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Liver fibrosis, acute liver injury or liver failure, liver tumors, and immune rejection after liver transplantation are common clinical liver diseases. Immune responses are the key to determining the prognosis of liver diseases. Liver transplantation could be the last resort for patients with liver failure. However, the use of liver transplantation is limited because of the scarcity of organ donors, immunological rejection in recipients, and high cost. Mesenchymal stem cells (MSCs) are pluripotent adult stem cells with extensive anti-inflammatory and immunomodulation effects. MSCs can be effectively used for treating liver diseases but without the limitations that are associated with liver transplantation. Therefore, several clinical trials have utilized MSCs for the treatment of refractory liver diseases and the related mechanism is increasingly being elucidated. We have mainly summarized the recent studies that focus on the immunomodulation mechanism of MSC therapy in liver diseases. Further, we have presented our insights on the prospects of using MSCs in the treatment of liver diseases.
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Hepatopatias , Falência Hepática , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Adulto , Humanos , Hepatopatias/terapia , ImunomodulaçãoRESUMO
BACKGROUND: Surgical resection is the only possible cure for pancreatic cancer, it remains controversial whether extend lymphadenectomy in pancreatoduodenectomy (EPD) is better than standard lymphadenectomy in pancreatoduodenectomy (SPD). The aim of this study was to compare the efficacy of EPD with SPD for pancreatic head adenocarcinoma. METHODS: A specific search of online databases including PubMed, Web of Science, Embase, and Cochrane library was conducted from January 1990 to October 2018. Relative perioperative outcomes were synthesized. Single-arm meta-analysis was also performed. RESULTS: A total of eight studies involving 687 (342 vs 345) patients were included for analysis in our study. The number of lymph nodes harvested [24.54 vs 13.29; weighted mean difference (WMD) -10.69, Pâ¯=â¯0.000], operative time (469.84â¯min vs 354.85â¯min; WMD -99.09, Pâ¯=â¯0.000), and diarrhea (postoperative three months) [45.1% vs 18.2%; odds radio (OR) 0.20, Pâ¯=â¯0.014] were significantly higher in patients who underwent EPD than SPD. The perioperative complications (35% vs 28.8%; OR 0.79, Pâ¯=â¯0.186), tumor size (3.27â¯cm vs 3.248â¯cm; WMD -0.11, Pâ¯=â¯0.256), lymph node metastasis (66% vs 55.9%; OR 0.71, Pâ¯=â¯0.105), and positive margin (10.4% vs 11.3%; OR 1.28, Pâ¯=â¯0.392) were no significant differences between EPD group and SPD group. Extended lymphadenectomy in pancreatoduodenectomy dose not contribute to the overall survival of patients with adenocarcinoma of the pancreatic head [hazard ratio (HR) 0.95; 95% CI 0.78-1.15; Pâ¯=â¯0.61]. CONCLUSION: The update meta-analysis shows that EPD failed to improve the overall survival, may even lead to increased morbidity.
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Excisão de Linfonodo/métodos , Metástase Linfática/prevenção & controle , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Humanos , Neoplasias PancreáticasRESUMO
Chronic Liver fibrosis may progress to liver cirrhosis and hepatocellular carcinoma (HCC), hence cause a substantial global burden. However, effective therapies for blocking fibrosis are still lacking. Although mesenchymal stem cells (MSCs) have been proven beneficial to liver regeneration after damage, the underlying mechanism of their therapeutic effects are not fully understood. Oxidative stress and mitochondrial functionality alteration directly contributes to the hepatocyte apoptosis and development of liver fibrosis. This study aims to elucidate the mechanism by which hUC-MSC alleviates liver fibrosis and mitochondrial dysfunction. RNA-sequencing was performed to characterize the transcriptomic changes after implantation of hUC-MSCs in mice with liver fibrosis. Next, western blot, RT-PCR, immunohistochemical and immunofluorescence staining were used to evaluate the expression of different genes in vitro and in vivo. Additionally, mitochondrial morphological and dynamic changes, ROS content, and ATP production were examined. Slc25a47, a newly identified liver-specific mitochondrial NAD+ transporter, was notably reduced in CCl4-treated mice and H2O2-stimulated hepatocytes. Conversely, hUC-MSCs increased the Slc25a47 expression and NAD+ level within mitochondria, thereby enhanced Sirt3 protein activity and alleviated mitochondrial dysfunction in the liver. Furthermore, Slc25a47 knockdown could partially abrogate the protective effects of hUC-MSCs on H2O2-induced mitochondrial fission and oxidative stress in hepatocytes. Our study illustrates that Slc25a47 is a key molecular for hUC-MSCs to improve liver fibrosis and regulates mitochondrial function through Sirt3 for the first time, and providing a theoretical basis for the clinical translation of hUC-MSCs transplantation in the treatment of patients with liver fibrosis/cirrhosis.
