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Background: Acute superior mesenteric venous thrombosis (ASMVT) decreases junction-associated protein expression and intestinal epithelial cell numbers, leading to intestinal epithelial barrier disruption. Pyroptosis has also recently been found to be one of the important causes of mucosal barrier defects. However, the role and mechanism of pyroptosis in ASMVT are not fully understood. Methods: Differentially expressed microRNAs (miRNAs) in the intestinal tissues of ASMVT mice were detected by transcriptome sequencing (RNA-Seq). Gene expression levels were determined by RNA extraction and reverse transcription-quantitative PCR (RT-qPCR). Western blot and immunofluorescence staining analysis were used to analyze protein expression. H&E staining was used to observe the intestinal tissue structure. Cell Counting Kit-8 (CCK-8) and fluorescein isothiocyanate/propidine iodide (FITC/PI) were used to detect cell viability and apoptosis, respectively. Dual-luciferase reporter assays prove that miR-138-5p targets NLRP3. Results: miR-138-5p expression was downregulated in ASMVT-induced intestinal tissues. Inhibition of miR-138-5p promoted NLRP3-related pyroptosis and destroyed tight junctions between IEC-6 cells, ameliorating ASMVT injury. miR-138-5p targeted to downregulate NLRP3. Knockdown of NLRP3 reversed the inhibition of proliferation, apoptosis, and pyroptosis and the decrease in tight junction proteins caused by suppression of miR-138-5p; however, this effect was later inhibited by overexpressing HMGB1. miR-138-5p inhibited pyroptosis, promoted intestinal epithelial tight junctions and alleviated ASMVT injury-induced intestinal barrier disruption via the NLRP3/HMGB1 axis.
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Proteína HMGB1 , Isquemia Mesentérica , MicroRNAs , Trombose , Animais , Camundongos , Doença Aguda , Proteína HMGB1/genética , Veias Mesentéricas/metabolismo , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genéticaRESUMO
OBJECTIVE: Acute mesenteric vein thrombosis (AMVT) is an acute abdominal disease with onset, rapid progression, and extensive intestinal necrosis that requires immediate surgical resection. The purpose of this study was to determine the risk factors for nosocomial intestinal resection in patients with AMVT. METHODS: We retrospectively analysed 64 patients with AMVT diagnosed by CTA at the Affiliated Hospital of Kunming University of Science and Technology from January 2013 to December 2021. We compared patients who underwent intestinal resection (42 patients) with those who did not undergo intestinal resection (22 patients). The area under the ROC curve was evaluated, and a forest map was drawn. RESULTS: Among the 64 patients, 6 (9.38%) had a fever, 60 (93.75%) had abdominal pain, 9 (14.06%) had a history of diabetes, 8 (12.5%) had a history of deep vein thrombosis (DVT), and 25 (39.06%) had ascites suggested by B ultrasound or CT after admission. The mean age of all patients was 49.86 ± 16.25 years. The mean age of the patients in the enterectomy group was 47.71 ± 16.20 years. The mean age of the patients in the conservative treatment group (without enterectomy) was 53.95 ± 15.90 years. In the univariate analysis, there were statistically significant differences in leukocyte count (P = 0.003), neutrophil count (P = 0.001), AST (P = 0.048), total bilirubin (P = 0.047), fibrinogen (P = 0.022) and DD2 (P = 0.024) between the two groups. The multivariate logistic regression analysis showed that admission white blood cell count (OR = 1.153, 95% CI: 1.039-1.280, P = 0.007) was an independent risk factor for intestinal resection in patients with AMVT. The ROC curve showed that the white blood cell count (AUC = 0.759 95% CI: 0.620-0.897; P = 0.001; optimal threshold: 7.815; sensitivity: 0.881; specificity: 0.636) had good predictive value for emergency enterectomy for AMVT. CONCLUSIONS: Among patients with AMVT, patients with a higher white blood cell count at admission were more likely to have intestinal necrosis and require emergency enterectomy. This study is helpful for clinicians to accurately determine whether emergency intestinal resection is needed in patients with AMVT after admission, prevent further intestinal necrosis, and improve the prognosis of patients.
