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Sadiasa A, Werkmeister JA, Gurung S, Gargett CE. Steps towards the clinical application of endometrial and menstrual fluid mesenchymal stem cells for the treatment of gynecological disorders. Expert Opin Biol Ther 2025:1-23. [PMID: 39925343 DOI: 10.1080/14712598.2025.2465826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 01/28/2025] [Accepted: 02/07/2025] [Indexed: 02/11/2025]
Abstract
INTRODUCTION The human endometrium is a highly regenerative tissue that contains mesenchymal stem/stromal cells (MSCs). These MSCs are sourced via office-based biopsies and menstrual fluid, providing a less invasive and readily available option for cell-based therapies. This review provides an update on endometrial-derived MSCs as a treatment option for gynecological diseases. AREAS COVERED This narrative review covers the characterization and therapeutic mechanisms of endometrium biopsy-derived MSCs (eMSCs) and menstrual fluid-derived mesenchymal stromal cells (MenSCs), highlighting similarities and differences. It also covers studies of their application in preclinical animal models and in clinical trials as potential cell-based therapies for gynecological diseases. EXPERT OPINION eMSCs and MenSCs from a homologous tissue source have the potential to promote regenerative activity as a treatment for gynecological diseases. Both eMSCs and MenSCs demonstrate therapeutic benefits through their paracrine activity in tissue regeneration, immunomodulation, angiogenesis, and mitigating fibrosis. Further research is essential to establish standardized isolation and characterization protocols, particularly for heterogeneous MenSCs, and to fully understand their mechanisms of action. Implementing SUSD2 magnetic bead sorting for purifying eMSCs from endometrial tissues and menstrual fluid is crucial for their use in future cell-based therapies. Optimization of production, storage, and delivery methods will maximize their therapeutic effectiveness.
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Affiliation(s)
- Alexander Sadiasa
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Jerome A Werkmeister
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Shanti Gurung
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Caroline E Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
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Yuan Y, Chen T, Yang Y, Han H, Xu L. E2F1/CDK5/DRP1 axis mediates microglial mitochondrial division and autophagy in the pathogenesis of cerebral ischemia-reperfusion injury. Clin Transl Med 2025; 15:e70197. [PMID: 39968698 PMCID: PMC11836619 DOI: 10.1002/ctm2.70197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 01/03/2025] [Accepted: 01/09/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND The integrity of brain function is at stake due to cerebral ischemia-reperfusion injury (CIRI), which encompasses mitochondrial dysfunction, autophagy, and neuroinflammation. The role of E2F1 in mediating these processes in microglia during CIRI remains unclear. METHODS A CIRI mouse model was utilized for single-cell RNA transcriptome sequencing of brain tissues. The research comprised diverse gene expression, gene ontology (GO), and the enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Experimental techniques included oxygen-glucose deprivation (OGD/R) cell models, RT-qPCR, Western Blot, ChIP assays, and microglia-neuron co-cultures. RESULTS A significant aspect highlighted in the study was the involvement of CDK5 in the induction of mitochondrial abnormalities associated with CIRI. Upregulation of E2F1 and CDK5 in post-CIRI microglia was observed. E2F1 facilitated CDK5 transcription, leading to DRP1 phosphorylation, exacerbating neurotoxic effects. Silencing E2F1 improved neurobehavioral outcomes in CIRI mice. CONCLUSIONS Activation of E2F1-mediated CDK5 drives mitochondrial division while inhibiting mitophagy in microglia, triggering inflammation, neuronal apoptosis, and exacerbating CIRI damage. Targeting this pathway could offer novel therapeutic strategies for mitigating CIRI-induced brain injury. KEY POINTS Identification of the E2F1/CDK5/DRP1 Axis in CIRI This study reveals that the E2F1 transcription factor upregulates CDK5 expression, which in turn phosphorylates DRP1, promoting excessive mitochondrial fission and inhibiting mitophagy in microglia. This mechanism plays a critical role in cerebral ischemia-reperfusion injury (CIRI). Mitochondrial Dysfunction and Neuroinflammation The activation of DRP1 leads to mitochondrial fragmentation and excessive ROS accumulation, triggering microglial activation and inflammatory responses, exacerbating neuronal apoptosis and brain injury in CIRI. Therapeutic Potential of E2F1 Silencing Knockdown of E2F1 in microglia effectively reduces mitochondrial damage, restores mitophagy, suppresses inflammation, and improves neurological outcomes in a CIRI mouse model, highlighting a promising therapeutic target for ischemic stroke intervention.
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Affiliation(s)
- Ya‐Jing Yuan
- Department of AnesthesiaTianjin Medical University Cancer Institute &HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Prevention and Therapy, TianjinTianjinChina
| | - Tingting Chen
- Department of Radiation OncologyTianjin Medical University Cancer Institute &HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Prevention and Therapy, TianjinTianjinChina
| | - Yan‐Ling Yang
- Department of Radiation OncologyTianjin Medical University Cancer Institute &HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Prevention and Therapy, TianjinTianjinChina
| | - Hao‐Nan Han
- Hubei Key Laboratory of Tumor Microenvironment and ImmunotherapyCollege of Basic Medical SciencesChina Three Gorges UniversityYichangChina
| | - Li‐Ming Xu
- Department of Radiation OncologyTianjin Medical University Cancer Institute &HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Prevention and Therapy, TianjinTianjinChina
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Correction to "Menstrual blood-derived mesenchymal stem cells attenuate inflammation and improve the mortality of acute liver failure combining with A2AR agonist in mice". J Gastroenterol Hepatol 2025; 40:553. [PMID: 39675749 PMCID: PMC11977675 DOI: 10.1111/jgh.16848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
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Wu Y, Liu L, Li Z, Zhang T, Wang Q, Cheng M. A Risk Model Based on Ferroptosis-Related Genes OSMR, G0S2, IGFBP6, IGHG2, and FMOD Predicts Prognosis in Glioblastoma Multiforme. CNS Neurosci Ther 2025; 31:e70161. [PMID: 39815665 PMCID: PMC11735466 DOI: 10.1111/cns.70161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 10/23/2024] [Accepted: 11/24/2024] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is a common and highly aggressive brain tumor with a poor prognosis. However, the prognostic value of ferroptosis-related genes (FRGs) and their classification remains insufficiently studied. OBJECTIVE This study aims to explore the significance of ferroptosis classification and its risk model in GBM using multi-omics approaches and to evaluate its potential in prognostic assessment. METHODS Ferroptosis-related genes (FRGs) were retrieved from databases such as FerrDB. The TCGA-GBM and CGGA-GBM datasets were used as training and testing cohorts, respectively. Univariate Cox regression and LASSO regression analyses were performed to establish a risk model comprising five genes (OSMR, G0S2, IGFBP6, IGHG2, FMOD). A Meta-analysis of integrated TCGA and GTEx data was conducted to examine the differential expression of these genes between GBM and normal tissues. Key gene protein expression differences were analyzed using CPTAC and HPA databases. Single-cell RNA sequencing (scRNA-seq) analysis was employed to explore the cell type-specific distribution of these genes. RESULTS The five-gene risk model demonstrated significant prognostic value in GBM. Meta-analysis revealed distinct expression patterns of the identified genes between GBM and normal tissues. Protein expression analysis confirmed these differences. scRNA-seq analysis highlighted the diverse distribution of these genes across different cell types, offering insights into their biological roles. CONCLUSION The ferroptosis-based risk model provides valuable prognostic insights into GBM and highlights potential therapeutic targets, emphasizing the biological significance of ferroptosis-related genes in tumor progression.