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Cirrose Hepática , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Doenças Mitocondriais , Proteínas de Transporte da Membrana Mitocondrial , Sirtuína 3 , Animais , Humanos , Camundongos , Peróxido de Hidrogênio/farmacologia , Cirrose Hepática/metabolismo , Cirrose Hepática/terapia , Células-Tronco Mesenquimais/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , NAD/metabolismo , Transdução de Sinais , Sirtuína 3/metabolismo , Cordão Umbilical/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismoRESUMO
The liver is an important metabolic and detoxification organ and hence demands a large amount of energy, which is mainly produced by the mitochondria. Liver tissues of patients with alcohol-related or non-alcohol-related liver diseases contain ultrastructural mitochondrial lesions, mitochondrial DNA damage, disturbed mitochondrial dynamics, and compromised ATP production. Overproduction of mitochondrial reactive oxygen species induces oxidative damage to mitochondrial proteins and mitochondrial DNA, decreases mitochondrial membrane potential, triggers hepatocyte inflammation, and promotes programmed cell death, all of which impair liver function. Mitochondrial DNA may be a potential novel non-invasive biomarker of the risk of progression to liver cirrhosis and hepatocellular carcinoma in patients infected with the hepatitis B virus. We herein present a review of the mechanisms of mitochondrial dysfunction in the development of acute liver injury and chronic liver diseases, such as hepatocellular carcinoma, viral hepatitis, drug-induced liver injury, alcoholic liver disease, and non-alcoholic fatty liver disease. This review also discusses mitochondrion-centric therapies for treating liver diseases.
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BACKGROUND: Hypertension and non-alcoholic fatty liver disease (NAFLD) share several pathophysiologic risk factors, and the exact relationship between the two remains unclear. Our study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 and Mendelian randomization (MR) analyses. METHODS: Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES 2017-2018. Subsequently, a two-sample MR study was performed using the genome-wide association study (GWAS) summary statistics to identify the causal association between hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and NAFLD. The primary inverse variance weighted (IVW) and other supplementary MR approaches were conducted to verify the causal association between hypertension and NAFLD. Sensitivity analyses were adopted to confirm the robustness of the results. RESULTS: A total of 3144 participants were enrolled for our observational study in NHANES. Weighted multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk (odds ratio [OR] = 1.677; 95% confidence interval [CI], 1.159-2.423). SBP ≥130 mmHg and DBP ≥80 mmHg were also significantly positively correlated with NAFLD. Moreover, hypertension was independently connected with liver steatosis ( ß = 7.836 [95% CI, 2.334-13.338]). The results of MR analysis also supported a causal association between hypertension (OR = 7.203 [95% CI, 2.297-22.587]) and NAFLD. Similar results were observed for the causal exploration between SBP (OR = 1.024 [95% CI, 1.003-1.046]), DBP (OR = 1.047 [95% CI, 1.005-1.090]), and NAFLD. The sensitive analysis further confirmed the robustness and reliability of these findings (all P >0.05). CONCLUSION: Hypertension was associated with an increased risk of NAFLD.
