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1.
Nat Commun ; 14(1): 4394, 2023 07 20.
Article in English | MEDLINE | ID: mdl-37474626

ABSTRACT

The incidence of rheumatoid arthritis (RA) is increasing with age. DNA fragments is known to accumulate in certain autoimmune diseases, but the mechanistic relationship among ageing, DNA fragments and RA pathogenesis remain unexplored. Here we show that the accumulation of DNA fragments, increasing with age and regulated by the exonuclease TREX1, promotes abnormal activation of the immune system in an adjuvant-induced arthritis (AIA) rat model. Local overexpression of TREX1 suppresses synovial inflammation in rats, while conditional genomic deletion of TREX1 in AIA rats result in higher levels of circulating free (cf) DNA and hence abnormal immune activation, leading to more severe symptoms. The dysregulation of the heterodimeric transcription factor AP-1, formed by c-Jun and c-Fos, appear to regulate both TREX1 expression and SASP induction. Thus, our results confirm that DNA fragments are inflammatory mediators, and TREX1, downstream of AP-1, may serve as regulator of cellular immunity in health and in RA.


Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Humans , Rats , Animals , Proto-Oncogene Proteins c-fos/genetics , Inflammation , Transcription Factor AP-1/metabolism
2.
Front Biosci (Landmark Ed) ; 26(6): 125-134, 2021 05 30.
Article in English | MEDLINE | ID: mdl-34162041

ABSTRACT

This study aimed to investigate the effects of advanced glycation end products (AGEs) on the calcification of human arterial smooth muscle cells (HASMCs) and to explore whether AGEs can promote the calcification of HASMCs by activating the phosphoinositide 3-kinase (PI3K)/AKT-glycogen synthase kinase 3 beta (GSK3-ß) axis. Cultured HASMCs were divided into five groups: blank control group, dimethyl sulfoxide (vehicle) group, AGEs group, LY294002 (AKT inhibitor) group, and TWS119 (GSK3-ß inhibitor) group. Cells were pretreated with either vehicle, LY294002, or TWS119 for 2 hours followed by incubation with AGEs (25 µg/mL) for 5 days, and the expression levels of proteins in each group were analyzed by western blotting. AGE treatment promoted HASMC calcification, which coincided with increased expression of p-AKT and p-GSK3-ß (serine 9). Also, AGEs upregulated the expression of osteoprotegerin and bone morphogenetic protein, and these effects were suppressed by LY294002 but enhanced by TWS119. In conclusion, AGEs promote calcification of HASMCs, and this effect is ameliorated by inhibition of AKT activity but potentiated by inhibition of GSK3-ß activity. Hence, AGEs trigger HASMC calcification by regulating PI3K/AKT-GSK3-ß signaling.


Subject(s)
Arteries/pathology , Calcinosis/physiopathology , Glycation End Products, Advanced/physiology , Glycogen Synthase Kinase 3 beta/metabolism , Muscle, Smooth, Vascular/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/physiology , Cells, Cultured , Humans
3.
Am J Transl Res ; 8(11): 4644-4656, 2016.
Article in English | MEDLINE | ID: mdl-27904668

ABSTRACT

OBJECTIVE: The present study aims to investigate whether RAGE promotes the calcification of human arterial smooth muscle cells (HASMCs) and determine the relationshipbetween RAGE and the Wnt/ß-catenin signaling pathway in this process. METHOD: In this study,there were four groups, namelythe blank control group, the non-transfection group, the empty vector group, and the RAGE transfection group.Cells were co-cultured with 10 mmol/L ß-glycerophosphoric acid, pyruvate and 20 mg/L AGE. The expression of osteogenic proteins in each group before and after the intervention wasdetected using Western blotting. Short interfering RNA (siRNA) targeting ß-catenin was used toinhibitthe expression of ß-catenin. HASMCs cultured under normal conditions were usedas the blank control. RESULTS: (1) High RAGE expression was successfully induced in HASMCs according to the results of GFP detection, flow cytometry and Western blotting. (2) Compared with the blank control group, non-transfection group and empty vector group, RAGE transfection enhanced the calcification of cells when incubated with calcification medium plus AGE. (3) The expression of RAGE, ß-catenin, OPG and Cbfa1 proteins in the blank control group, empty vector group and RAGE transfection group wasnot significantly enhanced after intervention. However, expression of the proteins in the RAGE transfection group was much higher than those of the other groups. (4) Compared with the RAGE transfection group and control siRNA group, the cells transfected with ß-catenin siRNA and cultured with interventional drugs showed significant inhibition of the expression of the downstream Cbfa1 and OPG genes. CONCLUSION: Increased expression of RAGE promoted calcification in HASMCs and up regulated the ß-catenin, OPG and Cbfa1 genes. RAGE may activate the downstream genes via the Wntß-catenin pathway, thereby promoting HASMC differentiation into osteogenic cells and calcification.

