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1.
Trends Cell Biol ; 2023 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-37723019

RESUMO

Polyamines - putrescine, spermidine, and spermine - are widely distributed aliphatic compounds known to regulate important biological processes in prokaryotic and eukaryotic cells. Therefore, spermidine insufficiency is associated with various physio-pathological processes, such as aging and cancers. Recent advances in immuno-metabolism and immunotherapy shed new light on the role of spermidine in immune cell regulation and anticancer responses. Here, we review novel works demonstrating that spermidine is produced by collective metabolic pathways of gut bacteria, bacteria-host co-metabolism, and by the host cells, including activated immune cells. We highlight the effectiveness of spermidine in enhancing antitumor responses in aged animals otherwise nonresponsive to immune checkpoint therapy and propose that spermidine supplementation could be used to enhance the efficacy of anti-PD-1 treatment.

2.
Ying Yong Sheng Tai Xue Bao ; 34(7): 1754-1762, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37694458

RESUMO

Uroteuthis edulis, an important fishery target species, plays an important role in the food web of the East China Sea. We collected U. edulis samples in the East China Sea from September 2020 to January 2021 to examine their feeding differences in autumn and winter based on fatty acid and stable isotope analyses. The results showed that the content of polyunsaturated fatty acids (PUFA) was the highest, followed by saturated fatty acids (SFA), and the lowest content of monounsaturated fatty acids (MUFA) in autumn and winter. Results of the similarity ana-lysis showed significant differences in PUFA and MUFA contents but no differences in SFA contents between autumn and winter. Results of non-metric multidimensional scale analysis showed that C18:1n9 could be used as signature fatty acids in autumn samples and C22:6n3 as characteristic fatty acids in winter samples. There was significant difference of δ15N between autumn and winter, but no difference of δ13C. The total area (TA), range of δ15N (NR), standard ellipse area (SEA) and the corrected version of the standard ellipse area (SEAC) in autumn were all smaller than those in winter, but range of δ13C (CR) was on the contrary. Results of the Spearman rank correlation test showed that there were differences between fatty acid content and stable isotope ratio of U. edulis and the dorsal mantle length in autumn and winter. Our results could provide basic data for understanding material and energy flow of the East China Sea food web, which is conducive to the sustainable development and utilization of U. edulis.


Assuntos
Ecologia , Ácidos Graxos , Animais , Estações do Ano , Ácidos Graxos Monoinsaturados , Decapodiformes , China , Isótopos
3.
Trends Immunol ; 43(12): 990-1005, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36347788

RESUMO

Metabolites are emerging as essential factors for the immune system that are involved in both metabolic circuits and signaling cascades. Accumulated evidence suggests that altered metabolic programs initiated by the activation and maturation of immune cell types are accompanied by the delivery of various metabolites into the local environment. We propose that, in addition to protein/peptide ligands, secreted immune metabolites (SIMets) are essential components of immune communication networks that fine-tune immune responses under homeostatic and pathological conditions. We summarize recent advances in our understanding of SIMets and discuss the potential mechanisms by which some metabolites engage in immunological responses through receptor-, transporter-, and post-translational-mediated regulation. These insights may contribute to understanding physiology and developing effective therapeutics for inflammatory and immune-mediated diseases.


Assuntos
Comunicação Celular , Doenças do Sistema Imunitário , Humanos , Transdução de Sinais , Ligantes
4.
Science ; 378(6618): eabj3510, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36302005

RESUMO

Spermidine (SPD) delays age-related pathologies in various organisms. SPD supplementation overcame the impaired immunotherapy against tumors in aged mice by increasing mitochondrial function and activating CD8+ T cells. Treatment of naïve CD8+ T cells with SPD acutely enhanced fatty acid oxidation. SPD conjugated to beads bound to the mitochondrial trifunctional protein (MTP). In the MTP complex, synthesized and purified from Escherichia coli, SPD bound to the α and ß subunits of MTP with strong affinity and allosterically enhanced their enzymatic activities. T cell-specific deletion of the MTP α subunit abolished enhancement of programmed cell death protein 1 (PD-1) blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation.


Assuntos
Linfócitos T CD8-Positivos , Mitocôndrias , Subunidade alfa da Proteína Mitocondrial Trifuncional , Subunidade beta da Proteína Mitocondrial Trifuncional , Neoplasias , Espermidina , Animais , Camundongos , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária , Mitocôndrias/metabolismo , Subunidade alfa da Proteína Mitocondrial Trifuncional/metabolismo , Subunidade beta da Proteína Mitocondrial Trifuncional/metabolismo , Espermidina/farmacologia , Espermidina/metabolismo , Neoplasias/imunologia
5.
Nature ; 599(7885): 471-476, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34732892

RESUMO

Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1-3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.


Assuntos
Linfócitos B/metabolismo , Interleucina-10/imunologia , Macrófagos/metabolismo , Neoplasias/imunologia , Ácido gama-Aminobutírico/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Feminino , Deleção de Genes , Glutamato Descarboxilase/deficiência , Glutamato Descarboxilase/genética , Humanos , Inflamação/imunologia , Inflamação/prevenção & controle , Macrófagos/imunologia , Masculino , Camundongos , Neoplasias/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Ácido gama-Aminobutírico/biossíntese
6.
Biol Trace Elem Res ; 189(2): 478-489, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30109551

RESUMO

Nanometer zinc oxide (nano-ZnO) is widely used in many kinds of fields. However, information about the toxicity and toxic mechanism of nano-ZnO is limited. The aims of this study were to investigate the long-term toxic effects of unmodified 50 nm ZnO administered by gavage in mice. After 90 days, hematological parameters, hepatic and renal functions, and oxidative and anti-oxidative status were measured. Pathological damages in livers, kidneys, and other tissues were also examined by hematoxylin and eosin (H&E) staining. The results showed that oral nano-ZnO exposure induced anemia and damages to liver and kidney, influenced the antioxidant system, and impacted functions of liver and kidney in mice after a 90-day exposure. The main cause for oxidative stress in vivo induced by nano-ZnO might be hydroxyl free radical. The lowest observed adverse effect level (LOAEL) was 40 mg/kg·bw, and the livers, kidneys, lungs, pancreas, and gastrointestinal tracts are the target organs.


Assuntos
Nanopartículas Metálicas/química , Óxido de Zinco/toxicidade , Anemia/induzido quimicamente , Animais , Feminino , Hematoxilina/química , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Nanopartículas Metálicas/efeitos adversos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Óxido de Zinco/química
7.
Nat Immunol ; 18(12): 1342-1352, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29058703

RESUMO

T cells reorganize their metabolic profiles after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored. Here we report that augmented T cell responses in Pdcd1-/- mice, which lack the inhibitory receptor PD-1, induced a metabolic serum signature characterized by depletion of amino acids. We found that the depletion of amino acids in serum was due to the accumulation of amino acids in activated Pdcd1-/- T cells in the lymph nodes. A systemic decrease in tryptophan and tyrosine led to substantial deficiency in the neurotransmitters serotonin and dopamine in the brain, which resulted in behavioral changes dominated by anxiety-like behavior and exacerbated fear responses. Together these data indicate that excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune system.


Assuntos
Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Medo/fisiologia , Ativação Linfocitária/imunologia , Receptor de Morte Celular Programada 1/genética , Linfócitos T/imunologia , Aminoácidos/sangue , Animais , Encéfalo/metabolismo , Dopamina/deficiência , Interferon gama/sangue , Cinurenina/sangue , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Morte Celular Programada 1/deficiência , Serotonina/deficiência , Linfócitos T/metabolismo , Triptofano/metabolismo , Tirosina/metabolismo
8.
Proc Natl Acad Sci U S A ; 113(30): 8490-5, 2016 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-27410049

RESUMO

PD-1 (programmed-death 1), an immune-inhibitory receptor required for immune self-tolerance whose deficiency causes autoimmunity with variable severity and tissue specificity depending on other genetic factors, is expressed on activated T cells, including the transcription factor FoxP3(+) Treg cells known to play critical roles in maintaining immune tolerance. However, whether PD-1 expression by the Treg cells is required for their immune regulatory function, especially in autoimmune settings, is still unclear. We found that mice with partial FoxP3 insufficiency developed early-onset lympho-proliferation and lethal autoimmune pancreatitis only when PD-1 is absent. The autoimmune phenotype was rescued by the transfer of FoxP3-sufficient T cells, regardless of whether they were derived from WT or PD-1-deficient mice, indicating that Treg cells dominantly protect against development of spontaneous autoimmunity without intrinsic expression of PD-1. The absence of PD-1 combined with partial FoxP3 insufficiency, however, led to generation of ex-FoxP3 T cells with proinflammatory properties and expansion of effector/memory T cells that contributed to the autoimmune destruction of target tissues. Altogether, the results suggest that PD-1 and FoxP3 work collaboratively in maintaining immune tolerance mostly through nonoverlapping pathways. Thus, PD-1 is modulating the activation threshold and maintaining the balance between regulatory and effector T cells, whereas FoxP3 is sufficient for dominant regulation through maintaining the integrity of the Treg function. We suggest that genetic or environmental factors that even moderately affect the expression of both PD-1 and FoxP3 can cause life-threatening autoimmune diseases by disrupting the T-cell homeostasis.


Assuntos
Doenças Autoimunes/imunologia , Fatores de Transcrição Forkhead/imunologia , Tolerância Imunológica/imunologia , Pancreatite/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Autoimunidade/genética , Autoimunidade/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica/imunologia , Humanos , Tolerância Imunológica/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pancreatite/genética , Pancreatite/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
9.
Infect Immun ; 84(9): 2653-61, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27382021

RESUMO

Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli (EHEC), can be classified into two subgroups, Stx1 and Stx2, each consisting of various closely related subtypes. Stx2 subtypes Stx2a and Stx2d are highly virulent and linked with serious human disorders, such as acute encephalopathy and hemolytic-uremic syndrome. Through affinity-based screening of a tetravalent peptide library, we previously developed peptide neutralizers of Stx2a in which the structure was optimized to bind to the B-subunit pentamer. In this study, we identified Stx2d-selective neutralizers by targeting Asn16 of the B subunit, an amino acid unique to Stx2d that plays an essential role in receptor binding. We synthesized a series of tetravalent peptides on a cellulose membrane in which the core structure was exactly the same as that of peptides in the tetravalent library. A total of nine candidate motifs were selected to synthesize tetravalent forms of the peptides by screening two series of the tetravalent peptides. Five of the tetravalent peptides effectively inhibited the cytotoxicity of Stx2a and Stx2d, and notably, two of the peptides selectively inhibited Stx2d. These two tetravalent peptides bound to the Stx2d B subunit with high affinity dependent on Asn16. The mechanism of binding to the Stx2d B subunit differed from that of binding to Stx2a in that the peptides covered a relatively wide region of the receptor-binding surface. Thus, this highly optimized screening technique enables the development of subtype-selective neutralizers, which may lead to more sophisticated treatments of infections by Stx-producing EHEC.


Assuntos
Aminoácidos/metabolismo , Peptídeos/metabolismo , Toxina Shiga II/metabolismo , Fatores de Virulência/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Escherichia coli Êntero-Hemorrágica/metabolismo , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Biblioteca de Peptídeos , Ligação Proteica/fisiologia , Células Vero
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