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1.
PLoS One ; 19(5): e0303516, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38728330

RESUMO

Increasingly prevalent, nontuberculous mycobacteria (NTM) infections affect approximately 20% of people with cystic fibrosis (CF). Previous studies of CF sputum identified lower levels of the host metabolite itaconate in those infected with NTM. Itaconate can inhibit the growth of M. tuberculosis (MTB) in vitro via the inhibition of the glyoxylate cycle enzyme (ICL), but its impact on NTM is unclear. To test itaconic acid's (IA) effect on NTM growth, laboratory and CF clinical strains of Mycobacterium abscessus and Mycobacterium avium were cultured in 7H9 minimal media supplemented with 1-10 mM of IA and short-chain fatty acids (SCFA). M. avium and M. abscessus grew when supplemented with SCFAs, whereas the addition of IA (≥ 10 mM) completely inhibited NTM growth. NTM supplemented with acetate or propionate and 5 mM IA displayed slower growth than NTM cultured with SCFA and ≤ 1 mM of IA. However, IA's inhibition of NTM was pH dependent; as similar and higher quantities (100 mM) of pH adjusted IA (pH 7) did not inhibit growth in vitro, while in an acidic minimal media (pH 6.1), 1 to 5 mM of non-pH adjusted IA inhibited growth. None of the examined isolates displayed the ability to utilize IA as a carbon source, and IA added to M. abscessus isocitrate lyase (ICL) decreased enzymatic activity. Lastly, the addition of cell-permeable 4-octyl itaconate (4-OI) to THP-1 cells enhanced NTM clearance, demonstrating a potential role for IA/itaconate in host defense against NTM infections.


Assuntos
Succinatos , Succinatos/farmacologia , Succinatos/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Micobactérias não Tuberculosas/efeitos dos fármacos , Micobactérias não Tuberculosas/crescimento & desenvolvimento , Células THP-1 , Infecções por Mycobacterium não Tuberculosas/microbiologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mycobacterium avium/efeitos dos fármacos , Mycobacterium avium/crescimento & desenvolvimento , Mycobacterium abscessus/efeitos dos fármacos , Mycobacterium abscessus/crescimento & desenvolvimento , Mycobacterium abscessus/metabolismo
2.
Respir Res ; 25(1): 205, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730297

RESUMO

BACKGROUND: Obesity is the main risk factor leading to the development of various respiratory diseases, such as asthma and pulmonary hypertension. Pulmonary microvascular endothelial cells (PMVECs) play a significant role in the development of lung diseases. Aconitate decarboxylase 1 (Acod1) mediates the production of itaconate, and Acod1/itaconate axis has been reported to play a protective role in multiple diseases. However, the roles of Acod1/itaconate axis in the PMVECs of obese mice are still unclear. METHODS: mRNA-seq was performed to identify the differentially expressed genes (DEGs) between high-fat diet (HFD)-induced PMVECs and chow-fed PMVECs in mice (|log2 fold change| ≥ 1, p ≤ 0.05). Free fatty acid (FFA) was used to induce cell injury, inflammation and mitochondrial oxidative stress in mouse PMVECs after transfection with the Acod1 overexpressed plasmid or 4-Octyl Itaconate (4-OI) administration. In addition, we investigated whether the nuclear factor erythroid 2-like 2 (Nrf2) pathway was involved in the effects of Acod1/itaconate in FFA-induced PMVECs. RESULTS: Down-regulated Acod1 was identified in HFD mouse PMVECs by mRNA-seq. Acod1 expression was also reduced in FFA-treated PMVECs. Acod1 overexpression inhibited cell injury, inflammation and mitochondrial oxidative stress induced by FFA in mouse PMVECs. 4-OI administration showed the consistent results in FFA-treated mouse PMVECs. Moreover, silencing Nrf2 reversed the effects of Acod1 overexpression and 4-OI administration in FFA-treated PMVECs, indicating that Nrf2 activation was required for the protective effects of Acod1/itaconate. CONCLUSION: Our results demonstrated that Acod1/Itaconate axis might protect mouse PMVECs from FFA-induced injury, inflammation and mitochondrial oxidative stress via activating Nrf2 pathway. It was meaningful for the treatment of obesity-caused pulmonary microvascular endotheliopathy.


Assuntos
Carboxiliases , Células Endoteliais , Pulmão , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Obesidade , Succinatos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Camundongos , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Carboxiliases/metabolismo , Carboxiliases/genética , Obesidade/metabolismo , Obesidade/complicações , Masculino , Succinatos/farmacologia , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/irrigação sanguínea , Células Cultivadas , Microvasos/metabolismo , Microvasos/efeitos dos fármacos , Microvasos/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Hidroliases
3.
Nat Commun ; 15(1): 4096, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750019

RESUMO

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKß independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.


