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1.
J Immunol ; 204(8): 2216-2231, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32169843

RESUMO

Nucleotide oligomerization domain-like receptors (NLRs) and RIG-I-like receptors (RLRs) detect diverse pathogen-associated molecular patterns to activate the innate immune response. The role of mammalian NLR NOD1 in sensing bacteria is well established. Although several studies suggest NOD1 also plays a role in sensing viruses, the mechanisms behind this are still largely unknown. In this study, we report on the synergism and antagonism between NOD1 and MDA5 isoforms in teleost. In zebrafish, the overexpression of NOD1 enhances the antiviral response and mRNA abundances of key antiviral genes involved in RLR-mediated signaling, whereas the loss of NOD1 has the opposite effect. Notably, spring viremia of carp virus-infected NOD1-/- zebrafish exhibit reduced survival compared with wild-type counterparts. Mechanistically, NOD1 targets MDA5 isoforms and TRAF3 to modulate the formation of MDA5-MAVS and TRAF3-MAVS complexes. The cumulative effects of NOD1 and MDA5a (MDA5 normal form) were observed for the binding with poly(I:C) and the formation of the MDA5a-MAVS complex, which led to increased transcription of type I IFNs and ISGs. However, the antagonism between NOD1 and MDA5b (MDA5 truncated form) was clearly observed during proteasomal degradation of NOD1 by MDA5b. In humans, the interactions between NOD1-MDA5 and NOD1-TRAF3 were confirmed. Furthermore, the roles that NOD1 plays in enhancing the binding of MDA5 to MAVS and poly(I:C) are also evolutionarily conserved across species. Taken together, our findings suggest that mutual regulation between NOD1 and MDA5 isoforms may play a crucial role in the innate immune response and that NOD1 acts as a positive regulator of MDA5/MAVS normal form-mediated immune signaling in vertebrates.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , RNA Helicases DEAD-box/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , RNA Viral/metabolismo , Transdução de Sinais/imunologia , Proteínas de Peixe-Zebra/metabolismo , Animais , Sítios de Ligação , Células Cultivadas , Células HEK293 , Células HeLa , Humanos , Imunidade Inata , Proteína Adaptadora de Sinalização NOD1/deficiência , Peixe-Zebra , Proteínas de Peixe-Zebra/deficiência
2.
J Asian Nat Prod Res ; 24(9): 810-819, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34762531

RESUMO

One new citrinin monomer derivative (1), and two new natural products α-pyrone analogues (2a and 2b), were isolated from the sponge derived fungus Penicillium sp. SCSIO 41302. Their structures were determined by extensive spectroscopic analysis, chiral-phase HPLC analysis, modified Mosher's method, ECD calculations, and X-ray single-crystal diffraction. Bioactivity screening showed that compounds 2b and 8 exhibited obvious inhibitory activities against pancreatic lipase and acetyl cholinesterase with IC50 values of 48.5 and 4.8 µM, respectively, which indicated that different chiral center between enantiomers (2a and 2b) might result in different biological activities (IC50 value against PL for 2a >100 µg/ml).


Assuntos
Produtos Biológicos , Citrinina , Penicillium , Produtos Biológicos/química , Colinesterases , Lipase , Estrutura Molecular , Penicillium/química , Pironas/farmacologia
3.
Fish Shellfish Immunol ; 94: 355-372, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31533079

RESUMO

Streptococcus agalactiae is a major aquaculture pathogen infecting various saltwater and freshwater fish. To better understand the mechanism of the immune responses to S. agalactiae in wildtype zebrafish, the transcriptomic profiles of two organs containing mucosal-associated lymphoid tissues from S. agalactiae-infected and non-infected groups were obtained using RNA-seq techniques. In the intestines, 6735 and 12908 differently expressed genes (DEGs) were identified at 24 hpi and 48 hpi, respectively. Among 66 and 116 significantly enriched pathways, 15 and 21 pathways were involved in immune system or signal transduction at 24 hpi and 48 hpi, respectively. A number of genes involved in Toll-like receptor signaling pathway, RIG-I-like receptor signaling pathway, NOD-like receptor signaling pathway, T cell receptor signaling pathway, B cell receptor signaling pathway, Antigen processing and presentation, NF-kappa B signaling pathway and PI3K-Akt signaling pathway were significantly downregulated. In the skins, 3113 and 4467 DEGs were identified at 24 hpi and 48 hpi, respectively. Among 24 and 56 significantly enriched pathways, 4 and 13 pathways were involved in immune system or signal transduction at 24 hpi and 48 hpi, respectively. More immune-related signaling pathways including Leukocyte transendothelial migration, Cytokine-cytokine receptor interaction, PI3K-Akt signaling pathway, IL-17 signaling pathway, MAPK signaling pathway, TNF signaling pathway, Complement and coagulation cascades, Hematopoietic cell lineage and Jak-STAT signaling pathway were differently enriched for upregulated DEGs at 48 hpi, which were completely different from that in the intestines. Furthmore, comparative transcriptome analysis revealed that the downregulated 1618 genes and upregulated 1622 genes existed both at 24 hpi and 48 hpi for the intestine samples. In the skins, the downregulated 672 genes and upregulated 428 genes existed both at 24 hpi and 48 hpi. Three pathways related to immune processes were significantly enriched for downregulated DEGs both in the intestines and skins collected at 24 hpi and 48 hpi, which included Antigen processing and presentation, Intestinal immune network for IgA production and Hematopoietic cell lineage. Interaction network analysis of DEGs identified the main DEGs in the sub-network of complement and coagulation cascades both in the intestines and skins. Twenty of DEGs involved in complement and coagulation cascades were further validated by Real-time quantitative PCR. Altogether, the results obtained in this study will provide insight into the immune response of zebrafish against S. agalactiae XQ-1 infection in fatal conditions, and reveal the discrepant expression pattern of complement and coagulation cascades in the intestines and skins.