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Affiliation(s)
- Yaqiu Wu
- Department of Neurosurgery Intensive Care Unit, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Ling Liu
- Department of Neurosurgery, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Zhili Li
- Department of Neurosurgery, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Tian Zhang
- Department of Neurosurgery, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Qi Wang
- Department of Neurosurgery, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Meixiong Cheng
- Department of Neurosurgery, Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduChina
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Wang W, Yang C, Xia J, Tan Y, Peng X, Xiong W, Li N. Novel insights into the role of quercetin and kaempferol from Carthamus tinctorius L. in the management of nonalcoholic fatty liver disease via NR1H4-mediated pathways. Int Immunopharmacol 2024; 143:113035. [PMID: 39378656 DOI: 10.1016/j.intimp.2024.113035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 08/19/2024] [Accepted: 08/26/2024] [Indexed: 10/10/2024]
Abstract
This study investigates the novel therapeutic potential of quercetin and kaempferol, two bioactive compounds derived from Carthamus tinctorius L., in treating nonalcoholic fatty liver disease (NAFLD) by modulating the bile acid receptor NR1H4 (Nuclear Receptor Subfamily 1 Group H Member 4) and its associated metabolic pathways. A rat model of NAFLD was established, and RNA sequencing and proteomics were carefully employed to identify differential gene expressions associated with the disease. The active components of Carthamus tinctorius L. were screened, followed by the construction of a comprehensive network that maps the interactions between these components, NR1H4 and NAFLD-related pathways. Both in vitro (using HepG2 cells) and in vivo experiments were conducted to evaluate the effects on NR1H4 expression levels through Western blot and RT-qPCR analyses. Our findings identify NR1H4 as a pivotal target in NAFLD. Network pharmacology analysis indicates that quercetin and kaempferol play crucial roles in combating NAFLD, with in vitro and in vivo experiments confirming their ability to mitigate hepatocyte steatosis by enhancing NR1H4 expression. Notably, the protective effects of these compounds were inhibited by the NR1H4 antagonist guggulsterone, highlighting the importance of NR1H4 upregulation. This study demonstrates the novel therapeutic efficacy of quercetin and kaempferol from Carthamus tinctorius L. in treating NAFLD through NR1H4 upregulation. This mechanism contributes to the regulation of lipid metabolism, improvement of liver function, reduction of inflammation, and alleviation of oxidative stress, offering a promising direction for future NAFLD treatment strategies.
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Affiliation(s)
- Wenxiang Wang
- Chongqing Three Gorges Medical College, Chongqing 404120, China; Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, China
| | - Ce Yang
- Chongqing Three Gorges Medical College, Chongqing 404120, China; Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, China
| | - Jing Xia
- Chongqing Three Gorges Medical College, Chongqing 404120, China; Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, China
| | - Ying Tan
- Chongqing Three Gorges Medical College, Chongqing 404120, China; Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, China
| | - Xiaoyuan Peng
- Chongqing Three Gorges Medical College, Chongqing 404120, China; Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, China
| | - Wei Xiong
- Chongqing Three Gorges Medical College, Chongqing 404120, China; Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, China.
| | - Ning Li
- Chongqing Three Gorges Medical College, Chongqing 404120, China; Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, Chongqing 404120, China.
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Chen W, Xu H, Guo L, Zheng F, Yao J, Wang L. Role of ACSL4 in modulating farnesoid X receptor expression and M2 macrophage polarization in HBV-induced hepatocellular carcinoma. MedComm (Beijing) 2024; 5:e706. [PMID: 39268355 PMCID: PMC11391271 DOI: 10.1002/mco2.706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 09/15/2024] Open
Abstract
The intricate relationship between bile acid (BA) metabolism, M2 macrophage polarization, and hepatitis B virus-hepatocellular carcinoma (HBV-HCC) necessitates a thorough investigation of ACSL4's (acyl-CoA synthetase long-chain family member 4) role. This study combines advanced bioinformatics and experimental methods to elucidate ACSL4's significance in HBV-HCC development. Using bioinformatics, we identified differentially expressed genes in HBV-HCC. STRING and gene set enrichment analysis analyses were employed to pinpoint critical genes and pathways. Immunoinfiltration analysis, along with in vitro and in vivo experiments, assessed M2 macrophage polarization and related factors. ACSL4 emerged as a pivotal gene influencing HBV-HCC. In HBV-HCC liver tissues, ACSL4 exhibited upregulation, along with increased levels of M2 macrophage markers and BA. Silencing ACSL4 led to heightened farnesoid X receptor (FXR) expression, reduced BA levels, and hindered M2 macrophage polarization, thereby improving HBV-HCC conditions. This study underscores ACSL4's significant role in HBV-HCC progression. ACSL4 modulates BA-mediated M2 macrophage polarization and FXR expression, shedding light on potential therapeutic targets and novel insights into HBV-HCC pathogenesis.
