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This study investigates the specific mechanisms of Huaier-induced mitochondrial apoptosis in colorectal cancer. HCT116 and SW480 cells were subjected to Huaier treatment. Cell proliferation and migration capabilities were examined through CCK-8 and scratch experiments, respectively. Apoptotic cells were clarified with Annexin-PE staining. DCFH-DA staining, malondialdehyde(MDA), and glutathione(GSH) were used to evaluate the oxidative stress damage level of cells. MitoSOX and JC-1 probes were used to selectively target mitochondria reactive oxygen species(mtROS) and mitochondria membrane potential(MMP) for the evaluation of mitochondria damage. Western blot(WB) experiment was performed to determine apoptosis proteins and PINK1/Parkin pathway. Experiments reveal that in different concentrations of Huaier treatment, the proliferation and migration capabilities of HCT116 and SW480 cells were both restrained. Additionally, mitochondrial apoptosis was activated. Compared with the control group, excessive ROS in colorectal cancer cells was generated in the Huaier group, while MDA increased, and GSH decreased, indicating oxidative stress damage. mtROS increased, and MMP decreased in colorectal cancer cells treated with Huaier, indicating mitochondrial damage. WB result revealed that Huaier suppressed the PINK1/Parkin pathway, hindered the clearance of impaired mitochondria, and subsequently facilitated apoptosis. In conclusion, Huaier impairs colorectal cancer cells through oxidative stress and mitochondria damage. Furthermore, it suppressed the PINK1/Parkin pathway, promoting mitochondria apoptosis in colorectal cancer cells.
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Apoptosis , Proliferación Celular , Neoplasias Colorrectales , Mitocondrias , Estrés Oxidativo , Especies Reactivas de Oxígeno , Humanos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/fisiopatología , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Medicamentos Herbarios Chinos/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Movimiento Celular/efectos de los fármacosRESUMEN
Allostery is a fundamental way to regulate the function of biomolecules playing crucial roles in cell metabolism and proliferation and is deemed the second secret of life. Given the limited understanding of the structure of natural allosteric molecules, the development of artificial allosteric molecules brings a huge opportunity to transform the allosteric mechanism into practical applications. In this study, the concept of bionics is introduced into the design of artificial allosteric molecules and an allosteric DNA switch with an activity site and an allosteric site based on two aptamers for selective inhibition of thrombin activity. Compared with the single aptamer, the allosteric switch possesses a significantly enhanced inhibition ability, which can be precisely regulated by converting the switch states. Moreover, the dynamic allosteric switch is further subjected to the control of the DNA threshold circuit for realizing automatic concentration determination and activity inhibition of thrombin. These compelling results confirm that this allosteric switch equipped with self-sensing and information-processing modules puts a new slant on the research of allosteric mechanisms and further application of allosteric tactics in chemical and biomedical fields.
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Aptámeros de Nucleótidos , Trombina , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/farmacología , Aptámeros de Nucleótidos/metabolismo , Regulación Alostérica , Trombina/metabolismo , Trombina/química , ADN/metabolismo , ADN/química , Sitio Alostérico , HumanosRESUMEN
The silent information regulator T1 (SIRT1) is linked to longevity and is a crucial mediator of osteoblast function. We investigated the direct role of Sirt1 during bone modeling and remodeling stages in vivo using Tamoxifen-inducible osteoblast-specific Sirt1 conditional knockout (cKO) mice. cKO mice exhibited lower trabecular and cortical bone mass in the distal femur. These phenotypes were coupled with lower bone formation and bone resorption. Metabolomics analysis revealed that the metabolites involved in glycolysis were significantly decreased in cKO mice. Further analysis of the quantitative acetylome revealed 11 proteins with upregulated acetylation levels in both the femur and calvaria of cKO mice. Cross-analysis identified four proteins with the same upregulated lysine acetylation site in both the femur and calvaria of cKO mice. A combined analysis of the metabolome and acetylome, as well as immunoprecipitation, gene knockout, and site-mutation experiments, revealed that Sirt1 deletion inhibited glycolysis by directly binding to and increasing the acetylation level of Glutamine oxaloacetic transaminase 1 (GOT1). In conclusion, our study suggested that Sirt1 played a crucial role in regulating osteoblast metabolism to maintain bone homeostasis through its deacetylase activity on GOT1. These findings provided a novel insight into the potential targeting of osteoblast metabolism for the treatment of bone-related diseases.
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Glucólisis , Homeostasis , Ratones Noqueados , Osteoblastos , Sirtuina 1 , Animales , Ratones , Acetilación , Huesos/metabolismo , Fémur/metabolismo , Osteoblastos/metabolismo , Osteogénesis , Sirtuina 1/metabolismo , Sirtuina 1/genéticaRESUMEN
Exosomal miRNAs are considered promising biomarkers for cancer diagnosis, but their accuracy is severely compromised by the low content of miRNAs and the large amount of exosomal miRNAs released from normal cells. Here, we presented a dual-specific miRNA's logical recognition triggered by an entropy-driven catalysis (EDC)-enhanced system in exosomes for accurate detection of liver cancer-cell-derived exosomal miR-21 and miR-122. Taking advantage of the accurate analytical performance of the logic device, the excellent membrane penetration of gold nanoparticles, and the outstanding amplification ability of the EDC reaction, this method exhibits high sensitivity and selectivity for the detection of tumor-derived exosomal miRNAs in situ. Moreover, due to its excellent performance, this logic device can effectively distinguish liver cancer patients from healthy donors by determining the amount of cancer-cell-derived exosomal miRNAs. Overall, this strategy has great potential for analyzing various types of exosomes and provides a viable tool to improve the accuracy of cancer diagnosis.
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Exosomas , Neoplasias Hepáticas , Nanopartículas del Metal , MicroARNs , Humanos , MicroARNs/genética , Oro , Entropía , Exosomas/genética , ADN , Neoplasias Hepáticas/diagnóstico , LógicaRESUMEN
Keratin 80 (KRT80) is a filament protein that participates in cell differentiation and the integrity of the epithelial barrier. Here, KRT80 expression was higher in gastric cancer compared with normal mucosa at both mRNA and protein levels by bioinformatic analysis, qRT-PCR and Western blot (p<0.05), however, the methylation of KRT80 was lower than in normal mucosa (p<0.05). There was a negative relationship between promoter methylation and expression level of KRT80 gene in gastric cancer (p<0.05). KRT80 mRNA and protein expression was positively correlated with the differentiation of gastric cancer (p<0.05), while KRT80 methylation was negatively associated with gastric cancer differentiation and p53 mutation (p<0.05). The expression of KRT80 mRNA was positively linked to the short survival time of gastric cancers (p<0.05). The differential genes of KRT80 mRNA were involved in ligand-receptor interaction, estrogen signal pathway, peptidase, filament and cytoskeleton, keratinocyte differentiation, vitamin D receptor, muscle contraction, and B cell-mediated immunity (p<0.05). KRT80-related genes were classified into cell adhesion and junction, cadherin binding, skin and epidermis development, and so forth (p<0.05). KRT80 knockdown suppressed proliferation, anti-apoptosis, anti-pyroptosis, migration, invasion and epithelial-mesenchymal transition in gastric cancer cells (p<0.05). These findings indicated that up-regulated expression of KRT80 played a crucial part in gastric carcinogenesis, and might be considered as a biological marker for aggressive behaviors and poor prognosis. Its silencing might be used as an approach of target therapy for gastric cancer patients.
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Neoplasias Gástricas , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Pronóstico , ARN Mensajero/metabolismo , Neoplasias Gástricas/metabolismoRESUMEN
Background Belonging to the G-protein coupled receptor 1 family, G protein-coupled receptor 176 (GPR176) is associated with the Gz/Gx G-protein subclass and is capable of decreasing cAMP production. Methods GPR176 expression was detected by qRT-PCR, bioinformatics analysis, Western blot and immunohistochemistry, and compared with clinicopathological characteristics of breast cancer. GPR176-related genes and pathways were subjected to bioinformatic analysis. We also explored the effects of GPR176 on the phenotypes of breast cancer cells. Results Lower expression of GPR176 mRNA was seen in breast cancer than in normal tissues, but the opposite pattern was found for its protein (p < 0.05). GPR176 mRNA was associated with female sex, low T staging, non-Her-2+ subtypes, non-mutant p53 status in breast cancer (p < 0.05). GPR176 methylation was negatively correlated with its mRNA level and T staging in breast cancer, and was higher in breast cancer than normal tissues (p < 0.05). GPR176 protein expression was positively correlated with older age, small tumor size, and non-luminal-B subtype of breast cancers (p < 0.05). The differential genes of GPR176 were involved in receptor-ligand interaction, RNA maturation, and so forth (p < 0.05). GPR176-related genes were categorized into cell mobility, membrane structure, and so on (p < 0.05). GPR176 knockdown weakened the proliferation, glucose catabolism, anti-apoptosis, anti-pyroptosis, migration, invasion, and epithelial-mesenchymal transition of breast cancer cells. Conclusion These results indicate that GPR176 might be involved in the tumorigenesis and subsequent progression of breast cancer by deteriorating aggressive phenotypes. It might be utilized as a potential biomarker to indicate the aggressive behaviors and poor prognosis of breast cancer and a potential target of genetic therapy (AU)
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Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Terapia Genética , Regulación Neoplásica de la Expresión Génica , ARN Mensajero/genética , Biomarcadores de Tumor , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Pronóstico , FenotipoRESUMEN
BACKGROUND: Regenerating gene 4 (REG4) has been proved to be carcinogenic in some cancers, but its manifestation and possible carcinogenic mechanisms in colorectal cancer (CRC) have not yet been elucidated. Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism. AIM: To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance. METHODS: We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC. The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells. We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells. Finally, we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells. RESULTS: Compared to normal mucosa, REG4 mRNA expression was high in CRC (P < 0.05) but protein expression was low. An inverse correlation existed between lymph node and distant metastases, tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression (P < 0.05), but vice versa for REG4 protein expression. REG4-related genes included: Chemokine activity; taste receptors; protein-DNA and DNA packing complexes; nucleosomes and chromatin; generation of second messenger molecules; programmed cell death signals; epigenetic regulation and DNA methylation; transcription repression and activation by DNA binding; insulin signaling pathway; sugar metabolism and transfer; and neurotransmitter receptors (P < 0.05). REG4 exposure or overexpression promoted proliferation, antiapoptosis, migration, and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway. REG4 was involved in chemoresistance not through de novo lipogenesis, but lipid droplet assembly. REG4 inhibited the transcription of acetyl-CoA carboxylase 1 (ACC1) and ATP-citrate lyase (ACLY) by disassociating the complex formation of anti-acetyl (AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY. CONCLUSION: REG4 may be involved in chemoresistance through lipid droplet assembly. REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.
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Neoplasias Colorrectales , Resistencia a Antineoplásicos , Gotas Lipídicas , Proteínas Asociadas a Pancreatitis , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , ADN , Resistencia a Antineoplásicos/genética , Epigénesis Genética , Histonas , Fosfatidilinositol 3-Quinasas , Proteínas Asociadas a Pancreatitis/genéticaRESUMEN
JC polyoma virus (JCPyV), a ubiquitous polyoma virus that commonly infects people, is identified as the etiologic factor for progressive multifocal leukoencephalopathy and has been closely linked to various human cancers. Transgenic mice of CAG-loxp-Laz-loxp T antigen were established. T-antigen expression was specifically activated in gastroenterological target cells with a LacZ deletion using a cre-loxp system. Gastric poorly-differentiated carcinoma was observed in T antigen-activated mice using K19-cre (stem-like cells) and PGC-cre (chief cells), but not Atp4b-cre (parietal cells) or Capn8-cre (pit cells) mice. Spontaneous hepatocellular and colorectal cancers developed in Alb-cre (hepatocytes)/T antigen and villin-cre (intestinal cells)/T antigen transgenic mice respectively. Gastric, colorectal, and breast cancers were observed in PGC-cre/T antigen mice. Pancreatic insulinoma and ductal adenocarcinoma, gastric adenoma, and duodenal cancer were detected in Pdx1-cre/T antigen mice. Alternative splicing of T antigen mRNA occurred in all target organs of these transgenic mice. Our findings suggest that JCPyV T antigen might contribute to gastroenterological carcinogenesis with respect to cell specificity. Such spontaneous tumor models provide good tools for investigating the oncogenic roles of T antigen in cancers of the digestive system.
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Poliomavirus , Neoplasias Gástricas , Ratones , Humanos , Animales , Antígenos Virales de Tumores/genética , Ratones Transgénicos , Células Epiteliales/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Belonging to the G-protein coupled receptor 1 family, G protein-coupled receptor 176 (GPR176) is associated with the Gz/Gx G-protein subclass and is capable of decreasing cAMP production. METHODS: GPR176 expression was detected by qRT-PCR, bioinformatics analysis, Western blot and immunohistochemistry, and compared with clinicopathological characteristics of breast cancer. GPR176-related genes and pathways were subjected to bioinformatic analysis. We also explored the effects of GPR176 on the phenotypes of breast cancer cells. RESULTS: Lower expression of GPR176 mRNA was seen in breast cancer than in normal tissues, but the opposite pattern was found for its protein (p < 0.05). GPR176 mRNA was associated with female sex, low T staging, non-Her-2+ subtypes, non-mutant p53 status in breast cancer (p < 0.05). GPR176 methylation was negatively correlated with its mRNA level and T staging in breast cancer, and was higher in breast cancer than normal tissues (p < 0.05). GPR176 protein expression was positively correlated with older age, small tumor size, and non-luminal-B subtype of breast cancers (p < 0.05). The differential genes of GPR176 were involved in receptor-ligand interaction, RNA maturation, and so forth (p < 0.05). GPR176-related genes were categorized into cell mobility, membrane structure, and so on (p < 0.05). GPR176 knockdown weakened the proliferation, glucose catabolism, anti-apoptosis, anti-pyroptosis, migration, invasion, and epithelial-mesenchymal transition of breast cancer cells. CONCLUSION: These results indicate that GPR176 might be involved in the tumorigenesis and subsequent progression of breast cancer by deteriorating aggressive phenotypes. It might be utilized as a potential biomarker to indicate the aggressive behaviors and poor prognosis of breast cancer and a potential target of genetic therapy.
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Terapia Genética , Neoplasias , Femenino , Animales , Biomarcadores , Movimiento Celular/genética , Fenotipo , ARN Mensajero/genética , Regulación Neoplásica de la Expresión Génica , Proliferación Celular , Línea Celular Tumoral , Pronóstico , Neoplasias/genéticaRESUMEN
Insulin resistance (IR) is one of the leading causes of Type 2 diabetes mellitus (T2DM). Inflammation, as a result of the disordered immune response, plays important roles in IR and T2DM. Interleukin-4-induced gene 1 (IL4I1) has been shown to regulate immune response and be involved in inflammation progress. However, there was little known about its roles in T2DM. Here, high glucose (HG)-treated HepG2 cells were used for T2DM investigation in vitro. Our results indicated that the expression of IL4I1 was up-regulated in peripheral blood samples of T2DM-patients and HG-induced HepG2 cells. The silencing of IL4I1 alleviated the HG-evoked IR through elevating the expressions of p-IRS1, p-AKT and GLUT4, and enhancing glucose consumption. Furthermore, IL4I1 knockdown inhibited inflammatory response by reducing the levels of inflammatory mediators, and suppressed the accumulation of lipid metabolites triglyceride (TG) and palmitate (PA) in HG-induced cells. Notably, IL4I1 expression was positively correlated with aryl hydrocarbon receptor (AHR) in peripheral blood samples of T2DM-patients. The silencing of IL4I1 inhibited the AHR signaling by reducing the HG-induced expressions of AHR and CYP1A1. Subsequent experiments confirmed that 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an agonist of AHR, reversed the suppressive effects of IL4I1 knockdown on HG-caused inflammation, lipid metabolism and IR in cells. In conclusion, we found that the silencing of IL4I1 attenuated inflammation, lipid metabolism and IR in HG-induced cells via inhibiting AHR signaling, suggesting that IL4I1 might be a potential therapy target for T2DM.