Assuntos
Imunidade Adaptativa/genética , Doenças dos Peixes/imunologia , Imunidade Inata/genética , Transcriptoma/genética , Transcriptoma/imunologia , Peixe-Zebra/genética , Peixe-Zebra/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Regulação da Expressão Gênica/imunologia , Filogenia , Alinhamento de Sequência/veterinária , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus agalactiae/fisiologia
4.
Fish Shellfish Immunol ; 54: 135-43, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27060200

RESUMO

TANK-binding kinase 1 (TBK1) is an essential serine/threonine-protein kinase required for Toll-like receptor (TLR)- and retinoic acid-inducible gene I (RIG-I) -mediated induction of type I IFN and host antiviral defense. In the present study, TBK1-like transcript, namely TBK1L, was cloned from zebrafish. Compared with TBK1, TBK1L contains an incomplete S_TKc domain, and lacks UBL_TBK1_like domain. Realtime PCR showed that TBK1L was constitutively produced in embryos, early larvae and ZF4 cells, and unchanged in ZF4 cells following SVCV infection. Overexpression of TBK1 but not TBK1L resulted in significant activation of zebrafish IFN1 and IFN3 promoters. Similarly, TBK1L had little impact on the antiviral state of the cells. However, the overexpression of TBK1L negatively regulated the induction of zebrafish IFN1 and/or IFN3 promoters mediated by the retinoic acid-inducible gene I-like receptors (RLRs), MAVS and TBK1. In addition, the overexpression of TBK1L in zebrafish embryos led to the decreased production of many IFN-stimulated genes induced by TBK1. Collectively, these data support that zebrafish TBK1L negatively regulates RLRs-MAVS-TBK1 pathway.


Assuntos
Doenças dos Peixes/imunologia , Imunidade Inata , Interferons/genética , Proteínas Serina-Treonina Quinases/genética , Infecções por Rhabdoviridae/veterinária , Rhabdoviridae/fisiologia , Proteínas de Peixe-Zebra/genética , Peixe-Zebra , Sequência de Aminoácidos , Animais , Doenças dos Peixes/virologia , Interferons/metabolismo , Filogenia , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Infecções por Rhabdoviridae/imunologia , Infecções por Rhabdoviridae/virologia , Transdução de Sinais , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/metabolismo
5.
Vet Res ; 46: 136, 2015 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-26589400

RESUMO

The emergence of an infectious viral disease caused by the Chinese giant salamander iridovirus (GSIV) has led to substantial economic losses. However, no more molecular information is available for the understanding of the mechanisms associated with virus-host interaction. In this study, de novo sequencing was used to obtain abundant high-quality ESTs and investigate differentially-expressed genes in the spleen of Chinese giant salamanders that were either infected or mock infected with GSIV. Comparative expression analysis indicated that 293 genes were down-regulated and 220 genes were up-regulated. Further enrichment analysis showed that the most enriched pathway is "complement and coagulation cascades", and significantly enriched diseases include "inherited thrombophilia", "immune system diseases", "primary immunodeficiency", "complement regulatory protein defects", and "disorders of nucleotide excision repair". Additionally, 30 678 simple sequence repeats (SSRs) from all spleen samples, 26 355 single nucleotide polymorphisms (SNPs) from the spleens of uninfected animals and 36 070 SNPs from the spleens of infected animals were detected. The large amount of variation was specific for the Chinese giant salamanders that were infected with GSIV. The results reported herein provided significant and new EST information that could contribute greatly in investigations into the molecular functions of immune genes in the Chinese giant salamander.


Assuntos
Infecções por Vírus de DNA/veterinária , Ranavirus/fisiologia , Transcriptoma , Urodelos , Animais , Infecções por Vírus de DNA/genética , Infecções por Vírus de DNA/virologia , Etiquetas de Sequências Expressas , Baço/metabolismo , Baço/virologia , Urodelos/genética
6.
Technol Health Care ; 32(1): 191-200, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37393446

RESUMO

BACKGROUND: Chronic heart failure (CHF) is the terminal stage of cardiovascular disease. OBJECTIVE: In this study, the "hospital-to-home + online-to-offline" (H2H + O2O) care scheme was implemented for patients with CHF during vulnerable periods, and its effect was evaluated. METHODS: Patients with CHF in the cardiovascular department of a Class III/Grade A hospital in Jiangxi Province from January to December 2020 were selected using a convenience sampling method and randomly divided into a control and intervention group (n= 100 each). The patients in the control group received routine in-hospital treatment and out-of-hospital follow-up, while in the intervention group, a multi-disciplinary cooperation team with CHF specialist nurses evaluated and stratified the patients before discharge and formulated individualized prescriptions and care plans. Based on the "Health & Happiness" chronic disease follow-up application designed for this study, the specialist nurses provided patients with one-to-one guidance. After three months, the cardiac function, heart failure knowledge, self-care behavior, and re-hospitalization rate of the patients were compared between the two groups. Cardiac function was evaluated by the serum B-type natriuretic peptide (BNP), the left ventricular ejection fraction (LVEF), and a six-minute walking test (6MWT). Heart failure knowledge and self-care behavior was assessed using specific questionaries. RESULTS: The level of cardiac function in the intervention group was significantly higher than that in the control group, and the difference was statistically significant (P< 0.001). The mastery of heart failure knowledge and self-care behavior in the intervention group were significantly higher than those in the control group, and the differences were statistically significant (P< 0.05). The re-hospitalization rate due to CHF in the intervention group was 21.0%, which was lower than that in the control group (35.0%), and the difference was statistically significant (P< 0.05). CONCLUSION: The H2H + O2O care scheme can be used for the transition of vulnerable patients with CHF from the hospital to family care to improve the patients' level of cardiac function, elevate their knowledge level and self-care abilities, and improve their overall health outcomes.


Assuntos
Insuficiência Cardíaca , Função Ventricular Esquerda , Humanos , Volume Sistólico , Insuficiência Cardíaca/terapia , Doença Crônica , Hospitais
7.
Adv Sci (Weinh) ; 11(10): e2307746, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38145346

RESUMO

Electrical stimulation (ES) is proposed as a therapeutic solution for managing chronic wounds. However, its widespread clinical adoption is limited by the requirement of additional extracorporeal devices to power ES-based wound dressings. In this study, a novel sandwich-structured photovoltaic microcurrent hydrogel dressing (PMH dressing) is designed for treating diabetic wounds. This innovative dressing comprises flexible organic photovoltaic (OPV) cells, a flexible micro-electro-mechanical systems (MEMS) electrode, and a multifunctional hydrogel serving as an electrode-tissue interface. The PMH dressing is engineered to administer ES, mimicking the physiological injury current occurring naturally in wounds when exposed to light; thus, facilitating wound healing. In vitro experiments are performed to validate the PMH dressing's exceptional biocompatibility and robust antibacterial properties. In vivo experiments and proteomic analysis reveal that the proposed PMH dressing significantly accelerates the healing of infected diabetic wounds by enhancing extracellular matrix regeneration, eliminating bacteria, regulating inflammatory responses, and modulating vascular functions. Therefore, the PMH dressing is a potent, versatile, and effective solution for diabetic wound care, paving the way for advancements in wireless ES wound dressings.


Assuntos
Diabetes Mellitus , Hidrogéis , Humanos , Biomimética , Proteômica , Cicatrização , Bandagens
8.
ACS Biomater Sci Eng ; 9(5): 2203-2219, 2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-37075172

RESUMO

Bone comprises mechanically different materials in a specific hierarchical structure. Mineralized collagen fibrils (MCFs), represented by tropocollagen molecules and hydroxyapatite nanocrystals, are the fundamental unit of bone. The mechanical characterization of MCFs provides the unique adaptive mechanical competence to bone to withstand mechanical load. The structural and mechanical role of MCFs is critical in the deformation mechanisms of bone and the marvelous strength and toughness possessed by bone. However, the role of MCFs in the mechanical behavior of bone across multiple length scales is not fully understood. In the present study, we shed light upon the latest progress regarding bone deformation at multiple hierarchical levels and emphasize the role of MCFs during bone deformation. We propose the concept of hierarchical deformation of bone to describe the interconnected deformation process across multiple length scales of bone under mechanical loading. Furthermore, how the deterioration of bone caused by aging and diseases impairs the hierarchical deformation process of the cortical bone is discussed. The present work expects to provide insights on the characterization of MCFs in the mechanical properties of bone and lays the framework for the understanding of the multiscale deformation mechanics of bone.


