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BACKGROUND: Two-dimensional shear-wave elastography (2D-SWE) is an ultrasound elastography technique that uses shear waves to quantitatively measure tissue stiffness and it has recently been developed as a safe, real-time, and noninvasive imaging technique. The purpose of this study was to investigate the value of 2D-SWE in the diagnosis and treatment of acute compartment syndrome (ACS). METHODS: 2D-SWE was used to measure the elasticity values of the main muscles in the superficial compartments of the calf in 212 healthy volunteers, and the difference in the muscle elasticity values between different gender and age groups were analyzed. Nine patients with clinical suspicion of ACS were included in this study and 2D-SWE was used to measure the elasticity values of the muscles on the affected and unaffected sides, and a comparative analysis was performed. RESULTS: The mean elasticity values of the tibialis anterior (TA), peroneus longus (PL), and gastrocnemius medialis (GA) muscles in the relaxed state of the 212 healthy volunteers were 25.4 ± 3.2 kPa, 15.7 ± 1.5 kPa, and 12.1 ± 2.1 kPa, respectively. No statistically significant differences was observed in the elasticity values of the same muscle under the state of relaxation in different gender and age groups (p > 0.05). A statistically significant difference in the elasticity values of the muscle between the affected and unaffected sides in the fasciotomy group (p < 0.05, n = 5) was observed. In contrast, no difference in the elasticity values of the muscle between the affected and unaffected sides in the conservative group (p > 0.05, n = 4) was observed. There was a statistically significant difference in the elasticity values of the muscle on the affected side in the two treatment groups (p < 0.05). CONCLUSIONS: When the ACS occurs, the muscle elasticity of the affected limb increases significantly. 2D-SWE is expected to be a new noninvasive technique for the assessment of ACS and may provide a potential basis for clinical diagnosis and treatment.
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Síndromes Compartimentais , Técnicas de Imagem por Elasticidade , Síndromes Compartimentais/diagnóstico por imagem , Elasticidade , Humanos , Músculo Esquelético/diagnóstico por imagem , UltrassonografiaRESUMO
Pathological scar is a common complication after wound healing. One of the most important factors that affects scar formation is inflammation. During this process, macrophages play a critical role in the wound healing process, as well as in scar formation. Notch signaling is reported to participate in inflammation and fibrosis; however, whether it affects scar formation is still unclear. In this study, RBP-J knockout mice, in which Notch signaling was down-regulated, and control mice were used, and a skin incision model was established. Sirius red staining and Masson staining suggested that RBP-J knockout could significantly reduce collagen sedimentation after wound healing. Western blot analysis and RT-PCR also confirmed the results. During wound healing, the expression of inflammatory cytokines and macrophage infiltration were decreased in RBP-J knockout mice. In vitro, it was also verified that RBP-J deficiency in macrophages effectively suppressed the expression of inflammatory cytokines and chemotaxis of macrophages after LPS stimulation. In conclusion, blocking Notch signaling in macrophages effectively alleviated scar formation by suppressing the inflammatory response and collagen sedimentation.
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Cicatriz Hipertrófica/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Cicatrização , Animais , Movimento Celular , Colágeno/metabolismo , Feminino , Fibroblastos/metabolismo , Fibrose/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Masculino , Camundongos , Camundongos KnockoutRESUMO
The severity of sepsis is associated with excessive inflammatory responses. MCP-1 induced protein (MCPIP1) could negatively regulate inflammatory responses by deubiquitinating K48 or K63 polyubiquitins of TNF receptor-associated factors. The function of MCPIP1 in negative regulation of inflammation is known, however, only the exact molecular pathway remains unknown. The aim of this study was to investigate whether and how MCPIP1 is involved in the regulation of lipopolysaccharides (LPS)-induced liver injury. Macrophages and a mouse model were induced by LPS treatment. Several in vitro assays, such as quantitative real-time PCR, immunoblotting, cell transfection, dual luciferase reporter assay, Enzyme-linked immunosorbent assay, and Hematoxylin-Eosin staining assay were used to explore the role of MCPIP1 and the interaction between MCPIP1, Sirtuin 1 (SIRT1), and microRNA-9 (miR-9). We found that the level of MCPIP1 increased and the level of SIRT1 decreased in LPS induced Kupffer cells or RAW 264.7 macrophages. Overexpression of MCPIP1 alleviated cytokine secretion and p65 nuclear translocation. Further study showed that MCPIP1 regulated p65 nuclear translocation by controlling p65 acetylation via promoting SIRT1 expression. Meanwhile, we found that miR-9 could directly regulate SIRT1 transcription by binding to the 3'-Untranslated Region of SIRT1 messenger RNA and that miR-9 was negatively regulated by MCPIP1. Importantly, overexpression of MCPIP1 in vivo could alleviate LPS-induced inflammation responses and liver injury in septic mice. These results demonstrated that MCPIP1 could alleviate inflammation responses and sepsis associated liver injury by promoting the expression of SIRT1, and miR-9 was involved in the MCPIP1-mediated regulation of SIRT1. Collectively, our results provide a possible novel signaling axis involving MCPIP1/miR-9/SIRT1 in LPS-induced septic mice.
