Publications by authors named "Yiwei Lin"

76 Publications

The Psychological Restorative Effects of Campus Environments on College Students in the Context of the COVID-19 Pandemic: A Case Study at Northwest A&F University, Shaanxi, China.

Int J Environ Res Public Health 2021 08 18;18(16). Epub 2021 Aug 18.

College of Landscape Architecture and Arts, Northwest A&F University, Xianyang 712100, China.

During the COVID-19 outbreak, college students experienced different periods of isolation on campus, which has had an impact on students' mental health. Based on ART theory, this study randomly selected students at Northwest A&F University, Shaanxi, China and distributed questionnaires in order to evaluate the psychological recovery effect of campus environment during the epidemic. The results showed that: (1) There were significant differences in the psychological restoration of four types of campus environments. Blue space had the greatest effect, followed by green space and sports grounds, while grey space had the least. (2) Time of stay had a very significant impact on psychological restoration. Longer time of exposure is not necessarily correlated with a better recovery experience. (3) In the different campus environments, extent is easier to be perceived followed by fascination and compatibility, and the weakest is being away. At the time of stay level, no significant difference was found in the perception of compatibility. Time of stay was negatively correlated with fascination and compatibility. These findings can provide theoretical and practical bases for campus environmental planning and construction following the COVID-19 epidemic.
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http://dx.doi.org/10.3390/ijerph18168731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391757PMC
August 2021

Merlin functions as a critical regulator in Staphylococcus aureus-induced osteomyelitis.

J Cell Physiol 2021 Aug 11. Epub 2021 Aug 11.

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Merlin is known as a tumor suppressor, while its role in osteomyelitis remains unclear. This study aimed to investigate the role of Merlin in Staphylococcus aureus-induced osteomyelitis and its underlying mechanisms. S. aureus-induced osteomyelitis mouse model was established in Merlin Lyz2 and Merlin Lyz2 mice. Bone marrow-derived macrophages (BMDMs) were isolated and stimulated by lipopolysaccharide (LPS). Bioassays, including quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot analysis, and enzyme-linked immunosorbent assays, were conducted to determine the levels of target genes or proteins. Immunoprecipitation was applied to determine the interactions between proteins. DCAF1 mice were further crossed with Lyz2-Cre mice to establish myeloid cell conditional knockout mice (DCAF1 Lyz2 ). It was found that the level of Merlin was elevated in patients with osteomyelitis and S. aureus-infected BMDMs. Merlin deficiency in macrophages suppressed the production of inflammatory cytokines and ameliorated the symptoms of osteomyelitis induced by S. aureus. Merlin deficiency in macrophages also suppressed the production of proinflammatory cytokines in BMDMs induced by LPS. The inhibitory effects of Merlin deficiency on the inflammatory response were associated with DDB1-Cul4-associated factor 1 (DCAF1). In summary, Merlin deficiency ameliorates S. aureus-induced osteomyelitis through the regulation of DCAF1.
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http://dx.doi.org/10.1002/jcp.30550DOI Listing
August 2021

Gallium Porphyrin and Gallium Nitrate Reduce the High Vancomycin Tolerance of MRSA Biofilms by Promoting Extracellular DNA-Dependent Biofilm Dispersion.

ACS Infect Dis 2021 08 4;7(8):2565-2582. Epub 2021 Aug 4.

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.

Biofilms, structured communities of bacterial cells embedded in a self-produced extracellular matrix (ECM) which consists of proteins, polysaccharide intercellular adhesins (PIAs), and extracellular DNA (eDNA), play a key role in clinical infections and are associated with an increased morbidity and mortality by protecting the embedded bacteria against drug and immune response. The high levels of antibiotic tolerance render classical antibiotic therapies impractical for biofilm-related infections. Thus, novel drugs and strategies are required to reduce biofilm tolerance and eliminate biofilm-protected bacteria. Here, we showed that gallium, an iron mimetic metal, can lead to nutritional iron starvation and act as dispersal agent triggering the reconstruction and dispersion of mature methicillin-resistant (MRSA) biofilms in an eDNA-dependent manner. The extracellular matrix, along with the integral bacteria themselves, establishes the integrated three-dimensional structure of the mature biofilm. The structures and compositions of gallium-treated mature biofilms differed from those of natural or antibiotic-survived mature biofilms but were similar to those of immature biofilms. Similar to immature biofilms, gallium-treated biofilms had lower levels of antibiotic tolerance, and our in vitro tests showed that treatment with gallium agents reduced the antibiotic tolerance of mature MRSA biofilms. Thus, the sequential administration of gallium agents (gallium porphyrin and gallium nitrate) and relatively low concentrations of vancomycin (16 mg/L) effectively eliminated mature MRSA biofilms and eradicated biofilm-enclosed bacteria within 1 week. Our results suggested that gallium agents may represent a potential treatment for refractory biofilm-related infections, such as prosthetic joint infections (PJI) and osteomyelitis, and provide a novel basis for future biofilm treatments based on the disruption of normal biofilm-development processes.
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http://dx.doi.org/10.1021/acsinfecdis.1c00280DOI Listing
August 2021

Comprehensive Analysis of Ferroptosis Regulators With Regard to PD-L1 and Immune Infiltration in Clear Cell Renal Cell Carcinoma.

Front Cell Dev Biol 2021 5;9:676142. Epub 2021 Jul 5.

Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Clear cell renal cell carcinoma (ccRCC) is one of the tumor types with sensitivity to ferroptosis, and immunotherapy has emerged as a standard pillar for metastatic ccRCC treatment, while it remains largely obscure whether ferroptosis influences the tumor immune microenvironment in ccRCC. Based on available data in The Cancer Genome Atlas, divergent expression profiles of ferroptosis regulators were noted in ccRCC and normal tissues, and we also found that the ferroptosis regulators correlated with the PD-L1 expression. Two independent subtypes were determined by consensus clustering analysis according to the expression level of ferroptosis regulators in ccRCC. Cluster 1 showed lower histological tumor stage and grade, more favorable prognosis, and higher PD-L1 expression compared to cluster 2. CIBERSORT analysis revealed that cluster 2 harbored higher infiltrated levels of CD8+ T cell, Tregs, and T follicular helper cell, while cluster 1 more correlated with the monocyte, M1 macrophage, and M2 macrophage. Gene set enrichment analysis indicated that the ERBB signaling and JAK_STAT signaling pathways were significantly enriched in cluster 1. We subsequently identified CARS as the potentially key immune infiltration-related ferroptosis regulator, whose high expression showed dismal prognosis and was positively correlated with PD-L1 expression in ccRCC. We also verified the upregulation of CARS in ccRCC tissues and cell lines qRT-PCR method. Additionally, a pan-cancer analysis demonstrated that CARS closely related to the expression of immune checkpoint-related genes (especially PD-L1) and an unfavorable prognosis in diverse cancer types. In summary, our study suggested the crucial role of ferroptosis in immune infiltration of ccRCC, and CARS is a potentially novel prognostic biomarker and potential target for cancer immunotherapy.
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http://dx.doi.org/10.3389/fcell.2021.676142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287329PMC
July 2021

Ddb1-Cullin4-Associated-Factor 1 in Macrophages Restricts the -Induced Osteomyelitis.

J Inflamm Res 2021 28;14:1667-1676. Epub 2021 Apr 28.

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China.

Introduction: Ddb1-cullin4-associated-factor 1 (DCAF1) is known to regulate protein ubiquitination, while the roles of DCAF1 in osteomyelitis remain unknown. This study aims to investigate the effects of DCAF1 deficiency in macrophages on osteomyelitis and elucidate the molecular mechanism.

Methods: -induced mouse model of osteomyelitis was established on the DCAF1Lyz2 and DCAF1Lyz2 (control) mice. Flow cytometry was conducted to analyze the populations of adaptive and innate immune cells. Lipopolysaccharides (LPS)-induced bone marrow-derived macrophages (BMDMs) were established. qRT-PCR and immunoblot analysis were used to determine the levels of inflammation-related biomarkers. ELISA was used to determine the release of inflammatory cytokines including IL-1β, IL-6, and TNF.

Results: The populations of immune cells in the bone marrow and spleen were not affected due to DCAF1 deficiency in macrophages. DCAF1 suppressed inflammatory cytokines in LPS-induced BMDMs. Additionally, DCAF1 deficiency in macrophages induced severe symptoms including less bacterial load in the femur, cortical bone loss, and reactive bone formation. Mechanistic study revealed that DCAF1 deficiency induced p38 hyperactivation.

Discussion: DCAF1 in macrophages suppressed the -induced mouse model of osteomyelitis.
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http://dx.doi.org/10.2147/JIR.S307316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091595PMC
April 2021

IKKe in osteoclast inhibits the progression of methylprednisolone-induced osteonecrosis.

Int J Biol Sci 2021 30;17(5):1353-1360. Epub 2021 Mar 30.

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.

Previous studies have described that NF-κB signaling mediated by NFκB-inducing kinase (NIK) plays a critical role of the differentiation of osteoclasts. We aim to explore the role of IKKe in methylprednisolone -induced osteonecrosis of the femoral head (ONFH). Methylprednisolone-induced ONFH mice model was successfully established, and subjected to micro computed tomography to detect the femoral head image of the mice. Bone marrow cells from experimental mice were collected and cultured. qPCR and immunoblot were performed to examine the possible signal pathways of IKKe involvement, and osteoclast-related gene expressions in IKKe and IKKe cells and were examined. It was found that the levels of IKKe decreased in ONFH patients, and IKKe interacted with NIK in the NF-κB signal pathway to suppress osteoclasts inhibiting the transcription of NIK. Furthermore, IKKe knockout promoted the osteoclastogenesis in mice model. Finally, IKKe knockout suppressed methylprednisolone-induced ONFH and pro-inflammatory responses in mice model. Our findings show a mechanism of IKKe inhibition of the progression of methylprednisolone-induced ONFH via the NIK/NF-κB pathway.
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http://dx.doi.org/10.7150/ijbs.57962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040464PMC
March 2021

Astragaloside IV ameliorates steroid-induced osteonecrosis of the femoral head by repolarizing the phenotype of pro-inflammatory macrophages.

Int Immunopharmacol 2021 Apr 6;93:107345. Epub 2021 Feb 6.

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address:

Osteonecrosis of the femoral head (ON-FH) is a common complication of steroid use. Pro-inflammatory macrophages play a crucial role in the apoptosis of osteocytes. The objective of the study was to evaluate a plant extract astragaloside IV (AS-IV) in treating ON-FN. Bone-marrow-derived macrophages (BMDMs) were treated with lipopolysaccharides (LPS), IFN-γ or IL-4 to induce M1 and M2-like phenotypes. Quantitative real-time PCR and Western blot were used to examine M1 and M2 phenotypic markers. Flow cytometry was used to analyze MHC II, CD206, F4/80, and CD11b levels and cell apoptosis. Glucocorticoid was used to induce ON-FN in mice. TNF-α and IL-1β levels in femoral head were determined using enzyme-linked immunosorbent assay. AS-IV repolarized macrophages from M1 to M2 phenotypes. Culture medium from AS-IV treated M1 macrophages induced less cell apoptosis osteocytes compared to that from untreated M1 macrophages. In ON-FH mice, the ratio of M1 macrophages was decreased in the femoral head by AS-IV, concomitant with a decrease in TNF-α and IL-1β levels. AS-IV is effective in alleviating ON-FH through its effects in repolarizing macrophages from M1-like phenotype to M2-like phenotype, promoting survival of osteocytes, reducing arthritic symptoms, and decreasing inflammatory cytokines.
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http://dx.doi.org/10.1016/j.intimp.2020.107345DOI Listing
April 2021

Tumor necrosis factor-α promotes Staphylococcus aureus-induced osteomyelitis through downregulating endothelial nitric oxide synthase.