Assuntos
Osso e Ossos , Colágeno , Osso Cortical , Matriz Extracelular , Durapatita
9.
Elife ; 122023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-37551884

RESUMO

Sauropterygia was a taxonomically and ecomorphologically diverse clade of Mesozoic marine reptiles spanning the Early Triassic to the Late Cretaceous. Sauropterygians are traditionally divided into two groups representing two markedly different body plans - the short-necked, durophagous Placodontia and the long-necked Eosauropterygia - whereas Saurosphargidae, a small clade of armoured marine reptiles, is generally considered as the sauropterygian sister-group. However, the early evolutionary history of sauropterygians and their phylogenetic relationships with other groups within Diapsida are still incompletely understood. Here, we report a new saurosphargid from the Early Triassic (Olenekian) of South China - Prosaurosphargis yingzishanensis gen. et sp. nov. - representing the earliest known occurrence of the clade. An updated phylogenetic analysis focussing on the interrelationships among diapsid reptiles recovers saurosphargids as nested within sauropterygians, forming a clade with eosauropterygians to the exclusion of placodonts. Furthermore, a clade comprising Eusaurosphargis and Palatodonta is recovered as the sauropterygian sister-group within Sauropterygomorpha tax. nov. The phylogenetic position of several Early and Middle Triassic sauropterygians of previously uncertain phylogenetic affinity, such as Atopodentatus, Hanosaurus, Majiashanosaurus, and Corosaurus, is also clarified, elucidating the early evolutionary assembly of the sauropterygian body plan. Finally, our phylogenetic analysis supports the placement of Testudines and Archosauromorpha within Archelosauria, a result strongly corroborated by molecular data, but only recently recovered in a phylogenetic analysis using a morphology-only dataset. Our study provides evidence for the rapid diversification of sauropterygians in the aftermath of the Permo-Triassic mass extinction event and emphasises the importance of broad taxonomic sampling in reconstructing phylogenetic relationships among extinct taxa.


Around 252 million years ago, just before the start of a period of time known as the Triassic, over 90% of animals, plants and other species on Earth went extinct in what was the worst mass extinction event in the planet's history. It is thought to have happened because of an increase in volcanic eruptions that led to global warming, acid rain and other catastrophic changes in the environment. The loss of so many species caused ecosystems to restructure as the surviving species evolved to fill niches left by those that had gone extinct. On land, reptiles diversified to give rise to dinosaurs, the flying pterosaurs, and the ancestors of modern crocodiles, lizards, snakes and turtles. Some of these land-based animals evolved to live in water, resulting in many species of marine reptiles emerging during the Triassic period. This included the saurosphargids, a group of marine reptiles that lived in the Middle Triassic around 247­237 million years ago. They were 'armoured' with a shield made of broadened ribs superficially similar to that of turtles, and a covering of bony plates. However, it is unclear how the saurosphargids evolved and how closely they are related to other marine reptiles. Here, Wolniewicz et al. studied a new species of saurosphargid named Prosaurosphargis yingzishanensis that was found fossilized in a quarry in South China. The animal was around 1.5 metres long and had a chest shield and armoured plates like other saurosphargids. The characteristics of the rock surrounding the fossil suggest that this individual lived in the Early Triassic, several million years before other saurosphargid species. The team used a phylogenetic approach to infer the evolutionary relationships between P. yingzishanensis and numerous other land-based and marine reptiles based on over 220 anatomical characteristics of the animals. The resulting evolutionary tree indicated that the saurosphargids represented an early stage in the evolution of a larger group of marine reptiles known as the sauropterygians. The analysis also identified the closest land-based relatives of sauropterygians. These findings provide evidence that marine reptiles rapidly diversified in the aftermath of the mass extinction event 252 million years ago. Furthermore, they contribute to our understanding of how ecosystems recover after a major environmental crisis.


Assuntos
Evolução Biológica , Répteis , Animais , Filogenia , Répteis/anatomia & histologia , Vertebrados , China , Fósseis
10.
Nat Prod Res ; 37(3): 389-396, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34498972

RESUMO

A new indole diketopiperazine alkaloid, named penilline D (1), together with five known indole alkaloid analogues (2-5, 11), two meroterpenoids (6 and 12), and four butenolide derivatives (7-10), were isolated from the Antarctic fungus Penicillium sp. SCSIO 05705. Extensive spectroscopic analysis and electronic circular dichroism (ECD) calculation were used to elucidate the structure of penilline D (1), including its absolute configuration. All isolated compounds (1-12) were evaluated for their cytotoxic, antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among them, compound 5 exhibited moderate in vitro cytotoxic activity against the 143B cell line with IC50 value of 12.64 ± 0.78 µM. Compound 6 showed strong inhibitory activity against AChE with IC50 value of 0.36 nM (IC50 18.7 nM for Tacrine), while compounds 6 and 11 showed weak PL enzyme inhibitory activity. Furthermore, an in silico molecular docking study was also performed between 6 and AChE.