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Resistencia a la Insulina/fisiología , Células Hep G2 , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/toxicidad , Glucosa/metabolismo , Inflamación/genética , L-Aminoácido OxidasaRESUMEN
Liver cirrhosis is currently the twelfth leading cause of death globally and the sixth leading cause of death in China. Its treatment is expensive. Changes in the composition of the serum bile acid pool are sensitive indicators of the severity of liver cirrhosis. In this study, a novel LC-tandem mass spectrometry (LC-MS/MS) method was developed and used to simultaneously determine 15 bile acids in human serum in patients with decompensated cirrhosis. Sample preparation involved spiking with isotope internal standards followed by protein precipitation. The analytical run time was 5 min. The LC-MS/MS method was fully validated according to Clinical and Laboratory Standards Institute (CLSI) C62A and the consensus of method development and validation of liquid chromatography-tandem mass spectrometry in clinical laboratories. The method achieved an acceptable coefficient of variation for precision (0.83%-14.80%) and accuracy (89.39%-107.62%). Finally, as proof of applicability, the method was applied to patients with decompensated cirrhosis in routine clinical sample analysis. The degree of variation of different bile acids was clearly shown. These results indicated that abnormal metabolic pathways might play important roles in decompensated cirrhosis.
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Ácidos y Sales Biliares , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/métodos , Cromatografía Liquida/métodos , Estándares de Referencia , Reproducibilidad de los ResultadosRESUMEN
Bone mass declines with age and its maintenance is tightly linked to osteoblasts (crucial bone-building cells). Although disruption of the peripheral circadian clock is involved in various pathologies including aging-related diseases, evidence regarding how the peripheral clock regulates bone mass remains elusive. In the present study, we aimed to elucidate the effects of Bmal1 (the key activator of the peripheral circadian clock system) knockdown by lentivirus-mediated shRNA on osteoblast differentiation and its related mechanisms. We found that the expression of osteogenic markers, alkaline phosphatase activity, and mineralization were decreased, whereas apoptosis and inflammatory response were increased in Bmal1 knockdown osteoblasts. In addition, Bmal1 knockdown promoted ERK and JNK phosphorylation, as well as mTOR activity, whereas mTOR inhibition by rapamycin abrogated Bmal1 knockdown-mediated effects on osteoblast differentiation and mineralization capacity. Remarkably, Bmal1 knockdown in osteoblasts inhibited GSK3ß/ß-catenin signaling with decreased ß-catenin expression and GSK-3ß phosphorylation at serine 9, while GSK3ß inhibition with TDZD-8, but not WNT3a or SKL2001, rescued Bmal1 knockdown-induced defects in osteoblast differentiation. Moreover, rapamycin partly nullified the suppression of Bmal1 knockdown on ß-catenin expression and GSK-3ß phosphorylation. Collectively, overall data indicated that circadian gene Bmal1 regulated osteoblast differentiation and inflammatory response in an mTOR/GSK3ß/ß-catenin-dependent manner, and thereby may contribute to the mineralization process and bone modeling/remodeling.
