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1.
J Microbiol Biol Educ ; : e0018123, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38700339

RESUMO

The COVID-19 global pandemic has prompted educators in universities to reconsider their teaching methods, mainly due to the social distancing measures imposed within the classroom settings. On the other hand, the growing importance of continuing education opportunities for adult learners after graduation has seen the need to transform traditional teaching modes that primarily depend on face-to-face interaction into virtual modes, which are deemed more time- and cost-efficient. These major shifts in social and economic developments have a significant impact on the evolution of curriculum planning in higher education. Education that has scientific inquiry components inevitably comes into question, as conventional beliefs that experiments should be hands-on and will not be as effective if conducted virtually cast doubts on the move to the online space. This paper discusses the background of an impending shift in a university's approach to more online-based laboratory classes in an immunology course, as well as the exploration of the potential of conducting online laboratory experiments based on student perceptions.

2.
Sci Rep ; 14(1): 2819, 2024 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-38307921

RESUMO

Viruses are a key component of the colon microbiome, but the relationship between virome and colorectal cancer (CRC) remains poorly understood. We seek to identify alterations in the viral community that is characteristic of CRC and examine if they persist after surgery. Forty-nine fecal samples from 25 non-cancer (NC) individuals and 12 CRC patients, before and 6-months after surgery, were collected for metagenomic analysis. The fecal virome of CRC patients demonstrated an increased network connectivity as compared to NC individuals. Co-exclusion of influential viruses to bacterial species associated with healthy gut status was observed in CRC, suggesting an altered virome induced a change in the healthy gut bacteriome. Network analysis revealed lower connectivity within the virome and trans-kingdom interactions in NC. After surgery, the number of strong correlations decreased for trans-kingdom and within the bacteria and virome networks, indicating lower connectivity within the microbiome. Some co-occurrence patterns between dominant viruses and bacteria were also lost after surgery, suggesting a possible return to the healthy state of gut microbiome. Microbial signatures characteristic of CRC include an altered virome besides an altered bacterial composition. Elevated viral correlations and network connectivity were observed in CRC patients relative to healthy individuals, alongside distinct changes in the cross-kingdom correlation network unique to CRC patients. Some patterns of dysbiosis persist after surgery. Future studies should seek to verify if dysbiosis truly persists after surgery in a larger sample size with microbiome data collected at various time points after surgery to explore if there is field-change in the remaining colon, as well as to examine if persistent dysbiosis correlates with patient outcomes.


Assuntos
Neoplasias Colorretais , Microbiota , Vírus , Humanos , Viroma , Disbiose/microbiologia , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/microbiologia
3.
Cell Death Differ ; 31(3): 280-291, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38383887

RESUMO

Detection of cytosolic nucleic acids by pattern recognition receptors, including STING and RIG-I, leads to the activation of multiple signalling pathways that culminate in the production of type I interferons (IFNs) which are vital for host survival during virus infection. In addition to protective immune modulatory functions, type I IFNs are also associated with autoimmune diseases. Hence, it is important to elucidate the mechanisms that govern their expression. In this study, we identified a critical regulatory function of the DUSP4 phosphatase in innate immune signalling. We found that DUSP4 regulates the activation of TBK1 and ERK1/2 in a signalling complex containing DUSP4, TBK1, ERK1/2 and IRF3 to regulate the production of type I IFNs. Mice deficient in DUSP4 were more resistant to infections by both RNA and DNA viruses but more susceptible to malaria parasites. Therefore, our study establishes DUSP4 as a regulator of nucleic acid sensor signalling and sheds light on an important facet of the type I IFN regulatory system.


Assuntos
Interferon Tipo I , Proteínas de Membrana , Proteínas Tirosina Fosfatases , Receptores de Superfície Celular , Proteínas Roundabout , Viroses , Animais , Camundongos , Imunidade Inata , Interferon Tipo I/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Viroses/imunologia , Viroses/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Roundabout/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Receptores de Superfície Celular/metabolismo
4.
Immune Netw ; 23(4): e34, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37670811

RESUMO

Lung cancer, particularly non-small cell lung cancer (NSCLC) which contributes more than 80% to totally lung cancer cases, remains the leading cause of cancer death and the 5-year survival is less than 20%. Continuous understanding on the mechanisms underlying the pathogenesis of this disease and identification of biomarkers for therapeutic application and response to treatment will help to improve patient survival. Here we found that a molecule known as DUSP10 (also known as MAPK phosphatase 5) is oncogenic in NSCLC. Overexpression of DUSP10 in NSCLC cells resulted in reduced activation of ERK and JNK, but increased activation of p38, which was associated with increased cellular growth and migration. When inoculated in immunodeficient mice, the DUSP10-overexpression NSCLC cells formed larger tumors compared to control cells. The increased growth of DUSP10-overexpression NSCLC cells was associated with increased expression of tumor-promoting cytokines including IL-6 and TGFß. Importantly, higher DUSP10 expression was associated with poorer prognosis of NSCLC patients. Therefore, DUSP10 could severe as a biomarker for NSCLC prognosis and could be a target for development of therapeutic method for lung cancer treatment.

5.
EMBO J ; 42(21): e112963, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37743772

RESUMO

The large intestine harbors microorganisms playing unique roles in host physiology. The beneficial or detrimental outcome of host-microbiome coexistence depends largely on the balance between regulators and responder intestinal CD4+ T cells. We found that ulcerative colitis-like changes in the large intestine after infection with the protist Blastocystis ST7 in a mouse model are associated with reduction of anti-inflammatory Treg cells and simultaneous expansion of pro-inflammatory Th17 responders. These alterations in CD4+ T cells depended on the tryptophan metabolite indole-3-acetaldehyde (I3AA) produced by this single-cell eukaryote. I3AA reduced the Treg subset in vivo and iTreg development in vitro by modifying their sensing of TGFß, concomitantly affecting recognition of self-flora antigens by conventional CD4+ T cells. Parasite-derived I3AA also induces over-exuberant TCR signaling, manifested by increased CD69 expression and downregulation of co-inhibitor PD-1. We have thus identified a new mechanism dictating CD4+ fate decisions. The findings thus shine a new light on the ability of the protist microbiome and tryptophan metabolites, derived from them or other sources, to modulate the adaptive immune compartment, particularly in the context of gut inflammatory disorders.


Assuntos
Microbioma Gastrointestinal , Microbiota , Animais , Camundongos , Eucariotos/metabolismo , Triptofano/metabolismo , Linfócitos T Reguladores
6.
NPJ Biofilms Microbiomes ; 9(1): 22, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-37185924

RESUMO

Blastocystis is a species complex that exhibits extensive genetic diversity, evidenced by its classification into several genetically distinct subtypes (ST). Although several studies have shown the relationships between a specific subtype and gut microbiota, there is no study to show the effect of the ubiquitous Blastocystis ST1 on the gut microbiota and host health. Here, we show that Blastocystis ST1 colonization increased the proportion of beneficial bacteria Alloprevotella and Akkermansia, and induced Th2 and Treg cell responses in normal healthy mice. ST1-colonized mice showed decreases in the severity of DSS-induced colitis when compared to non-colonized mice. Furthermore, mice transplanted with ST1-altered gut microbiota were refractory to dextran sulfate sodium (DSS)-induced colitis via induction of Treg cells and elevated short-chain fat acid (SCFA) production. Our results suggest that colonization with Blastocystis ST1, one of the most common subtypes in humans, exerts beneficial effects on host health through modulating the gut microbiota and adaptive immune responses.


Assuntos
Blastocystis , Colite , Microbioma Gastrointestinal , Microbiota , Humanos , Camundongos , Animais , Blastocystis/genética , Colite/induzido quimicamente , Colite/microbiologia , Bactérias
7.
Theranostics ; 13(3): 1165-1179, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36793854

