bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular insights into the effect L17A/F19A double mutation on the structure and dynamics of Aβ40: A molecular dynamics simulation study
Authors: Saini Rajneet Kaur , Shuaib Suniba , Goyal Deepti , Goyal Bhupesh
Published: August 2018

The aggregation of amyloid‐β (Aβ) peptide has been associated with the pathogenesis of Alzheimer disease. The recent studies highlighted that L17A/F19A double mutation increases the structural stability of Aβ40 and diminish Aβ40 aggregation. However, the underlying effect of L17A/F19A double mutation on the Aβ40 structure and dynamics remain elusive. In this regard, the influence of L17A/F19A double mutation on the structure and dynamics of Aβ40 was investigated using all‐atom molecular dynamics (MD) simulation. MD simulation reveals that mechanism behind modulation of Aβ40 aggregation is associated with a decrease in the β‐sheet content and dynamics of the salt bridge D23‐K28. The secondary structure analysis highlight more abundant α‐helix content in the central hydrophobic core and C‐terminal region of Aβ40 upon L17A/F19A double mutation that is consistent with circular dichroism (CD) results. The free‐energy landscape reveal that coil conformation is the most dominant conformation in Aβ40 whereas the helical conformation is the most‐populated and energetically favorable conformation in Aβ40(L17A/F19A). MD simulation, in accord with the experiment, highlight that L17A/F19A double mutation diminish Aβ40 aggregation as the population of the fibril‐prone state substantially decreased. The present study, in conjunction with experiment, highlight that L17 and F19 are the critical residues involved in the conformational change that triggers a neurotoxic cascade of Aβ40. Overall, MD simulation provides key structural and physical insights into the reduced Aβ40 aggregation upon L17A/F19A double mutation and an atomic picture of the L17A/F19A‐mediated conformational changes in Aβ40.
Retracted: MicroRNA‐136 promotes lipopolysaccharide‐induced ATDC5 cell injury and inflammatory cytokine expression by targeting myeloid cell leukemia 1
Authors: Wang Yang , Kong Daliang
Published: August 2018

Osteoarthritis is the most frequent chronic bone and joint diseases in older populations all over the world. Lipopolysaccharide (LPS)‐induced murine chondrogenic ATDC5 cell model has been widely used for testing new osteoarthritis therapeutic targets. This study aimed to explore the effects of microRNA‐136 (miR‐136) on LPS‐induced ATDC5 cell injury and inflammatory cytokine expression, as well as underlying potential mechanism. We found that LPS remarkably inhibited ATDC5 cell viability, induced ATDC5 cell apoptosis, and upregulated the expression of inflammatory cytokines, including interleukin 1β (IL‐1β), IL‐6, IL‐8, and tumor necrosis factor α (TNF‐α; P < .01 or  < .001). Moreover, LPS obviously upregulated the expression of miR‐136 in ATDC5 cells (P < .05). Overexpression of miR‐136 markedly exacerbated the LPS‐induced ATDC5 cell viability inhibition, cell apoptosis enhancement, and inflammatory cytokine expression (P < .05), and suppression of miR‐136 had opposite effects (P < .05). Myeloid cell leukemia 1 (Mcl‐1) was a direct target gene of miR‐136, which participated in the effect of miR‐136 on LPS‐induced ATDC5 cell inflammatory injury. Overexpression of Mcl‐1 alleviated the LPS‐induced inactivation of Wnt/β‐catenin and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways, while suppression of Mcl‐1 had opposite effects. To conclude, this study verified that miR‐136 promoted LPS‐induced ATDC5 cell injury and inflammatory cytokine expression by targeting Mcl‐1, and Mcl‐1 was involved in the regulatory effects of LPS on Wnt/β‐catenin and JAK/STAT signaling pathways in ATDC5 cells.
Role of microRNA‐410 in molecular oncology: A double edged sword
Authors: Wen Ru , Umeano Afoma C. , Essegian Derek J. , Sabitaliyevich Uteuliyev Yerzhan , Wang Kai , Farooqi Ammad Ahmad
Published: August 2018

MicroRNAs (miRNAs) are short non‐coding single‐stranded RNAs, which play significant roles in the regulation of a myriad of biological processes. Overwhelmingly increasing high‐impact research has also deepened our understanding about the central role of miRNAs in cancer development, metastatic spread, and development of resistance against various drugs. Recent studies have identified miRNAs that regulate RNA expression/processing and posttranscriptional expression of important oncogenes and tumor suppressors. Rapidly emerging experimentally verified data have started to shed light on the significance of miRNAs as biomarkers for diagnostic, prognostic, and monitoring purposes. Next‐generation sequencing and DNA microarray technologies have helped us tremendously in the identification of miRNA and mRNA signatures in different cancers and their subtypes on a genome‐wide scale. It is being increasing realized that miRNAs have diametrically opposite roles in different cancers. miR‐410 is context‐dependently involved in positive and negative regulation of cancers. miR‐410 negatively regulates BAK1, CETN3, and BRD7 to promote cancer. However, miR‐410 effectively targetes c‐MET, AGTR1, and SNAIL to suppress cancer. In this review, we will comprehensively summarize most recent evidence available related to the “split personality” of miR‐410 in different cancers.
Emerging themes of regulation of oncogenic proteins by Solanum nigrum and its bioactive molecules in different cancers
Authors: Butt Ghazala , Romero Mirna Azalea , Tahir Fatima , Farooqi Ammad Ahmad
Published: August 2018

