RNA binding protein, HuR during hypoxia‐induced autophagy in renal proximal tubular cells‐2 (HK‐2). HK‐2 cells showed upregulated expressions of HuR and autophagy‐related proteins such as autophagy related 7 (ATG7), autophagy related 16 like 1 (ATG16L1), and LC3II under hypoxia. Increased autophagosome formation was visualized as LC3 puncta in hypoxic cells. Further, short hairpin‐RNA‐mediated loss of HuR function in HK‐2 cells significantly decreased ATG7 and ATG16L1 protein expressions. Bioinformatics prediction revealed HuR motif binding on the coding region of ATG7 and AU‐rich element at 3′UTR ATG16L1 messnger RNA (mRNA). The RNA immunoprecipitation study showed that HuR was predominantly associated with ATG7 and ATG16L1 mRNAs under hypoxia. In addition, HuR enhanced autophagosome formation by regulating LC3II expressions. These results show that HuR regulates ATG7 and ATG16L1 expressions and thereby mediate autophagy in HK‐2 cells. Importantly, HuR knockdown cells underwent apoptosis during hypoxia as observed through the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Collectively, these findings show the crucial role of HuR under hypoxia by regulating autophagy and suppressing apoptosis in renal tubular cells.
Metabolic syndrome, Mediterranean diet, and polyphenols: Evidence and perspectives
Authors: Finicelli Mauro , Squillaro Tiziana , Di Cristo Francesca , Di Salle Anna , Melone Mariarosa Anna Beatrice , Galderisi Umberto , Peluso Gianfranco
Published: October 2018

Metabolic syndrome (MetS) is defined as the co‐occurrence of metabolic risk factors that includes insulin resistance, hyperinsulinemia, impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, and visceral obesity. The clinical significance of MetS consists of identifying a subgroup of patients sharing a common physiopathological state predisposing to chronic diseases. Clinical and scientific studies pinpoint lifestyle modification as an effective strategy aiming to reduce several features accountable for the risk of MetS onset. Among the healthy dietary patterns, the Mediterranean diet (MedDiet) emerges in terms of beneficial properties associated with longevity. Current evidence highlights the protective effect exerted by MedDiet on the different components of MetS. Interestingly, the effect exerted by polyphenols contained within the representative MedDiet components (i.e., olive oil, red wine, and nuts) seems to be accountable for the beneficial properties associated to this dietary pattern. In this review, we aim to summarize the principal evidence regarding the effectiveness of MedDiet–polyphenols in preventing or delaying the physiopathological components accountable for MetS onset. These findings may provide useful insights concerning the health properties of MedDiet–polyphenols as well as the novel targets destined to a tailored approach to MetS.
Crucial role of poly (ADP‐ribose) polymerase (PARP‐1) in cellular proliferation of Dictyostelium discoideum
Authors: Jubin Tina , Kadam Ashlesha , Saran Shweta , Begum Rasheedunnisa
Published: October 2018

The unicellular, as well as multicellular stages of Dictyostelium discoideum’s life cycle, make it an excellent model system for cell type determination, differentiation, development, and cell death studies. Our preliminary results show the involvement of poly (ADP‐ribose) polymerase‐1 (PARP‐1) during
D. discoideum growth by its constitutive downregulation as well as by its ortholog overexpression. The current study now analyzes and strengthens the role of the PARP‐1 ortholog in cellular proliferation of
D. discoideum.
ADPRT1A was knocked out (KO) from
D. discoideum and studied for its effect on cell growth, cell cycle, morphology, and oxidative stress. The present findings show that
ADPRT1A KO (
A KO) cells exhibited reduced cellular proliferation, stressed phenotype, and cell cycle arrest in G2‐M phase. Under oxidative stress,
A KO cells exhibited slower growth and DNA damage. This is the first report where the involvement of ADPRT1A in growth in
D. discoideum is established.
Predictive and therapeutic biomarkers in chimeric antigen receptor T‐cell therapy: A clinical perspective
Authors: Mirzaei Hamid Reza , Mirzaei Hamed , Namdar Afshin , Rahmati Majid , Till Brian G. , Hadjati Jamshid
Published: October 2018