RESUMO

Rationale: The gut microbiota plays a significant role in the pathogenesis of inflammatory bowel disease (IBD). However, the role of Blastocystis infection and Blastocystis-altered gut microbiota in the development of inflammatory diseases and their underlying mechanisms are not well understood. Methods: We investigated the effect of Blastocystis ST4 and ST7 infection on the intestinal microbiota, metabolism, and host immune responses, and then explored the role of Blastocystis-altered gut microbiome in the development of dextran sulfate sodium (DSS)-induced colitis in mice. Results: This study showed that prior colonization with ST4 conferred protection from DSS-induced colitis through elevating the abundance of beneficial bacteria, short-chain fatty acid (SCFA) production and the proportion of Foxp3+ and IL-10-producing CD4+ T cells. Conversely, prior ST7 infection exacerbated the severity of colitis by increasing the proportion of pathogenic bacteria and inducing pro-inflammatory IL-17A and TNF-α-producing CD4+ T cells. Furthermore, transplantation of ST4- and ST7-altered microbiota resulted in similar phenotypes. Conclusions: Our data showed that ST4 and ST7 infection exert strikingly differential effects on the gut microbiota, and these could influence the susceptibility to colitis. ST4 colonization prevented DSS-induced colitis in mice and may be considered as a novel therapeutic strategy against immunological diseases in the future, while ST7 infection is a potential risk factor for the development of experimentally induced colitis that warrants attention.


Assuntos
Blastocystis , Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Microbiota , Animais , Camundongos , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Colo/patologia
8.
Sci Rep ; 12(1): 9829, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35701595

RESUMO

There is growing interest in the role of gut microbiome in colorectal cancer (CRC), ranging from screening to disease recurrence. Our study aims to identify microbial markers characteristic of CRC and to examine if changes in bacteriome persist after surgery. Forty-nine fecal samples from 25 non-cancer (NC) individuals and 12 CRC patients, before and 6-months after surgery, were collected for analysis by bacterial 16S rRNA gene sequencing. Bacterial richness and diversity were reduced, while pro-carcinogenic bacteria such as Bacteroides fragilis and Odoribacter splanchnicus were increased in CRC patients compared to NC group. These differences were no longer observed after surgery. Comparison between pre-op and post-op CRC showed increased abundance of probiotic bacteria after surgery. Concomitantly, bacteria associated with CRC progression were observed to have increased after surgery, implying persistent dysbiosis. In addition, functional pathway predictions based on the bacterial 16S rRNA gene data showed that various pathways were differentially enriched in CRC compared to NC. Microbiome signatures characteristic of CRC comprise altered bacterial composition. Elements of these dysbiotic signatures persists even after surgery, suggesting possible field-change in remnant non-diseased colon. Future studies should involve a larger sample size with microbiome data collected at multiple time points after surgery to examine if these dysbiotic patterns truly persist and also correlate with disease outcomes.


Assuntos
Neoplasias Colorretais , Recidiva Local de Neoplasia , Bactérias/genética , Neoplasias Colorretais/diagnóstico , Disbiose/microbiologia , Humanos , Projetos Piloto , RNA Ribossômico 16S/genética
9.
Cell Mol Life Sci ; 79(5): 245, 2022 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-35435504

RESUMO

BACKGROUND: Blastocystis is a common gut protistan parasite in humans and animals worldwide, but its interrelationship with the host gut microbiota and mucosal immune responses remains poorly understood. Different murine models of Blastocystis colonization were used to examine the effect of a common Blastocystis subtype (ST4) on host gut microbial community and adaptive immune system. RESULTS: Blastocystis ST4-colonized normal healthy mice and Rag1-/- mice asymptomatically and was able to alter the microbial community composition, mainly leading to increases in the proportion of Clostridia vadinBB60 group and Lachnospiraceae NK4A136 group, respectively. Blastocystis ST4 colonization promoted T helper 2 (Th2) response defined by interleukin (IL)-5 and IL-13 cytokine production, and T regulatory (Treg) induction from colonic lamina propria in normal healthy mice. Additionally, we observed that Blastocystis ST4 colonization can maintain the stability of bacterial community composition and induce Th2 and Treg immune responses to promote faster recovery from experimentally induced colitis. Furthermore, fecal microbiota transplantation of Blastocystis ST4-altered gut microbiome to colitis mice reduced the severity of colitis, which was associated with increased production of short-chain fat acids (SCFAs) and anti-inflammatory cytokine IL-10. CONCLUSIONS: The data confirm our hypothesis that Blastocystis ST4 is a beneficial commensal, and the beneficial effects of Blastocystis ST4 colonization is mediated through modulating of the host gut bacterial composition, SCFAs production, and Th2 and Treg responses in different murine colonization models.


