Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.282
Filtrar
1.
Int J Mol Sci ; 23(16)2022 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-36012366

RESUMO

Human microbiota produces metabolites that may enter the bloodstream and exert systemic influence on various functions including mitochondrial. Mitochondria are not only a target for microbial metabolites, but also themselves, due to the inhibition of several enzymes, produce metabolites involved in infectious processes and immune response. The influence of indolic acids, microbial derivatives of tryptophan, as well as itaconic acid, formed in the tricarboxylic acid cycle under the action of bacterial lipopolysaccharides, on the activity of mitochondrial enzymes was studied by methyl thiazolyl tetrazolium (MTT), dichlorophenolindophenol (DCPIP) and pyridine nucleotide fluorescence assays. Thus, it was found that indolic acids suppressed succinate and glutamate oxidation, shifting the redox potential of pyridine nucleotides to a more oxidized state. Itaconic acid, in addition to the well-known inhibition of succinate oxidation, also decreased NAD reduction in reactions with glutamate as a substrate. Unlike itaconic acid, indolic acids are not direct inhibitors of succinate dehydrogenase and glutamate dehydrogenase as their effects could be partially eliminated by the thiol antioxidant dithiothreitol (DTT) and the scavenger of lipid radicals butyl-hydroxytoluene (BHT). Alkalization turned out to be the most effective means to decrease the action of these metabolites, including itaconic acid, which is due to the protective influence on redox-dependent processes. Thus, among mitochondrial oxidative enzymes, the most accessible targets of these microbial-related metabolites are succinate dehydrogenase and glutamate dehydrogenase. These are important in the context of the shifting of metabolic pathways involved in bacterial inflammation and sepsis as well as the detection of new markers of these pathologies.


Assuntos
Glutamato Desidrogenase , Succinato Desidrogenase , Glutamato Desidrogenase/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Inflamação/metabolismo , Mitocôndrias/metabolismo , Oxirredução , Piridinas/metabolismo , Succinato Desidrogenase/metabolismo , Succinatos/metabolismo , Succinatos/farmacologia , Ácido Succínico/metabolismo
2.
Front Endocrinol (Lausanne) ; 13: 885879, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937818

RESUMO

Progressive bone loss during aging makes osteoporosis one of the most common and life impacting conditions in geriatric populations. The bone homeostasis is maintained through persistent remodeling mediated by bone-forming osteoblast and bone-resorbing osteoclast. Inflammaging, a condition characterized by increased pro-inflammatory markers in the blood and other tissues during aging, has been reported to be associated with skeletal stem/progenitor cell dysfunction, which will result in impaired bone formation. However, the role of age-related inflammation and metabolites in regulation of osteoclast remains largely unknown. In the present study, we observed dichotomous phenotypes of anti-inflammatory metabolite itaconate in responding to inflammaging. Itaconate is upregulated in macrophages during aging but has less reactivity in responding to RANKL stimulation in aged macrophages. We confirmed the inhibitory effect of itaconate in regulating osteoclast differentiation and activation, and further verified the rescue role of itaconate in lipopolysaccharides induced inflammatory bone loss animal model. Our findings revealed that itaconate is a crucial regulatory metabolite during inflammaging that inhibits osteoclast to maintain bone homeostasis.


Assuntos
Osteoclastos , Succinatos , Envelhecimento , Animais , Osteoblastos/fisiologia , Osteoclastos/metabolismo , Succinatos/metabolismo , Succinatos/farmacologia , Succinatos/uso terapêutico
3.
Plant Physiol Biochem ; 188: 12-20, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35963050