J Microbiol Immunol Infect 2020 Aug 13. Epub 2020 Aug 13.

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address:

Background: Infections of Staphylococcus aureus (S. aureus) often result in osteomyelitis, which is the acute or chronic infections of the bone marrow or bones. TNF-α is long recognized as a key factor contributing to the pathogenesis of osteomyelitis, but little is known about the underlying molecular mechanism.

Methods: Expression levels of TNF-α, and several candidate genes, including endothelial nitric oxide synthase (eNOS), known to be downregulated by TNF-α were analysed in MC3T3-E1 cells with S. aureus infection and osteomyelitis patient blood. MicroRNA(miR)-129-5p was predicted and experimentally verified to target eNOS. Alizarin red sulfate (ARS) and alkaline phosphatase (ALP) staining assays were conducted on MC3T3-E1 cells with S. aureus infection to assess the role of TNF-α/miR-129-5p/eNOS on mineralization defect.

Results: TNF-α and miR-129-5p were upregulated while eNOS was downregulated in MC3T3-E1 cells with S. aureus infection and osteomyelitis patients, showing inversely correlated expression profiles. MiR-129-5p directly binds to the 3'-UTR of eNOS mRNA to suppress eNOS expression in MC3T3-E1 cells. TNF-α blocker inhibited miR-129-5p and elevated eNOS expression, likely contributing to rescued mineralization defect in S. aureus-infected MC3T3-E1 cells. During S. aureus infection, upregulated TNF-α increases endogenous miR-129-5p expression, which in turn inhibits eNOS, contributing to osteomyelitis.

Conclusion: Our study thereby proposes a novel signalling cascade involving TNF-α/miR-129-5p/eNOS in the pathogenesis of osteomyelitis, which may also serve as therapeutic targets.
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http://dx.doi.org/10.1016/j.jmii.2020.08.002DOI Listing
August 2020

MicroRNA-23b-3p participates in steroid-induced osteonecrosis of the femoral head by suppressing ZNF667 expression.

Steroids 2020 11 28;163:108709. Epub 2020 Jul 28.

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address:

Background: Clinical treatment with high-dose of steroid hormone causes steroid-induced osteonecrosis of the femoral head (SONFH), whereas the internal regulation mechanism remains elusive. Numerous studies have reported that microRNAs participated in the development of SONFH through modulating gene expression. The aim of the current study was to clarify the function of microRNA-23b-3p (miR-23b-3p) and ZNF667 in SONFH.

Experimental Design: Bioinformatics prediction and luciferase reporter system were utilized to confirm the target relation between miR-23b-3p and ZNF667. To examine the function of miR-23b-3p in vivo, rat SONFH models were established by specific inducers. The morphological changes, plasma viscosity, blood lipid, and inflammatory cytokines were measure by corresponding experiments.

Results: MiR-23b-3p and ZNF667 was negatively correlated in SONFH patient tissues, miR-23b-3p was down-regulated, while ZNF667 was up-regulated. MiR-23b-3p targeted ZNF667, the expression level of ZNF667 was suppressed by miR-23b-3p activation whereas strengthened by miR-23b-3p inhibition. SONHF rats with overexpressed miR-23b-3p displayed alleviated symptoms, including reduced plasma viscosity, declined blood lipids, decreased levels of pro-inflammatory cytokines and improved bone integrality. Moreover, elevation of ZNF667 reversed the repression of SONFH induced by miR-23b-3p overexpression.

Conclusions: We found that miR-23b-3p played a protective role in SONFH by targeting ZNF667, which provided a novel reference for SONFH prevention and therapy.
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http://dx.doi.org/10.1016/j.steroids.2020.108709DOI Listing
November 2020

Involvement of mechanosensitive ion channels in the effects of mechanical stretch induces osteogenic differentiation in mouse bone marrow mesenchymal stem cells.

J Cell Physiol 2021 01 27;236(1):284-293. Epub 2020 Jun 27.

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Bone marrow mesenchymal stem cells (BMSCs) can be induced to process osteogenic differentiation with appropriate mechanical and/or chemical stimuli. The present study described the successful culture of murine BMSCs under mechanical strain. BMSCs were subjected to 0%, 3%, 8%, 13%, and 18% cyclic tensile strain at 0.5 Hz for 8 hr/day for 3 days. The expression of osteogenic markers and mechanosensitive ion channels was evaluated with real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blot. The expression of alkaline phosphatase (ALP) and matrix mineralization were evaluated with histochemical staining. To investigate the effects of mechanosensitive ion channel expression on cyclic tensile strain-induced osteogenic differentiation, the expression of osteogenic markers was evaluated with real-time RT-PCR in the cells without mechanosensitive ion channel expression. This study revealed a significant augment in osteogenic marker in BMSC strained at 8% compared to other treatments; therefore, an 8% strain was used for further investigations. The ALP expression and matrix mineralization were enhanced in osteogenic induced BMSCs subjected to 8% strain after 7 and 14 days, respectively. Under the same conditions, the osteogenic marker and mechanosensitive ion channel expression were significantly promoted. However, the loss function of mechanosensitive ion channels resulted in the inhibition of osteogenic marker expression. This study demonstrated that strain alone can successfully induce osteogenic differentiation in BMSCs and the expression of mechanosensitive ion channels was involved in the process. The current findings suggest that mechanical stretch could function as efficient stimuli to induce the osteogenic differentiation of BMSCs via the activation of mechanosensitive ion channels.
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http://dx.doi.org/10.1002/jcp.29841DOI Listing
January 2021

IL-15 deficiency alleviates steroid-induced osteonecrosis of the femoral head by impact osteoclasts via RANKL-RANK-OPG system.