Research over the decades has sequentially and systematically provided a near‐complete resolution of multifaceted and therapeutically challenging nature of cancer. Drug discovery from plants has enjoyed a renaissance in the past few years. Natural products have provided many of the lead structures, which are currently being used as templates for the design and synthesis of novel compounds with biologically enhanced properties. With the maturity and diversification of technologies, there is a growing need to design high‐throughput functional assays for the evaluation of the myriad of compounds being catalogued. This review sheds light on the tumor suppressive properties of Solanum nigrum and its bioactive ingredients. Several worthy of mention include uttroside B, solanine, solamargine, and physalins, which have been tested for efficacy in cancer cell lines and xenografted mice. We have summarized the most recent findings related to S. nigrum‐mediated regulation of intracellular protein network in different cancers. α‐Solanine, an active component of S. nigrum, is involved in the regulation of microRNA‐21 (miRNA‐21) (oncogenic) and miRNA‐138 (tumor suppressor) in prostate cancer. However, this is the only available evidence that gives us a clue related to the tumor suppressive effects exerted by components of S. nigrum at a posttranscriptional level. More interestingly, S. nigrum and its components exerted inhibitory effects on different pathways including PI3K/AKT, JAK‐STAT, VEGF/VEGFR, and matrix metalloproteinases in different cancers. We also provide an overview of new tools, methodologies, and approaches, which will allow researchers to extract as much information as possible out of the tremendous data sets currently being generated. The use of computational tools will be helpful in processing structurally complex natural products and also in prediction of their macromolecular targets.
Immunomodulatory effects of mesenchymal stem cell–derived exosomes on experimental type‐1 autoimmune diabetes
Authors: Nojehdehi Shahrzad , Soudi Sara , Hesampour Ardeshir , Rasouli Shima , Soleimani Masoud , Hashemi Seyed Mahmoud
Published: August 2018

Exosomes derived from adipose tissue‐derived mesenchymal stem cells (AD‐MSCs) have immunomodulatory effects of T‐cell inflammatory response and reduction of clinical symptoms on streptozotocin‐induced of the type‐1 diabetes mellitus (T1DM). Beside control group and untreated T1DM mice, a group of T1DM mice was treated with intraperitoneal injections of characterized exosomes derived from autologous AD‐MSCs. Body weight and blood glucose levels were measured during the procedure. Histopathology and immunohistochemistry were used for evaluation of pancreatic islets using hemotoxylin and eosin (H&E) staining and anti‐insulin antibody. Isolated splenic mononuclear cells (MNCs) were subjected to splenocytes proliferation assay using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide, immunophenotyping of regulatory T cells and cytokines. A significant increase in the levels of interleukin‐4 (IL‐4), IL‐10, and transforming growth factor‐β, and a decrease in the levels of IL‐17 and interferon‐γ in concordance with the significant increase in the Treg cell ratio in splenic MNCs (P < 0.05) was shown in T1DM mice treated with AD‐MSC's exosomes as compared to T1DM untreated mice. This amelioration of autoimmune reaction after treatment of T1DM mice with the AD‐MSC exosomes was confirmed with a significant increase in islets using H&E staining and Immunohistochemistry analyses. As expected, body weight, blood glucose levels in a survival of T1DM mice treated with AD‐MSC's exosomes were maintained stable in comparison to untreated T1DM mice. It can be concluded that AD‐MSC's exosomes exert ameliorative effects on autoimmune T1DM through increasing regulatory T‐cell population and their products without a change in the proliferation index of lymphocytes, which makes them more effective and practical candidates.
Dynamic thiol/disulfide homeostasis in patients with lichen planus
Authors: Kalkan Göknur , Emre Selma , Alisik Murat , Aktaş Akın , Baran Pervin
Published: August 2018

Objective

Lichen planus (LP) is an autoimmune inflammatory disease of the mucocutaneous tissue, whose exact pathological course remains unclear. Abnormal thiol/disulfide homeostasis has been postulated to be responsible for a number of diseases predominated by chronic inflammation. To be able to contribute complicated and unclear pathogenesis of LP, we aimed to investigate dynamic thiol/disulfide homeostasis in patients with LP, using an original automated method developed by Erel and Neselioglu in this study.

Methods

The study group consisted of 81 unrelated patients with LP and 80 unrelated healthy controls with no LP lesions in their personal history or on clinical examination. Thiol/disulphide homeostasis tests have been measured with a novel automatic spectrophotometric method developed and the results have been compared statistically.

Results

Native thiol and total thiol levels were found as significantly higher in patients with LP than the control group (P = 0.026 and 0.035, respectively). There was no significant difference between the disulfide levels of the patients with LP and the control group.

Conclusions

We provide evidence that that thiol/disulphide homeostasis impaired in favor of thiol levels in LP patients compared to the control group based on the data of our study. To the best of our knowledge, the present study is the first examination on the correlation between thiol and disulfide homeostasis in patients with LP.
RETRACTED: Reversible permeabilization of the mitochondrial membrane promotes human cardiomyocyte differentiation from embryonic stem cells
Authors: Ghiasi Parisa , Hosseinkhani Saman , Ansari Hassan , Aghdami Nasser , Balalaei Saeed , Pahlavan Sara , Baharvand Hossein
Published: August 2018

Cell death and differentiation appear to share similar cellular features. In this study, we aimed to investigate whether differentiation and mitochondrial cell death use a common pathway. We assessed the hallmarks of apoptosis during cardiomyocyte differentiation of human embryonic stem cells and found remarkable changes in P53, reactive oxygen species, apoptotic protease‐activating factor 1, poly[ADP‐ribose]polymerase 1, cellular adenosine triphosphate, and mitochondrial complex I activity. Furthermore, we observed reversible mitochondrial membrane permeabilization during cardiomyocyte differentiation accompanied by reversible loss of mitochondrial membrane potential, and these changes coincided with the fluctuating patterns of cytosolic cytochrome c accumulation and subsequent caspase‐9 and ‐3/7 activation. Moreover, the use of apoptosis inhibitors (BCL2‐associated X protein [BAX] inhibitor and caspase‐3/7 inhibitor) during differentiation impaired cardiomyocyte development, resulting in substantial downregulation of T, MESP1, NKX2.5, and α‐MHC. Additionally, although the expression of specific differentiation markers (T, MESP1, NKX2.5, MEF2C, GATA4, and SOX17) was enhanced in doxorubicin‐induced human embryonic stem cells, the stemness‐specific markers (OCT4 and NANOG) showed significant downregulation. With increasing doxorubicin concentration (0.03–0.6 µM; IC50 = 0.5 µM), we observed a marked increase in the expression of mesoderm and endoderm markers. In summary, we suggest that reversible mitochondrial outer membrane permeabilization promotes cardiomyocyte differentiation through an attenuated mitochondria‐mediated apoptosis‐like pathway.
Inflammation stimulates hypoxia‐inducible factor‐1α regulatory activity in 3T3‐L1 adipocytes with conditioned medium from lipopolysaccharide‐activated RAW 264.7 macrophages
Authors: Lopez‐Pascual Amaya , Lorente‐Cebrián Silvia , Moreno‐Aliaga María J. , Martinez J. Alfredo , González‐Muniesa Pedro
Published: August 2018