RESUMO

The large economic costs and environmental impacts of iron-chelate treatments has led to the search for alternative methods and compounds to control iron (Fe) deficiency chlorosis. Strawberry plants (Fragaria x ananassa) were grown in Hoagland's nutrient solution in a greenhouse with two levels of Fe: 0 and 10 µM Fe(III)-EDDHA. After 20 days, plants growing without Fe showed typical symptoms of Fe deficiency chlorosis in young leaves. Then, the adaxial and abaxial sides of one mature or one young leaf in each plant were brushed with 10 mM malic (MA), citric (CA) or succinic (SA) acids. Eight applications were done over a two-week period. At the end of the experiment, the newly emerged (therefore untreated), young and mature leaves were sampled for nutritional and metabolomic analysis, to assess the effectiveness of treatments. Leaf regreening was monitored using a SPAD-502 apparatus, and the activity of the ferric chelate-reductase activity (FCR) was measured using root tips. Iron deficiency negatively affected biomass and leaf chlorophyll but did not increase FCR activity. Application of succinic acid alleviated the decrease in chlorophyll observed in other treatments, and the overall nutritional balance in the plant was also changed. The concentrations of two quinic acid derivatives increased under Fe deficiency and decreased in plants treated with succinic acid, and thus they are proposed as Fe stress markers. Data suggest that foliage treatments with carboxylates may be, in some cases, environmentally friendly alternatives to Fe(III)-chelates. The importance of Fe mobilization pathways in the formulation of new fertilizers is also discussed.


Assuntos
Anemia Hipocrômica , Fragaria , Anemia Hipocrômica/metabolismo , Clorofila/metabolismo , Compostos Férricos/farmacologia , Fragaria/metabolismo , Ferro/metabolismo , Folhas de Planta/metabolismo , Raízes de Plantas/metabolismo , Succinatos/metabolismo , Succinatos/farmacologia
4.
Nat Metab ; 4(7): 856-866, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35864246

RESUMO

Successful elimination of bacteria in phagocytes occurs in the phago-lysosomal system, but also depends on mitochondrial pathways. Yet, how these two organelle systems communicate is largely unknown. Here we identify the lysosomal biogenesis factor transcription factor EB (TFEB) as regulator for phago-lysosome-mitochondria crosstalk in macrophages. By combining cellular imaging and metabolic profiling, we find that TFEB activation, in response to bacterial stimuli, promotes the transcription of aconitate decarboxylase (Acod1, Irg1) and synthesis of its product itaconate, a mitochondrial metabolite with antimicrobial activity. Activation of the TFEB-Irg1-itaconate signalling axis reduces the survival of the intravacuolar pathogen Salmonella enterica serovar Typhimurium. TFEB-driven itaconate is subsequently transferred via the Irg1-Rab32-BLOC3 system into the Salmonella-containing vacuole, thereby exposing the pathogen to elevated itaconate levels. By activating itaconate production, TFEB selectively restricts proliferating Salmonella, a bacterial subpopulation that normally escapes macrophage control, which contrasts TFEB's role in autophagy-mediated pathogen degradation. Together, our data define a TFEB-driven metabolic pathway between phago-lysosomes and mitochondria that restrains Salmonella Typhimurium burden in macrophages in vitro and in vivo.


Assuntos
Lisossomos , Succinatos , Autofagia/fisiologia , Lisossomos/metabolismo , Macrófagos/metabolismo , Succinatos/metabolismo , Succinatos/farmacologia
5.
Proc Natl Acad Sci U S A ; 119(28): e2113465119, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35867735

RESUMO

The role of autophagy in cancer is complex. Both tumor-promoting and tumor-suppressive effects are reported, with tumor type, stage and specific genetic lesions dictating the role. This calls for analysis in models that best recapitulate each tumor type, from initiation to metastatic disease, to specifically understand the contribution of autophagy in each context. Here, we report the effects of deleting the essential autophagy gene Atg7 in a model of pancreatic ductal adenocarcinoma (PDAC), in which mutant KrasG12D and mutant Trp53172H are induced in adult tissue leading to metastatic PDAC. This revealed that Atg7 loss in the presence of KrasG12D/+ and Trp53172H/+ was tumor promoting, similar to previous observations in tumors driven by embryonic KrasG12D/+ and deletion of Trp53. However, Atg7 hemizygosity also enhanced tumor initiation and progression, even though this did not ablate autophagy. Moreover, despite this enhanced progression, fewer Atg7 hemizygous mice had metastases compared with animals wild type for this allele, indicating that ATG7 is a promoter of metastasis. We show, in addition, that Atg7+/- tumors have comparatively lower levels of succinate, and that cells derived from Atg7+/- tumors are also less invasive than those from Atg7+/+ tumors. This effect on invasion can be rescued by ectopic expression of Atg7 in Atg7+/- cells, without affecting the autophagic capacity of the cells, or by treatment with a cell-permeable analog of succinate. These findings therefore show that ATG7 has roles in invasion and metastasis that are not related to the role of the protein in the regulation of autophagy.


