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Loss of phosphatase and tensin homolog (PTEN) has been linked to an immunosuppressive tumor microenvironment, but its underlying mechanisms remain largely enigmatic. Here, we report that PTEN can be secreted by the transmembrane emp24 domain-containing protein 10 (TMED10)-channeled protein secretion pathway. Inhibiting PTEN secretion from tumor cells contributes to immunosuppression and impairs the tumor-suppressive role of PTEN, while intratumoral injection of PTEN protein promotes antitumor immunity and suppresses tumor growth in mice. Mechanistically, extracellular PTEN binds to the plexin domain-containing protein 2 (PLXDC2) on macrophages, triggering subsequent activation of JAK2-STAT1 signaling, which switches tumor-associated macrophages (TAMs) from the immunosuppressive to inflammatory phenotype, leading to enhanced activation of CD8+ T and natural killer cells. Importantly, PTEN treatment also enhances the therapeutic efficacy of anti-PD-1 treatment in mice and reverses the immune-suppressive phenotype of patient-derived primary TAMs. These data identify a cytokine-like role of PTEN in immune activation and tumor suppression and demonstrate the therapeutic potential for extracellular administration of PTEN in cancer immunotherapy.
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Mammalian target of rapamycin complex 1 (mTORC1) monitors cellular amino acid changes for function, but the molecular mediators of this process remain to be fully defined. Here, we report that depletion of cellular amino acids, either alone or in combination, leads to the ubiquitination of mTOR, which inhibits mTORC1 kinase activity by preventing substrate recruitment. Mechanistically, amino acid depletion causes accumulation of uncharged tRNAs, thereby stimulating GCN2 to phosphorylate FBXO22, which in turn accrues in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner. Accordingly, mutation of mTOR Lys2066 abolished mTOR ubiquitination in response to amino acid depletion, rendering mTOR insensitive to amino acid starvation both in vitro and in vivo. Collectively, these data reveal a novel mechanism of amino acid sensing by mTORC1 via a previously unknown GCN2-FBXO22-mTOR pathway that is uniquely controlled by uncharged tRNAs.
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Proteínas Serina-Treonina Quinases , Serina-Treonina Quinases TOR , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Aminoácidos/metabolismo , RNA de Transferência/genética , RNA de Transferência/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismoRESUMO
Liver fibrosis (LF) is an important reparative process in response to acute or chronic hepatic injury, which has the potential to advance towards cirrhosis and hepatocellular carcinoma. Dietary naringin consumption contributes to protection against LF in animal studies, while the exact protective mechanism of naringin remains unclear. This study aimed to investigate the molecular mechanisms behind the potential protective effect of naringin against TAA-induced LF in zebrafish. In this study, we utilized zebrafish to create the LF model and investigate the therapeutic mechanism of naringin. Firstly, we evaluated the changes in hepatic fibrosis and lipid accumulation in the liver following naringin treatment with oil red O, Nile red, and Sirius red and immunohistochemistry. In addition, we employed an ROS probe to directly measure oxidative stress and monitor inflammatory cell migration in a zebrafish transgenic line. Morpholino was used in the knockdown of IDO1 in order to verify its vital role in LF. Our findings demonstrated that naringin exhibited anti-inflammatory and anti-fibrotic action in conjunction with a reversal in lipid accumulation, oxidative stress and suppression of macrophage infiltration and activation of hepatic stellate cells. Furthermore, the results showed that the antifibrotic effect of naringin was removed upon IDO1 knockdown, proving that naringin exerts a protective effect by regulating IDO1. Naringin demonstrates remarkable protective effects against LF, effectively counteracting inflammation and hepatic steatosis in zebrafish liver. These findings suggest that naringin may function as an effective IDO1 inhibitor, holding the potential for clinical translation as a therapeutic agent for the treatment of LF.
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Metabolismo dos Lipídeos , Peixe-Zebra , Animais , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Fígado/metabolismo , Fibrose , Células Estreladas do Fígado/metabolismo , Lipídeos/farmacologiaRESUMO
Red mud (RM) was constantly reported to immobilize soil cadmium (Cd) and reduce Cd uptake by crops, but few studies investigated whether and how RM influenced rhizobacteria communities, which was a vital factor determining Cd bioavailability and plant growth. To address this concern, high-throughput sequencing and bioinformatics were used to analyze microbiological mechanisms underlying RM application reducing Cd accumulation in edible amaranth. Based on multiple statistical models (Detrended correspondence analysis, Bray-Curtis, weighted UniFrac, and Phylogenetic tree), this study found that RM reduced Cd content in plants not only through increasing rhizosphere soil pH, but by reshaping rhizobacteria communities. Special taxa (Alphaproteobacteria, Gammaproteobacteria, Actinobacteriota, and Gemmatimonadota) associated with growth promotion, anti-disease ability, and Cd resistance of plants preferentially colonized in the rhizosphere. Moreover, RM distinctly facilitated soil microbes' proliferation and microbial biofilm formation by up-regulating intracellular organic metabolism pathways and down-regulating cell motility metabolic pathways, and these microbial metabolites/microbial biofilm (e.g., organic acid, carbohydrates, proteins, S2-, and PO43-) and microbial cells immobilized rhizosphere soil Cd via the biosorption and chemical chelation. This study revealed an important role of reshaped rhizobacteria communities acting in reducing Cd content in plants after RM application.
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Alphaproteobacteria , Poluentes do Solo , Alphaproteobacteria/metabolismo , Bactérias/metabolismo , Cádmio/análise , Produtos Agrícolas/metabolismo , Filogenia , Rizosfera , Solo/química , Poluentes do Solo/análiseRESUMO
The combined toxic effects of nanoplastics and heavy metals on aquatic organisms have attracted widespread attention; however, the results are inconsistent and the mechanisms remain unclear. In this study, the single and combined toxicity effects of Cu and two types of polystyrene nanoplastics (PS-NPs; 50 nm PS and 55 nm PS-COOH) on Platymonas helgolandica var. tsingtaoensis were investigated, including growth inhibition, chlorophyll content, and oxidative stress. An adverse dose-response relationship on growth inhibition was found in the Cu treatment groups, which was related to the decrease in chlorophyll content and damage to cell membranes. The growth inhibitory effect of PS-NPs on microalgae increased with exposure time and concentration, and no significant difference was found in the two types of PS-NPs because of the negligible contribution of functional groups. A more significant increase in chlorophyll content was found in PS treatments than in PS-COOH treatments at 96 h because of the microscale aggregates formed by PS. Higher concentrations (≥ 50 mg/L) of PS-NPs caused membrane lipid peroxidation, which might be responsible for growth inhibition. In the combined exposure experiments, a synergistic effect on the growth inhibition rate was obtained using the independent action model and Abbott model. Combined exposure triggered more severe oxidative damage to the microalgae. Adsorption experiment results showed that there was no adsorption between PS-NPs and Cu, while the interaction of Cu and algal cells could be promoted due to the presence of the PS-NPs, which explained the increasing combined toxicity. This study could improve our understanding of the combined toxicity of nanoplastics and heavy metals and could provide a new explanation for the mechanism of combined toxicity.
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Clorófitas , Microalgas , Nanopartículas , Poluentes Químicos da Água , Clorofila , Cobre/toxicidade , Microplásticos , Nanopartículas/toxicidade , Estresse Oxidativo , Poliestirenos/toxicidade , Poluentes Químicos da Água/toxicidadeRESUMO
INTRODUCTION: The thyroid cancer incidence has been increasing all over the world. However, the aetiology of thyroid cancer remains unclear. A growing body of evidence suggested exposure to persistent organic pollutants (POPs) may play a role in the initiation of thyroid cancer, but the results are generally inconsistent across studies. This review aims to synthesise the evidence for the health effects of POPs on the risk of thyroid cancer. METHODS AND ANALYSIS: This protocol was reported in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA) statements. A comprehensive search, including electronic database search (eg, PubMed, Embase, ProQuest and CNKI), website search and manual search, will be performed to identify all eligible studies. The Population, Exposure, Comparator and Outcome framework was used to clarify the inclusion and exclusion criteria. The Newcastle-Ottawa Scale will be used to assess the quality of included studies. Maximally adjusted effect estimates from individual studies will be summarised with random-effect models in a conservative manner. I2 statistics and Q-tests will be used to test the heterogeneity across studies. We will perform extensive sensitivity analyses, such as confounding risk ratio (confounding), E-value, fixed-effect models, excluding the most relatively weighted study, including only the high-quality studies and many predesigned subgroup analyses, etc. The findings will be reported in accordance to the PRISMA guidelines. ETHICS AND DISSEMINATION: Ethical approval is not required in this systematic review of published literatures. The results will be published in a peer-reviewed journal and presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42020181343.
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Poluentes Orgânicos Persistentes , Neoplasias da Glândula Tireoide , Humanos , Incidência , Metanálise como Assunto , Pesquisa Qualitativa , Revisões Sistemáticas como Assunto , Neoplasias da Glândula Tireoide/induzido quimicamente , Neoplasias da Glândula Tireoide/epidemiologiaRESUMO
Graphene oxide (GO) is widely used in various fields and has raised concerns regarding its potential environmental fate and effect. However, there are few studies on its influence on coexisting pollutants. In this study, the phototransformation of GO and coexisting sulfamethazine (SMZ) under UV irradiation was investigated, with a focus on the role of reactive oxygen species. The results demonstrated that GO promoted the degradation of SMZ under UV irradiation. The higher the concentration of GO, the higher the degradation rate of SMZ, and the faster the first-order reaction rate. Two main radicals, âOH and 1O2, both contributed greatly in terms of regulating the removal of SMZ. Cl-, SO42-, and pH mainly promoted SMZ degradation by increasing the generation of âOH, while humic acid inhibited SMZ degradation due to the reduction of âOH. Moreover, after UV illumination, the GO suspension changed from light yellow to dark brown with increasing absorbance at a wavelength of 225 nm. Raman spectra revealed that the ID/IG ratio slightly decreased, indicating that some of the functional groups on the surface of GO were removed under low-intensity UV illumination. This study revealed that GO plays important roles in the photochemical transformation of environmental pollutants, which is helpful for understanding the environmental behaviors and risks of nanoparticles in aquatic environments.
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Both bone mineral density (BMD) and lean body mass (LBM) are important physiological measures with strong genetic determination. Besides, BMD and LBM might have common genetic factors. Aiming to identify pleiotropic genomic loci underlying BMD and LBM, we performed bivariate genome-wide association study meta-analyses of femoral neck bone mineral density and LBM at arms and legs, and replicated in the large-scale UK Biobank cohort sample. Combining the results from discovery meta-analysis and replication sample, we identified three genomic loci at the genome-wide significance level (p < 5.0 × 10-8): 2p23.2 (lead SNP rs4477866, discovery p = 3.47 × 10-8, replication p = 1.03 × 10-4), 16q12.2 (rs1421085, discovery p = 2.04 × 10-9, replication p = 6.47 × 10-14) and 18q21.32 (rs11152213, discovery p = 3.47 × 10-8, replication p = 6.69 × 10-6). Our findings not only provide useful insights into lean mass and bone mass development, but also enhance our understanding of the potential genetic correlation between BMD and LBM.
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Colo do Fêmur/metabolismo , Loci Gênicos , Pleiotropia Genética , Predisposição Genética para Doença , Osteoporose/genética , Sarcopenia/genética , Povo Asiático , População Negra , Índice de Massa Corporal , Densidade Óssea , Feminino , Colo do Fêmur/patologia , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/etnologia , Osteoporose/metabolismo , Osteoporose/patologia , Polimorfismo de Nucleotídeo Único , Sarcopenia/etnologia , Sarcopenia/metabolismo , Sarcopenia/patologia , Magreza/genética , Magreza/metabolismo , População BrancaRESUMO
BACKGROUND: It is unclear whether bisphosphonates are associated with risk of cancers. Therefore, this meta-analysis aimed to evaluate the effect of bisphosphonates on overall cancers. METHODS: A search in Pubmed, Embase, Cochrane Library and Web of Science databases was conducted, from the inception date of each resource to September 26, 2019. The summarised effect estimates with 95% CIs were calculated using a random-effect model. Heterogeneity and publication bias were explored. RESULTS: Thirty-four articles were included in this study (4,508,261 participants; 403,196 cases). The results revealed that bisphosphonates significantly decreased the risk of colorectal cancer (RR = 0.89, 95% CI: 0.81-0.98), breast cancer (RR = 0.87, 95% CI: 0.82-0.93) and endometrial cancer (RR = 0.75, 95% CI: 0.61-0.94), but no significant association was observed in all-cause cancer. Furthermore, nitrogen-containing bisphosphonates only had protective effects both on breast cancer (RR = 0.94, 95% CI: 0.90-0.99) and endometrial cancer (RR = 0.70, 95% CI: 0.54-0.92). Non-nitrogen-containing bisphosphonates tended to increase the risk of liver cancer (RR = 2.14, 95% CI: 1.23-3.72) and pancreas cancer (RR = 1.75, 95% CI: 1.32-2.33). CONCLUSION: Bisphosphonates are significantly associated with risk reduction of colorectal, breast and endometrial cancer, especially nitrogen-containing bisphosphonates. It should be noted that non-nitrogen-containing bisphosphonates might increase the risk of liver and pancreas cancer. Large prospective cohort studies are needed to find the causal association between bisphosphonates and risk of cancers.
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Difosfonatos/uso terapêutico , Neoplasias/epidemiologia , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/etiologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etiologia , Citoproteção/efeitos dos fármacos , Difosfonatos/química , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/etiologia , Feminino , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia , Compostos de Nitrogênio/química , Compostos de Nitrogênio/uso terapêutico , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/etiologia , Prevalência , Fatores de RiscoRESUMO
BACKGROUND: Fat mass and lean mass are two biggest components of body mass. Both fat mass and lean mass are under strong genetic determinants and are correlated. METHODS: We performed a bivariate genome-wide association meta-analysis of (lean adjusted) leg fat mass and (fat adjusted) leg lean mass in 12,517 subjects from 6 samples, and followed by in silico replication in large-scale UK biobank cohort sample (N = 370 097). RESULTS: We identified four loci that were significant at the genome-wide significance (GWS, α = 5.0 × 10-8) level at the discovery meta-analysis, and successfully replicated in the replication sample: 2q36.3 (rs1024137, pdiscovery = 3.32 × 10-8, preplication = 4.07 × 10-13), 5q13.1 (rs4976033, pdiscovery = 1.93 × 10-9, preplication = 6.35 × 10-7), 12q24.31 (rs4765528, pdiscovery = 7.19 × 10-12, preplication = 1.88 × 10-11) and 18q21.32 (rs371326986, pdiscovery = 9.04 × 10-9, preplication = 2.35 × 10-95). The above four pleiotropic loci may play a pleiotropic role for fat mass and lean mass development. CONCLUSIONS: Our findings further enhance the understanding of the genetic association between fat mass and lean mass and provide a new theoretical basis for their understanding.
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Adiposidade/genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Adulto , Idoso , Genótipo , Humanos , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Reino UnidoRESUMO
Sarcopenia is a complex polygenic disease, and its molecular mechanism is still unclear. Whole lean body mass (WLBM) is a heritable trait predicting sarcopenia. To identify genomic loci underlying, we performed a whole-exome sequencing (WES) of WLBM variation with high sequencing depth (more than 40*) in 101 Chinese subjects. We then replicated in the major findings in the large-scale UK Biobank (UKB) cohort (N = 217,822) for WLBM. The results of four single-nucleotide polymorphisms (SNPs) were significant both in the discovery stage and replication stage: SNP rs740681 (discovery p = 1.66 × 10-6 , replication p = .05), rs2272303 (discovery p = 3.20 × 10-4 , replication p = 3.10 × 10-4 ), rs11170413 (discovery p = 3.99 × 10-4 , replication p = 2.90 × 10-4 ), and rs2272302 (discovery p = 9.13 × 10-4 , replication p = 3.10 × 10-4 ). We combined p values of the significant SNPs. Functional annotations highlighted two candidate genes, including FZR1 and SOAT2, that may exert pleiotropic effects to the development of body mass. Our findings provide useful insights that further enhance our understanding of genetic interplay in sarcopenia.