4.
Int J Clin Exp Med ; 8(11): 19969-81, 2015.
Article in English | MEDLINE | ID: mdl-26884909

ABSTRACT

OBJECTIVE: To investigate whether high glucose in vitro activating TNFR1 and further promote rat marrow endothelial progenitor cells (EPCs) apoptosis. METHODS: Rat morrow endothelial progenitor cells were cultured and identified by Confocal Microscopy; then were treated with high glucose (5.5, 15, 30, 60 mmol/L), mannitol (15, 30, 60, 90 mmol/L), high glucose + Tempol and high glucose+ MAB430. Apoptosis rate of the above cells were detected by flow cytometry. ROS and MDA level and anti-O2- were detected by colorimetric technique; the expression level of TNFR1 induced signal pathway related proteins were detected by Western blotting. RESULTS: High glucose can induce endothelial progenitor cells apoptosis, which is mostly in the later stage (72 h-96 h) instead of the earlier stage (24 h-48 h); high glucose can also induce oxidative stress reaction and the produces ROS and MDA increase significantly in the later stage (after 72 h), but anti-O2- decrease significantly. TNF apoptosis signal pathway related protein expression level not increase in the earlier stage (before 24 h) but increase significantly in the later stage (after 72 h). Tempol and MAB430 down-regulate TNF apoptosis signal pathway related protein expression and reduce EPCs apoptosis. CONCLUSION: High glucose activates the TNFR1 of TPCs through oxidative stress reaction and further induces cell apoptosis.

5.
PLoS One ; 9(8): e105131, 2014.
Article in English | MEDLINE | ID: mdl-25116125

ABSTRACT

All-trans retinoic acid (ATRA) is a revolutionary agent for acute promyelocytic leukemia (APL) treatment via differentiation induction. However, ATRA treatment also increases cytokine, chemokine, and adhesive molecule (mainly ICAM-1) expression, which can cause clinical complications, including a severe situation known as differentiation syndrome (DS) which can cause death. Therefore, it is of clinical significance to find a strategy to specifically blunt inflammatory effects while preserving differentiation. Here we report that the natural compound, celastrol, could effectively block lung infiltrations in DS animal models created by loading ATRA-induced APL cell line NB4. In ATRA-treated NB4 cells, celastrol could potently inhibit ICAM-1 elevation and partially reduce TNF-α and IL-1ß secretion, though treatment showed no effects on IL-8 and MCP-1 levels. Celastrol's effect on ICAM-1 in ATRA-treated NB4 was related to reducing MEK1/ERK1 activation. Strikingly and encouragingly, celastrol showed no obvious effects on ATRA-induced NB4 differentiation, as determined by morphology, enzymes, and surface markers. Our results show that celastrol is a promising and unique agent for managing the side effects of ATRA application on APL, and suggest that hyper-inflammatory ability is accompanied by, but not necessary for, APL differentiation. Thus we offered an encouraging novel strategy to further improve differentiation therapy.


Subject(s)
Cell Differentiation/drug effects , Leukemia, Promyelocytic, Acute/drug therapy , Lung/drug effects , Tretinoin/adverse effects , Triterpenes/pharmacology , Animals , Cell Line, Tumor , Humans , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Leukemia, Promyelocytic, Acute/metabolism , Leukemia, Promyelocytic, Acute/pathology , Lung/metabolism , Lung/pathology , MAP Kinase Signaling System/drug effects , Male , Mice , Mice, Inbred NOD , Mice, SCID , Pentacyclic Triterpenes , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Syndrome , Tretinoin/therapeutic use , Tumor Necrosis Factor-alpha/metabolism
6.
Zhonghua Zhong Liu Za Zhi ; 33(11): 816-21, 2011 Nov.
Article in Chinese | MEDLINE | ID: mdl-22335945

ABSTRACT

OBJECTIVE: To explore the feasibility of IGF2 imprinting system in target gene therapy for tumors. METHODS: The mouse H19 enhancer, DMD and promoter H19 were amplified by PCR from mouse genomic DNA and then cloned into the plasmid pDC312. The EGFP and DT-A fragments were amplified by PCR and cloned into the recombinant plasmid, and then the shuttle plasmid were transfected into HEK293 cells together with the adenoviral vector Ad5, namely, Ad-EGFP and Ad-DT-A. Adenovirus hexon gene expression was applied to confirm the presence of adenovirus infections. The effect of the IGF2 imprinting system was tested by fluorescence microscopy. RT-PCR and Western blotting after transfection of the recombinant adenoviral vectors into cancer cells were used to show loss of IGF2 imprinting (LOI) and maintenance of IGF2 imprinting (MOI), respectively. The anti-tumor effect was assessed by MTT and flow cytometry after the HCT-8 (LOI). Human breast cancer cell line MCF-7 (MOI) and human normal gastric epithelial GES-1 (MOI) cell line were transfected with Ad-DT-A in vitro. The anti-tumor effect was detected by injecting the Ad-DT-A in nude mice carrying HCT-8 tumors. RESULTS: The expression of EGFP protein, DT-A mRNA and DT-A protein were seen to be positive only in the HCT-8 tumor cell line. Infection with Ad-DT-A resulted in obviously growth inhibition in HCT-8 cells (75.4 ± 6.4)% compared with that in the control group, and increased the percentage of apoptosis in the HCT-8 cells (20.8 ± 5.9)%. The anti-tumor effect was further confirmed by injecting the recombinant adenoviruses in HCT-8 tumor-bearing nude mice, and the results showed that the Ad-DT-A inhibited the tumor growth, with on inhibition rate of 36.4%. CONCLUSIONS: The recombinant adenoviruses carrying IGF2 imprinting system and DT-A gene have been successfully constructed, while Ad-DT-A can effectively kill the tumor cells showing loss of IGF2 imprinting. It might play an important role in future target gene therapy against malignant tumors based on loss of IGF2 imprinting.


Subject(s)
Apoptosis , Colonic Neoplasms/pathology , Diphtheria Toxin/biosynthesis , Genomic Imprinting , Insulin-Like Growth Factor II/genetics , Peptide Fragments/biosynthesis , Adenoviridae/genetics , Animals , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Colonic Neoplasms/genetics , Colonic Neoplasms/therapy , Diphtheria Toxin/genetics , Female , Genetic Therapy/methods , Genetic Vectors , Green Fluorescent Proteins/biosynthesis , Green Fluorescent Proteins/genetics , Humans , Insulin-Like Growth Factor II/metabolism , MCF-7 Cells , Mice , Mice, Nude , Neoplasm Transplantation , Peptide Fragments/genetics , Plasmids , RNA, Messenger/metabolism , Random Allocation , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/genetics , Transfection
7.
Article in Chinese | MEDLINE | ID: mdl-21166216

ABSTRACT

AIM: To investigate the preventive effects of Panax notoginseng saponins (PNS) and Ginkgo biloba extracts (GbE) on acute oxygen toxicity and the possible mechanisms. METHODS: Mice were injected intraperitoneally with PNS and GbE for 5 days, then were exposed to 500 kPa hyperbaric oxygen (HBO) for 60 min, the convulsion latency, times and interval were observed. Moreover, reactive oxygen (RO) unit, MDA, NO, GSH levels and GSH-Px, CAT, MAO activities of mice brain were determined after they were exposed to HBO for 15 min. RESULTS: PNS and GbE could markedly prolong the convulsion latency and interval, reduce convulsion times, decrease contents of MDA and NO in mice brain, keep RO unit, GSH and GSH-Px at higher levels, but had no effects on CAT and MAO activities. CONCLUSION: PNS and GbE could effectively prevent acute oxygen toxicity, which were related to their antioxidant activities.


Subject(s)
Ginkgo biloba , Oxygen/poisoning , Panax notoginseng , Plant Extracts/pharmacology , Saponins/pharmacology , Animals , Antioxidants/pharmacology , Diving/adverse effects , Hyperbaric Oxygenation/adverse effects , Male , Mice , Phytotherapy
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