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1.
Cancers (Basel) ; 14(9)2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35565396

RESUMO

The tumor microenvironment of ovarian cancer is the peritoneal cavity wherein adipose tissue is a major component. The role of the adipose tissue in support of ovarian cancer progression has been elucidated in several studies from the past decades. The adipocytes, in particular, are a major source of factors, which regulate all facets of ovarian cancer progression such as acquisition of chemoresistance, enhanced metastatic potential, and metabolic reprogramming. In this review, we summarize the relevant studies, which highlight the role of adipocytes in ovarian cancer progression and offer insights into unanswered questions and possible future directions of research.

2.
Int J Biol Sci ; 18(6): 2406-2418, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35414772

RESUMO

A successful pregnancy requires the maternal immune system to tolerate an allogeneic fetus. The incidence of preeclampsia and other complications related to impaired fetal tolerance is lower during the second pregnancy than during the first pregnancy. At the same time, compared with normal pregnant women in the previous pregnancy, patients with pregnancy complications in the previous pregnancy also have an increased risk of the disease when they become pregnant again. This difference may be related to the immunological memory of pregnancy. Regulatory T cells (Tregs) are immunosuppressive CD4+ T cells that play a predominant role in maintaining immune tolerance. In addition, Tregs possess immunological memory properties, including fetal or paternal-specific memory Tregs and Tregs expressing memory cell makers, forming an immunoregulatory memory against fetal antigens. In this review, we provide an overview of the characteristics of memory Tregs in pregnancy, evidence regarding the existence of memory Tregs in human pregnancy, as well as in mouse models. We also discuss the mechanism of memory Tregs induction, maintenance, and action. In addition, we described their changes during the first pregnancy, second pregnancy, postpartum, and pathological pregnancy in order to provide new targets for the diagnosis and treatment of pregnancy related diseases.


Assuntos
Memória Imunológica , Linfócitos T Reguladores , Animais , Antígenos , Feminino , Feto , Humanos , Tolerância Imunológica , Camundongos , Gravidez
3.
Immunol Rev ; 2022 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-35306673

RESUMO

Pregnancy is a unique condition where the maternal immune system is continuously adapting in response to the stages of fetal development and signals from the environment. The placenta is a key mediator of the fetal/maternal interaction by providing signals that regulate the function of the maternal immune system as well as provides protective mechanisms to prevent the exposure of the fetus to dangerous signals. Bacterial and/or viral infection during pregnancy induce a unique immunological response by the placenta, and type I interferon is one of the crucial signaling pathways in the trophoblast cells. Basal expression of type I interferon-ß and downstream ISGs harbors physiological functions to maintain the homeostasis of pregnancy, more importantly, provides the placenta with the adequate awareness to respond to infections. The disruption of type I interferon signaling in the placenta will lead to pregnancy complications and can compromise fetal development. In this review, we focus the important role of placenta-derived type I interferon and its downstream ISGs in the regulation of maternal immune homeostasis and protection against viral infection. These studies are helping us to better understand placental immunological functions and provide a new perspective for developing better approaches to protect mother and fetus during infections.

4.
Immunol Rev ; 2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35234305

RESUMO

Successful pregnancy is a unique situation requires the maternal immune system to recognize and tolerate a semi-identical fetus and allow normal invasion of trophoblast cells. Although efforts have been made, the deep mechanisms of the maternal-fetal crosstalk have not yet been fully deciphered. Immune checkpoint molecules (ICMs) are a group of negative modulators of the immune response that avoid immune damage. They have been extensively studied in the fields of oncology and transplantation, while the latest evidence suggests that they are closely associated with pregnancy outcomes via multiple inhibitory mechanisms. Although studies have mostly demonstrated the regulatory role of the well-known PD-1, CTLA-4 at the maternal-fetal interface, what is unique about the newly discovered multiple ICMs remains a mystery. Here, we review the latest knowledge on ICMs, focusing on the first generation of checkpoints (PD-1, CTLA-4) and the next generation (Tim-3, Tigit, Lag-3, VISTA) highlighting their immunoregulatory roles in maternal-fetal tolerance and decidual vascular remodeling, and their involvement in pathological pregnancies. The content covers three aspects: the characteristics they possess, the dynamic expression profile of their expression at the maternal-fetal interface, and their involvement in pathological pregnancy. In immunotherapy strategies for pregnancy complications, upregulation of immune checkpoints may play a role. Meanwhile, the impact on pregnancy outcomes when using ICMs in clinical cancer treatment during pregnancy is a topic worth exploring. These may serve as a guide for future basic research and clinical applications of maternal-fetal immunity.

5.
Int J Biol Sci ; 18(2): 599-616, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35002512

RESUMO

Lactic acid (LA) metabolism in the tumor microenvironment contributes to the establishment and maintenance of immune tolerance. This pathway is characterized in tumor associated macrophages. However, the role and pathway of LA metabolism at maternal-fetal interface during early pregnancy, especially in decidual macrophage differentiation, are still unclear. Herein, for the first time, we discovered that LA can trigger either M2 or M1 macrophage polarization via oxidative phosphorylation and glycolysis regulation under normoxia or hypoxia, respectively. Also, LA metabolism played a vital role in decidual macrophages-mediated recurrent pregnancy loss (RPL), through HIF-1α/SRC/LDHA pathway. Moreover, blockade of LA intake with AZD3965 (MCT-1 inhibitor) could rescue pregnancy in an abortion-prone mouse model, suggesting a potential therapeutic target in RPL. Collectively, the present study identifies the previously unknown functions of LA metabolism in the differentiation of decidual macrophages in early normal pregnancy and RPL, and provides a potential therapeutic strategy in RPL by manipulating decidual macrophages' functions through LA metabolic pathway.


Assuntos
Aborto Espontâneo/metabolismo , Ácido Láctico/metabolismo , Macrófagos/metabolismo , Gravidez/metabolismo , Trofoblastos/metabolismo , Adulto , Animais , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Humanos , L-Lactato Desidrogenase/metabolismo , Masculino , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Transdução de Sinais , Quinases da Família src/metabolismo
6.
FASEB J ; 36(1): e22073, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34847253

RESUMO

Programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) are important immune checkpoint receptors that prevent an overreacted maternal immune response to fetal antigens during pregnancy. Disruption of complex immune regulation mechanisms is associated with adverse pregnancy outcomes, including preeclampsia (PE). Our recent study showed that the Tim-3 pathway was involved in the regulation of decidual macrophage polarization. Decidual macrophages polarized to the M1 phenotype may impair uterine vessel remodeling during placentation, accounting for the occurrence of PE. Co-blockade of the PD-1/Tim-3 pathway was shown to successfully control tumor growth in preclinical cancer models. However, the effects of activating both PD-1 and Tim-3 pathways as a combined intervention strategy in PE are never reported. Herein, we observed the skew of decidual macrophage polarization toward the M1 phenotype in patients with PE and lipopolysaccharide (LPS)-induced PE-like rat model. Moreover, we found that the activation of PD-1/Tim-3 pathway by using PD-L1 and Gal-9 fusion proteins could alleviate the manifestation of the LPS-induced PE-like rats and protect their offspring. Compared with the single intervention, the combination of PD-L1and Gal-9 fusion proteins exhibited obvious advantages in the relief of PE-like symptoms, trophoblast invasion, and fetal vascular development, indicating a synergistic effect of the activated PD-1/Tim-3 pathway. The in vitro study also revealed that the combined intervention using PD-L1 and Gal-9 fusion proteins inhibited the LPS-induced M1 macrophage polarization via the synergic activation of the ERK/GSK3ß/ß-catenin signaling pathway. Together, our findings provide the first evidence that simultaneous activation of PD-1/Tim-3 signaling pathways may have an optimal protective effect and serve as a new potential target for PE intervention.


Assuntos
Decídua/metabolismo , Sistema de Sinalização das MAP Quinases , Macrófagos/metabolismo , Pré-Eclâmpsia/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Decídua/patologia , Modelos Animais de Doenças , Feminino , Humanos , Lipopolissacarídeos/toxicidade , Pré-Eclâmpsia/induzido quimicamente , Pré-Eclâmpsia/patologia , Gravidez , Ratos , Ratos Sprague-Dawley
8.
Front Immunol ; 12: 737401, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790194

RESUMO

Successful implantation requires the coordinated migration and invasion of trophoblast cells from out of the blastocyst and into the endometrium. This process relies on signals produced by cells in the maternal endometrium. However, the relative contribution of stroma cells remains unclear. The study of human implantation has major technical limitations, therefore the need of in vitro models to elucidate the molecular mechanisms. Using a recently described 3D in vitro models we evaluated the interaction between trophoblasts and human endometrial stroma cells (hESC), we assessed the process of trophoblast migration and invasion in the presence of stroma derived factors. We demonstrate that hESC promotes trophoblast invasion through the generation of an inflammatory environment modulated by TNF-α. We also show the role of stromal derived IL-17 as a promoter of trophoblast migration through the induction of essential genes that confer invasive capacity to cells of the trophectoderm. In conclusion, we describe the characterization of a cellular inflammatory network that may be important for blastocyst implantation. Our findings provide a new insight into the complexity of the implantation process and reveal the importance of inflammation for embryo implantation.


Assuntos
Movimento Celular , Implantação do Embrião , Endométrio/efeitos dos fármacos , Interleucina-17/metabolismo , Comunicação Parácrina/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Trofoblastos/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Adesão Celular , Diferenciação Celular , Linhagem Celular , Endométrio/imunologia , Endométrio/metabolismo , Feminino , Humanos , Interleucina-17/genética , Receptores Tipo I de Fatores de Necrose Tumoral/agonistas , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Via Secretória , Transdução de Sinais , Células Estromais/imunologia , Células Estromais/metabolismo , Trofoblastos/imunologia
9.
Placenta ; 115: 146-150, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34626893

RESUMO

There is inadequate screening for SARS-COV-2 during pregnancy. We aimed to determine the impact of maternal and neonatal cord blood SARS-COV-2 antibodies and placental transfer ratios in a region with a low screening plan. We performed a blind study in one of the SARS-CoV-2 epicenters in South America. 32% of pregnant women were serological positive. Importantly, there is an efficient passive immunization of the fetus to SARS-CoV-2. We report high incidence of SARS-CoV-2 infection during pregnancy, which is higher than officially reported. Therefore the need of active immunization to enhance maternal protection and fetal passive immunization.


Assuntos
COVID-19/epidemiologia , Sangue Fetal/imunologia , Complicações Infecciosas na Gravidez/epidemiologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , COVID-19/sangue , COVID-19/imunologia , Equador/epidemiologia , Feminino , Sangue Fetal/metabolismo , Humanos , Imunização Passiva/estatística & dados numéricos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Incidência , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/imunologia , Estudos Soroepidemiológicos , Adulto Jovem
10.
EMBO Rep ; 22(10): e52450, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34405956

RESUMO

Zika virus is a positive-sense single-stranded RNA virus, which can be transmitted across the placenta and has adverse effects on fetal development during pregnancy. The severity of these complications highlights the importance of prevention and treatment. However, no vaccines or drugs are currently available. In this study, we characterize the IFNß-mediated anti-viral response in trophoblast cells in order to identify critical components that are necessary for the successful control of viral replication and determine whether components of the IFN-induced response can be used as a replacement therapy for ZIKA virus infection during pregnancy. We identify and characterize interferon-stimulated gene 20 (ISG20) as playing a central role in controlling Zika virus infection in trophoblast cells and successfully establish a recombinant ISG20-Fc protein that effectively decreases viral titers in vitro and in vivo by maintaining its exonuclease activity and displaying potential immune modulatory functions. Recombinant ISG20-Fc has thus the potential to be further developed as an anti-viral treatment against ZIKA viral infection in high-risk populations, particularly in pregnant women.


Assuntos
Infecção por Zika virus , Zika virus , Antivirais/farmacologia , Exorribonucleases , Feminino , Humanos , Interferons , Placenta , Gravidez , Replicação Viral , Zika virus/genética , Infecção por Zika virus/tratamento farmacológico
11.
Placenta ; 112: 45-53, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34273713

RESUMO

INTRODUCTION: Maternal metabolism undergoes dynamic changes during pregnancy. A deviation from this physiological metabolic status might be involved in the pathogenesis of pregnancy complications, such as recurrent pregnancy loss (RPL). Decidua is an important uterine tissue, which provides immunological protection as well as nutritional support to the developing embryo during early pregnancy. Previous studies have shown that aberrant metabolism of the decidua is related to the etiology of RPL. However, the metabolic profile of the decidua in RPL has not yet been fully elucidated. METHODS: In the current study, decidual samples from RPL patients (n = 23) and normal pregnancy (NP) women (n = 30) were collected, and hydrophilic and hydrophobic metabolites were extracted and measured using a liquid chromatography electrospray ionization tandem mass spectrometry system. Besides, the mRNA expression of several critical enzymes involved in sphingolipid metabolism and glycerophospholipid metabolism was detected. RESULTS: The OSC-PLS-DA scores plot illustrates that metabolic differences are present in the decidual tissue of RPL patients compared with that of NP women. Combining multivariate analysis with univariate statistical analysis, a total of 62 metabolites related to RPL were selected, including carnitine, glycerophospholipids, sphingomyelin (SM), ceramide, organic acids and their derivatives, and amino acid metabolomics. KEGG analysis showed that abnormalities in multiple metabolic pathways occurred in RPL decidua, including vitamin digestion and absorption, tryptophan metabolism, citrate cycle, arginine biosynthesis, glycerophospholipid metabolism, sphingolipid metabolism, and sphingolipid signaling pathway. Increased SM synthase and decreased Phospholipase A2 Group IIE mRNA levels were detected in RPL compared with NP group. DISCUSSION: Disruption of decidual metabolism, especially glycerophospholipid metabolism and sphingolipid metabolism, might be involved in the occurrence of RPL.


Assuntos
Aborto Habitual/metabolismo , Decídua/metabolismo , Glicerofosfolipídeos/metabolismo , Metaboloma , Esfingolipídeos/metabolismo , Adulto , Carnitina/análogos & derivados , Carnitina/metabolismo , Estudos de Casos e Controles , Feminino , Fosfolipases A2 do Grupo II/metabolismo , Humanos , Lipidômica , Gravidez , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
12.
Front Immunol ; 12: 657552, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122414

RESUMO

Recurrent pregnancy loss (RPL) is a disturbing disease in women, and 50% of RPL is reported to be associated with immune dysfunction. Most previous studies of RPL focused mainly on the relationship between RPL and either T cells or natural killer (NK) cells in peripheral blood and the decidua; few studies presented the systemic profiles of the peripheral immune cell subsets in RPL women. Herein, we simultaneously detected 63 immune cell phenotypes in the peripheral blood from nonpregnant women (NPW), women with a history of normal pregnancy (NP) and women with a history of RPL (RPL) by multi-parameter flow cytometry. The results demonstrated that the percentages of naïve CD4+ T cells, central memory CD4+ T cells, naïve CD8+ T cells, mature NK cells, Vδ1+ T cells and the ratio of Vδ1+ T cells/Vδ2+ T cells were significantly higher in the RPL group than those in the NPW and NP groups, whereas the percentages of terminal differentiated CD4+ T cells, effective memory CD4+ T cells, immature NK cells and Vδ2+ T cells were significantly lower in the RPL group than those in the NPW and NP groups. Interestingly, we found that peripheral T helper (TPH) cells were more abundant in the NPW group than in the NP and RPL groups. In addition, we also determined the 5th percentile lower limit and 95th percentile upper limit of the significantly changed immunological parameters based on the files of the NPW group. Taken together, this is the first study to simultaneously characterize the multiple immune cell subsets in the peripheral blood at a relatively large scale in RPL, which might provide a global readout of the immune status for clinicians to identify clinically-relevant immune disorders and guide them to make clear and individualized advice and treatment plans.


Assuntos
Aborto Habitual/etiologia , Suscetibilidade a Doenças/imunologia , Adulto , Biomarcadores , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Gravidez , Valores de Referência , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
13.
Front Immunol ; 12: 686676, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163485

RESUMO

During pregnancy, the maternal immune system undergoes major adaptive modifications that are necessary for the acceptance and protection of the fetus. It has been postulated that these modifications are temporary and limited to the time of pregnancy. Growing evidence suggests that pregnancy has a long-term impact on maternal health, especially among women with pregnancy complications, such as preeclampsia (PE). In addition, the presence of multiple immunological-associated changes in women that remain long after delivery has been reported. To explain these long-term modifications, we hypothesized that pregnancy induces long-term immunological memory with effects on maternal well-being. To test this hypothesis, we evaluated the immunological phenotype of circulating immune cells in women at least 1 year after a normal pregnancy and after pregnancy complicated by PE. Using multiparameter flow cytometry (FCM) and whole-genome bisulfite sequencing (WGBS), we demonstrate that pregnancy has a long-term effect on the maternal immune cell populations and that this effect differs between normal pregnancy and pregnancy complicated by PE; furthermore, these modifications are due to changes in the maternal methylation status of genes that are associated with T cell and NK cell differentiation and function. We propose the existence of an "immunological memory of pregnancy (IMOP)" as an evolutionary advantage for the success of future pregnancies and the proper adaptation to the microchimeric status established during pregnancy. Our findings demonstrate that the type of immune cell populations modified during pregnancy may have an impact on subsequent pregnancy and future maternal health.


Assuntos
Epigênese Genética/fisiologia , Memória Imunológica/fisiologia , Células Matadoras Naturais/fisiologia , Pré-Eclâmpsia/fisiopatologia , Complicações na Gravidez/fisiopatologia , Adaptação Fisiológica/fisiologia , Adulto , Decídua/imunologia , Feminino , Citometria de Fluxo , Humanos , Metilação , Paridade/fisiologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/imunologia , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/imunologia , Resultado da Gravidez , Sequenciamento Completo do Genoma , Adulto Jovem
14.
Methods Mol Biol ; 2255: 1-12, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34033089

RESUMO

Apoptosis is a type of programmed cell death induced by a cascade of biochemical events, which leads to distinct morphological changes characterized by cell shrinkage, membrane blebbing, chromatin condensation, and DNA fragmentation. Apoptosis is executed by a class of cysteine proteases called caspases. Caspases are synthesized as inactive pro-caspases and activated by a series of cleavage reactions. Active caspases cleave cellular substrates and are thus the main effectors of the apoptotic cell death pathway. Detection of caspase cleavage by western blot analysis is a conventional method to demonstrate the induction of apoptosis. In the context of apoptosis, the proper analysis of western blot results depends on the understanding of the mechanisms and outcomes of caspase processing during the course of its activation. In this chapter, we describe the step-by-step methodology in the western blot analysis of caspase cleavage during apoptosis. We detail protocols for protein extraction, quantitation, casting, and running gel electrophoresis and western blot analysis of caspase -8 and caspase -9 activation. The described methods can be applied to any particular protein of interest.


Assuntos
Apoptose , Western Blotting/métodos , Caspase 8/metabolismo , Caspase 9/metabolismo , Neoplasias Ovarianas/patologia , Ativação Enzimática , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Células Tumorais Cultivadas
15.
Methods Mol Biol ; 2255: 21-26, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34033091

RESUMO

Within the cell, proteins are segregated into different organelles depending on their function and activation status. In response to stimulus, posttranslational modifications or loss of organelle membrane integrity lead to the movement of proteins from one compartment to another. This movement of proteins or protein translocation, exerts a significant effect on protein function. This is clearly demonstrated in the context of apoptosis wherein the cytoplasmic translocation of the mitochondrial resident protein, cytochrome C, initiates the activation of the intrinsic arm of the apoptotic pathway. Experimentally, protein translocation can be demonstrated by subcellular fractionation and subsequent western blot analysis of the isolated fractions. This chapter describes the step-by-step procedure in obtaining mitochondrial and cytoplasmic fractions from cell pellets and determining their purity and integrity.