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Isquemia Mesentérica , Trombose , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Veias Mesentéricas/cirurgia , Doença Aguda , Prognóstico , Isquemia Mesentérica/cirurgia , Contagem de Leucócitos , Trombose/complicações , Necrose , Curva ROCRESUMO
Background: Endoplasmic reticulum (ER) stress plays a pro-apoptotic role in colorectal adenocarcinoma (COAD). This study aimed to develop a novel ER-stress-related prognostic risk model for COAD and provide support for COAD cohorts with different risk score responses to immune checkpoint inhibitor therapies. Methods: TCGA-COAD and GSE39582 were included in this prospective study. Univariate and multivariate Cox analyses were performed to identify prognostic ER stress-related genes (ERSGs). Accordingly, the immune infiltration landscape and immunotherapy response in different risk groups were assessed. Finally, the expression of prognostic genes in 10 normal and 10 COAD tissue samples was verified using reverse transcription-quantitative polymerase chain reaction. Results: Eight prognostic genes were selected to establish an ERSG-based signature in the training set of the TCGA-COAD cohort. The accuracy of this was confirmed using a testing set of TCGA-COAD and GSE39582 cohorts. Gene set variation analysis indicated that differential functionality in high-low-risk groups was related to immune-related pathways. Corresponding to this, CD36, TIMP1, and PTGIS were significantly associated with 19 immune cells with distinct proportions between the different risk groups, such as central memory CD4T cells and central memory CD8T cells. Moreover, the risk score was considered effective for predicting the clinical response to immunotherapy, and the immunotherapy response was significantly and negatively correlated with the risk score of individuals with COAD. Furthermore, the immune checkpoint inhibitor treatment was less effective in the high-risk group, where the expression levels of PD-L1 and tumor immune dysfunction and exclusion scores in the high-risk group were significantly increased. Finally, the experimental results demonstrated that the expression trends of prognostic genes in clinical samples were consistent with the results from public databases. Conclusion: Our study established a novel risk signature to predict the COAD prognosis of patients and provide theoretical support for the clinical treatment of COAD.
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Adenocarcinoma , Neoplasias Colorretais , Humanos , Prognóstico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Estudos Prospectivos , Imunoterapia , Adenocarcinoma/genética , Adenocarcinoma/terapia , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapiaRESUMO
ABSTRACT: Damage to the abdominal aortic wall and the local inflammatory response are key factors resulting in abdominal aortic aneurysm (AAA) formation. During this process, macrophage polarization plays a key role. However, in AAA, the regulatory mechanism of macrophages is still unclear, and further research is needed. In this study, we found that the transcription factor TCF3 was expressed at low levels in AAA. We overexpressed TCF3 and found that TCF3 could inhibit MMP and inflammatory factor expression and promote M2 macrophage polarization, thereby inhibiting the progression of AAA. Knocking down TCF3 could promote M1 polarization and MMP and inflammatory factor expression. In addition, we found that TCF3 increased miR-143-5p expression through transcriptional activation of miR-143-5p , which further inhibited expression of the downstream chemokine CCL20 and promoted M2 macrophage polarization. Our research indicates that TCF3-mediated macrophage polarization plays a key regulatory role in AAA, complementing the role and mechanism of macrophages in the occurrence and development of AAA and providing a scientific basis for AAA treatment.
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Aneurisma da Aorta Abdominal , MicroRNAs , Humanos , Fatores de Transcrição/metabolismo , Quimiocina CCL20/genética , Quimiocina CCL20/metabolismo , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Macrófagos/metabolismo , Inflamação/genética , Inflamação/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismoRESUMO
Prior research has indicated that animal models of abdominal aortic aneurysm (AAA) utilizing porcine pancreatic elastase (PPE) exhibit a perfusion duration of 30 min, and extended perfusion durations are associated with elevated mortality rates. Similarly, the AAA model, which relies solely on balloon dilation (BD), is limited by the occurrence of self-healing aneurysms. Consequently, we constructed a novel AAA model by PPE combined with balloon expansion to shorten the modeling time and improve the modeling success rate. The findings indicated that 5 min was the optimal BD time for rabbits, 3 min BD was ineffective for aneurysm formation, and 10 min BD had a high mortality rate. The model, constructed in combination with PPE and 5 min BD, exhibited a 100% model formation rate and a 244.7% ± 9.83% dilation rate. HE staining exhibited that severe disruption of the inner, middle, and outer membranes of the abdominal aorta, with a marked decrease in smooth muscle cells and elastase, and a marked increase in fibroblasts of the middle membrane, and many infiltrating inflammatory cells were seen in all three layers, especially in the middle membrane. EVG staining displayed that the elastic fibers of the abdominal aortic wall were fractured and degraded, and lost their normal wavy appearance. The protein expression of inflammatory factor (IL-1ß, IL-6 and TNF-α) as well as extracellular matrix components (MMP-2 and MMP-9) were significantly increased compared to PPE and 5 min BD alone. In conclusion, PPE combined with BD allows the establishment of a novel AAA model that closely mimics human AAA in terms of histomorphology, inflammatory cell infiltration, and vascular stromal destruction. This model provides an ideal animal model for understanding the pathogenesis of AAA.
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OBJECTIVE: To analyze the clinical characteristics of patients with overweight acute type A aortic dissection, and to explore the risk factors of acute kidney injury in patients with overweight acute type A aortic dissection. METHODS: From March 2019 to February 2022, the clinical data of 71 patients with acute type a aortic dissection diagnosed by CTA and undergoing surgical treatment with BMI > 24 in the First People's Hospital of Yunnan Province were retrospectively analyzed, and analyzed by univariate and logistic multivariate analysis methods. RESULTS: The mean BMI of all included patients was 27.23, The mean surface area of all included human populations was 1.833. The mean age of all patients was (52.06 ± 10.71) years old, and 35 patients developed acute kidney injury after surgery. Multi-factor Logistics regression analysis confirmed the risk factors for postoperative acute kidney injury in overweight patients with acute type A aortic dissection, including gender, CPB transit time and intraoperative infusion of suspended red blood cells. Seven patients in the AKI group died in hospital after surgery and two patients died in the non-AKI group. CONCLUSIONS: Among patients with overweight acute Type A aortic dissection, the incidence of AKI is 49.30%. According to multi-factor Logistics regression analysis, gender, CPB transit time and intraoperative suspended red blood cell volume are independent risk factors for postoperative acute kidney injury in patients with overweight acute Type A aortic dissection.
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Injúria Renal Aguda , Dissecção Aórtica , Humanos , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Sobrepeso/complicações , China/epidemiologia , Dissecção Aórtica/complicações , Dissecção Aórtica/cirurgia , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Fatores de Risco , Complicações Pós-Operatórias/epidemiologiaRESUMO
Background: Abdominal aortic aneurysm (AAA) manifest as a natural inflammatory process with permanent dilation and terminal rupture. Nevertheless, the pathogenesis of AAA remains a mystery, and treatment is still controversial. Lipid metabolism and immune system are involved in AAA progression, which has been well documented. However, lipid- and immune-related (LIR) biomarkers need to be further elucidated. Methods: The AAA-related datasets were retrieved from the GEO database, and the datasets were analyzed for differential gene expression by NetworkAnalyst. GO and KEGG pathway enrichment analysis of differentially expressed mRNA (DE-mRNA) was performed using Metscape, and LIR DE-mRNA was further screened. AAA rat model was constructed using porcine pancreatic elastase to verify the differential expression of LIR DE-mRNA. Results: The GSE47472 and GSE57691 datasets respectively identified 614 (containing 381 down-regulated and 233 up-regulated DE-mRNAs) and 384 (containing 218 down-regulated and 164 up-regulated DE-mRNAs) DE-mRNAs. Intersection and union of DE-mRNAs were 13 and 983, respectively. The main terms involved in the union of DE-mRNAs included "immune system process", "metabolic process", "Chemokine signaling pathway", "hematopoietic cell lineage" and "Cholesterol metabolism". In vivo experiments revealed that LIR DE-mRNAs of PDIA3, TYROBP, and HSPA1A were significantly low expression in AAA abdominal aortic tissues, and HCK and SERPINE1 were significantly high expression, which is consistent with the bioinformatics analysis. Conclusions: PDIA3, TYROBP, HSPA1A, HCK and SERPINE1 may serve as LIR biomarkers of AAA, which provides new insights and theoretical guidance for the future treatment, early prevention and progression of AAA.