Immun Ageing 2020 12;17:19. Epub 2020 Jun 12.

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233 China.

Background: Whether IL-15 is involved in the development of steroid-induced osteonecrosis of the femoral head (ONFH) is investigated.

Methods: C57BL/6 J and l15mice were injected with methylprednisolone to induce wide type osteonecrosis (WT ON) and IL-15 deficiency osteonecrosis (IL-15 ON). Hematoxylin-Eosin (H&E) staining and micro-computed tomography (micro-CT) scanning was used to detect the microstructure. The differentiation and formation of osteoclasts were determined with colony-forming unit-granulocyte macrophages (CFU-GM), colony-forming unit-macrophage/mononuclear (CFU-M) per tibia, and tartrate-resistant acid phosphatase (TRACP or TRAP) positive cells. Serum interleukin (IL)-15, osteocalcin, bone alkaline phosphatase (BAP), bone Gla protein (BGP), and TRACP were assayed with enzyme-linked immunosorbent assay (ELISA). The receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) in the femoral heads were detected by Western blot. CD34 staining was performed to detect microvascular density.

Results: IL-15 secretion was increased in the femoral heads and the serum of steroid-induced ONFH mice. IL-15 deficiency may lead to up-regulated vessel remodeling, improved microstructure, and up-regulated serum osteocalcin, BAP, and BGP secretion. Both the expression of RANKL/RANK/OPG and osteoclast differentiation and formation can be down-regulated by IL-15 deficiency.

Conclusion: IL-15 deficiency alleviates steroid-induced ONFH by impact osteoclasts via RANKL-RANK-OPG system.
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http://dx.doi.org/10.1186/s12979-020-00190-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291529PMC
June 2020

AMBMP activates WNT pathway and alleviates stress-induced behaviors in maternal separation and chronic stress models.

Eur J Pharmacol 2020 Aug 12;881:173192. Epub 2020 May 12.

Department of Psychiatry, The First Hospital of China Medical University, Shenyang, Liaoning Province, China. Electronic address:

Depressive disorders are both prevalent and debilitating, and a proportion of patients have treatment resistance to classic antidepressants. Recent evidence has implicated the intracellular WNT signaling pathway as having a key role in the pathogenesis of major depressive disorder. In the present study, we investigated the role of β-catenin and transcription factor-4 (TCF4) in the depression-like and anxiety-like behaviors exhibited by mice exposed to maternal separation, or chronic mild stress. Both rodent models of childhood and adulthood stress showed depression and anxiety-like behaviors. During the last three weeks of medication, we applied AMBMP (2-Amino-4-[3,4- (methylenedioxy)benzylamino]-6-(3-methoxyphenyl)pyrimidine) to the maternal separation and chronic stress model for the first time. The drug alleviated the depression-like index in saccharin preference test (SPT) and forced swim test (FST), and anxiety-like index in open field test (OFT) and elevated-plus maze (EPM), and reversed the disruption of β-catenin and TCF4 in stressed mice by upregulating the WNT pathway specifically. Therefore, the WNT pathway may be involved in the mediation of patient recovery and could be a target for novel antidepressants.
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http://dx.doi.org/10.1016/j.ejphar.2020.173192DOI Listing
August 2020

miR-26a Attenuated Bone-Specific Insulin Resistance and Bone Quality in Diabetic Mice.

Mol Ther Nucleic Acids 2020 Jun 29;20:459-467. Epub 2020 Mar 29.

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address:

Diabetes mellitus is a prevalent disease result in several complications, including bone problems. Previous studies have shown that microRNA (miR)-26a regulates glucose metabolism and plays a protective role in diabetes. However, whether miR-26a also affects bone quality in diabetes remains unknown. In the present study, we evaluated the potential effects of miR-26a on bone in diabetic mice. We administrated miR-26a in streptozotocin-induced diabetic mice. The metabolic parameters, bone quality, osteoblast and osteoclast markers, and insulin signaling activation were measured. miR-26a ameliorated insulin resistance and glucose tolerance, improved bone microarchitecture and quality, increased osteoblasts and bone formation, decreased osteoclasts, and promoted the insulin signaling pathway in diabetic mice. These effects were abolished in insulin receptor-compromised Col1a1-Insr mice. In conclusion, miR-26a could ameliorate bone-specific insulin resistance and bone quality in diabetic mice, which depended on the insulin receptors on osteoblasts. Our findings highlight the potential of miR-26a as a therapeutic target for diabetes mellitus-related bone metabolism and diseases.
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http://dx.doi.org/10.1016/j.omtn.2020.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150437PMC
June 2020

Correction: Lithium-containing biomaterials inhibit osteoclastogenesis of macrophages in vitro and osteolysis in vivo.

J Mater Chem B 2019 04 25;7(15):2566. Epub 2019 Mar 25.

Department of Orthopaedic, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Correction for 'Lithium-containing biomaterials inhibit osteoclastogenesis of macrophages in vitro and osteolysis in vivo' by Chenhao Pan et al., J. Mater. Chem. B, 2018, 6, 8115-8126.
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http://dx.doi.org/10.1039/c9tb90039jDOI Listing
April 2019

Fine-tuning the diradical character of molecular systems via the heteroatom effect.

Chem Commun (Camb) 2020 Jan 8;56(9):1405-1408. Epub 2020 Jan 8.

Department School of Optoelectronic Science and Engineering Institution University of Electronic Science and Technology of China (UESTC), Chengdu 610054, China.

Heteroatoms were introduced as a novel modification strategy for fine-tuning the diradical character of molecular systems. Both the diradical character and the singlet-triplet energy gaps of diketopyrrolopyrrole based phenoxyl diradicaloids decreased as the size of the substituted heteroatoms (from O, S to Se atom) increased.
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http://dx.doi.org/10.1039/c9cc08538fDOI Listing
January 2020

Quinonoid Zwitterion: An Amphiphilic Cathode Interlayer with Initial Thickness-Insensitive and Self-Organizing Properties for Inverted Polymer Solar Cells.

ACS Appl Mater Interfaces 2020 Jan 7;12(3):3792-3799. Epub 2020 Jan 7.

School of Optoelectronic Science and Engineering , University of Electronic Science and Technology of China (UESTC) , Chengdu 610054 , P. R. China.

Orthogonal solvent processability is generally considered as one of the key requirements for an efficient interfacial material. Here, we showed that in inverted polymer solar cells (PSCs), solvent orthogonality is not required for an effective and reliable cathode interlayer. A quinonoid zwitterionic molecule with amphiphilic property [dissolved in both methanol and -dichlorobenzene (-DCB)] named ZW-Bu was first applied as the cathode interlayer in inverted PSCs. For three different photoactive systems, the devices with ZW-Bu cathode buffer layers (CBLs) exhibited better performance than those with commonly used ZnO CBLs. Most importantly, the device efficiency was fairly insensitive to the initial thickness of ZW-Bu. In addition, due to the high surface energy of the ZW-Bu film, it was successfully used as a self-organized CBL in poly(3-hexylthiophene) (P3HT):[6,6]-phenyl-C-butyric acid methyl ester (PCBM) systems, yielding a desirable efficiency compared to the PSCs fabricated via the layer-by-layer deposition method.
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http://dx.doi.org/10.1021/acsami.9b17208DOI Listing
January 2020

The promotion of bone regeneration through CS/GP-CTH/antagomir-133a/b sustained release system.

Nanomedicine 2020 02 28;24:102116. Epub 2019 Oct 28.

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. Electronic address:

Few studies reported the application of miRNA in bone regeneration. In this study, the expression of miR133a and miR133b in murine BMSCs was inhibited via antagomiR-133a/b and the osteogenic differentiation in murine BMSCs was evaluated. The RT-PCR, flow cytometry, cell counting kit-8, and annexin V-FITC/PI double staining assays were performed. Double knockdown miR133a and miR133b can promote BMSC osteogenic differentiation. At optimum N/P ration (15:1), the loading efficiency can reach over 90%. CTH-antagomiR-133a/b showed no cytotoxicity to BMSCs and diminished miR133a and miR133b expression in BMSCs. Furthermore, chitosan-based sustained delivery system can facilitate continuous dosing of antagomiR-133a/b, which enhanced calcium deposition and osteogenic specific gene expression in vitro. The new bone formation was enhanced after the sustained delivery system containing CTH-antagomiR-133a/b nanoparticles was used in mouse calvarial bone defect model. Our results demonstrate that CTH nanoparticles could facilitate continuous dosing of antagomiR133a/b, which can promote osteogenic differentiation.
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http://dx.doi.org/10.1016/j.nano.2019.102116DOI Listing
February 2020

Fecal microbiota transplantation from chronic unpredictable mild stress mice donors affects anxiety-like and depression-like behavior in recipient mice via the gut microbiota-inflammation-brain axis.

Stress 2019 09 24;22(5):592-602. Epub 2019 May 24.

b Department of Psychiatry, The First Hospital of China Medical University , Shenyang , China.

Recent studies have demonstrated that there are significant changes in the gut microbiota (GM) of humans with depression and animal models of depression and chronic stress. In our present study, we determined whether an alteration in GM is a decisive factor in anxiety-like and depression-like behavior and its impact on brain neurochemistry. An antibiotic cocktail was used to deplete the GM of mice before they were colonized, via fecal microbiota transplantation (FMT), by the GM of control mice or mice that had been exposed to chronic unpredictable mild stress (CUMS donors). The CUMS-donor group of mice and the mice that were colonized by their microbiota (the CUMS-recipient group) both showed higher levels of anxiety- and depression-like behavior compared to the controls. The GM community of the CUMS-donor and CUMS-recipient was distinctively different from the controls, with the CUMS group characterized by a lower relative abundance of and a higher relative abundance of . Interestingly, FMT affected both behavior and neuroinflammation. Mice given the CUMS microbiota had significant elevations of interferon-γ (IFN-γ) and the tumor necrosis factor-alpha (TNF-α) in the hippocampus, which were accompanied by upregulated indoleamine 2,3-dioxygenase 1 (IDO1) in the hippocampus. These results suggest that GM modulates pro-inflammatory cytokines in the hippocampus through dysfunctional microbiota-gut-brain axis, exacerbating anxiety- and depression-like phenotypes. Key Points Chronic unpredictable mild stress increased anxiety- and depression-like behavior in mice. Mice colonized with gut microbiota (GM) from stressed mice showed similar behaviors. The GM composition of the donor and recipient mice was also comparable. Their relative pattern of two bacteria has been tied to neuroinflammatory activity. The results suggest a link between GM, brain function, and anxiety and depression.
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http://dx.doi.org/10.1080/10253890.2019.1617267DOI Listing
September 2019

Prostatic-type polyp located in the bladder of an adolescent: A case report and overview.

J Int Med Res 2019 Apr 28;47(4):1787-1792. Epub 2019 Feb 28.

1 Department of Urology, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, China.

Prostatic-type polyps are uncommon lesions in the urinary tract. They are sometimes found in the lower urinary tract, particularly on the posterior urethra, but are rarely found in the bladder. We report a case of 15-year-old boy who presented with dysuria. Routine ultrasonography showed a mass in the bladder arising near the internal orifice of urethra. Further inspection with cystoscopy followed by transurethral resection and pathology confirmed the lesion to be a prostatic-type polyp. An overview of other similar case studies showed that the pathogenesis of this condition is controversial, haematuria and dysuria are common clinical symptoms and endoscopic transurethral resection is the best treatment option. Since the polyp is benign, recurrence and progression of this disorder is unlikely to occur.
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http://dx.doi.org/10.1177/0300060519828122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460601PMC
April 2019

Correction: Up-regulation of p16 by miR-877-3p inhibits proliferation of bladder cancer.

Oncotarget 2019 01 18;10(6):684. Epub 2019 Jan 18.

Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, PR China.

[This corrects the article DOI: 10.18632/oncotarget.10575.].
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http://dx.doi.org/10.18632/oncotarget.26624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363010PMC
January 2019

20(S)-Protopanaxadiol Inhibits Titanium Particle-Induced Inflammatory Osteolysis and RANKL-Mediated Osteoclastogenesis via MAPK and NF-κB Signaling Pathways.

Front Pharmacol 2018 18;9:1538. Epub 2019 Jan 18.

Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Osteolysis is a principal reason for arthroplasty failure like aseptic loosening induced by Titanium (Ti) particle. It is a challenge for orthopedic surgeons. Recent researches show that 20(S)-protopanaxadiol can inhibit inflammatory cytokine release . This study aims to assess the effect of 20(S)-protopanaxadiol on Ti particle-induced osteolysis and RANKL-mediated osteoclastogenesis. Micro-CT and histological analysis indicated the inhibitory effects of 20(S)-protopanaxadiol on osteoclastogenesis and the excretion of inflammatory cytokines. Next, we demonstrated that 20(S)-protopanaxadiol inhibited osteoclast differentiation, bone resorption area, and F-actin ring formation in a dose-dependent manner. Moreover, mechanistic studies suggested that the suppression of MAPK and NF-κB signaling pathways were found to mediate the inhibitory effects of 20(S)-protopanaxadiol. In conclusion, 20(S)-protopanaxadiol may suppress osteoclastogenesis in a dose- dependent manner and it could be a potential treatment of Ti particle-induced osteolysis.
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http://dx.doi.org/10.3389/fphar.2018.01538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345703PMC
January 2019

Lithium-containing biomaterials inhibit osteoclastogenesis of macrophages in vitro and osteolysis in vivo.

J Mater Chem B 2018 Dec 21;6(48):8115-8126. Epub 2018 Nov 21.

Department of Orthopaedic, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Osteolysis, which is caused by aging, neoplasia, infection, or trauma, is a type of intractable systemic or local syndrome of bone destruction (e.g., peri-implant osteolysis (PIO)). The activation of osteoclasts differentiated from macrophages plays a decisive role in such diseases. To conquer this challenge, herein, a biomaterial capable of inhibiting osteoclastogenesis and osteolysis was designed. Recent research has shown that lithium (Li) can inhibit pro-inflammatory cytokine release in vitro via affecting the pharmacotherapy of psychiatric illnesses. Therefore, we synthesized a pure-phase lithium-calcium-silicate (LiCaSiO, LCS) bioceramic and further prepared extracts to assess the effect of LCS on RANKL-induced osteoclastogenesis in vitro and Ti particle-induced osteolysis in vivo as well as the corresponding mechanism. The results demonstrated that LCS inhibited RANKL-induced osteoclastogenesis of macrophages, bone resorption area, and F-actin ring formation in a dose-dependent manner. The mechanism is related to the suppression of the NF-kB signaling pathways mediating the inhibitory effects of LCS. Moreover, LCS was found to be able to inhibit calvarial osteolysis in a mouse model through micro-CT and histological analysis. These findings suggest that LCS may be a promising biomaterial for suppressing osteolysis, thus paving the way for the treatment of osteoporosis using bioactive inorganic materials.
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http://dx.doi.org/10.1039/c8tb02678eDOI Listing
December 2018

Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer.

Nat Commun 2018 12 5;9(1):5200. Epub 2018 Dec 5.

Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, 40506, USA.

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer.
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http://dx.doi.org/10.1038/s41467-018-07258-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281582PMC
December 2018

Oral Probiotics Ameliorate the Behavioral Deficits Induced by Chronic Mild Stress in Mice via the Gut Microbiota-Inflammation Axis.

Front Behav Neurosci 2018 6;12:266. Epub 2018 Nov 6.

Department of Psychiatry, The First Hospital of China Medical University, Shenyang, China.

