Publications by authors named "Fangxia Guan"

99 Publications

TFAP2A-induced SLC2A1-AS1 promotes cancer cell proliferation.

Biol Chem 2021 Feb 19. Epub 2021 Feb 19.

School of Life Sciences, Zhengzhou University, Zhengzhou450001, China.

Long non-coding RNAs (lncRNAs) are involved in the occurrence and development of human cancers including lung adenocarcinoma (LUAD). SLC2A1-AS1 is a novel lncRNA that has been reported to be exceptionally expressed in several cancer types. However, the expression and role of SLC2A1-AS1 in cancer remains largely unclear. In this study, it was revealed that lncRNA SLC2A1-AS1 was notably over-expressed in LUAD and was closely correlated with patients' overall survival (OS). Knockdown of SLC2A1-AS1 could significantly restrain cell proliferation of LUAD , while over-expression of SLC2A1-AS1 had the accelerative effect. SLC2A1-AS1 enriched in the cytoplasm of LUAD cells could directly bind to miR-508-5p and negatively regulate its level. The inhibitory effect of miR-508-5p on LUAD cell proliferation was in part abrogated by SLC2A1-AS1 manipulation. Moreover, the transcription factor activating enhancer binding protein 2 α (TFAP2A) was highly expressed in LUAD and predicted worse patients' OS. TFAP2A could directly bind to the promoter region of SLC2A1-AS1 encoding gene and positively regulate the transcription of SLC2A1-AS1 in LUAD cells. Furthermore, TFAP2A-induced SLC2A1-AS1 promoted cell proliferation of lung squamous cell carcinoma (LUSC) and pancreatic adenocarcinoma (PAAD). Collectively, these findings suggest that TFAP2A-mediated lncRNA SLC2A1-AS1 works as an oncogene to drive cancer cell proliferation.
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http://dx.doi.org/10.1515/hsz-2020-0290DOI Listing
February 2021

HOXD1 functions as a novel tumor suppressor in kidney renal clear cell carcinoma.

Cell Biol Int 2021 Feb 9. Epub 2021 Feb 9.

School of Life Sciences, Zhengzhou University, Zhengzhou, China.

Kidney renal clear cell carcinoma (KIRC) is a common malignant tumor in human genitourinary system. Previous studies have shown that the homeobox-D (HOXD) cluster genes, which belong to the homeobox (HOX) family, are involved in the progression of multiple types of cancer. However, the expression profile and prognostic values of the HOXD genes in KIRC remain largely unknown. Herein, we comprehensively analyzed the transcriptional levels and prognosis of HOXD genes in KIRC using four online The Cancer Genome Atlas analysis databases (GEPIA, UALCAN, starBase v3.0, and LinkedOmics). We found that several members of the HOXD gene family were abnormally expressed in KIRC and correlated with patient prognosis. The messenger RNA levels of HOXD1, HOXD8, and HOXD10 were significantly downregulated in KIRC tissues as compared with the normal tissues. Low expression of HOXD1 or HOXD8 predicted poor overall survival (OS) of KIRC patients, and downregulated HOXD1, HOXD3, or HOXD4 indicated unfavorable patient disease-free survival (DFS) in KIRC. Through integrated analysis, we found that HOXD1 was lowly expressed in KIRC and correlated with patient OS, DFS and advanced tumor stages. Moreover, gene set enrichment analysis showed that HOXD1 may be mainly implicated in cell cycle regulation, tumor growth factor-β (TGF-β) and Wnt signaling pathways in KIRC. Furthermore, both loss-of-function and gain-of-function experiments demonstrated that HOXD1 inhibited cell proliferation, cell cycle and the TGF-β signaling in KIRC. Taken together, our findings suggest that HOXD1 is a novel potential tumor suppressor in KIRC.
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http://dx.doi.org/10.1002/cbin.11568DOI Listing
February 2021

Aging and age-related diseases: from mechanisms to therapeutic strategies.

Biogerontology 2021 Jan 27. Epub 2021 Jan 27.

School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.

Aging is a physiological process mediated by numerous biological and genetic pathways, which are directly linked to lifespan and are a driving force for all age-related diseases. Human life expectancy has greatly increased in the past few decades, but this has not been accompanied by a similar increase in their healthspan. At present, research on aging biology has focused on elucidating the biochemical and genetic pathways that contribute to aging over time. Several aging mechanisms have been identified, primarily including genomic instability, telomere shortening, and cellular senescence. Aging is a driving factor of various age-related diseases, including neurodegenerative diseases, cardiovascular diseases, cancer, immune system disorders, and musculoskeletal disorders. Efforts to find drugs that improve the healthspan by targeting the pathogenesis of aging have now become a hot topic in this field. In the present review, the status of aging research and the development of potential drugs for aging-related diseases, such as metformin, rapamycin, resveratrol, senolytics, as well as caloric restriction, are summarized. The feasibility, side effects, and future potential of these treatments are also discussed, which will provide a basis to develop novel anti-aging therapeutics for improving the healthspan and preventing aging-related diseases.
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http://dx.doi.org/10.1007/s10522-021-09910-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838467PMC
January 2021

Dual-enzymatically cross-linked gelatin hydrogel enhances neural differentiation of human umbilical cord mesenchymal stem cells and functional recovery in experimental murine spinal cord injury.

J Mater Chem B 2021 01;9(2):440-452

School of Life Science, Zhengzhou University, 100 Science Road, Zhengzhou 450001, P. R. China. and Institute of Neuroscience, Zhengzhou University, Zhengzhou 450000, P. R. China.