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Factores de Transcripción ARNTL , beta Catenina , Glucógeno Sintasa Quinasa 3 beta/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Factores de Transcripción ARNTL/farmacología , Diferenciación Celular , Osteogénesis/genética , Osteoblastos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Sirolimus/farmacología , Vía de Señalización WntRESUMEN
Chlorophenols (CPs) are widespread pollutants in nature. CPs have raised significant concern due to their potential hepatotoxic effects on humans. This research aimed to ascertain the inhibitory potential of eleven CPs (2-CP, 3-CP, 4-CP, 2,4-DCP, 2,3,4-TCP, 2,4,5-TCP, 2,4,6-TCP, 2,3,4,5-TeCP, 2,3,4,6-TeCP, 2,3,5,6-TeCP, and PCP) on nine human CYP isoforms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4). The CPs that inhibit the activity of CYP isoforms were detected with human liver microsomes (HLM) using a cocktail approach in vitro. The results demonstrated that trichlorophenols, tetrachlorophenols, and PCP strongly inhibited CYP2C8 and CYP2C9. The half inhibition concentration (IC50) value of 2,3,4,6-TeCP and PCP for CYP2C8 inhibition was 27.3 µM and 12.3 µM, respectively. The IC50 for the inhibition of 2,4,6-TCP, 2,3,4,6-TeCP and PCP towards CYP2C9 were calculated to be 30.3 µM, 5.8 µM and 2.2 µM, respectively. 2,3,4,6-TeCP, and PCP exhibited non-competitive inhibition towards CYP2C8. 2,4,6-TCP, 2,3,4,6-TeCP, and PCP exhibited competitive inhibition towards CYP2C9. The inhibition kinetics parameters (Ki) were 51.51 µM, 22.28 µM, 37.86 µM, 7.27 µM, 0.68 µM for 2,3,4,6-TeCP-CYP2C8, PCP-CYP2C8, 2,4,6-TCP-CYP2C9, 2,3,4,6-TeCP-CYP2C9, PCP-CYP2C9, respectively. This study also defined clear structure-activity relationships (SAR) of CPs on CYP2C8, supported by molecular docking studies. Overall, CPs were found to cause inhibitory effects on CYP isoforms in vitro, and this finding may provide a basis for CPs focused on CYP isoforms inhibition endpoints.
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Clorofenoles , Inhibidores Enzimáticos del Citocromo P-450 , Humanos , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9/farmacología , Simulación del Acoplamiento Molecular , Inhibidores Enzimáticos del Citocromo P-450/toxicidad , Sistema Enzimático del Citocromo P-450 , Microsomas Hepáticos , Clorofenoles/toxicidadRESUMEN
Introduction: This study aimed to explore relationships between long-chain saturated fatty acids (LSFAs) and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes (T2D); and whether insulin action had an interactive effect with LSFAs on NAFLD progression. Methods: From April 2018 to April 2019, we extracted the electronic medical records of 481 patients with T2D who meet the inclusion and exclusion criteria from the Second Affiliated Hospital of Dalian Medical University. Ultrasound was used to estimate NAFLD at admission. Logistic regression analysis were used to estimate odds ratios (OR) and 95% confidence intervals (CI). The additive interaction was carried out to estimate interactions between LSFAs and insulin resistance (IR) in NAFLD patients with T2D. Results: Myristic acid (14:0) and palmitic acid (16:0) were positively associated with the risk of NAFLD (OR for myristic acid (14:0): 7.516, 3.557-15.882 and OR for palmitic acid (16:0): 4.071, 1.987-8.343, respectively). After adjustment for traditional risk factors, these associations were slightly attenuated but still highly significant. Co-presence of myristic acid (14:0)>72.83 µmol/L and IR>4.89 greatly increased OR of NAFLD to 9.691 (4.113-22.833). Similarly, co-presence of palmitic acid (16:0)>3745.43µmol/L and IR>4.89 greatly increased OR of NAFLD to 6.518(2.860-14.854). However, stearic acid (18:0) and risk of NAFLD have no association. Moreover, there was no association between very-long-chain SFAs (VLSFAs) and risk of NAFLD. Discussion: Myristic acid (14:0) and palmitic acid (16:0) were positively associated with the risk of NAFLD in T2D patients in China. High IR amplified the effect of high myristic acid (14:0) and high palmitic acid (16:0) on NAFLD.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Pueblos del Este de Asia , Ácidos Grasos , Ácido Palmítico , Ácidos MirísticosRESUMEN
Taking advantage of the remarkable processivity and membrane penetrability, the gold nanoparticle (AuNP)-based three-dimensional (3D) DNA walking nanomachine has induced tremendous promise in molecular diagnostics and cancer therapy, whereas the executive ability of this nanomachine was eventually limited because of the disordered assembly between the walker and the track. Therefore, we developed a well-directed 3D DNA walking nanomachine by employing a DNA dendrimer as the track for intracellular imaging with high directionality and controllability. The nanomachine was constructed on a DNA dendrimer decorated with a substrate strand serving as the DNA track and a DNAzyme restrained by a locking strand as the walker. In this system, the distribution of the substrate strand and DNAzyme on the DNA dendrimer could be precisely regulated to achieve expected goals because of the specificity and predictability of the Watson-Crick base pairing, paving an explicit route for each walker to move along the track. Moreover, such a DNA dendrimer-based nanomachine owned prominent stability and anti-interference ability. By choosing microRNA-21 as a model analyte, the nanomachine was applied for the imaging of microRNA-21 in different cell lines and the monitoring of the dynamic microRNA-21 expression level in cancer cells. Therefore, we believe that this directed DNA walking nanomachine will have a variety of applications in molecular diagnostics and biological function modulation.