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BACKGROUND: M2 macrophages have been reported to be important in the progression of coronary artery disease (CAD). Thus, the present study aims at exploring the diagnostic value of M2 macrophage-associated genes in CAD. METHODS: Transcriptome profile of CAD and control samples were downloaded from Gene Expression Omnibus database. The proportion of immune cells was analyzed using cell type identification by estimating relative subsets of RNA transcripts. Weighted Gene Co-expression Network Analysis (WGCNA) was carried out to screen the relevant module associated with M2 macrophages. Differential CAD and control samples of expressed genes (DEGs) were identified by the limma R package. Functional enrichment analysis by means of the clusterProfiler R package. Least absolute shrinkage and selection operator (LASSO) and random forest (RF) algorithms were carried out to select signature genes. Receiver operating curves (ROC) were plotted to evaluate the diagnostic value of selected signature genes. The expressions of potential diagnostic markers were validated by RT-qPCR. The ceRNA network of diagnostic biomarkers was constructed via miRwalk and Starbase database. CMap database was used to screen candidate drugs in the treatment of CAD by targeting diagnostic biomarkers. RESULTS: A total of 166 M2 macrophage-associated genes were identified by WGCNA. By intersecting those genes with 879 DEGs, 53 M2 macrophage-associated DEGs were obtained in the present study. By LASSO, RF, and ROC analyses, C1orf105, CCL22, CRYGB, FRK, GAP43, REG1P, CALB1, and PTPN21 were identified as potential diagnostic biomarkers. RT-qPCR showed the consistent expression patterns of diagnostic biomarkers between GEO dataset and clinical samples. Perhexiline, alimemazine and mecamylamine were found to be potential drugs in the treatment of CAD. CONCLUSION: We identified eight M2 macrophage-associated diagnostic biomarkers and candidate drugs for the CAD treatment.
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Doença da Artéria Coronariana , Humanos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Redes Reguladoras de Genes , Perfilação da Expressão Gênica , Transcriptoma , Macrófagos/metabolismo , Biomarcadores/metabolismoRESUMO
Objectives: Abdominal aortic aneurysm (AAA) has a high risk of rupture of the aorta and is one of the leading causes of death in older adults. This study is aimed at confirming the influence and mechanism of the abnormally expressed ANXA6 gene in AAA. Methods: Clinical samples were collected for proteome sequencing to screen for differentially expressed proteins. An Ang II-induced vascular smooth muscle cell (VSMC) aging model as well as an AAA animal model was used. Using RT-qPCR to detect the mRNA levels of EZH2, ANXA6, IK-6, and IL-8 in cells and tissues were assessed. Western blotting and immunohistochemistry staining were used apply for the expression of associated proteins in cells and tissues. SA-ß-gal staining, flow cytometry, and DHE staining were used to detect senescent cells and the level of ROS. The cell cycle was assessed by flow cytometry. Arterial pathology was observed by HE staining. The aging of VSMCs in arterial tissue was assessed by coimmunofluorescence for α-SMA and p53. Results: There were 24 differentially expressed proteins in the AAA clinical samples, including 10 upregulated protein and 14 downregulated protein, and the differential expression of ANXA6 was associated with vascular disease. Our study found that ANXA6 was highly expressed and EZH2 was lowly expressed in an Ang II-induced VSMC aging model. Knockdown of ANXA6 or overexpression of EZH2 inhibited Ang II-induced ROS, inhibited cell senescence, decreased Ang II evoked G1 arrest, and increased cells in G2 phase, while overexpression of ANXA6 played the opposite role. Overexpression of EZH2 inhibited ANXA6 expression by increasing H3K27me3 modification at the ANXA6 promoter. Simultaneous overexpression of EZH2 and the protective effect of EZH2 on cell senescence were partially reversed by ANXA6. Similarly, ANXA6 was highly expressed and EZH2 was lowly expressed in an Ang II-induced AAA animal model. Knockdown of ANXA6 and overexpression of EZH2 alleviated Ang II-induced VSMC senescence and inhibited AAA progression, while simultaneous overexpression of EZH2 and ANXA6 partially reversed the protective effect of EZH2 on AAA. Conclusion: EZH2 regulates the ANXA6 promoter H3K27me3 modification, inhibits ANXA6 expression, alleviates Ang II-induced VSMC senescence, and inhibits AAA progression.
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Angiotensina II , Músculo Liso Vascular , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Senescência Celular , Modelos Animais de Doenças , Histonas/metabolismo , Interleucina-8/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteoma/metabolismo , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Objectives: Intestinal epithelial barrier function is an important mechanical barrier to maintain intestinal homeostasis and resist the invasion of intestinal pathogens and microorganisms. However, intestinal epithelial barrier function is vulnerable to damage under intestinal ischemia-reperfusion (I/R) injury. Under a category of pathophysiological conditions, including I/R, autophagy plays a crucial role. This study is aimed at discussing the role of autophagy inhibitors and activators in intestinal epithelial barrier function after intestinal I/R by changing autophagy levels. Methods: Mice with intestinal IR underwent 45 minutes of surgery for superior mesenteric artery occlusion. The autophagy inhibitor 3-MA and the autophagy inducer rapamycin (RAP) were used to change the level of autophagy, and then, the expressions of tight junction proteins and intestinal barrier function were detected. Results: The results showed that the autophagy inhibitor 3-MA aggravated intestinal epithelial barrier dysfunction, while the autophagy inducer RAP attenuated intestinal epithelial barrier dysfunction. In addition, promoting autophagy may promote occludin expression by inhibiting claudin-2 expression. Conclusion: Upregulation of autophagy levels by autophagy inducers can enhance intestinal epithelial barrier function after intestinal I/R.