Assuntos
Proteína 7 Relacionada à Autofagia , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/secundário , Linhagem Celular Tumoral , Camundongos , Mutação , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Succinatos/metabolismo , Succinatos/farmacologia
6.
Front Immunol ; 13: 859806, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757749

RESUMO

Ulcerative colitis (UC) is a chronic inflammatory bowel disease worldwide. Infiltration of pro-inflammatory macrophages (M1 macrophages) contributes to the occurrence of bowel inflammation. Transplantation of mesenchymal stem cells (MSCs) is a promising therapeutic strategy for UC, but the exact mechanism remains unknow yet. Here, we treated DSS-induced colitis mice with adipose-derived mesenchymal stem cells (ADMSCs) and revealed that ADMSCs alleviated colon inflammation by reducing the infiltration of M1 macrophages. Moreover, ADMSCs exerted this therapeutic effect by inhibiting succinate accumulation, increasing PHD2 to prevent M1 macrophages from overexpressing HIF-1α and thereby reprogramming the glycolytic pathway of M1 macrophages. Meanwhile, the succinate secreted by M1 macrophages triggered ADMSCs to secrete PGE2 in return, which could also shift macrophages from M1 phenotype to M2. Our work demonstrated an immunomodulatory effect of ADMSCs and provided a novel perspective on UC therapy.


Assuntos
Colite Ulcerativa , Colite , Células-Tronco Mesenquimais , Animais , Colite/tratamento farmacológico , Colite/terapia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/terapia , Inflamação/metabolismo , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Succinatos/metabolismo , Succinatos/farmacologia , Succinatos/uso terapêutico
7.
Mol Cell ; 82(15): 2844-2857.e10, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35662396

RESUMO

Lysosomes are the main organelles in macrophages for killing invading bacteria. However, the precise mechanism underlying lysosomal biogenesis upon bacterial infection remains enigmatic. We demonstrate here that LPS stimulation increases IRG1-dependent itaconate production, which promotes lysosomal biogenesis by activating the transcription factor, TFEB. Mechanistically, itaconate directly alkylates human TFEB at cysteine 212 (Cys270 in mice) to induce its nuclear localization by antagonizing mTOR-mediated phosphorylation and cytosolic retention. Functionally, abrogation of itaconate synthesis by IRG1/Irg1 knockout or expression of an alkylation-deficient TFEB mutant impairs the antibacterial ability of macrophages in vitro. Furthermore, knockin mice harboring an alkylation-deficient TFEB mutant display elevated susceptibility to Salmonella typhimurium infection, whereas in vivo treatment of OI, a cell-permeable itaconate derivative, limits inflammation. Our study identifies itaconate as an endogenous metabolite that functions as a lysosomal inducer in macrophages in response to bacterial infection, implying the potential therapeutic utility of itaconate in treating human bacterial infection.


Assuntos
Lisossomos , Succinatos , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Humanos , Imunidade Inata , Lisossomos/metabolismo , Camundongos , Succinatos/metabolismo , Succinatos/farmacologia
8.
Nat Commun ; 13(1): 3731, 2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35768446

RESUMO

Tigecycline is regarded as the last line of defense to combat multidrug-resistant Klebsiella pneumoniae. However, increasing utilization has led to rising drug resistance and treatment failure. Here, we design a D-alpha tocopheryl polyethylene glycol succinate-modified and S-thanatin peptide-functionalized nanorods based on calcium phosphate nanoparticles for tigecycline delivery and pneumonia therapy caused by tigecycline-resistant Klebsiella pneumoniae. After incubation with bacteria, the fabricated nanorods can enhance tigecycline accumulation in bacteria via the inhibitory effect on efflux pumps exerted by D-alpha tocopheryl polyethylene glycol succinate and the targeting capacity of S-thanatin to bacteria. The synergistic antibacterial capacity between S-thanatin and tigecycline further enhances the antibacterial activity of nanorods, thus overcoming the tigecycline resistance of Klebsiella pneumoniae. After intravenous injection, nanorods significantly reduces the counts of white blood cells and neutrophils, decreases bacterial colonies, and ameliorates neutrophil infiltration events, thereby largely increasing the survival rate of mice with pneumonia. These findings may provide a therapeutic strategy for infections caused by drug-resistant bacteria.


Assuntos
Infecções por Klebsiella , Nanotubos , Pneumonia , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos , Resistência a Medicamentos , Farmacorresistência Bacteriana , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae , Camundongos , Testes de Sensibilidade Microbiana , Polietilenoglicóis/farmacologia , Succinatos/farmacologia , Tigeciclina/farmacologia , Vitamina E
9.
Arch Biochem Biophys ; 726: 109232, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35660297

RESUMO

Much evidence indicates that superoxide is generated from O2 in a cyanide-sensitive reaction involving a reduced component of complex III of the mitochondrial respiratory chain, particularly when antimycin A is present. Although it is generally believed that ubisemiquinone is the electron donor to O2, little experimental evidence supporting this view has been reported. Experiments with succinate as electron donor in the presence of antimycin A in intact rat heart mitochondria, which contain much superoxide dismutase but little catalase, showed that myxothiazol, which inhibits reduction of the Rieske iron-sulfur center, prevented formation of hydrogen peroxide, determined spectrophotometrically as the H2O2-peroxidase complex. Similarly, depletion of the mitochondria of their cytochrome c also inhibited formation of H2O2, which was restored by addition of cytochrome c. These observations indicate that factors preventing the formation of ubisemiquinone also prevent H2O2 formation. They also exclude ubiquinol, which remains reduced under these conditions, as the reductant of O2. Since cytochrome b also remains fully reduced when myxothiazol is added to succinate- and antimycin A-supplemented mitochondria, reduced cytochrome b may also be excluded as the reductant of O2. These observations, which are consistent with the Q-cycle reactions, by exclusion of other possibilities leave ubisemiquinone as the only reduced electron carrier in complex III capable of reducing O2 to O2-.


Assuntos
Mitocôndrias Cardíacas , Superóxidos , Animais , Antimicina A/metabolismo , Antimicina A/farmacologia , Citocromos b/metabolismo , Citocromos c/metabolismo , Transporte de Elétrons , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Elétrons , Peróxido de Hidrogênio/metabolismo , Mitocôndrias Cardíacas/metabolismo , Oxirredução , Ratos , Substâncias Redutoras/metabolismo , Succinatos/metabolismo , Succinatos/farmacologia , Ácido Succínico , Superóxidos/metabolismo , Ubiquinona/análogos & derivados
10.
Nat Metab ; 4(5): 524-533, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35655024

RESUMO

Since its discovery in inflammatory macrophages, itaconate has attracted much attention due to its antimicrobial and immunomodulatory activity1-3. However, instead of investigating itaconate itself, most studies used derivatized forms of itaconate and thus the role of non-derivatized itaconate needs to be scrutinized. Mesaconate, a metabolite structurally very close to itaconate, has never been implicated in mammalian cells. Here we show that mesaconate is synthesized in inflammatory macrophages from itaconate. We find that both, non-derivatized itaconate and mesaconate dampen the glycolytic activity to a similar extent, whereas only itaconate is able to repress tricarboxylic acid cycle activity and cellular respiration. In contrast to itaconate, mesaconate does not inhibit succinate dehydrogenase. Despite their distinct impact on metabolism, both metabolites exert similar immunomodulatory effects in pro-inflammatory macrophages, specifically a reduction of interleukin (IL)-6 and IL-12 secretion and an increase of CXCL10 production in a manner that is independent of NRF2 and ATF3. We show that a treatment with neither mesaconate nor itaconate impairs IL-1ß secretion and inflammasome activation. In summary, our results identify mesaconate as an immunomodulatory metabolite in macrophages, which interferes to a lesser extent with cellular metabolism than itaconate.