The adoptive transfer of genetically engineered T cells modified to express a chimeric antigen receptor (CAR) has shown remarkable activity and induces long‐term remissions in patients with advanced hematologic malignancies. To date, little is known about predictive indicators of therapeutic efficacy or serious toxicity after CAR T‐cell therapy in clinical practice. Biomarkers are not only potentially able to inform physicians and researchers of immunotherapy targets in particular but could also be used to monitor the effectiveness of treatments and to predict incidence of side effects in some circumstances. Identification of new biomarkers can therefore not only contribute to the development of new therapeutic and prognostic strategies for CAR T‐cell therapy for cancer but also help to generate improved clinical practices for early recognition and minimization of adverse effects while preserving the antitumor activity of the CAR T cells. Herein, we will consider a variety of predictive and therapeutic biomarkers in CAR T‐cell therapy and the state of current understanding of their clinical utility. The incorporation of biomarker studies in CAR T‐cell clinical trials and practice will help to realize the potential clinical benefit of biomarker‐guided therapy.
Physalin D regulates macrophage M1/M2 polarization via the STAT1/6 pathway
Authors: Ding Ning , Wang Yuxing , Dou Ce , Liu Feila , Guan Ge , Wei Keyu , Yang Jingyuan , Yang Mingcan , Tan Ju , Zeng Wen , Zhu Chuhong
Published: October 2018

The in vitro and in vivo effects of physalin D on macrophage M1/M2 polarization were investigated. In silico analysis was first performed for biological function prediction of different physalins. The results suggest physalins have similar predicted biological functions due to their similarities in chemical structures. The cytotoxicity of physalins was then analyzed based on cell apoptosis rate and cell viability evaluation. Physalin D was chosen for further study due to its minimal cytotoxicity. Bone marrow macrophages were isolated and induced with lipopolysaccharide/interferon (IFN)‐γ for M1 polarization and interleukin (IL)‐4/IL‐13 for M2 polarization. The results showed that physalin D can repolarize M1 phenotype cells toward M2 phenotype. In addition, physalin D is protective in M2 macrophages to maintain the M2 phenotype in the presence of IFN‐γ. On the molecular level, we found that physalin D suppressed the signal transducers and activators of transcription (STAT)1 activation and blocked STAT1 nuclear translocation. Conversely, physalin D can also activate STAT6 and enhance STAT6 nuclear translocation for M2 polarization. Taken together, these results suggested that physalin D regulates macrophage M1/M2 polarization via the STAT1/6 pathway.
Notch signaling inhibits cardiac fibroblast to myofibroblast transformation by antagonizing TGF‐β1/Smad3 signaling
Authors: Zhou Xue‐liang , Fang Yi‐hu , Wan Li , Xu Qi‐rong , Huang Huang , Zhu Rong‐rong , Wu Qi‐cai , Liu Ji‐chun
Published: October 2018

Purpose

During myocardial infarction (MI), cardiac fibroblasts (CFs) transform into myofibroblast (CMT). This study aimed to investigate the crosstalk of Notch1 and transforming growth factor‐β1 (TGF‐β1)/Smad3 signaling in the regulation of CMT and myocardial fibrosis.

Methods

Primary CFs were isolated from young rats and treated with TGF‐β1 or adenovirus to overexpress or knockdown Notch1 intracellular domain (N1ICD) or Smad3.

Results

TGF‐β1 decreased the expression of fibroblast markers but increased the expression of myofibroblast markers in rat CFs. TGF‐β1 increased the proliferation, invasion, and adhesion, and the secretion of collagen I of CFs, and these effects were inhibited by N1ICD overexpression. Moreover, endogenous Smad3 phosphorylation in CFs was enhanced by N1ICD knockdown, whereas TGF‐β1 induced Smad3 phosphorylation was antagonized by the N1ICD overexpression. Conversely, endogenous N1ICD activation in CFs was antagonized by Smad3, whereas TGF‐β1 induced N1ICD inactivation was antagonized by Smad3 knockdown. Coimmunoprecipitation showed that N1ICD interacted with Smad3 and immunostaining revealed the colocalization of N1ICD and Smad3 in the nuclei of CFs. Moreover, we demonstrated the functional antagonism of N1ICD and Smad3 on the phenotypes of CFs. Finally, TGF‐β1/Smad3 signaling promoted whereas Notch signaling inhibited myocardial fibrosis in rat MI model.

Conclusion

Notch signaling inhibits CMT by antagonizing TGF‐β1/Smad3 signaling. Notch signaling activators and TGF‐β1/Smad3 signaling inhibitors could be exploited for therapeutic intervention to inhibit myocardial fibrosis after MI.
P2X7, a critical regulator and potential target for bone and joint diseases
Authors: Zeng Dehui , Yao Pingbo , Zhao Hong
Published: October 2018

Abundant evidence indicted that P2X7 receptor show a essential role in human health and some human diseases including hypertension, atherosclerosis, pulmonary inflammation, tuberculosis infection, psychiatric disorders, and cancer. P2X7 receptor also has an important role in some central nervous system diseases such as neurodegenerative disorders. Recently, more research suggested that P2X7 receptor also plays a crucial role in bone and joint diseases. But the effect of P2X7 receptor on skeletal and joint diseases has not been systematically reviewed. In this article, the role of P2X7 receptor in skeletal and joint diseases is elaborated. The activation of P2X7 receptor can ameliorate osteoporosis by inducing a fine balance between osteoclastic resorption and osteoblastic bone formation. The activation of P2X7 receptor can relieve the stress fracture injury by increasing the response to mechanical loading and inducing osteogenesis. But the activation of P2X7 receptor mediates the cell growth and cell proliferation in bone cancer. In addition, the activation of P2X7 receptor can aggravate the process of some joint diseases such as osteoarthritis, rheumatoid arthritis, and acute gouty arthritis. The inhibition of P2X7 receptor can alleviate the pathological process of joint disease to some extent. In conclusion, P2X7 receptor may be a critical regulator and therapeutic target for bone and joint diseases.
Analysis of gene expression and methylation datasets identified ADAMTS9, FKBP5, and PFKBF3 as biomarkers for osteoarthritis
Authors: Li ZhaoFang , Zhang RongQiang , Yang XiaoLi , Zhang DanDan , Li BaoRong , Zhang Di , Li Qiang , Xiong YongMin
Published: October 2018

Background: Osteoarthritis (OA) is a kind of chronic osteoarthropathy and degenerative joint disease. Epigenetic regulation in the gene expression dynamics has become increasingly important in OA. We performed a combined analysis of two types of microarray datasets (gene expression and DNA methylation) to identify methylation‐based key biomarkers to provide a better understanding of molecular biological mechanisms of OA.

Methods: We obtained two expression profiling datasets (GSE55235, GSE55457) and one DNA methylation profiling data set (GSE63695) from the Gene Expression Omnibus. First, differentially expressed genes (DEGs) between patients with OA and controls were identified using the Limma package in R(v3.4.4). Then, function enrichment analysis of DEGs was performed using a DAVID database. For DNA methylation datasets, ChAMP methylation analysis package was used to identify differential methylation genes (DMGs). Finally, a comprehensive analysis of DEGs and DMGs was conducted to identify genes that exhibited differential expression and methylation simultaneously.

Results: We identified 112 DEGs and 2,896 DMGs in patients with OA compared with controls. Functional analysis of DEGs obtained that inflammatory responses, immune responses, and positive regulation of apoptosis, tumor necrosis factor (TNF) signaling pathway, and osteoclast differentiation may be involved in the pathogenesis of OA. Cross‐analysis revealed 26 genes that exhibited differential expression and methylation in OA. Among them, ADAMTS9, FKBP5, and PFKBF3 were identified as valuable methylation‐based biomarkers for OA.

Conclusion: In summary, our study identified different molecular features between patients with OA and controls. This may provide new clues for clarifying the pathogenetic mechanisms of OA.
Mutations in GAS5 affect the transformation from benign prostate proliferation to aggressive prostate cancer by affecting the transcription efficiency of GAS5
Authors: Zhu Lizhen , Zhu Qi , Wen Huihuang , Huang Xiang , Zheng Ge
Published: October 2018

Background

In this study, we aimed to explore the effects of GAS5 single‐nucleotide polymorphisms (SNPs) on GAS5 expression. And the signaling pathways underlying the function of GAS5 during the pathogenesis of prostate cancer (PC) were clarified.

Materials and methods

Patients with PC were recruited and grouped according to their specific genotypes of rs55829688 and rs145204276. Kaplan–Meier overall survival curves were calculated and compared among different groups. Real‐time polymerase chain reaction (RT‐PCR), western blot, and immunohistochemistry (IHC) assays were conducted to examine the expression of different factors involved in PC. And computational analyses and luciferase assays were conducted to clarify the regulatory relationships among the above factors. MTT (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide), flow cytometry, and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays were used to evaluate cell viability and apoptosis.