Assuntos
Terapia Viral Oncolítica , Vírus Oncolíticos , Succinatos , Animais , Humanos , Terapia Viral Oncolítica/métodos , Succinatos/farmacologia , Camundongos , Linhagem Celular Tumoral , Interferon Tipo I/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias do Colo/terapia , Neoplasias do Colo/imunologia , Neoplasias do Colo/tratamento farmacológico , Antivirais/farmacologia , NF-kappa B/metabolismo , Quinase I-kappa B/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Inflamação/tratamento farmacológico , Feminino , Vírus da Estomatite Vesicular Indiana/fisiologia , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
4.
J Neuroinflammation ; 21(1): 132, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760862

RESUMO

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common neurological problems occurring in the perinatal period. However, there still is not a promising approach to reduce long-term neurodevelopmental outcomes of HIE. Recently, itaconate has been found to exhibit anti-oxidative and anti-inflammatory effects. However, the therapeutic efficacy of itaconate in HIE remains inconclusive. Therefore, this study attempts to explore the pathophysiological mechanisms of oxidative stress and inflammatory responses in HIE as well as the potential therapeutic role of a derivative of itaconate, 4-octyl itaconate (4OI). METHODS: We used 7-day-old mice to induce hypoxic-ischemic (HI) model by right common carotid artery ligation followed by 1 h of hypoxia. Behavioral experiments including the Y-maze and novel object recognition test were performed on HI mice at P60 to evaluate long-term neurodevelopmental outcomes. We employed an approach combining non-targeted metabolomics with transcriptomics to screen alterations in metabolic profiles and gene expression in the hippocampal tissue of the mice at 8 h after hypoxia. Immunofluorescence staining and RT-PCR were used to evaluate the pathological changes in brain tissue cells and the expression of mRNA and proteins. 4OI was intraperitoneally injected into HI model mice to assess its anti-inflammatory and antioxidant effects. BV2 and C8D1A cells were cultured in vitro to study the effect of 4OI on the expression and nuclear translocation of Nrf2. We also used Nrf2-siRNA to further validate 4OI-induced Nrf2 pathway in astrocytes. RESULTS: We found that in the acute phase of HI, there was an accumulation of pyruvate and lactate in the hippocampal tissue, accompanied by oxidative stress and pro-inflammatory, as well as increased expression of antioxidative stress and anti-inflammatory genes. Treatment of 4OI could inhibit activation and proliferation of microglial cells and astrocytes, reduce neuronal death and relieve cognitive dysfunction in HI mice. Furthermore, 4OI enhanced nuclear factor erythroid-2-related factor (Nfe2l2; Nrf2) expression and nuclear translocation in astrocytes, reduced pro-inflammatory cytokine production, and increased antioxidant enzyme expression. CONCLUSION: Our study demonstrates that 4OI has a potential therapeutic effect on neuronal damage and cognitive deficits in HIE, potentially through the modulation of inflammation and oxidative stress pathways by Nrf2 in astrocytes.


Assuntos
Animais Recém-Nascidos , Astrócitos , Hipóxia-Isquemia Encefálica , Fator 2 Relacionado a NF-E2 , Fármacos Neuroprotetores , Succinatos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/patologia , Camundongos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Succinatos/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Modelos Animais de Doenças
5.
Int J Biol Macromol ; 268(Pt 2): 131947, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38685542

RESUMO

Trimethoprim (TMP), an antibiotic contaminant, can be effectively removed from water by using the innovative magnetic metal-organic framework (MOF) composite sponge Fe3O4@Rh-MOF@PIC, which is shown in this study. The composite is made up of magnetite (Fe3O4) nanoparticles and a rhodium MOF embedded in a poly(itaconic acid) grafted chitosan matrix. The structure and characteristics of the synthesized material were confirmed by thorough characterization employing SEM, FTIR, XPS, XRD, and BET techniques. Notably, the composite shows a high magnetic saturation of 64 emu g-1, which makes magnetic separation easier, according to vibrating sample magnetometry. Moreover, BET analysis revealed that the Fe3O4@Rh-MOF@PIC sponge had an incredibly high surface area of 1236.48 m2/g. Its outstanding efficacy was confirmed by batch adsorption tests, which produced a maximum adsorption capacity of 391.9 mg/g for the elimination of TMP. Due to its high porosity, magnetic characteristics, and superior trimethoprim uptake, this magnetic MOF composite sponge is a promising adsorbent for effective removal of antibiotics from contaminated water sources. An adsorption energy of 24.5 kJ/mol was found by batch investigations on the Fe3O4@Rh-MOF@PIC composite sponge for trimethoprim (TMP) adsorption. The fact that this value was up 8 kJ/mol suggests that the main mechanism controlling TMP absorption onto the sponge adsorbent is chemisorption. Chemisorption requires creating strong chemical interactions between adsorbate and adsorbent surface groups, unlike weaker physisorption. The magnetic composite sponge exhibited strong removal capabilities and high adsorption capacities for the antibiotic pollutant. The Fe3O4@Rh-MOF@PIC composite sponge also showed magnetism, which allowed for easy magnetic separation after adsorption. Over the course of 6 cycles, it showed outstanding reusability, and XRD confirmed that its composition was stable. The high surface area MOF's pore filling, hydrogen bonding, π-π stacking, and electrostatic interactions were the main trimethoprim adsorption mechanisms. This magnetic composite is feasible and effective for removing antibiotics from water because of its separability, reusability, and synergistic adsorption mechanisms via electrostatics, H-bonding, and π-interactions. The adsorption results were optimized using Box Behnken-design (BBD).


Assuntos
Quitosana , Estruturas Metalorgânicas , Trimetoprima , Águas Residuárias , Poluentes Químicos da Água , Purificação da Água , Quitosana/química , Estruturas Metalorgânicas/química , Trimetoprima/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/isolamento & purificação , Adsorção , Purificação da Água/métodos , Águas Residuárias/química , Termodinâmica , Cinética , Succinatos
6.
Int J Biol Macromol ; 268(Pt 2): 131604, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38641270

RESUMO

This study aims to develop pH-sensitive and controlled release of ciprofloxacin from ciprofloxacin-loaded grafted chitosan-coated zinc oxide nanoparticles (Cip@Gchit/Zn-NPs) for the treatment of bacterial infections in the human colon. For this aim, first, the chitosan-g-poly(itaconic acid) [Chit-g-poly (Itac)] was synthesized via grafting of itaconic acid onto chitosan in the presence of cerium ammonium nitrate (CAN) under an inert atmosphere using conventional methods, while zinc oxide nanoparticles (Zn-NPs) were prepared via sol-gel technique. Characterization of the synthesized Cip@Gchit/Zn-NPs was analyzed using XRD, FT-IR, SEM, TGA, and zeta potential analysis. The antibacterial efficacy of Cip@Gchit/Zn-NPs against three pathogenic bacteria, namely Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus, was superior to that of tetracycline reference drugs, as evidenced by larger inhibition zones. Cytotoxicity assessment of Cip@Gchit/Zn-NPs on the human chondrocyte cell line C28/I2 via MTT assay revealed 100 % cell viability at a concentration of 500 µg/mL. The loading efficiency of ciprofloxacin into Gchit/Zn-NPs was evaluated at various ratios, demonstrating lower loading efficiency; however, sustained release of ciprofloxacin from Cip@Gchit/Zn-NPs was excellent, with 98.13 % release observed at pH 7.2 over 10 h. Kinetic analysis of ciprofloxacin release followed the first-order kinetic models.


Assuntos
Antibacterianos , Quitosana , Ciprofloxacina , Portadores de Fármacos , Succinatos , Quitosana/química , Ciprofloxacina/farmacologia , Ciprofloxacina/química , Ciprofloxacina/administração & dosagem , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Concentração de Íons de Hidrogênio , Portadores de Fármacos/química , Succinatos/química , Humanos , Nanopartículas/química , Liberação Controlada de Fármacos , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Óxido de Zinco/química , Óxido de Zinco/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
7.
Int J Biol Macromol ; 268(Pt 1): 131746, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38653425

RESUMO

Biodegradable poly(L-lactic acid) (PLLA) has seldom used for dairy packaging due to medium permeability and brittleness. Novel PLLA copolymers, poly (L-lactic acid-co-butylene itaconate-co-glycolic acid) (PLBIGA), were developed by integrating glycolic acid (GA) and poly(butylene itaconate) (PBI) into PLLA's structure using low molecular weight PLLA as a key initiator. Then, packaging materials with better barrier and mechanical properties were obtained by blended PLBIGA with PLLA. Both PLLA/PLBIGA films and polyethylene nylon composite film (PE/NY) were used for stirred yogurt packaging and storage at 4 °C for 25 days. Results revealed that yogurt packed by PLLA/PLBIGA films maintained stabler water-holding capacity, color, and viscosity over the storage period. Moreover, the integrity of the gel structure and the total viable count of lactic acid bacteria in yogurt packaged in PLLA/40-PLBIGA8 were also found to be superior to those in PE/NY packages, highlighting its eco-friendly advantages in dairy packaging.


Assuntos
Embalagem de Alimentos , Armazenamento de Alimentos , Poliésteres , Iogurte , Iogurte/microbiologia , Poliésteres/química , Embalagem de Alimentos/métodos , Armazenamento de Alimentos/métodos , Succinatos/química , Conservação de Alimentos/métodos , Glicolatos/química , Viscosidade , Polímeros/química
8.
Life Sci Alliance ; 7(7)2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38631900

RESUMO

Immunometabolism investigates the intricate relationship between the immune system and cellular metabolism. This study delves into the consequences of mitochondrial frataxin (FXN) depletion, the primary cause of Friedreich's ataxia (FRDA), a debilitating neurodegenerative condition characterized by impaired coordination and muscle control. By using single-cell RNA sequencing, we have identified distinct cellular clusters within the cerebellum of an FRDA mouse model, emphasizing a significant loss in the homeostatic response of microglial cells lacking FXN. Remarkably, these microglia deficient in FXN display heightened reactive responses to inflammatory stimuli. Furthermore, our metabolomic analyses reveal a shift towards glycolysis and itaconate production in these cells. Remarkably, treatment with butyrate counteracts these immunometabolic changes, triggering an antioxidant response via the itaconate-Nrf2-GSH pathways and suppressing the expression of inflammatory genes. Furthermore, we identify Hcar2 (GPR109A) as a mediator involved in restoring the homeostasis of microglia without FXN. Motor function tests conducted on FRDA mice underscore the neuroprotective attributes of butyrate supplementation, enhancing neuromotor performance. In conclusion, our findings elucidate the role of disrupted homeostatic function in cerebellar microglia in the pathogenesis of FRDA. Moreover, they underscore the potential of butyrate to mitigate inflammatory gene expression, correct metabolic imbalances, and improve neuromotor capabilities in FRDA.


Assuntos
Frataxina , Ataxia de Friedreich , Succinatos , Animais , Camundongos , Butiratos , Frataxina/genética , Ataxia de Friedreich/genética , Ataxia de Friedreich/metabolismo , Ataxia de Friedreich/patologia , Glucose , Microglia/metabolismo
9.
Clin Transl Med ; 14(4): e1661, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38644791

RESUMO

BACKGROUND: Spinal cord injury (SCI)-induced neuroinflammation and oxidative stress (OS) are crucial events causing neurological dysfunction. Aconitate decarboxylase 1 (ACOD1) and its metabolite itaconate (Ita) inhibit inflammation and OS by promoting alkylation of Keap1 to induce Nrf2 expression; however, it is unclear whether there is another pathway regulating their effects in inflammation-activated microglia after SCI. METHODS: Adult male C57BL/6 ACOD1-/- mice and their wild-type (WT) littermates were subjected to a moderate thoracic spinal cord contusion. The degree of neuroinflammation and OS in the injured spinal cord were assessed using qPCR, western blot, flow cytometry, immunofluorescence, and trans-well assay. We then employed immunoprecipitation-western blot, chromatin immunoprecipitation (ChIP)-PCR, dual-luciferase assay, and immunofluorescence-confocal imaging to examine the molecular mechanisms of ACOD1. Finally, the locomotor function was evaluated with the Basso Mouse Scale and footprint assay. RESULTS: Both in vitro and in vivo, microglia with transcriptional blockage of ACOD1 exhibited more severe levels of neuroinflammation and OS, in which the expression of p62/Keap1/Nrf2 was down-regulated. Furthermore, silencing ACOD1 exacerbated neurological dysfunction in SCI mice. Administration of exogenous Ita or 4-octyl itaconate reduced p62 phosphorylation. Besides, ACOD1 was capable of interacting with phosphorylated p62 to enhance Nrf2 activation, which in turn further promoted transcription of ACOD1. CONCLUSIONS: Here, we identified an unreported ACOD1-p62-Nrf2-ACOD1 feedback loop exerting anti-inflammatory and anti-OS in inflammatory microglia, and demonstrated the neuroprotective role of ACOD1 after SCI, which was different from that of endogenous and exogenous Ita. The present study extends the functions of ACOD1 and uncovers marked property differences between endogenous and exogenous Ita. KEY POINTS: ACOD1 attenuated neuroinflammation and oxidative stress after spinal cord injury. ACOD1, not itaconate, interacted with p-p62 to facilitate Nrf2 expression and nuclear translocation. Nrf2 was capable of promoting ACOD1 transcription in microglia.