Assuntos
Blastocystis , Colite , Microbioma Gastrointestinal , Animais , Bactérias , Colite/induzido quimicamente , Citocinas , Modelos Animais de Doenças , Imunidade , Camundongos , Camundongos Endogâmicos C57BL
10.
Theranostics ; 12(1): 48-58, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34987633

RESUMO

Background & Aims: Dysbiosis is associated with gastric cancer (GC) development. However, no longitudinal study was carried out to identify key bacteria that could predict for GC progression. Here, we aimed to investigate changes in bacterial metagenome prior to GC and develop a microbiome-based predictive model to accurately classify patients at risk of GC. Methods: Bacterial 16S rDNA was sequenced from 89 gastric antral biopsies obtained from 43 participants. This study was nested in a prospective, longitudinal study, whereby study participants underwent screening gastroscopy, with further 1-2 yearly surveillance gastroscopies for at least 5 years. Putative bacterial taxonomic and functional features associated with GC carcinogenesis were identified by comparing between controls, patients with gastric intestinal metaplasia (IM) and patients with early gastric neoplasia (EGN). Results: Patients with EGN had enrichment of Proteobacteria (in particular Proteus genus) and depletion of Bacteroidetes (in particular S24-7 family) in their gastric mucosa. Sequencing identified more patients with Helicobacter pylori compared to histopathological assessment, while H. pylori was also significantly enriched in EGN. Furthermore, a total of 261 functional features, attributing to 97 KEGG pathways were differentially abundant at baseline between patients who subsequent developed EGN (n = 13/39) and those who did not. At the same time, a constellation of six microbial taxonomic features present at baseline, provided the highest classifying power for subsequent EGN (AUC = 0.82). Conclusion: Our study highlights early microbial changes associated with GC carcinogenesis, suggesting a potential role for prospective microbiome surveillance for GC.


Assuntos
Disbiose/microbiologia , Mucosa Gástrica/microbiologia , Microbioma Gastrointestinal , Neoplasias Gástricas/microbiologia , Helicobacter pylori , Humanos , Estudos Longitudinais , Estudos Prospectivos
11.
J Immunol ; 207(8): 2107-2117, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526375

RESUMO

A multifunctional glycoprotein, osteopontin (OPN), can modulate the function of macrophages, resulting in either protective or deleterious effects in various inflammatory diseases and infection in the lungs. Although macrophages play the critical roles in mediating host defenses against cryptococcosis or cryptococcal pathogenesis, the involvement of macrophage-derived OPN in pulmonary infection caused by fungus Cryptococcus has not been elucidated. Thus, our current study aimed to investigate the contribution of OPN to the regulation of host immune response and macrophage function using a mouse model of pulmonary cryptococcosis. We found that OPN was predominantly expressed in alveolar macrophages during C. neoformans infection. Systemic treatment of OPN during C. neoformans infection resulted in an enhanced pulmonary fungal load and an early onset of type 2 inflammation within the lung, as indicated by the increase of pulmonary eosinophil infiltration, type 2 cytokine production, and M2-associated gene expression. Moreover, CRISPR/Cas9-mediated OPN knockout murine macrophages had enhanced ability to clear the intracellular fungus and altered macrophage phenotype from pathogenic M2 to protective M1. Altogether, our data suggested that macrophage-derived OPN contributes to the elaboration of C. neoformans-induced type 2 immune responses and polarization of M2s that promote fungal survival and proliferation within macrophages.


Assuntos
Criptococose/imunologia , Cryptococcus neoformans/fisiologia , Eosinófilos/imunologia , Pulmão/patologia , Macrófagos/imunologia , Osteopontina/metabolismo , Células Th2/imunologia , Animais , Diferenciação Celular , Processos de Crescimento Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Osteopontina/genética , Equilíbrio Th1-Th2
12.
Cell Death Differ ; 28(11): 3022-3035, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34091599

RESUMO

Dysfunction of adipocytes and adipose tissue is a primary defect in obesity and obesity-associated metabolic diseases. Interferon regulatory factor 3 (IRF3) has been implicated in adipogenesis. However, the role of IRF3 in obesity and obesity-associated disorders remains unclear. Here, we show that IRF3 expression in human adipose tissues is positively associated with insulin sensitivity and negatively associated with type 2 diabetes. In mouse pre-adipocytes, deficiency of IRF3 results in increased expression of PPARγ and PPARγ-mediated adipogenic genes, leading to increased adipogenesis and altered adipocyte functionality. The IRF3 knockout (KO) mice develop obesity, insulin resistance, glucose intolerance, and eventually type 2 diabetes with aging, which is associated with the development of white adipose tissue (WAT) inflammation. Increased macrophage accumulation with M1 phenotype which is due to the loss of IFNß-mediated IL-10 expression is observed in WAT of the KO mice compared to that in wild-type mice. Bone-marrow reconstitution experiments demonstrate that the nonhematopoietic cells are the primary contributors to the development of obesity and both hematopoietic and nonhematopoietic cells contribute to the development of obesity-related complications in IRF3 KO mice. This study demonstrates that IRF3 regulates the biology of multiple cell types including adipocytes and macrophages to prevent the development of obesity and obesity-related complications and hence, could be a potential target for therapeutic interventions for the prevention and treatment of obesity-associated metabolic disorders.


Assuntos
Tecido Adiposo/fisiopatologia , Inflamação/fisiopatologia , Fator Regulador 3 de Interferon/genética , Obesidade/genética , Animais , Diferenciação Celular , Humanos , Masculino , Camundongos
13.
Nat Commun ; 12(1): 2284, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863904

RESUMO

Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Fosfatases de Especificidade Dupla/metabolismo , Mitocôndrias/efeitos dos fármacos , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Neoplasias/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Fracionamento Celular , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Fosfatases de Especificidade Dupla/análise , Feminino , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Fosfatases da Proteína Quinase Ativada por Mitógeno/análise , Neoplasias/mortalidade , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismo
14.
Front Cell Dev Biol ; 9: 586150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33598459

RESUMO

Liver cancer is the third most common cause of cancer death in the world. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1/MAZR) is a transcription factor associated with various cancers. However, the role of PATZ1 in cancer progression remains controversial largely due to lack of genome-wide studies. Here we report that PATZ1 regulates cell proliferation by directly regulating CDKN1B (p27) in hepatocellular carcinoma cells. Our PATZ1 ChIP-seq and gene expression microarray analyses revealed that PATZ1 is strongly related to cancer signatures and cellular proliferation. We further discovered that PATZ1 depletion led to an increased rate of colony formation, elevated Ki-67 expression and greater S phase entry. Importantly, the increased cancer cell proliferation was accompanied with suppressed expression of the cyclin-dependent kinase inhibitor CDKN1B. Consistently, we found that PATZ1 binds to the genomic loci flanking the transcriptional start site of CDKN1B and positively regulates its transcription. Notably, we demonstrated that PATZ1 is a p53 partner and p53 is essential for CDKN1B regulation. In conclusion, our study provides novel mechanistic insights into the inhibitory role of PATZ1 in liver cancer progression, thereby yielding a promising therapeutic intervention to alleviate tumor burden.

15.
Chem Sci ; 11(45): 12329-12335, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34094441

RESUMO

We present herein an unconventional tandem [3,3]-sigmatropic rearrangement/[2 + 2] cycloaddition of simple dipropargylphosphonates to deliver a range of bicyclic polysubstituted cyclobutenes and cyclobutanes under Ag/Co relay catalysis. An interesting switch from allene-allene to allene-alkyne cycloaddition was observed based on the substitution of the substrates, which further diversified the range of compounds accessible from this practical method. Significantly, preliminary biological screening of these new compounds identified promising candidates as suppressors of cellular proliferation.

16.
Hepatol Commun ; 3(6): 748-762, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31168510

RESUMO

Nonalcoholic fatty liver disease is currently the most common liver disease and is a leading cause of liver-related morbidity and mortality. However, its pathogenesis remains largely unclear. We previously showed that mice deficient in mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP5) spontaneously developed insulin resistance and glucose intolerance, which are associated with visceral obesity and adipose tissue inflammation. In this study, we discovered that mice deficient in MKP5 developed more severe hepatic steatosis and steatohepatitis with age or with feeding on a high-fat diet (HFD) compared to wild-type (WT) mice, and this was associated with increased expression of proinflammatory cytokines and collagen genes. Increased p38 activation in MKP5 knockout (KO) liver compared to that in WT liver was detected, which contributed to increased expression of lipid droplet-associated protein cell death-inducing DFF45-like effector A (CIDEA) and CIDEC/fat-specific protein 27 but not CIDEB through activating transcription factor 2 (ATF2). In addition, MKP5 KO liver had higher peroxisome proliferator-activated receptor gamma (PPARγ) expression compared with WT liver. On the other hand, overexpression of MKP5 or inhibition of p38 activation in hepatocytes resulted in reduced expression of PPARγ. Inhibition of p38 resulted in alleviation of hepatic steatosis in KO liver in response to HFD feeding, and this was associated with reduced expression of CIDEA, CIDEC, and proinflammatory cytokines. Conclusion: MKP5 prevents the development of nonalcoholic steatohepatitis by suppressing p38-ATF2 and p38-PPARγ to reduce hepatic lipid accumulation, inflammation, and fibrosis.

17.
Microbiome ; 7(1): 30, 2019 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-30853028

RESUMO

BACKGROUND: Blastocystis is a common gut eukaryote detected in humans and animals. It has been associated with gastrointestinal disease in the past although recent metagenomic studies also suggest that it is a member of normal microbiota. This study investigates interactions between pathogenic human isolates belonging to Blastocystis subtype 7 (ST7) and bacterial representatives of the gut microbiota. RESULTS: Generally, Blastocystis ST7 exerts a positive effect on the viability of representative gut bacteria except on Bifidobacterium longum. Gene expression analysis and flow cytometry indicate that the bacterium may be undergoing oxidative stress in the presence of Blastocystis. In vitro assays demonstrate that Blastocystis-induced host responses are able to decrease Bifidobacterium counts. Mice infected with Blastocystis also reveal a decrease in beneficial bacteria Bifidobacterium and Lactobacillus. CONCLUSIONS: This study shows that particular isolates of Blastocystis ST7 cause changes in microbiota populations and potentially lead to an imbalance of the gut microbiota. This study suggests that certain isolates of Blastocystis exert their pathogenic effects through disruption of the gut microbiota and provides a counterpoint to the increasing reports indicating the commensal nature of this ubiquitous parasite.


Assuntos
Infecções por Blastocystis/microbiologia , Blastocystis/crescimento & desenvolvimento , Gastroenteropatias/microbiologia , Microbioma Gastrointestinal , Perfilação da Expressão Gênica/métodos , Animais , Proteínas de Bactérias/genética , Bifidobacterium longum/genética , Bifidobacterium longum/crescimento & desenvolvimento , Blastocystis/classificação , Blastocystis/isolamento & purificação , Blastocystis/patogenicidade , Técnicas de Cocultura , Modelos Animais de Doenças , Fezes/microbiologia , Regulação Bacteriana da Expressão Gênica , Células HT29 , Humanos , Lactobacillus/genética , Lactobacillus/crescimento & desenvolvimento , Metagenômica , Camundongos
18.
Front Immunol ; 8: 1259, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29062315

RESUMO

The mitogen-activated protein kinase (MAPK) cascades are activated in innate immune cells such as macrophages upon the detection of microbial infection, critically regulating the expression of proinflammatory cytokines and chemokines such as TNF-α, IL-6, and MCP-1. As a result, activation of MAPKs is tightly regulated to ensure appropriate and adequate immune responses. Dual-specificity phosphatases (DUSPs) are a family of proteins which specifically dephosphorylates threonine and tyrosine residues essential for MAPK activation to negatively regulate their activation. DUSP12 is a member of atypical DUSPs that lack MAPK-binding domain. Its substrate and function in immune cells are unknown. In this study, we demonstrated that DUSP12 is able to interact with all the three groups of MAPKs, including extracellular signal-regulated protein kinase, JNK, and p38. To investigate the function of DUSP12 in macrophages in response to TLR activation and microbial infection, we established RAW264.7 cell lines stably overexpressing DUSP12 and found that overexpression of DUSP12 inhibited proinflammatory cytokine and chemokine production in response to TLR4 activation, heat-inactivated Mycobacterium tuberculosis stimulation as well as infections by intracellular bacteria including Listeria moncytogenesis and Mycobacterium bovis BCG by specifically inhibiting p38 and JNK. In addition, a scaffold protein known as signal transducing adaptor protein 2 (STAP2), was found to mediate the interaction between DUSP12 and p38. Thus, DUSP12 is a bona fide MAPK phosphatase, playing an important role in MAPK-regulated responses to bacterial infection. Our study provides a model where atypical DUSPs regulate MAPKs via scaffold, thereby regulating immune responses to microbial infection.

