RESUMO
OBJECTIVE: This investigation aims to explore the expression levels of serine protease 8 (PRSS8) in gefitinib-resistant Non-Small Cell Lung Cancer (NSCLC) cell lines (PC9/GR) and elucidate its mechanism of action. METHODOLOGY: We measured PRSS8 expression in gefitinib-resistant (PC9/GR) and sensitive (PC9) NSCLC cell lines using Western blot analysis. PRSS8-specific small interfering RNA (PRSS8-siRNA), a recombinant plasmid, and a corresponding blank control were transfected into PC9/GR cells. Subsequently, Western blot analyses were conducted to assess the expression levels of PRSS8, phosphorylated AKT (p-AKT), AKT, phosphorylated mTOR (p-mTOR), mTOR, and various apoptosis-related proteins within each group. Additionally, a cell proliferation assay utilizing Cell Counting Kit-8 (CCK8) was performed on each group treated with gefitinib. RESULT: PRSS8 expression was markedly higher in PC9/GR cells compared to PC9 cells (p < 0.05). The group treated with PRSS8-siRNA exhibited significantly reduced protein expression levels of PRSS8, p-AKT, p-mTOR, ß-catenin, and BCL-2 compared to the control siRNA (Con-siRNA) group, whereas expressions of Caspase9 and Bax were significantly increased. In the untransfected PC9/GR cells, protein expressions of PRSS8, p-AKT, pmTOR, and BCL-2 were significantly elevated when compared with the plasmid-transfected group, which also showed a significant reduction in Bax expression. The proliferative activity of the PRSS8-siRNA group postgefitinib treatment was significantly diminished at 24, 48, and 72 hours in comparison to the Con-siRNA group. CONCLUSION: The findings indicate that PRSS8 contributes to the acquisition of resistance to gefitinib in NSCLC, potentially through regulation of the AKT/mTOR signaling pathway.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Ftalazinas , Piperazinas , Proteína 1 Parceira de Translocação de RUNX1 , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Ftalazinas/administração & dosagem , Ftalazinas/uso terapêutico , Proteína 1 Parceira de Translocação de RUNX1/genética , Idoso , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Fusão Oncogênica/genética , Resultado do Tratamento , Masculino , Feminino , Recidiva , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologiaRESUMO
OBJECTIVE: To explore the involvement of TFEB-mediated autophagy-lysosomal mechanisms in multiple myeloma (MM) during bortezomib treatment. METHODS: MM cells were exposed to bortezomib or subjected to TFEB knockdown. CCK assay was used to assess the cell proliferation. Western blotting and fluorescent staining were conducted to examine autophagy and lysosomes. The TFEB expression pattern was analyzed, and whole transcriptome sequencing was carried out. Additionally, TFEB target genes were predicted using the GTRD(http://gtrd.biouml.org/) website, and pathway analysis was performed. RESULTS: Bortezomib demonstrated a dose-dependent and time dependent inhibition of cell proliferation. In MM cells treated with bortezomib, LC3B, Beclin-1, TFEB, and Lamp1 exhibited upregulation in a time- and concentration-dependent manner. LysoTracker dye labeling showed an increase in lysosomes in the bortezomib-treated group. Moreover, bortezomib elevated the expression of lysosome-associated factor Lamp1. Bortezomib promoted the nuclear translocation of TFEB, leading to decreased cytoplasmic TFEB and increased nuclear TFEB. TFEB gene silencing reversed bortezomib's inhibitory effect on MM cell lines, significantly reducing autophagosome expression and lysosome numbers. Furthermore, bioinformatic analysis identified the MAPK pathway as a potential downstream target of TFEB. CONCLUSION: Bortezomib effectively inhibits MM cell proliferation and induces autophagy, partly through TFEB-mediated mechanisms, with potential involvement of the MAPK pathway.
Assuntos
Mieloma Múltiplo , Humanos , Bortezomib/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Autofagia , Autofagossomos/metabolismo , Lisossomos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genéticaRESUMO
OBJECTIVE: To analyse the relationship between the polymorphisms of the H-type hypertensive methylenetetrahydrofolate reductase (MTHFR) C677T gene and neutrophil gelatinase-associated lipocalin (NGAL) in early kidney injury. METHOD: A total of 279 hospitalised patients with hypertension were selected and grouped according to their homocysteine (Hcy) level. If their blood Hcy level was ≥ 10 µmol/L they were assigned to the H-type hypertensive group, and if it was < 10 µmol/L they were assigned to the non-H-type hypertensive group. Blood lipid indexes, renal function indexes and blood glucose indexes were collected, and the differences between the two groups were compared. Furthermore, MTHFR C677T genotype distribution and allele frequency and Hcy level of MTHFR C677T genotype were compared, and logistic multiple regression analysis was conducted for the correlation of different genotypes of MTHFR C677T and the early kidney injury marker NGAL. RESULTS: In the non-H-type hypertensive group, the levels of Hcy and NGAL, cystatin, blood urea nitrogen, serum creatinine, uric acid, serum ß2-microglobulin and urinary microalbumin-to-creatinine ratio increased significantly, and the glomerular filtration rate level decreased significantly, when compared with the H-type hypertensive group, with statistical differences (p < 0.05). The H-type hypertensive group and the non-H-type hypertensive group had significant differences in the CC, CT and TT genotypes and allele frequencies at the MTHFR C677T locus. The MTHFR C677T gene mutation rate of the H-type hypertensive group was significantly higher than that of the non-H-type hypertensive group. The H-type hypertensive group had higher levels of the TT genotype and CT genotype Hcy. There was a statistical difference (p < 0.05). CONCLUSION: Methylenetetrahydrofolate reductase C677T polymorphism is correlated with the Hcy level, and its gene polymorphism will affect the Hcy level. Methylenetetrahydrofolate reductase C677T polymorphism has an interactive effect with NGAL. Screening NGAL and reducing Hcy levels are valuable methods for the prevention and treatment of early renal injury in patients with H-type hypertension and help improve the prognosis of patients and their quality of life.
Assuntos
Hipertensão , Metilenotetra-Hidrofolato Redutase (NADPH2) , Humanos , Genótipo , Homocisteína , Hipertensão/diagnóstico , Hipertensão/genética , Rim , Lipocalina-2/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Qualidade de VidaRESUMO
In this study, we aimed to determine whether liraglutide could effectively reduce insulin resistance (IR) by regulating Sestrin2 (SESN2) expression in L6 rat skeletal muscle cells by examining its interactions with SESN2, autophagy, and IR. L6 cells were incubated with liraglutide (10-1000 nM) in the presence of palmitate (PA; 0.6 mM), and cell viability was detected using the cell counting kit-8 (CCK-8) assay. IR-related and autophagy-related proteins were detected using western blotting, and IR and autophagy-related genes were analyzed using quantitative real-time polymerase chain reaction. Silencing SESN2 was used to inhibit the activities of SESN2. A reduction in insulin-stimulated glucose uptake was observed in PA-treated L6 cells, confirming IR. Meanwhile, PA decreased the levels of GLUT4 and phosphorylation of Akt and affected SESN2 expression. Further investigation revealed that autophagic activity decreased following PA treatment, but that liraglutide reversed this PA-induced reduction in autophagic activity. Additionally, silencing SESN2 inhibited the ability of liraglutide to up-regulate the expression of IR-related proteins and activate autophagy signals. In summary, the data showed that liraglutide improved PA-induced IR in L6 myotubes by increasing autophagy mediated by SESN2.
Assuntos
Resistência à Insulina , Ratos , Animais , Resistência à Insulina/fisiologia , Palmitatos/farmacologia , Palmitatos/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Liraglutida/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Insulina/metabolismo , Autofagia , Músculo Esquelético/metabolismoRESUMO
In this study, we explored the relationship between inflammatory adipokine levels and coronary artery disease (CAD). We collected subcutaneous adipose tissues(SAT), pericardial adipose tissues(PAT), and epicardial adipose tissues (EAT) and serum samples from 26 inpatients with CAD undergone coronary artery bypass grafting and 20 control inpatients without CAD. Serum inflammatory adipokines were measured by ELISA. Quantitative real-time PCR and western blot were used to measure gene and protein expression. Adipocyte morphology was assessed by H&E staining. Immunohistochemistry and immunofluorescence were used to measure endothelial and inflammatory markers. Serum pro- and anti-inflammatory adipokine levels were higher and lower, respectively, in the CAD group than those in the control group (P < 0.05). In CAD, the pro-inflammatory adipokine levels via ELISA in EAT and PAT were elevated. Pro-inflammatory adipokine mRNA expression was increased, while anti-inflammatory adipokine mRNA expression decreased, in CAD relative to NCAD in EAT and PAT rather than SAT. In EAT, adipocyte area and macrophage-specific staining were lower, while lymphatic vessel marker expression was higher in CAD. Additionally, the endothelial marker expression in EAT was higher than PAT in CAD. The three tissue types had different blood vessel amounts in CAD. The regulation and imbalance expression of the novel biomarkers, including inflammatory adipokine, macrophage infiltration, angiogenesis, and lymphangiogenesis in EAT and PAT, may be related to the pathogenesis of CAD. The serum levels of inflammatory adipokines may correlate to CAD, which requires large sample size studies to get further validation before clinic practice.
