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Mesenchymal stem cells (MSCs) have been widely documented for their potential role in the treatment of various clinical disorders, including acute lung injury (ALI). ALI represents a clinical syndrome associated with histopathological diffuse alveolar damage. Recent evidence has demonstrated that exosomes derived from MSCs may serve as a reservoir of anti-apoptotic microRNAs (miRs) conferring protection from certain diseases. Hence, the current study was performed with the aim of investigating whether MSCs-exosomal miR-30b-3p could confer protection against ALI. A bioinformatic analysis and a dual luciferase assay were initially performed to verify that SAA3 was highly-expressed in ALI which was confirmed to be a target gene of miR-30b-3p. Next, the lipopolysaccharide (LPS)-treated type II alveolar epithelial cells (AECs) (MLE-12) were transfected with mimics or inhibitors of miR-30b-3p, or sh-SAA3. It was revealed that LPS induced AEC apoptosis, which could be inhibited by overexpressing miR-30b-3p by down-regulating the expression of SAA3. After co-culture of PKH26-labeled exosomes with MLE-12â¯cells, we found that the number of PKH26-labeled exosomes endocytosed by MLE-12â¯cells gradually increased. Furthermore, the LPS-treated MLE-12â¯cells co-cultured with MSC-exosomes overexpressing miR-30b-3p exhibited increased miR-30b-3p, decreased SAA3 level, as well as increased cell proliferation, accompanied by diminished cell apoptosis in LPS-treated MLE-12â¯cells. Finally, the protective effect of MSCs-exosomal miR-30b-3p on the AECs in vivo was investigated in an ALI mouse model with tail vein injection of MSC-exosomes with elevated miR-30b-3p, showing that overexpression of miR-30b-3p in MSC-exosomes conferred protective effects against ALI. Taken together, these findings highlighted the potential of MSC-exosomes overexpressing miR-30b-3p in preventing ALI. The exosomes derived from MSCs hold potential as future therapeutic strategies in the treatment of ALI.
Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/prevenção & controle , Exossomos/fisiologia , Lipopolissacarídeos , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Proteína Amiloide A Sérica/genética , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Animais , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Regulação para Baixo/genética , Exossomos/genética , Exossomos/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Substâncias Protetoras/metabolismo , Proteína Amiloide A Sérica/metabolismoRESUMO
Purpose: To compare the efficacy and safety of two distinct doses of ulinastatin on late-onset acute renal failure (LARF) following orthotopic liver transplantation (OLT).Methods: The high-risk recipients that underwent OLT were divided into two groups according to ulinastatin dose: low-dose (LD) ulinastatin group, 0.8 million U/d; high-dose (HD) ulinastatin group, 1.6 million U/d. The primary outcome was the incidence of LARF, which was defined the newly onset acute kidney injury (AKI) stage III (KDIGO, 2012) within 7-28 post-transplant days. The second outcomes were early multiple organ retrieval assessments, length of hospital stay and safety events.Results: A total of 174 recipients were included (LD ulinastatin group, n = 55; HD ulinastatin group, n = 119). There was no significant difference in the incidence of LARF between LD (8/55, 14.50%) and HD (9/119, 7.56%) ulinastatin groups (HD vs. LD, HR, 0.49; 95%CI, 0.17-1.37; p = .1295). Multivariate Cox proportion risk regression model revealed HD ulinastatin (HR, 0.57; 95%CI, 0.38-0.98; p = .0464) was an independent protective factor for LARF. Early lactate level, oxygenation, AKI stage, graft function, and sequential organ failure assessment [SOFA] score were significantly improved in HD ulinastatin group versus LD ulinastatin group. No significant adverse events were observed in either group.Conclusions: Higher dose of ulinastatin (1.6 million U/d) might be preferable to prevent LARF after OLT, and it may contribute to the enhancement of early multiple organ recovery and thus attenuate the incidence of LARF.
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Injúria Renal Aguda/prevenção & controle , Glicoproteínas/administração & dosagem , Transplante de Fígado/efeitos adversos , Inibidores da Tripsina/administração & dosagem , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/mortalidade , Adulto , Feminino , Humanos , Incidência , Unidades de Terapia Intensiva , Tempo de Internação , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Estudos Retrospectivos , Fatores de Risco , Análise de SobrevidaRESUMO
OBJECTIVE: To investigate the application and security of plasmapheresis combined with hemofiltration in the treatment of severe liver disease in middle and late pregnancy. METHODS: Clinical data of 29 patients of middle and late pregnancy with severe liver disease from March 2009 to November 2013 in the Third Affiliated Hospital of Sun Yat-sen University was analyzed retrospectively. According to the therapeutic schedule, patients were divided into control group (n=16, 18-29 years old, median age of 24 years old) and treatment group (n=13, 21-28 years old, median age of 25 years old). The informed consents of all patients were obtained and the ethical committee approval was received. The control group was given the treatment of resisting infection, protecting liver, reducing jaundice, supplying albumin and globulin, infusing blood coagulation and so on. The treatment group was given plasmapheresis and hemofiltration on the basis of the above-mentioned treatment. The differences of major clinical indicators such as MELD scores, APACHEII scores, total bilirubin (TB), albumin (ALB), prothrombin time activity (PTA) , fasting blood glucose (FPG), serum creatinine (Scr) of peripheral venous blood and arterial lactic acid (Lac) in patients of two groups were observed 6 hours before and 1, 3, 5 days after the treatment. The major clinical indicators in patients of two groups were compared by t test and the clinical efficient were compared by χ² test. RESULTS: There were no statistical differences of the clinical indicators between the two groups 6 hours before the treatment (all P>0.05). The MELD scores, APACHEII scores, TB, ALB, PTA, FPG, Scr, Lac were (25 ± 6) scores, (22 ± 5) scores, (197 ± 69) µmol/L, (30 ± 7) g/L, (55 ± 24)%, (5.7 ± 2.4) mmol/L, (111 ± 42) µmol/L, (2.3 ± 0.6) mmol/L in treatment group 1 day after treatment, and were (33 ± 8) scores, (30 ± 7) scores, (299 ± 113) µmol/L, (24 ± 6) g/L, (33 ± 11)%, (3.7 ± 1.7) mmol/L, (165 ± 82) µmol/L, (4.4 ± 1.5) mmol/L in control group, which improved significantly in the treated group compared to those in the control group. There was also significant improvement in those posttreatment d3, and 5 lab findings in the treatment group (P<0.05). The effective rate was higher in the treatment group (92%, 12/13) than the control group (56%, 9/16) (χ² =4.215, P<0.05). Kaplan-Meier analysis showed the combined treatment could significantly improve the 42 d survival rate in postpartum patients with liver function failure. One patient had transitional hypotension after plasma infusion and hemofiltration in the treatment group, but the blood pressure returned to normal 1 h after small dose of vasoconstrictor. CONCLUSION: The therapeutic effect of plasmapheresis combined with hemofiltration on the treatment of severe liver disease in middle and late pregnancy is safe and effective, and it could improve the clinical outcomes and survival rate.
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Hemofiltração , Hepatopatias , Plasmaferese , Adolescente , Adulto , Pressão Sanguínea , Feminino , Humanos , Estimativa de Kaplan-Meier , Gravidez , Complicações na Gravidez , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Perforated peptic ulcer (PPU) is a common emergency surgical condition and a significant cause of morbidity and mortality worldwide. While advances in surgical techniques have improved outcomes for patients with PPU, many factors still affect postoperative hospital stay and overall prognosis. One potential factor is the serum albumin (SA) level, a widely utilized marker of nutritional status that has been associated with length of stay and complications in various surgical procedures. AIM: To clarify the correlation of SA level on postoperative day 2 with hospital length of stay (HLOS) in patients undergoing emergency surgery for perforated peptic ulcer (PPU). METHODS: We retrospectively collected and analyzed clinical baseline data, including blood routine and SA levels, of patients who underwent emergency PPU surgery and postoperative treatment at the Lingnan Hospital, the Third Affiliated Hospital of Sun Yat-sen University between December 2012 and September 2021. Patients were grouped according to HLOS with 7 d as the cut-off value, and relevant indicators were analyzed using SPSS 26.0. RESULTS: Of the 37 patients undergoing emergency surgery for PPU referred to our department, 33 had gastric and 4 had duodenal ulcer perforation. The median HLOS was 10 d. There were 8 patients in the ≤ 7-d group (median HLOS: 7 d) and 29 patients in the > 7-d group (median HLOS: 10 d). The ≤ 7-d group had markedly higher SA on postoperative day 2 than the > 7-d group (37.7 g/L vs 32.6g/L; P < 0.05). The SA level on postoperative day 2 was a protective factor for patients with HLOS > 7 d (Odds ratio = 0.629, P = 0.015). The cut-off of SA on postoperative day 2 was 30.6g/L, with an area under the curve of 0.86 and a negative predictive value of 100% for the prediction of HLOS ≤ 7 d. CONCLUSION: The SA level on postoperative day 2 was associated with the HLOS in patients undergoing emergency surgery for PPU. The pre- and post-operative albumin levels should be monitored, and infusion of human SA should be considered in a timely manner.