Recently, an advanced stem cell and tissue engineering approach has been recognized as an emerging and fascinating strategy to promote neural repair in spinal cord injury (SCI). Hydrogels can be properly engineered to encapsulate cells, enhance cell viability and neural differentiation, and provide the advantage of flexible adaptation to irregular defects. In this study, a dual-enzymatically cross-linked gelatin hydrogel with hydrogen horseradish peroxidase (HRP) and galactose oxidase (GalOx) was proposed to combine human umbilical cord mesenchymal stem cells (hUC-MSCs) for facilitating nerve regeneration post-SCI. In vitro, hUC-MSCs in this 3D gelatin hydrogel displayed good viability, proliferation, and neuronal differentiation. To further evaluate the neural regeneration effect of hUC-MSCs loaded into gelatin hydrogels in vivo, a clinically-relevant and force-controlled contusion model of mouse spinal cords was established. We found that implantation of a hydrogel loaded with hUC-MSCs significantly promoted the motor function recovery evaluated by Basso Mouse Scale (BMS) and footprint tests. Further histological analysis showed that the hydrogel and hUC-MSC combined transplantation dramatically decreased inflammation, inhibited apoptosis and promoted neurogenesis. Overall, implantation of this dual-enzymatically cross-linked and MSC-laden 3D gelatin hydrogel is a promising therapeutic strategy for SCI treatment.
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http://dx.doi.org/10.1039/d0tb02033hDOI Listing
January 2021

Pan-cancer analysis identifies ESM1 as a novel oncogene for esophageal cancer.

Esophagus 2020 Nov 11. Epub 2020 Nov 11.

School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.

Background: Recent studies highlight the crucial role of endothelial cell-specific molecule 1 (ESM1) in the development of multiple cancer types. However, its aberrant expression and prognostic value in human pan-cancer have largely not been described.

Methods And Results: In this study, we used The Cancer Genome Atlas (TCGA) analysis databases to explore the expression level and prognostic significance of ESM1 in 33 types of human cancer. ESM1 was shown to be over-expressed in 12 cancer types, including BLCA, BRCA, COAD, CHOL, ESCA, HNSC, KIRC, KICH, LIHC, STAD, THCA, and UCEC. The expression of ESM1 was significantly correlated with the overall survival (OS) of patients in CESC, ESCA, KIRC, and KIRP. In addition, high ESM1 level indicated poor disease-free survival (DFS) of patients with ACC, ESCA, PRAD, LIHC, KIRP, and UCS. Through comparative analysis, we discovered that ESM1 was dramatically up-regulated in esophageal cancer (ESCA) and associated with worse patient OS and DFS. The elevation of ESM1 in ESCA was confirmed by the datasets from Cancer RNA-Seq Nexus (CRN) and Gene Expression Omnibus (GEO). Based on Gene Set Enrichment Analysis (GSEA), we analyzed the co-expressed genes of ESM1 in ESCA, and found that ESM1 was closely implicated in cell proliferation and migration and the regulation of Janus kinase (JAK) signaling pathway. Functionally, knockdown of ESM1 significantly suppressed cell proliferation and migration, and decreased the protein level of JAK1.

Conclusions: Taken together, our results suggest for the first time that ESM1 functions as an oncogene and may be a clinical biomarker and/or therapeutic target in ESCA.
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http://dx.doi.org/10.1007/s10388-020-00796-9DOI Listing
November 2020

Sodium alginate/collagen hydrogel loaded with human umbilical cord mesenchymal stem cells promotes wound healing and skin remodeling.

Cell Tissue Res 2021 Feb 7;383(2):809-821. Epub 2020 Nov 7.

School of Life Sciences, Zhengzhou University, No. 100 Science Avenue, Zhengzhou, 450001, Henan, China.

Stem cell transplantation is a promising therapy for wound healing, but the low retention and survival of transplanted stem cells limit their application. Injectable hydrogels exert beneficial effects in skin tissue engineering. In this study, an injectable hydrogel composed of sodium alginate (SA) and collagen type I (Col) was synthesized as a tissue scaffold to improve the efficacy of stem cells in a full-thickness excision wound model. Our results showed that SA/Col hydrogel was injectable, biodegradable, and exhibited low immunogenicity, which could promote the retention and survival of hUC-MSCs in vivo. SA/Col loaded with hUC-MSCs showed reduced wound size (p < 0.05). Histological and immunofluorescence results confirmed that SA/Col loaded with hUC-MSCs significantly promoted the formation of granulation, enhanced collagen deposition and angiogenesis, increased VEGF and TGF-β1 expression (p < 0.05), and mitigated inflammation evidenced by lower production of TNF-α and IL-1β and higher release of IL-4 and IL-10 (p < 0.05). Furthermore, SA/Col loaded with hUC-MSCs significantly lowered the expression of NLRP3 inflammasome-related proteins (p < 0.05). Taken together, our results suggest that SA/Col loaded with hUC-MSCs promotes skin wound healing via partly inhibiting NLRP3 pathway, which has potential to the treatment of skin wounds.
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http://dx.doi.org/10.1007/s00441-020-03321-7DOI Listing
February 2021

Synergistically Enhances the Anti-Tumor E Corrigendum to "β-Carotene synergistically enhances the anti-tumor effect of 5-fluorouracil on esophageal squamous cell carcinoma in vivo and in vitro" [Toxicol. Lett. 261 (2016) 49-58].

Toxicol Lett 2020 Oct 11;333:327-328. Epub 2020 Aug 11.

The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China; School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China. Electronic address:

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http://dx.doi.org/10.1016/j.toxlet.2020.07.019DOI Listing
October 2020

MG53 Protects hUC-MSCs against Inflammatory Damage and Synergistically Enhances Their Efficacy in Neuroinflammation Injured Brain through Inhibiting NLRP3/Caspase-1/IL-1β Axis.

ACS Chem Neurosci 2020 09 17;11(17):2590-2601. Epub 2020 Aug 17.

School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan, China.