Assuntos
Antineoplásicos , Penicillium , Policetídeos , Acetilcolinesterase , Dicroísmo Circular , Dicetopiperazinas , Alcaloides Indólicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Penicillium/química , Policetídeos/química
11.
J Appl Physiol (1985) ; 135(6): 1390-1401, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37942531

RESUMO

Resistance exercise is an indispensable mode of exercise rehabilitation for heart failure. Here we elucidate the cardiac effects of resistance training alone or combined with different aerobic trainings on heart failure and explore the critical regulation of mitophagy. The chronic heart failure model was constructed by transverse aortic constriction surgery, followed by 8 wk of resistance training (RT), moderate-intensity continuous training combined with resistance training (MRT), and high-intensity interval training combined with resistance training (HRT), and subsequently analyzed the changes of maximum load, cardiac structure and function, and myocardial mitophagic activity. The role and signaling of mitophagy in exercise protection of heart failure were investigated by knockdown of Hif1α and Parkin genes in primary neonatal cardiomyocytes. RT and especially MRT improved maximum load (P < 0.0001), myocardial morphology and fibrosis (P < 0.0001), reduced left ventricular diameter and enhanced left ventricular systolic function (P < 0.01), and enhanced myocardial mitophagic activity and HIF1α expression (P < 0.05) in heart failure mice. However, HRT had no obvious protective effect on ventricular diameter and function or mitophagy. The abilities of exercise stimulation to regulate reactive oxygen species, adenosine triphosphate, and brain natriuretic peptide were impaired after knockdown of Hif1α and Parkin genes inhibited mitophagy in failing cardiomyocytes (P < 0.05). Different exercise modalities provide discrepant cardiovascular effects on heart failure, and MRT exhibits optimal protection. The HIF1α-Parkin-mitophagy pathway is involved in the protection and regulation of exercise on heart failure.NEW & NOTEWORTHY Impaired myocardial mitophagy is implicated in the pathogenesis of heart failure. Resistance training alone or combined with different aerobic trainings provide discrepant cardiovascular effects on heart failure, and the cardioprotective function depends on HIF1α-Parkin-mitophagy pathway.


Assuntos
Insuficiência Cardíaca , Treinamento Resistido , Humanos , Camundongos , Animais , Mitofagia , Miócitos Cardíacos/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
12.
Behav Brain Res ; 431: 113952, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35688293

RESUMO

Cognitive dysfunction is a common symptom in Parkinson's disease (PD). Serotonin4 (5-HT4) receptors are richly expressed in the dorsal hippocampus (dHIPP) and play an important role in cognitive activities. However, the mechanism underlying the role of dHIPP 5-HT4 receptors in PD-related cognitive dysfunction remains unclear. Here we found that unilateral 6-hydroxydopamine lesions of the medial forebrain bundle increased the protein expression of 5-HT4 receptors in the dHIPP, decreased hippocampal theta rhythm, and impaired working memory and hippocampus-dependent memory in the T-maze and hole-board test, respectively. Both activation and blockade of dHIPP 5-HT4 receptors (agonist BIMU8 and antagonist GR113808) improved working memory and hippocampus-dependent memory in the lesioned rats, but not in sham rats. Activation of dHIPP 5-HT4 receptors increased hippocampal theta rhythm in the lesioned rats. The neurochemical studies showed that injection of BIMU8, GR113808 or GR113808/BIMU8 in the dHIPP increased the levels of dopamine in the medial prefrontal cortex (mPFC), dHIPP and amygdala, and the level of 5-HT in the amygdala in the lesioned rats, but not in sham rats. Injection of GR113808 or GR113808/BIMU8 into the dHIPP also increased the levels of noradrenaline in the mPFC, dHIPP and amygdala only in the lesioned rats. These results suggest that activation or blockade of dHIPP 5-HT4 receptors may improve the cognitive impairments in parkinsonian rats, which may be due to the increase of hippocampal theta rhythm, up-regulated expressions of 5-HT4 receptors in the dHIPP and the changes in the levels of monoamines in the relative brain areas.


Assuntos
Doença de Parkinson , Transtornos Parkinsonianos , Animais , Hipocampo/metabolismo , Oxidopamina , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo
13.
Nat Prod Res ; 36(5): 1197-1204, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33356598

RESUMO

A new diketopiperazine, cyclo-(d-8-acetoxyl-Pro-l-Leu) (1), together with eight known compounds (2-9) including three enterotoxins (2-4), four diketopiperazines (5-8) and maltol (9), were isolated from the mangrove derived-soil Streptomyces sp. SCSIO 41400. The planar structures of all compounds were determined from analysis of NMR spectra, MS, optical rotation and comparing with literature data. The absolute configuration of compound 1 was assigned by electronic circular dichroism (ECD). The isolated compounds (1-9) were tested for their acetyl cholinesterase (AChE) and pancreatic lipase (PL) enzyme inhibitory activities. Among them, the new diketopiperazine (1) displayed preferable PL enzyme inhibitory activity with IC50 value of 27.3 µg/mL, while compounds 2, 5 and 6 showed weak PL enzyme inhibitory activity. Further molecular docking simulation exhibited that compound 1 could be well bind with the catalytic pocket of the PL. Besides, compound 9 showed moderate antibacterial activity against Methicillin-resistant Staphylococcus aureus with MIC value of 12.5 µg/mL, which was comparable to that of the positive control ampicillin with MIC value of 3.125 µg/mL.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Streptomyces , Antibacterianos/química , Dicetopiperazinas/química , Enterotoxinas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Solo , Streptomyces/química
14.
Dev Comp Immunol ; 114: 103859, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32896535

RESUMO

The nucleotide-binding domain and leucine-rich repeat-containing family (NLR) proteins are innate immune sensors which recognize highly conserved pathogen-associated molecular patterns (PAMPs). Mammals have small numbers of NLR proteins, whereas in some species such as in invertebrates and jawless vertebrates, NLRs have expanded into very large families. Nearly 400 NLR proteins are identified in the zebrafish genome. Members of the NLR family can be divided into two functional sub-groups based on their ability to either positively or negatively regulate host immune response or inflammatory signaling cascades. Mammalian NLRC3 has been identified as an inhibitory NLR, and serves as a negative regulator in the NF-κB-mediated inflammatory response, STING-mediated DNA sensing and PI3K-mTOR pathways. Different from mammalian NLRC3, the analysis from genomes or transcriptomes revealed that the expansions of NLRC3 existed in different species of fish. Furthermore, piscine NLRC3-like genes were confirmed to have a negative or positive regulatory function in response to different kinds of pathogen infections and in the production of proinflammatory cytokines. In this review, we summarize recent advances in our understanding of the expanding and function of NLRC3 or NLRC3-like genes in teleost fish, and give our view of important directions for future studies. The knowledge of piscine NLRC3 or expansive NLRC3-like genes-mediated biological functions in homeostasis and diseases will shed new light on the prevention and control of inflammatory and/or infectious diseases.


Assuntos
Proteínas de Peixes/metabolismo , Peixes/metabolismo , Infecções/imunologia , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Proteínas de Peixes/genética , Peixes/imunologia , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mamíferos , NF-kappa B/metabolismo , Moléculas com Motivos Associados a Patógenos/imunologia , Transdução de Sinais , Proteínas de Peixe-Zebra/genética
15.
Int J Gen Med ; 14: 1507-1511, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33911895

RESUMO

OBJECTIVE: The aim of this study is to evaluate the impact on blood pressure (BP) of a 10°C change in room temperature (between 18°C and 28°C). METHODS: A total of 112 volunteers, 56 males and 56 females, 55 with and 57 without hypertension, were enrolled in the study. First, the participants were placed in a 25°C room. Second, they were randomly assigned to either a 28°C (group A) or an 18°C room (group B). Finally, they were moved from the 28°C to the 18°C room, or vice versa. They stayed in each room for 20 minutes. Seated BP was measured at the 17th and 19th minute in each room, and the average was used. The difference in the subject's BP between the second two rooms was recorded as delta BP. RESULTS: The baseline systolic BP (SBP), age, gender distribution, and incidence of hypertension were similar between the two groups. In group A, the decrease in room temperature of 10°C induced a mean rise in SBP of 4.1 mmHg. In group B, the increase of 10°C caused SBP to decrease by 4.0 mmHg. When compared with the group without hypertension, the group with hypertension had a significantly higher rise in mean SBP (6.8 vs 1.2 mmHg) as a result of the decrease in temperature and a significantly higher drop in SBP (7.3 vs 1.2 mmHg) as a result of the increase in temperature. The participants in the group with hypertension were older. CONCLUSION: A 10°C change in room temperature, from 18°C to 28°C, for 20 min can cause a significant change in SBP. The extent of this change is more obvious in the older group.

16.
Front Immunol ; 11: 580864, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101307

RESUMO

TANK-binding kinase 1 (TBK1), an IKK-related serine/threonine kinase, is pivotal for the induction of antiviral type I interferon (IFN) by TLR and RLR signaling pathways. In a previous study, we demonstrated that TBK1 spliced isoforms (TBK1_tv1 and TBK1_tv2) from zebrafish were dominant negative regulators in the RLR antiviral pathway by targeting the functional TBK1-IRF3 complex formation. In this study, we show that the third TBK1 isoform (namely TBK1_tv3) inhibits zebrafish type I IFN production by promoting TBK1 and IRF3 degradation. First, ectopic expression of TBK1_tv3 suppresses poly(I:C)- and Spring viremia of carp virus-induced type I IFN response, and also inhibits the up-regulation of IFN promoter activities stimulated by RIG-I, MDA5, MAVS, TBK1, and IRF3. Second, TBK1_tv3 targets TBK1 and IRF3 to impair the formation of TBK1 dimer, TBK1-IRF3 complex, and IRF3 dimer. Notably, TBK1_tv3 promotes the degradation of TBK1 through the ubiquitin-proteasome pathway and the degradation of IRF3 through the lysosomal pathway. Further analysis demonstrates that TBK1_tv3 promotes the degradation of TBK1 for K48-linked ubiquitination by targeting the K251, K256, and K271 sites of TBK1. Collectively, our results suggest a novel TBK1 isoform-mediated negative regulation mechanism, which serves to balance the production of type I IFN and ISGs.