Results

The expression of GAS5, PDCD4, PTEN, and AKT was decreased gradually in the order of patient Group 1–4, whereas the expression of microRNA‐21 (miR‐21) and miR‐1284 showed an opposite trend. GAS5 was identified to target miR‐21 and miR‐1284, whereas miR‐21 and miR‐1284 regulated the expression of PDCD4/PTEN and AKT, respectively. Moreover, the GAS5/miR‐21/PDCD4/PTEN and GAS5/miR‐1284/AKT signaling pathway was found to be closely related to the tumorigenesis of PC.

Conclusions

GAS5 SNPs affected the survival rate and prognosis in patients with PC via regulating the expression of miR‐21/miR‐1284, which in turn affected the expression of PDCD4, PTEN, and AKT. GAS5 downregulated the expression of miR‐21/miR‐1284, thus leading to the elevated expression of key regulators of apoptosis. Therefore, the GAS5 SNPs may be used as key indicators for the diagnosis and prognosis prediction of PC.
Zebrafish znfl1s regulate left‐right asymmetry patterning through controlling the expression of fgfr1a
Authors: Li Jingyun , Gao Feng , Zhao Yingmin , He Luqingqing , Huang Yun , Yang Xiaojing , Zhou Yahui , Yu Lingling , Zhao Qingshun , Dong Xiaohua
Published: October 2018

Proper left‐right (LR) axis establishment is critical for organogenesis in vertebrates. Previously, we reported that zinc finger transcription factors zinc finger transcription factor 1 (znfl1s) are expressed in the tailbud and axial mesoderm in zebrafish. However, a role of
znfl1s in LR axis development has not been demonstrated. Here, we discovered that the knockdown of
znfl1s using morpholino (MO) in whole embryos or dorsal forerunner cells (DFCs) interrupted LR asymmetry and normal development of the heart, liver, and pancreas. Whole‐embryo knockdown of
znfl1s by MO or clustered regularly interspaced short palindromic repeat (CRISPR) interference (CRISPRi) resulted in the absent expression of nodal gene
spaw and Nodal signaling‐related genes
lft1,
lft2, and
pitx2c in the left lateral plate mesoderm (LPM), and Spaw, Lft1, Lft2, and Pitx2c play important roles in LR axis development in zebrafish. However, specific knockdown of
znfl1s in DFCs resulted in random expression of
spaw,
lft1,
lft2, and
pitx2c. Knockdown of
znfl1s led to abnormal cilia formation by the downregulation of
fgfr1a and
foxj1a expression. The expression of
spaw,
lft1,
lft2, and
pitx2c was partially rescued by the overexpression of
fgfr1a mRNA in
znfl1s morphants. Taken together, our results suggest that
znfl1s regulate laterality development in zebrafish embryos through controlling the expression of
fgfr1a.
Spindlin1 alters the metaphase to anaphase transition in meiosis I through regulation of BUB3 expression in porcine oocytes
Authors: Choi Jeong‐Woo , Zhou Wenjun , Nie Zheng‐Wen , Niu Ying‐Jie , Shin Kyung‐Tae , Cui Xiang‐Shun
Published: October 2018

Spindlin 1 (SPIN1), which contains Tudor‐like domains, regulates maternal transcripts via interaction with a messenger RNA (mRNA)‐binding protein. SPIN1 is involved in tumorigenesis in somatic cells and is highly expressed in cancer cells. Nevertheless, the role of SPIN1 in porcine oocyte maturation remains totally unknown. To explore the function of SPIN1 in porcine oocyte maturation, knockdown, and overexpression techniques were used. SPIN1 mRNA was identified in maternal stages ranging from GV to MII. SPIN1 was localized in the cytoplasm and to chromosomes during meiosis. SPIN1 knockdown accelerated first polar body extrusion. Oocytes with overexpressed SPIN1 were arrested at the MI stage. SPIN1 depletion caused meiotic spindle defects and chromosome instability. The BUB3 signal was investigated, confirming that SPIN1 affects the stability of Bub3 mRNA as well as BUB3 expression. Further, overexpression of SPIN1 inhibited the degradation and regulation of G2/mitotic‐specific cyclin‐B1. In summation, SPIN1 regulates the meiotic cell cycle by modulating the activation of the spindle assembly checkpoint.
Long noncoding RNA APTR contributes to osteosarcoma progression through repression of miR‐132‐3p and upregulation of yes‐associated protein 1
Authors: Guan Hongya , Shang Guowei , Cui Yuanbo , Liu Jiu , Sun Xiaoya , Cao Wei , Wang Yisheng , Li Yuebai
Published: October 2018