Assuntos
Tecido Adiposo , Doença da Artéria Coronariana , Pericárdio , Humanos , Adipocinas/sangue , Adipocinas/genética , Adipocinas/metabolismo , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Linfangiogênese/fisiologia , Neovascularização Patológica/sangue , Neovascularização Patológica/metabolismo , Neovascularização Patológica/fisiopatologia , Pericárdio/metabolismo , Pericárdio/fisiopatologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND AND AIMS: This study investigates the expression of novel adipocytokines and inflammatory cells infiltration in epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) between 27 coronary artery disease (CAD) and 21 non-CAD (NCAD) patients enrolled from September 2020 to September 2021. METHODS AND RESULTS: Serum, gene, and protein expression levels of the novel adipocytokines were determined using ELISA, RT-qPCR, and western blot analyses. The number of blood vessels and adipocytes morphology were measured via hematoxylin-eosin staining, and inflammatory cells infiltration was examined via immunohistochemistry. Serum ANGPTL8, CTRP5, and Wnt5a levels were higher in the CAD than in the NCAD group, while serum CTRP3, Sfrp5, and ZAG levels were lower in the CAD than in the NCAD group. Compared to the EAT of NCAD and SAT of CAD patients, the EAT of CAD patients had higher mRNA levels of ANGPTL8, CTRP5, and Wnt5a while lower levels of CTRP3, Sfrp5, and ZAG; higher protein expression levels of ANGPTL8 and CTRP5 but lower levels of CTRP3; more blood vessels; and higher infiltration rates of macrophages (CD68 + ), pro-inflammatory M1 macrophages (CD11c + ), mast cells (Tryptase + ), T lymphocytes (CD3 + ), and B lymphocytes (CD20 + ) but lower infiltration rates of anti-inflammatory M2 macrophages (CD206 + ). CONCLUSION: Novel adipocytokines and inflammatory cells infiltration are dysregulated in human EAT, and could be important pathophysiological mechanisms and novelly promising medicating targets of CAD.
Assuntos
Doença da Artéria Coronariana , Hormônios Peptídicos , Humanos , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Tecido Adiposo/metabolismo , Gordura Subcutânea/metabolismo , Adipocinas/metabolismo , Inflamação/metabolismo , Pericárdio/metabolismo , Proteína 8 Semelhante a AngiopoietinaRESUMO
BACKGROUND: Recent studies have demonstrated that microRNAs (miRNAs) play an essential role in the regulation of allergic rhinitis (AR), but the underlying mechanism is still unclear. OBJECTIVE: This case-control study aimed to measure the expression levels of serum miRNAs in children with AR, to evaluate their potential as diagnostic markers, and investigate the association between miRNAs and IL-4, total nasal symptom score (TNSS), and specific IgE (Artemisia). METHODS: Twenty allergic rhinitis patients and 20 healthy controls were included. The expression levels of serum miR-18a-5p, miR-142-5p, miR-155-5p, and miR-3687 were measured using quantitative real-time polymerase chain reaction. Serum cytokine levels were measured using IL-4 enzyme-linked immunosorbent assay kits. Nasal symptoms were assessed using the TNSS. A receiver operating characteristic (ROC) curve was used to test the diagnostic ability of the study parameters. RESULTS: The AR case group had a higher serum expression of miR-142-5p, miR-155-5p, and IL-4 than did the control group. However, there were no significant differences in the serum miR-18a-5p and miR-3687 expression levels between the two groups. We found that serum miR-142-5p and miR-155-5p levels were positively correlated with the expression of specific IgE (Artemisia). TNSS did not correlate with miR-142-5p or miR-155-5p levels. In addition, no significant correlation was identified between miR-142-5p and IL-4 expression, whereas miR-155-5p was positively correlated with IL-4 expression. The receiver operating characteristic curve did not look promising. The AUC was around 0.7 and it was not high enough for diagnostic tool. CONCLUSION: The expression levels of serum miR-142-5p and miR-155-5p were upregulated in children with AR; however, they were insufficient as diagnostic tools for AR. MiR-155-5p may be involved in T helper type 2 cell-mediated immune response.
Assuntos
MicroRNAs , Rinite Alérgica , Humanos , Criança , Interleucina-4 , Estudos de Casos e Controles , MicroRNAs/genética , Rinite Alérgica/diagnóstico , Rinite Alérgica/genética , Imunoglobulina ERESUMO
The distribution characteristics of Methylenetetrahydrofolate Reductase (MTHFR) gene C677 T polymorphism and its influence on early morning blood pressure in elderly female patients with H-type hypertension are investigated. A total of 220 elderly female patients with hypertension who received diagnosis and treatment in our hospital from March to September 2021 are selected. All patients received serum index detection in our hospital and are grouped according to blood homocysteine (Hcy) level. Patients with Hcy>10 µmol/L are classified as H-type hypertension and included in H-type hypertension group (n = 166). Patients with Hcy≤10 µmol/L are included in the non-H-type hypertension group (n = 54). Both groups underwent 24-hour ambulatory blood pressure monitoring. Base frequency and allele distribution of MTHFR gene C677 T locus are compared between the two groups, and the relationship between different bases of MTHFR gene C677 T locus and morning blood pressure and Hcy level is analyzed. The risk factors of morning hypertension in patients with H-type hypertension are analyzed by binary logistic regression. Binary logistic regression analysis shows that smoking history, drinking history, high-salt diet, MTHFR gene C677 T genotype, and abnormal 24 h systolic blood pressure are the risk factors for the occurrence of morning hypertension in H-type hypertension patients. The frequency of TT homozygous mutation at the C677 T site of the MTHFR gene is high in patients with H-type hypertension, and the mutation of the C677 T site of the MTHFR gene had an effect on systolic blood pressure and Hcy level.
Assuntos
Hipertensão , Metilenotetra-Hidrofolato Redutase (NADPH2) , Humanos , Feminino , Idoso , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pressão Sanguínea/genética , Monitorização Ambulatorial da Pressão Arterial , Polimorfismo Genético , Hipertensão/genética , Homocisteína/genéticaRESUMO
BACKGROUND AND AIMS: Novel pro- and anti-inflammatory adipocytokines affect inflammation, energy metabolism, and insulin signaling. However, their role in acute coronary syndrome (ACS) development is unclear. We evaluated the diagnostic and risk predictive value of such adipocytokines for ACS. METHODS: We enrolled 168 consecutive inpatients with suspected ACS and detected serum PLIN1, PLIN2, PLIN5, CTRP6, CTRP7, CTRP11, WISP1, FAM19A5, TNF-α, and adiponectin levels. Multivariate logistic regression analysis and Spearman's test were used to assess risk factors for ACS and correlations between serum adipocytokines and continuous variables, respectively. RESULTS: Serum levels of the adipocytokines differed between ACS and Non-ACS groups (p < 0.05). After adjusting for confounding factors, serum PLIN1, PLIN2, PLIN5, CTRP6, CTRP7, CTRP11, WISP1, and FAM19A5 levels were independently associated with ACS (p < 0.05). Increasing tertiles of serum PLIN1, PLIN2, CTRP7, CTRP11, and WISP1 levels increased the ACS risk, which decreased gradually with increasing PLIN5 and CTRP6 tertiles (p for trend <0.05). Serum PLIN1, PLIN5, CTRP6, CTRP7, CTRP11, WISP1, and FAM19A5 levels correlated with ACS severity. CONCLUSIONS: PLIN1, PLIN2, CTRP7, CTRP11, and WISP1 were identified as independent ACS risk factors, whereas PLIN5, CTRP6, and FAM19A5 were independent protective factors for ACS. These serum adipocytokines are novel potential clinical biomarkers of ACS.
Assuntos
Síndrome Coronariana Aguda , Insulinas , Adipocinas , Adiponectina , Anti-Inflamatórios , Biomarcadores , Humanos , Fator de Necrose Tumoral alfaRESUMO
Background: The C1q/TNF-related protein (CTRP) family affects inflammation regulation, energy metabolism, and insulin signaling. However, their role in acute coronary syndrome (ACS) development is unclear. In this cross-sectional study, we aimed to investigate the association between CTRP family and ACS. Methods: We enrolled 289 consecutive inpatients with suspected ACS. Serum CTRP family, tumor necrosis factor-α (TNF-α), and adiponectin (ADP) levels were assessed using enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression and subgroup analyses were used to assess risk factors for ACS. Spearman's tests were used to analyze correlations between CTRP family and continuous variables. Results: Serum CTRP family levels differed significantly between ACS and Control groups (p < 0.05). After adjusting for confounding factors, CTRP family were independently associated with ACS (p < 0.05). The association between serum CTRP family levels and ACS was stable in various subgroups according to sex, age, diabetes mellitus, and dyslipidemia status (p for interaction > 0.05). Increasing tertiles of serum CTRP1 levels, significantly increased ACS risks, which decreased gradually with increasing CTRP2, CTRP12, and CTRP13 tertiles (p for trend < 0.05). Additionally, serum CTRP1, CTRP2, CTRP13, and CTRP15 levels were weakly correlated with the severity of coronary artery stenosis. Conclusion: CTRP1 and CTRP5 were identified as independent ACS risk factors, whereas CTRP2, CTRP3, CTRP9, CTRP12, CTRP13, and CTRP15 were independent protective factors for ACS. CTRP family, especially CTRP1 and CTRP3 could be novel potential clinical biomarkers of ACS.
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OBJECTIVE: The current diagnostic methods for multiple myeloma (MM) include bone marrow aspiration and biopsy, which are not only complicated but also invasive, causing great pain to patients. Micro ribonucleotides (miRNA) exist stably in circulating plasma and could be easily detected, making them promising specific diagnostic markers for MM. METHODS: The expression of plasma miR-448 in MM patients was detected by real-time quantitative PCR analysis. Spearman correlation was used to analyze correlations between miR-448 expression and various clinic pathological characteristics of MM patients. The ROC and the AUC (95% confidence interval) were exploited to evaluate the potential of miR-448 acting as a diagnostic marker for MM patients. RESULTS AND DISCUSSION: In this study, we found that the expression level of miR-448 in patients with MM was significantly higher than that in normal people and showed statistically differential expression in different stages of MM. Besides, we observed that the abundance of miR-448 in the plasma of newly diagnosed MM patients was positively correlated with the proportion of plasma cells (PC) in the bone marrow and the concentration of serum M protein (MP), respectively. In addition, ROC analysis demonstrated the sensitivity and specificity of the diagnostic value of miR-448 for MM are 92.90% and 87.50%, respectively. CONCLUSION: Taken together, these results indicated that miR-448 may serve as a potential molecular diagnostic marker for MM.
Assuntos
MicroRNAs , Mieloma Múltiplo , Biomarcadores Tumorais , Humanos , MicroRNAs/genética , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Curva ROC , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Methods: Cells were divided into 5 groups-control, high-fat, 10 nmol/L LR + 0.6 mmol/L palmitic acid (PA) (10LR), 100 nmol/L LR + 0.6 mmol/L PA (100LR), and 1000 nmol/L LR + 0.6 mmol/L PA (1000LR). CCK-8 method to detect cell viability, GPO-PAP enzymatic method to detect intracellular triglyceride content, and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting methods to detect fatty acid translocase CD36 (FAT/CD36) and fatty acid binding protein 4 (FABP4) in L6 cells, glucose-regulated protein 78 (GRP78), glucose transporter 4 (GLUT4) expression at the mRNA and protein levels, respectively, were performed. Results: We found that after PA intervention for 24 h, the cell viability decreased significantly; the cell viability of the LR group was higher than that of the high-fat group (P < 0.01). After PA intervention, compared with those in the high-fat group, GRP-78, FAT/CD36, FABP4 mRNA ((4.36 ± 0.32 vs. 8.15 ± 0.35); (1.00 ± 0.04 vs. 2.46 ± 0.08); (2.88 ± 0.55 vs. 8.29 ± 0.52), P < 0.01) and protein ((3338.13 ± 333.15 vs. 4963.98 ± 277.29); (1978.85 ± 124.24 vs. 2676.07 ± 100.64); (3372.00 ± 219.84 vs. 6083.20 ± 284.70), both P < 0.01) expression decreased in the LR group. The expression levels of GLUT4 mRNA ((0.75 ± 0.04 vs. 0.34 ± 0.03), P < 0.01) and protein ((3443.71 ± 191.89 vs. 2137.79 ± 118.75), P < 0.01) increased. Conclusion: Therefore, we conclude that LR can reverse PA-induced cell inactivation and lipid deposition, which may be related to the change in GRP-78, FAT/CD36, FABP4, GLUT4, and other factors.
Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1 , Ácido Palmítico , Ácido Palmítico/farmacologia , Ácido Palmítico/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Proteínas/metabolismo , Antígenos CD36/metabolismo , RNA Mensageiro/genética , Mioblastos/metabolismoRESUMO
Multiple myeloma (MM) is a malignant disease of plasma cells with complex pathology, causing significant morbidity due to its end-organ destruction. The outcomes of patients with myeloma have significantly improved in the past couple of decades with the introduction of novel agents, such as proteasome inhibitors, immunomodulators, and monoclonal antibodies. However, MM remains incurable and presents considerable individual heterogeneity. MicroRNAs (miRNAs) are short, endogenous noncoding RNAs of 19-22 nucleotides that regulate gene expression at the posttranscriptional level. Numerous studies have shown that miRNA deregulation is closely related to MM pathology, including tumor initiation, progression, metastasis, prognosis, and drug response, which make the complicated miRNA network an attractive and marvelous area of investigation for novel anti-MM therapeutic approaches. Herein, we mainly summarized the current knowledge on the roles of miRNAs, which are of great significance in regulating pathological factors involved in MM progressions, such as bone marrow microenvironment, methylation, immune regulation, genomic instability, and drug resistance. Meanwhile, their potential as novel prognostic biomarkers and therapeutic targets was also discussed.
Assuntos
MicroRNAs/genética , Mieloma Múltiplo/genética , Humanos , Mieloma Múltiplo/patologiaRESUMO
BACKGROUND: This study aimed to investigate the correlations of long non-coding RNA maternally expressed gene 3 (lnc-MEG3), microRNA (miR)-21, and lnc-MEG3/miR-21 axis with disease risk, inflammation, disease severity, and 28-day mortality of sepsis. METHODS: Totally, 219 sepsis patients and 219 health controls (HCs) were enrolled. Plasma samples were obtained from sepsis patients within 24 hours after admission and from HCs on enrollment to detect lnc-MEG3 and miR-21 expressions by real-time quantitative polymerase chain reaction. RESULTS: The lnc-MEG3 expression and lnc-MEG3/miR-21 axis were increased, while miR-21 expression was decreased in sepsis patients compared with HCs. Lnc-MEG3 (area under the curve (AUC): 0.887, 95% confidence interval (CI): 0.856-0.917) and lnc-MEG3/miR-21 axis (AUC: 0.934, 95% CI: 0.909-0.958) had good values for predicting elevated sepsis risk, while miR-21 (AUC: 0.801, 95% CI: 0.758-0.844) presented a good predictive value for reduced sepsis risk. Furthermore, lnc-MEG3 expression and lnc-MEG3/miR-21 axis positively correlated with, whereas miR-21 expression negatively correlated with acute pathologic and chronic health evaluation II, sequential organ failure assessment score, serum creatinine, C-reactive protein, tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-17 in sepsis patients. Additionally, lnc-MEG3 (AUC: 0.704, 95% CI: 0.626-0.783) and lnc-MEG3/miR-21 axis (AUC: 0.669, 95% CI: 0.589-0.750) exhibited acceptable values in predicting higher 28-day mortality risk, while miR-21 (AUC: 0.588, 95% CI: 0.505-0.672) presented a poor predictive value for lower 28-day mortality risk in sepsis patients. CONCLUSION: Lnc-MEG3 might serve as a potential biomarker for the development, progression, and prognosis prediction of sepsis via interacting with miR-21.
Assuntos
MicroRNAs/genética , RNA Longo não Codificante/genética , Sepse/genética , Sepse/mortalidade , Síndrome de Resposta Inflamatória Sistêmica/genética , APACHE , Idoso , Biomarcadores/metabolismo , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Prognóstico , Fatores de Risco , Sepse/etiologia , Sepse/terapia , Síndrome de Resposta Inflamatória Sistêmica/etiologiaRESUMO
BACKGROUND: This study aimed to investigate the value of microRNA (miR)-21 for predicting sepsis risk and its correlation with inflammation, disease severity as well as 28-day mortality in sepsis patients. METHODS: Totally, 219 sepsis patients and 219 healthy controls (HCs) were recruited. Plasma samples were obtained from sepsis patients within 24 hours after admission and from HCs at the enrollment to detect miR-21 expressions by real-time quantitative polymerase chain reaction. Besides, the clinical characteristics of sepsis patients were recorded and the 28-day mortality of sepsis patients was evaluated. RESULTS: MiR-21 expression was decreased in sepsis patients compared with HCs, and further receiver operating characteristic (ROC) curve analysis revealed that miR-21 was of a good value in predicting sepsis risk (area under the curve [AUC]: 0.801, 95% CI: 0.758-0.844). Besides, miR-21 expression was negatively associated with acute pathologic and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA) score in sepsis patients. Furthermore, miR-21 expression was negatively correlated with serum creatinine, C-reactive protein, tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-17, while positively correlated with albumin in sepsis patients. However, there was no correlation of miR-21 expression with white blood cell, smoke, or comorbidities in sepsis patients. Additionally, ROC curve analysis displayed that miR-21 exhibited a poor predictive value for 28-day mortality risk in sepsis patients (AUC: 0.588, 95% CI: 0.505-0.672). CONCLUSION: MiR-21 might serve as a potential biomarker for the development and progression of sepsis, while not for prognosis prediction in sepsis patients.
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Inflamação/genética , MicroRNAs/genética , Sepse/genética , Sepse/mortalidade , Índice de Gravidade de Doença , APACHE , Comorbidade , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Valor Preditivo dos Testes , Fatores de Risco , Fumar/efeitos adversosRESUMO
BACKGROUND: This study was conducted to investigate the treatment efficacies and immunological mechanisms of action of dioscin in mice with chicken collagen type II-induced arthritis (CIA). METHODS: The CIA mice was randomly divided into the model group (M), dioscin group (D), and tripterygium group (T); a normal control group (C) was also included. Each group was orally administered with related drugs or an equal volume of solvent (group C) starting on the 21st day of primary immunity, after which the levels of T helper 17 cells (Th17), regulatory T cells (Tregs), and their related factors were detected on the 35th day. RESULTS: Compared to group C, group M exhibited significantly increased levels of interleukin 17 (IL-17) and IL-6 and decreased IL-27 (p < 0.05). Group D exhibited significantly decreased levels of IL-17 and IL-6 compared with group M (p < 0.05). Group M showed a significantly increased ratio of Th17 cells (p < 0.05), while dioscin significantly reduced this ratio (p < 0.05). Groups M and C showed no significant difference in the ratio of Tregs (p > 0.05) but dioscin significantly increased this ratio (p < 0.05). Group M significantly increased signal transducer and activator of transcription 3 (STAT3) and STAT5 compared with that in group C (p < 0.05), while the T and D groups showed significantly reduced levels of STAT3 and STAT5 (p < 0.05). CONCLUSION: Dioscin may affect the differentiation of Th17 and Tregs and secretion of related factors by regulating CD4 T cell subset-related signal transduction and the expression of transcription-activating factor STAT3 and STAT5, thus exerting useful immunoregulatory roles in CIA mice.