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Hipertensão , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Inquéritos Nutricionais , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Reprodutibilidade dos Testes , Hipertensão/genéticaRESUMO
Pancreatic cancer (PC) responds weakly to conventional immunotherapy. RNA N6-methyladenosine (m6A) modification has an essential role in the immune response, while its potential role in PC tumor microenvironment (TME) immune cell infiltration remains unknown. In this study, we thoroughly assessed the m6A modification patterns of 472 PC samples using 19 m6A regulators, and we systematically correlated these modification patterns with TME immune cell infiltration characteristics. We also created the m6Ascore and evaluated the m6A modification patterns of individual tumors, identified three different m6A modification patterns, and explored the role of the important m6A "writer" RBM15 in the regulation of macrophage function in PC. Two independent PC cohorts confirmed that patients with higher m6Ascore showed significant survival benefit. We verified that knockdown of RBM15 has the ability to inhibit PC growth and to promote macrophage infiltration and enhance phagocytosis of PC cells by macrophages. In conclusion, m6A modifications play a non-negligible role in the formation of TME diversity and complexity in PC. We reveal that inhibition of RBM15 suppresses PC development and modulates macrophage phagocytosis, and provide a more effective immunotherapeutic strategy for PC.
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Adenosina , Macrófagos , Neoplasias Pancreáticas , Fagocitose , Proteínas de Ligação a RNA , Microambiente Tumoral , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Humanos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Adenosina/análogos & derivados , Adenosina/metabolismo , Microambiente Tumoral/imunologia , Linhagem Celular Tumoral , AnimaisRESUMO
Background and Aims: Accumulating evidence highlights the association between the gut microbiota and liver cirrhosis. However, the role of the gut microbiota in liver cirrhosis remains unclear. Methods: We first assessed the differences in the composition of the bacterial community between CCl4-induced liver cirrhosis and control mice using 16S rRNA sequencing. We then performed a two-sample Mendelian randomization (MR) analysis to reveal the underlying causal relationship between the gut microbiota and liver cirrhosis. Causal relationships were analyzed using primary inverse variance weighting (IVW) and other supplemental MR methods. Furthermore, fecal samples from liver cirrhosis patients and healthy controls were collected to validate the results of the MR analysis. Results: Analysis of 16S rRNA sequencing indicated significant differences in gut microbiota composition between the cirrhosis and control groups. IVW analyses suggested that Alphaproteobacteria, Bacillales, NB1n, Rhodospirillales, Dorea, Lachnospiraceae, and Rhodospirillaceae were positively correlated with the risk of liver cirrhosis, whereas Butyricicoccus, Hungatella, Marvinbryantia, and Lactobacillaceae displayed the opposite effects. However, the weighted median and MR-PRESSO estimates further showed that only Butyricicoccus and Marvinbryantia presented stable negative associations with liver cirrhosis. No significant heterogeneity or horizontal pleiotropy was observed in the sensitivity analysis. Furthermore, the result of 16S rRNA sequencing also showed that healthy controls had a higher relative abundance of Butyricicoccus and Marvinbryantia than liver cirrhosis patients. Conclusions: Our study provides new causal evidence for the link between gut microbiota and liver cirrhosis, which may contribute to the discovery of novel strategies to prevent liver cirrhosis.
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Background and Aims: Liver cirrhosis can lead to liver failure and eventually death. Macrophages are the main contributors to cirrhosis and have a bidirectional role in regulating matrix deposition and degradation. Macrophage-based cell therapy has been developed as an alternative to liver transplantation. However, there is insufficient evidence regarding its safety and efficacy. In this study, we aimed to explore the effect of combining insulin-like growth factor 2 (IGF2) with bone marrow-derived macrophages (BMDMs) to treat mice with liver cirrhosis. Methods: We assessed liver inflammation, fibrosis regression, liver function, and liver regeneration in mice with CCl4-induced cirrhosis and treated with BMDM only or IGF2 + BMDM. We performed in vitro experiments in which activated hepatic stellate cells (HSCs) were co-cultured with macrophages in the presence or absence of IGF2. The polarity of macrophages and the degree of inhibition of HSCs were examined. The effect of IGF2 on macrophages was also verified by the overexpression of IGF2. Results: Combining IGF2 with BMDM reduced liver inflammation and fibrosis and increased hepatocyte proliferation. Combining IGF2 with BMDM was more effective than using BMDM alone. In vitro experiments demonstrated that IGF2 inhibited HSCs activation by upregulating NR4A2 to promote the anti-inflammatory macrophages phenotype. IGF2 also increased the synthesis of matrix metalloproteinases (MMPs) by macrophages, which may explain why administering IGF2 combined with BMDM was more effective than administering BMDM only. Conclusions: Our study provides a theoretical basis for the future use of BMDM-based cell therapy to treat liver cirrhosis.
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Liver cirrhosis remains a significant global public health concern, with liver transplantation standing as the foremost effective treatment currently available. Therefore, investigating the pathogenesis of liver cirrhosis and developing novel therapies is imperative. Mitochondrial dysfunction stands out as a pivotal factor in its development. This study aimed to elucidate the relationship between mitochondria dysfunction and liver cirrhosis using bioinformatic methods to unveil its pathogenesis. Initially, we identified 460 co-expressed differential genes (co-DEGs) from the GSE14323 and GSE25097 datasets, alongside their combined datasets. Functional analysis revealed that these co-DEGs were associated with inflammatory cytokines and cirrhosis-related signaling pathways. Utilizing weighted gene co-expression network analysis (WCGNA), we screened module genes, intersecting them with co-DEGs and oxidative stress-related mitochondrial genes. Two algorithms (least absolute shrinkage and selection operator (LASSO) regression and SVE-RFE) were then employed to further analyze the intersecting genes. Finally, COX7A1 and IFI27 emerged as identifying genes for liver cirrhosis, validated through a receiver operating characteristic (ROC) curve analysis and related experiments. Additionally, immune infiltration highlighted a strong correlation between macrophages and cirrhosis, with the identifying genes (COX7A1 and IFI27) being significantly associated with macrophages. In conclusion, our findings underscore the critical role of oxidative stress-related mitochondrial genes (COX7A1 and IFI27) in liver cirrhosis development, highlighting their association with macrophage infiltration. This study provides novel insights into understanding the pathogenesis of liver cirrhosis.
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Cirrose Hepática , Transplante de Fígado , Humanos , Cirrose Hepática/genética , Algoritmos , Biologia Computacional , Citocinas , Proteínas de MembranaRESUMO
Pancreatic cancer (PC) is a deadly disease, and its post-transcriptional gene regulation mechanism remains unclear. The abundant extracellular matrix (ECM) in PC plays an important role in tumor progression. This study is the first to focus on the role of N6 -methyladenosine (m6 A) RNA methylation, an emerging post-transcriptional regulatory mechanism, in the regulation of the ECM in PC. Here, we found that ADAMTS2, COL12A1, and THBS2 were associated with the prognosis of PC by comprehensive analysis of differentially expressed genes from two independent GEO expression profile datasets and m6 A-related genes in RMVar database (PAAD). GO and KEGG enrichment analysis found that these m6 A-related targets are chiefly functionally concentrated in the ECM region and participate in ECM signal transduction. Correlation analysis revealed that these genes can be regulated by the demethylase FTO. Cell biology function assays showed that knockdown of FTO-inhibited PC cell abilities to migrate and invade in vitro. qRT-PCR and MeRIP experiments showed that after knockdown of FTO, the mRNA levels of ADAMTS2, COL12A1, and THBS2 and their m6 A modification levels were significantly reduced. These results indicate that m6 A RNA demethylation is associated with the regulation of ECM in PC. In conclusion, m6 A RNA demethylase FTO regulates ECM-related genes and promotes PC cell abilities to migrate and invade, our work provides a new perspective on the molecular mechanism of PC progression.
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Dioxigenase FTO Dependente de alfa-Cetoglutarato , Matriz Extracelular , Neoplasias Pancreáticas , Humanos , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Movimento Celular , Matriz Extracelular/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
BACKGROUND: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have garnered considerable attention as prospective modalities of treatment for liver fibrosis (LF). The inhibition of hepatic stellate cell (HSC) activation underlies the anti-fibrotic effects of hUC-MSCs. However, the precise mechanism by which hUC-MSCs impede HSC activation remains unclarified. We aimed to elucidate the intrinsic mechanisms underlying the therapeutic effects of hUC-MSCs in LF patients. METHODS: Mice with liver cirrhosis induced by carbon tetrachloride (CCl4) were used as experimental models and administered hUC-MSCs via tail-vein injection. The alterations in inflammation and fibrosis were evaluated through histopathological examinations. RNA sequencing (RNA-seq) and bioinformatics analysis were then conducted to investigate the therapeutic mechanism of hUC-MSCs. Finally, an in-vitro experiment involving the co-cultivation of hUC-MSCs or hUC-MSC-derived exosomes (MSC-Exos) with LX2 cells was performed to validate the potential mechanism underlying the hepatoprotective effects of hUC-MSCs in LF patients. RESULTS: hUC-MSC therapy significantly improved liver function and alleviated LF in CCl4-induced mice. High-throughput RNA-Seq analysis identified 1142 differentially expressed genes that were potentially involved in mediating the therapeutic effects of hUC-MSCs. These genes play an important role in regulating the extracellular matrix. miRNA expression data (GSE151098) indicated that the miR-148a-5p level was downregulated in LF samples, but restored following hUC-MSC treatment. miR-148a-5p was delivered to LX2 cells by hUC-MSCs via the exosome pathway, and the upregulated expression of miR-148a-5p significantly suppressed the expression of the activated phenotype of LX2 cells. SLIT3 was identified within the pool of potential target genes regulated by miR-148a-5p. Furthermore, hUC-MSC administration upregulated the expression of miR-148a-5p, which played a crucial role in suppressing the expression of SLIT3, thereby palliating fibrosis. CONCLUSIONS: hUC-MSCs inhibit the activation of HSCs through the miR-148a-5p/SLIT3 pathway and are thus capable of alleviating LF.
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Células-Tronco Mesenquimais , MicroRNAs , Humanos , Camundongos , Animais , Estudos Prospectivos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/terapia , MicroRNAs/genética , MicroRNAs/metabolismo , Fibrose , Células-Tronco Mesenquimais/metabolismo , Cordão Umbilical , Proteínas de Membrana/metabolismoRESUMO
Chronic liver disease inevitably progresses to liver cirrhosis, significantly compromising patients' overall survival and quality of life. However, a glimmer of hope emerges with the emergence of mesenchymal stem cells, possessing remarkable abilities for self-renewal, differentiation, and immunomodulation. Leveraging their potential, MSCs have become a focal point in both basic and clinical trials, offering a promising therapeutic avenue to impede fibrosis progression and enhance the life expectancy of individuals battling hepatic cirrhosis. This comprehensive review serves to shed light on the origin of MSCs, the intricate mechanisms underlying cirrhosis treatment, and the cutting-edge advancements in basic and clinical research surrounding MSC-based therapies for liver cirrhosis patients.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Humanos , Qualidade de Vida , Cirrose Hepática/terapia , Diferenciação CelularRESUMO
BACKGROUND: Few effective anti-fibrotic therapies are currently available for liver cirrhosis. Mesenchymal stromal cells (MSCs) ameliorate liver fibrosis and contribute to liver regeneration after cirrhosis, attracting much attention as a potential therapeutic strategy for the disease. However, the underlying molecular mechanism of their therapeutic effect is still unclear. Here, we investigated the effect of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) in treating liver cirrhosis and their underlying mechanisms. METHODS: We used carbon tetrachloride (CCl4)-induced mice as liver cirrhosis models and treated them with hUC-MSCs via tail vein injection. We assessed the changes in liver function, inflammation, and fibrosis by histopathology and serum biochemistry and explored the mechanism of hUC-MSCs by RNA sequencing (RNA-seq) using liver tissues. In addition, we investigated the effects of hUC-MSCs on hepatic stellate cells (HSC) and macrophages by in vitro co-culture experiments. RESULTS: We found that hUC-MSCs considerably improved liver function and attenuated liver inflammation and fibrosis in CCl4-injured mice. We also showed that these cells exerted therapeutic effects by regulating the Hippo/YAP/Id1 axis in vivo. Our in vitro experiments demonstrated that hUC-MSCs inhibit HSC activation by regulating the Hippo/YAP signaling pathway and targeting Id1. Moreover, hUC-MSCs also alleviated liver inflammation by promoting the transformation of macrophages to an anti-inflammatory phenotype. CONCLUSIONS: Our study reveals that hUC-MSCs relieve liver cirrhosis in mice through the Hippo/YAP/Id1 pathway and macrophage-dependent mechanisms, providing a theoretical basis for the future use of these cells as a potential therapeutic strategy for patients with liver cirrhosis.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Humanos , Camundongos , Fibrose , Inflamação/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/terapia , Cirrose Hepática/metabolismo , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Cordão Umbilical , Via de Sinalização Hippo , Proteínas de Sinalização YAP/metabolismo , Proteína 1 Inibidora de Diferenciação/metabolismoRESUMO
Nonoperative treatments for Stress Urinary Incontinence (SUI) represent an ideal treatment method. Mesenchymal stem cell (MSCs) treatment is a new modality, but there is a lack of research in the field of gynecological pelvic floor and no good method to induce internal MSC homing to improve SUI. Herein, we develop an injectable and self-healing hydrogel derived from ß-chitin which consists of an amino group of quaternized ß-chitin (QC) and an aldehyde group of oxidized dextran (OD) between the dynamic Schiff base linkage.it can carry bFGF and SDF-1a and be injected into the vaginal forearm of mice in a non-invasive manner. It provides sling-like physical support to the anterior vaginal wall in the early stages. In the later stage, it slowly releasing factors and promoting the homing of MSCs in vivo, which can improve the local microenvironment, increase collagen deposition, repair the tissue around urethra and finally improve SUI (Scheme 1). This is the first bold attempt in the field of pelvic floor using hydrogel mechanical support combined with MSCs homing and the first application of chitin hydrogel in gynecology. We think the regenerative medicine approach based on bFGF/SDF-1/chitin hydrogel may be an effective non-surgical approach to combat clinical SUI.
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Células-Tronco Mesenquimais , Incontinência Urinária por Estresse , Feminino , Camundongos , Animais , Hidrogéis/farmacologia , Quitina/farmacologia , Incontinência Urinária por Estresse/tratamento farmacológico , ColágenoRESUMO
Background: To determine effective biomarkers for the diagnosis of acute liver failure (ALF) and explore the characteristics of the immune cell infiltration of ALF. Methods: We analyzed the differentially expressed genes (DEGs) between ALF and control samples in GSE38941, GSE62029, GSE96851, GSE120652, and merged datasets. Co-expressed DEGs (co-DEGs) identified from the five datasets were analyzed for enrichment analysis. We further constructed a PPI network of co-DEGs using the STRING database. Then, we integrated the two kinds of machine-learning strategies to identify diagnostic biomarkers of top hub genes screened based on MCC and Degree methods. And the potential diagnostic performance of the biomarkers for ALF was estimated using the AUC values. Data from GSE14668, GSE74000, and GSE96851 databases was performed as external verification sets to validate the expression level of potential diagnostic biomarkers. Furthermore, we analyzed the difference in the protein level of diagnostic biomarkers between normal and ALF mice models. Finally, we used CIBERSORT to estimate relative infiltration levels of 22 immune cell subsets in ALF samples and further analyzed the relationships between the diagnostic biomarkers and infiltrated immune cells. Results: A total of 200 co-DEGs were screened. Enrichment analyses depicted that they are highly enriched in metabolism and matrix collagen production-associated processes. The top 28 hub genes were obtained by integrating MCC and Degree methods. Then, the collagen type IV alpha 2 chain (COL4A2) was regarded as the diagnostic biomarker and showed excellent specificity and sensitivity. COL4A2 also showed a statistically significant difference and excellent diagnostic effectiveness in the verification set. In addition, there was a significant upregulation in the COL4A2 protein level in ALF mice models compared with the normal group. CIBERSORT analysis showed that activated CD4 T cells, plasma cells, macrophages, and monocytes may be implicated in the progress of ALF. In addition, COL4A2 showed different degrees of correlation with immune cells. Conclusion: In conclusion, COL4A2 may be a diagnostic biomarker for ALF, and immune cell infiltration may have important implications for the occurrence and progression of ALF.