Obesity is a multifactorial, chronic, inflammatory disease that involves different processes, such as adipose tissue hypoxia. The aim of the current study was to characterize the effects of conditioned medium (CM) from lipopolysaccharide (LPS)‐activated macrophages on the regulation of hypoxia‐inducible factor 1α (HIF‐1α)‐related genes in murine adipocytes. For the in vitro analyses, 3T3‐L1 murine adipocytes (9 days postdifferentiation) were incubated either in CM (25% medium of RAW 264.7 murine macrophages with 24 hr 500 ng/ml LPS), LPS at 500 ng/ml, or hypoxia (Hx; 1% O2, 94% N2, 5% CO2) for 24 hr. For the in vivo experiments, mice were fed a high‐fat diet. Both epididymal white adipose tissue (eWAT) and adipocytes in CM showed upregulation of Glut1, Mcp1, Il10, Tnf, and Il1b. The secretion of IL‐6, TNF‐α, and MCP‐1 was also increased in CM‐treated adipocytes. Moreover, increased levels of HIF‐1α subunit and nuclear factor kappa B p65 were found after CM treatment, linking Hx, and inflammation. HIF‐1α directly bound vascular endothelial growth factor A (Vegfa) and uncoupling protein 2 (Ucp2) genes, up‐ and downregulating its expression, respectively. Furthermore, the oxygen consumption rate was 30% lower in CM. The siRNA knockdown of mammalian target of rapamycin (Mtor) reversed the induction of HIF‐1α found in CM. The macrophage infiltration simulated through CM seems to be a similar environment to an abnormally enlarged eWAT. We have evidenced that HIF‐1α plays a regulatory role in the expression of Vegfa and Ucp2 in CM. Finally, the inhibition of the mTOR pathway prevented the HIF‐1α activation induced by CM. The involvement of HIF‐1α under proinflammatory conditions provides insight into the origins of Hx in obesity.
The chick embryo chorioallantoic membrane as an in vivo experimental model to study human neuroblastoma
Authors: Ribatti Domenico , Tamma Roberto
Published: August 2018

The chick embryo chorioallantoic membrane (CAM) has long been a favored system for the study of tumor angiogenesis because at the stage of development when generally tumor grafts are placed (6–10 days of incubation), the chick’s immunocompetent system is not fully developed and the conditions for rejection have not yet been established. All studies for mammalian neoplasms, including neuroblastoma, have used tumor cell lines, tumor bioptic specimens, cell suspensions derived from tumors, and mouse tumor xenografts bioptic specimens. CAM can also be used to study the effects of antiangiogenic molecules on tumor cell suspensions of tumor bioptic specimens. This review article summarizes and discusses the literature data on the use of the CAM as an in vivo experimental model to study human neuroblastoma.
Molecular mechanism of Notch signaling with special emphasis on microRNAs: Implications for glioma
Authors: Yan Du , Hao Chen , Xiao‐feng Li , Yu‐chen Lu , Yu‐bin Feng , Lei Zhang
Published: August 2018

Glioma is the most aggressive primary brain tumor and is notorious for resistance to chemoradiotherapy. Although its associated mechanisms are still not completely understood, Notch signaling, an evolutionarily conserved pathway, appears to be the key processes involved. Nevertheless, its mechanisms are sophisticated, due to a variety of targets and signal pathways, especially microRNA. MicroRNAs, which are small noncoding regulatory RNA molecules, have been proposed as one of the key mechanisms in glioma pathogenesis. Among the known glioma associated microRNA, microRNA‐129, microRNA‐34 family, and microRNA‐326 have been shown to influence the progress of glioma through Notch signaling. Evidence also indicates that recurrence is due to development or persistence of the glioma stem‐like cells and active angiogenesis, which are tightly regulated by a variety of factors, including Notch signaling. In this review, we summarize the recent progress regarding the functional roles of Notch signaling in glioma, including Notch ligand, microRNA, intracellular crosstalk, glioma stem‐like cells and active angiogenesis and explore their clinical implications as diagnostic or prognostic biomarkers and molecular therapeutic targets for glioma.
Postnatal deletion of Alk5 gene in meniscal cartilage accelerates age‐dependent meniscal degeneration in mice
Authors: Wang Quan , Tan Qiaoyan , Xu Wei , Kuang Liang , Zhang Bin , Wang Zuqiang , Ni Zhenhong , Su Nan , Jin Min , Li Can , Jiang Wanling , Huang Junlan , Li Fangfang , Zhu Ying , Chen Hangang , Du Xiaolan , Chen Di , Deng Chuxia , Qi Huabing , Xie Yangli , Chen Lin
Published: August 2018