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Técnicas Biosensibles , ADN Catalítico , Nanopartículas del Metal , MicroARNs , Oro/química , MicroARNs/genética , MicroARNs/metabolismo , Nanopartículas del Metal/química , Técnicas Biosensibles/métodos , ADN/química , ADN Catalítico/química , Límite de DetecciónRESUMEN
All-trans retinoic acid (ATRA) exerts tumor-inhibitory effects on acute leukemia and certain types of solid tumors. This study was designed to evaluate the mechanism on ATRA-mediated suppression of colon cancer based on the sonic hedgehog (Shh) signaling pathway. METHODS: Normal intestinal epithelial cells and three colon cancer cell lines were studied to evaluate the inhibitory effect of ATRA on tumor cell activity. The inhibitory effect of ATRA on colon cancer was evaluated by cell invasion, migration, and apoptosis of HCT116 cells. Retinoic acid receptor (RAR)- and Shh-related protein expression was assessed. RESULTS: ATRA administration inhibited the activity of three different colon cancer lines, but did not inhibit the activity of normal intestinal epithelial cells. Administration of ATRA induced apoptosis and restricted invasion and migration of HCT116 colon cancer cells. Administration of ATRA also increased expression of RAR and transmembrane receptor patched 1 (Ptch1), and decreased expression of the smoothened (Smo) and glioma-associated oncogene homolog1 (Gli-1). RARα and RARß agonists inhibited Shh signaling, and the mediating effect of ATRA on Shh signaling was abolished by RARα or RARß antagonists. The combination of purmorphamine (Smo agonist) and ATRA partially abolished the inhibitory effect of ATRA on the proliferation of colon cancer cells. In vivo studies showed that ATRA inhibited tumor growth, which was accompanied by down-regulation of the Shh signaling pathway. CONCLUSIONS: ATRA inhibits the growth of colon cancer by downregulating the Shh pathway, which further verifies the anticancer activity of ATRA.
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We aimed to analyze the computed tomography (CT) imaging signs of bowel wall ischemia in patients with acute intestinal obstruction and construct an imaging prediction model to guide clinical treatment. The CT imaging signs of patients with acute intestinal obstruction diagnosed in our center in recent 6 years were collected for retrospective analysis. The etiology of intestinal obstruction and incidence rate of bowel wall ischemia were recorded, and the specific CT findings of bowel wall ischemia, including mesenteric edema, bowel wall thickening, and fish tooth sign, were analyzed. Among the 302 patients selected, 130 surgically treated patients were eligible for analysis. Bowel wall ischemia in acute intestinal obstruction showed an incidence rate of 14.90%, and the incidence rates of bowel wall ischemia in intra-abdominal hernia, intussusception, incarcerated external abdominal hernia, and volvulus were about 92.30%, 50%, 35.71%, 33.33%, and 12.59%, respectively. The incidence rate of bowel wall ischemia in simple adhesive intestinal obstruction was about 12.59%, and that in malignancy-induced intestinal obstruction was about 6.56%. Univariate analysis revealed 5 factors with statistical significance, including bowel wall thickening, mesenteric edema, bowel wall pneumatosis, ascites, and fish tooth sign. Multivariate logistic regression analysis indicated that fish tooth sign, bowel wall thickening, and mesenteric edema were able to predict bowel wall ischemia, and the corresponding partial regression coefficients were 2.164, 1.129, and 1.173, odds ratios (ORs) were 8.707, 3.093, and 3.232, sensitivity was 0.356, 0.400, and 0.844, and specificity was 0.859, 0.835, and 0.529, respectively. Imaging signs of bowel wall thickening, mesenteric edema, and fish tooth sign are valuable in predicting bowel wall ischemia, among which bowel wall thickening and mesenteric edema have relatively high specificity and fish tooth sign has a relatively high sensitivity. Furthermore, a fish tooth sign has the most favorable predictive value for bowel wall ischemia in acute intestinal obstruction, followed by bowel wall thickening and mesenteric edema.