A growing amount of evidence has shown that long noncoding RNAs (lncRNAs) play crucial roles in osteosarcoma (OS). However, little knowledge is available about the functional roles and molecular mechanisms of lncRNA Alu‐mediated p21 transcriptional regulator (APTR) in OS. Herein, APTR expression was demonstrated to be significantly upregulated in OS tumor tissues and four OS cell lines (including MG63, 143B, Saos‐2, and HOS) compared with the adjacent tissues and human osteoblast cell line hFOB1.19, respectively. We confirmed miR‐132‐3p to be a target for APTR, and its expression was demonstrated to be inhibited by APTR. In functional terms, knockdown of APTR and overexpression of miR‐132‐3p both, remarkably repressed human OS cell proliferation, invasion and migration, and induced apoptosis. Also, Yes‐associated protein 1 (YAP1) was determined as an inhibitory target of miR‐132‐3p. Moreover, our findings demonstrated that the repression of YAP1 protein expression and the suppression of Ki‐67, MMP9, and Bcl2 expression induced by APTR knockdown required increased miR‐132‐3p. Thus, APTR contributed to OS progression through repression of miR‐132‐3p and upregulation of YAP1 expression. Therefore, we have uncovered a novel regulatory mechanism by which the APTR/miR‐132‐3p/YAP1 axis can regulate OS progression.
Identification of TAF1, HNF4A, and CALM2 as potential therapeutic target genes for liver fibrosis
Authors: Ji Dong , Chen Guo‐Feng , Wang Jin‐Cheng , Cao Li‐Hua , Lu Fengmin , Mu Xiao‐Xin , Zhang Xiao‐Yu , Lu Xiao‐Jie
Published: October 2018

The molecular mechanism of liver fibrosis caused by hepatitis C virus (HCV) is not clear. The aim of this study is to understand the molecular mechanism of liver fibrosis induced by HCV and to identify potential therapeutic targets for hepatic fibrosis. We analyzed gene expression patterns between high liver fibrosis and low liver fibrosis samples, and identified genes related to liver fibrosis. We identified TAF1, HNF4A, and CALM2 were related to the development of liver fibrosis. HNF4A is important for hepatic fibrogenesis, and upregulation of HNF4A is an ideal choice for treating liver fibrosis. The gene expression of CALM2 is significantly lower in liver fibrosis samples than nonfibrotic samples. TAF1 may serve as a biomarker for liver fibrosis. The results were further validated by an independent data set GSE84044. In summary, our study described changes in the gene expression during the occurrence and development of liver fibrosis. The TAF1, HNF4A, and CALM2 may serve as novel targets for the treatment of liver fibrosis.
Overview of CD24 as a new molecular marker in ovarian cancer
Authors: Tarhriz Vahideh , Bandehpour Mojgan , Dastmalchi Siavoush , Ouladsahebmadarek Elaheh , Zarredar Habib , Eyvazi Shirin
Published: October 2018

Ovarian cancer (OC) is the fifth leading cause of cancer‐related death among women. The high mortality rate is due to lack of early symptoms, late diagnosis, limited treatment options, and also emerging of drug resistance. Todays, molecular markers have become promising in tumor‐targeted therapy. Several molecular markers have been known in OC immunotherapy. Identification of the specific molecular markers with prognostic significance is interested. CD24 is a small sialoglycoprotein which is localized in lipid rafts through its glycosylphosphatidylinositol (GPI) anchor. It has been reported that CD24 is overexpressed in many cancers including OC. Also, CD24 is identified as a cancer stem cell marker in OC. The CD24 expression is associated with the development, invasion, and metastasis of cancer cells. The exact role of CD24 in cancer cells is not clearly understood. Recently, CD24 has been identified as an independent prognostic marker of survival in patients with OC. In this study, we reviewed the molecular targets in OC immune‐targeted therapy and also presented an overview of the new molecular marker CD24 and its association with the OC by reviewing the recent literature.
Oleuropein inhibits migration ability through suppression of epithelial‐mesenchymal transition and synergistically enhances doxorubicin‐mediated apoptosis in MCF‐7 cells
Authors: Choupani Jalal , Alivand Mohammad R. , M. Derakhshan Sima , Zaeifizadeh Mohammad , S. Khaniani Mahmoud
Published: October 2018