Assuntos
Carboxiliases , Hidroliases , Microglia , Fator 2 Relacionado a NF-E2 , Traumatismos da Medula Espinal , Succinatos , Animais , Masculino , Camundongos , Carboxiliases/metabolismo , Carboxiliases/genética , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Sequestossoma-1/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/complicações , Succinatos/farmacologia , Succinatos/metabolismo
10.
Redox Biol ; 72: 103123, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38615489

RESUMO

Redox signaling, a mode of signal transduction that involves the transfer of electrons from a nucleophilic to electrophilic molecule, has emerged as an essential regulator of inflammatory macrophages. Redox reactions are driven by reactive oxygen/nitrogen species (ROS and RNS) and redox-sensitive metabolites such as fumarate and itaconate, which can post-translationally modify specific cysteine residues in target proteins. In the past decade our understanding of how ROS, RNS, and redox-sensitive metabolites control macrophage function has expanded dramatically. In this review, we discuss the latest evidence of how ROS, RNS, and metabolites regulate macrophage function and how this is dysregulated with disease. We highlight the key tools to assess redox signaling and important questions that remain.


Assuntos
Macrófagos , Oxirredução , Espécies Reativas de Nitrogênio , Espécies Reativas de Oxigênio , Transdução de Sinais , Succinatos , Macrófagos/metabolismo , Humanos , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais
11.
Nature ; 629(8010): 184-192, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38600378

RESUMO

Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.


Assuntos
Anti-Inflamatórios , Glucocorticoides , Inflamação , Macrófagos , Mitocôndrias , Succinatos , Animais , Feminino , Humanos , Masculino , Camundongos , Anti-Inflamatórios/farmacologia , Carboxiliases/metabolismo , Carboxiliases/antagonistas & inibidores , Ciclo do Ácido Cítrico/efeitos dos fármacos , Ciclo do Ácido Cítrico/genética , Citocinas/imunologia , Citocinas/metabolismo , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Hidroliases/deficiência , Hidroliases/genética , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Complexo Piruvato Desidrogenase/metabolismo , Receptores de Glucocorticoides/metabolismo , Succinatos/metabolismo , Ativação Enzimática/efeitos dos fármacos
12.
Lancet Glob Health ; 12(5): e744-e755, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38614628

RESUMO

BACKGROUND: Expanding universal health coverage (UHC) might not be inherently beneficial to poorer populations without the explicit targeting and prioritising of low-income populations. This study examines whether the expansion of UHC between 2000 and 2019 is associated with reduced socioeconomic inequalities in infant mortality in low-income and middle-income countries (LMICs). METHODS: We did a retrospective analysis of birth data compiled from Demographic and Health Surveys (DHSs). We analysed all births between 2000 and 2019 from all DHSs available for this period. The primary outcome was infant mortality, defined as death within 1 year of birth. Logistic regression models with country and year fixed effects assessed associations between country-level progress to UHC (using WHO's UHC service coverage index) and infant mortality (overall and by wealth quintile), adjusting for infant-level, mother-level, and country-level variables. FINDINGS: A total of 4 065 868 births to 1 833 011 mothers were analysed from 177 DHSs covering 60 LMICs between 2000 and 2019. A one unit increase in the UHC index was associated with a 1·2% reduction in the risk of infant death (AOR 0·988, 95% CI 0·981-0·995; absolute measure of association, 0·57 deaths per 1000 livebirths). An estimated 15·5 million infant deaths were averted between 2000 and 2019 because of increases in UHC. However, richer wealth quintiles had larger associated reductions in infant mortality from UHC (quintile 5 AOR 0·983, 95% CI 0·973-0·993) than poorer quintiles (quintile 1 0·991, 0·985-0·998). In the early stages of UHC, UHC expansion was generally beneficial to poorer populations (ie, larger reductions in infant mortality for poorer households [infant deaths per 1000 per one unit increase in UHC coverage: quintile 1 0·84 vs quintile 5 0·59]), but became less so as overall coverage increased (quintile 1 0·64 vs quintile 5 0·57). INTERPRETATION: Since UHC expansion in LMICs appears to become less beneficial to poorer populations as coverage increases, UHC policies should be explicitly designed to ensure lower income groups continue to benefit as coverage expands. FUNDING: UK National Institute for Health and Care Research.