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Autofagia , Traumatismo por Reperfusão , Animais , Mucosa Intestinal/metabolismo , Isquemia , Camundongos , Reperfusão , Traumatismo por Reperfusão/metabolismo , Proteínas de Junções Íntimas/metabolismoRESUMO
5Fluorouracil (5FU) is the preferred chemotherapeutic drug used in the treatment of colon cancer; however, drug resistance affects its clinical efficacy. Visfatin, an adipokine that promotes tumour development, has the potential to increase resistance to chemotherapy. The present study aimed to verify the effects of visfatin on the sensitivity of colon cancer cells to 5FU and to elucidate the potential mechanisms involved. Tissue microarrays (TMAs) were used to analyse visfatin differential expression in normal colon and colon cancer tissues, and the data were further validated in vitro. Cell Counting Kit8, clone formation, caspase3/7 activity assays, as well as other analyses were used to verify the effects of visfatin on sensitivity to 5FU. TMA and correlation analyses were used to predict and verify the correlation between visfatin and stromal cellderived factor1 (SDF1). Rescue experiments and PI3K/Akt inhibitors were used to verify the role of the visfatin/SDF1/Akt axis in the sensitivity of colon cancer cells to 5FU. Visfatin was found to be highly expressed in colon cancer tissues and cell lines. Moreover, visfatin knockdown increased apoptosis, reduced cell proliferation and enhanced the chemosensitivity of DLD1 and SW48 cells to 5FU. A positive correlation between visfatin and SDF1 was observed, with the knockdown of visfatin enhancing cell sensitivity to 5FU chemotherapy by targeting the SDF1/CXC chemokine receptor type 4 (CXCR4) axis. Furthermore, the Akt signalling pathway downstream of SDF1/CXCR4 proved to be critical in the decreased sensitisation of colon cancer cells to 5FU induced by visfatin. On the whole, the present study demonstrates that visatin can potentially decrease colon cancer cell apoptosis, promote proliferation and decrease colon cancer cell sensitivity to 5FU via the visfatin/SDF1/Akt axis.
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Neoplasias do Colo , Nicotinamida Fosforribosiltransferase , Apoptose , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Nicotinamida Fosforribosiltransferase/metabolismo , Nicotinamida Fosforribosiltransferase/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismoRESUMO
BACKGROUND: Thoracoabdominal aortic aneurysms (TAAAs) are one of the most complex aortic aneurysms to treat. Traditional open surgery for TAAAs is highly invasive and total endovascular treatment still has many limitations. Hybrid surgery offers a viable option for TAAA patients, but currently it often alters the original hemodynamics. Therefore, we have developed and applied a hybrid surgery protocol for anatomically suitable TAAA patients. Here we analyzed the short-term outcomes of these patients and evaluated the effectiveness and safety of this procedure. METHODS: A new method was used to perform the required artificial revascularization of the abdominal aorta and its branches. A new visceral debranching and reconstruction approach was used to complete an anatomy-conforming open surgery. Finally, a new vascular access was used for the endovascular operation to complete the implantation of stent-grafts. The clinical data of 10 patients with TAAAs treated at our center with the anatomy-conforming hybrid technique during the period from May 2018 to June 2020 was retrospectively analyzed. The intraoperative and 30-day postoperative key indicators, including survival rates and complications, were analyzed. RESULTS: The hybrid surgery was smoothly performed in all 10 patients. One patient died from non-aortic causes (sepsis/infectious toxic shock) 30 days after surgery, yielding a case-fatality rate of 10.0% (1/10). Two patients (2/10) experienced serious complications within 30 days postoperatively, including multi-organ failure due to infection in one patient and lower limb ischemia in another patient who went on to develop permanent paraplegia. No endoleak after stent implantation was noted and the blood supply of each reconstructed visceral artery was good. CONCLUSIONS: Based on the short-term outcomes, the anatomy-conforming hybrid surgical protocol is safe and effective in treating TAAA patients.
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Aneurisma da Aorta Torácica , Implante de Prótese Vascular , Aneurisma da Aorta Torácica/cirurgia , Prótese Vascular , Humanos , Complicações Pós-Operatórias , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
The growth differentiation factor-15 (GDF-15) may be involved in atherosclerosis. However, the role of GDF-15 in atherosclerosis remains unclear. The main goal of this study was to verify the role and mechanism of GDF-15 in atherogenesis. We first compared the serum GDF-15 level between patients with coronary atherosclerosis and healthy people. And then one ApoE-/- mouse model of atherosclerosis was used to explore the effects of GDF-15 on oxidized low-density lipoprotein (oxLDL) accumulation, atherosclerosis-related gene expression, and lipid accumulation-related protein expression in mouse macrophages. As a result, the level of serum GDF-15 in patients with coronary atherosclerosis was significantly higher than that in healthy people. In the mouse model, GDF-15 expression was elevated in the core of plaque, and it was secreted mainly by the macrophages. In addition, GDF-15 decreased oxLDL-induced lipid accumulation and inflammation activation in macrophages. GDF-15 decreased the mRNA expressions of CD36, LOX1, and TLR4 that are associated with lipoprotein accumulation in macrophages. Further study showed that GDF-15 might suppress oxLDL-induced lipoprotein accumulation via inhibiting CD36 and LOX1 and decrease inflammation in macrophages by inhibiting TLR4. Thus, GDF-15 may suppress atherosclerosis and plaque formation by inhibiting lipoprotein accumulation and inflammation activation.
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BACKGROUND: Studies have shown that the thrombomodulin gene (THBD) c.1418C>T polymorphism is associated with a variety of cardiovascular diseases. However, the study of THBD c.1418C>T polymorphism in deep vein thrombosis (DVT) is rare. This study aimed to reveal the correlation between the THBD c.1418C>T mutation and the occurrence of DVT, and to reveal partial molecular mechanism of endothelial progenitor cells (EPCs) participating in the onset of DVT. METHODS: Whole blood samples of patients with lower extremity DVT (N.=100) and normal volunteers (N.=100) were collected to analyze the distribution of genotype of THBD c.1418C>T polymorphism using PCR and DNA sequencing. The pCMV6-entry vectors containing wild-type (WT) or mutated THBD cDNA (p. Ala473Val) were transfected into bone marrow derived EPCs. And the successful transfection of recombinant THBD and the stable expression of p. Ala473Val variant were determined by ELISA, respectively. Wound healing assay and Transwell migration assay were used to determine the migration ability of EPCs, and the cell angiogenesis ability was determined by tube formation assay. Western blotting was used to detect the expression level of related proteins. RESULTS: The frequencies of CC, CT and TT genotypes were 56%, 36%, 8% in patients with lower extremity DVT and 72%, 25%, 3% in controls group, respectively, and THBD c.1418C>T polymorphism was related with increased risk of DVT, especially in women. High level of p. Ala473Val variant inhibited the EPCs migration, the p. Ala473Val variant significantly decreased the activation of protein C and the expressions of VEGFRs and MMP1, MMP2, MMP3. Furthermore, p. Ala473Val variant also weaken the angiogenesis of EPCs and decreased the expression level of VE-cadherin, Flk-1, eNOS, and TIE-2. CONCLUSIONS: THBD c.1418C>T polymorphism is related with the lower extremity DVT, this may partially because of the inhibition of migration and angiogenesis of EPCs.
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Células Progenitoras Endoteliais , MicroRNAs , Trombomodulina , Trombose Venosa , Feminino , Humanos , Extremidade Inferior , Polimorfismo Genético , Trombomodulina/genética , Trombose Venosa/genéticaRESUMO
BACKGROUND: Obesity is characterized by excessive body fat, insulin resistance and dyslipidemia, which increases the chances of developing chronic diseases like type 2 diabetes, cardiovascular diseases, hypertension, nonalcoholic fatty liver diseases, some types of cancers and neurodegenerative diseases. Kukoamine B (Kuk B) is a spermine alkaloid obtained from Lycium chinense, and it has been shown to possess antidiabetic, antioxidant and anti-inflammatory properties. In this study, we evaluated the therapeutic effect of Kuk B on high-fat diet/high-fructose (HFDFr)-induced insulin resistance and obesity in experimental rats. MATERIALS AND METHODS: Rats were fed with either normal rat diet or HFDFr for 10 consecutive weeks. The groups that were fed with HFDFr received Kuk B (25 and 50 mg/kg) from the beginning of the 6th week to the 10th week. After treatment, the effect of Kuk B on body weight, food, water intake, insulin, blood glucose, serum biochemical parameters, hepatic oxidative stress (malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and proinflammatory cytokine (interleukin (IL)-6, interleukin (IL)-1ß and tumor necrosis factor alpha (TNF-α)) levels was determined. Histopathological analysis of the liver tissues was also performed. RESULTS: HFDFr-fed rats showed a significant increase in body weight, fasting blood glucose, insulin, lipid accumulation and liver function enzymes. In addition, HFDFr diet increased hepatic MDA, TNF-α, IL-1ß and IL-6 and decreased hepatic SOD, CAT and GSH-Px activities. On the other hand, Kuk B significantly attenuated body weight, insulin resistance, lipid accumulation, oxidative stress and inflammation. CONCLUSION: These results indicated that Kuk B showed protective effect against HFDFr-induced metabolic disorders by downregulating lipid accumulation, oxidative stress and inflammatory factors.