The inflammatory microenvironment in a lesion is not conducive to the survival of stem cells. Improving the inflammatory microenvironment may be an alternative strategy to enhance the efficacy of stem cells. We evaluated the therapeutic effect and molecular mechanism of mitsugumin53 (MG53) on lipopolysaccharide (LPS)-induced damage in human umbilical cord mesenchymal stem cells (hUC-MSCs) and in C57/BL6 mice. MG53 significantly promoted the proliferation and migration of hUC-MSCs, protected hUC-MSCs against LPS-induced apoptosis and mitochondrial dysfunction, and reversed LPS-induced inflammatory cytokine release. Furthermore, MG53 combined with hUC-MSCs transplantation improved LPS-induced memory impairment and activated neurogenesis by promoting the migration of hUC-MSCs and enhancing βIII-tubulin and doublecortin (DCX) expression. MG53 protein combined with hUC-MSCs improved the M1/M2 phenotype polarization of microglia accompanied by lower inducible nitric oxide synthase (iNOS) expression and higher arginase 1 (ARG1) expression. MG53 significantly suppressed the expression of tumor necrosis factor α (TNF-α), Toll-like receptor 4 (TLR4), nucleotide oligomerization domain-like receptor protein 3 (NLRP3), cleaved-caspase-1, and interleukin (IL)-1β to alleviate LPS-induced neuroinflammation on hUC-MSCs and C57/BL6 mice. In conclusion, our results indicated that MG53 could protect hUC-MSCs against LPS-induced inflammatory damage and facilitate their efficacy in LPS-treated C57/BL6 mice partly by inhibiting the NLRP3/caspase-1/IL-1β axis.
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http://dx.doi.org/10.1021/acschemneuro.0c00268DOI Listing
September 2020

Correction to: Downregulation of nicotinamide N-methyltransferase inhibits migration and epithelial-mesenchymal transition of esophageal squamous cell carcinoma via Wnt/β-catenin pathway.

Mol Cell Biochem 2020 Sep;472(1-2):263-264

College of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.

Fig. 2C has been published incorrectly in the original article. The correct version of the Fig. 6 is provided in this erratum.
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http://dx.doi.org/10.1007/s11010-020-03829-0DOI Listing
September 2020

Control the fate of human umbilical cord mesenchymal stem cells with dual-enzymatically cross-linked gelatin hydrogels for potential applications in nerve regeneration.

J Tissue Eng Regen Med 2020 09 13;14(9):1261-1271. Epub 2020 Jul 13.

School of Life Science, Zhengzhou University, Zhengzhou, P. R. China.

Stem-cell-based therapy is a promising strategy to treat challenging neurological diseases, while its application is hindered primarily by the low viability and uncontrolled differentiation of stem cell. Hydrogel can be properly engineered to share similar characteristics with the target tissue, thus promoting cell viability and directing cell differentiation. In this study, we proposed a new dual-enzymatically cross-linked and injectable gelatin hydrogel for regulating survival, proliferation, and differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) in a three-dimensional matrix. This injectable gelatin hydrogel was formed by oxidative coupling of gelatin-hydroxyphenyl acid conjugates catalyzed by hydrogen horseradish peroxidase (HRP) and choline oxidase (ChOx). Modulus and H O release can be well controlled by ChOx activity. Results from calcein-AM/PI staining and Ki67 immunofluorescence tests demonstrated that the survival and proliferation behavior of hUC-MSCs were highly enhanced in HRP ChOx hydrogel with lower modulus and less H O release compared with other groups. Attractively, the expression of neuron-specific markers β-III tubulin, neurofilament light chain (NFL), and synapsin-1 was significantly increased in HRP ChOx hydrogel as well. Additionally, in vitro hemolysis test and in vivo HE staining data highlighted the good biocompatibility. Undoubtedly, this injectable gelatin hydrogel's ability to control hUC-MSCs' fate holds enormous potentials in nervous disorders' therapy and nerve regeneration.
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http://dx.doi.org/10.1002/term.3098DOI Listing
September 2020

Correction to: Environmental Circadian Disruption Worsens Neurologic Impairment and Inhibits Hippocampal Neurogenesis in Adult Rats After Traumatic Brain Injury.

Cell Mol Neurobiol 2021 Apr;41(3):615-616

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.

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http://dx.doi.org/10.1007/s10571-020-00913-3DOI Listing
April 2021

Corrigendum to: Resveratrol Exerts Dosage-Dependent Effects on the Self-Renewal and Neural Differentiation of hUC-MSCs.

Mol Cells 2020 Jun;43(6):590

The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.

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http://dx.doi.org/10.14348/molcells.2020.1345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332360PMC
June 2020

LncRNA WDFY3-AS2 suppresses proliferation and invasion in oesophageal squamous cell carcinoma by regulating miR-2355-5p/SOCS2 axis.

J Cell Mol Med 2020 07 14;24(14):8206-8220. Epub 2020 Jun 14.

School of Life Sciences, Zhengzhou University, Zhengzhou, China.

Long non-coding RNAs (lncRNAs) widely participate in ESCC development and progression; however, the prognostic factors and therapeutic strategies implicated in ESCC development and progression remain to be under investigation. The purpose of the current study was to explore whether WDFY3-AS2 may be a potential prognostic factor and investigate its biological functions in ESCC. Here, WDFY3-AS2 was frequently down-regulated in ESCC tissues and cells, and its expression was correlated with TNM stage, lymph node metastasis and poor prognosis of ESCC patients. Moreover, WDFY3-AS2 down-regulation significantly promoted cell proliferation and invasion, whereas WDFY3-AS2 up-regulation markedly suppressed cell proliferation and invasion in ESCC EC9706 and TE1 cells, coupled with EMT phenotype alterations. WDFY3-AS2 functioned as a competing endogenous RNA (ceRNA) for sponging miR-2355-5p, further resulted in the up-regulation of its target gene SOCS2, followed by suppression of JAK2/Stat5 signalling pathway, to suppress ESCC cell proliferation and invasion in EC9706 and TE1 cells. These findings suggest that WDFY3-AS2 may participate in ESCC development and progression, and may be a novel prognostic factor for ESCC patients, and thus targeting WDFY3-AS2/miR-2355-5p/SOCS2 signalling axis may be a novel therapeutic strategy for ESCC patients.
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http://dx.doi.org/10.1111/jcmm.15488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348145PMC
July 2020

LncRNA linc00460 sponges miR-1224-5p to promote esophageal cancer metastatic potential and epithelial-mesenchymal transition.