Assuntos
Carboplatina/análogos & derivados , Países em Desenvolvimento , Succinatos , Cobertura Universal do Seguro de Saúde , Lactente , Humanos , Estudos Retrospectivos , Mortalidade Infantil , Morte do Lactente , Política de Saúde
13.
Mol Biol Rep ; 51(1): 533, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38642169

RESUMO

BACKGROUND: Sepsis may be linked to oxidative stress and can be controlled by itaconate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nevertheless, the itaconate impact on sepsis-associated acute kidney injury (SA-AKI) has yet to be definitively established. METHODS: We employed SA-AKI mouse model through a cecal ligation and puncture (CLP) procedure for the in vivo investigation of the potential nephroprotective effect of itaconate in this study. A plasmid was transfected into RAW264.7 cells to examine the Nrf2 pathway function after itaconate administration. Finally, the immune-responsive gene 1-knockout (IRG1-/-) mice were used to study the itaconate impacts on oxidative stress-induced SA-AKI. RESULTS: We have shown that 4-octyl itaconate (OI) significantly reduced CD11b-positive macrophage aggregation and activated the Nrf2 pathway in the bone marrow-derived macrophages (BMDM). The impacts of Nrf2 inhibitor ML385 on the anti-inflammatory and antioxidant properties of itaconate were found to be partial. OI inhibited lipopolysaccharide-induced oxidative stress injury in RAW264.7 macrophages and activated Nrf2 in the nucleus to hinder the expression of nuclear factor kappa B p65, thereby suppressing oxidative stress injury in the macrophages. Additionally, the introduction of the transfected plasmid resulted in a partial inhibition of the anti-inflammatory impact of itaconate. The kidney injury caused by sepsis exhibited greater severity in the IRG1-/- mice than in the wild type mice. Exogenous OI partially attenuated the kidney injury induced by sepsis in the IRG1-/- mice and suppressed the oxidative stress injury in macrophages. CONCLUSIONS: This investigation offers new proof to support the itaconate function in the development and progression of SA-AKI and shows a new possible therapeutic agent for the SA-AKI treatment.


Assuntos
Injúria Renal Aguda , Sepse , Succinatos , Camundongos , Animais , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ativação de Macrófagos , Estresse Oxidativo , Injúria Renal Aguda/etiologia , Anti-Inflamatórios/farmacologia , Sepse/complicações
14.
Biochemistry (Mosc) ; 89(2): 279-298, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38622096

RESUMO

An increase in mitochondrial DNA (mtDNA) mutations and an ensuing increase in mitochondrial reactive oxygen species (ROS) production have been suggested to be a cause of the aging process ("the mitochondrial hypothesis of aging"). In agreement with this, mtDNA-mutator mice accumulate a large amount of mtDNA mutations, giving rise to defective mitochondria and an accelerated aging phenotype. However, incongruously, the rates of ROS production in mtDNA mutator mitochondria have generally earlier been reported to be lower - not higher - than in wildtype, thus apparently invalidating the "mitochondrial hypothesis of aging". We have here re-examined ROS production rates in mtDNA-mutator mice mitochondria. Using traditional conditions for measuring ROS (succinate in the absence of rotenone), we indeed found lower ROS in the mtDNA-mutator mitochondria compared to wildtype. This ROS mainly results from reverse electron flow driven by the membrane potential, but the membrane potential reached in the isolated mtDNA-mutator mitochondria was 33 mV lower than that in wildtype mitochondria, due to the feedback inhibition of succinate oxidation by oxaloacetate, and to a lower oxidative capacity in the mtDNA-mutator mice, explaining the lower ROS production. In contrast, in normal forward electron flow systems (pyruvate (or glutamate) + malate or palmitoyl-CoA + carnitine), mitochondrial ROS production was higher in the mtDNA-mutator mitochondria. Particularly, even during active oxidative phosphorylation (as would be ongoing physiologically), higher ROS rates were seen in the mtDNA-mutator mitochondria than in wildtype. Thus, when examined under physiological conditions, mitochondrial ROS production rates are indeed increased in mtDNA-mutator mitochondria. While this does not prove the validity of the mitochondrial hypothesis of aging, it may no longer be said to be negated in this respect. This paper is dedicated to the memory of Professor Vladimir P. Skulachev.


