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1.
Development ; 2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35029658

RESUMO

Worldwide prevalence of obesity is associated with the increase of lifestyle-related diseases. The accumulation of intermuscular adipose tissue (IMAT) is considered a major problem whereby obesity leads to sarcopenia and metabolic disorders and thus is a promising target for treating these pathological conditions. However, whereas obesity-associated IMAT is suggested to originate from PDGFRα+ mesenchymal progenitors, processes underlying their adipogenesis remain largely unexplored. Here, we comprehensively investigated intra- and extracellular changes associated with these processes using single-cell RNA sequencing (scRNA-Seq) and mass spectrometry. Our scRNA-Seq analysis identified a small PDGFRα+ cell population in obese mice directed strongly toward adipogenesis. Proteomic analysis showed that the appearance of this cell population is accompanied by an increase in galectin-3 in interstitial environments, which was found to activate adipogenic PPARγ signals in PDGFRα+ cells. Moreover, IMAT formation during muscle regeneration was significantly suppressed in galectin-3 KO mice. Our findings, together with these multi-omics datasets, could unravel microenvironmental networks during muscle regeneration highlighting possible therapeutic targets against IMAT formation in obesity.

2.
Life Sci ; : 120215, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34890590

RESUMO

AIMS: Radiation-induced esophagitis, experienced during radiation therapy for lung cancer and head and neck cancer, is a major dose-limiting side effect of the treatment. This study aimed to elucidate the role of interferon-α (IFN-α) in radiation-induced esophagitis. MAIN METHODS: C57BL/6 mice were exposed to 10 and 25Gy of single thoracic irradiation. Mucosal damage and inflammatory reactions were assessed for 5 days after irradiation. KEY FINDINGS: Irradiation induced esophagitis, characterized by reduction in the thickness of epithelial layer, upregulation of proinflammatory cytokines and chemokines, infiltration of inflammatory cells into the esophageal mucosa, and apoptosis of epithelial cells. Irradiation upregulated the level of gene expression for IFN-α in the esophageal tissue, and the neutralizing antibody against IFN-α ameliorated radiation-induced esophageal mucosal damage, while administration of IFN-α receptor agonist (RO8191) had an inverse effect. Depletion of plasmacytoid dendritic cells (pDCs) by anti-CD317 antibody or pharmacological inactivation with bortezomib suppressed radiation-induced mucosal inflammation and damage, accompanied by decrease in IFN-α expression level. SIGNIFICANCE: These findings suggest that IFN-α and pDCs exert proinflammatory properties in the pathophysiology of radiation-induced esophagitis.

3.
Microorganisms ; 9(12)2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34946163

RESUMO

We determined the bone mineral density (BMD) and the expression of serum bone formation marker (procollagen type I N-terminal propeptide: PINP) and bone resorption marker (C-terminal telopeptide of collagen: CTX) by ELISA to evaluate ovariectomy-induced osteoporosis in ovariectomized (OVX) mice. The intestinal microbiota of the mice was assessed using 16S rRNA gene sequencing. OVX mice exhibited a lower BMD of 87% with higher serum levels of CTX and PINP compared to sham-operated (sham) mice. The cecum microbiome of OVX mice showed lower bacterial diversity than that of sham mice. TNFα mRNA levels in the colon were 1.6 times higher, and zonula occludens-1 mRNA and protein expression were lower in OVX mice than in sham mice, suggesting that ovariectomy induced inflammation and increased intestinal permeability. Next, we used antibiotic treatment followed by fecal microbiota transplantation (FMT) to remodel the gut microbiota in the OVX mice. A decrease in PINP was observed in antibiotic-treated mice, while there was no change in BMD or CTX between mice with and without antibiotic treatment. Oral transplantation of the luminal cecal content of OVX or sham mice to antibiotic-treated mice did not affect the BMD or PINP and CTX expression. Additionally, transplantation of the luminal contents of OVX or sham mice to antibiotic-treated OVX mice had similar effects on BMD, PINP, and CTX. In conclusion, although ovariectomy induces dysbiosis in the colon, the changes in the gut microbiota may only have a minor role in ovariectomy-induced osteoporosis.

4.
Front Cell Infect Microbiol ; 11: 646467, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34084754

RESUMO

HIV-1 infected individuals under antiretroviral therapy can control viremia but often develop non-AIDS diseases such as cardiovascular and metabolic disorders. Gut microbiome dysbiosis has been indicated to be associated with progression of these diseases. Analyses of gut/fecal microbiome in individual regions are important for our understanding of pathogenesis in HIV-1 infections. However, data on gut/fecal microbiome has not yet been accumulated in West Africa. In the present study, we examined fecal microbiome compositions in HIV-1 infected adults in Ghana, where approximately two-thirds of infected adults are females. In a cross-sectional case-control study, age- and gender-matched HIV-1 infected adults (HIV+; n = 55) and seronegative controls (HIV-; n = 55) were enrolled. Alpha diversity of fecal microbiome in HIV+ was significantly reduced compared to HIV- and associated with CD4 counts. HIV+ showed reduction in varieties of bacteria including Faecalibacterium, the most abundant in seronegative controls, but enrichment of Proteobacteria. Ghanaian HIV+ exhibited enrichment of Dorea and Blautia; bacteria groups whose depletion has been reported in HIV-1 infected individuals in several other cohorts. Furthermore, HIV+ in our cohort exhibited a depletion of Prevotella, a genus whose enrichment has recently been shown in men having sex with men (MSM) regardless of HIV-1 status. The present study revealed the characteristics of dysbiotic fecal microbiome in HIV-1 infected adults in Ghana, a representative of West African populations.


Assuntos
Infecções por HIV , HIV-1 , Microbiota , Adulto , Estudos de Casos e Controles , Estudos Transversais , Disbiose , Feminino , Gana , Humanos , Masculino
5.
Gastroenterology ; 160(6): 2089-2102.e12, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33577875

RESUMO

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI). However, the overall mechanisms underlying FMT success await comprehensive elucidation, and the safety of FMT has recently become a serious concern because of the occurrence of drug-resistant bacteremia transmitted by FMT. We investigated whether functional restoration of the bacteriomes and viromes by FMT could be an indicator of successful FMT. METHODS: The human intestinal bacteriomes and viromes from 9 patients with rCDI who had undergone successful FMT and their donors were analyzed. Prophage-based and CRISPR spacer-based host bacteria-phage associations in samples from recipients before and after FMT and in donor samples were examined. The gene functions of intestinal microorganisms affected by FMT were evaluated. RESULTS: Metagenomic sequencing of both the viromes and bacteriomes revealed that FMT does change the characteristics of intestinal bacteriomes and viromes in recipients after FMT compared with those before FMT. In particular, many Proteobacteria, the fecal abundance of which was high before FMT, were eliminated, and the proportion of Microviridae increased in recipients. Most temperate phages also behaved in parallel with the host bacteria that were altered by FMT. Furthermore, the identification of bacterial and viral gene functions before and after FMT revealed that some distinctive pathways, including fluorobenzoate degradation and secondary bile acid biosynthesis, were significantly represented. CONCLUSIONS: The coordinated action of phages and their host bacteria restored the recipients' intestinal flora. These findings show that the restoration of intestinal microflora functions reflects the success of FMT.


Assuntos
Enterocolite Pseudomembranosa/terapia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Viroma , Adulto , Idoso , Bacteriófagos , Clostridioides difficile , Enterocolite Pseudomembranosa/microbiologia , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Trato Gastrointestinal/virologia , Humanos , Masculino , Metagenômica , Microviridae , Pessoa de Meia-Idade , Proteobactérias , Viroma/genética
6.
Parasit Vectors ; 14(1): 70, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482904

RESUMO

BACKGROUND: Schistosomes are trematode worms that dwell in their definitive host's blood vessels, where females lay eggs that need to be discharged into the environment with host excreta to maintain their life-cycle. Both worms and eggs require type 2 immunity for their maturation and excretion, respectively. However, the immune molecules that orchestrate such immunity remain unclear. Interleukin (IL)-33 is one of the epithelium-derived cytokines that induce type 2 immunity in tissues. The aim of this study was to determine the role of IL-33 in the maturation, reproduction and excretion of Schistosoma mansoni eggs, and in the maintenance of egg-induced pathology in the intestines of mice. METHODS: The morphology of S. mansoni worms and the number of eggs in intestinal tissues were studied at different time points post-infection in S. mansoni-infected IL-33-deficient (IL-33-/-) and wild-type (WT) mice. IL-5 and IL-13 production in the spleens and mesenteric lymph nodes were measured. Tissue histology was performed on the terminal ilea of both infected and non-infected mice. RESULTS: Worms from IL-33-/- and WT mice did not differ morphologically at 4 and 6 weeks post-infection (wpi). The number of eggs in intestinal tissues of IL-33-/- and WT mice differed only slightly. At 6 wpi, IL-33-/- mice presented impaired type 2 immunity in the intestines, characterized by a decreased production of IL-5 and IL-13 in mesenteric lymph nodes and fewer inflammatory infiltrates with fewer eosinophils in the ilea. There was no difference between IL-33-/- and WT mice in the levels of IL-25 and thymic stromal lymphopoietin (TSLP) in intestinal tissues. CONCLUSIONS: Despite its ability to initiate type 2 immunity in tissues, IL-33 alone seems dispensable for S. mansoni maturation and its absence may not affect much the accumulation of eggs in intestinal tissues. The transient impairment of type 2 immunity observed in the intestines, but not spleens, highlights the importance of IL-33 over IL-25 and TSLP in initiating, but not maintaining, locally-induced type 2 immunity in intestinal tissues during schistosome infection. Further studies are needed to decipher the role of each of these molecules in schistosomiasis and clarify the possible interactions that might exist between them.


Assuntos
Interações Hospedeiro-Parasita/imunologia , Interleucina-33/imunologia , Intestinos/patologia , Intestinos/parasitologia , Schistosoma mansoni/imunologia , Esquistossomose mansoni/imunologia , Animais , Feminino , Interleucina-33/análise , Interleucina-33/genética , Interleucina-5/análise , Interleucina-5/imunologia , Intestinos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Contagem de Ovos de Parasitas , Schistosoma mansoni/fisiologia
7.
Mucosal Immunol ; 14(3): 640-651, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33299086

RESUMO

Oral immunotherapy (OIT) is an effective approach to controlling food allergy. Although the detailed molecular and cellular mechanisms of OIT are unknown currently, they must be understood to advance the treatment of allergic diseases in general. To elucidate the mechanisms of OIT, especially during the immunological transition from desensitization to allergy regulation, we generated a clinical OIT murine model and used it to examine immunological events of OIT. We found that in mice that completed OIT successfully, desensitized mast cells (MCs) showed functionally beneficial alterations, such as increased induction of regulatory cytokines and enhanced expansion of regulatory T cells. Importantly, these regulatory-T-cell-mediated inhibitions of allergic responses were dramatically decreased in mice lacking OIT-induced desensitized MC. Collectively, these findings show that the desensitization process modulates the activation of MCs, leading directly to enhanced induction of regulatory-T-cell expansion and promotion of clinical allergic unresponsiveness. Our results suggest that efficiently inducing regulatory MCs is a novel strategy for the treatment of allergic disease.

8.
Jpn J Infect Dis ; 74(1): 42-47, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-32611986

RESUMO

Recent studies have indicated an association between gut microbiome composition and various disorders, including infectious diseases. The composition of the microbiome differs among ethnicities and countries, possibly resulting in diversified interactions between host immunity and the gut microbiome. Characterization of baseline microbiome composition in healthy people is an essential step for better understanding of the biological interactions associated with individual populations. However, data on the gut/fecal microbiome have not been accumulated for individuals in West Africa. In the present study, we examined the fecal microbiome composition in healthy adults in Ghana. Toward this, 16S rRNA gene libraries were prepared using bacterial fractions derived from 55 Ghanaian adults, which were then subjected to next-generation sequencing. The fecal microbiome of the Ghanaian adults was dominated by Firmicutes (Faecalibacterium, Subdoligranulum, and Ruminococcaceae UCG-014), Proteobacteria (Escherichia-Shigella and Klebsiella), and Bacteroidetes (Prevotella 9 and Bacteroides), consistent with previous observations in African cohorts. Further, our analysis revealed differences in microbiome composition and a lower diversity of the fecal microbiome in the Ghanaian cohort compared with those reported in non-African countries. This is the first study to describe substantial fecal microbiome data obtained using high-throughput metagenomic tools on samples derived from a cohort in Ghana. The data may provide a valuable basis for determining the association between the fecal microbiome and progression of various diseases in West African populations.


Assuntos
Fezes/microbiologia , Microbioma Gastrointestinal/genética , Adulto , Bacteroidetes/genética , Estudos Transversais , Feminino , Firmicutes/genética , Gana , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Metagenômica , Microbiota , Pessoa de Meia-Idade , Proteobactérias/genética , RNA Bacteriano/isolamento & purificação , RNA Ribossômico 16S/genética
9.
Commun Biol ; 3(1): 686, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208821

RESUMO

Numerous host extrinsic and intrinsic factors affect the gut microbiota composition, but their cumulative effects do not sufficiently explain the variation in the microbiota, suggesting contributions of missing factors. The Japanese population possesses homogeneous genetic features suitable for genome-wide association study (GWAS). Here, we performed GWASs for human gut microbiota using 1068 healthy Japanese adults. To precisely evaluate genetic effects, we corrected for the impacts of numerous host extrinsic and demographic factors by introducing them as covariates, enabling us to discover five loci significantly associated with microbiome diversity measures: HS3ST4, C2CD2, 2p16.1, 10p15.1, and 18q12.2. Nevertheless, these five variants explain only a small fraction of the variation in the gut microbiota. We subsequently investigated the heritability of each of the 21 core genera and found that the abundances of six genera are heritable. We propose that the gut microbiota composition is affected by a highly polygenic architecture rather than several strongly associated variants in the Japanese population.


Assuntos
/genética , Bactérias/classificação , Microbioma Gastrointestinal , Estudo de Associação Genômica Ampla , Adulto , Bactérias/genética , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Filogenia , Polimorfismo de Nucleotídeo Único
10.
Sci Rep ; 10(1): 15878, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985508

RESUMO

Alcohol-based disinfectants are widely used for the sanitization of microorganisms, especially those that cause infectious diseases, including viruses. However, since the germicidal mechanism of alcohol is lipolysis, alcohol-based disinfectants appear to have a minimal effect on non-enveloped viruses, such as noroviruses. Because there is no cultivation method for human norovirus (HuNoV) in vitro, murine norovirus and feline calicivirus have been used as surrogates for HuNoV to analyze the efficacy of disinfectant regents. Therefore, whether these disinfectants and their conditions are effective against HuNoVs remain unknown. In this study, we report that ethanol or isopropanol alone can sufficiently suppress GII.4 genotype HuNoV replication in human iPSC-derived intestinal epithelial cells. Additionally, pH adjustments and salting-out may contribute toward the virucidal effect of alcohol against other HuNoV genotypes and cancel the impediment of organic substance contamination, respectively. Therefore, similar to sodium hypochlorite, alcohol-based disinfectants containing electrolytes can be used for HuNoV inactivation.


Assuntos
2-Propanol/farmacologia , Desinfetantes/farmacologia , Etanol/farmacologia , Norovirus/efeitos dos fármacos , Inativação de Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Infecções por Caliciviridae/virologia , Células Epiteliais/virologia , Humanos , Concentração de Íons de Hidrogênio
11.
Cell Host Microbe ; 28(3): 380-389.e9, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32652061

RESUMO

The application of bacteriophages (phages) is proposed as a highly specific therapy for intestinal pathobiont elimination. However, the infectious associations between phages and bacteria in the human intestine, which is essential information for the development of phage therapies, have yet to be fully elucidated. Here, we report the intestinal viral microbiomes (viromes), together with bacterial microbiomes (bacteriomes), in 101 healthy Japanese individuals. Based on the genomic sequences of bacteriomes and viromes from the same fecal samples, the host bacteria-phage associations are illustrated for both temperate and virulent phages. To verify the usefulness of the comprehensive host bacteria-phage information, we screened Clostridioides difficile-specific phages and identified antibacterial enzymes whose activity is confirmed both in vitro and in vivo. These comprehensive metagenome analyses reveal not only host bacteria-phage associations in the human intestine but also provide vital information for the development of phage therapies against intestinal pathobionts.


Assuntos
Bacteriófagos/genética , Clostridioides difficile/virologia , Endopeptidases/genética , Microbioma Gastrointestinal/genética , Terapia por Fagos/métodos , Prófagos/genética , Animais , Antibacterianos/farmacologia , Bacteriófagos/isolamento & purificação , Infecções por Clostridium/terapia , Modelos Animais de Doenças , Endopeptidases/farmacologia , Fezes/microbiologia , Feminino , Genoma Bacteriano , Genoma Viral , Humanos , Metagenoma , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de DNA , Organismos Livres de Patógenos Específicos , Proteínas Virais/genética , Proteínas Virais/farmacologia
12.
World J Gastroenterol ; 26(21): 2758-2767, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32550752

RESUMO

Progress in genomic analysis has resulted in the proposal that the intestinal microbiota is a crucial environmental factor in the development of multifactorial diseases, such as obesity, diabetes, rheumatoid arthritis, and inflammatory bowel diseases represented by Crohn's disease and ulcerative colitis. Dysregulated gut microbiome contributes to the pathogenesis of such disorders; however, there are few effective treatments for controlling only disease-mediating bacteria. Here, we review current knowledge about the intestinal microbiome in health and disease, and discuss a regulatory strategy using a parenteral vaccine with emulsified curdlan and CpG oligodeoxynucleotides, which we have recently developed. Unlike other conventional injectable immunizations, our vaccine contributes to the induction of antigen-specific systemic and mucosal immunity. This vaccine strategy can prevent infectious diseases such as Streptococcus pneumoniae infection, and control metabolic symptoms mediated by intestinal bacteria (e.g. Clostridium ramosum) by induction of high titers of antigen-specific IgA at target mucosal sites. In the future, our vaccination approach could be an effective therapy for common infectious diseases and dysbiosis-related disorders that have been difficult to control so far.


Assuntos
Vacinas Bacterianas/administração & dosagem , Disbiose/terapia , Microbioma Gastrointestinal/imunologia , Polissacarídeos Bacterianos/administração & dosagem , Administração através da Mucosa , Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Artrite Reumatoide/terapia , Vacinas Bacterianas/imunologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/terapia , Disbiose/complicações , Disbiose/imunologia , Disbiose/microbiologia , Humanos , Imunidade nas Mucosas , Esquemas de Imunização , Imunização Secundária , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/terapia , Injeções Intramusculares , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Obesidade/imunologia , Obesidade/microbiologia , Obesidade/terapia , Oligodesoxirribonucleotídeos/administração & dosagem , Oligodesoxirribonucleotídeos/imunologia , Polissacarídeos Bacterianos/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , beta-Glucanas/administração & dosagem , beta-Glucanas/imunologia
13.
Neurogastroenterol Motil ; 32(7): e13841, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32319196

RESUMO

BACKGROUND: Intestinal permeability and psychological stress are considered the key mechanism(s) in functional dyspepsia (FD). Although proton pump inhibitors (PPIs) are commonly used for the treatment of FD, the effect of PPIs on intestinal permeability has not been elucidated. This study investigated the effect of PPI on intestinal permeability under stressed conditions. METHODS: C57BL/6J mice were subjected to water avoidance stress (WAS) and administered rabeprazole (40 mg/kg) or vehicle treatment (VT). We then evaluated intestinal permeability both in vivo and ex vivo using plasma fluorescein isothiocyanate-dextran and by assessing the paracellular permeability and transepithelial electrical resistance (TEER) in an Ussing chamber, respectively. Furthermore, we evaluated the effect of PPI-treated fecal microbiota transplant (FMT) on intestinal permeability in vivo. Microbiota profiles of donor feces were assessed by 16S rRNA gene analysis using MiSeq and QIIME2. KEY RESULTS: In the WAS treatment, PPI significantly enhanced intestinal permeability in vivo compared to that in VT. Moreover, PPI significantly increased paracellular permeability and decreased TEER in the duodenum and jejunum, respectively, compared to those in VT under stressed conditions. Moreover, both vasoactive intestinal peptide (VIP) receptor antagonist and ketotifen significantly reversed the effect of PPI on intestinal permeability. Furthermore, PPI-treated FMT significantly increased the intestinal permeability in vivo compared to that in vehicle-treated FMT. Proton pump inhibitors treatment altered the gut microbiota composition, indicating that PPI induced dysbiosis. CONCLUSIONS AND INFERENCES: Under stressed conditions, PPI enhances intestinal permeability via dysbiosis of gut microbiota. Vasoactive intestinal peptide and mast cells are also implicated in the underlying mechanisms.


Assuntos
Disbiose/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Inibidores da Bomba de Prótons/administração & dosagem , Rabeprazol/administração & dosagem , Estresse Psicológico/metabolismo , Animais , Corticosterona/sangue , Masculino , Camundongos Endogâmicos C57BL , Permeabilidade/efeitos dos fármacos , Estresse Psicológico/sangue
14.
Biomed Pharmacother ; 121: 109581, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31715374

RESUMO

BACKGROUND: Accumulation of myeloid-derived suppressor cells (MDSCs) to tumors is related to cancer prognosis. We investigated the contribution of host stromal microsomal prostaglandin E synthase-1 (mPGES-1) to the accumulation of MDSCs in metastasized lungs of prostate cancer in mice. MATERIAL AND METHODS: Eight-week-old male C57Bl/6 wild type (WT) mice and mPGES-1 knock out mice (mPGES-1KO) were injected with RM9 murine prostate cancer cell line (5 × 106 cells/mL). Lung metastasis was evaluated by the number of colonies, the weight of the lung, and the number of MDSCs (CD11b+Gr1+ cells) in the lung. RESULTS: Intravenous injections of RM9, a murine prostate cancer cell line to WT mice revealed that lung metastasis and accumulation of MDCSs were suppressed with treatments with a Gr1 antibody, a COX-2 inhibitor, and an mPGES-1 inhibitor. Lung metastasis and accumulation of CD11b+Gr1+MDSCs were suppressed in mPGES-1KO mice. The mRNA level of stromal cell-derived factor-1 (SDF-1) in the lung and the number of accumulated SDF-1-expressing CD11b+Gr1+ MDSCs were elevated at an early stage in lung metastasis of C-X-C chemokine receptor type 4 (CXCR4)-expressing RM9 in an mPGES-1-dependent manner. The number of CXCR4-expressing CD11b+Gr1+MDSCs in WT mice was higher than that in mPGES-1KO mice. RM9 lung metastasis and accumulation of CD11b+Gr1+MDSCs were suppressed by CXCR4 antibody in WT mice but not in mPGES-1KO. WT mice transplanted with mPGES-1 KO bone marrow (BM) showed a significant reduction in lung metastasis and accumulation of CD11b+Gr1+MDSCs. CONCLUSION: These results suggest that mPGES-1 enhances tumor metastasis by inducing accumulation of BM-derived MDSCs. Selective mPGES-1 inhibitors might, therefore, represent valuable therapeutic tools for the suppression of tumor metastasis.


Assuntos
Neoplasias Pulmonares/patologia , Células Supressoras Mieloides/metabolismo , Prostaglandina-E Sintases/genética , Animais , Antígenos Ly/metabolismo , Células da Medula Óssea/citologia , Antígeno CD11b/metabolismo , Quimiocina CXCL12/metabolismo , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Metástase Neoplásica , RNA Mensageiro/metabolismo , Receptores CXCR4/metabolismo
15.
Int Immunol ; 32(9): 597-603, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-31882997

RESUMO

Our bodies are constantly exposed to a wide variety of pathogenic micro-organisms through mucosal sites. Therefore, effective vaccines that can protect at the mucosa are vital; however, only a few clinically established mucosal vaccines are available. Although conventional injectable vaccines can induce antigen-specific serum immunoglobulin G (IgG) and prevent severe infection, it is difficult to efficiently inhibit the invasion of pathogens at mucosal surfaces because of the inadequate ability to induce antigen-specific IgA. Recently, we have developed a parenteral vaccine with emulsified curdlan and CpG oligodeoxynucleotides and reported its application. Unlike other conventional injectable vaccines, this immunization contributes to the induction of antigen-specific mucosal and systemic immune responses. Even if antigen-specific IgA at the mucosa disappears, this immunization can induce high-titer IgA after boosting with a small amount of antigen on the target mucosal surface. Indeed, vaccination with Streptococcus pneumoniae antigen effectively prevented lung infection induced by this bacterium. In addition, vaccination with Clostridium ramosum, which is a representative pathobiont associated with obesity and diabetes in humans, reduced obesity in mice colonized with this microorganism. This immunization approach might be an effective treatment for intestinal bacteria-mediated diseases that have been difficult to regulate so far, as well as common infectious diseases.


Assuntos
Membrana Mucosa/imunologia , Vacinas/imunologia , Animais , Humanos , Imunidade nas Mucosas/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia
16.
Sci Rep ; 9(1): 16796, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727909

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) cause damage in the small intestine in a bacteria-dependent manner. As high-fat diet (HFD) is a potent inducer of gut dysbiosis, we investigated the effects of HFD on bacterial flora in the small intestine and NSAID-induced enteropathy. 16S rRNA gene analysis revealed that the population of Bifidobacterium spp. significantly decreased by fold change of individual operational taxonomic units in the small intestine of mice fed HFD for 8 weeks. HFD increased intestinal permeability, as indicated by fluorescein isothiocyanate-dextran absorption and serum lipopolysaccharide levels, accompanied by a decrease in the protein expressions of ZO-1 and occludin and elevated mRNA expression of interleukin (IL)-17A in the small intestine. HFD-fed mice exhibited increased susceptibility to indomethacin-induced damage in the small intestine; this phenotype was observed in normal diet-fed mice that received small intestinal microbiota from HFD-fed mice. Administration of neutralizing antibodies against IL-17A to HFD-fed mice reduced intestinal permeability and prevented exacerbation of indomethacin-induced damage. Thus, HFD-induced microbial dysbiosis in small intestine caused microinflammation through the induction of IL-17A and increase in intestinal permeability, resulting in the aggravation of NSAID-induced small intestinal damage.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Disbiose/microbiologia , Interleucina-17/genética , Intestino Delgado/microbiologia , RNA Ribossômico 16S/genética , Animais , Bifidobacterium/classificação , Bifidobacterium/efeitos dos fármacos , Bifidobacterium/isolamento & purificação , Dextranos/metabolismo , Modelos Animais de Doenças , Disbiose/sangue , Disbiose/induzido quimicamente , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Indometacina/efeitos adversos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/imunologia , Lipopolissacarídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade/efeitos dos fármacos , Análise de Sequência de DNA , Regulação para Cima
17.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509948

RESUMO

As glucose-dependent insulinotropic polypeptide (GIP) possesses pro-adipogenic action, the suppression of the GIP hypersecretion seen in obesity might represent a novel therapeutic approach to the treatment of obesity. However, the mechanism of GIP hypersecretion remains largely unknown. In the present study, we investigated GIP secretion in two mouse models of obesity: High-fat diet-induced obese (DIO) mice and leptin-deficient Lepob/ob mice. In DIO mice, plasma GIP was increased along with an increase in GIP mRNA expression in the lower small intestine. Despite the robust alteration in the gut microbiome in DIO mice, co-administration of maltose and the α-glucosidase inhibitor (α-GI) miglitol induced the microbiome-mediated suppression of GIP secretion. The plasma GIP levels of Lepob/ob mice were also elevated and were suppressed by fat transplantation. The GIP mRNA expression in fat tissue was not increased in Lepob/ob mice, while the expression of an interleukin-1 receptor antagonist (IL-1Ra) was increased. Fat transplantation suppressed the expression of IL-1Ra. The plasma IL-1Ra levels were positively correlated with the plasma GIP levels. Accordingly, although circulating GIP levels are increased in both DIO and Lepob/ob mice, the underlying mechanisms differ, and the anti-obesity actions of α-GIs and leptin sensitizers may be mediated partly by the suppression of GIP secretion.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Polipeptídeo Inibidor Gástrico/metabolismo , Leptina/deficiência , Obesidade/metabolismo , Animais , Polipeptídeo Inibidor Gástrico/sangue , Polipeptídeo Inibidor Gástrico/genética , Expressão Gênica , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Leptina/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores dos Hormônios Gastrointestinais/genética , Receptores dos Hormônios Gastrointestinais/metabolismo
18.
Gastroenterology ; 157(6): 1530-1543.e4, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31445037

RESUMO

BACKGROUND & AIMS: Dysregulation of the microbiome has been associated with development of complex diseases, such as obesity and diabetes. However, no method has been developed to control disease-associated commensal microbes. We investigated whether immunization with microbial antigens, using CpG oligodeoxynucleotides and/or curdlan as adjuvants, induces systemic antigen-specific IgA and IgG production and affects development of diseases in mice. METHODS: C57BL/6 mice were given intramuscular injections of antigens (ovalbumin, cholera toxin B-subunit, or pneumococcal surface protein A) combined with CpG oligodeoxynucleotides and/or curdlan. Blood and fecal samples were collected weekly and antigen-specific IgG and IgA titers were measured. Lymph nodes and spleens were collected and analyzed by enzyme-linked immunosorbent assay for antigen-specific splenic T-helper 1 cells, T-helper 17 cells, and memory B cells. Six weeks after primary immunization, mice were given a oral, nasal, or vaginal boost of ovalbumin; intestinal lamina propria, bronchial lavage, and vaginal swab samples were collected and antibodies and cytokines were measured. Some mice were also given oral cholera toxin or intranasal Streptococcus pneumoniae and the severity of diarrhea or pneumonia was analyzed. Gnotobiotic mice were gavaged with fecal material from obese individuals, which had a high abundance of Clostridium ramosum (a commensal microbe associated with obesity and diabetes), and were placed on a high-fat diet 2 weeks after immunization with C ramosum. Intestinal tissues were collected and analyzed by quantitative real-time polymerase chain reaction. RESULTS: Serum and fecal samples from mice given injections of antigens in combination with CpG oligodeoxynucleotides and curdlan for 3 weeks contained antigen-specific IgA and IgG, and splenocytes produced interferon-gamma and interleukin 17A. Lamina propria, bronchial, and vaginal samples contained antigen-specific IgA after the ovalbumin boost. This immunization regimen prevented development of diarrhea after injection of cholera toxin, and inhibited lung colonization by S pneumoniae. In gnotobiotic mice colonized with C ramosum and placed on a high-fat diet, the mice that had been immunized with C ramosum became less obese than the nonimmunized mice. CONCLUSIONS: Injection of mice with microbial antigens and adjuvant induces antigen-specific mucosal and systemic immune responses. Immunization with S pneumoniae antigen prevented lung infection by this bacteria, and immunization with C ramosum reduced obesity in mice colonized with this microbe and placed on a high-fat diet. This immunization approach might be used to protect against microbe-associated disorders of intestine.