Assuntos
Macrófagos , Succinatos , Animais , Inflamassomos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Succinatos/metabolismo , Succinatos/farmacologia
11.
Front Immunol ; 13: 748375, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35265064

RESUMO

A Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model of in vitro myogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopie the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere with in vitro myogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. We also show 4-octyl itaconate suppresses injury-induced MYOG expression in vivo. More importantly, our findings suggest the therapeutic potential of itaconate, and its derivatives could be limited due to deleterious effects on myogenesis.


Assuntos
Succinatos , Ácido Succínico , Desenvolvimento Muscular , Transdução de Sinais , Succinatos/metabolismo , Succinatos/farmacologia , Succinatos/uso terapêutico , Ácido Succínico/metabolismo , Ácido Succínico/farmacologia
12.
Nat Cell Biol ; 24(3): 353-363, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35256775

RESUMO

As one of the most induced genes in activated macrophages, immune-responsive gene 1 (IRG1) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses.


Assuntos
Dioxigenases , Animais , DNA , Dioxigenases/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Succinatos/metabolismo , Succinatos/farmacologia
13.
Cancer Sci ; 113(5): 1779-1788, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35253340

RESUMO

Intraperitoneal administration of anticancer nanoparticles is a rational strategy for preventing peritoneal dissemination of colon cancer due to the prolonged retention of nanoparticles in the abdominal cavity. However, instability of nanoparticles in body fluids causes inefficient retention, reducing its anticancer effects. We have previously developed anticancer nanoparticles containing tocopheryl succinate, which showed high in vivo stability and multifunctional anticancer effects. In the present study, we have demonstrated that peritoneal dissemination derived from colon cancer was prevented by intraperitoneal administration of tocopheryl succinate nanoparticles. The biodistribution of tocopheryl succinate nanoparticles was evaluated using inductively coupled plasma mass spectroscopy and imaging analysis in mice administered quantum dot encapsulated tocopheryl succinate nanoparticles. Intraperitoneal administration of tocopheryl succinate nanoparticles showed longer retention in the abdominal cavity than by its intravenous (i.v.) administration. Moreover, due to effective biodistribution, tumor growth was prevented by intraperitoneal administration of tocopheryl succinate nanoparticles. Furthermore, the anticancer effect was attributed to the inhibition of cancer cell proliferation and improvement of the intraperitoneal microenvironment, such as decrease in the levels of vascular endothelial growth factor A, interleukin 10, and M2-like phenotype of tumor-associated macrophages. Collectively, intraperitoneal administration of tocopheryl succinate nanoparticles is expected to have multifaceted antitumor effects against colon cancer with peritoneal dissemination.


Assuntos
Neoplasias do Colo , Nanopartículas , Animais , Neoplasias do Colo/tratamento farmacológico , Humanos , Camundongos , Nanopartículas/química , Succinatos/farmacologia , Distribuição Tecidual , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular , alfa-Tocoferol/química , alfa-Tocoferol/farmacologia
14.
Mediators Inflamm ; 2022: 5766434, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35310452

RESUMO

4-Octyl itaconate (OI) is a novel anti-inflammatory metabolite that exerts protective effects in many various disease models. However, its function in autoimmune hepatitis- (AIH-) associated hepatic injury has not been investigated. In this study, we successfully used concanavalin A (Con A) to establish an AIH-associated liver injury model. Furthermore, we investigated the effect of OI in Con A-induced liver injury and found that OI mitigated Con A-induced histopathological damage. OI administration reduced serum levels of alanine transaminase and aspartate transaminase in Con A-treated mice and attenuated the infiltration of macrophages induced by Con A. Moreover, OI effectively inhibited the expression of proinflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and IL-1ß induced by Con A. Furthermore, OI decreased hepatocyte apoptosis and malondialdehyde levels and increased the reduced glutathione/oxidized glutathione ratio in the Con A-induced liver injury model. In addition, we found that OI inhibited Con A-induced hepatocyte apoptosis in vitro, while Nrf2 deletion eliminated this effect. Furthermore, we administrated the Nrf2 inhibitor ML385 in OI+Con A-treated mice and found that ML385 eliminated the protective effect of OI in vivo. In addition, OI inhibited Con A-induced activation of nuclear factor-kappa B (NF-𝜅B) and the expression of proinflammatory cytokines in macrophages. Therefore, OI protected mice from Con A-induced liver damage and may be associated with Nrf2 activation and NF-𝜅B inhibition. Finally, our study revealed that OI inhibited TNF-α, or supernatants from Con A-treated RAW264.7 cells induced hepatocyte apoptosis. In conclusion, our study indicated that OI alleviated Con A-induced hepatic damage by reducing inflammatory response, oxidative stress, and apoptosis.