Distinct metastasis is one of the main causes of breast cancer (BC)‐related mortality and epithelial‐mesenchymal transition (EMT) is a primary step in metastasis dissemination. On the other hand, doxorubicin (DOX) is an effective chemotherapeutic agent against BC; unfortunately, its clinical use is limited by dose‐dependent side effects. Therefore, extensive efforts have been dedicated to suppressing metastasis of BC and also to overcome DOX side effects together with keeping its antitumor efficacy. Studies supported the role of oleuropein (OLEU) in reducing DOX‐induced side effects besides its antitumor actions. In this study, the antimigratory effect of OLEU was assessed and real‐time PCR (RT‐PCR) was used to detect OLEU effect on the expression level of EMT markers, in MCF‐7 cells. The cytotoxic effect of OLEU and DOX was assessed by MTT assay, whereas the ratio of apoptosis was investigated by flow cytometry. The results showed that migration ability of MCF‐7 cells remarkably decreased in OLEU treated group and RT‐PCR results showed that OLEU may exert its antimigratory action by suppressing EMT through downregulation of sirtuin1 (SIRT1). Also, the results indicated that both OLEU and DOX were cytotoxic to MCF‐7 cells, whereas DOX‐OLEU cotreatment led to additive cytotoxicity and apoptosis rate. This study provides evidence regarding the suppressive role of OLEU on MCF‐7 cells migration ability through suppression of EMT, and for the first time, it was proposed that SIRT1 downregulation can be involved in the OLEU antimigratory effect. Also, the findings demonstrated that OLEU can reduce DOX‐induced side effects by reducing its effective dose.
LIN28A activates the transcription of NANOG in dairy goat male germline stem cells
Authors: Ma Fanglin , Du Xiaomin , Wei Yudong , Zhou Zhe , Clotaire Daguia Zambe John , Li Na , Peng Sha , Li Guangpeng , Hua Jinlian
Published: October 2018

LIN28A serves as a crucial marker of dairy goat male germline stem cells (GmGSCs). In our previous study, we demonstrated that
LIN28A promotes proliferation, self‐renewal, and maintains the stemness of GmGSCs. Here, we found that
LIN28A could activate the transcription of
NANOG in a
let‐7g independent manner. We cloned the 5′ upstream of two
NANOG genes which were located on chromosome 15 (
NANOG‐ch15) and chromosome 5 (
NANOG‐ch5), respectively, and then examined their promoter activities and promoter methylation levels. Results showed that
NANOG‐ch15 is a pseudogene whereas
NANOG‐ch5 is active in
Capra hircus. Bioinformatics analysis indicated that the 5′ upstream region of
NANOG‐ch5 does not have typical CpG islands but contains several CG enrichment regions and several
LIN28A binding sites. Deletion analysis suggested that
NANOG‐ch5 promoter can be activated by
LIN28A directly binding to the site ‐210 but not by the indirect effect from the inhibition of
let‐7g, which is known to be downregulated by
LIN28A. Mechanistically,
LIN28A recruits and interacts with 5‐methylcytosine‐dioxygenase Ten‐Eleven translocation 1 (TET1) to
NANOG‐ch5 gene promoter binding sites to orchestrate 5‐methylcytosine and 5‐hydroxymethylcytosine dynamics. These results revealed the role of
LIN28A in
NANOG transcriptional regulation via epigenetic DNA modifications to maintain the stemness of GmGSC.
Physiological and structural changes of the lung tissue in male albino rat exposed to immobilization stress
Authors: Saber Entesar Ali , Abd El Aleem Mohammed Mustafa , Aziz Neven Makram , Ibrahim Randa Ahmed
Published: October 2018

In case of a life‐threatening, stressful event, the body prepares for an emergency. Indeed, the lung is unique in which alveolar cells are constantly exposed to physical and chemical stresses. This study aimed to study the impact of immobilization stress on the blood–air barrier and how it initiate and maintain an inflammatory response, plus determining the resolution of lung inflammation and repair. There was a significant increase in the plasma levels of stress markers “corticosterone and catecholamines” with a decrease in surfactant protein A (a lung‐injury marker). Chronic stress produced a significant increase in the pulmonary oxidative and inflammatory markers malondialdehyde, tumor necrosis factor α, and induced nitric oxide synthase when compared with that of acute stress. Both stresses provoked marked pulmonary morphological and ultrastructural changes with a significant increase in caspase‐3 immunoexpression. There was increasing evidence of lung’s capacity for repair. This process involved edema resolution, cell proliferation, and tissue remodeling in improving the lung‐injury, oxidative, and inflammatory markers.