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Affiliation(s)
- Wenbiao Chen
- Department of Gastroenterology Shenzhen People's Hospital The Second Clinical Medical College Jinan University The First Affiliated Hospital Southern University of Science and Technology Shenzhen China
| | - Huixuan Xu
- Department of Rheumatology and Immunology The Second Clinical Medical College Jinan University (Shenzhen People's Hospital) Shenzhen China
| | - Liliangzi Guo
- Department of Gastroenterology Shenzhen People's Hospital The Second Clinical Medical College Jinan University The First Affiliated Hospital Southern University of Science and Technology Shenzhen China
| | - Fengping Zheng
- Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center Peking University Shenzhen Hospital Shenzhen Guangdong China
| | - Jun Yao
- Department of Gastroenterology Shenzhen People's Hospital The Second Clinical Medical College Jinan University The First Affiliated Hospital Southern University of Science and Technology Shenzhen China
| | - Lisheng Wang
- Department of Gastroenterology Shenzhen People's Hospital The Second Clinical Medical College Jinan University The First Affiliated Hospital Southern University of Science and Technology Shenzhen China
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Cheng G, Zhao Y, Sun F, Zhang Q. Novel insights into STIM1's role in store-operated calcium entry and its implications for T-cell mediated inflammation in trigeminal neuralgia. Front Mol Neurosci 2024; 17:1391189. [PMID: 38962804 PMCID: PMC11221526 DOI: 10.3389/fnmol.2024.1391189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 04/30/2024] [Indexed: 07/05/2024] Open
Abstract
This investigation aims to elucidate the novel role of Stromal Interaction Molecule 1 (STIM1) in modulating store-operated calcium entry (SOCE) and its subsequent impact on inflammatory cytokine release in T lymphocytes, thereby advancing our understanding of trigeminal neuralgia (TN) pathogenesis. Employing the Gene Expression Omnibus (GEO) database, we extracted microarray data pertinent to TN to identify differentially expressed genes (DEGs). A subsequent comparison with SOCE-related genes from the Genecards database helped pinpoint potential target genes. The STRING database facilitated protein-protein interaction (PPI) analysis to spotlight STIM1 as a gene of interest in TN. Through histological staining, transmission electron microscopy (TEM), and behavioral assessments, we probed STIM1's pathological effects on TN in rat models. Additionally, we examined STIM1's influence on the SOCE pathway in trigeminal ganglion cells using techniques like calcium content measurement, patch clamp electrophysiology, and STIM1- ORAI1 co-localization studies. Changes in the expression of inflammatory markers (TNF-α, IL-1β, IL-6) in T cells were quantified using Western blot (WB) and enzyme-linked immunosorbent assay (ELISA) in vitro, while immunohistochemistry and flow cytometry were applied in vivo to assess these cytokines and T cell count alterations. Our bioinformatic approach highlighted STIM1's significant overexpression in TN patients, underscoring its pivotal role in TN's etiology and progression. Experimental findings from both in vitro and in vivo studies corroborated STIM1's regulatory influence on the SOCE pathway. Furthermore, STIM1 was shown to mediate SOCE-induced inflammatory cytokine release in T lymphocytes, a critical factor in TN development. Supportive evidence from histological, ultrastructural, and behavioral analyses reinforced the link between STIM1-mediated SOCE and T lymphocyte-driven inflammation in TN pathogenesis. This study presents novel evidence that STIM1 is a key regulator of SOCE and inflammatory cytokine release in T lymphocytes, contributing significantly to the pathogenesis of trigeminal neuralgia. Our findings not only deepen the understanding of TN's molecular underpinnings but also potentially open new avenues for targeted therapeutic strategies.
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Affiliation(s)
- Guangyu Cheng
- Translational Medicine Research Center of Traditional Chinese Medicine, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yu Zhao
- Department of Acupuncture, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fujia Sun
- Department of Acupuncture, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Qi Zhang
- Preventive Treatment Center, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
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Wang X, Zhan P, Zhang Q, Li R, Fan H. Staphylococcus aureus acquires resistance to glycopeptide antibiotic vancomycin via CXCL10. Int Immunopharmacol 2024; 132:111780. [PMID: 38603853 DOI: 10.1016/j.intimp.2024.111780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND Glycopeptide antibiotic vancomycin is a bactericidal antibiotic available for the infection to Staphylococcus aureus (SA), however, SA has a strong adaptive capacity and thereby acquires resistance to vancomycin. This study aims to illuminate the possible molecular mechanism of vancomycin resistance of SA based on the 16S rRNA sequencing data and microarray profiling data. METHODS 16S rRNA sequencing data of control samples and urinary tract infection samples were retrieved from the EMBL-EBI (European Molecular Biology Laboratory - European Bioinformatics Institute) database. Correlation of gut flora and clinical indicators was evaluated. The possible targets regulated by SA were predicted by microarray profiling and subjected to KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. CXCL10 gene knockout and overexpression were introduced to evaluate the effect of CXCL10 on the virulence of SA and the resistance to vancomycin. SA strains were co-cultured with urethral epithelial cells in vitro. The presence of SA virulence factors was detected using PCR. Biofilm formation of SA strains was assessed using the microtiter plate method. Furthermore, the antibiotic sensitivity of SA strains was evaluated through vancomycin testing. RESULTS Gut flora and its species abundance had significant difference between urinary tract infection and control samples. SA was significantly differentially expressed in urinary tract infection samples. Resistance of SA to vancomycin mainly linked to the D-alanine metabolism pathway. SA may participate in the occurrence of urinary tract infection by upregulating CXCL10. In addition, CXCL10 mainly affected the SA resistance to vancomycin through the TLR signaling pathway. In vitro experimental results further confirmed that the overexpression of CXCL10 in SA increased SA virulence and decreased its susceptibility to vancomycin. In vitro experimental validation demonstrated that the knockout of CXCL10 in urethral epithelial cells enhanced the sensitivity of Staphylococcus aureus (SA) to vancomycin. CONCLUSION SA upregulates the expression of CXCL10 in urethral epithelial cells, thereby activating the TLR signaling pathway and promoting resistance to glycopeptide antibiotics in SA.