Assuntos
Artrite Experimental/tratamento farmacológico , Diosgenina/análogos & derivados , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Artrite Experimental/imunologia , Galinhas , Colágeno Tipo II , Diosgenina/farmacologia , Interleucina-17/sangue , Interleucina-6/sangue , Interleucinas/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Fator de Transcrição STAT3/análise , Fator de Transcrição STAT5/análise , Linfócitos T Reguladores/imunologia , Células Th17/imunologiaRESUMO
The aim of the current study was to investigate the regulatory effect of sericin on the hepatic insulin-phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in a type 2 diabetes rat model. Male Sprague Dawley rats were randomly divided into four groups: Control group, diabetic model group, high-dose sericin group and low-dose sericin group, with 12 rats in each group. Fasting blood glucose was detected by the glucose oxidase method, and hepatic glycogen was determined by periodic acid-Schiff staining. The morphology of the liver was observed by hematoxylin and eosin staining. Immunohistochemical staining, western blotting and reverse transcription-quantitative polymerase chain reaction were used to determine the protein and mRNA expression levels of insulin receptor (IR), IR substrate-1 (IRS-1), PI3K and AKT. Compared with the control group, the blood glucose of the diabetic model group was significantly increased (P<0.05). The glycogen content and the expression levels of IR, IRS-1, PI3K and AKT in the diabetic model group were significantly lower (P<0.05), and the liver morphological structure of the diabetic model group exhibited obvious pathological changes compared with the control group. Compared with the diabetic model group, the blood glucose of the high- and low-dose sericin groups was significantly reduced, while the glycogen content and the expression levels of IR, IRS-1, PI3K and AKT in the sericin treatment groups were significantly increased (P<0.05). Additionally, the liver pathological changes of high-dose and low-dose sericin groups were markedly reduced. Sericin may enhance the signaling transduction effect of insulin by upregulating the expression levels of key factors (IR, IRS-1, PI3K and AKT) in the liver insulin-PI3K/AKT signaling pathway, thus promoting glucose transport and liver glycogen synthesis, and further reducing blood glucose.
RESUMO
The aim of this study was to detect the therapeutic effect of dioscin on collagen-induced arthritis (CIA). Mice model of CIA was induced by chicken collagen II and arthritis index was assessed. After suspension of dioscin (100mg/kg/d) or triptolide was intragastrically administered, the left paw swelling and body weight of each mouse were measured. Then tissue samples were assayed by histopathological analysis. The levels of Th1 and Th2 were detected by flow cytometry. The expression of p-STAT1, p-STAT4 and p-STAT6 was demonstrated by western blot analysis, and T-bet and GATA-3 expression was detected by RT-PCR. The paw swelling and arthritis index were decreased and body weight was increased in the high dose of dioscin group compared to the model group (P<0.05). Histopathological analysis revealed that the damage of synovium tissue in dioscin and triptolide group alleviated. The ratio of Th1/Th2 in the dioscin group (0.82±0.24) and triptolide group (0.99±0.44) was lower than that in the model group (1.84±0.70, P<0.05). Additionally, p-STAT4 expression was decreased, and both p-STAT6 and GATA3 expression was increased in the dioscin group than that in the model group (P<0.05). Dioscin might have some therapeutic effects on CIA through regulating the proportion of Th1/Th2 cells, which could reduce the expression of p-STAT4, increase the expression of p-STAT6 and GATA3 in the synovial tissue.
Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Dioscorea/imunologia , Diosgenina/análogos & derivados , Membrana Sinovial/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Animais , Colágeno Tipo II/imunologia , Diosgenina/uso terapêutico , Modelos Animais de Doenças , Diterpenos/uso terapêutico , Compostos de Epóxi/uso terapêutico , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos DBA , Fenantrenos/uso terapêutico , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Membrana Sinovial/patologia , Células Th1/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Células Th2/imunologiaRESUMO
BACKGROUND: This study aimed to determine the effects of total saponins from Rhizoma Dioscoreae Nipponicae (TS-RDN) on the expression of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2 and Tie-2 (endothelial tyrosine kinase receptor) receptors in the synovium of rats with rheumatoid arthritis (RA) (collagen-induced arthritis; CIA), and to examine the mechanisms of TS-RDN in alleviating RA. METHODS: The CIA rat model was established and the animals were randomly divided into control, CIA model, TS-RDN, diosgenin, and tripterygium groups. Fluorescent polymerase chain reaction was performed to detect VEGF expression in the rat knee joint synovium. Additionally, immunohistochemical assay was used to detect protein expression of Ang-2 and Tie-2 in the rat knee joint synovium. RESULTS: Expression of VEGF, Ang-2, and Tie-2 in the model group was significantly higher than in the control group (p < 0.01). After TS-RDN, tripterygium and diosgenin treatment, VEGF and Ang-2 expression was lower than in the model group (p < 0.01). However, Tie-2 expression showed no significant difference. The effects of TS-RDN on VEGF expression were more marked than those of tripterygium and diosgenin (p < 0.01). CONCLUSION: TS-RDN might reduce the expression of VEGF, Ang-2, and Tie-2 in the synovium, thus inhibiting synovial angiogenesis and playing a therapeutic role in RA.