Activation of transforming growth factor‐β (TGF‐β) signaling has been used to enhance healing of meniscal degeneration in several models. However, the exact role and molecular mechanism of TGF‐β signaling in meniscus maintenance and degeneration are still not understood due to the absence of in vivo evidence. In this study, we found that the expression of activin receptor‐like kinases 5 (ALK5) in the meniscus was decreased with the progression of age and/or osteoarthritis induced meniscal degeneration. Col2α1 positive cells were found to be specifically distributed in the superficial and inner zones of the anterior horn, as well as the inner zone of the posterior horn in mice, indicating that Col2α1‐CreERT2 mice can be a used for studying gene function in menisci. Furthermore, we deleted Alk5 in Col2α1 positive cells in meniscus by administering tamoxifen. Alterations in the menisci structure were evaluated histologically. The expression levels of genes and proteins associated with meniscus homeostasis and TGF‐β signaling were analyzed by quantitative real‐time PCR analysis (qRT‐PCR) and immunohistochemistry (IHC). Our results revealed severe and progressive meniscal degeneration phenotype in 3‐ and 6‐month‐old Alk5 cKO mice compared with Cre‐negative control, including aberrantly increased hypertrophic meniscal cells, severe fibrillation, and structure disruption of meniscus. qRT‐PCR and IHC results showed that disruption of anabolic and catabolic homeostasis of chondrocytes may contribute to the meniscal degeneration phenotype observed in Alk5 cKO mice. Thus, TGF‐β/ALK5 signaling plays a chondro‐protective role in menisci homeostasis, in part, by inhibiting matrix degradation and maintaining extracellular matrix proteins levels in meniscal tissues.
MiR‐139 promotes differentiation of bovine skeletal muscle‐derived satellite cells by regulating DHFR gene expression
Authors: Zhou Shuang , Li Shuang , Zhang Weiwei , Tong Huili , Li Shufeng , Yan Yunqin
Published: August 2018

MicroRNAs play an important regulatory role in the proliferation and differentiation of skeletal muscle‐derived satellite cells (MDSCs). In particular, miR‐139 can inhibit tumor cell proliferation and invasion, and its expression is down‐regulated during C2C12 myoblast differentiation. The aim of this study was thus to examine the effect and potential mechanism of miR‐139 in bovine MDSCs. The expression of miR‐139 was found to be significantly increased during bovine MDSC differentiation by stem‐loop reverse transcription‐polymerase chain reaction amplification. Statistical analysis of the myotube fusion rate was done through immunofluorescence detection of desmin, and western blotting was used to measure the change in protein expression of the muscle differentiation marker genes MYOG and MYH3. The results showed that the miR‐139 mimic could enhance the differentiation of bovine MDSCs, whereas the inhibitor had the opposite effect. By using the dual‐luciferase reporter system, miR‐139 was found to target the 3′‐untranslated region of the dihydrofolate reductase (DHFR) gene and regulate its expression. In addition, the expression of miR‐139 was found to be regulated by its host gene phosphodiesterase 2A (PDE2A) via inhibition of the latter by CRISPR interference (CRISPRi). Overall, our findings indicate that miR‐139 plays an important role in regulating the differentiation of bovine MDSCs.
In vivo study: Th1–Th17 reduction in pristane‐induced systemic lupus erythematosus mice after treatment with tolerogenicLactobacillusprobiotics
Authors: Mardani Fatemeh , Mahmoudi Mahmoud , Esmaeili Seyed‐Alireza , Khorasani Sahar , Tabasi Nafiseh , Rastin Maryam
Published: August 2018

Uncontrolled inflammation in systemic lupus erythematosus (SLE) could cause dysfunction in multiple organs. T helper 17 (Th17) cells are a main branch of inflammatory responses in the pathogenesis of SLE, and by producing interleukin 17 (IL‐17), represent a major functional tool in the progression of inflammation. Animal models provide a special field for better studies of the pathogenesis of diseases. Tolergenic probiotics could decrease inflammation in autoimmune diseases by modulating the immune system and maintaining homeostasis. The aim of this project was to evaluate the effects ofLactobacillus rhamnosusandLactobacillus delbrueckiion Th17 cells and their related mediators in a pristane‐induced BALB/c mice model of SLE. The mice were divided into pretreatment groups, which received probiotics or prednisolone at Day 0, and treatment groups, which received probiotics and prednisolone 2 months after injection. The presence of antinuclear antibody (ANA), anti‐double‐stranded DNA (anti‐dsDNA), and anti‐ribonucleoprotein (anti‐RNP) and lipogranuloma was evaluated; also, the population of Th1–Th17 cells as well as interferon γ (IFN‐γ), IL‐17, and IL‐10 levels, and the expression of RAR‐related orphan related receptor gamma (RORγt) and IL‐17 were determined. We observed that probiotics and prednisolone could delay SLE in pretreatment and treatment mice groups, with a reduction in ANA, anti‐dsDNA, anti‐RNP, and mass of lipogranuloma. Probiotics and prednisolone decreased the population of Th1–Th17 cells and reduced IFN‐γ and IL‐17 as inflammatory cytokines in the pretreatment and treatment groups in comparison with SLE‐induced mice. Our results indicated that, due to their anti‐inflammatory properties and reduction of Th17, Th1, and cytotoxic T lymphocyte (CTL) cells, the use of these probiotics could probably represent a new tool for the better management of SLE.
CSDC2, a cold shock domain RNA‐binding protein in decidualization
Authors: Vallejo Griselda , Mestre‐Citrinovitz Ana Cecilia , Winterhager Elke , Saragüeta Patricia Esther
Published: August 2018

RNA‐binding proteins (RBPs) have been described for cancer cell progression and differentiation, although there is still much to learn about their mechanisms. Here, using in vivo decidualization as a model, we describe the role of RBP cold shock domain containing C2 (CSDC2) in the endometrium. Csdc2 messenger RNA expression was differentially regulated depending on time and areas of decidua development, with the most variation in antimesometrium (AM) and, to a lesser degree, in the junctional zone (JZ). Immunohistochemistry of CSDC2 showed a preferentially cytoplasmic localization at AM and JZ, and nuclear localization in underneath myometrium and mesometrium (M). Cytoplasmic localization coincided with differentiated, DESMIN‐marked areas, while nuclear localization coincides with proliferative zones. Uterine suppression of CSDC2 through intrauterine‐injected‐specific small interfering RNA (siRNA) led to abnormal decidualization in early pregnancy, with more extended antimesometrial area and with poor M development if compared with control siRNA‐injected animals. These results suggest that CSDC2 could be a regulator during decidua development.
Long noncoding RNA GAS5 regulates the proliferation, migration, and invasion of glioma cells by negatively regulating miR‐18a‐5p
Authors: Liu Qian , Yu Wei , Zhu Shujuan , Cheng Ke , Xu Hong , Lv Yalan , Long Xuan , Ma Lan , Huang Juan , Sun Shanquan , Wang Kejian
Published: August 2018

Intention

Long noncoding RNAs, transcribed from a recently discovered class of noncoding genes, may play a critical role in regulating cellular processes, such as cell proliferation and apoptosis, as well as in cancer progression and metastasis. We previously detected the induction of growth arrest–specific 5 (GAS5) during glioma cell death. However, the function and underlying mechanism of GAS5 in human gliomas remain to be elucidated.

Methods

Cell proliferation was detected using CellTiter 96® AQueous Non‐Radioactive Cell Proliferation Assay (MTS) and tumorigenicity assay in nude mice. Wound‐healing assay and transwell assay were utilized to examine the effects of GAS5 expression on glioma cells migration and invasion. In situ hybridization (ISH) was performed to evaluate GAS5 and microRNA (miR)‐18a‐5p levels in tissue microarrays. The relationship between GAS5 and miR‐18a‐5p was evaluated by quantitative reverse‐transcription polymerase chain reaction and RNA precipitation.

Results

In this study, we demonstrated that overexpression of GAS5 inhibits malignant phenotypes in glioma cells, including proliferation, migration, and invasion, whereas GAS5 knockdown enhances these phenotypes. We further observed Argonaute 2–dependent reciprocal repression between GAS5 and miR‐18a‐5p in glioma cells. Downregulation of GAS5 and upregulation of miR‐18a‐5p were observed in glioma tissue microarrays relative to normal brain tissue by ISH. By deletion analysis, we identified one miR‐18a‐5p‐binding site within exon 2 of GAS5 that is partially responsible for the tumor‐suppressor functions of GAS5.

Conclusion

Taken together, our findings suggest that GAS5 is a tumor suppressor in human gliomas that acts in part by repressing miR‐18a‐5p.
Anticancer effect of SZC015 on pancreatic cancer via mitochondria‐dependent apoptosis and the constitutive suppression of activated nuclear factor κB and STAT3 in vitro and in vivo
Authors: Song Yanlin , Gao Lei , Tang Zhongyuan , Li Hailong , Sun Bin , Chu Peng , Qaed Eskandar , Ma Xiaodong , Peng Jinyong , Wang Shisheng , Hu Min , Tang Zeyao
Published: August 2018

Pancreatic cancer is the fourth leading cause of cancer‐related death worldwide. Advances in therapeutic strategies such as chemotherapy have improved the clinical outcomes for pancreatic cancer patients. However, developing new therapeutic compounds against pancreatic cancer is still urgent due to the poor prognosis. Here, we show that SZC015, an oleanolic acid derivative, exhibits potent inhibitory effect on both pancreatic cancer cells in vitro and the corresponding xenograft tumors in vivo. Mechanistically, the activation of intrinsic apoptosis and G1 phase arrest resulting from mitochondria damage caused by SZC015 contribute significantly to the anticancer effects of SZC015. SZC015 also has remarkably inhibitory effects on the transcription factors that are extensively activated in pancreatic cancer tissues. As a constitutively activated transcription factor in pancreatic cancer, the nuclear factor κB is highly suppressed after SZC015 treatment in vitro or administration in vivo. Based on the bioinformatics analysis of microarray data, we validate that JAK2/STAT3 signaling is indeed activated in the human pancreatic cancer tissues and SZC015 also shows inhibitory effect on this signaling both in vitro and in vivo. These data suggest the potent effects of SZC015 on pancreatic cancer and also provided novel insights into the mechanisms of SZC015 as a new potent candidate for treating pancreatic cancer.
Keratins and epidermolysis bullosa simplex
Authors: Khani Pouria , Ghazi Farideh , Zekri Ali , Nasri Farzad , Behrangi Elham , Aghdam Arad Mobasher , Mirzaei Hamed
Published: August 2018

Keratin intermediate filaments play an important role in maintaining the integrity of the skin structure. Understanding the importance of this subject is possible with the investigation of keratin defects in epidermolysis bullosa simplex (EBS). Nowadays, in addition to clinical criteria, new molecular diagnostic methods, such as next generation sequencing, can help to distinguish the subgroups of EBS more precisely. Because the most important and most commonly occurring molecular defects in these patients are the defects of keratins 5 and14 (KRT5 and KRT14), comprehending the nature structure of these proteins and their involved processes can be very effective in understanding the pathophysiology of this disease and providing new and effective therapeutic platforms to treat it. Here, we summarized the various aspects of the presence of KRT5 and KRT14 in the epidermis, their relation to the incidence and severity of EBS phenotypes, and the processes with which these proteins can affect them.
Senescence and odontoblastic differentiation of dental pulp cells
Authors: Nozu Aoi , Hamano Sayuri , Tomokiyo Atsushi , Hasegawa Daigaku , Sugii Hideki , Yoshida Shinichiro , Mitarai Hiromi , Taniguchi Shuntaro , Wada Naohisa , Maeda Hidefumi
Published: August 2018

Cellular senescence has been suggested to be involved in physiological changes of cytokine production. Previous studies showed that the concentration of tumor necrosis factor‐α (TNF‐α) is higher in the blood of aged people compared with that of young people. So far, the precise effects of TNF‐α on the odontoblastic differentiation of pulp cells have been controversial. Therefore, we aimed to clarify how this cytokine affected pulp cells during aging. Human dental pulp cells (HDPCs) were cultured until reaching the plateau of their growth, and the cells were isolated at actively (young HDPCs; yHDPCs) or inactively (senescent HDPCs; sHDPCs) proliferating stages. sHDPCs expressed senescence‐related molecules while yHDPCs did not. When these HDPCs were cultured in an odontoblast‐inductive medium, both young and senescent cells showed mineralization, but mineralization in sHDPCs was lower compared with yHDPCs. However, the administration of TNF‐α to this culture medium altered these responses: yHDPCs showed downregulated mineralization, while sHDPCs exhibited significantly increased mineralization. Furthermore, the expression of tumor necrosis factor receptor 1 (TNFR1), a receptor of TNF‐α, was significantly upregulated in sHDPCs compared with yHDPCs. Downregulation of TNFR1 expression led to decreased mineralization of TNF‐α‐treated sHDPCs, whereas restored the reduction in TNF‐α‐treated yHDPCs. These results suggested that sHDPCs preserved the odontoblastic differentiation capacity and TNF‐α promoted odontoblastic differentiation of HDPCs with the progress of their population doublings through increased expression of TNFR1. Thus, TNF‐α might exert a different effect on the odontoblastic differentiation of HDPCs depending on their proliferating activity. In addition, the calcification of pulp chamber with age may be related with increased reactivity of pulp cells to TNF‐α.
Mechanics of PAK1—A new molecular player in the arena of skin cancer
Authors: Beesetti Swarnalatha , Surabhi Rohan P. , Rayala Suresh K. , Venkatraman Ganesh
Published: August 2018

Despite regular exposure of skin to solar UV‐B irradiation, most individuals enjoy cancer‐free existence, which is a testimony of the inherent capacity of human keratinocytes to either repair or restore cells damged by UV exposure. In this manuscript, we focus on delineating the mechanistic role of p21 activated kinase (Pak1) in UV‐B provoked skin lesions. Molecular mechanistic studies revealed that Pak1 is triggered as a consequence to UV‐B exposure via epidermal growth factor receptor (EGFR) and cyclobutane pyrimidine dimers (CPD) pathways, and both these membranous (EGFR) and nuclear (CPDs) events converge at Pak1 activation and contribute in a coordinated manner for yielding a complete response to UV‐B via upregulating Ataxia–Telangiectasia and Rad3 related (ATR). This is the first study that evaluates the mechanistic role of a signaling molecule, Pak1, in premalignant skin lesions caused by sun exposure and designate that expression and instigation of Pak1 could operate as an alarming indicator of succession towards aggressive form of skin cancer, if neglected.
Hypoxic conditioned medium derived from bone marrow mesenchymal stromal cells protects against ischemic stroke in rats
Authors: Jiang Run‐Hao , Wu Chen‐Jiang , Xu Xiao‐Quan , Lu Shan‐Shan , Zu Qing‐Quan , Zhao Lin‐Bo , Wang Jun , Liu Sheng , Shi Hai‐Bin
Published: August 2018

In recent years, studies have shown that the secretome of bone marrow mesenchymal stromal cells (BMSCs) contains many growth factors, cytokines, and antioxidants, which may provide novel approaches to treat ischemic diseases. Furthermore, the secretome may be modulated by hypoxic preconditioning. We hypothesized that conditioned medium (CM) derived from BMSCs plays a crucial role in reducing tissue damage and improving neurological recovery after ischemic stroke and that hypoxic preconditioning of BMSCs robustly improves these activities. Rats were subjected to ischemic stroke by middle cerebral artery occlusion and then intravenously administered hypoxic CM, normoxic CM, or Dulbecco modified Eagle medium (DMEM, control). Cytokine antibody arrays and label‐free quantitative proteomics analysis were used to compare the differences between hypoxic CM and normoxic CM. Injection of normoxic CM significantly reduced the infarct area and improved neurological recovery after stroke compared with administering DMEM. These outcomes may be associated with the attenuation of apoptosis and promotion of angiogenesis. Hypoxic preconditioning significantly enhanced these therapeutic effects. Fourteen proteins were significantly increased in hypoxic CM compared with normoxic CM as measured by cytokine arrays. The label‐free quantitative proteomics analysis revealed 163 proteins that were differentially expressed between the two groups, including 107 upregulated proteins and 56 downregulated proteins. Collectively, our results demonstrate that hypoxic CM protected brain tissue from ischemic injury and promoted functional recovery after stroke in rats and that hypoxic CM may be the basis of a potential therapy for stroke patients.
Circulating exosomal CPNE3 as a diagnostic and prognostic biomarker for colorectal cancer
Authors: Sun Bo , Li Yiming , Zhou Yiming , Ng Tien Khee , Zhao Chao , Gan Qiaoqiang , Gu Xiaodong , Xiang Jianbin
Published: August 2018

Exosomal proteins are emerging as relevant diagnostic and prognostic biomarkers for cancer. This study was aimed at illustrating the clinical significance of exosomal Copine III (CPNE3) purified from the plasma of colorectal cancer (CRC) patients. The CPNE3 expression levels in CRC tissues were analyzed by real‐time PCR, western blot, and immunohistochemistry. Plasma exosomes were isolated to examine the CPNE3 level using ELISA. Pearson’s correlation analysis was performed to investigate the CPNE3 levels between CRC tissues and matched plasma samples. Receiver operating characteristic curve analysis was developed to measure the diagnostic performance of exosomal CPNE3. The Kaplan–Meier method and Cox's proportional hazards model were utilized to determine statistical differences in survival times. CPNE3 showed increased expressions in the CRC tissues. A moderately significant correlation was found between CPNE3 expression in CRC tissues by immunohistochemistry and matched serum exosomal CPNE3 expression by ELISA (r = 0.645,(r = 0.645, p < 0.001). < 0.001). Exosomal CPNE3 yielded a sensitivity of 67.5% and a specificity of 84.4% in CRC at the cutoff value of 0.143 pg per 1ug1 ug exosome. Combined data from carcinoembryonic antigen and exosomal CPNE3 achieved 84.8% sensitivity and 81.2% specificity as a diagnostic tool. CRC patients with lower exosomal CPNE3 levels had substantially better disease‐free survival (hazard ratio [HR], 2.9; 95% confidence interval [CI]: 1.3–6.4; p = 0.009) = 0.009) and overall survival (HR, 3.4; 95% CI: 1.2–9.9; p = 0.026) = 0.026) compared with those with higher exosomal CPNE3 levels. Exosomal CPNE3 show potential implications in CRC diagnosis and prognosis.
MicroRNAs in alcoholic liver disease: Recent advances and future applications
Authors: Xu Tao , Li Li , Hu Hua‐Qing , Meng Xiao‐Ming , Huang Cheng , Zhang Lei , Qin Jian , Li Jun
Published: August 2018

Alcoholic liver disease (ALD) is characterized by hepatocyte damage, inflammatory cell activation, and increased intestinal permeability leading to the clinical manifestations of alcoholic hepatitis. Selected members of the family of microRNAs (miRNAs) are affected by alcohol, resulting in an abnormal miRNA profile in the liver and circulation in ALD. Increasing evidence suggests that miRNAs that regulate inflammation, lipid metabolism and promote cancer are affected by excessive alcohol administration in mouse models of ALD. This communication highlights recent findings in miRNA expression and functions as they relate to the pathogenesis of ALD. The cell‐specific distribution of miRNAs, as well as the significance of circulating extracellular miRNAs, is discussed as potential biomarkers. Finally, the prospects of miRNA‐based therapies are evaluated in ALD.
Therapeutic potential of microRNAs in osteoporosis function by regulating the biology of cells related to bone homeostasis
Authors: Zhao Wenhua , Shen Gengyang , Ren Hui , Liang De , Yu Xiang , Zhang Zhida , Huang Jinjing , Qiu Ting , Tang Jingjing , Shang Qi , Yu Peiyuan , Wu Zixian , Jiang Xiaobing
Published: August 2018

MicroRNAs (miRNAs) are novel regulatory factors that play important roles in numerous cellular processes through the posttranscriptional regulation of gene expression. Recently, deregulation of the miRNA‐mediated mechanism has emerged as an important pathological factor in osteoporosis. However, a detailed molecular mechanism between miRNAs and osteoporosis is still not available. In this review, the roles of miRNAs in the regulation of cells related to bone homeostasis as well as miRNAs that deregulate in human or animal are discussed. Moreover, the miRNAs that act as clusters in the biology of cells in the bone microenvironment and the difference of some important miRNAs for bone homeostasis between bone and other organs are mentioned. Overall, miRNAs that contribute to the pathogenesis of osteoporosis and their therapeutic potential are considered.
Hyaluronidase2 (Hyal2) modulates low shear stress‐induced glycocalyx impairment via the LKB1/AMPK/NADPH oxidase‐dependent pathway
Authors: Yang Hongfeng , Zhu Linlin , Chao Yuelin , Gu Yue , Kong Xiangquan , Chen Mingxing , Ye Peng , Luo Jie , Chen Shaoliang
Published: August 2018

The endothelium glycocalyx layer (ECL), presents on the apical surface of endothelial cells, creates a barrier between circulating blood and the vessel wall. Low shear stress (LSS) may accelerate the degradation of the glycocalyx via hyaluronidase2 (Hyal2) and then alter the cell polarity. Yet the liver kinase B1 (LKB1) signaling pathway plays an important role in regulating cell polarity. However, the relationship between LKB1 and glycocalyx during LSS is not clear. In the current study, we demonstrate that LSS attenuates LKB1 and AMP‐activated protein kinase activation as well as activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47phox) and Hyal2 in the human umbilical vein endothelial cell (HUVEC). Pretreatment with 5‐Aminoimidazole‐4‐carboxamide1‐β‐D‐ribofuranoside (AICAR), or diphenyleneiodonium (DPI chloride) and transfection with LKB1 overexpression vector and p47phox small interfering RNA downregulated LSS‐induced Hyal2 activation. By coimmunoprecipitation, we discovered the existence of p47phox/Hyal2 complex. LSS induced the dissociation of p47phox/Hyal2 complex, which was inhibited by LKB1 overexpression and AICAR. Furthermore, knockdown of Hyal2 performed a positive feedback on LKB1 activity. In addition, we also show that LSS enhanced LKB1 translocation from the cytosol to the nucleus. Taken together, these data indicate that Hyal2 regulates LSS‐induced injury of the glycocalyx via LKB1/AMPK/NADPH oxidase signaling cascades.
Cellular senescence: Molecular mechanisms and pathogenicity
Authors: Wei Wenqiang , Ji Shaoping
Published: August 2018

Cellular senescence is the arrest of normal cell division. Oncogenic genes and oxidative stress, which cause genomic DNA damage and generation of reactive oxygen species, lead to cellular senescence. The senescence‐associated secretory phenotype is a distinct feature of senescence. Senescence is normally involved in the embryonic development. Senescent cells can communicate with immune cells to invoke an immune response. Senescence emerges during the aging process in several tissues and organs. In fact, increasing evidence shows that cellular senescence is implicated in aging‐related diseases, such as nonalcoholic fatty liver disease, obesity and diabetes, pulmonary hypertension, and tumorigenesis. Cellular senescence can also be induced by microbial infection. During cellular senescence, several signaling pathways, including those of p53, nuclear factor‐κB (NF‐κB), mammalian target of rapamycin, and transforming growth factor‐beta, play important roles. Accumulation of senescent cells can trigger chronic inflammation, which may contribute to the pathological changes in the elderly. Given the variety of deleterious effects caused by cellular senescence in humans, strategies have been proposed to control senescence. In this review, we will focus on recent studies to provide a brief introduction to cellular senescence, including associated signaling pathways and pathology.
AhR ligand aminoflavone suppresses α6‐integrin–Src–Akt signaling to attenuate tamoxifen resistance in breast cancer cells
Authors: Campbell Petreena S. , Mavingire Nicole , Khan Salma , Rowland Leah K. , Wooten Jonathan V. , Opoku‐Agyeman Anna , Guevara Ashley , Soto Ubaldo , Cavalli Fiorella , Loaiza‐Pérez Andrea Irene , Nagaraj Gayathri , Denham Laura J. , Adeoye Olayemi , Jenkins Brittany D. , Davis Melissa B. , Schiff Rachel , Brantley Eileen J.
Published: August 2018

More than 40% of patients with luminal breast cancer treated with endocrine therapy agent tamoxifen demonstrate resistance. Emerging evidence suggests tumor initiating cells (TICs) and aberrant activation of Src and Akt signaling drive tamoxifen resistance and relapse. We previously demonstrated that aryl hydrocarbon receptor ligand aminoflavone (AF) inhibits the expression of TIC gene α6‐integrin and disrupts mammospheres derived from tamoxifen‐sensitive breast cancer cells. In the current study, we hypothesize that tamoxifen‐resistant (TamR) cells exhibit higher levels of α6‐integrin than tamoxifen‐sensitive cells and that AF inhibits the growth of TamR cells by suppressing α6‐integrin–Src–Akt signaling. In support of our hypothesis, TamR cells and associated mammospheres were found to exhibit elevated α6‐integrin expression compared with their tamoxifen‐sensitive counterparts. Furthermore, tumor sections from patients who relapsed on tamoxifen showed enhanced α6‐integrin expression. Gene expression profiling from the TCGA database further revealed that basal‐like breast cancer samples, known to be largely unresponsive to tamoxifen, demonstrated higher α6‐integrin levels than luminal breast cancer samples. Importantly, AF reduced TamR cell viability and disrupted TamR mammospheres while concomitantly reducing α6‐integrin messenger RNA and protein levels. In addition, AF and small interfering RNA against α6‐integrin blocked tamoxifen‐stimulated proliferation of TamR MCF‐7 cells and further sensitized these cells to tamoxifen. Moreover, AF reduced Src and Akt signaling activation in TamR MCF‐7 cells. Our findings suggest elevated α6‐integrin expression is associated with tamoxifen resistance and AF suppresses α6‐integrin–Src–Akt signaling activation to confer activity against TamR breast cancer.
Tumor‐associated macrophages and epithelial–mesenchymal transition in cancer: Nanotechnology comes into view
Authors: Vakili‐Ghartavol Roghayyeh , Mombeiny Reza , Salmaninejad Arash , Sorkhabadi Seyed Mahdi Rezayat , Faridi‐Majidi Reza , Jaafari Mahmoud Reza , Mirzaei Hamed
Published: August 2018

Tumor‐associated macrophages (TAMs) are an important component of the leukocytic infiltrate of the tumor microenvironment. There is persuasive preclinical and clinical evidence that TAMs induce cancer inanition and malignant progression of primary tumors toward a metastatic state through a highly conserved and fundamental process known as epithelial–mesenchymal transition (EMT). Tumor cells undergoing EMT are distinguished by increased motility and invasiveness, which enable them to spread to distant sites and form metastases. In addition, besides becoming resistant to apoptosis and antitumor drugs, they also contribute to immunosuppression and get a cancer stem‐cell like phenotype. Here, we will focus on selected molecular pathways underlying EMT—in particular, the role of TAMs in the induction and maintenance of EMT—and further discuss how the targeting of TAMs through the application of nanotechnology tools allows the development of a whole new range of therapeutics.
Demethoxycurcumin: A naturally occurring curcumin analogue with antitumor properties
Authors: Hatamipour Mahdi , Ramezani Mahin , Tabassi Sayyed Abolghasem Sajadi , Johnston Thomas P. , Ramezani Mahnaz , Sahebkar Amirhosein
Published: August 2018

The eradication of cancer in a patient remains an elusive challenge despite advances in early detection and diagnosis, chemo‐ and immunotherapy, pinpoint radiation treatments, and expert surgical intervention. Although significant gains have been made in our understanding of cancer cell biology, a definite cure for most cancers does not exist at present. Thus, it is not surprising that the research and medical communities continue to explore the importance and therapeutic potential of natural products in their multimodality cancer treatment approach. Curcuminoids found in turmeric are one such class of natural products that have been extensively investigated for their potential to halt the progression of cancer cell proliferation and, more important, to stop metastasis from occurring. In this review, we examine one curcuminoid (demethoxycurcumin [DMC]) largely because of its increased stability and better aqueous solubility at physiological pH, unlike the more well‐known curcuminoid (curcumin), which is largely unabsorbed after oral ingestion. The present review will focus on the signaling pathways that DMC utilizes to modulate the growth, invasion, and metastasis of cancer cells in an effort to provide enhanced mechanistic insight into DMC’s action as it pertains to brain, ovarian, breast, lung, skin, and prostate cancer. Additionally, this review will attempt to provide an overview of DMC’s mechanism of action by modulating apoptosis, cell cycle, angiogenesis, metastasis, and chemosensitivity. Lastly, it is hoped that increased understanding will be gained concerning DMC’s interactive role with microRNA‐551a, 5′ adenosine monophosphate‐activated protein kinase, nuclear factor‐κB, Wnt inhibitory factor‐1, and heat shock protein 70 to affect the progression of cancer.