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Dev Comp Immunol ; 106: 103641, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32045589


Perception of extracellular ATP (eATP), a common endogenous damage-associated molecular pattern, is through its receptor P2X7R. If eATP/P2X7R signaling is conserved throughout animal evolution is unknown. Moreover, little information is currently available regarding P2X7R in invertebrates. Here we demonstrated that the coral P2X7-like receptor, AdP2X7RL, the amphioxus P2X7-like receptor, BjP2X7RL and the flounder P2X7 receptor, PoP2X7R, shared common features characteristic of mammalian P2X7R, and their 3D structures displayed high resemblance to that of human P2X7R. Expression of Adp2x7rl, Bjp2x7rl and Pop2x7r was all subjected to the regulation by LPS and ATP. We also showed that AdP2X7RL, BjP2X7RL and PoP2X7R were distributed on the plasma membrane in AdP2X7RL-, BjP2X7RL- and PoP2X7R-expressing HEK cells, and had strong affinity to eATP. Importantly, the binding of AdP2X7RL, BjP2X7RL and PoP2X7R to eATP all induced similar downstream responses, including induction of cytokines (IL-1ß, IL-6, IL-8 and CCL-2), enhancement of phagocytosis and activation of AKT/ERK-associated signaling pathway observed for mammalian P2X7R. Collectively, our results indicate for the first time that both coral and amphioxus P2X7RL as well as flounder P2X7R can interact with eATP, and induce events that trigger mammalian mechanisms, suggesting the high conservation of eATP perception throughout multicellular animal evolution.

Mol Immunol ; 117: 160-167, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31801102


The naturally occurring polysaccharide, ß-1,3-glucans, a well-known immunostimulant, has been highly valued for many years for their health-promoting and anti-aging properties, but its mode of action is poorly understood. In this study, we first showed that oral administration of ß-1,3-glucans did not affect the general condition and physiology of male mice throughout the trial period. We then showed that dietary intake of ß-1,3-glucans induced a significant increase in T helper cells (CD4+) in young, middle-aged and aged male mice. We also showed that ß-1,3-glucans supplementation considerably increased the delayed-type hypersensitivity (DTH) response, a T cell-mediated immune response, in young and aged mice. In addition, we found that ß-1,3-glucans supplementation remarkably promoted the production of total anti-keyhole limpet hemocyanin (KLH) immunoglobulin G (IgG), anti-KLH IgG1, and anti-KLH IgG2a in young and aged mice without disturbing immune homeostasis. These data together indicate that oral administration of ß-1,3-glucans enhanced the adaptive immune responses of aged mice without disturbing their general condition and physiology, supporting the idea that ß-1,3-glucans are capable of counteracting the immunosenescence in mice. They also suggest that ß-1,3-glucans can be clinically useful to help the elderly generate an improved response to vaccine with stronger humoral and cell-mediated immune responses.

Rejuvenation Res ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31591931


One of the widely accepted conjectures regarding mechanisms of aging is probably the oxidative stress hypothesis. ß-1,3-Glucans, well-known immunostimulants, have been shown to increase nonspecific immunity and resistance against infections or pathogenic bacteria in several fish species, but its antiaging function remains poorly understood. By feeding of ß-1,3-glucans to the annual fish, Nothobranchius guentheri, we detected the survivorship of the fish and estimated the development of age-related biomarkers at different stages. We first showed that administration of ß-1,3-glucans was able to prolong the lifespan of the fish (p < 0.05). We then showed that ß-1,3-glucans clearly reduced the accumulation of lipofuscin in the gills and the senescence-associated ß-galactosidase in the caudal fins. Moreover, ß-1,3-glucans were able to lower the levels of protein oxidation, lipid peroxidation, and reactive oxygen species (ROS) in the muscles. Finally, ß-1,3-glucans could promote the activities of the antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase in the fish, and slow down the increase of P66shc, a critical factor involved in the regulation of intracellular ROS contents. These data together suggest for the first time that ß-1,3-glucans can extend the lifespan, delay the onset of age-related biomarkers and exert an antioxidant action of the aged fish, N. guentheri. It also implies that ß-1,3-glucans may be potentially useful for health care in the elderly, including extension of the lifespan.