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Developing an efficient and available material for improved cutaneous tissue regeneration is a major challenge in healthcare. Inspired by the concept of moist wound healing, the injectable and self-healing adenine-modified chitosan (AC) hydrogels are designed to significantly accelerate wound healing without the addition of therapeutic drugs. A series of AC derivatives with degree of substitution (DS) ranging from 0.21 to 0.55 were synthesized in aqueous solutions, and the AC hydrogels were prepared by a simple heating/cooling process. AC hydrogels presented good self-healing, low swelling rate capacity, biocompatibility, promote cell proliferation and excellent hemostatic effect. The hydrogels displayed excellent antibacterial activities against gram-negative bacteria, gram-positive bacteria, fungi and drug-resistance bacteria. Moreover, the full-thickness skin defect model experiments showed that AC hydrogels could reduce inflammatory cell infiltration and accelerate wound healing significantly. The hydrogel can shed new light on designing of the multifunctional dressings for wound healing.
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Antibacterianos/farmacologia , Quitosana/farmacologia , Hidrogéis/farmacologia , Cicatrização/efeitos dos fármacos , Adenina/química , Animais , Bandagens , Materiais Biocompatíveis/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quitosana/química , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Hemostáticos/farmacologia , Humanos , Hidrogéis/química , Injeções/métodos , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacosRESUMO
(1) Background: The aim of this study was to identify risk factors for distant metastasis of pancreatic ductal adenocarcinoma (PDAC) and develop a valid predictive model to guide clinical practice; (2) Methods: We screened 14328 PDAC patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. Lasso regression analysis combined with logistic regression analysis were used to determine the independent risk factors for PDAC with distant metastasis. A nomogram predicting the risk of distant metastasis in PDAC was constructed. A receiver operating characteristic (ROC) curve and consistency-index (C-index) were used to determine the accuracy and discriminate ability of the nomogram. A calibration curve was used to assess the agreement between the predicted probability of the model and the actual probability. Additionally, decision curve analysis (DCA) and clinical influence curve were employed to assess the clinical utility of the nomogram; (3) Results: Multivariate logistic regression analysis revealed that risk factors for distant metastasis of PDAC included age, primary site, histological grade, and lymph node status. A nomogram was successfully constructed, with an area under the curve (AUC) of 0.871 for ROC and a C-index of 0.871 (95% CI: 0.860-0.882). The calibration curve showed that the predicted probability of the model was in high agreement with the actual predicted probability. The DCA and clinical influence curve showed that the model had great potential clinical utility; (4) Conclusions: The risk model established in this study has a good predictive performance and a promising potential application, which can provide personalized clinical decisions for future clinical work.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Nomogramas , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
Mesenchymal stem cell (MSC) transplantation, as an alternative strategy to orthotopic liver transplantation, has been evaluated for treating end-stage liver disease. Although the therapeutic mechanism of MSC transplantation remains unclear, accumulating evidence has demonstrated that MSCs can regenerate tissues and self-renew to repair the liver through differentiation into hepatocyte-like cells, immune regulation, and anti-fibrotic mechanisms. Multiple clinical trials have confirmed that MSC transplantation restores liver function and alleviates liver damage. A sufficient number of MSCs must be home to the target tissues after administration for successful application. However, inefficient homing of MSCs after systemic administration is a major limitation in MSC therapy. Here, we review the mechanisms and clinical application status of MSCs in the treatment of liver disease and comprehensively summarize the molecular mechanisms of MSC homing, and various strategies for promoting MSC homing to improve the treatment of liver disease.