Pathol Res Pract 2020 Jul 21;216(7):153026. Epub 2020 May 21.

School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address:

Background: Increasing studies highlight the crucial role of long non-coding RNAs (lncRNAs) in carcinogenesis of various human cancer types, including esophageal cancer (ESCA). Long intergenic non-coding RNA 00460 (Linc00460), a novel oncogenic lncRNA, has been reported to accelerate ESCA cell growth. This study aimed to investigate the role and possible regulatory mechanism of linc00460 in ESCA metastasis.

Methods: Bioinformatics analysis and quantitative real time polymerase chain reaction (qRT-PCR) were used to detect linc00460 expression in ESCA. Wound healing assay, Transwell assay and Western blot were utilized to examine migration, invasion and epithelial-mesenchymal transition (EMT) of ESCA cells. The direct binding effect between linc00460 and microRNA-1224-5p (miR-1224-5p) was evaluated by the dual luciferase reporter assay.

Results: In this study, we discovered that lncRNA linc00460 was obviously over-expressed in ESCA, both in tissues and cell lines. Down-regulation of linc00460 significantly suppressed the metastatic potential (including cell migration and invasion) and EMT of ESCA cells. In addition, miR-1224-5p, a potential tumor suppressor, was negatively correlated with linc00460 in ESCA. Linc00460 and miR-1224-5p could bind directly in ESCA cells. Inhibition of miR-1224-5p partially abrogated the effects of linc00460 decrease on metastatic potential and EMT of ESCA cells.

Conclusions: Taken together, linc00460 may function as a molecular sponge to adsorb miR-1224-5p, thereby promoting ESCA metastasis and EMT. Our findings suggest that linc00460/miR-1224-5p is a possible clinical target for ESCA.
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http://dx.doi.org/10.1016/j.prp.2020.153026DOI Listing
July 2020

MicroRNA-128-3p Enhances the Chemosensitivity of Temozolomide in Glioblastoma by Targeting c-Met and EMT.

Sci Rep 2020 06 11;10(1):9471. Epub 2020 Jun 11.

Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.

Temozolomide is a first line anti-tumor drug used for the treatment of patients with Glioblastoma multiforme (GBM). However, the drug resistance to temozolomide limits its clinical application. Therefore, novel strategies to overcome chemoresistance are desperately needed for improved treatment of human GBM. Recent studies have demonstrated that miRNAs are closely related to resistance to cancer chemotherapy. This study aimed to further validate the biological role of miR-128-3p and to investigate whether miR-128-3p can enhance the chemosensitivity of glioblastoma to temozolomide (TMZ) and the underlying mechanisms. The effects of miR-128-3p and TMZ on the proliferation of glioblastoma cells were investigated by cell counting kit-8 (cck8). Transwell and intracerebral invasion assays were applied to determine the effects of the combination of miR-128-3p and TMZ on the invasion and migration of glioblastoma in vitro and in vivo. Flow cytometry was used to detect apoptosis in each group, and immunofluorescence was used to determine the expression levels of EMT-related proteins. RT-PCR and Western-blot were applied to detect EMT-transformed proteins (c-Met, PDGFRα, Notch1, and Slug) and EMT phenotype-associated proteins (Vim, CD44, and E-cadherin) at both mRNA and protein levels. Based on the microRNA.org database, we predicted the target genes of miR-128-3p. The target-relationship between miR-128-3p and c-Met and PDGFRα was verified by dual luciferase reporter gene. The tumor volume, weight and the expression levels of the proteins described above were measured in subcutaneously transplanted tumor model in nude mice. We found that the expression of miR-128-3p was down-regulated in glioblastoma tissue samples and cell lines. miR-128-3p suppressed the proliferation, migration, and invasion of GBM both in vitro and in vivo; miR-128-3p enhanced the therapeutic effect of TMZ via inhibition of proliferation, invasion and migration of glioblastoma cells and induction of apoptosis. Overexpression of miR-128-3p down-regulated the expression levels of EMT-transformed proteins (c-Met, PDGFRα, Notch1 and Slug) to enhance the effect of TMZ. In addition, we found that miR-128-3p targeted and bound c-Met. More importantly, the upregulation of c-Met significantly prompted U87 and U251 cell proliferation. This effect could be abolished when c-Met was silenced. The investigation in tumor bearing nude mice showed that miR-128-3p in combination with TMZ reduced tumor volume and the invasion extent, and increased the sensitivity of glioblastoma to TMZ. miR-128-3p is capable of enhancing the sensitivity of glioblastoma to TMZ through regulating c-Met/EMT.
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http://dx.doi.org/10.1038/s41598-020-65331-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289811PMC
June 2020

Over-Expression and Prognostic Significance of HHLA2, a New Immune Checkpoint Molecule, in Human Clear Cell Renal Cell Carcinoma.

Front Cell Dev Biol 2020 19;8:280. Epub 2020 May 19.

Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

HHLA2, a newly identified B7 family member, regulates T cell functions. However, the expression and prognostic value of HHLA2 in solid tumors is ill defined. This study aimed to reveal the expression landscape of HHLA2 in various solid tumors, and to evaluate its prognostic value in kidney clear cell carcinoma (KIRC). Using The Cancer Genome Atlas (TCGA) database, we investigated the expression pattern of HHLA2 across 22 types of cancer. HHLA2 and CD8 protein expression was determined via immunohistochemistry (IHC). KIRC-specific findings were further analyzed with R software and the prognostic value was validated on tissue microarrays. HHLA2 was widely expressed in cancers at both the mRNA and protein levels. Among all tested tumors, KIRC showed the highest transcript level of HHLA2, and HHLA2 levels were significantly higher in tumor tissues than in matched normal samples, as evidenced by both TCGA and IHC data. HHLA2 was also positively correlated with survival rates in KIRC based on TCGA and clinical data. Receiver operating characteristic curves data showed the prognostic value of HHLA2 for patients with KIRC in TCGA. Moreover, HHLA2 was positively correlated with immune-related genes, while HHLA2 and CD8 expression exhibited a consistent trend in KIRC tumor samples. In conclusion, HHLA2 is highly expressed in KIRC and predicts a favorable survival outcome, highlighting that it may work as a potential target for KIRC therapy.
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http://dx.doi.org/10.3389/fcell.2020.00280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248229PMC
May 2020

Comprehensive analysis of the HOXA gene family identifies HOXA13 as a novel oncogenic gene in kidney renal clear cell carcinoma.

J Cancer Res Clin Oncol 2020 Aug 22;146(8):1993-2006. Epub 2020 May 22.

Department of Translational Medicine Center, Zhengzhou Central Hospital Affiliated To Zhengzhou University, Zhengzhou, 450007, China.

Objectives: Kidney renal clear cell carcinoma (KIRC) is one of the most common lethal cancers in the human urogenital system. As members of the Homeobox (HOX) family, Homeobox-A (HOXA) cluster genes have been reported to be involved in the development of many cancer types. However, the expression and clinical significance of HOXA genes in KIRC remain largely unknown.

Materials And Methods: In this study, we comprehensively analyzed the mRNA expression and prognostic values of HOXA genes in KIRC using The Cancer Genome Atlas (TCGA) analysis databases online. Colony formation assay, flow cytometry and Western blot were used to detect cell proliferation, apoptosis, cell cycle, and protein level of the indicated gene.

Results: We found that the HOXA genes were differentially expressed in KIRC tissues when compared with normal tissues. The expression of HOXA4 and HOXA13 were significantly up-regulated, while HOXA7 and HOXA11 were down-regulated in KIRC. High mRNA levels of HOXA2, HOXA3 and HOXA13, and low level of HOXA7 predicted poor overall survival (OS) of KIRC patients. High mRNA level of HOXA13 further indicated a poor disease-free survival (DFS) of KIRC patients. Functionally, knockdown of HOXA13 significantly suppressed cell proliferation of KIRC in vitro, increased the protein level of p53 and decreased the protein level of cyclin D1 in KIRC cells. Over-expression of HOXA13 had the opposite effects on KIRC cells.

Conclusion: Collectively, our findings suggest that HOXA13 functions as a novel oncogene in KIRC and may be a potential biomarker for this malignancy.
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http://dx.doi.org/10.1007/s00432-020-03259-xDOI Listing
August 2020

Nicotinamide N-methyltransferase decreases 5-fluorouracil sensitivity in human esophageal squamous cell carcinoma through metabolic reprogramming and promoting the Warburg effect.

Mol Carcinog 2020 08 4;59(8):940-954. Epub 2020 May 4.

School of Life Sciences, Zhengzhou University, Zhengzhou.

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with poor prognosis. And different individuals respond to the same drug differently. Increasing evidence has confirmed that metabolism reprogramming was involved in the drug sensitivity of tumor cells. However, the potential molecular mechanism of 5-fluorouracil (5-FU) sensitivity remains to be elucidated in ESCC cells. In this study, we found that the 5-FU sensitivity of TE1 cells was lower than that of EC1 and Eca109 cells. Gas chromatography-mass spectrometry analysis results showed that nicotinate and nicotinamide metabolism and tricarboxylic acid cycle were significantly different in these three cell lines. Nicotinamide N-methyltransferase (NNMT), a key enzyme of nicotinate and nicotinamide metabolism, was significantly higher expressed in TE1 cells than that in EC1 and Eca109 cells. Therefore, the function of NNMT on 5-FU sensitivity was analyzed in vitro and in vivo. NNMT downregulation significantly increased 5-FU sensitivity in TE1 cells. Meanwhile, the glucose consumption and lactate production were decreased, and the expression of glycolysis-related enzymes hexokinase 2, lactate dehydrogenase A, and phosphoglycerate mutase 1 were downregulated in NNMT knockdown TE1 cells. Besides, overexpression of NNMT in EC1 and Eca109 cells caused the opposite effects. Moreover, when glycolysis was inhibited by 2-deoxyglucose, the roles of NNMT on 5-FU sensitivity was weakened. In vivo experiments showed that NNMT knockdown significantly increased the sensitivity of xenografts to 5-FU and suppressed the Warburg effect. Overall, these results demonstrated that NNMT decreases 5-FU sensitivity in human ESCC cells through promoting the Warburg effect, suggesting that NNMT may contribute to predict the treatment effects of the clinical chemotherapy in ESCC.
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http://dx.doi.org/10.1002/mc.23209DOI Listing
August 2020

Resveratrol Preincubation Enhances the Therapeutic Efficacy of hUC-MSCs by Improving Cell Migration and Modulating Neuroinflammation Mediated by MAPK Signaling in a Mouse Model of Alzheimer's Disease.

Front Cell Neurosci 2020 27;14:62. Epub 2020 Mar 27.