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Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Lipopolissacarídeos/toxicidade , MicroRNAs/metabolismo , Ribonucleases/metabolismo , Sirtuína 1/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células de Kupffer , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Células RAW 264.7 , Sirtuína 1/genéticaRESUMO
Hypertrophic scar (HS) is a fibroproliferative disease after serious burns; the underlying mechanism remains unknown. The study was performed to clarify the effect of high glucose (HG) on HS. The expression of Col1, Col3 and α-SMA was upregulated in HS-derived fibroblasts (HSF) exposed to HG (20 and 30 mmol/L), and HG activated the phosphorylated protein expression of IGF/Akt/mTOR signalling pathway in HSF. Dpp4, a marker targeted the treatment of diabetes mellitus, was overexpressed in HG-induced HSF. Linagliptin, a Dpp4 inhibitor, played the antifibrotic role in HSF exposed to HG, the levels of Col1, Col3 and α-SMA were significantly downregulated, and the cell proliferation and migration were also inhibited. Furthermore, linagliptin alleviated the phosphorylated protein expression of IGF/Akt/mTOR signalling pathway. Moreover, the mTOR inhibitor (rapamycin) mimicked the effect of linagliptin on the collagen and α-SMA that means linagliptin may inhibit HG-induced transdifferentiation of HSF to myofibroblasts via IGF/Akt/mTOR signalling pathway.
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Transdiferenciação Celular , Cicatriz Hipertrófica/tratamento farmacológico , Linagliptina/farmacologia , Miofibroblastos/citologia , Transdução de Sinais , Actinas/metabolismo , Adulto , Proliferação de Células , Cicatriz Hipertrófica/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Fibroblastos/citologia , Glucose , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Cicatrização , Adulto JovemRESUMO
Severe inflammation may lead to multiple organs dysfunction syndrome, which has a high mortality. MicroRNA is found participated in this process. In this study we developed a lipopolysaccharide-induced inflammation cell model on macrophages and a lipopolysaccharide-induced inflammation mouse model. It was found that during inflammation, microRNA-9 was increased, accompanied with the up-regulation of pro-inflammatory cytokines and anti-inflammatory cytokines. Down-regulation of microRNA-9 inhibited the up-regulation of inflammatory cytokines, promoted the up-regulation of anti-inflammatory cytokines and induced the remission of organ damage, showing a protective effect in inflammation. Bioinformatics analysis combined with luciferase reporter assay showed that SIRT1 was the target gene of microRNA-9. Transfection of microRNA-9 inhibitor could increase the level of SIRT1 and decrease the activation of NF-κB pathway in macrophages. Myeloid specific sirt1 knockout mice were included and we found that lack of SIRT1 in mice macrophages led to aggravated inflammation, cell apoptosis and organ injury, and eliminated the protective property of microRNA-9 inhibitor. In conclusion, we demonstrated that inhibition of microRNA-9 could alleviate inflammation through the up-regulation of SIRT1 and then suppressed the activation of NF-κB pathway. This is a meaningful explore about the specific mechanism of microRNA-9 in inflammation.