Assuntos
Hepatite Autoimune , Animais , Concanavalina A/toxicidade , Hepatite Autoimune/tratamento farmacológico , Camundongos , Succinatos/farmacologia , Succinatos/uso terapêutico
15.
Allergy ; 77(9): 2677-2687, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35122266

RESUMO

BACKGROUND: SUCNR1 is a sensor of extracellular succinate, a Krebs cycle intermediate generated in excess during oxidative stress and has been linked to metabolic regulation and inflammation. While mast cells express SUCNR1, its role in mast cell reactivity and allergic conditions such as asthma remains to be elucidated. METHODS: Cord blood-derived mast cells and human mast cell line LAD-2 challenged by SUCNR1 ligands were analyzed for the activation and mediator release. Effects on mast cell-dependent bronchoconstriction were assessed in guinea pig trachea and isolated human small bronchi challenged with antigen and anti-IgE, respectively. RESULTS: SUCNR1 is abundantly expressed on human mast cells. Challenge with succinate, or the synthetic non-metabolite agonist cis-epoxysuccinate, renders mast cells hypersensitive to IgE-dependent activation, resulting in augmented degranulation and histamine release, de novo biosynthesis of eicosanoids and cytokine secretion. The succinate-potentiated mast cell reactivity was attenuated by SUCNR1 knockdown and selective SUCNR1 antagonists and could be tuned by pharmacologically targeting protein kinase C and extracellular signal-regulated kinase. Both succinate and cis-epoxysuccinate dose-dependently potentiated antigen-induced contraction in a mast cell-dependent guinea pig airway model, associated with increased generation of cysteinyl-leukotrienes and histamine in trachea. Similarly, cis-epoxysuccinate aggravated IgE-receptor-induced contraction of human bronchi, which was blocked by SUCNR1 antagonism. CONCLUSION: SUCNR1 amplifies IgE-receptor-induced mast cell activation and allergic bronchoconstriction, suggesting a role for this pathway in aggravation of allergic asthma, thus linking metabolic perturbations to mast cell-dependent inflammation.


Assuntos
Asma , Hipersensibilidade , Animais , Broncoconstrição , Cobaias , Humanos , Hipersensibilidade/metabolismo , Imunoglobulina E , Inflamação/metabolismo , Mastócitos , Succinatos/metabolismo , Succinatos/farmacologia
16.
Oxid Med Cell Longev ; 2022: 2206167, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35126808

RESUMO

Nrf2 is a critical regulator of the antioxidant defense systems in cellular protection. Emerging evidence has shown that four-octyl itaconate (OI) activates Nrf2 cascade. In this study, the chondroprotective effects of OI on H2O2-stimulated chondrocytes and DMM-induced osteoarthritis (OA) progression were investigated. In primary murine chondrocytes, OI interrupted the binding of Keap1 and Nrf2, leading to accumulation and nuclear translocation of Nrf2 protein, as well as transcription and expression of Nrf2-dependent genes, such as HO-1, NQO1, and GCLC. Furthermore, OI inhibited cell death and apoptosis, as well as H2O2-stimulated ROS generation, lipid peroxidation, superoxide accumulation, and mitochondrial depolarization in chondrocytes, which were abolished by the silence or depletion of Nrf2. In addition, in vivo experiments revealed the therapeutic effects of OI on OA progression in a DMM mouse model. Collectively, these results suggested that OI might serve as a potential treatment for OA progression.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Succinatos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Condrócitos/citologia , Condrócitos/metabolismo , Modelos Animais de Doenças , Peróxido de Hidrogênio/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/deficiência , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/genética , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoartrite/patologia , Espécies Reativas de Oxigênio/metabolismo , Succinatos/química , Succinatos/uso terapêutico
17.
Int J Mol Sci ; 23(4)2022 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-35216146