Assuntos
DNA Mitocondrial , Mitocôndrias , Camundongos , Animais , DNA Mitocondrial/genética , Espécies Reativas de Oxigênio , Mitocôndrias/genética , Envelhecimento/genética , Mutação , Succinatos
15.
Gut Microbes ; 16(1): 2341457, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38630030

RESUMO

With an increasing interest in dietary fibers (DFs) to promote intestinal health and the growth of beneficial gut bacteria, there is a continued rise in the incorporation of refined DFs in processed foods. It is still unclear how refined fibers, such as guar gum, affect the gut microbiota activity and pathogenesis of inflammatory bowel disease (IBD). Our study elucidated the effect and underlying mechanisms of guar gum, a fermentable DF (FDF) commonly present in a wide range of processed foods, on colitis development. We report that guar gum containing diet (GuD) increased the susceptibility to colonic inflammation. Specifically, GuD-fed group exhibited severe colitis upon dextran sulfate sodium (DSS) administration, as evidenced by reduced body weight, diarrhea, rectal bleeding, and shortening of colon length compared to cellulose-fed control mice. Elevated levels of pro-inflammatory markers in both serum [serum amyloid A (SAA), lipocalin 2 (Lcn2)] and colon (Lcn2) and extensive disruption of colonic architecture further affirmed that GuD-fed group exhibited more severe colitis than control group upon DSS intervention. Amelioration of colitis in GuD-fed group pre-treated with antibiotics suggest a vital role of intestinal microbiota in GuD-mediated exacerbation of intestinal inflammation. Gut microbiota composition and metabolite analysis in fecal and cecal contents, respectively, revealed that guar gum primarily enriches Actinobacteriota, specifically Bifidobacterium. Guar gum also altered multiple genera belonging to phyla Bacteroidota and Firmicutes. Such shift in gut microbiota composition favored luminal accumulation of intermediary metabolites succinate and lactate in the GuD-fed mice. Colonic IL-18 and tight junction markers were also decreased in the GuD-fed group. Importantly, GuD-fed mice pre-treated with recombinant IL-18 displayed attenuated colitis. Collectively, unfavorable changes in gut microbiota activity leading to luminal accumulation of lactate and succinate, reduced colonic IL-18, and compromised gut barrier function following guar gum feeding contributed to increased colitis susceptibility.


Guar gum increased susceptibility to colitisGuar gum-induced exacerbation of colitis is gut microbiota dependentGuar gum-induced shift in microbiota composition favored the accumulation of luminal intermediate metabolites succinate and lactateGuar gum-fed mice exhibited reduced colonic level of IL-18 and tight junction molecules.Exogenous IL-18 administration partly rescued mice from guar gum-induced colitis susceptibility.


Assuntos
Colite , Galactanos , Microbioma Gastrointestinal , Mananas , Gomas Vegetais , Animais , Camundongos , Interleucina-18 , Inflamação , Colite/induzido quimicamente , Fibras na Dieta , Ácido Láctico , Succinatos
16.
FASEB J ; 38(7): e23607, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38581245

RESUMO

Pathogenic Th17 cells play a crucial role in autoimmune diseases like uveitis and its animal model, experimental autoimmune uveitis (EAU). Dimethyl itaconate (DMI) possesses potent anti-inflammatory effects. However, there is still a lack of knowledge about the role of DMI in regulating pathogenic Th17 cells and EAU. Here, we reported that intraperitoneal administration of DMI significantly inhibited the severity of EAU via selectively suppressing Th17 cell responses. In vitro antigen stimulation studies revealed that DMI dramatically decreased the frequencies and function of antigen-specific Th17, but not Th1, cells. Moreover, DMI hampered the differentiation of naive CD4+ T cells toward pathogenic Th17 cells. DMI-treated DCs produced less IL-1ß, IL-6, and IL-23, and displayed an impaired ability to stimulate antigen-specific Th17 activation. Mechanistically, DMI activated the NRF2/HO-1 pathway and suppressed STAT3 signaling, which subsequently restrains p-STAT3 nuclear translocation, leading to decreased pathogenic Th17 cell responses. Thus, we have identified an important role for DMI in regulating pathogenic Th17 cells, supporting DMI as a promising therapy in Th17 cell-driven autoimmune diseases including uveitis.


Assuntos
Doenças Autoimunes , Succinatos , Uveíte , Animais , Camundongos , Células Th17 , Fator 2 Relacionado a NF-E2/metabolismo , Inflamação/metabolismo , Doenças Autoimunes/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Células Th1
17.
Proc Natl Acad Sci U S A ; 121(15): e2400675121, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38564634

RESUMO

Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested the therapeutic potential of the IRG1-itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found that IRG1 is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic Irg1-deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1ß. Mechanistically, absence of Irg1 increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1ß release. Conversely, supplementation of the Irg1-itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1ß levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1-itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.