In recent years, a burgeoning body of research has revealed links between depression and the gut microbiota, leading to the therapeutic use of probiotics for stress-related disorders. In this study, we explored the potential antidepressant efficacy of a multi-strain probiotics treatment (, , and ) in a chronic mild stress (CMS) mouse model of depression and determined its probable mechanism of action. Our findings revealed that mice subjected to CMS exhibited anxiety- and depressive-like behaviors in the sucrose preference test, elevated plus maze, and forced swim test, along with increased interferon-γ, tumor necrosis factor-α, and indoleamine 2,3-dioxygenase-1 levels in the hippocampus. Moreover, the microbiota distinctly changed from the non-stress group and was characterized by highly diverse bacterial communities associated with significant reductions in species. Probiotics attenuated CMS-induced anxiety- and depressive-like behaviors, significantly increased abundance, and reversed the CMS-induced immune changes in the hippocampus. Thus, the possible mechanism involved in the antidepressant-like activity of probiotics is correlated with species via the gut microbiota-inflammation-brain axis.
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http://dx.doi.org/10.3389/fnbeh.2018.00266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232506PMC
November 2018

JSH-23 prevents depressive-like behaviors in mice subjected to chronic mild stress: Effects on inflammation and antioxidant defense in the hippocampus.

Pharmacol Biochem Behav 2018 06 21;169:59-66. Epub 2018 Apr 21.

Department of Medical Psychiatry, General Hospital of Shenyang Military Command, Shenyang, Liaoning Province, China. Electronic address:

Nuclear factor-kappa B (NF-κB), which is reported to play an important role in the pathogenesis of depression, also has a central role in the genesis and progression of inflammation. Here, we have targeted the nuclear translocation of NF-κB using 4-methyl-N1-(3-phenyl-propyl)-benzene-1,2-diamine (JSH-23) to elucidate its role in depression. We investigated the antidepressant-like effects of JSH-23 in the chronic mild stress (CMS) mouse model, which is a valid, reasonably reliable, and useful model of depression. The antidepressant-like effects of JSH-23 were evaluated using the sucrose preference test (SPT) and the forced swimming test (FST). We also assessed inflammatory markers [interleukin (IL)-6 and tumor necrosis factor-α (TNF-α)] and components of antioxidant defense [superoxide dismutase (SOD) and nuclear factor erythroid-2-related factor 2 (Nrf 2)] in the hippocampus. Fluoxetine, a classical antidepressant, was used in this study as a positive control. Administration of JSH-23 significantly prevented the decreased sucrose preference in the SPT and prevented the increased immobility time in the FST caused by CMS, but had no effect on locomotor activity. Expression of NF-κB p65 protein in the hippocampus was decreased, and elevated levels of IL-6 and TNF-α were reduced, after JSH-23 administration. In addition to its anti-inflammatory effect, JSH-23 treatment increased the expression of SOD and Nrf 2 in the hippocampus, suggesting that it strengthens antioxidant defense. The current study demonstrated that inhibiting the NF-κB signaling cascade using JSH-23 prevented depressive-like behaviors by decreasing inflammation and improving antioxidant defense in the hippocampus. We concluded that NF-κB activation plays an important role in the pathophysiology of depression and that targeting NF-κB signaling may provide a novel and effective therapy for depression. Additional preclinical studies and clinical trials are, however, needed to further elucidate the effects of this therapeutic strategy.
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http://dx.doi.org/10.1016/j.pbb.2018.04.005DOI Listing
June 2018

CRISPR-ON-Mediated KLF4 overexpression inhibits the proliferation, migration and invasion of urothelial bladder cancer and .

Oncotarget 2017 Nov 27;8(60):102078-102087. Epub 2017 Oct 27.

Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, P.R. China.

Kruppel like factor 4 (KLF4), a transcription factor associated with carcinogenesis and tumor progression, plays an important role in various malignancies. In the present study, we utilized the CRISPR-ON system to upregulate KLF4 expression level and subsequently investigated the effect and mechanism of KLF4 in the carcinogenesis and progression of urothelial bladder cancer (UBC). Immunohistochemistry (IHC) and quantitative RT-PCR (qRT-PCR) were used to evaluate the expression of KLF4. The CpG methylation status of the promoter region was analyzed using bisulfite-sequencing PCR (BSP). CRISPR-ON system comprised sgRNA and dCas9 protein combined with a transcriptional activation domain. The cell proliferation and cell cycle were assessed by CCK-8 assay, flow cytometry and colony formation assay. The cell motility ability was evaluated using trans-well assay. tumorigenesis assay and lung metastasis model were also performed. The KLF4 expression was significantly downregulated in UBC tissues. The high CpG methylation status in the promoter of KLF4 was confirmed using BSP. KLF4 overexpression was successfully achieved via CRISPR-ON system, which inhibited the proliferation and induced G1-phase arrest in T24 cells through the regulation of AKT/p21 signal. Furthermore, enforced expression of KLF4 also abrogated the migration and invasion of T24 cells by suppressing EMT progression. Finally, models indicated that the upregulation of KLF4 could inhibit tumorigenesis and lung metastasis in nude mice. In conclusion, KLF4 overexpression mediated by CRISPR-ON inhibits tumorigenesis and EMT progression in UBC cells, representing a potential therapeutic target, and CRISPR-ON system could be a therapeutic strategy for UBC in the future.
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http://dx.doi.org/10.18632/oncotarget.22158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731936PMC
November 2017

MicroRNA-193a-3p inhibits cell proliferation in prostate cancer by targeting cyclin D1.

Oncol Lett 2017 Nov 1;14(5):5121-5128. Epub 2017 Sep 1.

Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.