School of Life Sciences, Zhengzhou University, Zhengzhou, China.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are promising for the treatment of Alzheimer's disease (AD). However, their low rate of migration and survival in the brain limit their clinical applicability. This study is designed to improve the therapeutic potential of hUC-MSCs by preincubating them with resveratrol, a natural polyphenol capable of regulating cell destiny. Herein, we demonstrate that resveratrol preincubation enhances the migration of hUC-MSCs , as well as their survival and homing into the hippocampus of AD mice . Moreover, resveratrol-primed MSCs were better able to inhibit amyloid-β peptide (Aβ) deposition, Tau hyperphosphorylation, and oxidative stress, all while improving learning and memory. Notably, we found that hUC-MSCs inhibited neuroinflammation by reacting with astrocytes and microglial cells and suppressing mitogen-activated protein kinases (MAPKs), extracellular signal kinases (ERK), p38 kinases (p38), and c-Jun N-terminal kinases (JNK) signaling pathways in the hippocampus of AD mice. Furthermore, resveratrol pretreatment enhanced these effects. Conclusively, the current study revealed that resveratrol preconditioning protected hUC-MSCs against the hostile microenvironment characteristic of AD and enhanced their viability and homing into the brain of AD mice. The use of resveratrol-pretreated hUC-MSCs is thereby proposed to be a promising therapy for AD.
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http://dx.doi.org/10.3389/fncel.2020.00062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118399PMC
March 2020

CASC5 is a potential tumour driving gene in lung adenocarcinoma.

Cell Biochem Funct 2020 Aug 13;38(6):733-742. Epub 2020 Apr 13.

School of Life Sciences, Zhengzhou University, Zhengzhou, China.

Previous studies have shown that cancer susceptibility candidate 5 (CASC5) plays important roles in several types of cancer. But its expression and clinical significance in human pan-cancer remain largely unclear. In the present study, we comprehensively analysed the expression profile and prognostic values of CASC5 in pan-cancer across 33 cancer types based on the online TCGA analysis databases. CASC5 was found to be abnormally expressed in 16 types of cancer. In addition, dysregulated expression of CASC5 was closely associated with patient overall survival (OS) in kidney renal papillary cell carcinoma (KIRP), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD) and thymoma (THYM). By comparative analysis, we found that CASC5 was significantly up-regulated in LUAD and predicted poor patient OS. High CASC5 expression was closely correlated with tumour advanced stages of patients with LUAD. Through GSEA based on the KEGG database, CASC5 was found to be closely related to DNA replication and microRNA regulation in LUAD. Functionally, knockdown of CASC5 could inhibit cell proliferation of LUAD cells in vitro, rather than affecting cell migration and invasion. Mechanistically, CASC5 promoted proliferation of LUAD cells by targeting miR-139-5p. Collectively, our findings reveal that CASC5 is a novel oncogenic gene in LUAD and may be a potential clinical target and (or) biomarker for this human malignancy. SIGNIFICANCE OF THE STUDY: In this study, we for the first time comprehensively analysed the transcriptional level and prognostic significance of CASC5 in human pan-cancer across 33 cancer types using online TCGA databases. Our study indicates that CASC5 is aberrantly expressed in many tumours and is closely related to the patient overall survival of several tumour types. Our findings reveal that CASC5 is a novel oncogene in LUAD based on bioinformatic analysis and functional experiments. Mechanistically, CASC5 promoted LUAD proliferation by targeting miR-139-5p. Results of this study suggest that CASC5 is a potential clinical target and (or) biomarker for LUAD.
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http://dx.doi.org/10.1002/cbf.3540DOI Listing
August 2020

MS-275 combined with cisplatin exerts synergistic antitumor effects in human esophageal squamous cell carcinoma cells.

Toxicol Appl Pharmacol 2020 05 23;395:114971. Epub 2020 Mar 23.

School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China. Electronic address:

MS-275 has been demonstrated to inhibit the growth of esophageal squamous cell carcinoma (ESCC) cells in our previous study, but its role in ESCC remains to be further explored. Cisplatin (cis-diamminedichloroplatinum II, DDP) is the first-line chemotherapeutic drug widely used in clinic for ESCC patients. However, the side effects of nephrotoxicity and drug resistance limit its clinical use. This study aimed to evaluate the anticancer effects of MS-275 combined with DDP on ESCC cell line EC9706 both in vitro and in vivo, and to investigate the possible mechanisms that mediate these effects. We found that MS-275 combined with DDP showed synergistic antitumor effects on EC9706 cells in vitro by decreasing cell proliferation, increasing apoptosis and oxidative damage, and inhibiting migration and stemness. The combination of MS-275 and DDP triggered pro-survival autophagy in EC9706. Moreover, MS-275 combined with DDP suppressed EC9706 xenografts growth and promoted apoptosis in vivo. Further study displayed that MS-275 combined with DDP suppressed Wnt/β-catenin signaling in EC9706 cells and xenografts. These results indicate that MS-275 combined with DDP exerts synergistic antitumor effects by enhancing the chemosensitivity of EC9706 cells to DDP, which may be a potential therapeutic strategy for the treatment of patients with ESCC.
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http://dx.doi.org/10.1016/j.taap.2020.114971DOI Listing
May 2020

A chitosan-based thermosensitive scaffold loaded with bone marrow-derived mesenchymal stem cells promotes motor function recovery in spinal cord injured mice.

Biomed Mater 2020 04 29;15(3):035020. Epub 2020 Apr 29.

School of Life Science, Zhengzhou University, 100 Science Road, Zhengzhou 450001, People's Republic of China.