Assuntos
Apoptose , Caspases/metabolismo , Citocromos c/metabolismo , Citoplasma/metabolismo , Mitocôndrias/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Western Blotting , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Células Tumorais Cultivadas
16.
Methods Mol Biol ; 2255: 241-261, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34033108

RESUMO

Transcription factors orchestrate complex regulatory networks of gene expression. A better understanding of the common transcription factors, and their shared interactions, among a set of coregulated or differentially expressed genes can provide powerful insights into the key pathways governing such expression patterns. Critically, such information must also be considered in the context of the frequency in which a transcription factor is present in a properly selected background, and in the context of existing evidence of gene and transcription factor interaction. Given the vast amount of publicly available gene expression data that can be further scrutinized by the user-friendly analysis tools described here, many useful insights are assuredly to be revealed. The proceeding methods for application of the analysis tool CiiiDER for transcription factor-binding site identification, enrichment analysis, and coregulatory factor identification should be applicable to any dataset comparing differential gene expression in response to various stimuli and gene coexpression datasets. These methods should assist the researcher in identifying the most relevant regulators within a gene set, and refining the list of targets for future study to those which may share biologically important regulatory networks.


Assuntos
Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Fatores de Transcrição/metabolismo , Sítios de Ligação , Humanos , Ligação Proteica , Software , Fatores de Transcrição/genética
17.
Am J Reprod Immunol ; 86(4): e13438, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33960055

RESUMO

PROBLEM: The aim of this study was to investigate the possible relationship between vaginal/rectal microbiome disbalances and miRNA expression with infertility. METHOD OF STUDY: Observational, exploratory, preliminary study. A total of 287 multiple IVF failure infertile patients were recruited. Twenty fertile women, not IVF failure, were recruited as the control group. Swab samples were collected from the vagina and rectum. Microbial composition by NGS and miRNA expression by real-time PCR of vaginal and rectal samples was measured. Immunometabolic markers from blood (insulin, vitamin D, LDL-cholesterol, ANA, TPO, Tg, and ASCA antibodies) and saliva (sIgA) were analyzed. RESULT(S): Infertile patients showed a lower bacterial richness and increased Firmicutes/Bacteroidetes ratio at rectal level and an increased Lactobacillus brevis/Lactobacillus iners ratio in vaginal samples regarding the fertile group. In the same rectal swab samples, we found that miR-21-5p, which is associated with tight junction disruption and yeast overgrowth, is upregulated and that miR-155-5p, which is associated with inflammation, is overexpressed in the unexplained infertile group (*p < .05). These deregulated miRNAs were also upregulated in the vaginal samples from the same patients (*p < .05). CONCLUSION: miRNAs could be potential biomarkers of the inflammatory impact of microbiome disbalances in unexplained infertile women.


Assuntos
Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Infertilidade Feminina/diagnóstico , Vagina/microbiologia , Adulto , Biomarcadores , Feminino , Humanos , Infertilidade Feminina/microbiologia , MicroRNAs , Adulto Jovem
18.
Bioinformatics ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33693506

RESUMO

MOTIVATION: COVID-19 has several distinct clinical phases: a viral replication phase, an inflammatory phase, and in some patients, a hyper-inflammatory phase. High mortality is associated with patients developing cytokine storm syndrome. Treatment of hyper-inflammation in these patients using existing, approved therapies with proven safety profiles could address the immediate need to reduce mortality. RESULTS: We analyzed the changes in the gene expression, pathways and putative mechanisms induced by SARS-CoV2 in NHBE, and A549 cells, as well as COVID-19 lung vs. their respective controls. We used these changes to identify FDA approved drugs that could be repurposed to help COVID-19 patients with severe symptoms related to hyper-inflammation. We identified methylprednisolone (MP) as a potential leading therapy. The results were then confirmed in five independent validation data sets including Vero E6 cells, lung and intestinal organoids, as well as additional patient lung sample vs. their respective controls. Finally, the efficacy of MP was validated in an independent clinical study. Thirty-day all-cause mortality occurred at a significantly lower rate in the MP-treated group compared to control group (29.6% vs. 16.6%, p = 0.027). Clinical results confirmed the in silico prediction that MP could improve outcomes in severe cases of COVID-19. A low number needed to treat (NNT = 5) suggests MP may be more efficacious than dexamethasone or hydrocortisone. AVAILABILITY: iPathwayGuide is available at https://ipathwayguide.advaitabio.com/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

19.
J Reprod Immunol ; 145: 103305, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33725526

RESUMO

Air pollution is associated with preterm birth (PTB), potentially via inflammation. We recently showed the mixture benzene, toluene, ethylbenzene, and xylene (BTEX) is associated with PTB. We examined if ambient BTEX exposure is associated with mid-pregnancy inflammation in a sample of 140 African-American women residing in Detroit, Michigan. The Geospatial Determinants of Health Outcomes Consortium study collected outdoor air pollution measurements in Detroit; these data were coupled with Michigan Air Sampling Network measurements to develop monthly BTEX concentration estimates at a spatial density of 300 m2. First trimester and mid-pregnancy BTEX exposure estimates were assigned to maternal address. Mid-pregnancy (mean 21.3 ± 3.7 weeks gestation) inflammatory biomarkers (high-sensitivity C-reactive protein, interleukin [IL]-6, IL-10, IL-1ß, and tumor necrosis factor-α) were measured with enzyme immunoassays. After covariate adjustment, for every 1-unit increase in first trimester BTEX, there was an expected mean increase in log-transformed IL-1ß of 0.05 ± 0.02 units (P = 0.014) and an expected mean increase in log-transformed tumor necrosis factor-α of 0.07 ± 0.02 units (P = 0.006). Similarly, for every 1-unit increase in mid-pregnancy BTEX, there was a mean increase in log IL-1ß of 0.06 ± 0.03 units (P = 0.027). There was no association of either first trimester or mid-pregnancy BTEX with high-sensitivity C-reactive protein, IL-10, or IL-6 (all P > 0.05). Ambient BTEX exposure is associated with inflammation in mid-pregnancy in African-American women. Future studies examining if inflammation mediates associations between BTEX exposure and PTB are needed.


Assuntos
Afro-Americanos/estatística & dados numéricos , Poluentes Atmosféricos/efeitos adversos , Interleucina-1beta/sangue , Nascimento Prematuro/imunologia , Fator de Necrose Tumoral alfa/sangue , Adolescente , Adulto , Benzeno/efeitos adversos , Derivados de Benzeno/efeitos adversos , Biomarcadores/sangue , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Interleucina-1beta/imunologia , Exposição Materna/estatística & dados numéricos , Gravidez , Nascimento Prematuro/sangue , Tolueno/efeitos adversos , Fator de Necrose Tumoral alfa/imunologia , Xilenos/efeitos adversos , Adulto Jovem
20.
Front Immunol ; 12: 631044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33613576

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has been raging around the world since January 2020. Pregnancy places the women in a unique immune scenario which may allow severe COVID-19 disease. In this regard, the potential unknown effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on mothers and fetuses have attracted considerable attention. There is no clear consistent evidence of the changes in the immune status of pregnant women after recovery from COVID-19. In this study, we use multiparameter flow cytometry and Luminex assay to determine the immune cell subsets and cytokines, respectively, in the peripheral blood and umbilical cord blood from pregnant women recovering from COVID-19 about 3 months (n=5). Our results showed decreased percentages of Tc2, Tfh17, memory B cells, virus-specific NK cells, and increased percentages of naive B cells in the peripheral blood. Serum levels of IL-1ra and MCP-1 showed a decreased tendency in late recovery stage (LRS) patients. Meanwhile, there was no significant difference in immune cell subsets in the umbilical cord blood. The placentas from LRS patients showed increased CD68+ macrophages infiltration and mild hypoxic features. The inflammatory damage of the placenta may be related to the antiviral response. Since the receptors, ACE2 and TMPRSS2, utilized by SARS-CoV-2 are not co-expressed in the placenta, so it is extremely rare for SARS-CoV-2 to cause infection through this route and the impact on the fetus is negligible.


Assuntos
Linfócitos B/imunologia , COVID-19/imunologia , Sangue Fetal/imunologia , Centro Germinativo/imunologia , Placenta/imunologia , SARS-CoV-2/fisiologia , Células Th17/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Autoantígenos/metabolismo , Feminino , Citometria de Fluxo , Humanos , Memória Imunológica , Imunofenotipagem , Células Matadoras Naturais , Gravidez , Receptores de Interleucina-1/metabolismo , Serina Endopeptidases/metabolismo
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