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Hepatopatias , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Diferenciação Celular , Humanos , Cirrose Hepática/terapia , Hepatopatias/terapiaRESUMO
Liver fibrosis is a wound-healing process that occurs in response to severe injuries and is hallmarked by the excessive accumulation of extracellular matrix or scar tissues within the liver. Liver fibrosis can be either acute or chronic and is induced by a variety of hepatotoxic causes, including lipid deposition, drugs, viruses, and autoimmune reactions. In advanced fibrosis, liver cirrhosis develops, a condition for which there is no successful therapy other than liver transplantation. Although liver transplantation is still a viable option, numerous limitations limit its application, including a lack of donor organs, immune rejection, and postoperative complications. As a result, there is an immediate need for a different kind of therapeutic approach. Recent research has shown that the administration of mesenchymal stromal cells (MSCs) is an attractive treatment modality for repairing liver injury and enhancing liver regeneration. This is accomplished through the cell migration into liver sites, immunoregulation, hepatogenic differentiation, as well as paracrine mechanisms. MSCs can also release a huge variety of molecules into the extracellular environment. These molecules, which include extracellular vesicles, lipids, free nucleic acids, and soluble proteins, exert crucial roles in repairing damaged tissue. In this review, we summarize the characteristics of MSCs, representative clinical study data, and the potential mechanisms of MSCs-based strategies for attenuating liver cirrhosis. Additionally, we examine the processes that are involved in the MSCs-dependent modulation of the immune milieu in liver cirrhosis. As a result, our findings lend credence to the concept of developing a cell therapy treatment for liver cirrhosis that is premised on MSCs. MSCs can be used as a candidate therapeutic agent to lengthen the survival duration of patients with liver cirrhosis or possibly reverse the condition in the near future.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/terapia , Regeneração Hepática , Células-Tronco Mesenquimais/metabolismoRESUMO
Hepatitis B virus (HBV) infection remains the leading cause of liver fibrosis (LF) worldwide, especially in China. Identification of decisive diagnostic biomarkers for HBV-associated liver fibrosis (HBV-LF) is required to prevent chronic hepatitis B (CHB) from progressing to liver cancer and to more effectively select the best treatment strategy. We obtained 43 samples from CHB patients without LF and 81 samples from CHB patients with LF (GSE84044 dataset). Among these, 173 differentially expressed genes (DEGs) were identified. Functional analysis revealed that these DEGs predominantly participated in immune-, extracellular matrix-, and metabolism-related processes. Subsequently, we integrated four algorithms (LASSO regression, SVM-RFE, RF, and WGCNA) to determine diagnostic biomarkers for HBV-LF. These analyses and receive operating characteristic curves identified the genes for phosphatidic acid phosphatase type 2C (PPAP2C) and versican (VCAN) as potentially valuable diagnostic biomarkers for HBV-LF. Single-sample gene set enrichment analysis (ssGSEA) further confirmed the immune landscape of HBV-LF. The two diagnostic biomarkers also significantly correlated with infiltrating immune cells. The potential regulatory mechanisms of VCAN underlying the occurrence and development of HBV-LF were also analyzed. These collective findings implicate VCAN as a novel diagnostic biomarker for HBV-LF, and infiltration of immune cells may critically contribute to the occurrence and development of HBV-LF.