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BACKGROUND: Tumor-associated macrophages (TAMs) are key components of colorectal cancer (CRC) microenvironment, but their role in CRC prognosis is not fully defined. OBJECTIVE: This study aimed to evaluate prognostic value of different types and distribution of TAMs in CRC. METHODS: Total 27 studies with 6115 patients were searched from PubMed and Embase and analyzed to determine the association between TAMs, including distinct TAM subsets and infiltration location, and CRC survival. The prognostic impact of TAMs on CRC was further stratified by tumor type and mismatch repair system (MMR) status. RESULTS: A pooled analysis indicated that high density of TAMs in CRC tissue was significantly associated with favorable 5-year overall survival (OS) but not with disease-free survival (DFS). CD 68+ TAM subset correlated with better 5-year OS, while neither CD68+NOS2+ M1 subset nor CD163+ M2 subset was correlated with 5-year OS. Increased CD68+ TAM infiltration in tumor stroma but not in tumor islet predicted improved 5-year OS. Stratification by tumor type and MMR status showed that in colon cancer or MMR-proficient CRC, elevated TAM density was associated with better 5-year OS. CONCLUSIONS: High infiltration of CD68+ TAMs could be a favorable prognostic marker in CRC. Future therapies stimulating CD68+ TAM infiltration may be promising in CRC treatment.
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Neoplasias do Colo , Macrófagos Associados a Tumor , Antígenos de Diferenciação Mielomonocítica , Humanos , Macrófagos , Prognóstico , Microambiente TumoralRESUMO
Abdominal aortic aneurysm (AAA) is a serious, life-threatening vascular disease that presents as an enlarged area of the aorta, which is the main artery that carries blood away from the heart. AAA may occur at any location in the aorta, but it is mainly found in the abdominal region. A ruptured AAA causes serious health issues, including death. Traditional imaging techniques, such as computed tomography angiogram, magnetic resonance imaging, and ultrasound sonography, have been used to identify AAAs. Circulating biomarkers have recently become attractive for diagnosing AAAs due to their cost-effectiveness compared to imaging. Insulin-like growth factor 1 (IGF-1), a secreted hormone vital for human atherosclerotic plaque stability, has been found to be an efficient biomarker for AAA identification. In this report, immunosensing was performed by using an InterDigitated electrode (IDE) sensor to detect circulating levels of IGF-1. The detection limit of IGF-1 was found to be 100 fM with this sensor. Moreover, related protein controls (IGF-2 and IGFBP3) were not detected with the same antibody, indicating selective IGF-1 detection. Thus, immunosensing by using an IDE sensor may help to effectively diagnose AAAs and represents a basic platform for further development.
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Aneurisma da Aorta Abdominal/diagnóstico , Técnicas Biossensoriais , Técnicas Eletroquímicas , Fator de Crescimento Insulin-Like I/análise , Anticorpos Imobilizados/química , Biomarcadores/análise , Eletrodos , Humanos , Propriedades de SuperfícieRESUMO
OBJECTIVE: Bone-marrow-derived endothelial progenitor cells (EPCs) can accelerate the dissolution of thrombi. However, EPC functions are weakened in deep vein thrombosis (DVT), and miR-130a-3p is downregulated in DVT. As little is known about the function of miR-130a-3p in EPCs, we aimed to explore the effects of miR-130a-3p on EPC functions and the mechanisms of miR-130a-3p regulation of EPCs in DVT. METHODS: The EPCs were transfected with miR-130a-3p mimics or miR-130a-3p inhibitor. Migration and angiogenesis of EPCs were detected by wound healing, Transwell, and tube formation assays. Dual luciferase assay was used to test the relation of miR-130a-3p and phosphatase and tensin homolog (PTEN). Protein and mRNA levels of associated genes were measured by western blotting (WB) and qRT-PCR. RESULTS: miR-103a-3p could promote EPC migration and angiogenesis, and it was also downregulated in EPCs isolated from DVT patients. Moreover, PTEN was a target of miR-130a-3p. Upregulation of PTEN rescued the auxoaction of miR-130a-3p in EPC function. CONCLUSIONS: Downregulation of miR-103a-3p contributes to EPC dysfunction in DVT via targeting PTEN. Thus, miR-130a-3p may be a potential target for DVT treatment.