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Proteínas Cdh1/genética , Polimorfismo de Nucleotídeo Único , Sarcopenia/genética , Esterol O-Aciltransferase/genética , Adulto , Índice de Massa Corporal , China , Exoma , Feminino , Pleiotropia Genética , Humanos , Masculino , Esterol O-Aciltransferase 2RESUMO
Whole body lean mass (WBLM) is a heritable trait predicting sarcopenia. To identify genomic locus underlying WBLM, we performed a genome-wide association study of fat-adjusted WBLM in the Framingham Heart Study (FHS, N = 6,004), and replicated in the Kansas City Osteoporosis Study (KCOS, N = 2,207). We identified a novel locus 3p27.1 that was associated with WBLM (lead SNP rs3732593 P = 7.19 × 10-8) in the discovery FHS sample, and the lead SNP was successfully replicated in the KCOS sample (one-sided P = 0.04). Bioinformatics analysis found that this SNP and its adjacent SNPs had the function of regulating enhancer activity in skeletal muscle myoblasts cells, further confirming the regulation of WBLM by this locus. Our finding provides new insight into the genetics of WBLM and enhance our understanding of sarcopenia.
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Composição Corporal , Cromossomos Humanos Par 3/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Sarcopenia/genética , Sarcopenia/patologia , Magreza/genética , Feminino , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
Sarcopenia is characterized by low skeletal muscle, a complex trait with high heritability. With the dramatically increasing prevalence of obesity, obesity and sarcopenia occur simultaneously, a condition known as sarcopenic obesity. Fat mass and obesity-associated (FTO) gene is a candidate gene of obesity. To identify associations between lean mass and FTO gene, we performed a genome-wide association study (GWAS) of lean mass index (LMI) in 2207 unrelated Caucasian subjects and replicated major findings in two replication samples including 6,004 unrelated Caucasian and 38,292 unrelated Caucasian. We found 29 single nucleotide polymorphisms (SNPs) in FTO significantly associated with sarcopenia (combined p-values ranging from 5.92 × 10-12 to 1.69 × 10-9). Potential biological functions of SNPs were analyzed by HaploReg v4.1, RegulomeDB, GTEx, IMPC and STRING. Our results provide suggestive evidence that FTO gene is associated with lean mass.
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Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/fisiologia , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Magreza/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Sarcopenia/genética , População Branca/genéticaRESUMO
Intestinal lipases are fat-digesting enzymes, which play vital roles in lipid absorption in the intestine. To study the regulation of intestinal lipase activity in systemic lipid metabolism in fish, especially in the metabolic diseases caused by high-fat diet (HFD) feeding, we inhibited intestinal lipases in Nile tilapia to investigate the physiological consequences. In the present study, Nile tilapia were firstly fed with HFD (12% fat) for 6 weeks to establish a fatty fish model. Afterwards, Orlistat as a potent intestinal lipase inhibitor was added into the HFD for the following 5-week feeding trial, with two dietary doses (Orlistat16 group, 16 mg/kg body weight; Orlistat32 group, 32 mg/kg body weight). After the trial, both doses of Orlistat treatment significantly reduced intestinal lipase activity, fat absorption, hepatic lipid accumulation, and gene expression of lipogenesis, whereas increased gene expression of lipid catabolism. Moreover, intestinal lipase inhibition increased immune enzyme activities, antioxidant capacity, and gene expression of anti-inflammatory cytokines, whereas lowered gene expression of pro-inflammatory cytokines. Besides, Orlistat could also improve the structure of the intestine and increase expression of intestinal tight-coupling protein. Taken together, intestinal lipase inhibition alleviated the adverse effects caused by HFD in Nile tilapia. Thus, intestinal lipases played key roles in absorbing dietary lipid and could be a promising target in regulating systemic lipid metabolism in fish.
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Ciclídeos/fisiologia , Dieta Hiperlipídica , Lipase , Animais , Gorduras na Dieta , Suplementos Nutricionais , Metabolismo dos Lipídeos , LipogêneseRESUMO
Autophagy is a conserved cellular degradation process through which intracellular components are degraded by the lysosome, but its roles in fish metabolism have not been studied in depth. Therefore, the present study aimed to investigate whether autophagy plays a key role in maintaining metabolic homeostasis in fish. In an 8-week feeding trial, Nile tilapia were fed either a control diet with medium fat and medium carbohydrate (Control), or a control diet supplemented with a classic autophagy inhibitor (chloroquine, CQ). CQ supplementation significantly inhibited autophagy and impaired fish growth and protein synthesis, and the glycolysis was stimulated, accompanied by fat accumulation, high oxidative stress and inflammation. Physiological status and gene expressions suggested that impaired autophagy might be at least one cause of the metabolic diseases which has been commonly seen in aquaculture. These results indicate that inhibition of autophagy could significantly affect the metabolism of lipid, carbohydrate and protein in fish; hence, autophagy could play important roles in maintaining homeostasis of nutrient metabolism in cultured fish.
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Autofagia , Ciclídeos/metabolismo , Nutrientes/metabolismo , Animais , Antioxidantes/metabolismo , Autofagia/genética , Ciclídeos/genética , Ciclídeos/crescimento & desenvolvimento , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Glicogênio/metabolismo , Metabolismo dos Lipídeos/genética , Oxirredução , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
While tumor-infiltrating cytotoxic T lymphocytes play a critical role in controlling tumor development, they are generally impotent in an acidic tumor microenvironment. Systemic treatment to neutralize tumor acidity thus holds promise for the reversal of the anergic state of T cells and the improvement of T cell-associated immunotherapy. Herein, we report a proof-of-concept of RNAi nanoparticle-mediated therapeutic reversion of tumor acidity to restore the antitumor functions of T cells and potentiate the checkpoint blockade therapy. Our strategy utilized an in vivo optimized vesicular cationic lipid-assisted nanoparticle, as opposed to its micellar counterpart, to mediate systematic knockdown of lactate dehydrogenase A (LDHA) in tumor cells. The treatment resulted in the reprogramming of pyruvate metabolism, a reduction of the production of lactate, and the neutralization of the tumor pH. In immunocompetent syngeneic melanoma and breast tumor models, neutralization of tumor acidity increased infiltration with CD8+ T and NK cells, decreased the number of immunosuppressive T cells, and thus significantly inhibited the growth of tumors. Furthermore, the restoration of tumoral pH potentiated checkpoint inhibition therapy using the antibody of programmed cell death protein 1 (PD-1). However, in immunodeficient B6/ Rag1 -/- and NOG mice, the same treatment failed to control tumor growth, further proving that the attenuation of tumor growth by tumor acidity modulation was attributable to the activation of tumor-infiltrating immune cells.
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Imunoterapia , Melanoma Experimental/tratamento farmacológico , Nanopartículas/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ácidos/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Proteínas de Transporte/genética , Proliferação de Células/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Concentração de Íons de Hidrogênio , L-Lactato Desidrogenase/genética , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Nanopartículas/química , Microambiente Tumoral/efeitos dos fármacosRESUMO
l-Carnitine is essential for mitochondrial ß-oxidation and has been used as a lipid-lowering feed additive in humans and farmed animals. d-Carnitine is an optical isomer of l-carnitine and dl-carnitine has been widely used in animal feeds. However, the functional differences between l- and d-carnitine are difficult to study because of the endogenous l-carnitine background. In the present study, we developed a low-carnitine Nile tilapia model by treating fish with a carnitine synthesis inhibitor, and used this model to investigate the functional differences between l- and d-carnitine in nutrient metabolism in fish. l- or d-carnitine (0·4 g/kg diet) was fed to the low-carnitine tilapia for 6 weeks. l-Carnitine feeding increased the acyl-carnitine concentration from 3522 to 10 822 ng/g and alleviated the lipid deposition from 15·89 to 11·97 % in the liver of low-carnitine tilapia. However, as compared with l-carnitine group, d-carnitine feeding reduced the acyl-carnitine concentration from 10 822 to 5482 ng/g, and increased lipid deposition from 11·97 to 20·21 % and the mRNA expression of the genes involved in ß-oxidation and detoxification in the liver. d-Carnitine feeding also induced hepatic inflammation, oxidative stress and apoptosis. A metabolomic investigation further showed that d-carnitine feeding increased glycolysis, protein metabolism and activity of the tricarboxylic acid cycle and oxidative phosphorylation. Thus, l-carnitine can be physiologically utilised in fish, whereas d-carnitine is metabolised as a xenobiotic and induces lipotoxicity. d-Carnitine-fed fish demonstrates increases in peroxisomal ß-oxidation, glycolysis and amino acid degradation to maintain energy homeostasis. Therefore, d-carnitine is not recommended for use in farmed animals.
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Carnitina/farmacologia , Tilápia/metabolismo , Ração Animal , Animais , Apoptose , Carnitina/administração & dosagem , Carnitina/química , Glucose/metabolismo , Fígado/metabolismo , Metabolômica , Modelos Animais , Oxirredução , Estresse Oxidativo , Proteínas/metabolismo , RNA Mensageiro/genética , EstereoisomerismoRESUMO
BACKGROUND: Brucellosis is associated with inflammation and the oxidative stress response. Heme oxygenase-1 (HO-1) is a cytoprotective stress-responsive enzyme that has anti-inflammatory and anti-oxidant effects. Nevertheless, the role of HO-1 in human brucellosis has not yet been studied. The aim of this study was to examine the plasma levels of HO-1 in patients with brucellosis and to evaluate the ability of plasma HO-1 levels as an auxiliary diagnosis, a severity predictor, and a monitor for brucellosis treatments. METHODS: A total of 75 patients with brucellosis were divided into the acute, subacute, chronic active, and chronic stable groups. An additional 20 volunteers were included as the healthy control group. The plasma HO-1 levels and other laboratory parameters were measured in all groups. Furthermore, the plasma levels of HO-1 in the acute group were compared before and after treatment. RESULTS: The plasma HO-1 levels were considerably increased in the acute (4.97 ± 3.55), subacute (4.98 ± 3.23), and chronic active groups (4.43 ± 3.00) with brucellosis compared to the healthy control group (1.03 ± 0.63) (p < 0.01). In the acute group, the plasma HO-1 levels in the post-treatment group (2.33 ± 2.39) were significantly reduced compared to the pre-treatment group (4.97 ± 3.55) (p < 0.01). On the other hand, the plasma HO-1 levels were higher in the chronic active group (4.43 ± 3.00) than the chronic stable group (2.74 ± 2.23) (p < 0.05). However, the plasma HO-1 levels in the chronic stable group (2.74 ± 2.23) remained higher than the levels in the healthy control group (1.03 ± 0.63) (p < 0.05). The HO-1 levels were positively correlated with the C-reactive protein (CRP) levels in patients with brucellosis (r = 0.707, p < 0.01). CONCLUSIONS: The plasma HO-1 levels can reflect patients' brucellosis status and may be used as a supplementary plasma marker for diagnosing brucellosis and monitoring its treatment.
