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1.
Acta Pharmacol Sin ; 41(1): 47-55, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31607752

RESUMO

T cell metabolic activation plays a crucial role in inflammation of atherosclerosis. Shikonin (SKN), a natural naphthoquinone with anti-inflammatory activity, has shown to exert cardioprotective effects, but the effect of SKN on atherosclerosis is unclear. In addition, SKN was found to inhibit glycolysis via targeting pyruvate kinase muscle isozyme 2 (PKM2). In the present study, we investigated the effects of SKN on hyperhomocysteinemia (HHcy)-accelerated atherosclerosis and T cell inflammatory activation in ApoE-/- mice and the metabolic mechanisms in this process. Drinking water supplemented with Hcy (1.8 g/L) was administered to ApoE-/- mice for 2 weeks and the mice were injected with SKN (1.2 mg/kg, i.p.) or vehicle every 3 days. We showed that SKN treatment markedly attenuated HHcy-accelerated atherosclerosis in ApoE-/- mice and significantly decreased inflammatory activated CD4+ T cells and proinflammatory macrophages in plaques. In splenic CD4+ T cells isolated from HHcy-ApoE-/- mice, SKN treatment significantly inhibited HHcy-stimulated PKM2 activity, interferon-γ secretion and the capacity of these T cells to promote macrophage proinflammatory polarization. SKN treatment significantly inhibited HHcy-stimulated CD4+ T cell glycolysis and oxidative phosphorylation. Metabolic profiling analysis of CD4+ T cells revealed that Hcy administration significantly increased various glucose metabolites as well as lipids and acetyl-CoA carboxylase 1, which were reversed by SKN treatment. In conclusion, our results suggest that SKN is effective to ameliorate atherosclerosis in HHcy-ApoE-/- mice and this is at least partly associated with the inhibition of SKN on CD4+ T cell inflammatory activation via PKM2-dependent metabolic suppression.

2.
Cardiovasc Res ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31782769

RESUMO

AIMS: Overactivated B cells secrete pathological antibodies, which in turn accelerate the formation of abdominal aortic aneurysms (AAAs). Hyperhomocysteinemia (HHcy) aggravates AAA in mice; however, the underlying mechanisms remain largely elusive. In this study, we further investigated whether homocysteine (Hcy)-activated B cells produce antigen-specific antibodies that ultimately contribute to AAA formation. METHODS AND RESULTS: ELISA assays showed that HHcy induced the secretion of anti-beta 2 glycoprotein I (anti-ß2GPI) antibody from B cells both in vitro and in vivo. Mechanistically, Hcy increased the accumulation of various lipid metabolites in B cells tested by LC-MS/MS, which contributed to elevated anti-ß2GPI IgG secretion. By using the Toll-like receptor 4 (TLR4)-specific inhibitor TAK-242 or TLR4-deficient macrophages, we found that culture supernatants from Hcy-activated B cells and HHcy plasma IgG polarized inflammatory macrophages in a TLR4-dependent manner. In addition, HHcy markedly increased the incidence of elastase- and CaPO4-induced AAA in male BALB/c mice, which was prevented in µMT mice. To further determine the importance of IgG in HHcy-aggravated AAA formation, we purified plasma IgG from HHcy or control mice and then transferred the IgG into µMT mice, which were subsequently subjected to elastase- or CaPO4-induced AAA. Compared with µMT mice that received plasma IgG from control mice, µMT mice that received HHcy plasma IgG developed significantly exacerbated elastase- or CaPO4-induced AAA accompanied by increased elastin degradation, MMP2/9 expression, and anti-ß2GPI IgG deposition in vascular lesions, as shown by immunofluorescence histochemical staining. CONCLUSION: Our findings reveal a novel mechanism by which Hcy-induced B cell-derived pathogenic anti-ß2GPI IgG might, at least in part, contribute to HHcy-aggravated chronic vascular inflammation and AAA formation. TRANSLATIONAL PERSPECTIVE: HHcy is an independent risk factor for cardiovascular diseases in which B cell secretion of IgG antibodies play a key role. However, whether the antigen specific antibody production is changed during HHcy-accelerated AAA remains unclear. Our results provided the first evidence supporting the important role of activated B cell-derived anti-ß2GPI IgG in HHcy-aggravated chronic vascular inflammation and AAA formation. It sheds new light on understanding pathogenesis of HHcy-accelerated AAA. In addition, anti-ß2GPI IgG may be a potential diagnostic marker and therapeutic target for HHcy-related vascular injury.