Assuntos
Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Proteínas de Bactérias/imunologia , Toxina da Cólera/imunologia , Diarreia/diagnóstico , Diarreia/imunologia , Diarreia/microbiologia , Modelos Animais de Doenças , Disbiose/microbiologia , Feminino , Vida Livre de Germes , Humanos , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Pneumonia/diagnóstico , Pneumonia/imunologia , Pneumonia/microbiologia , Índice de Gravidade de Doença
19.
Neurobiol Dis ; 124: 81-92, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30423474

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by the loss of nigrostriatal dopaminergic neurons. Although increased production of prostaglandin E2 (PGE2) has been implicated in tissue damage in several pathological settings, the role of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE2 synthesis, in dopaminergic neurodegeneration remains unclear. Here we show that mPGES-1 is up-regulated in the dopaminergic neurons of the substantia nigra of postmortem brain tissue from PD patients and in neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice. The expression of mPGES-1 was also up-regulated in cultured dopaminergic neurons stimulated with 6-OHDA. The genetic deletion of mPGES-1 not only abolished 6-OHDA-induced PGE2 production but also inhibited 6-OHDA-induced dopaminergic neurodegeneration both in vitro and in vivo. Nigrostriatal projections, striatal dopamine content, and neurological functions were significantly impaired by 6-OHDA administration in wild-type (WT) mice, but not in mPGES-1 knockout (KO) mice. Furthermore, in cultured primary mesencephalic neurons, addition of PGE2 to compensate for the deficiency of 6-OHDA-induced PGE2 production in mPGES-1 KO neurons recovered 6-OHDA toxicity to almost the same extent as that seen in WT neurons. These results suggest that induction of mPGES-1 enhances 6-OHDA-induced dopaminergic neuronal death through excessive PGE2 production. Thus, mPGES-1 may be a valuable therapeutic target for treatment of PD.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Prostaglandina-E Sintases/metabolismo , Substância Negra/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Oxidopamina/administração & dosagem , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Cultura Primária de Células , Prostaglandina-E Sintases/genética
20.
J Endocrinol ; 239(3): 267-276, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30400014

RESUMO

Mechanisms of carbohydrate-induced secretion of the two incretins namely glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are considered to be mostly similar. However, we found that mice exhibit opposite secretory responses in response to co-administration of maltose plus an α-glucosidase inhibitor miglitol (maltose/miglitol), stimulatory for GLP-1, as reported previously, but inhibitory for GIP. Gut microbiota was shown to be involved in maltose/miglitol-induced GIP suppression, as the suppression was attenuated in antibiotics (Abs)-treated mice and abolished in germ-free mice. In addition, maltose/miglitol administration increased plasma levels of short-chain fatty acids (SCFAs), carbohydrate-derived metabolites, in the portal vein. GIP suppression by maltose/miglitol was not observed in mice lacking a SCFA receptor Ffar3, but it was normally seen in Ffar2-deficient mice. Similar to maltose/miglitol administration, co-administration of glucose plus a sodium glucose transporter inhibitor phloridzin (glucose/phloridzin) induced GIP suppression, which was again cancelled by Abs treatment. In conclusion, oral administration of carbohydrates with α-glucosidase inhibitors suppresses GIP secretion through a microbiota/SCFA/FFAR3 pathway.


Assuntos
Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , 1-Desoxinojirimicina/análogos & derivados , Animais , Metabolismo dos Carboidratos , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/fisiologia , Inibidores de Glicosídeo Hidrolases , Incretinas/metabolismo , Canais KATP/metabolismo , Maltose , Camundongos , Receptores Acoplados a Proteínas G/metabolismo
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