FASEB J ; 33(11): 12983-13001, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31518507


Previous studies have shown that ATP synthase α subunit (ATP5A1) plays multiple roles, but our understanding of its biologic functions remains poor and incomprehensive. Here, we clearly demonstrated that zebrafish ATP5A1 was a newly characterized lipoteichoic acid (LTA)- and LPS-binding protein abundantly stored in the eggs and embryos of zebrafish. Zebrafish ATP5A1 acted not only as a pattern recognition receptor, capable of identifying LTA and LPS, but also as an effector molecule, capable of inhibiting the growth of both gram-positive and -negative bacteria. ATP5A1 could disrupt the bacterial membranes by a combined action of membrane depolarization and permeabilization. We also found that the N-terminal 65 residues were critical for the antibacterial activity of zebrafish ATP5A1. In particular, we showed that microinjection of exogenous recombinant (r)ATP5A1 into early embryos could promote their resistance against pathogenic Aeromonas hydrophila challenge, and this pathogen-resistant activity was markedly reduced by the coinjection of anti-ATP5A1 antibody or by the knockdown with morpholino for atp5a1 but not by the coinjection of anti-actin antibody. Moreover, each egg/embryo contains a sufficient amount of ATP5A1 in vivo to kill A. hydrophila. Furthermore, the N-terminal 65 residues 1-65 of ATP5A1 α subunit (rA1-65) with in vitro antibacterial activity also promoted the resistance of embryos against A. hydrophila, but the N-terminal 69 residues 66-134 (rA66-134) or C-terminal residues 135-551 (rA135-551) of ATP5A1 α subunit without in vitro antibacterial activity did not. Finally, we showed that the antibacterial activity of the N-terminal 65 residues of ATP5A1 α subunit was conserved throughout animal evolution. Collectively, these results indicate that ATP5A1 is a novel maternal immunocompetent factor that can protect the early embryos of zebrafish from bacterial infection. This work also provides a new viewpoint for understanding the biologic roles of ATP5A1, which is ubiquitously present in animals.-Ni, S., Zhou, Y., Chen, Y., Du, X., Zhang, S. Identification of ATP synthase α subunit as a new maternal factor capable of protecting zebrafish embryos from bacterial infection.

Biogerontology ; 20(4): 433-443, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30726519


One of the most studied and widely accepted conjectures of aging process is the oxidative stress theory. Current studies have generated disputes on the effects of GDF11 and GDF8, a closely related member of GDF11, on rejuvenation and anti-aging properties. In this study, we first demonstrated that when recombinant GDF8 (rGDF8) and GDF11 (rGDF11) of the fish Nothobranchius guentheri were injected into 20-month-old male mice, their serum GDF8 and GDF11 levels were clearly increased. We also showed that injection of rGDF8 and rGDF11 had little influences on the body weight and serological parameters of the mice, indicating their general condition and physiology were not affected. Based on these findings, we started to test the effects of administration of piscine rGDF11 and rGDF8 on the aging process of male mice and to explore the underlying mechanisms. It was found that rGDF11 was able to reduce the levels of AGEs, protein oxidation and lipid peroxidation, and to slow down the accumulation of age-related histological markers, while rGDF8 was not. Moreover, rGDF11 significantly prevented the decrease in CAT, GPX and SOD activities, but rGDF8 did not. Collectively, these results suggest that it is GDF11 but not GDF8 that can exert rejuvenation and anti-aging activities via the action of antioxidant system. It is also the first report that shows the activity of GDF11 is not species-specific, implicating potential usefulness of piscine GDF11 in prolonging the lifespan of the elderly.

Envelhecimento , Ciprinodontiformes , Proteínas de Peixes/farmacologia , Miostatina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Rejuvenescimento/fisiologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Fatores de Diferenciação de Crescimento/classificação , Fatores de Diferenciação de Crescimento/metabolismo , Fatores de Diferenciação de Crescimento/farmacologia , Masculino , Camundongos , Proteínas Recombinantes/farmacologia , Resultado do Tratamento
Biogerontology ; 20(2): 225-239, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30519861


Current studies have generated disputes on the age-related change in the concentration of growth differentiation factor 11 (GDF11) and its role in the genesis of rejuvenation conditions. In this study we showed for the first time that both GDF11 gene expression and its protein abundance decreased with age in the fish Nothobranchius guentheri. We also showed that rGDF11 fed was indeed absorbed by the fish. Importantly, we demonstrated that dietary intake of recombinant GDF11 had little influences on the body weight and length of aging N. guentheri, but it delayed the development of age-related biomarkers and extended both the median and maximum life span of the fish. Our results clearly demonstrate that piscine GDF11 has rejuvenation and anti-aging capacity, the first data as such in non-mammalian vertebrates.

Envelhecimento , Fatores de Diferenciação de Crescimento , Longevidade/fisiologia , Rejuvenescimento/fisiologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Ciprinodontiformes , Fatores de Diferenciação de Crescimento/metabolismo , Fatores de Diferenciação de Crescimento/farmacologia , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia