PReD-Bench/PRed-Bench huggingface dataset:
Hesperetin suppresses RANKL‐induced osteoclastogenesis and ameliorates lipopolysaccharide‐induced bone loss
Authors: Hui Huang
Jun Xiao
Dahu Qi
Cong Cai
Libo Zhao
Liming Zhao
Changyu Liu
Meipeng Zhu
Yutong Gao
Fengjing Guo
Yonghui Dong
Hui Liu
Journal: Journal of Cellular Physiology (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: MAPKs; NF-κB; Nrf2; hesperetin; osteoclastogenesis.
Affiliations: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Department of Orthopaedics, Henan Provincial People's Hospital, Zhengzhou, China., Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract:  Destructive bone diseases caused by osteolysis are increasing in incidence. They are characterized by an excessive imbalance of osteoclast formation and activation. During osteolysis, the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways are triggered by receptor activator of NF-κB ligand (RANKL), inflammatory factors, and oxidative stress. Previous studies have indicated that the common flavanone glycoside compound hesperetin exhibits anti-inflammatory and antioxidant activity by inhibition of NF-κB and MAPK signaling pathways. However, the direct relationship between hesperetin and osteolysis remain unclear. In the present study, we investigated the effects of hesperetin on lipopolysaccharide (LPS)-induced osteoporosis and elucidated the related mechanisms. Hesperetin effectively suppressed RANKL-induced osteoclastogenesis, osteoclastic bone resorption, and F-actin ring formation in a dose-dependent manner. It also significantly suppressed the expression of osteoclast-specific markers including tartrate-resistant acid phosphatase, matrix metalloproteinase-9, cathepsin K, c-Fos, and nuclear factor of activated T-cells cytoplasmic 1. Furthermore, it inhibited osteoclastogenesis by inhibiting activation of NF-κB and MAPK signaling, scavenging reactive oxygen species, and activating the nuclear factor E2 p45-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway. Consistent with in vitro results, hesperetin effectively ameliorated LPS-induced bone loss, reduced osteoclast numbers, and decreased the RANKL/OPG ratio in vivo. As such, our results suggest that hesperetin may be a great candidate for developing a novel drug for destructive bone diseases such as periodontal disease, tumor bone metastasis, rheumatoid arthritis, and osteoporosis. 

Retracted: No

PubPeer comments:
 In Figure 6b, an image is duplicated and presented as something else. In Figure 7c, the similar ultrastructure of the HO-1 stained SHAM and Hesp samples, indicate that they origin from the same tissue. ![file] ,
Matrix metalloproteinase (MMP) 9 transcription in mouse brain induced by fear learning
Authors: Ewelina Knapska
Marta Mikosz
Krishnendu Ganguly
Evgeni Nikolaev
Emilia Rejmak
Leszek Kaczmarek
Journal: Journal of Biological Chemistry (2013)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: AP1 Transcription Factor; Amygdala; Electroporation; Fear Learning; Fos
Affiliations: Laboratory of Neurobiology, Nencki Institute, Pasteur 3, 02-093 Warsaw, Poland. 

Abstract:  Memory formation requires learning-based molecular and structural changes in neurons, whereas matrix metalloproteinase (MMP) 9 is involved in the synaptic plasticity by cleaving extracellular matrix proteins and, thus, is associated with learning processes in the mammalian brain. Because the mechanisms of MMP-9 transcription in the brain are poorly understood, this study aimed to elucidate regulation of MMP-9 gene expression in the mouse brain after fear learning. We show here that contextual fear conditioning markedly increases MMP-9 transcription, followed by enhanced enzymatic levels in the three major brain structures implicated in fear learning, i.e. the amygdala, hippocampus, and prefrontal cortex. To reveal the role of AP-1 transcription factor in MMP-9 gene expression, we have used reporter gene constructs with specifically mutated AP-1 gene promoter sites. The constructs were introduced into the medial prefrontal cortex of neonatal mouse pups by electroporation, and the regulation of MMP-9 transcription was studied after contextual fear conditioning in the adult animals. Specifically, -42/-50- and -478/-486-bp AP-1 binding motifs of the mouse MMP-9 promoter sequence have been found to play a major role in MMP-9 gene activation. Furthermore, increases in MMP-9 gene promoter binding by the AP-1 transcription factor proteins c-Fos and c-Jun have been demonstrated in all three brain structures under investigation. Hence, our results suggest that AP-1 acts as a positive regulator of MMP-9 transcription in the brain following fear learning. 

Retracted: No

PubPeer comments:
 Fig. 3B Is there an explanation for the block in the middle of the figure (box) and the lines and discontinuities (arrows)? Is this a mere pixilation problem? Perhaps the original high-resolution image could be posted? https: imgur.com a J8eWd5q , 
 Indeed, this is mere a pixilation problem. Unfortunately, we do not have anymore the original TIF photo taken from the microscope. ,
Targeted regulation of miR-195 on MAP2K1 for suppressing ADM drug resistance in prostate cancer cells
Authors: Y-N Li
W-B Liu
Z-L Pan
X Mu
J-Y Zhang
Journal: European Review for Medical and Pharmacological Sciences (2018)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: ERK/MAPK signaling pathway; miR-195; MAP2K1; prostate cancer; apoptosis
Affiliations: Department of Urology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, Fujian, China. .

Abstract:  Objective: Extra-cellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway participates in cell proliferation, cycle and apoptosis. MAPK kinase 1 (MAP2K1) activates the ERK/MAPK pathway. The down-regulation of miR-195 is correlated with the onset and drug resistance of prostate cancer. Bioinformatics analysis identified complementary binding sites between miR-195 and MAP2K1. This study aimed to investigate the effect of miR-195 on the proliferation, apoptosis and adriamycin (ADM) resistance of prostate cancer cells. Materials and methods: Dual-Luciferase reporter gene assay confirmed targeted regulation between miR-195 and MAP2K1. ADM resistant cell line DU145/ADM and PC-3/ADM were generated for comparing the miR-195 and MAP2K1 expression. Apoptosis was measured by flow cytometry and caspase-3 activity was quantified. Cultured cells were treated with miR-195 mimic, followed by quantitative real-time PCR (qRT-PCR) was used for MAP2K1 expression. Western blot measured MAP2K1, ERK1/2 and phosphorylated ERK1/2 (p-ERK1/2) expression, and flow cytometry quantified cell apoptosis, followed by EdU staining for cell proliferation. Results: Targeted regulation existed between miR-195 and MAP2K1 mRNA. Drug-resistant cells had lower miR-195 than parental cells, whilst MAP2K1 expression was higher. Under ADM treatment with IC50 concentration, drug resistant cells showed lower apoptosis. The transfection of miR-195 decreased MAP2K1 expression and p-ERK1/2, elevated cell apoptosis and suppressed EdU positive rate or cell proliferation. Conclusions: The down-regulation of miR-195 is correlated with ADM resistance of prostate cancer cells. The over-expression of miR-195 weakens cancer cell proliferation, facilitates cell apoptosis and decreases ADM resistance via targeted inhibition on MAP2K1 expression and ERK/MAPK signal pathway. 

Retracted: Yes

PubPeer comments:
 Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, u201cTargeted regulation of miR-195 on MAP2K1 for suppressing ADM drug resistance in prostate cancer cells, by J.-Y. Zhang, Y.-N. Li, X. Mu, Z.-L. Pan, W.-B. Liu, published in Eur Rev Med Pharmacol Sci 2018; 22 (24): 8599-8608u2013DOI: 10.26355 eurrev_201812_16623u2013PMID: 30575899u201d has been withdrawn. [The Publisher apologizes for any inconvenience this may cause] . ![file] ,
Neuronal Development-Related miRNAs as Biomarkers for Alzheimer's disease, Depression, Schizophrenia and Ionizing Radiation Exposure
Authors: Hong Wang
Li Yun Chan
Renu Chandra Segaran
Feng Ru Tang
Gautam Sethi
Journal: Current medicinal chemistry (2020)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Alzheimer disease; Venn diagram; blood; brain tissue; cerebrospinal fluid
Affiliations: Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, CREATE Tower, Singapore 138602. Singapore., Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600. Singapore.

Abstract:  Radiation exposure may induce Alzheimer's disease (AD), depression or schizophrenia. A number of experimental and clinical studies suggest the involvement of miRNA in the development of these diseases, and also in the neuropathological changes after brain radiation exposure. The current literature review indicated the involvement of 65 miRNAs in neuronal development in the brain. In the brain tissue, blood, or cerebral spinal fluid (CSF), 11, 55, or 28 miRNAs are involved in the development of AD respectively, 89, 50, 19 miRNAs in depression, and 102, 35, 8 miRNAs in schizophrenia. We compared miRNAs regulating neuronal development to those involved in the genesis of AD, depression and schizophrenia and also those driving radiation-induced brain neuropathological changes by reviewing the available data. We found that 3, 11, or 8 neuronal developmentrelated miRNAs from the brain tissue, 13, 16 or 14 miRNAs from the blood of patient with AD, depression and schizophrenia respectively were also involved in radiation-induced brain pathological changes, suggesting a possibly specific involvement of these miRNAs in radiation-induced development of AD, depression and schizophrenia respectively. On the other hand, we noted that radiationinduced changes of two miRNAs, i.e., miR-132, miR-29 in the brain tissue, three miRNAs, i.e., miR- 29c-5p, miR-106b-5p, miR-34a-5p in the blood were also involved in the development of AD, depression and schizophrenia, thereby suggesting that these miRNAs may be involved in the common brain neuropathological changes, such as impairment of neurogenesis and reduced learning memory ability observed in these three diseases and also after radiation exposure. 

Retracted: No

PubPeer comments:
  Radiation exposure may induce Alzheimer disease (AD), depression or schizophrenia - highly speculative first sentence of this manuscript review. Another review previously published by the same author in an OMICS journal. https: www.omicsonline.org open-access radiation-and-alzheimers-disease-ad-2161-0460-1000418-99049.html https: www.omicsonline.org open-access radiation-and-alzheimers-disease-ad-2161-0460-1000418-99049.html All claims without any experimental data! ,
Propofol inhibits proliferation, migration and invasion of gastric cancer cells by up-regulating microRNA-195
Authors: Yang Wang
Bin Song
Yan Zheng
Wenyu Zhang
Zhihua Zhu
Journal: International Journal of Biological Macromolecules (2018)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Gastric cancer; MicroRNA-195; Propofol.
Affiliations: Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China., Department of Orthopaedics, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China., Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China. Electronic address: .

Abstract:  Purpose: This study investigated the effects of propofol on gastric cancer MKN45 cell proliferation, migration, invasion and apoptosis, as well as underlying potential mechanisms. Methods: The viability, proliferation, apoptosis, migration and invasion of MKN45 cells were assessed using CCK-8 assay, BrdU incorporation assay, Annexin V-FITC/PI staining, two-chamber migration (invasion) assay and western blotting, respectively. qRT-PCR was performed to measure the expression of microRNA-195 (miR-195). Cell transfection was conducted to down-regulate the expression of miR-195. Results: Propofol treatment suppressed MKN45 cell proliferation, migration and invasion, but promoted cell apoptosis. The expression of miR-195 was increased after propofol treatment. Suppression of miR-195 reversed the propofol-induced MKN45 cell proliferation, migration and invasion inhibition, as well as apoptosis. Moreover, Propofol treatment inactivated JAK/STAT and NF-κB pathways in MKN45 cells. Suppression of miR-195 reversed the propofol-induced inactivation of JAK/STAT and NF-κB pathways. Inhibition of JAK/STAT and NF-κB pathways reversed the effects of miR-195 suppression on propofol-induced MKN 45 cell proliferation, migration and invasion inhibition, as well as apoptosis enhancement. Conclusion: Propofol inhibited proliferation, migration and invasion of gastric cancer MKN45 cells by up-regulating miR-195 and then inactivating JAK/STAT and NF-κB pathways. Propofol could be as an effective therapeutic medicine for gastric cancer treatment. 

Retracted: Yes

PubPeer comments:
 duplication ![file] Disclaimer: These potential image duplications have been detected automatically using ImageTwin http: dx.doi.org 10.1145 3019612.3019875 Although results have been curated, the automatic algorithm may have generated false positive results and cannot take into account all scientific explanations for apparent duplications like stripped and reprobed blots, time series, serial sections and reused controls. ,
Structure of the human mTOR complex I and its implications for rapamycin inhibition
Authors: Seong A Kang
Kazuyoshi Murata
David M Sabatini
Calvin K Yip
Thomas Walz
Journal: Molecular Cell (2010)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: mTORC1; cell growth; nutrient; energy status; human cancers
Affiliations: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

Abstract:  The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth in response to the nutrient and energy status of the cell, and its deregulation is common in human cancers. Little is known about the overall architecture and subunit organization of this essential signaling complex. We have determined the three-dimensional (3D) structure of the fully assembled human mTORC1 by cryo-electron microscopy (cryo-EM). Our analyses reveal that mTORC1 is an obligate dimer with an overall rhomboid shape and a central cavity. The dimeric interfaces are formed by interlocking interactions between the mTOR and raptor subunits. Extended incubation with FKBP12-rapamycin compromises the structural integrity of mTORC1 in a stepwise manner, leading us to propose a model in which rapamycin inhibits mTORC1-mediated phosphorylation of 4E-BP1 and S6K1 through different mechanisms. 

Retracted: No

PubPeer comments:
 Figure 6b appears to have a series of overlaps. *** ![file] ,
Transformation of human and murine fibroblasts without viral oncoproteins
Authors: Sara E Bulmer
Meghan T Hession
William C Hahn
Jesse S Boehm
Journal: Molecular and cellular biology (2005)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: murine embryo fibroblasts; human cells; oncogenes; tumorigenicity; transformation
Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St., Dana 710C, Boston, MA 02115-6013, USA.

Abstract:  Murine embryo fibroblasts are readily transformed by the introduction of specific combinations of oncogenes; however, the expression of those same oncogenes in human cells fails to convert such cells to tumorigenicity. Using normal human and murine embryonic fibroblasts, we show that the transformation of human cells requires several additional alterations beyond those required to transform comparable murine cells. The introduction of the c-Myc and H-RAS oncogenes in the setting of loss of p53 function efficiently transforms murine embryo fibroblasts but fails to transform human cells constitutively expressing hTERT, the catalytic subunit of telomerase. In contrast, transformation of multiple strains of human fibroblasts requires the constitutive expression of c-Myc, H-RAS, and hTERT, together with loss of function of the p53, RB, and PTEN tumor suppressor genes. These manipulations permit the development of transformed human fibroblasts with genetic alterations similar to those found associated with human cancers and define specific differences in the susceptibility of human and murine fibroblasts to experimental transformation. 

Retracted: No

PubPeer comments:
 In Figure 4b an image has been horizontally compressed and reused. ![file] , 
 Dear colleague, Thank you for pointing out this mistake in our manuscript. We are very sorry for this mistake and will immediately contact the journal to file a correction. We provide the original images to clarify this mistake. This mistake in Figure 4B most likely happened during cropping in photoshop and wrong labeling of cropped phenotype pictures. Sometimes during the cropping procedure images were compressed. The image is clearly Xcv delta hrpB1, see below![file] You can see Xcv delta hrpB1 AvrRpt2-SseF clone 1 here (abbreviated hrpB1-1) together with another hrpB1 infiltration. This image will be used to replace the image in the middle representing the AvrRpt2-SseF clone 1 infiltration. ![file] Here we provide the uncropped picture of the AvrRpt2-SseF clone 2 (hrpB1-2) infiltration used in the publication. ![file] In addition you can also see below repetition of the experiment here: Xcv delta hrpB1 AvrRpt2-SseF clone 1 (abbreviated hrpB1-1) was infiltrated together with the HR inducing Xcv SseF clone 1 and 2 strains. ![file] And here is another infiltration showing that Xcv delta hrpB1 AvrRpt2-SseF clone 2 (abbreviated hrpB1-2) is not eliciting HR. ![file] We again apologize for this mistake and thank Aneurus Inconstans for pointing out this mistake. We will try to make a corrections asap. Best, Suayb , 
 #2 Could the authors please update on the status of this paper? ,
The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth
Authors: I Alamo Jr
Q Zhan
K A Lord
D Ron
F Carrier
A J Fornace Jr
D A Liebermann
B Hoffman
K W Kohn
M C Hollander
Journal: Molecular and Cellular Biology (1994)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: gadd genes; MyD genes; genotoxic stress; growth arrest; MyD116
Affiliations: Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland 20892.

Abstract:  A remarkable overlap was observed between the gadd genes, a group of often coordinately expressed genes that are induced by genotoxic stress and certain other growth arrest signals, and the MyD genes, a set of myeloid differentiation primary response genes. The MyD116 gene was found to be the murine homolog of the hamster gadd34 gene, whereas MyD118 and gadd45 were found to represent two separate but closely related genes. Furthermore, gadd34/MyD116, gadd45, MyD118, and gadd153 encode acidic proteins with very similar and unusual charge characteristics; both this property and a similar pattern of induction are shared with mdm2, whic, like gadd45, has been shown previously to be regulated by the tumor suppressor p53. Expression analysis revealed that they are distinguished from other growth arrest genes in that they are DNA damage inducible and suggest a role for these genes in growth arrest and apoptosis either coupled with or uncoupled from terminal differentiation. Evidence is also presented for coordinate induction in vivo by stress. The use of a short-term transfection assay, in which expression vectors for one or a combination of these gadd/MyD genes were transfected with a selectable marker into several different human tumor cell lines, provided direct evidence for the growth-inhibitory functions of the products of these genes and their ability to synergistically suppress growth. Taken together, these observations indicate that these genes define a novel class of mammalian genes encoding acidic proteins involved in the control of cellular growth. 

Retracted: No

PubPeer comments:
 Undeclared gel slice sites in Fig.2A (red arrow). Could authors give an explanation? ![file] ,
N-cadherin promotes epithelial-mesenchymal transition and cancer stem cell-like traits via ErbB signaling in prostate cancer cells
Authors: Wei Guo
Zeyu Wang
Shuai Huang
Dong Ren
Qiji Li
Min Wang
Xinsheng Peng
Libing Song
Hong Du
Journal: International Journal of Oncology (2016)
Discipline: CLINICAL MEDICINE
Keywords: N-cadherin; metastasis; poor prognosis; prostate cancer; invasion
Affiliations: Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China., Department of Pathology, The First People's Hospital of Guangzhou City, Guangzhou, Guangdong 510180, P.R. China., State Key Laboratory of Oncology in Southern China/Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.

Abstract:  N-cadherin has been reported to be upregulated and associated with metastasis and poor prognosis in prostate cancer patients, however the underlying mechanism still remains puzzling. In the present study, we found that upregulation of N-cadherin enhanced, while downregulation of N-cadherin impaired the invasion, migration, and epithelial to mesenchymal transition (EMT) of prostate cancer (PCa) cells. Overexpression of N-cadherin increased the efficiency of colony and tumor spheroid formation and the stemness factor expression (including c-Myc, Klf4, Sox2 and Oct4), and vice versa. Furthermore, microarray analysis and western blot analysis mechanistically proved that N-cadherin activated ErbB signaling pathway by upregulating the expression of Grb2, pShc and pERK1/2. Importantly, the regulation of N-cadherin on EMT and stemness was counteracted by lapatinib, a specific ErbB signaling pathway inhibitor. Collectively, these findings demonstrate that N-cadherin regulates EMT and stemness of PCa cells via activating ErbB signaling pathway, which indicates the pivotal role of N-cadherin/ErbB axis in the metastasis of prostate cancer. 

Retracted: No

PubPeer comments:
 Figure 6A and Figure 6C. More similar than expected. ![file] ,
Intracellular expression of IRF9 Stat fusion protein overcomes the defective Jak-Stat signaling and inhibits HCV RNA replication
Authors: Partha K Chandra
Luis A Balart
Feyza Gunduz
Bret Poat
Sidhartha Hazari
Robert F Garry
Srikanta Dash
Xavier Alvarez
Journal: Virology Journal (2010)
Discipline: MICROBIOLOGY
Keywords: Interferon alpha; Jak-Stat signaling pathway; IRF9; Stat1; Stat2
Affiliations: Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA-70112, USA.

Abstract:  Interferon alpha (IFN-α) binds to a cell surface receptor that activates the Jak-Stat signaling pathway. A critical component of this pathway is the translocation of interferon stimulated gene factor 3 (a complex of three proteins Stat1, Stat2 and IRF9) to the nucleus to activate antiviral genes. A stable sub-genomic replicon cell line resistant to IFN-α was developed in which the nuclear translocation of Stat1 and Stat2 proteins was prevented due to the lack of phosphorylation; whereas the nuclear translocation of IRF9 protein was not affected. In this study, we sought to overcome defective Jak-Stat signaling and to induce an antiviral state in the IFN-α resistant replicon cell line by developing a chimera IRF9 protein fused with the trans activating domain (TAD) of either a Stat1 (IRF9-S1C) or Stat2 (IRF9-S2C) protein. We show here that intracellular expression of fusion proteins using the plasmid constructs of either IRF9-S1C or IRF9-S2C, in the IFN-α resistant cells, resulted in an increase in Interferon Stimulated Response Element (ISRE) luciferase promoter activity and significantly induced HLA-1 surface expression. Moreover, we show that transient transfection of IRF9-S1C or IRF9-S2C plasmid constructs into IFN-α resistant replicon cells containing sub-genomic HCV1b and HCV2a viruses resulted in an inhibition of viral replication and viral protein expression independent of IFN-α treatment. The results of this study indicate that the recombinant fusion proteins of IRF9-S1C, IRF9-S2C alone, or in combination, have potent antiviral properties against the HCV in an IFN-α resistant cell line with a defective Jak-Stat signaling. 

Retracted: No

PubPeer comments:
 Figures 7A: Unexpected similarities with Figure 1C and 8 in Poat et al. PLOS ONE (2010), DOI: 10.1371 journal.pone.0013117 - https: pubpeer.com publications 21473A782D6FC8E699DB6804721724 * Red boxes: Two of the panels in Figure 7A look similar to each other and to two panels in Figure 8 of the PLOS ONE paper. * Blue boxes: One of the panels in Figure 7A looks similar to a panel in Figure 1C of the PLOS ONE paper. * Green boxes: One of the panels in Figure 7A looks similar to a panel in Figure 1C of the PLOS ONE paper. From looking at the labels, these appear to represent different experiments, but maybe the authors can clarify. ![file] ,
Upregulation of circular RNA circ_0001721 predicts unfavorable prognosis in osteosarcoma and facilitates cell progression via sponging miR-569 and miR-599
Authors: Yanming Pan
Guanghao Yu
Ling Guo
Yanjing Zhao
Liandi Li
Guohua Yin
Journal: Biomedicine & Pharmacotherapy (2019)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Circular RNA; Osteosarcoma; circ_0001721; miR-569; miR-599.
Affiliations: Department of Anesthesiology, Second Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, 157000, China., Department of Pathology, Second Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, 157000, China., Department of Nursing, Second Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, 157000, China., Department of Image Equipment, Mudanjiang Medical University, Mudanjiang, 157000, China. Electronic address: ., Department of Emergency, Second Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, 157000, China. Electronic address: ., Department of Anatomy, Mudanjiang Medical University, Mudanjiang, 157000, China. Electronic address: .

Abstract:  Osteosarcoma (OS) is the most frequent bone malignancy in human. Growing evidence suggests that circular RNAs (circRNAs) play a significant role in regulating tumorigenesis and progression. Previously, circ_0001721 was identified upregulated in OS tissues screened by circRNA microarrays. In the current study, circ_0001721 expression in OS tissue samples and cells were measured by qRT-PCR. Its clinical value was also explored. For the part of functional assays, CCK-8, clone-forming, flow cytometric, Transwell, xenograft assays were performed. Dual luciferase reporter assays were used to examine the mechanism of circ_0001721. We found that circ_0001721 was enhanced in OS tissue samples and cell lines and the overexpression of circ_0001721 is closely related to clinical severity. In addition, circ_0001721 may be used as a prognostic indicator for OS patients. What's more, loss-of-function and gain-of-function assays demonstrated circ_0001721 facilitates cell progression in OS. Circ_0001721 could sponge miR-569 and miR-599. The oncogenic properties of circ_0001721 is partly attributed to its repression on miR-569 and miR-599. Collectively, the present data reveal the participation of circ_0001721 in tumorigenesis of OS cells, and may indicate a novel therapeutic target. 

Retracted: No

PubPeer comments:
 Figure 2F: * The metal ruler shown with the tumors looks remarkably similar to the ruler in Figure 2D of Tongmiao Liu et al., Biochem Biophys Res Comm (2018), DOI: 10.1016 j.bbrc.2018.07.070 - see: https: pubpeer.com publications 6F1EDF470204A0784D62616CEC1F8E . Note the stains under the  1 . * The tumors appear to float on the background. Could the authors please provide an explanation? Both research groups are located in different hospitals in different cities (albeit in the same province). ![file] ,
Interactions between intestinal microbiota and innate immune system in pediatric inflammatory bowel disease
Authors: Marina Aloi
Salvatore Cucchiara
Laura Stronati
Journal: Journal of Clinical Gastroenterology (2012)
Discipline: CLINICAL MEDICINE
Keywords: Inflammatory bowel disease; immune homeostasis; gut microbiota; chronic inflammation; innate immune system
Affiliations: Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy. 

Abstract:  Inflammatory bowel disease (IBD) is the result of an altered immune homeostasis within the intestinal mucosa against the gut microbiota, leading to chronic inflammation in genetically predisposed individuals. Under normal conditions, the immune system defends against pathogens and prevents the passage of excessive intestinal bacteria; regulatory pathways must maintain a low-grade, controlled inflammation in a healthy gut, but also induce a protective response against pathogens. The innate immune system is the first-line defense from microbes; dendritic cells, macrophages, and epithelial cells produce an initial, immediate response. The immune system constantly controls commensal bacteria and utilizes constitutive antimicrobial mechanisms to sustain immune homeostasis. The discovery that several genes linked to IBD modulate microbial recognition and innate immune pathways, such as nucleotide oligomerization domain 2 (Nod2), and genes that mediate autophagy (ie, ATG16L1, IRGM), has highlighted the critical role of host-microbe interactions in controlling intestinal immune homeostasis. Commensal microorganisms actively interact with the intestinal mucosa and influence the activity of the immune system as well as the amplitude of the immune response. In contrast, host factors can influence microbes, which in turn modulate disease susceptibility. In this paper, we focus on the mechanisms that mediate host-microbe interactions and how the disruption of this balance leads to chronic intestinal inflammation in IBD. 

Retracted: Yes

PubPeer comments:
 This article has been retracted in July 2014, although it is not obvious from the publisher s landing page of the article, and it is still available to buy. The Retraction Notice can be found here: https: journals.lww.com jcge Citation 2014 07000 Interactions_Between_Intestinal_Microbiota_and.23.aspx Here is a screenshot of the Notice in which the young students are thrown under the proverbial bus, and the senior researcher remains  well respected . ![file] And here is a screenshot of the textual similarities, marked with highlights. Each color reflects a different source document (n=15, 9 of which were not listed in the citations). ![file] ,
MiR-17 targets PTEN and facilitates glial scar formation after spinal cord injuries via the PI3K/Akt/mTOR pathway
Authors: Mo Chen
Yongxin Luan
Lixiang Zhou
Journal: Brain Research Bulletin (2017)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Glial scar formation; MiR-17; PI3K/Akt/mTOR; PTEN; Spinal cord injury.
Affiliations: Department of Neurosurgery, The First Hospital of Jilin University, Changchun, 130021 Jilin, China., Jilin Province People's Hospital, Changchun, 130000 Jilin, China., Department of Neurosurgery, The First Hospital of Jilin University, Changchun, 130021 Jilin, China. Electronic address: .

Abstract:  Objectives: We attempted to discover the regulatory role of miR-17 and PTEN in glial scar formation accompanied with spinal cord injuries. Methods: We established a spinal cord injury (SCI) model in mice which were transfected with different groups of adenoviruses: miR-17 mimics, miR-17 inhibitors and PTEN cDNAs. The improvement of hind limb functions was assessed using the 21-point Basso-Beattie-Bresnahan (BBB) locomotion scale. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein (GFAP), Vimentin and neurofilaments. The expression of miR-17 was quantified using Real time-PCR (RT-PCR). Western blot was conducted to detect the expressions of PTEN, PI3K, Akt, mTOR and S6. Finally, dual luciferase reporter gene assay was conducted to confirm the target relationship between miR-17 and PTEN. Results: The model group exhibited significantly increased expression levels of GFAP, Vimentin, miR-17, PTEN, PI3K, Akt and mTOR. The above trend was enhanced by the transfection of miR-17 mimics (P&lt;0.05). By contrast, the transfection of miR-17 inhibitors significantly down-regulated the expression of GFAP, Vimentin, PTEN, PI3K, Akt, mTOR and p-S6 whereas the expression of GFAP, Vimentin, PI3K, Akt, mTOR and p-S6 in the cells transfected with PTEN cDNAs significantly decreased (P&lt;0.05). Also, the transfection of miR-17 inhibitors and PTEN cDNAs alleviated the astrogliosis in SCI lesions, contributed to the regeneration of nerve filament and improved the functional recovery of the hind limb of mice. Finally, the targeting relationship between miR-17 and PTEN was verified by the dual luciferase reporter gene assay. Conclusion: MiR-17 is able to target PTEN and stimulate the PI3K/Akt/mTOR pathway. The formation of glial scar resulted from spinal cord injuries can be reduced either by inhibiting miR-17 or by overexpressing PTEN. 

Retracted: No

PubPeer comments:
 Fig 3.  The expression levels of GFAP, Vimentin and NF in the lesion area on 30 DPI detected via immunohistochemistry. A Immunohistochemistry staining for GFAP and Vimentin in the six experimental groups. B Immunohistochemistry staining for GFAP and NF in the six experimental groups. Some overlaps are marked. ![file] , 
 Fig 2A. Green box: A pair of panels are very similar in the GFAP channel, differing mainly in intensity. ![file] Red boxes: In the Vimentin, channel, two panels contain internal details that differ only by a 140-deg rotation. Purple boxes: Same localised, rotated similarity for another pair of panels. ,
Dynamic interdomain interactions contribute to the inhibition of matrix metalloproteinases by tissue inhibitors of metalloproteinases
Authors: Dmitri V Rozanov
Alex Y Strongin
Sergey A Shiryaev
Boguslaw Stec
Albert G Remacle
Ilian A Radichev
Journal: Journal of Biological Chemistry (2011)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: matrix metalloproteinases (MMPs); drug targets; malignancies; structure; catalytic domain
Affiliations: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.

Abstract:  Because of their important function, matrix metalloproteinases (MMPs) are promising drug targets in multiple diseases, including malignancies. The structure of MMPs includes a catalytic domain, a hinge, and a hemopexin domain (PEX), which are followed by a transmembrane and cytoplasmic tail domains or by a glycosylphosphatidylinositol linker in membrane-type MMPs (MT-MMPs). TIMPs-1, -2, -3, and -4 are potent natural regulators of the MMP activity. These are the inhibitory N-terminal and the non-inhibitory C-terminal structural domains in TIMPs. Based on our structural modeling, we hypothesized that steric clashes exist between the non-inhibitory C-terminal domain of TIMPs and the PEX of MMPs. Conversely, a certain mobility of the PEX relative to the catalytic domain is required to avoid these obstacles. Because of its exceedingly poor association constant and, in contrast with TIMP-2, TIMP-1 is inefficient against MT1-MMP. We specifically selected an MT1-MMP·TIMP-1 pair to test our hypothesis, because any improvement of the inhibitory potency would be readily recorded. We characterized the domain-swapped MT1-MMP chimeras in which the PEX of MMP-2 (that forms a complex with TIMP-2) and of MMP-9 (that forms a complex with TIMP-1) replaced the original PEX in the MT1-MMP structure. In contrast with the wild-type MT1-MMP, the diverse proteolytic activities of the swapped-PEX chimeras were then inhibited by both TIMP-1 and TIMP-2. Overall, our studies suggest that the structural parameters of both domains of TIMPs have to be taken into account for their re-engineering to harness the therapeutic in vivo potential of the novel TIMP-based MMP antagonists with constrained selectivity. 

Retracted: No

PubPeer comments:
 ![file] Figure 3 , 
 ![file] , 
 Figure 3B, a third concern marked in blue: ![file] ,
Intracellular alpha-fetoprotein interferes with all-trans retinoic acid induced ATG7 expression and autophagy in hepatocellular carcinoma cells
Authors: Huiguo Ding
Dexi Chen
Shanshan Wang
Chenguang Zhang
Honglei Weng
Rilu Feng
Ying Shi
Journal: Scientific Reports (2021)
Discipline: Multidisciplinary
Keywords: Retinoic acid; retinoid acid receptor; hepatocellular carcinoma; autophagy; apoptosis
Affiliations: Beijing Institute of Hepatology, Beijing You' An Hospital, Capital Medical University, Beijing, 100069, China., Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany., Department of Gastroenterology and Hepatology, Beijing You'An Hospital, Capital Medical University, Beijing, 100069, China., Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. .

Abstract:  Retinoic acid and retinoid acid receptor (RA-RAR) signaling exhibits suppressive functions in the progression of hepatocellular carcinoma (HCC) through multiple mechanisms. However, whether RA-RAR signaling induces autophagy that contributes its anti-tumor activity in HCC remains elusive. In the current study, the effects of RA-RAR pathway on autophagy were investigated in two HCC cell lines: alpha-fetoprotein (AFP) positive PLC/PRF/5 and AFP negative HLE cells. Cell autophagy was analyzed with western blot for detection of LC3 conversion and p62/SQSTM1 degradation while autophagy flux was assayed using the mRFP-GFP-LC3 reporter. Cell apoptosis and viability were analyzed by caspase-3 activity, TdT-mediated dUTP nick end labeling (TUNEL) assay, and Cell Counting Kit (CCK)-8, respectively. Chromatin immunoprecipitation (ChIP) was employed to detect the binding of RAR onto the promoter of autophagy-relevant 7 (ATG7), and co-immunoprecipitation (CoIP) was used to analyze the interaction of AFP and RAR. The results showed that ATRA dosage and time-dependently induced high levels of cell autophagy in both the PLC/PRF/5 and HLE cells, which was accompanied with up-regulation of ATG7. ChIP assay showed that RAR was able to bind to its responsive elements on ATG7 promoter. Impairment of ATG7 induction or blockade of autophagy with chloroquine aggravated ATRA induced apoptosis of HCC cells. Furthermore, intracellular AFP was able to complex with RAR in PLC/PRF/5 cells. Knockdown of AFP in PLC/PRF/5 cells augmented the up-regulation of ATG7 by ATRA while overexpression of AFP in HLE cells attenuated ATRA induced ATG7 expression and autophagy. Thus, ATRA induced ATG7 and autophagy participated in its cytotoxicity on HCC cells and AFP interfere with the induction of ATG7 and autophagy through forming complex with RAR. 

Retracted: No

PubPeer comments:
 Could the authors please comment on the similarity between the images below from Figure 4C and Figure 5A (red boxes). These seem to be described as different cells. *** ![file] ,
Targeted Protein Internalization and Degradation by ENDosome TArgeting Chimeras (ENDTACs)
Authors: Stacey-Lynn Paiva
Dhanusha A Nalawansha
Mariell Pettersson
Liena Qin
Craig M Crews
Diane N Rafizadeh
Journal: ACS Central Science (2019)
Discipline: CHEMISTRY
Keywords: Targeted protein degradation; PROTACs; extracellular targets; growth factors; cytokines
Affiliations: Department of Molecular, Cellular and Developmental Biology, Yale University, 219 Prospect Street, New Haven, Connecticut 06511, United States., Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States., Department of Pharmacology, Yale University, New Haven, Connecticut 06511, United States.

Abstract:  Targeted protein degradation has generated excitement in chemical biology and drug discovery throughout academia and industry. By hijacking the machinery responsible for protein degradation via the ubiquitin proteasome system (UPS), various cellular targets have been selectively degraded. However, since the tools used, often termed PROteolysis TArgeting Chimeras (PROTACs), hijack the intracellular quality control machinery, this technology can only access targets within the cell. Extracellular targets such as growth factors, cytokines, and chemokines bind to cell surface receptors, often initiating aberrant signaling in multiple diseases such as cancer and inflammation. However, efforts to develop small molecule inhibitors for these extracellular target proteins have been challenging. Herein, we developed a proof-of-concept approach to evaluate if extracellular proteins can be internalized and degraded via the receptor-mediated endolysosomal pathway. Using a heterodimeric molecule, termed "ENDosome TArgeting Chimera" (ENDTAC), internalization and degradation of an extracellular recombinant eGFP-HT7 fusion protein was achieved by hijacking the decoy GPCR receptor, CXCR7. This proof-of-concept study suggests that using ENDTACs to co-opt the endosomal-lysosomal degradation pathway, in contrast to PROTACs using the UPS, may provide an avenue for degrading extracellular targets such as cytokines. Overall, the technology described herein provides a novel expansion to the field of targeted protein degradation. 

Retracted: Yes

PubPeer comments:
 **RETRACTION of  Targeted Protein Internalization and Degradation by ENDosome TArgeting Chimeras (ENDTACs) **  The authors retract this article after further experiments resynthesizing compounds ENDTAC-1 and ENDTAC-neg were unable to reproduce the presented findings on small molecule-directed targeting of extracellular proteins for degradation via the lysosome. The original Article was published on May 9, 2019, and retracted on January 23, 2020. https: pubs.acs.org doi 10.1021 acscentsci.0c00021 ,
Novel role for insulin as an autocrine growth factor for malignant brain tumour cells
Authors: Simone M Schoenwaelder
Ana S Guerreiro
Danielle Boller
Michael A Grotzer
Alexandre Arcaro
Olivier Delattre
Barbara Fischer
Tarek Shalaby
Kathrin T Doepfner
Shaun P Jackson
Journal: Biochemical Journal (2007)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: AT/RTs; CNS; childhood malignancies; survival rates; chemotherapy resistance
Affiliations: Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland. , Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland, Department of Oncology, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland, Australian Centre for Blood Diseases, Monash University, 6th Floor, Burnet Building, Alfred Medical Research and Education Precinct, Prahran, VIC 3181, Australia, Institut Curie, Laboratoire de Pathologie Moléculaire des Cancers, 26 rue d'Ulm, Paris 75248, France, INSERM U509, Paris 75248, France

Abstract:  AT/RTs (atypical teratoid/rhabdoid tumours) of the CNS (central nervous system) are childhood malignancies associated with poor survival rates due to resistance to conventional treatments such as chemotherapy. We characterized a panel of human AT/RT and MRT (malignant rhabdoid tumour) cell lines for expression of RTKs (receptor tyrosine kinases) and their involvement in tumour growth and survival. When compared with normal brain tissue, AT/RT cell lines overexpressed the IR (insulin receptor) and the IGFIR (insulin-like growth factor-I receptor). Moreover, insulin was secreted by AT/RT cells grown in serum-free medium. Insulin potently activated Akt (also called protein kinase B) in AT/RT cells, as compared with other growth factors, such as epidermal growth factor. Pharmacological inhibitors, neutralizing antibodies, or RNAi (RNA interference) targeting the IR impaired the growth of AT/RT cell lines and induced apoptosis. Inhibitors of the PI3K (phosphoinositide 3-kinase)/Akt pathway also impaired basal and insulin-stimulated AT/RT cell proliferation. Experiments using RNAi and isoform-specific pharmacological inhibitors established a key role for the class I(A) PI3K p110alpha isoform in AT/RT cell growth and insulin signalling. Taken together, our results reveal a novel role for autocrine signalling by insulin and the IR in growth and survival of malignant human CNS tumour cells via the PI3K/Akt pathway. 

Retracted: No

PubPeer comments:
null, 
null, 
 #1 Figure 1A. Differential (no same in all panels) spicing. ![file] , 
 #2 Figure 1A. Finer detail. Vertical, sharp changes in signal not at the same place in different panels. ![file] ,
STAT3 negatively regulates thyroid tumorigenesis
Authors: Jorge Lima
Valdemar Máximo
Laura Daly
Jeffrey A Knauf
Joana Pinto Couto
Jacqueline F Bromberg
Manuel Sobrinho-Simões
Paula Soares
James A Fagin
Ana Almeida
David Lyden
Journal: Proceedings of the National Academy of Sciences of the United States of America (2012)
Discipline: Multidisciplinary
Keywords: tyrosine-phosphorylated; STAT3; thyroid cancer; tumorigenesis; papillary thyroid carcinoma
Affiliations: Department of Cancer Biology,  Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto,  Portugal.

Abstract:  Although tyrosine-phosphorylated or activated STAT3 (pY-STAT3) is a well-described mediator of tumorigenesis, its role in thyroid cancer has not been investigated. We observed that 63 of 110 (57%) human primary papillary thyroid carcinoma (PTC) cases expressed nuclear pY-STAT3 in tumor cells, preferentially in association with the tumor stroma. An inverse relationship between pY-STAT3 expression with tumor size and the presence of distant metastases was observed. Using human thyroid cancer-derived cell lines [harboring rearranged during transfection (RET)/PTC, v-RAF murine sarcoma viral oncogene homolog B (BRAF), or rat sarcoma virus oncogene (RAS) alterations], we determined that IL-6/gp130/JAK signaling is responsible for STAT3 activation. STAT3 knockdown by shRNA in representative thyroid cancer cell lines that express high levels of pY-STAT3 had no effect on in vitro growth. However, xenografted short hairpin STAT3 cells generated larger tumors than control cells. Similarly, STAT3 deficiency in a murine model of BRAFV600E-induced PTC led to thyroid tumors that were more proliferative and larger than those tumors expressing STAT3wt. Genome expression analysis revealed that STAT3 knockdown resulted in the down-regulation of multiple transcripts, including the tumor suppressor insulin-like growth factor binding protein 7. Furthermore, STAT3 knockdown led to an increase in glucose consumption, lactate production, and expression of Hypoxia-inducible factor 1 (HIF1α) target genes, suggesting that STAT3 is a negative regulator of aerobic glycolysis. Our studies show that, in the context of thyroid cancer, STAT3 is paradoxically a negative regulator of tumor growth. These findings suggest that targeting STAT3 in these cancers could enhance tumor size and highlight the complexities of the role of STAT3 in tumorigenesis. 

Retracted: No

PubPeer comments:
 This paper appears to be generated by SCIgen either in part or entirely. * Extensible modalities and Web services have garnered significant interest from both biologists and cyberneticists in the last several years. Our objective here is to set the record straight and confirm the development of super pages. and so on... Published by Elsevier. , 
 I emailed the corresponding author, on the off chance this was an attempt at a hoax. He denied using SciGen. ,