Assuntos
Proteínas de Peixes/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Lisossomos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Células Cultivadas , Proteínas de Peixes/genética , Células HEK293 , Humanos , Interferon Tipo I/metabolismo , Isoformas de Proteínas/genética , Proteínas Serina-Treonina Quinases/genética , Proteólise , Transdução de Sinais , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
17.
Dev Comp Immunol ; 112: 103769, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32634524

RESUMO

Both NLRC3 and NOD1 belong to regulatory NLR subfamily based on their best-characterized function. In mammals, NLRC3 was reported to function by attenuating signaling cascades initiated by other families of PRRs. In teleosts, multiple NLRC3-like genes were identified through transcriptome sequencing. However, the functions of many NLRC3-like genes, especially the fish-specific NLRC3-like genes, remain unclear. In the present study, we report the functional characterization of a novel category of NLRC3-like proteins (named as NLRC3-like 1) from the zebrafish, which consists of a fish-specific FISNA, a conserved NACHT and five C-terminal LRRs domains. The expression of zebrafish NLRC3-like 1 was inducible in response to Edwardsiella piscicida infection. During bacterial infection, the in vitro and in vivo studies revealed that zebrafish NLRC3-like 1 overexpression facilitated bacterial growth and dissemination, together with the decreased survival rate of zebrafish larvae infected with E. piscicida. The attenuated response by zebrafish NLRC3-like 1 in response to bacterial infection were characterized by the impaired expression of antibacterial genes, proinflammatory cytokines and Nox genes. Furthermore, zebrafish NLRC3-like 1 interacted with the adaptor protein RIPK2 of NODs signaling via the FISNA (Fish-specific NACHT associated domain) and NACHT domains. However, the interaction between zebrafish NLRC3-like 1 and RIPK2 inhibited the assembly of the NOD1-RIPK2 complex. Importantly, zebrafish NLRC3-like 1 inhibited NOD1-mediated antibacterial activity, NF-κB and MAPK pathways and proinflammatory cytokine production. All together, these results firstly demonstrate that zebrafish NLRC3-like 1 inhibits NOD1-RIPK2 antibacterial pathway via targeting the adaptor protein RIPK2.


Assuntos
Edwardsiella/fisiologia , Infecções por Enterobacteriaceae/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Células Cultivadas , Citocinas/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Imunomodulação , Mediadores da Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , NF-kappa B/metabolismo , Transdução de Sinais , Peixe-Zebra/imunologia , Proteínas de Peixe-Zebra/genética
18.
Front Immunol ; 9: 726, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29692779

RESUMO

RIP2 is an adaptor protein which is essential for the activation of NF-κB and NOD1- and NOD2-dependent signaling. Although NOD-RIP2 axis conservatively existed in the teleost, the function of RIP2 was only reported in zebrafish, goldfish, and rainbow trout in vitro. Very little is known about the role and mechanisms of piscine NOD-RIP2 axis in vivo. Our previous study showed the protective role of zebrafish NOD1 in larval survival through CD44a-mediated activation of PI3K-Akt signaling. In this study, we examined whether RIP2 was required for larval survival with or without pathogen infection, and determined the signaling pathways modulated by RIP2. Based on our previous report and the present study, our data demonstrated that NOD1-RIP2 axis was important for larval survival in the early ontogenesis. Similar to NOD1, RIP2 deficiency significantly affected immune system processes. The significantly enriched pathways were mainly involved in immune system, such as "Antigen processing and presentation" and "NOD-like receptor signaling pathway" and so on. Furthermore, both transcriptome analysis and qRT-PCR revealed that RIP2 was a critical regulator for expression of NLRs (NOD-like receptors) and those genes involved in MHC antigen presentation. Different from NOD1, the present study showed that NOD1, but not RIP2 deficiency significantly impaired protein levels of MAPK pathways. Although RIP2 deficiency also significantly impaired the expression of CD44a, the downstream signaling of CD44a-Lck-PI3K-Akt pathway remained unchanged. Collectively, our works highlight the similarity and discrepancy of NOD1 and RIP2 in the regulation of immune signaling pathways in the zebrafish early ontogenesis, and confirm the crucial role of RIP2 in NLRs signaling and MHC antigen presentation, but not for MAPK and PI3K/Akt pathways.