3.
FASEB J ; 33(11): 12780-12799, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31480861

RESUMO

Intercellular communication between lymphocytes plays a fundamental role in numerous immune responses. Previously, we demonstrated that hyperhomocysteinemia (HHcy) induced T cell intracellular glycolytic-lipogenic reprogramming and IFN-γ secretion via pyruvate kinase muscle isozyme 2 (PKM2) to accelerate atherosclerosis. Usually, B cells partially obtain help from T cells in antibody responses. However, whether PKM2 activation in T cells regulates B cell antibody production is unknown. Extracellular vesicles (EVs) are important cellular communication vehicles. Here, we found that PKM2 activator TEPP46-stimulated T-cell-derived EVs promoted B-cell IgG secretion. Conversely, EVs secreted from PKM2-null T cells were internalized into B cells and markedly inhibited B-cell mitochondrial programming, activation, and IgG production. Mechanistically, lipidomics analyses showed that increased ceramides in PKM2-activated T-cell EVs were mainly responsible for enhanced B cell IgG secretion induced by these EVs. Finally, quantum dots (QDs) were packaged with PKM2-null T cell EVs and anti-CD19 antibody to exert B-cell targeting and inhibit IgG production, eventually ameliorating HHcy-accelerated atherosclerosis in vivo. Thus, PKM2-mediated EV ceramides in T cells may be an important cargo for T-cell-regulated B cell IgG production, and QD-CD19-PKM2-null T cell EVs hold high potential to treat B cell overactivation-related diseases.-Yang, J., Dang, G., Lü, S., Liu, H., Ma, X., Han, L., Deng, J., Miao, Y., Li, X., Shao, F., Jiang, C., Xu, Q., Wang, X., Feng, J. T-cell-derived extracellular vesicles regulate B-cell IgG production via pyruvate kinase muscle isozyme 2.

4.
Redox Biol ; 20: 46-59, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30292945

RESUMO

Endothelial dysfunction induced by hyperhomocysteinemia (HHcy) plays a critical role in vascular pathology. However, little is known about the role of endoplasmic reticulum (ER) redox homeostasis in HHcy-induced endothelial dysfunction. Here, we show that Hcy induces ER oxidoreductin-1α (Ero1α) expression with ER stress and inflammation in human umbilical vein endothelial cells and in the arteries of HHcy mice. Hcy upregulates Ero1α expression by promoting binding of hypoxia-inducible factor 1α to the ERO1A promoter. Notably, Hcy rather than other thiol agents markedly increases the GSH/GSSG ratio in the ER, therefore allosterically activating Ero1α to produce H2O2 and trigger ER oxidative stress. By contrast, the antioxidant pathway mediated by ER glutathione peroxidase 7 (GPx7) is downregulated in HHcy mice. Ero1α knockdown and GPx7 overexpression protect the endothelium from HHcy-induced ER oxidative stress and inflammation. Our work suggests that targeting ER redox homeostasis could be used as an intervention for HHcy-related vascular diseases.


Assuntos
Retículo Endoplasmático/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Homeostase , Homocisteína/metabolismo , Oxirredução , Animais , Humanos , Espécies Reativas de Oxigênio/metabolismo
5.
J Econ Entomol ; 111(6): 2884-2893, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30265342

RESUMO

The brown planthopper (BPH), Nilaparvata lugens Stål (Hemiptera: Delphacidae), is a serious rice pest because of its destructive feeding. The salivary glands of the BPH play a key role in successful feeding. In this study, we explored the salivary gland transcriptome (sialotranscriptome) of adult BPHs using Illumina sequencing and a total of 55,913 transcripts and 45,421 unigenes were obtained. We identified one reference gene RPL9 (Ribosomal protein L9) and 19 salivary protein genes from the BPH sialotranscripome, which were categorized as those involved in sugar metabolism, extra-oral digestion of cell wall components, detoxification, and suppression of plant defenses. Tissue expression profiles of 19 salivary protein genes analysis revealed that the expression level of alpha-glucosidase family 31 had no difference in five tissues, suggesting that it may have functions in the whole-body parts. Glucose dehydrogenase (flavine adenine dinucleotide, quinone)-like was expressed highly in the salivary gland, which might play putative role in insect feeding. Glucose dehydrogenase (acceptor) was expressed the highest level in head without salivary gland. Other salivary protein genes were highly expressed in gut or malpighian tubule, suggesting that they may play roles in digestive and detoxification mechanism. Moreover, we detected RPL9 is one of the genes that is most consistently present for acquisition of gene expression in different tissues. Thus, RPL9 can be a new reference for expression studies of BPH. The obtained BPH sialotranscripome provides a list of genes that have potential roles in feeding and interaction between BPHs and rice plants.