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Inflamação/induzido quimicamente , Lipopolissacarídeos/farmacologia , MicroRNAs/genética , Sirtuína 1/genética , Animais , Inflamação/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Células RAW 264.7RESUMO
OBJECTIVE: Chronic wounds are a devastating complication of diabetes and can lead to amputations or even death. Current medical therapies are insufficient to accelerate its repair. The objective of this study was to explore the role of Sirtuin1 (SIRT1) in diabetic wounds. METHODS AND MATERIALS: Perilesional skin tissue samples from diabetic ulcers and normoglycemic trauma wounds were used to detect SIRT1 expression and oxidative stress levels. In a diabetic mouse model, SIRT1 was pharmacologically activated to attenuate angiogenesis and accelerate wound closure. Finally, in vitro experiments were performed to elucidate some of the mechanisms by which SIRT1 activation promotes angiogenesis in diabetic wound healing. RESULTS: We found that skin tissue from diabetes patients showed lower expression of SIRT1 and severe oxidative stress. Decreased SIRT1 expression was observed in skin tissue from streptozocin (STZ)-induced diabetic mice and was associated with impaired wound healing. In addition, the wounds of STZ-induced diabetic mice treated with SRT1720 (a specific SIRT1 activator) demonstrated locally improved wound healing and angiogenesis. In the in vitro experiment, similar results were observed. Under hyperglycemia conditions, human umbilical vein endothelial cells (HUVECs) showed lower expression of SIRT1 and higher levels of reactive oxygen species (ROS) production. Furthermore, the migration, proliferation and in vitro tube formation ability of HUVECs were impaired under hyperglycemia conditions, and SRT1720 treatment rescued these impairments and decreased ROS production in HUVECs. CONCLUSIONS: This study provides experimental evidence that SIRT1 activation could improve angiogenesis in wounds in vitro and in vivo and that sirtuin1 activation accelerates wound healing in diabetic mice by promoting angiogenesis. These positive therapeutic effects may be mediated by protecting vascular endothelial cells from oxidative stress injury. This study suggested that SIRT1 may serve as a potentially important and potent therapeutic target for treating diabetic ulcers.
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Angiopatias Diabéticas/enzimologia , Células Endoteliais da Veia Umbilical Humana/enzimologia , Neovascularização Patológica/enzimologia , Estresse Oxidativo , Sirtuína 1/metabolismo , Ferimentos e Lesões/enzimologia , Animais , Angiopatias Diabéticas/patologia , Feminino , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Masculino , Camundongos , Neovascularização Patológica/patologia , Ferimentos e Lesões/patologiaRESUMO
Systemic inflammatory response syndrome (SIRS) is associated with excessive inflammatory response, however, the pathophysiology of inflammation is poorly understood. The retinoid-related orphan receptor α (RORα) is a key inflammatory regulator, but the mechanisms underlying its role remain unclear. The aim of this study was to investigate how RORα was involved in the regulation of inflammatory response. Here we put forward a hypothesis that RORα might negatively regulate inflammatory response by controlling silent information regulator Sirtuin 1 (SIRT1) expression. Stimulation of macrophages in vitro with LPS and LPS administration in vivo were used to explore the function of RORα and the relationship between RORα and SIRT1. We found that the level of RORα was suppressed in macrophages stimulated with LPS and overexpression or knockdown of RORα by transfection with lentivirus or siRNAs significantly decreased or increased, respectively, the pro-inflammatory cytokines IL-1ß, TNF, IL-6 and MCP-1. Importantly, overexpression of RORα suppressed inflammation and alleviated LPS-induced organ injury in vivo. Further study showed that RORα could regulate SIRT1 expression and, consequently, affect deacetyation and nuclear translocation of nuclear factor-kappa B (NF-κB) subunit p65. Moreover, the activation of SIRT1 by its specific agonist, SR1720, could reduce the expression of proinflammatory cytokines in RORα knockdown macrophages stimulated with LPS. In conclusion, we demonstrated that RORα could alleviate LPS-induced inflammation and organ injury both in vivo and in vitro by blocking NF-κB p65 nuclear translocation and restricting acetylation of NF-κB p65 at lysine 310 via the regulation of SIRT1 expression. Targeting RORα might be a promising therapeutic strategy to regulate inflammatory disorders.
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Inflamação/fisiopatologia , Macrófagos/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Transdução de Sinais/fisiologia , Sirtuína 1/metabolismo , Acetilação , Animais , Citocinas/metabolismo , Inflamação/induzido quimicamente , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Fator de Transcrição RelA/metabolismoRESUMO
Colorectal cancer (CRC) is one of the most common cancer diagnoses. Histone deacetylase (HDAC) overactivity in CRC could promote cancer progression. HDAC1, a member of the HDAC family, is found aberrantly expressed in CRC, but it remains unclear whether the expression of HDAC1 can be regulated by microRNA. In the present study, we confirmed the overexpression status of HDAC1 in CRC tissues and cell lines, and its overexpression could promote CRC cell proliferation and invasion in vitro. We saw that HDAC1 was a direct target gene of miR-761 in CRC by bioinformatic and luciferase reporter analyses. HDAC1 expression could be regulated and was negatively correlated with miR-761 in CRC. We also indicated that the expression of miR-761 was abnormally downregulated in CRC. Transfection with a miR-761 mimic impeded the growth and invasion of CRC cells. In addition, we showed that ectopic expression of miR-761 mitigated HDAC1 stimulation of CRC cell proliferation and invasion. Our results demonstrate that miR-761 represents a potential strategy against CRC.