Spinal cord injury is a devastating trauma with high mortality and disability, for which there is no effective treatment. Stem cell-based tissue engineering has been reported to promote functional neural recovery. At present, building a neural scaffold with excellent biocompatibility for cells and tissues is still challenging. In this study, a new thermosensitive composite hydrogel based on chitosan, hydroxyethyl cellulose, collagen and β-phosphoglycerate (CS-HEC-Col/GP hydrogel) is developed to encapsulate murine bone marrow-derived mesenchymal stem cells (BMSCs) to improve therapeutic efficacy in spinal cord injured mice. This composite hydrogel possesses a good cytocompatibility to mouse BMSCs by live/dead staining, minimized inflammatory reaction in vivo by hematoxylin and eosin staining and suitable rheological behavior similar to neural tissue, ranging from 100 to 1000 Pa. Furthermore, the data from animal experiments indicated that BMSC-loaded CS-HEC-Col/GP hydrogel could enhance the survival or proliferation of endogenous nerve cells, probably by secreting neurotrophic factors and inhibiting apoptosis, and thereby promote the recovery of motor function in the hindlimbs of a murine spinal cord injury model.
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http://dx.doi.org/10.1088/1748-605X/ab785fDOI Listing
April 2020

Dual-enzymatically crosslinked hyaluronic acid hydrogel as a long-time 3D stem cell culture system.

Biomed Mater 2020 06 12;15(4):045013. Epub 2020 Jun 12.

School of Life Science, Zhengzhou University, 100 Science Road, Zhengzhou 450001, People's Republic of China.

Stem cell-based tissue engineering shows enormous potential for regenerative medicine. Three-dimensional (3D) stem cell culture is the most basic aspect of tissue engineering. However, achievement of a perfect scaffold for highly efficient 3D cell culture is currently still limited. Herein, a new hyaluronic acid hydrogel dual-enzymatically crosslinked by horseradish peroxidase and choline oxidase is developed as a 3D stem cell culture system. This hydrogel possesses superior stability over two months, controllable biodegradability with hyaluronidases, a high swelling ratio exceeding 6000%, and excellent cytocompatibility in vitro and biocompatibility in vivo. More importantly, a long-time and highly cellular activity 3D culture of bone marrow-derived mesenchymal stem cells was achieved in vitro over 20 days. All these encouraging results highlight the great potential of this new hydrogel for 3D culture and tissue engineering.
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http://dx.doi.org/10.1088/1748-605X/ab712eDOI Listing
June 2020

HOXC11 functions as a novel oncogene in human colon adenocarcinoma and kidney renal clear cell carcinoma.

Life Sci 2020 Feb 7;243:117230. Epub 2020 Jan 7.

School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address:

Aims: Accumulating evidence has confirmed the involvement of the homeobox (HOX) gene family in carcinogenesis. HOXC11, belongs to the homeobox-C (HOXC) gene cluster, has been reported to play important roles in the development of several cancers. However, its expression and clinical value in pan-cancer remain elusive.

Materials And Methods: Bioinformatics analysis, CCK-8 assay, Flow cytometry and Western blot were used to analyze gene expression and patient survival, cell proliferation, cell apoptosis and protein level, respectively.

Key Findings: In this study, we comprehensively analyzed the expression profile and prognostic value of HOXC11 in human pan-cancer using online The Cancer Genome Atlas (TCGA) databases. HOXC11 was widely up-regulated in tumor tissues when compared with the normal tissues in pan-cancer across nine cancer types. In addition, high mRNA level of HOXC11 predicted poor overall survival (OS) of patients with adrenocortical carcinoma (ACC), colon adenocarcinoma (COAD), kidney renal clear cell carcinoma (KIRC), mesothelioma (MESO) and pancreatic adenocarcinoma (PAAD), respectively. By comparative analysis, we found that HOXC11 was up-regulated and closely correlated patient OS in COAD and KIRC. Functionally, down-regulation of HOXC11 inhibited cell proliferation but promoted apoptosis of COAD and KIRC in vitro. Mechanistically, HOXC11 promoted cell proliferation of COAD and KIRC might by inactivating the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway.

Significance: Our findings suggest that HOXC11 may act as a tumor driving gene in COAD and KIRC.
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http://dx.doi.org/10.1016/j.lfs.2019.117230DOI Listing
February 2020

The mechanism of PDA/PEI/5-Fu coated esophageal stent material on inhibiting cancer associated pathological cells.

J Biomed Mater Res A 2020 03 13;108(3):814-821. Epub 2019 Dec 13.

School of Life Science, Zhengzhou University, Zhengzhou, PR China.

Metal stent implantation is usually applied to alleviate nonoperative palliative esophageal obstruction for esophageal cancer in the later period. However, in-stent restenosis after stent implantation limits the esophageal stents' performance due to lack of effective suppression of pathological cells from cancer microenvironment. In previous work, we modified the esophageal stent material 317L stainless steel (317LSS) surface with a poly-dopamine/poly-ethylenimine/5-fluorouracil layer (PDA/PEI/5-Fu), which had strong anti-tumor and anti-restenosis functions. Nevertheless, the mechanism of PDA/PEI/5-Fu layer against tumor and inflammation remains unclear. In this work, we revealed the mechanism of PDA/PEI/5-Fu suppressing the esophageal cancer related pathological cells (esophageal tumor cells, epithelial cells, and fibroblast) and inflammatory cells (macrophages) via series of experiments. Our data suggested that the PEI inhibited viability and E-cadherin expression of the pathological cells, and blocked the NF-κB signal pathway (reducing levels of p-NF-κB proteins). The loaded 5-Fu inhibited the inflammatory factors (TNF-α and IL-1β) release and promoted the anti-inflammation/anti-tumor factors (IL-10 and IL-4) release from macrophages, and also suppressed pathological cells migration; both the PEI and 5-Fu contributed to the upregulation of Bax and Caspase-3 (pro-tumor-apoptosis factor), as well as the downregulation of Bcl-2 (anti-tumor-apoptosis factor) in esophageal tumor cells. All the results showed that PDA/PEI/5-Fu coating had potential multipath anti-cancer and anti-inflammatory effects in the surface modification of esophageal stents.
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http://dx.doi.org/10.1002/jbm.a.36860DOI Listing
March 2020

The TRIM protein Mitsugumin 53 enhances survival and therapeutic efficacy of stem cells in murine traumatic brain injury.

Stem Cell Res Ther 2019 11 28;10(1):352. Epub 2019 Nov 28.

School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.

Background: Traumatic brain injury (TBI) is a common neurotrauma leading to brain dysfunction and death. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold promise in the treatment of TBI. However, their efficacy is modest due to low survival and differentiation under the harsh microenvironment of the injured brain. MG53, a member of TRIM family protein, plays a vital role in cell and tissue damage repair. The present study aims to test whether MG53 preserves hUC-MSCs against oxidative stress and enhances stem cell survival and efficacy in TBI treatment.

Methods: In this study, we performed a series of in vitro and in vivo experiments in hUC-MSCs and mice to define the function of MG53 enhancing survival, neurogenesis, and therapeutic efficacy of stem cells in murine traumatic brain injury.

Results: We found that recombinant human MG53 (rhMG53) protein protected hUC-MSCs against HO-induced oxidative damage and stimulated hUC-MSC proliferation and migration. In a mouse model of contusion-induced TBI, intravenous administration of MG53 protein preserved the survival of transplanted hUC-MSCs, mitigated brain edema, reduced neurological deficits, and relieved anxiety and depressive-like behaviors. Co-treatment of MG53 and hUC-MSCs enhanced neurogenesis by reducing apoptosis and improving PI3K/Akt-GSK3β signaling.

Conclusion: MG53 enhances the efficacy of hUC-MSCs in the recovery of TBI, indicating that such adjunctive therapy may provide a novel strategy to lessen damage and optimize recovery for brain injury.
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http://dx.doi.org/10.1186/s13287-019-1433-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883632PMC
November 2019

Case Study: The Recurrent Fusion RNA DUS4L-BCAP29 in Noncancer Human Tissues and Cells.

Methods Mol Biol 2020 ;2079:243-258

Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA, USA.

Traditional gene fusions are involved in the development of various neoplasias. DUS4L-BCAP29, a chimeric fusion RNA, has been reported to be a cancer-related fusion in prostate and gastric cancers. This chimeric RNA is believed to play a tumorigenic role. Here, we showed that the DUS4L-BCAP29 fusion transcript exists in a variety of normal tissues. It is also present in noncancerous epithelial and fibroblast cell lines. Quantitatively, the fusion transcript has a similar expression level in noncancerous gastric and prostate cell lines and tissues to its expression in cancerous cell lines and tissues. Previously, a loss-of-function approach was used to report a probable functionality for this fusion. However, this approach is not sufficient to prove such functionality. Alternatively, a gain-of-function approach showed that overexpression of DUS4L-BCAP29 promotes cell growth and motility, even in noncancerous cell lines. Finally, we provide further evidence that the fusion transcript is a product of cis-splicing between adjacent genes. In summary, we believe that in contrast to traditional gene fusions, DUS4L-BCAP29 cannot be used as a cancer biomarker. Instead, it is a fusion transcript that exists in normal physiology and its progrowth effect is not unique to cancer situations.
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http://dx.doi.org/10.1007/978-1-4939-9904-0_19DOI Listing
December 2020

The B7x Immune Checkpoint Pathway: From Discovery to Clinical Trial.

Trends Pharmacol Sci 2019 11 31;40(11):883-896. Epub 2019 Oct 31.

Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Urology, Albert Einstein College of Medicine, New York, NY 10461, USA. Electronic address:

B7x (B7 homolog x, also known as B7-H4, B7S1, and VTCN1) was discovered by ourselves and others in 2003 as the seventh member of the B7 family. It is an inhibitory immune checkpoint of great significance to human disease. Tissue-expressed B7x minimizes autoimmune and inflammatory responses. It is overexpressed in a broad spectrum of human cancers, where it suppresses antitumor immunity. Further, B7x and PD-L1 tend to have mutually exclusive expression in cancer cells. Therapeutics targeting B7x are effective in animal models of cancers and autoimmune disorders, and early-phase clinical trials are underway to determine the efficacy and safety of targeting B7x in human diseases. It took 15 years moving from the discovery of B7x to clinical trials. Further studies will be necessary to identify its receptors, reveal its physiological functions in organs, and combine therapies targeting B7x with other treatments.
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http://dx.doi.org/10.1016/j.tips.2019.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907741PMC
November 2019

Sustained elevation of MG53 in the bloodstream increases tissue regenerative capacity without compromising metabolic function.

Nat Commun 2019 10 11;10(1):4659. Epub 2019 Oct 11.

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, 43210, USA.

MG53 is a muscle-specific TRIM-family protein that presides over the cell membrane repair response. Here, we show that MG53 present in blood circulation acts as a myokine to facilitate tissue injury-repair and regeneration. Transgenic mice with sustained elevation of MG53 in the bloodstream (tPA-MG53) have a healthier and longer life-span when compared with littermate wild type mice. The tPA-MG53 mice show normal glucose handling and insulin signaling in skeletal muscle, and sustained elevation of MG53 in the bloodstream does not have a deleterious impact on db/db mice. More importantly, the tPA-MG53 mice display remarkable dermal wound healing capacity, enhanced muscle performance, and improved injury-repair and regeneration. Recombinant human MG53 protein protects against eccentric contraction-induced acute and chronic muscle injury in mice. Our findings highlight the myokine function of MG53 in tissue protection and present MG53 as an attractive biological reagent for regenerative medicine without interference with glucose handling in the body.
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http://dx.doi.org/10.1038/s41467-019-12483-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789113PMC
October 2019