MicroRNAs (miRNAs) are small non-coding RNAs that affect various biological processes by altering the expression of a target gene. An miRNA microarray analysis has previously revealed a significant decrease in miR-193a-3p levels in prostate cancer tissues compared with that in their benign prostate hyperplasia counterparts. However, the role of miR-193a-3p has yet to be elucidated. In the present study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the expression levels of miR-193a-3p in two human prostate cancer cell lines. Forced overexpression of miR-193a-3p was established by transfecting mimics into DU-145 and PC3 cell lines. Cell proliferation and the cell cycle were assessed using a cell viability assay, flow cytometry and a colony formation assay. In addition, the target gene of miR-193a-3p was determined by a luciferase assay, RT-qPCR and western blot analysis. The regulation of the cell cycle by miR-193a-3p was also evaluated by western blotting. The results demonstrated that miR-193a-3p expression levels were lower in prostate cancer cell lines as compared with the RWPE normal prostate epithelium cell line. Subsequent gain-of-function studies revealed that stable miR-193a-3p transfection inhibited cell viability, proliferation and colony formation, and induced G phase arrest in prostate cancer cells. A luciferase assay and western blot analysis identified cyclin D1 () as a direct target gene of miR-193a-3p. In addition, the forced expression of was able to counter the inhibitory effects of miR-193a-3p transfection in the prostate cancer cells. In summary, the results suggest that miR-193a-3p may inhibit the viability, proliferation and survival of prostate cancer cells by regulating the expression profile of , and that miR-193a-3p may be a novel therapeutic biomarker for prostate cancer.
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http://dx.doi.org/10.3892/ol.2017.6865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666665PMC
November 2017

c-Met, CREB1 and EGFR are involved in miR-493-5p inhibition of EMT via AKT/GSK-3β/Snail signaling in prostate cancer.

Oncotarget 2017 Oct 19;8(47):82303-82313. Epub 2017 Jul 19.

Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.

miR-493-5p downregulation has emerged as a critical player in cancer progression yet, the underlying mechanisms of miR-493-5p expression pattern and its function in prostate cancer remains to be elucidated. Here, we illustrate that miR-493-5p is frequently downregulated in prostate cancer, at least partially due to altered DNA methylation. miR-493-5p functions as a tumor suppressor in prostate cancer cells. c-Met, CREB1 and EGFR are downstream target genes of miR-493-5p. miR-493-5p inhibits EMT via AKT/GSK-3β/Snail signaling in prostate cancer. Taken together, our study identified c-Met, CREB1, EGFR and miR-493-5p establish a regulatory loop in prostate cancer, which could prove useful in the development of effective and therapies against prostate cancer.
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http://dx.doi.org/10.18632/oncotarget.19398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669891PMC
October 2017

Stabilization of the transcription factors slug and twist by the deubiquitinase dub3 is a key requirement for tumor metastasis.

Oncotarget 2017 Sep 24;8(43):75127-75140. Epub 2017 Aug 24.

Department of Pharmacology & Nutritional Sciences, Lexington, KY, USA.

The epithelial-mesenchymal transition (EMT) represents a cellular de-differentiation process that provides cells with the increased plasticity required during embryonic development, tissue remodeling, wound healing and metastasis. Slug and Twist are two key EMT transcription factors (EMT-TFs) that are tightly regulated via ubiquitination and degradation. How Slug and Twist escape degradation and become stabilized in cancer cells remains unclear. One plausible mechanism of Slug and Twist stabilization involves removal of ubiquitin by deubiquitinases (DUBs). In this study, we identified Dub3 as a novel DUB for both Slug and Twist. We further found that Dub3 overexpression increased Slug and Twist protein levels in a dose-dependent manner, whereas Dub3-knockdown decreased their protein levels. Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of breast cancer cells. Intriguingly, Dub3 was identified as an early response gene that was upregulated after exposure to inflammatory cytokines such as IL-6, which plays a critical role in the growth and metastasis of breast cancer cells, as well as the maintenance of breast CSCs. We found that Dub3 played an essential role in IL-6 induced EMT through stabilization of Slug and Twist. Our study has uncovered an IL-6-Dub3-Slug/Twist signaling axis during EMT and suggests potential approaches that could target Dub3 to prevent metastatic breast tumor.
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http://dx.doi.org/10.18632/oncotarget.20561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650406PMC
September 2017

Alpha7 nAChR Agonists for Cognitive Deficit and Negative Symptoms in Schizophrenia: A Meta-analysis of Randomized Double-blind Controlled Trials.

Shanghai Arch Psychiatry 2017 Aug;29(4):191-199

Department of Psychiatry, the First Hospital of China Medical University, Shenyang, China.

Background: Previous clinical trials of α7-nicotinic acetylcholine receptor agonists (α7-nAChR agonists) showed mixed results in treating the cognitive and negative symptoms of schizophrenia.

Aims: To assess the efficacy and safety of α7-nAChR agonists in treating the cognitive and negative symptoms in schizophrenia.

Methods: A literature search was conducted to identify randomized double-blind placebo-controlled trials for schizophrenia published before May 26, 2017, by searching PubMed, Embase, ClinicalTrials.gov, the Cochrane Library and the Chinese language databases CNKI, Wanfang, and VIP Data. The effects of α7-nAChR agonists were evaluated for overall cognitive function and negative symptoms by calculating standard mean difference (SMDs) between active drugs and placebo added to antipsychotics.

Results: 8 studies with low bias were included. We found no statistically significant effects of α7 nAChR agonists on the overall cognitive function (SMD=-0.10[-0.46, 0.25], =88%) and negative symptoms (SMD=0.13 [-0.04, 0.30], =64%) in patients with schizophrenia. Sensitivity analysis showed these results to be firm. And this drug is generally safe and well tolerated with no significant difference from placebo based on adverse events (RR=1.02, [0.85, 1.23]) and dropouts (RR=1.04, [0.61, 1.78]) data. Evidence based on outcomes from the meta-analysis was rated as 'moderate' as per the GRADE guidelines.

Conclusion: α7-nAChR agonists may not be effective in reversing overall cognitive impairments and negative symptoms in patients with schizophrenia as adjunctive therapies.
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http://dx.doi.org/10.11919/j.issn.1002-0829.217044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608991PMC
August 2017
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