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Affiliation(s)
- Xu Wang
- Department of Urology, The Second Hospital of Jilin University, Changchun 130022, PR China
| | - Peng Zhan
- Department of Urology, The Second Hospital of Jilin University, Changchun 130022, PR China
| | - Qiushuang Zhang
- Department of Urology, The Second Hospital of Jilin University, Changchun 130022, PR China
| | - Ranwei Li
- Department of Urology, The Second Hospital of Jilin University, Changchun 130022, PR China
| | - Haitao Fan
- Department of Urology, The Second Hospital of Jilin University, Changchun 130022, PR China.
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Chen W, Guo L, Xu H, Dai Y, Yao J, Wang L. NAC1 transcriptional activation of LDHA induces hepatitis B virus immune evasion leading to cirrhosis and hepatocellular carcinoma development. Oncogenesis 2024; 13:15. [PMID: 38704368 PMCID: PMC11069585 DOI: 10.1038/s41389-024-00515-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 04/08/2024] [Accepted: 04/16/2024] [Indexed: 05/06/2024] Open
Abstract
Our study aimed to elucidate the molecular mechanisms underlying NAC1 (nucleus accumbens associated 1) transcriptional regulation of LDHA and its role in HBV immune evasion, thus contributing to the development of cirrhosis and hepatocellular carcinoma (HCC). Utilizing public datasets, we performed differential gene expression and weighted gene co-expression network analysis (WGCNA) on HBV-induced cirrhosis/HCC data. We identified candidate genes by intersecting differentially expressed genes with co-expression modules. We validated these genes using the TCGA database, conducting survival analysis to pinpoint key genes affecting HBV-HCC prognosis. We also employed the TIMER database for immune cell infiltration data and analyzed correlations with identified key genes to uncover potential immune escape pathways. In vitro, we investigated the impact of NAC1 and LDHA on immune cell apoptosis and HBV immune evasion. In vivo, we confirmed these findings using an HBV-induced cirrhosis model. Bioinformatics analysis revealed 676 genes influenced by HBV infection, with 475 genes showing differential expression in HBV-HCC. NAC1 emerged as a key gene, potentially mediating HBV immune escape through LDHA transcriptional regulation. Experimental data demonstrated that NAC1 transcriptionally activates LDHA, promoting immune cell apoptosis and HBV immune evasion. Animal studies confirmed these findings, linking NAC1-mediated LDHA activation to cirrhosis and HCC development. NAC1, highly expressed in HBV-infected liver cells, likely drives HBV immune escape by activating LDHA expression, inhibiting CD8 + T cells, and promoting cirrhosis and HCC development.
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Affiliation(s)
- Wenbiao Chen
- Department of Gastroenterology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, China
| | - Liliangzi Guo
- Department of Gastroenterology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, China
| | - Huixuan Xu
- Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, China
| | - Yong Dai
- Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, China.
| | - Lisheng Wang
- Department of Gastroenterology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, China.
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Gong Y, Luo G, Zhang S, Chen Y, Hu Y. Transcriptome sequencing analysis reveals miR-30c-5p promotes ferroptosis in cervical cancer and inhibits growth and metastasis of cervical cancer xenografts by targeting the METTL3/KRAS axis. Cell Signal 2024; 117:111068. [PMID: 38286198 DOI: 10.1016/j.cellsig.2024.111068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 01/18/2024] [Accepted: 01/26/2024] [Indexed: 01/31/2024]
Abstract
Cervical cancer is the most common malignant tumor in the female reproductive system worldwide, and its molecular mechanisms remain complex and poorly understood. Various techniques, including transcriptome sequencing, RT-qPCR, ELISA, immunofluorescence, Western blot, CCK-8 assay, Transwell assay, and xenograft models, were employed to investigate gene/miRNA expression, cellular proliferation, migration, and the interactions between miR-30c-5p, METTL3, and KRAS. Our transcriptome sequencing results demonstrated a significant downregulation of miR-30c-5p in cervical cancer cells. Further investigations using RNA pull-down, dual-luciferase reporter assay, Me-RIP, and PAR-CLIP confirmed METTL3 as one of the downstream targets of miR-30c-5p, while KRAS was identified as an iron-death suppressor gene susceptible to m6A modification. Notably, our Me-RIP analysis demonstrated the involvement of METTL3 in m6A modification of KRAS. In vitro experiments revealed that miR-30c-5p facilitated ferroptosis in cervical cancer cells by inhibiting the METTL3/KRAS axis, thus suppressing proliferation and migration. Additionally, in vivo studies demonstrated that miR-30c-5p repressed the growth and metastasis of cervical cancer xenografts through the inhibition of the METTL3/KRAS axis. Overall, this study highlights the critical role of miR-30c-5p in modulating cervical cancer progression by targeting the METTL3/KRAS axis, providing new insights into the molecular mechanisms underlying cervical cancer growth and metastasis.
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Affiliation(s)
- Yangmei Gong
- The First Affiliated Hospital, Center for a combination of Obstetrics and Gynecology & Reproductive medicine, Henyang Medical School, University of South China, Hengyang 421001, China
| | - Guifang Luo
- The First Affiliated Hospital, Center for a combination of Obstetrics and Gynecology & Reproductive medicine, Henyang Medical School, University of South China, Hengyang 421001, China
| | - Shufen Zhang
- The First Affiliated Hospital, Center for a combination of Obstetrics and Gynecology & Reproductive medicine, Henyang Medical School, University of South China, Hengyang 421001, China
| | - Yijing Chen
- The First Affiliated Hospital, Center for a combination of Obstetrics and Gynecology & Reproductive medicine, Henyang Medical School, University of South China, Hengyang 421001, China
| | - Yi Hu
- The First Affiliated Hospital, Center for a combination of Obstetrics and Gynecology & Reproductive medicine, Henyang Medical School, University of South China, Hengyang 421001, China.