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Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Histona Desacetilase 1/genética , MicroRNAs/genética , Materiais Biomiméticos/administração & dosagem , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Neoplasias Colorretais/patologia , Feminino , Células HCT116 , Células HT29 , Histona Desacetilase 1/biossíntese , Humanos , Masculino , MicroRNAs/biossíntese , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , TransfecçãoRESUMO
Intensive insulin therapy during critical illness protects the endothelium and thereby prevents organ failure. This study tested the hypothesis that insulin directly affects the attenuation of burn injury-induced damage to pulmonary endothelial tight junction and investigated the underlying mechanisms. Sprague Dawley rats with severe burn injury were randomized to treatment with insulin dissolved in normal saline (maintenance of blood glucose at a level between 5.0 and 7.0 mmol/L) or normal saline alone (in vivo treatment). Pulmonary damage was evaluated. Rat pulmonary microvascular endothelial cells were treated with 20% burn serum or 20% burn serum + insulin (in vitro treatment). Selected cultures were pretreated with phosphatidylinositol 3-kinase/protein kinase B (AKT) inhibitor (LY294002). Permeability was assessed by migration of bovine serum albumin across cell monolayers. Cells were stained with rhodamine phalloidin and were examined. Cell extracts were obtained to assess zonula occludens-1, occludin, and phosphorylated AKT levels by immunoblotting. Treatment with insulin attenuated the pulmonary edema, hemorrhage, and inflammatory cell infiltration of rats with severe burn injury. Burn serum significantly enhanced monolayer permeability to albumin, whereas treatment with insulin (10(-7 ) mol/L) limited this effect. Meanwhile, insulin (10(-7 ) mol/L) reduced burn serum-induced F-actin stress fiber formation and decreased zonula occludens-1 expression. LY294002 decreased cytoplasmic AKT phosphorylation and inhibited the protection effects of insulin. Through the phosphatidylinositol 3-kinase/AKT pathway, insulin independent of glucose toxicity can attenuate increased pulmonary endothelial permeability induced by burn injury. The effect is attributed to the attenuation of the architectural disruption of protein components of the endothelial tight junction. This result is useful in inhibiting multiple organ failure after burn injury.
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Actinas/metabolismo , Queimaduras/tratamento farmacológico , Cromonas/farmacologia , Endotélio Vascular/patologia , Inibidores Enzimáticos/farmacologia , Insulina/farmacologia , Morfolinas/farmacologia , Proteína Oncogênica v-akt/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Mucosa Respiratória/patologia , Junções Íntimas/patologia , Cicatrização , Proteína da Zônula de Oclusão-1/metabolismo , Actinas/biossíntese , Animais , Glicemia/metabolismo , Queimaduras/metabolismo , Queimaduras/patologia , Queimaduras/fisiopatologia , Permeabilidade da Membrana Celular , Células Cultivadas , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Ativação Enzimática , Hemorragia/prevenção & controle , Insuficiência de Múltiplos Órgãos/prevenção & controle , Proteína Oncogênica v-akt/antagonistas & inibidores , Fosforilação , Edema Pulmonar/prevenção & controle , Ratos , Ratos Sprague-Dawley , Mucosa Respiratória/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Proteína da Zônula de Oclusão-1/biossínteseRESUMO
BACKGROUND/AIMS: Colorectal cancer (CRC) ranks third among malignancies in terms of global incidence and has a poor prognosis. The identification of effective diagnostic and prognostic biomarkers is critical for CRC treatment. This study intends to explore novel genes associated with CRC progression via bioinformatics analysis. MATERIALS AND METHODS: Dataset GSE184093 was selected from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) between CRC and noncancerous specimens. Functional enrichment analyses were implemented for probing the biological functions of DEGs. Gene Expression Profiling Interactive Analysis and Kaplan-Meier plotter databases were employed for gene expression detection and survival analysis, respectively. Western blotting and real-time quantitative polymerase chain reaction were employed for detecting molecular protein and messenger RNA levels, respectively. Flow cytometry, Transwell, and CCK-8 assays were utilized for examining the effects of GBA2 and ST3GAL5 on CRC cell behaviors. RESULTS: There were 6464 DEGs identified, comprising 3005 downregulated DEGs (dDEGs) and 3459 upregulated DEGs (uDEGs). Six dDEGs were significantly associated with the prognoses of CRC patients, including PLCE1, PTGS1, AMT, ST8SIA1, ST3GAL5, and GBA2. Upregulating ST3GAL5 or GBA2 repressed the malignant behaviors of CRC cells. CONCLUSION: We identified 6 genes related to CRC progression, which could improve the disease prognosis and treatment.