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Brucelose/enzimologia , Heme Oxigenase-1/sangue , Adulto , Brucelose/diagnóstico , Proteína C-Reativa/análise , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To compare the differences in the clinical efficacy on tinnitus between the spinal balancing intervention and the conventional acupuncture. METHODS: The randomized controlled trial were adopted. One hundred and twenty cases of tinnitus were randomized into a spinal balancing group and a conventional acupuncture group, 60 cases in each one. In the spinal balancing group, the comprehensive therapy of acu-puncture and Tuina was applied to the spine, the Back-shu points, Jiaji (EX-B 2), Tinggong (SI 19), Yifeng (TE 17), Fengchi (GB 20), Yuzhen (BL 9), Tianzhu (BL 10), etc. for the balancing intervention. In the conventional acupuncture group, acupuncture was applied to the local points and the points along the affected meridians. In each group, after 3 sessions of treatment, the degree of tinnitus and the accompanied symptoms were scored and compared before and after treatment. The comprehensive efficacy was assessed. RESULTS: In the spinal balancing group, the clinical curative rate was 70.0% (42/60) and the total effective rate was 98.3% (59/60), which were significantly better than 45.0% (27/60) and 86.7% (52/60) in the conventional acupuncture group separately (P < 0.01, P < 0.05). After treatment, the degree of tinnitus and the accompanied symptom scores were all reduced in both groups (all P < 0.05), but the improvements in the spinal balancing group were better than those in the conventional acupuncture group (all P < 0.05). In 3-month follow-up visit after treatment, the recurrence rate in the spinal balancing group was lower than that in the conventional acupuncture group [5.1% (3/59) vs 13.5% (7/52)] (P < 0.05). CONCLUSION: The spinal balancing intervention therapy relieves the symptoms of the patients with tinnitus remarkably. Its clinical efficacy is superior significantly to that of the conventional acupuncture and the recurrence rate is lower.
Assuntos
Terapia por Acupuntura , Coluna Vertebral/fisiopatologia , Zumbido/terapia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Zumbido/fisiopatologia , Resultado do TratamentoRESUMO
OBJECTIVE: To compare the therapeutic effects and safety of herpes zoster treated by the cotton sheet moxibustion combined with the plum-blossom-needle tapping therapy to western medicine. METHODS: The multicentral random controlled method was adopted, 120 cases of herpes zoster were randomly divided into a comprehensive treatment group and a western medication group, 60 cases in each one. In the comprehensive treatment group, the tapping therapy of plum blossom needle was applied to the foci, corresponding Jiaji (EX-B 2), Quchi (LI 11), Waiguan (TE 5), Zusanli (ST 36), Taichong (LR 3), etc. Afterward, the cotton sheet moxibustion was given. In western medication group, Acyclovir ointment for external application, Valaciclovir Hydrochloride tablets and Vitamin B1 for oral administration were prescribed. In 7 days of treatment, the clinical symptom score, effect time, efficacy and safety were observed before and after treatment between two groups. The recurrence of disease was followed up for 1 month. RESULTS: In the comprehensive treatment group, the cured rate and the total effective rate were 80.0% (48/60) and 98.3% (59/60) separately, which were significantly better than 45.0% (27/60) and 71.7% (43/60) in western medication group separately (P < 0.01, P < 0.05). After treatment, in either group, the scores of clinical symptoms such as pain rating index (PRI), Visual Analogue Scale (VAS), present pain intensity (PPI), skin lesion and sleeping score, etc. were all reduced significantly (P < 0.01, P < 0.05). The score reducing was much more obvious in the comprehensive treatment group (P < 0.01, P < 0.05). In the comprehensive treatment group, the time of pain stopping, the time of blister stopping, the time of scarring and the time of healing were all shorter tha tn those in western medication group (P < 0.01, P < 0.05). In the follow-up observation, 1 case (1.6%) was recurred in the comprehensive treatment group and 8 cases (13.3%) were in western medication group. In western medication group, 6 cases presented mild adverse reactions. CONCLUSION: The cotton sheet moxibustion combined with the plum-blossom-needle tapping therapy is advantageous at good efficacy, quick effect and short-time treatment for herpes zoster, which is apparently superior to the treatment with Acyclovir ointment for external application, Valaciclovir Hydrochloride tablets and Vitamin B1 for oral administration. It is the safe and effective therapy.