Asunto(s)
Obstrucción Intestinal , Enfermedad Aguda , Humanos , Obstrucción Intestinal/complicaciones , Obstrucción Intestinal/diagnóstico por imagen , Obstrucción Intestinal/cirugía , Intestinos/cirugía , Isquemia , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodosRESUMEN
The dysfunction of chondrocytes is thought to play a role in the initiation and progression of osteoarthritis (OA). Brucine possesses wide pharmacological activities. But the protective mechanism of the brucine on chondrocytes remains unclear. This study is aimed to determine the therapeutic effects of brucine on the mouse chondrocyte OA model by sodium nitroprusside (SNP). The primary chondrocytes were obtained from the knee articular cartilage of a healthy suckling mouse donor. The cultured chondrocytes were divided into the control group, SNP group, brucine group, brucine-SNP group, brucine-SNP-GSK-3ß antagonist group (brucine-SNP- group), and brucine-SNP-GSK-3ß agonist group (brucine-SNP-GSK-3ß+ group). After 24â¯h, the chondrocytes from different treated groups were collected to detect chondrocyte proliferation and ultrastructure, regulation factors, apoptosis, oxidative stress, and GSK-3ß/ß-catenin pathway. Compared to the SNP group, chondrocyte proliferation, and regulation factors were promoted, and chondrocyte apoptosis, oxidative stress, and the GSK-3ß/ß-catenin pathway were inhibited by brucine. It indicates that the adverse effect of SNP is reversed by the brucine on the chondrocyte. Compared to the brucine-SNP group, the effect of brucine on the chondrocyte proliferation, regulation factothe apoptosis, and oxidative stress were promoted by the GSK-3ß antagonist. It indicates that the chondrocyte is protected agairucine through buying the GSK-3ß/ß-catenin pathway.
RESUMEN
OBJECTIVE: Mesenchymal stem cells-derived extracellular vesicles (MSCs-EVs) can improve intervertebral disc degeneration (IDD). Considering that, their concrete mechanisms from microRNA-194-5p/tumor receptor-associated factor 6 (miR-194-5p/TRAF6) axis in IDD ask for disclosure in a scientific way. METHODS: Nucleus pulposus (NP) cells and MSCs were obtained. EVs were isolated from the obtained MSCs and identified. miR-194-5p expression in MSC-EVs was altered by sequence transfection. Subsequently, MSCs-EVs were co-cultured with NP cells intervened by tumor necrosis factor α (TNF-α). NP cell proliferation and apoptosis, along with their osteogenic differentiation ability were evaluated. miR-194-5p and TRAF6 expression and their interaction were determined. RESULTS: In TNF-α-intervened NP cells, miR-194-5p was down-regulated and TRAF6 was up-regulated. Restoring miR-194-5p effectively enhanced proliferation and osteogenic differentiation, and reduced apoptosis of TNF-α-intervened NP cells. miR-194-5p-enriched MSCs-EVs protected TNF-α-intervened NP cells. miR-194-5p targeted TRAF6, TRAF6 overexpression exerted negatively for the growth of TNF-α-intervened NP cells, and could reduce the protective effects of miR-194-5p on TNF-α-intervened NP cells. CONCLUSION: It is elucidated that miR-194-5p derived from MSCs-EVs protects TNF-α-intervened NP cells through restricting TRAF6, replenishing a potential target for IDD treatment.