19.
Oncotarget ; 7(34): 55473-55490, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27487154

RESUMO

The non-keratinizing undifferentiated subtype of nasopharyngeal carcinoma (NPC) is a malignancy characterized by an intimate relationship between neoplastic cells and a non-neoplastic lymphoid component. Tumor-associated macrophages (TAMs) foster tumor progression through production of soluble mediators that support proliferation, angiogenesis, survival and invasion of malignant cells. However, the role of macrophages in the progression of NPC remains poorly understood. This study aims to investigate the functional and phenotypic changes that occur to macrophages in macrophage-NPC cell co-culture systems, and how these changes influence tumor cells. We found that monocytes, including THP-1 cells and primary human monocytes, co-cultured with C666-1 NPC cells upregulate expression of pro-inflammatory cytokines at the early stages, followed by the induction of metastasis-related genes and interferon-stimulated genes at the later stage of coculture, indicating that TAMs are "educated" by NPC cells for cancer progression. Importantly, the induction of these factors from the TAMs was also found to enhance the migratory capabilities of the NPC cells. We have also identified one of these macrophage-derived factor, phospholipase A2 Group 7 (PLA2G7), to be important in regulating tumor cell migration and a novel tumor-promoting factor in NPC. Further studies to characterize the role of PLA2G7 in tumor metastasis may help determine its potential as a therapeutic target in NPC.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/fisiologia , Carcinoma/patologia , Comunicação Celular , Macrófagos/fisiologia , Monócitos/fisiologia , Neoplasias Nasofaríngeas/patologia , Linhagem Celular Tumoral , Movimento Celular , Técnicas de Cocultura , Citocinas/genética , Humanos , Carcinoma Nasofaríngeo , Invasividade Neoplásica , Metástase Neoplásica
20.
PLoS One ; 11(8): e0160458, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27508942

RESUMO

Blastocystis spp. are widely prevalent extra cellular, non-motile anerobic protists that inhabit the gastrointestinal tract. Although Blastocystis spp. have been associated with gastrointestinal symptoms, irritable bowel syndrome and urticaria, their clinical significance has remained controversial. We established an ex vivo mouse explant model to characterize adhesion in the context of tissue architecture and presence of the mucin layer. Using confocal microscopy with tissue whole mounts and two axenic isolates of Blastocystis spp., subtype 7 with notable differences in adhesion to intestinal epithelial cells (IEC), isolate B (ST7-B) and isolate H (more adhesive, ST7-H), we showed that adhesion is both isolate dependent and tissue trophic. The more adhesive isolate, ST7-H was found to bind preferentially to the colon tissue than caecum and terminal ileum. Both isolates were also found to have mucinolytic effects. We then adapted a DSS colitis mouse model as a susceptible model to study colonization and acute infection by intra-caecal inoculation of trophic Blastocystis spp.cells. We found that the more adhesive isolate ST7-H was also a better colonizer with more mice shedding parasites and for a longer duration than ST7-B. Adhesion and colonization was also associated with increased virulence as ST7-H infected mice showed greater tissue damage than ST7-B. Both the ex vivo and in vivo models used in this study showed that Blastocystis spp. remain luminal and predominantly associated with mucin. This was further confirmed using colonic loop experiments. We were also successfully able to re-infect a second batch of mice with ST7-H isolates obtained from fecal cultures and demonstrated similar histopathological findings and tissue damage thereby coming closer to proving Koch's postulates for this parasite.


Assuntos
Infecções por Blastocystis/patologia , Blastocystis/fisiologia , Animais , Blastocystis/isolamento & purificação , Infecções por Blastocystis/parasitologia , Colite/induzido quimicamente , Colite/patologia , Colo/parasitologia , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Gastroenteropatias/parasitologia , Gastroenteropatias/patologia , Humanos , Mucosa Intestinal/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Mucinas/metabolismo , Virulência
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