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Zhang M, Yang J, Liang G, Yuan H, Wu Y, Li L, Yu T, Zhang Y, Wang J. FOXA1-Driven pathways exacerbate Radiotherapy-Induced kidney injury in colorectal cancer. Int Immunopharmacol 2024; 131:111689. [PMID: 38471364 DOI: 10.1016/j.intimp.2024.111689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 02/07/2024] [Accepted: 02/09/2024] [Indexed: 03/14/2024]
Abstract
OBJECTIVE This study aimed to investigate the role of FOXA1 in acute kidney injury (AKI) induced by radiotherapy in colorectal cancer. Although FOXA1 is known to be aberrantly expressed in malignant tumors, its contribution to AKI remains unclear. This study aimed to explore the involvement of FOXA1 in AKI induced by radiotherapy in colorectal cancer and its influence on the regulation of downstream target genes. METHODS Firstly, a transcriptome analysis was performed on mice to establish a radiation-induced AKI model, and qPCR was used to determine the expression of FOXA1 in renal cell injury models induced by X-ray irradiation. Additionally, FOXA1 was silenced using lentiviral vectors to investigate its effects on the apoptosis of mice with radiation-induced AKI and HK-2 cells. Next, bioinformatics analysis and various experimental validation methods such as ChIP assays, co-immunoprecipitation, and dual-luciferase reporter assays were employed to explore the relationship between FOXA1 and the downstream regulatory factors ITCH promoter and the ubiquitin ligase-degradable TXNIP. Finally, lentiviral overexpression or knockout techniques were used to investigate the impact of the FOXA1/ITCH/TXNIP axis on oxidative stress and the activation of inflammatory body NLRP3. RESULTS This study revealed that FOXA1 was significantly upregulated in the renal tissues of mice with radiation-induced AKI and in the injured HK-2 cells. Furthermore, in vitro cell experiments and animal experiments demonstrated that FOXA1 suppressed the transcription of the E3 ubiquitin ligase ITCH, thereby promoting apoptosis of renal tubular cells and causing renal tissue damage. Further in vivo animal experiments confirmed that TXNIP, a protein degraded by ITCH ubiquitination, could inhibit oxidative stress and the activation of NLRP3 inflammasome in the AKI mouse model. CONCLUSION FOXA1 enhances oxidative stress, cell apoptosis, and NLRP3 inflammasome activation by regulating the ITCH/TXNIP axis, thereby exacerbating radiotherapy-induced AKI.
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Affiliation(s)
- Minhai Zhang
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Jingyuan Yang
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University, Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China
| | - Guodong Liang
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Huiqiong Yuan
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Yanni Wu
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Li Li
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Tao Yu
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Yuling Zhang
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China.
| | - Jingfeng Wang
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou 510120, China.
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12
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Zhou R, Li S, Wang Q, Bi Y, Li X, Wang Q. Silencing of GDF11 suppresses hepatocyte apoptosis to relieve LPS/D-GalN acute liver failure. J Biochem Mol Toxicol 2024; 38:e23577. [PMID: 37934488 DOI: 10.1002/jbt.23577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 08/29/2023] [Accepted: 10/20/2023] [Indexed: 11/08/2023]
Abstract
In this paper, we generated a short hairpin RNA growth differentiation factor-11 (sh-GDF11) and evaluated the effects of sh-GDF11 on the pathogenesis of acute liver failure (ALF) in vitro and in vivo. Through bioinformatics study, the key gene related to ALF was assayed. Lipopolysaccharide (LPS) and D-galactoamine (D-GalN) were applied to establish the mouse model of LPS/D-GalN-induced liver injury, and TNF-α and D-Gal were used to construct an in vitro cell model, followed by treatment of sh-GDF11 for analysis of liver cell proliferation. Bioinformatics analysis showed that the protective effect of sh-GDF11 on ALF may be mediated by phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. The results of in vitro study found that sh-GDF11 could promote cell proliferation and inhibit death by blocking the PI3K/Akt/mTOR signaling pathway. In vivo animal experiments further confirmed that sh-GDF11 could suppress hepatocyte apoptosis by inhibiting the PI3K/Akt/mTOR signaling pathway. sh-GDF11 relieved LPS/D-GalN-induced ALF by blocking the PI3K/Akt/mTOR signaling pathway, emphasizing its critical role in LPS/D-GalN-induced ALF treatment.
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Affiliation(s)
- Rongsheng Zhou
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuang Li
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qun Wang
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yang Bi
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaogang Li
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qiang Wang
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Chen L, Zhang N, Huang Y, Zhang Q, Fang Y, Fu J, Yuan Y, Chen L, Chen X, Xu Z, Li Y, Izawa H, Xiang C. Multiple Dimensions of using Mesenchymal Stem Cells for Treating Liver Diseases: From Bench to Beside. Stem Cell Rev Rep 2023; 19:2192-2224. [PMID: 37498509 DOI: 10.1007/s12015-023-10583-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2023] [Indexed: 07/28/2023]
Abstract
Liver diseases impose a huge burden worldwide. Although hepatocyte transplantation has long been considered as a potential strategy for treating liver diseases, its clinical implementation has created some obvious limitations. As an alternative strategy, cell therapy, particularly mesenchymal stem cell (MSC) transplantation, is widely used in treating different liver diseases, including acute liver disease, acute-on-chronic liver failure, hepatitis B/C virus, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Here, we summarize the status of MSC transplantation in treating liver diseases, focusing on the therapeutic mechanisms, including differentiation into hepatocyte-like cells, immunomodulating function with a variety of immune cells, paracrine effects via the secretion of various cytokines and extracellular vesicles, and facilitation of homing and engraftment. Some improved perspectives and current challenges are also addressed. In summary, MSCs have great potential in the treatment of liver diseases based on their multi-faceted characteristics, and more accurate mechanisms and novel therapeutic strategies stemming from MSCs will facilitate clinical practice.
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Affiliation(s)
- Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yuqi Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Lu Chen
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Xin Chen
- Department of Hematology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310027, People's Republic of China
| | - Zhenyu Xu
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Hiromi Izawa
- Jingugaien Woman Life Clinic, Jingu-Gaien 3-39-5 2F, Shibuya-Ku, Tokyo, Japan
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China.
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China.
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Zhang D, Zhang S, He Z, Chen Y. Cytosine-phosphate-guanine oligodeoxynucleotides alleviate radiation-induced kidney injury in cervical cancer by inhibiting DNA damage and oxidative stress through blockade of PARP1/XRCC1 axis. J Transl Med 2023; 21:679. [PMID: 37773127 PMCID: PMC10541701 DOI: 10.1186/s12967-023-04548-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 09/20/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND Radiotherapy can cause kidney injury in patients with cervical cancer. This study aims to investigate the possible molecular mechanisms by which CpG-ODNs (Cytosine phosphate guanine-oligodeoxynucleotides) regulate the PARP1 (poly (ADP-ribose) polymerase 1)/XRCC1 (X-ray repair cross-complementing 1) signaling axis and its impact on radiation kidney injury (RKI) in cervical cancer radiotherapy. METHODS The GSE90627 dataset related to cervical cancer RKI was obtained from the Gene Expression Omnibus (GEO) database. Bioinformatics databases and R software packages were used to analyze the target genes regulated by CpG-ODNs. A mouse model of RKI was established by subjecting C57BL/6JNifdc mice to X-ray irradiation. Serum blood urea nitrogen (BUN) and creatinine levels were measured using an automated biochemical analyzer. Renal tissue morphology was observed through HE staining, while TUNEL staining was performed to detect apoptosis in renal tubular cells. ELISA was conducted to measure levels of oxidative stress-related factors in mouse serum and cell supernatant. An in vitro cell model of RKI was established using X-ray irradiation on HK-2 cells for mechanism validation. RT-qPCR was performed to determine the relative expression of PARP1 mRNA. Cell proliferation activity was assessed using the CCK-8 assay, and Caspase 3 activity was measured in HK-2 cells. Immunofluorescence was used to determine γH2AX expression. RESULTS Bioinformatics analysis revealed that the downstream targets regulated by CpG-ODNs in cervical cancer RKI were primarily PARP1 and XRCC1. CpG-ODNs may alleviate RKI by inhibiting DNA damage and oxidative stress levels. This resulted in significantly decreased levels of BUN and creatinine in RKI mice, as well as reduced renal tubular and glomerular damage, lower apoptosis rate, decreased DNA damage index (8-OHdG), and increased levels of antioxidant factors associated with oxidative stress (SOD, CAT, GSH, GPx). Among the CpG-ODNs, CpG-ODN2006 had a more pronounced effect. CpG-ODNs mediated the inhibition of PARP1, thereby suppressing DNA damage and oxidative stress response in vitro in HK-2 cells. Additionally, PARP1 promoted the formation of the PARP1 and XRCC1 complex by recruiting XRCC1, which in turn facilitated DNA damage and oxidative stress response in renal tubular cells. Overexpression of either PARP1 or XRCC1 reversed the inhibitory effects of CpG-ODN2006 on DNA damage and oxidative stress in the HK-2 cell model and RKI mouse model. CONCLUSION CpG-ODNs may mitigate cervical cancer RKI by blocking the activation of the PARP1/XRCC1 signaling axis, inhibiting DNA damage and oxidative stress response in renal tubule epithelial cells.
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Affiliation(s)
- Deyu Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang, 110004, China
| | - Shitai Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang, 110004, China
| | - Zheng He
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang, 110004, China
| | - Ying Chen
- Department of Nephrology, The First Hospital of China Medical University, No. 155 Nanjing Bei Street, Shenyang, 110001, Liaoning, China.
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15
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Wang YH, Chen EQ. Mesenchymal Stem Cell Therapy in Acute Liver Failure. Gut Liver 2023; 17:674-683. [PMID: 36843422 PMCID: PMC10502502 DOI: 10.5009/gnl220417] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/04/2022] [Accepted: 11/18/2022] [Indexed: 02/28/2023] Open
Abstract
Acute liver failure (ALF) is a severe liver disease syndrome with rapid deterioration and high mortality. Liver transplantation is the most effective treatment, but the lack of donor livers and the high cost of transplantation limit its broad application. In recent years, there has been no breakthrough in the treatment of ALF, and the application of stem cells in the treatment of ALF is a crucial research field. Mesenchymal stem cells (MSCs) are widely used in disease treatment research due to their abundant sources, low immunogenicity, and no ethical restrictions. Although MSCs are effective for treating ALF, the application of MSCs to ALF needs to be further studied and optimized. In this review, we discuss the potential mechanisms of MSCs therapy for ALF, summarize some methods to enhance the efficacy of MSCs, and explore optimal approaches for MSC transplantation.