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Neoplasias Colorretais , Mapas de Interação de Proteínas , Humanos , Mapas de Interação de Proteínas/genética , Redes Reguladoras de Genes , Prognóstico , Neoplasias Colorretais/diagnóstico , Biologia Computacional , Biomarcadores/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/genéticaRESUMO
Breast cancer (BC) cells have a high risk of metastasis due to epithelial-mesenchymal transition (EMT). Palbociclib (CDK4/6 inhibitor) is an approved drug for BC treatment. However, the drug resistance and metastasis can impair the treatment outcome of Palbociclib. Understanding the mechanisms of EMT and Palbociclib drug resistance in BC is conducive to the formulation of novel therapeutic strategy. Here, we investigated the role of circHIAT1/miR-19a-3p/CADM2 axis in modulating EMT and Palbociclib resistance in BC. circHIAT1 and CADM2 were down-regulated in BC tissues and cell lines, and miR-19a-3p showed an up-regulation. circHIAT1 could interact with miR-19a-3p and suppress its activity, while miR-19a-3p functioned to negatively regulate CADM2. Forced over-expression of circHIAT1 could impaired the EMT status and migratory ability of BC cells, and this effect was inhibited by miR-19a-3p mimic. In addition, we also generated Palbociclib resistant BC cells, and showed that circHIAT1 and CADM2 were down-regulated in the resistant BC cells while miR-19a-3p showed an up-regulation. Forced circHIAT1 over-expression re-sensitized BC cells to Palbociclib treatment. Quercetin, a bioactive flavonoid, could suppressed the migration and invasion of BC cells, and re-sensitized BC cells to Palbociclib. The anti-cancer effect of quercetin could be attributed to its regulatory effect on circHIAT1/miR-19a-3p/CADM2 axis. In vivo tumorigenesis experiment further revealed that quercetin administration enhanced the anti-cancer effect of Palbociclib, an effect was dependent on the up-regulation of circHIAT1 by quercetin. In summary, this study identified quercetin as a potential anti-cancer compound to reverse Palbociclib resistance and impair EMT in BC cells by targeting circHIAT1/miR-19a-3p/CADM2 axis.
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Neoplasias da Mama , Quinase 6 Dependente de Ciclina , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , MicroRNAs , Piperazinas , Piridinas , Quercetina , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Piridinas/farmacologia , Piperazinas/farmacologia , Linhagem Celular Tumoral , Quercetina/farmacologia , Animais , Camundongos , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Movimento Celular/efeitos dos fármacos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: This study explored the association of the elasticity modulus and shear wave velocity (SWV) of the tibialis anterior muscle, as measured by two-dimensional shear wave elastography (2D-SWE), with the intracompartmental pressure (ICP) determined using the Whitesides method in a New Zealand rabbit model of acute compartment syndrome (ACS). Additionally, it evaluated the viability of 2D-SWE as a noninvasive, quantitative tool for the early detection of ACS. METHODS: An ACS model was established through direct external compression by applying pressure bandaging to the lower legs of 15 New Zealand rabbits using neonatal blood pressure cuffs. Another five animals represented a non-modeled control group. To measure the elasticity modulus and SWV of the tibialis anterior muscles, 2D-SWE was employed. Blood oxygen saturation, serum creatine kinase (CK), and myoglobin levels were monitored. Subsequently, the anterior tibial compartment was dissected, and the tibialis anterior was removed for hematoxylin and eosin staining to assess muscle injury. RESULTS: The elasticity modulus and SWV of the tibialis anterior muscle increased with compression duration, as did serum CK and myoglobin levels. ICP was strongly positively correlated with these parameters, particularly mean velocity (r=0.942, P<0.001) and CK (r=0.942, P<0.001). Blood oxygen saturation was negatively correlated with ICP (r=-0.887, P<0.001). Histological analysis indicated progressive muscle cell swelling over time, with damage transitioning from reversible to irreversible and culminating in necrosis. CONCLUSION: In a rabbit ACS model, ICP was strongly positively correlated with muscle elasticity modulus/SWV. Consequently, 2D-SWE may represent a novel tool for assessing early-phase ACS.