Assuntos
Proteína Adaptadora de Sinalização NOD1/imunologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/imunologia , Proteínas de Peixe-Zebra/imunologia , Animais , Apresentação de Antígeno , Edwardsiella , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/veterinária , Doenças dos Peixes/imunologia , Antígenos de Histocompatibilidade/imunologia , Larva , Proteínas Quinases Ativadas por Mitógeno/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Transdução de Sinais , Peixe-Zebra
19.
Dev Comp Immunol ; 84: 153-163, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29454830

RESUMO

NOD-like receptors (NLRs) are a family of intracellular pattern recognition receptors (PRRs) that play critical roles in innate immunity against pathogens infection. NLRC5, the largest member of NLR family, has been characterized as a regulator of innate immunity and MHC class I expression. Alternative splicing of NLRC5 is only reported in human and zebrafish. However, the function of NLRC5 isoforms in the innate immune responses remains unknown. In the present study, we report the functional characterization of zfNLRC5a and zfNLRC5d, two splicing isoforms of zebrafish NLRC5. zfNLRC5a and zfNLRC5d are generated by exon skipping, and whose alternative splicing sites exist in the region of LRRs. Fluorescence microscopy showed that zfNLRC5 isoforms were located throughout the entire cell including nuclear staining. The expression of zfNLRC5 isoform was inducible in response to bacterial and viral infections. During SVCV infection, the in vitro and in vivo studies found that zfNLRC5d overexpression increased protection against viral infection; however zfNLRC5a overexpression had no significant effect on antiviral activity. Interestingly, zfNLRC5 isoforms but not zfNLRC5 were involved in transcriptional regulation of TLRs and NF-κB signaling. Overexpression of zfNLRC5 isoforms also contributed to negative regulation of antibacterial immune response, with the decreased expression of nfkbiaa (IκBα). All together, these results firstly demonstrate the function of NLRC5 isoforms in antiviral and antibacterial immune responses both in vitro and in vivo.


Assuntos
Edwardsiella/fisiologia , Infecções por Enterobacteriaceae/imunologia , Fibroblastos/imunologia , Infecções por Flavobacteriaceae/imunologia , Flavobacterium/fisiologia , Proteínas NLR/genética , Infecções por Rhabdoviridae/imunologia , Rhabdoviridae/fisiologia , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/imunologia , Animais , Linhagem Celular , Clonagem Molecular , Fibroblastos/microbiologia , Fibroblastos/virologia , Humanos , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , NF-kappa B/metabolismo , Proteínas NLR/metabolismo , Isoformas de Proteínas/genética , Transdução de Sinais , Receptores Toll-Like/metabolismo , Proteínas de Peixe-Zebra/metabolismo
20.
Front Immunol ; 9: 84, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29441066

RESUMO

TANK-binding kinase 1 (TBK1) is an important serine/threonine-protein kinase that mediates phosphorylation and nuclear translocation of IRF3, which contributes to induction of type I interferons (IFNs) in the innate antiviral response. In mammals, TBK1 spliced isoform negatively regulates the virus-triggered IFN-ß signaling pathway by disrupting the interaction between retinoic acid-inducible gene I (RIG-I) and mitochondria antiviral-signaling protein (MAVS). However, it is still unclear whether alternative splicing patterns and the function of TBK1 isoform(s) exist in teleost fish. In this study, we identify two alternatively spliced isoforms of TBK1 from zebrafish, termed TBK1_tv1 and TBK1_tv2. Both TBK1_tv1 and TBK1_tv2 contain an incomplete STKc_TBK1 domain. Moreover, the UBL_TBK1_like domain is also missing for TBK1_tv2. TBK1_tv1 and TBK1_tv2 are expressed in zebrafish larvae. Overexpression of TBK1_tv1 and TBK1_tv2 inhibits RIG-I-, MAVS-, TBK1-, and IRF3-mediated activation of IFN promoters in response to spring viremia of carp virus infection. Also, TBK1_tv1 and TBK1_tv2 inhibit expression of IFNs and IFN-stimulated genes induced by MAVS and TBK1. Mechanistically, TBK1_tv1 and TBK1_tv2 competitively associate with TBK1 and IRF3 to disrupt the formation of a functional TBK1-IRF3 complex, impeding the phosphorylation of IRF3 mediated by TBK1. Collectively, these results demonstrate that TBK1 spliced isoforms are dominant negative regulators in the RIG-I/MAVS/TBK1/IRF3 antiviral pathway by targeting the functional TBK1-IRF3 complex formation. Identification and functional characterization of piscine TBK1 spliced isoforms may contribute to understanding the role of TBK1 expression in innate antiviral response.


Assuntos
Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/biossíntese , Proteínas Serina-Treonina Quinases/metabolismo , Processamento Alternativo , Sequência de Aminoácidos , Animais , Sequência de Bases , Biomarcadores , Linhagem Celular , Expressão Gênica , Genes Reporter , Humanos , Imunidade Inata , Fosforilação , Ligação Proteica , Isoformas de Proteínas , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Peixe-Zebra
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