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Affiliation(s)
- Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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16
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Shao B, Ren SH, Wang ZB, Wang HD, Zhang JY, Qin H, Zhu YL, Sun CL, Xu YN, Li X, Wang H. CD73 mediated host purinergic metabolism in intestine contributes to the therapeutic efficacy of a novel mesenchymal-like endometrial regenerative cells against experimental colitis. Front Immunol 2023; 14:1155090. [PMID: 37180168 PMCID: PMC10167049 DOI: 10.3389/fimmu.2023.1155090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 04/14/2023] [Indexed: 05/15/2023] Open
Abstract
Background The disruption of intestinal barrier functions and the dysregulation of mucosal immune responses, mediated by aberrant purinergic metabolism, are involved in the pathogenesis of inflammatory bowel diseases (IBD). A novel mesenchymal-like endometrial regenerative cells (ERCs) has demonstrated a significant therapeutic effect on colitis. As a phenotypic marker of ERCs, CD73 has been largely neglected for its immunosuppressive function in regulating purinergic metabolism. Here, we have investigated whether CD73 expression on ERCs is a potential molecular exerting its therapeutic effect against colitis. Methods ERCs either unmodified or with CD73 knockout (CD73-/-ERCs), were intraperitoneally administered to dextran sulfate sodium (DSS)-induced colitis mice. Histopathological analysis, colon barrier function, the proportion of T cells, and maturation of dendritic cells (DCs) were investigated. The immunomodulatory effect of CD73-expressing ERCs was evaluated by co-culture with bone marrow-derived DCs under LPS stimulation. FACS determined DCs maturation. The function of DCs was detected by ELISA and CD4+ cell proliferation assays. Furthermore, the role of the STAT3 pathway in CD73-expressing ERCs-induced DC inhibition was also elucidated. Results Compared with untreated and CD73-/-ERCs-treated groups, CD73-expressing ERCs effectively attenuated body weight loss, bloody stool, shortening of colon length, and pathological damage characterized by epithelial hyperplasia, goblet cell depletion, the focal loss of crypts and ulceration, and the infiltration of inflammatory cells. Knockout of CD73 impaired ERCs-mediated colon protection. Surprisingly, CD73-expressing ERCs significantly decreased the populations of Th1 and Th17 cells but increased the proportions of Tregs in mouse mesenteric lymph nodes. Furthermore, CD73-expressing ERCs markedly reduced the levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and increased anti-inflammatory factors (IL-10) levels in the colon. CD73-expressing ERCs inhibited the antigen presentation and stimulatory function of DCs associated with the STAT-3 pathway, which exerted a potent therapeutic effect against colitis. Conclusions The knockout of CD73 dramatically abrogates the therapeutic ability of ERCs for intestinal barrier dysfunctions and the dysregulation of mucosal immune responses. This study highlights the significance of CD73 mediates purinergic metabolism contributing to the therapeutic effects of human ERCs against colitis in mice.
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Affiliation(s)
- Bo Shao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Shao-hua Ren
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhao-bo Wang
- School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Hong-da Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing-yi Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yang-lin Zhu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Cheng-lu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yi-ni Xu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
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17
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Li H, Wei J, Zhang Z, Li J, Ma Y, Zhang P, Lin J. Menstrual blood-derived endometrial stem cells alleviate neuroinflammation by modulating M1/M2 polarization in cell and rat Parkinson's disease models. Stem Cell Res Ther 2023; 14:85. [PMID: 37055866 PMCID: PMC10099022 DOI: 10.1186/s13287-023-03330-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 04/05/2023] [Indexed: 04/15/2023] Open
Abstract
BACKGROUND Neuroinflammation is closely related to the development of Parkinson's disease (PD). Because of the extensive sources, non-invasive and periodical collection method, human menstrual blood-derived endometrial stem cells (MenSCs) have been explored as a promising tool for treatment of PD. This study aimed to investigate if MenSCs could inhibit neuroinflammation in PD rats by regulating M1/M2 polarization and to excavate the underlying mechanisms. METHODS MenSCs were co-cultured with 6-OHDA-exposed microglia cell lines. Then the morphology of microglia cells and the level of inflammatory factors were assessed by immunofluorescence and qRT-PCR. After MenSCs were transplanted into the brain of PD rats, animal motor function, the expression of tyrosine hydroxylase, and the level of inflammatory factors in the cerebrospinal fluid (CSF) and serum were detected to evaluate the therapeutic potential of MenSCs. Meanwhile, the expression of M1/M2 phenotype related genes was detected by qRT-PCR. One protein array kit containing 1000 kinds of factors was used to detect the protein components in the conditioned medium of MenSCs. Finally, bioinformatic analysis was performed to analyze the function of factors secreted by MenSCs and the signal pathways involved in. RESULTS MenSCs could suppress 6-OHDA-induced microglia cell activation and significantly decrease inflammation in vitro. After transplantation into the brain of PD rats, MenSCs improved animal motor function, which was indicated by the increased movement distance, ambulatory episodes, exercise time on the rotarod, and less contralateral rotation. Additionally, MenSCs reduced the loss of dopaminergic neurons and down-regulated the level of pro-inflammatory factors in the CSF and serum. Moreover, q-PCR and WB results showed the transplantation of MenSCs significantly down-regulated the expression of M1 phenotype cell markers and meanwhile up-regulated the expression of M2 phenotype cell markers in the brain of PD rats. 176 biological processes including inflammatory response, negative regulation of apoptotic process, and microglial cell activation were enriched by GO-BP analysis. 58 signal pathways including PI3K/Akt and MAPK were enriched by KEGG analysis. CONCLUSIONS In conclusion, our results provide preliminary evidence for the anti-inflammation capacity of MenSCs by regulating M1/M2 polarization. We firstly demonstrated the biological process of factors secreted by MenSCs and the signal pathways involved in using protein array and bioinformatic analysis.
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Affiliation(s)
- Han Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Jinghui Wei
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Zhigang Zhang
- Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 45003, China
| | - Junyao Li
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Yaokai Ma
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Ping Zhang
- Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 45003, China
| | - Juntang Lin
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China.
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18
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Shi Y, Liu Y, Zhang B, Li X, Lin J, Yang C. Human Menstrual Blood-Derived Endometrial Stem Cells Promote Functional Recovery by Improving the Inflammatory Microenvironment in a Mouse Spinal Cord Injury Model. Cell Transplant 2023; 32:9636897231154579. [PMID: 36786359 PMCID: PMC9932767 DOI: 10.1177/09636897231154579] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
Spinal cord injury (SCI) is a traumatic injury of the central nervous system. Because neurons are damaged and difficult to regenerate after SCI, its repair remains challenging. However, recent research on stem cell therapy have favored its use after SCI. In this study, based on the establishment of a mouse SCI model, human menstrual blood-derived endometrial stem cells (MenSCs) were intrathecally injected to explore the role and molecular mechanism of MenSCs in SCI. MenSCs were transplanted following SCI in the animal model, and behavioral evaluations showed that MenSC transplantation improved functional recovery. Therefore, samples were collected after 7 days, and transcriptome sequencing was performed. Gene Ontology (GO) enrichment analysis revealed that SCI is closely related to immune system processes. After transplantation of MenSCs, the immune response was significantly activated. In the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, MenSC transplantation was found to be closely related to Th1, Th2, and Th17 cell differentiation pathways. Neuronal damage and glial cell proliferation and activation in the different groups were detected by fluorescence immunohistochemistry and Western blotting 7 days after SCI. Simultaneously, the activation of different types of microglia was detected and the expression of pro-inflammatory and anti-inflammatory factors was quantitatively analyzed. The results showed that MenSC transplantation and sonic hedgehog (Shh)-induced MenSCs accelerated neuronal recovery at the injured site, inhibited the formation of glial cells and microglial activation at the injured site, inhibited the expression of inflammatory factors, and improved the inflammatory microenvironment to achieve functional recovery of SCI. This study provides an experimental basis for the study of the role and molecular mechanism of MenSCs in SCI repair, and a reference for the role of Shh-induced MenSCs in SCI repair.
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Affiliation(s)
- Yaping Shi
- Stem Cells and Biotherapy Engineering
Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and
Biotherapy, School of Life Science and Technology, Xinxiang Medical University,
Xinxiang, China
| | - Yunfei Liu
- Stem Cells and Biotherapy Engineering
Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and
Biotherapy, School of Life Science and Technology, Xinxiang Medical University,
Xinxiang, China
| | - Bichao Zhang
- Stem Cells and Biotherapy Engineering
Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and
Biotherapy, School of Life Science and Technology, Xinxiang Medical University,
Xinxiang, China
| | - Xiaoying Li
- Stem Cells and Biotherapy Engineering
Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and
Biotherapy, School of Life Science and Technology, Xinxiang Medical University,
Xinxiang, China
| | - Juntang Lin
- Stem Cells and Biotherapy Engineering
Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and
Biotherapy, School of Life Science and Technology, Xinxiang Medical University,
Xinxiang, China,Henan Key Laboratory of Medical Tissue
Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Ciqing Yang
- Stem Cells and Biotherapy Engineering
Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and
Biotherapy, School of Life Science and Technology, Xinxiang Medical University,
Xinxiang, China,Henan Key Laboratory of Medical Tissue
Regeneration, Xinxiang Medical University, Xinxiang, China,Henan Key Laboratory of
Neurorestoratology, The First Affiliated Hospital of Xinxiang Medical University,
Xinxiang, China,Ciqing Yang, Stem Cells and Biotherapy
Engineering Research Center of Henan, National Joint Engineering Laboratory of
Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang
Medical University, Xinxiang 453003, China.
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Ma JF, Gao JP, Shao ZW. Acute liver failure: A systematic review and network meta-analysis of optimal type of stem cells in animal models. World J Stem Cells 2023; 15:1-15. [PMID: 36713788 PMCID: PMC9850664 DOI: 10.4252/wjsc.v15.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/23/2022] [Accepted: 12/23/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND The therapeutic effects of various stem cells in acute liver failure (ALF) have been demonstrated in preclinical studies. However, the specific type of stem cells with the highest therapeutic potential has not been determined.
AIM To validate the efficacy of stem cells in ALF model and to identify the most promising stem cells.
METHODS A search was conducted on the PubMed, Web of Science, Embase, Scopus, and Cochrane databases from inception to May 3, 2022, and updated on November 16, 2022 to identify relevant studies. Two independent reviewers performed the literature search, identification, screening, quality assessment, and data extraction.
RESULTS A total of 89 animal studies were included in the analysis. The results of traditional meta-analysis showed that stem cell therapy could significantly reduce the serum levels of alanine aminotransferase [weighted mean difference (WMD) = -181.05 (-191.71, -170.39)], aspartate aminotransferase [WMD = -309.04 (-328.45, -289.63)], tumor necrosis factor-alpha [WMD = -8.75 (-9.93, -7.56)], and interleukin-6 [WMD = -10.43 (-12.11, -8.76)] in animal models of ALF. Further subgroup analysis and network meta-analysis showed that although mesenchymal stem cells are the current research hotspot, the effect of liver stem cells (LSCs) on improving liver function is significantly better than that of the other five types of stem cells. In addition, the ranking results showed that the possibility of LSCs improving liver function ranked first. This fully proves the great therapeutic potential of LSCs, which needs to be paid more attention in the future.
CONCLUSION LSCs may have a higher therapeutic potential. Further high-quality animal experiments are needed to explore the most effective stem cells for ALF.
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Affiliation(s)
- Jun-Feng Ma
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou 730030, Gansu Province, China
| | - Jian-Ping Gao
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou 730030, Gansu Province, China
| | - Zi-Wei Shao
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou 730030, Gansu Province, China
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He Y, Han Y, Ye Y. Therapeutic Potential of Menstrual Blood-Derived Stem Cell Transplantation for Intrauterine Adhesions. Front Surg 2022; 9:847213. [PMID: 35274000 PMCID: PMC8901573 DOI: 10.3389/fsurg.2022.847213] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 01/24/2022] [Indexed: 12/27/2022] Open
Abstract
An increasing number of women experience intrauterine adhesion as a result of intrauterine operations, such as induced abortion, which can cause infertility, recurrent abortion and amenorrhea. Although some strategies have been applied clinically, such as hysteroscopy adhesiolysis of intrauterine adhesions, the results have not been promising. As regenerative medicine develops, research on menstrual blood-derived stem cell transplantation is increasing due to the properties of these cells, including self-renewal, differentiation, angiogenesis, anti-inflammation and immunomodulation. As a result, menstrual blood-derived stem cells may be an ideal cell source for the treatment of intrauterine adhesion. Excitingly, it has been reported that autologous menstrual blood stem cells could recovery injured endometrium and improve infertility in patients with refractory intrauterine adhesion. In this review, we discuss the possible potential of menstrual blood-derived stem cell transplantation for intrauterine adhesion, including the antifibrosis, angiogenesis, anti-inflammation and immunoregulation properties of the cells, which brings hopes for clinical therapy.
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Affiliation(s)
- Yantao He
- Department of Gynecology and Obstetrics, Zhongshan City People's Hospital, Zhongshan, China
| | - Yanhua Han
- Department of Gynecology and Obstetrics, Zhongshan City People's Hospital, Zhongshan, China
| | - Yun Ye
- Centre for Reproductive Medicine, Zhongshan City People's Hospital, Zhongshan, China
- *Correspondence: Yun Ye
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