RESUMO

Chicoric acid (CA), a polyphenolic acid compound extracted from chicory and echinacea, possesses antiviral, antioxidative and anti-inflammatory activities. Growing evidence supports the pivotal roles of brain-spleen and brain-gut axes in neurodegenerative diseases, including Parkinson's disease (PD), and the immune response of the spleen and colon is always the active participant in the pathogenesis and development of PD. In this study, we observe that CA prevented dopaminergic neuronal lesions, motor deficits and glial activation in PD mice, along with the increment in striatal brain-derived neurotrophic factor (BDNF), dopamine (DA) and 5-hydroxyindoleacetic acid (5-HT). Furthermore, CA reversed the level of interleukin-17(IL-17), interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-ß) of PD mice, implicating its regulatory effect on the immunological response of spleen and colon. Transcriptome analysis revealed that 22 genes in the spleen (21 upregulated and 1 downregulated) and 306 genes (190 upregulated and 116 downregulated) in the colon were significantly differentially expressed in CA-pretreated mice. These genes were functionally annotated with GSEA, GO and KEGG pathway enrichment, providing the potential target genes and molecular biological mechanisms for the modulation of CA on the spleen and gut in PD. Remarkably, CA restored some gene expressions to normal level. Our results highlighted that the neuroprotection of CA might be associated with the manipulation of CA on brain-spleen and brain-gut axes in PD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ácidos Cafeicos/uso terapêutico , Intoxicação por MPTP/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Succinatos/uso terapêutico , Transcriptoma , Animais , Anti-Inflamatórios/farmacologia , Ácidos Cafeicos/farmacologia , Colo/efeitos dos fármacos , Colo/metabolismo , Citocinas/genética , Citocinas/metabolismo , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Baço/efeitos dos fármacos , Baço/metabolismo , Succinatos/farmacologia
18.
Food Funct ; 13(4): 2019-2032, 2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35103734

RESUMO

Chicoric acid (CA), a polyphenolic acid obtained from chicory and purple coneflower (Echinacea purpurea), has been regarded as a nutraceutical to combat inflammation, viruses and obesity. Parkinson's disease (PD) is a common neurodegenerative disorder, and the microbiota-gut-brain axis might be the potential mechanism in the pathogenesis and development of PD. The results obtained in this study demonstrated that oral pretreatments of CA significantly prevented the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunctions and death of nigrostriatal dopaminergic neurons along with the inhibition of glial hyperactivation and the increment in striatal neurotrophins. 16S rRNA sequence results showed that CA significantly reduced MPTP-induced microbial dysbiosis and partially restored the composition of the gut microbiota to normal, including decreased phylum Bacteroidetes and genera Parabacteroide, as well as increased phylum Firmicutes, genera Lactobacillus and Ruminiclostridium. Besides, CA promoted colonic epithelial integrity and restored normal SCFA production. We also observed that proinflammatory cytokines such as TNF-α and IL-1ß in the serum, striatum and colon were reduced by CA, indicating that CA prevented neuroinflammation and gut inflammation, in which the suppression of the TLR4/MyD88/NF-κB signaling pathway might be the underlying molecular mechanism. These findings demonstrated that CA had neuroprotective effects on MPTP-induced PD mice possibly via modulating the gut microbiota and inhibiting inflammation throughout the brain-gut axis.


Assuntos
Ácidos Cafeicos/uso terapêutico , Echinacea , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Succinatos/uso terapêutico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Ácidos Cafeicos/farmacologia , Suplementos Nutricionais , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/metabolismo , Doença de Parkinson/microbiologia , Fitoterapia , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Succinatos/farmacologia , Receptor 4 Toll-Like/metabolismo
19.
Oxid Med Cell Longev ; 2022: 5180242, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35222799

RESUMO

Nonalcoholic fatty liver disease (NAFLD), characterized with oxidative stress and hepatic steatosis, is a serious threat to human health. As a specific activator of nuclear factor E2-related factor 2 (Nrf2), the 4-octyl itaconate (4-OI) has the beneficial effects in antioxidant and anti-inflammation; however, whether 4-OI can alleviate hepatic steatosis and its mechanism is still unknown. The present study was aimed at investigating the protective effects of 4-OI on free fat acid- (FFA-) induced lipid metabolism disorder and its potential molecular mechanism in hepatocytes. The results showed that 4-OI treatment markedly alleviated FFA-induced oxidative stress and excessive lipid accumulation in hepatocytes. Mechanistically, 4-OI significantly suppressed the overproduction of reactive oxygen species (ROS) through activation of Nrf2; the downregulation of ROS level induced a downregulation of AMP-dependent protein kinase (AMPK) phosphorylation level which finally ameliorated excessive lipid accumulation in FFA-stimulated hepatocytes. In general, our data demonstrated that 4-OI relieves the oxidative stress and lipid metabolism disorder in FFA-stimulated hepatocytes; and these beneficial effects were achieved by activating the Nrf2-AMPK signaling pathway. These data not only expand the new biological function of 4-OI but also provide a theoretical basis for 4-OI to protect against lipid metabolism disorders and related diseases, such as NAFLD.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Graxos não Esterificados/toxicidade , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Succinatos/farmacologia , Animais , Linhagem Celular , Hepatócitos/metabolismo , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
PLoS Pathog ; 18(1): e1010219, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35025971

RESUMO

Excessive inflammation is a major cause of morbidity and mortality in many viral infections including influenza. Therefore, there is a need for therapeutic interventions that dampen and redirect inflammatory responses and, ideally, exert antiviral effects. Itaconate is an immunomodulatory metabolite which also reprograms cell metabolism and inflammatory responses when applied exogenously. We evaluated effects of endogenous itaconate and exogenous application of itaconate and its variants dimethyl- and 4-octyl-itaconate (DI, 4OI) on host responses to influenza A virus (IAV). Infection induced expression of ACOD1, the enzyme catalyzing itaconate synthesis, in monocytes and macrophages, which correlated with viral replication and was abrogated by DI and 4OI treatment. In IAV-infected mice, pulmonary inflammation and weight loss were greater in Acod1-/- than in wild-type mice, and DI treatment reduced pulmonary inflammation and mortality. The compounds reversed infection-triggered interferon responses and modulated inflammation in human cells supporting non-productive and productive infection, in peripheral blood mononuclear cells, and in human lung tissue. All three itaconates reduced ROS levels and STAT1 phosphorylation, whereas AKT phosphorylation was reduced by 4OI and DI but increased by itaconate. Single-cell RNA sequencing identified monocytes as the main target of infection and the exclusive source of ACOD1 mRNA in peripheral blood. DI treatment silenced IFN-responses predominantly in monocytes, but also in lymphocytes and natural killer cells. Ectopic synthesis of itaconate in A549 cells, which do not physiologically express ACOD1, reduced infection-driven inflammation, and DI reduced IAV- and IFNγ-induced CXCL10 expression in murine macrophages independent of the presence of endogenous ACOD1. The compounds differed greatly in their effects on cellular gene homeostasis and released cytokines/chemokines, but all three markedly reduced release of the pro-inflammatory chemokines CXCL10 (IP-10) and CCL2 (MCP-1). Viral replication did not increase under treatment despite the dramatically repressed IFN responses. In fact, 4OI strongly inhibited viral transcription in peripheral blood mononuclear cells, and the compounds reduced viral titers (4OI>Ita>DI) in A549 cells whereas viral transcription was unaffected. Taken together, these results reveal itaconates as immunomodulatory and antiviral interventions for influenza virus infection.


Assuntos
Vírus da Influenza A/imunologia , Macrófagos/imunologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Succinatos/farmacologia , Células A549 , Animais , Carboxiliases/deficiência , Carboxiliases/imunologia , Citocinas/genética , Citocinas/imunologia , Humanos , Macrófagos/virologia , Camundongos , Camundongos Knockout , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Células THP-1
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...