Assuntos
Hemípteros/metabolismo , Animais , Hemípteros/genética , Glândulas Salivares/metabolismo , Transcriptoma
6.
Redox Biol ; 17: 386-399, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29860106

RESUMO

The adaptive immune system plays a critical role in hyperhomocysteinemia (HHcy)-accelerated atherosclerosis. Recent studies suggest that HHcy aggravates atherosclerosis with elevated oxidative stress and reduced S-nitrosylation level of redox-sensitive protein residues in the vasculature. However, whether and how S-nitrosylation contributes to T-cell-driven atherosclerosis remain unclear. In the present study, we report that HHcy reduced the level of protein S-nitrosylation in T cells by inducing S-nitrosoglutathione reductase (GSNOR), the key denitrosylase that catalyzes S-nitrosoglutathione (GSNO), which is the main restored form of nitric oxide in vivo. Consequently, secretion of inflammatory cytokines [interferon-γ (IFN-γ) and interleukin-2] and proliferation of T cells were increased. GSNOR knockout or GSNO stimulation rectified HHcy-induced inflammatory cytokine secretion and T-cell proliferation. Site-directed mutagenesis of Akt at Cys224 revealed that S-nitrosylation at this site was pivotal for the reduced phosphorylation at Akt Ser473, which led to impaired Akt signaling. Furthermore, on HHcy challenge, as compared with GSNOR+/+ApoE-/- littermate controls, GSNOR-/-ApoE-/- double knockout mice showed reduced T-cell activation with concurrent reduction of atherosclerosis. Adoptive transfer of GSNOR-/- T cells to ApoE-/- mice fed homocysteine (Hcy) decreased atherosclerosis, with fewer infiltrated T cells and macrophages in plaques. In patients with HHcy and coronary artery disease, the level of plasma Hcy was positively correlated with Gsnor expression in peripheral blood mononuclear cells and IFN-γ+ T cells but inversely correlated with the S-nitrosylation level in T cells. These data reveal that T cells are activated, in part via GSNOR-dependent Akt denitrosylation during HHcy-induced atherosclerosis. Thus, suppression of GSNOR in T cells may reduce the risk of atherosclerosis.


Assuntos
Aldeído Oxirredutases/genética , Apolipoproteínas E/genética , Aterosclerose/genética , Hiper-Homocisteinemia/genética , Proteínas Proto-Oncogênicas c-akt/genética , Imunidade Adaptativa/genética , Idoso , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Feminino , Humanos , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Interferon gama/genética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Oxirredução , Estresse Oxidativo/genética , Fosforilação/genética , S-Nitrosoglutationa/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
7.
PLoS One ; 13(5): e0193831, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29727440

RESUMO

The white-backed planthopper, Sogatella furcifera, is a phloem sap feeder that secretes watery and gelling saliva during feeding. In this study, we identified the major proteins in watery saliva of S. furcifera by shotgun LC-MS/MS analysis combined with transcriptomic analysis. A total of 161 proteins were identified, which were divided into 8 function categories, including enzymes, transporter, calcium ion binding protein, salivary sheath protein, cytoskeleton protein, DNA-, RNA-, and protein-binding or regulating proteins, other non-enzyme proteins and unknown proteins. Gene expression pattern of 11 secretory proteins were analyzed by real time quantitative-PCR. We detected the mucin-like protein, which had a unique expression level in salivary gland, most likely to be a candidate effector involved in regulation of plant defense. This study identified the watery saliva component of S. furcifera and it provided a list of proteins which may play a role in interaction between S. furcifera and rice.


Assuntos
Hemípteros/metabolismo , Proteínas de Insetos/metabolismo , Proteoma/análise , Proteômica/métodos , Saliva/metabolismo , Animais , Espectrometria de Massas em Tandem
8.
J Mol Med (Berl) ; 96(6): 585-600, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29732501