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BACKGROUND: The presence of breast cancer in the brain, also known as brain metastasis (BMS), is the primary reason for a bad prognosis in cases of breast cancer. Breast cancer is the most prevalent malignant tumor seen in women in developing nations. At present, there is no effective method to inhibit brain metastasis of breast cancer. Therefore, it is necessary to conduct a systematic study on BMS of breast cancer, which will not provide ideas and sites for follow-up studies on the treatment and inhibition of BMS. METHODS: In this study, data set GSE43837 was screened from gene expression omnibus database, and then R language tool was used for differential analysis of its expression spectrum, The gene ontology functional enrichment and Kyoto encyclopedia of genes and genomes signal pathway enrichment analyses, as well as the interactive gene retrieval tool for hub-gene analysis, were performed. RESULTS: According to the findings, the primary genes linked to breast cancer brain metastases are those that involve interactions between cytokines and their respective receptors and between neuroactive ligands and their respective receptors. The majority of the gene ontology enrichment took place in the extracellular structural tissues, the extracellular matrix tissues, and the second message-mediated signaling. We were able to identify 8 genes that are linked to breast cancer spreading to the brain. The gene score for matrix metallopeptidase1 (MMP-1) was the highest among them, and the genes MMP10, tumor necrosis factor alpha-inducible protein 8, collagen type I alpha 2 chain, vascular cell adhesion molecule 1, and TNF superfamily member 11 were all connected to 1 another in an interaction way. CONCLUSIONS: There is a possibility that the 8 key genes that were identified in this research are connected to the progression of BMS in breast cancer. Among them, MMP1 is 1 that has the potential to have a role in the diagnosis and treatment of BMS in breast cancer.
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Neoplasias Encefálicas , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Perfilação da Expressão Gênica/métodos , Detecção Precoce de Câncer , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Biologia ComputacionalRESUMO
Background: Non-healing wounds are an intractable problem of major clinical relevance. Evidence has shown that dermal papilla cells (DPCs) may regulate the wound-healing process by secreting extracellular vesicles (EVs). However, low isolation efficiency and restricted cell viability hinder the applications of DPC-EVs in wound healing. In this study, we aimed to develop novel 3D-DPC spheroids (tdDPCs) based on self-feeder 3D culture and to evaluate the roles of tdDPC-EVs in stimulating angiogenesis and skin wound healing. Methods: To address the current limitations of DPC-EVs, we previously developed a self-feeder 3D culture method to construct tdDPCs. DPCs and tdDPCs were identified using immunofluorescence staining and flow cytometry. Subsequently, we extracted EVs from the cells and compared the effects of DPC-EVs and tdDPC-EVs on human umbilical vein endothelial cells (HUVECs) in vitro using immunofluorescence staining, a scratch-wound assay and a Transwell assay. We simultaneously established a murine model of full-thickness skin injury and evaluated the effects of DPC-EVs and tdDPC-EVs on wound-healing efficiency in vivo using laser Doppler, as well as hematoxylin and eosin, Masson, CD31 and α-SMA staining. To elucidate the underlying mechanism, we conducted RNA sequencing (RNA-seq) of tdDPC-EV- and phosphate-buffered saline-treated HUVECs. To validate the RNA-seq data, we constructed knockdown and overexpression vectors of Krüppel-like factor 4 (KLF4). Western blotting, a scratch-wound assay, a Transwell assay and a tubule-formation test were performed to detect the protein expression, cell migration and lumen-formation ability of KLF4 and vascular endothelial growth factor A (VEGFA) in HUVECs incubated with tdDPC-EVs after KLF4 knockdown or overexpression. Dual-luciferase reporter gene assays were conducted to verify the activation effect of KLF4 on VEGFA. Results: We successfully cultured tdDPCs and extracted EVs from DPCs and tdDPCs. The tdDPC-EVs significantly promoted the proliferation, lumen formation and migration of HUVECs. Unlike DPC-EVs, tdDPC-EVs exhibited significant advantages in terms of promoting angiogenesis, accelerating wound healing and enhancing wound-healing efficiency both in vitro and in vivo. Bioinformatics analysis and further functional experiments verified that the tdDPC-EV-regulated KLF4/VEGFA axis is pivotal in accelerating wound healing. Conclusions: 3D cultivation can be utilized as an innovative optimization strategy to effectively develop DPC-derived EVs for the treatment of skin wounds. tdDPC-EVs significantly enhance wound healing via KLF4/VEGFA-driven angiogenesis.