Assuntos
Aterosclerose , Placa Aterosclerótica , Animais , Humanos , Camundongos , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Colesterol , Inflamação/metabolismo , Leucócitos Mononucleares/metabolismo , Lipídeos , Placa Aterosclerótica/tratamento farmacológico , Succinatos/metabolismo
18.
J Neuroinflammation ; 21(1): 104, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38649932

RESUMO

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice. METHODS: A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated. RESULTS: Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1ß and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1ß and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway. CONCLUSIONS: Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.


Assuntos
Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Neurogênese , Doenças Neuroinflamatórias , Complicações Cognitivas Pós-Operatórias , Succinatos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Masculino , Camundongos , Neurogênese/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Complicações Cognitivas Pós-Operatórias/metabolismo , Doenças Neuroinflamatórias/metabolismo , Succinatos/farmacologia , Succinatos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Anestesia
19.
Free Radic Biol Med ; 219: 64-75, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38604314

RESUMO

Cardiovascular diseases (CVDs) are the leading cause of death globally, resulting in a major health burden. Thus, an urgent need exists for exploring effective therapeutic targets to block progression of CVDs and improve patient prognoses. Immune and inflammatory responses are involved in the development of atherosclerosis, ischemic myocardial damage responses and repair, calcification, and stenosis of the aortic valve. These responses can involve both large and small blood vessels throughout the body, leading to increased blood pressure and end-organ damage. While exploring potential avenues for therapeutic intervention in CVDs, researchers have begun to focus on immune metabolism, where metabolic changes that occur in immune cells in response to exogenous or endogenous stimuli can influence immune cell effector responses and local immune signaling. Itaconate, an intermediate metabolite of the tricarboxylic acid (TCA) cycle, is related to pathophysiological processes, including cellular metabolism, oxidative stress, and inflammatory immune responses. The expression of immune response gene 1 (IRG1) is upregulated in activated macrophages, and this gene encodes an enzyme that catalyzes the production of itaconate from the TCA cycle intermediate, cis-aconitate. Itaconate and its derivatives have exerted cardioprotective effects through immune modulation in various disease models, such as ischemic heart disease, valvular heart disease, vascular disease, heart transplantation, and chemotherapy drug-induced cardiotoxicity, implying their therapeutic potential in CVDs. In this review, we delve into the associated signaling pathways through which itaconate exerts immunomodulatory effects, summarize its specific roles in CVDs, and explore emerging immunological therapeutic strategies for managing CVDs.


Assuntos
Doenças Cardiovasculares , Succinatos , Humanos , Succinatos/metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/patologia , Ciclo do Ácido Cítrico , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Carboxiliases
20.
J Physiol Biochem ; 80(2): 393-405, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38427168

RESUMO

Corticosterone (CORT) damages hippocampal neurons as well as induces neuroinflammation. The tricarboxylic acid cycle metabolite itaconate has an anti-inflammatory role. Necroptosis is a form of programmed cell death, also known as inflammatory cell death. Menin is a multifunctional scaffold protein, which deficiency aggravates neuroinflammation. In this study, we explored whether itaconate inhibits CORT-induced neuroinflammation as well as necroptosis and further investigated the mediatory role of Menin in this protective effect of itaconate by using an exposure of CORT to HT22 cells (a hippocampal neuronal cell line). The viability of HT22 cells was examined by the cell counting kit 8 (CCK-8). The morphology of HT22 cells was observed by transmission electron microscope (TEM). The expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) were evaluated by western blotting. The contents of inflammatory factors were detected by an enzyme-linked immunosorbent assay (ELISA) kit. Our results showed that CORT increases the contents of pro-inflammatory factors (IL-1ß, TNF-α) as well as decreases the contents of anti-inflammatory factors (IL-4, IL-10) in HT22 cells. We also found that CORT increases the expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) and decreases the cell viability in HT22 cells, indicating that CORT induces necroptosis in HT22 cells. Itaconate improves CORT-induced neuroinflammation and necroptosis. Furthermore, itaconate upregulates the expression of Menin in CORT-exposed HT22 cells. Importantly, silencing Menin abolishes the antagonistic effect of itaconate on CORT-induced necroptosis and neuroinflammation. In brief, these results indicated that itaconate protects HT22 cells against CORT-induced neuroinflammation and necroptosis via upregulating Menin.


Assuntos
Corticosterona , Hipocampo , Necroptose , Proteínas Proto-Oncogênicas , Succinatos , Regulação para Cima , Animais , Necroptose/efeitos dos fármacos , Succinatos/farmacologia , Camundongos , Linhagem Celular , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Regulação para Cima/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/induzido quimicamente , Doenças Neuroinflamatórias/patologia , Sobrevivência Celular/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
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