RESUMO

Inflammation mediated by activated T cells plays an important role in the initiation and progression of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis in ApoE-/- mice. Homocysteine (Hcy) activates T cells to secrete proinflammatory cytokines, especially interferon (IFN)-γ; however, the precise mechanisms remain unclear. Metabolic reprogramming is critical for T cell inflammatory activation and effector functions. Our previous study demonstrated that Hcy regulates T cell mitochondrial reprogramming by enhancing endoplasmic reticulum (ER)-mitochondria coupling. In this study, we further explored the important role of glycolysis-mediated metabolic reprogramming in Hcy-activated CD4+ T cells. Mechanistically, Hcy-activated CD4+ T cell increased the protein expression and activity of pyruvate kinase muscle isozyme 2 (PKM2), the final rate-limiting enzyme in glycolysis, via the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin signaling pathway. Knockdown of PKM2 by small interfering RNA reduced Hcy-induced CD4+ T cell IFN-γ secretion. Furthermore, we generated T cell-specific PKM2 knockout mice by crossing LckCre transgenic mice with PKM2fl/fl mice and observed that Hcy-induced glycolysis and oxidative phosphorylation were both diminished in PKM2-deficient CD4+ T cells with reduced glucose and lipid metabolites, and subsequently reduced IFN-γ secretion. T cell-depleted apolipoprotein E-deficient (ApoE-/-) mice adoptively transferred with PKM2-deficient CD4+ T cells, compared to mice transferred with control cells, showed significantly decreased HHcy-accelerated early atherosclerotic lesion formation. In conclusion, this work indicates that the PKM2-dependent glycolytic-lipogenic axis, a novel mechanism of metabolic regulation, is crucial for HHcy-induced CD4+ T cell activation to accelerate early atherosclerosis in ApoE-/- mice. KEY MESSAGES: Metabolic reprogramming is crucial for Hcy-induced CD4+ T cell inflammatory activation. Hcy activates the glycolytic-lipogenic pathway in CD4+ T cells via PKM2. Targeting PKM2 attenuated HHcy-accelerated early atherosclerosis in ApoE-/- mice in vivo.


Assuntos
Aterosclerose/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Hiper-Homocisteinemia/metabolismo , Piruvato Quinase/metabolismo , Animais , Células Cultivadas , Feminino , Glicólise , Homocisteína/sangue , Lipídeos/sangue , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Piruvato Quinase/genética , RNA Interferente Pequeno/genética
9.
Biomed Res Int ; 2018: 4901591, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29670900

RESUMO

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by bone loss. Degree of inflammation has been identified as an important initiator of skeletal damage in RA. Iguratimod (T-614) is an anti-inflammatory agent which has been reported to show the inhibitory effect of bone destruction in RA. However, the role of T-614 in osteoblast differentiation is still not clear. In this study, we intended to find the effect of T-614 on the osteogenesis process. We detected osteogenesis markers and transcription factors associated with osteoblastic lineage and bone formation in the culture of mesenchymal stem cells which differentiate osteoblast. The contents and activity of alkaline phosphatase, levels of collagen type I and bone gla protein, and calcium nodule formation were increased significantly after T-614 treated. Meanwhile, the mRNAs expressions of Osterix and Dlx5 were also found to be increased significantly by real-time PCR. The changes of levels of phosphorylation of p38 and NF-κB were also detected by Western blot. The results showed that T-614 promotes osteoblastic differentiation by increasing the expression of Osterix and Dlx5 and increasing the activation of P38. T-614 could advance the ectopic expression of NF-κB to suppress inflammation, which indirectly inhibits the damage of the osteoblasts.


Assuntos
Benzopiranos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proteínas de Homeodomínio/metabolismo , NF-kappa B/metabolismo , Osteoblastos/efeitos dos fármacos , Sulfonamidas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Biomarcadores/metabolismo , Linhagem Celular , Colágeno Tipo I/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fator de Transcrição Sp7/metabolismo , Fatores de Transcrição/metabolismo
10.
Mediators Inflamm ; 2015: 356040, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26713003

RESUMO

OBJECTIVE: To expand upon the role of iguratimod (T-614) in the treatment of rheumatoid arthritis (RA), we investigated whether the Th1, Th17, follicular helper T cells (Tfh), and regulatory T cells (Treg) imbalance could be reversed by iguratimod and the clinical implications of this reversal. METHODS: In this trial, 74 patients were randomized into iguratimod-treated (group A) and control (broup B) group for a 24-week treatment period. In the subsequent 28 weeks, both groups were given iguratimod. Frequencies of Th1, Th17, Tfh, and Treg were quantified using flow cytometry, and serum cytokines were detected by enzyme-linked immunosorbent assay. mRNA expression of cytokines and transcriptional factor were quantified by RT-PCR. The composite Disease Activity Score, erythrocyte sedimentation rate, and C-reactive protein were assessed at each visit. RESULT: The clinical scores demonstrated effective suppression of disease after treatment with iguratimod. In addition, iguratimod downregulated Th1, Th17-type response and upregulated Treg. Furthermore, the levels of Th1, Th17, and Tfh associated inflammatory cytokines and transcription factors were reduced after treatment with iguratimod, while the levels of Treg associated cytokines and transcription factors were increased.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Cromonas/uso terapêutico , Citocinas/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Adulto , Artrite Reumatoide/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Linfócitos T Reguladores/efeitos dos fármacos
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