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Background: The combined use of various flap techniques has rapidly improved the reconstruction quality of auricle defects that are complicated by a scarcity of periauricular skin after severe burns. Nevertheless, there is still no preferable method when the optimal alternative skin to cover the auricular framework is unavailable and the periauricular vascular network is devastated. Case Description: Copious scars were observed in the periauricular region, neck, forearm, and supraclavicular region of a 19-year-old man. He had been burned by high-voltage electricity and exhibited a right auricular defect. We innovatively created a prefabricated expanded island flap constructed with an anastomosed vascular pedicle buried in the anterior thoracic chest, followed by flap transfer, tissue re-expansion, and sculpted autologous costal cartilage implantation. The remnant ear was successfully reconstructed in a three-stage surgical procedure. Conclusions: All the flaps survived well without any complications. The reconstructed right ear had a natural shape and a clear structure without apparent displacement and deformation during follow-up. The patient was satisfied with the final appearance, and his neck mobility markedly improved. Advantages and disadvantages were discussed. This procedure explored a novel solution to construct an auricular framework covering for patients who do not have high-quality donor skin and lack anastomotic vessels in the recipient area.
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Background: Acute lung injury (ALI) is a common complication following severe burns. The underlying mechanisms of ALI are incompletely understood; thus, available treatments are not sufficient to repair the lung tissue after ALI. Methods: To investigate the relationship between the Notch pathway and burn-induced lung injury, we established a rat burn injury model by scalding and verified lung injury via lung injury evaluations, including hematoxylin and eosin (H&E) staining, lung injury scoring, bronchoalveolar lavage fluid and wet/dry ratio analyses, myeloperoxidase immunohistochemical staining and reactive oxygen species (ROS) accumulation analysis. To explore whether burn injury affects Notch1 expression, we detected the expression of Notch1 and Hes1 after burn injury. Then, we extracted pulmonary microvascular endothelial cells (PMVECs) and conducted Notch pathway inhibition and activation experiments, via a γ-secretase inhibitor (GSI) and OP9-DLL1 coculture, respectively, to verify the regulatory effect of the Notch pathway on ROS accumulation and apoptosis in burn-serum-stimulated PMVECs. To investigate the regulatory effect of the Notch pathway on ROS accumulation, we detected the expression of oxidative-stress-related molecules such as superoxide dismutase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 2, NOX4 and cleaved caspase-3. NOX4-specific small interfering RNA (siRNA) and the inhibitor GKT137831 were used to verify the regulatory effect of the Notch pathway on ROS via NOX4. Results: We successfully established a burn model and revealed that lung injury, excessive ROS accumulation and an inflammatory response occurred. Notch1 detection showed that the expression of Notch1 was significantly increased after burn injury. In PMVECs challenged with burn serum, ROS and cell death were elevated. Moreover, when the Notch pathway was suppressed by GSI, ROS and cell apoptosis levels were significantly increased. Conversely, these parameters were reduced when the Notch pathway was activated by OP9-DLL1. Mechanistically, the inhibition of NOX4 by siRNA and GKT137831 showed that the Notch pathway reduced ROS production and cell apoptosis by downregulating the expression of NOX4 in PMVECs. Conclusions: The Notch pathway reduced ROS production and apoptosis by downregulating the expression of NOX4 in burn-stimulated PMVECs. The Notch-NOX4 pathway may be a novel therapeutic target to treat burn-induced ALI.
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Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, with high morbidity and mortality rates worldwide. Therefore, there is an urgent need to develop more effective treatments for CRC patients. In recent years, there has been some success in the immunotherapy of tumors, and immunotherapy has been used in many solid tumors including CRC. To date, the clinical efficacy of immunotherapy for CRC is limited, so more effective immunotherapy methods need to be explored. In patients with CRC, the CC chemokine CCL5 plays a role in the development of CRC and the recruitment and activation of immune cells, suggesting that it has potential for immunotherapy. This review mainly introduces the latest advances in the study of CCL5 acting as a marker of CRC and related mechanisms of immunotherapy, as well as the latest understanding of how CCL5 is involved in the invasion and development of CRC.
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BACKGROUND: Transplantation of allogeneic donor bone marrow (BM) into sufficiently conditioned recipients is an effective approach to induce immune tolerance as assessed by mixed chimerism. However, this approach is hampered by the lack of feasible protocols devoid of cytoreductive conditioning. We investigated whether mixed chimerism could be established by intra-bone marrow-bone marrow transplantation (IBM-BMT) combined with bone marrow-derived mesenchymal stem cells (BMSCs) treatment without additional cytoreductive conditioning. MATERIALS AND METHODS: The recipient mice (C57BL/6) accepted BMSCs from donor mice (Balb/c) through daily tail vein injection for 4 d followed by IBM-BMT immediately. Full-thickness skin grafts from donor mice as well as from the third party mice (ICR) were transplanted to the dorsum of the recipient mice after the combined IBM-BMT with BMSCs treatment. The immune tolerance was assessed by the survival time of skin allografts. The establishment of mixed chimerism and cytokine expression profile in recipient peripheral blood were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively. RESULTS: IBM-BMT combined with BMSCs treatment led to stable mixed chimerism and donor-specific skin graft tolerance. The flow cytometry analysis revealed that recipient mice developed 20%-25% chimerism levels among the myeloid lineage. The skin allografts survived more than 1 y and the hair re-grew normally on the grafts. Cytokine profile showed that IBM-BMT combined with BMSCs treatment prolonged humoral tolerance in recipient chimeras. CONCLUSIONS: Our results demonstrate that donor specific immune tolerance can be effectively induced by IBM-BMT combined with BMSCs treatment without any additional cytoreductive recipient treatment. This approach provides a promising allograft transplantation strategy when the donor bone marrow is available.
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Transplante de Medula Óssea/imunologia , Transplante de Medula Óssea/métodos , Tolerância Imunológica/imunologia , Transplante de Células-Tronco Mesenquimais/métodos , Imunologia de Transplantes/imunologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células Cultivadas , Citometria de Fluxo , Sobrevivência de Enxerto/imunologia , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Teste de Cultura Mista de Linfócitos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Transplante de Pele/imunologia , Transplante de Pele/métodos , Fator de Crescimento Transformador beta1/metabolismo , Quimeras de Transplante , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
Long non-coding RNAs (lncRNAs) play a vital regulatory role in many human cancers. However, their underlying effect and molecular mechanism in chemoresistance need to be fully researched. This study found that lncRNA CYTOR expression was significantly up-regulated in colon carcinoma tissue and cells. Silencing lncRNA CYTOR in vitro facilitated L-OHP sensitivity of colon carcinoma cells and restrained epithelial-mesenchymal transition (EMT). Furthermore, lncRNA CYTOR could inhibit miR-378a-5p expression, while suppressing miR-378a-5p could attenuate the inhibition of lncRNA CYTOR silencing on L-OHP resistance and EMT. The downstream target mRNA of miR-378a-5p was further explored, and it was discovered that miR-378a-5p restrained SERPINE1 expression. Rescue assay indicated that overexpressing miR-378a-5p or silencing SERPINE1 expression counteracted the promotion of lncRNA CYTOR overexpression on L-OHP resistance and EMT of colon carcinoma cells. In vivo experiment exhibited that silencing lncRNA CYTOR repressed colon carcinoma growth, while miR-378a-5p inhibition diminished the suppression of silencing lncRNA CYTOR on colon carcinoma. These results testified that lncRNA CYTOR enhanced L-OHP drug resistance and induced EMT in colon carcinoma. It was also suggested that lncRNA CYTOR/miR-378a-5p/SERPINE1 axis was a regulatory pathway of L-OHP resistance in colon carcinoma. They could be potential therapeutic targets and prognostic biomarkers.Abbreviations: ATG: autophagy related; EPG: ectopic PGL granules; GFP: green fluorescent protein; LGG-1: LC3, GABARAP and GATE-16 family; LPLA-2: lysosomal phospholipase A2; PGL: P granule abnormality protein; PLA2: phospholipase A2; SD: standard deviation; SEPA-1: suppressor of ectopic P granules in autophagy mutant; SQST-1: sequestosome related.
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Carcinoma , MicroRNAs , RNA Longo não Codificante , Carcinoma/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Colo , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Mechanical stimuli on cells and mechanotransduction are essential in many biological and pathological processes. Glucocorticoid is an important hormone, roles, and mechanisms of which in cellular mechanotransduction remain unknown. Here, we report that glucocorticoid counteracted cellular mechanoresponses dependently on a novel long noncoding RNA (lncRNA), LINC01569 Further, LINC01569 mediated glucocorticoid effects on mechanotransduction by destabilizing messenger RNA (mRNA) of mechanosensors including early growth response protein 1 (EGR1), Cbp/P300-interacting transactivator 2 (CITED2), and bone morphogenic protein 7 (BMP7) in glucocorticoid receptor-mediated mRNA decay (GMD) manner. Mechanistically, LINC01569 directly bound to the GMD factor Y-box-binding protein 1 (YBX1). Then, the LINC01569-YBX1 complex was guided to the mRNAs of EGR1, CITED2, and BMP7 through specific LINC01569-mRNA interaction, thereby contributing to the successful assembly of GMD complex and triggering GMD. Our results uncovered roles of glucocorticoid in cellular mechanotransduction and novel lncRNA-dependent GMD machinery and provided potential strategy for early intervention in mechanical disorder-associated diseases.