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Pneumonia is one of the leading causes of death in patients with acute ischemic stroke (AIS). Antibiotics fail to improve prognosis of patients with post-stroke pneumonia, albeit suppressing infection, due to adverse impacts on the immune system. The current study reports that bone marrow mesenchymal stem cells (BM-MSC) downregulate bacterial load in the lungs of stroke mice models. RNA-sequencing of the lung from BM-MSC-treated stroke models indicates that BM-MSC modulates pulmonary macrophage activities after cerebral ischemia. Mechanistically, BM-MSC promotes the bacterial phagocytosis of pulmonary macrophages through releasing migrasomes, which are migration-dependent extracellular vesicles. With liquid chromatography-tandem mass spectrometry (LC-MS/MS), the result shows that BM-MSC are found to load the antibacterial peptide dermcidin (DCD) in migrasomes upon bacterial stimulation. Besides the antibiotic effect, DCD enhances LC3-associated phagocytosis (LAP) of macrophages, facilitating their bacterial clearance. The data demonstrate that BM-MSC is a promising therapeutic candidate against post-stroke pneumonia, with dual functions of anti-infection and immunol modulation, which is more than a match for antibiotics treatment.
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Dermocidinas , AVC Isquêmico , Células-Tronco Mesenquimais , Pneumonia , Acidente Vascular Cerebral , Camundongos , Animais , Macrófagos Alveolares , Cromatografia Líquida , Espectrometria de Massas em Tandem , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapia , Fagocitose , AntibacterianosRESUMO
BACKGROUND: Nuclear transcription factor Y subunit C antisense RNA 1 (NFYC-AS1) was revealed to be a potential prognostic biomarker in lung adenocarcinoma (LAUD) by analyzing The Cancer Genome Atlas (TCGA) database. However, the function of NFYC-AS1 has not been verified in cancers, including LAUD. We plan to verify the function of NFYC-AS1 in LAUD through this study. METHODS: We determined NFYC-AS1 expression in 4 LAUD cell lines, and 1 normal lung cell line (HBE) by quantitative real-time reverse transcription PCR (qRT-PCR). small interfering RNA (siRNA) was employed to specifically knockdown NFYC-AS1 in H1299 and PC9 cell lines. Cell growth and invasion activity of LAUD cells was assessed by WST-1, colony formation and transwell assay, respectively. The effect of NFYC-AS1 expression on cell apoptosis was then assessed by flow cytometry assay. Furthermore, the expression of downstream proteins of NFYC-AS1 was investigated by Western blot. RESULTS: The proliferation, migration, and invasion of cells were inhibited and apoptosis was increased after NFYC-AS1 knockdown in LAUD cells. The cells transfected with NFYC-AS1 siRNA had a higher rate of apoptosis compared with that in control cells. The apoptosis-related proteins p53 and PARP were upregulated. These suggested NFYC-AS1 could inhibit the apoptosis of LAUD cells. In terms of the expression of major autophagy proteins, p62 was downregulated while Beclin 1 was upregulated after NFYC-AS1 knockdown, which suggested that autophagy was activated. The expression of oncogenic proteins MET and c-Myc was downregulated. CONCLUSIONS: In summary, the above results suggest that NFYC-AS1 may promote the proliferation of LAUD through autophagy and apoptosis.
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This work was supported by National 13th Five-Year Science and Technology Plan Major Projects of China (2017ZX10203205-006-001); National Key R&D Plan (2017YFA0104304); National Natural Science Foundation of China (81770648 81972286); Guangdong Natural Science Foundation (2015A030312013, 2018A0303130305); Science and Technology Program of Guangdong Province (2017B020209004, 20169013, 2017B030314027). This has now been corrected in both the PDF and HTML versions of the Article.
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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the severe lung damage and respiratory failure without effective therapy. However, there was a lack of understanding of the mechanism by which exosomes regulate autophagy during ALI/ARDS. Here, we found lipopolysaccharide (LPS) significantly increased inflammatory factors, administration of exosomes released by human umbilical cord mesenchymal stem cells (hucMSCs) successfully improved lung morphometry. Further studies showed that miR-377-3p in the exosomes played a pivotal role in regulating autophagy, leading to protect LPS induced ALI. Compared to exosomes released by human fetal lung fibroblast cells (HFL-1), hucMSCs-exosomes overexpressing miR-377-3p more effectively suppressed the bronchoalveolar lavage (BALF) and inflammatory factors and induced autophagy, causing recoveration of ALI. Administration of miR-377-3p expressing hucMSCs-exosomes or its target regulatory-associated protein of mTOR (RPTOR) knockdown significantly reduced ALI. In summary, miR-377-3p released by hucMSCs-exosomes ameliorated Lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy in vivo and in vitro.