Assuntos
Células Progenitoras Endoteliais/enzimologia , MicroRNAs/metabolismo , Neovascularização Fisiológica , PTEN Fosfo-Hidrolase/metabolismo , Trombose Venosa/enzimologia , Estudos de Casos e Controles , Movimento Celular , Células Cultivadas , Regulação para Baixo , Células Progenitoras Endoteliais/patologia , Humanos , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Trombose Venosa/genética , Trombose Venosa/patologiaRESUMO
Clinical efficacy and adverse reactions of pemetrexed combined with stereotactic gamma-ray radiotherapy in the treatment of patients with lung adenocarcinoma brain metastasis in The First People's Hospital of Yunnan Province were evaluated. A total of 67 patients with lung adenocarcinoma brain metastasis in experimental group were treated with simple pemetrexed chemotherapy, and then with radiotherapy, followed by pemetrexed chemotherapy. Their treatment results were compared with those of 53 patients treated with simple gamma knife in control group. The results were analyzed by comparing the clinical efficacy, side reactions, serum level changes, and survival between the two groups. Among 67 patients in the experimental group, there were 16 cases of complete response (CR), 39 cases of partial response (PR), 7 cases of stable disease (SD) and 5 cases of progressive disease (PD), with an effective rate of 82.09% (55/67) and a tumor local control rate of 92.54% (62/67). Among 53 patients in the control group, there were 13 cases of CR, 20 cases of PR, 9 cases of SD and 11 cases of PD, with an effective rate of 62.26% (33/53) and a tumor local control rate of 79.25% (42/53). There were statistically significant differences in the effective rate and local control rate between the two groups (P<0.05). The 6-, 12- and 24-month survival rates in experimental group were higher than those in control group (P<0.05). The main adverse reactions after pemetrexed combined with radiotherapy were lower than those after simple radiotherapy (P<0.05). The expression levels of the tumor markers carcinoembryonic antigen (CEA) and cytokeratin fragment antigen 21-1 (CYFRA21-1) in the two groups of patients after treatment were lower than those before treatment (P<0.05). After treatment, the expression levels of serum CEA and CYFRA21-1 in the experimental group were significantly lower than those in the control group (P<0.05). Pemetrexed combined with radiotherapy in the treatment of lung adenocarcinoma brain metastasis is more effective than simple radiotherapy, with lighter adverse reactions, worthy of clinical application and promotion.
RESUMO
Gastric cancer is one of the prevalent types of cancers and despite improvements in its treatment, the overall survival is still far from descent. The dearth of efficient biomarkers, chemotherapeutic agents and therapeutic targets form a major hurdle in the treatment of the gastric cancer. Accumulating evidences suggest that MicroRNAs (miRs) may prove important therapeutic targets/agents for the management of cancers including gastric cancer. Herein, we examined the expression of miR-19a by qRT-PCR in gastric cancer and attempted to explore its potential role. It was found that the expression of miR-19a is significantly (pâ¯<â¯0.05) enhanced in the gastric cancer tissues as well as the gastric cancer cell lines. Inhibition of miR-19a in gastric cancer cells suppressed the proliferation migration and invasion of the gastric cancer cells. Bioinformatic analysis revealed CUL5 to be the potential target of miR-19a. Contrary, to the expression of miR-19a, the expression of CUL5 was significantly (pâ¯<â¯0.05) downregulated in all the gastric cancer tissues and cell lines. However, inhibition of miR-19a in SNU-16 gastric cancer cells could cause upsurge of CUL5 expression. Overexpression of CUL-5 was found to exhibit similar effects on the proliferation, migration and invasion of the SNU-16 gastric cancer cells as that of miR-19a suppression. Additionally, overexpression of CUL5 could at least partially abolish the effects of miR-19a suppression on the proliferation, migration and invasion of SNU-16 gastric cancer cells. Finally, overexpression of miR-19a caused inhibition of the xenografted tumors in vivo indicating the potential of miR-19a as therapeutic target for gastric cancer.