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1.
Open Life Sci ; 16(1): 1164-1174, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722888

RESUMO

Storkhead box 1 (STOX1) is a winged helix transcription factor structurally and functionally related to the forkhead family of transcription factors. Recent studies have highlighted its role in the central nervous system and revealed hints in the development of glioma. However, the expression profiles of STOX1, its association with clinicopathological characteristics, and potential functions in glioma remain unknown. In this study, we analyzed three publicly available datasets including CGGA, TCGA, and Rembrandt and revealed a grade-dependent reduction in STOX1 expression in glioma (P < 0.001). Chi-square test demonstrated that low STOX1 expression was significantly associated with older age at initial diagnosis (P < 0.001), less IDH1 mutation (P < 0.001), and advanced WHO grade (P < 0.001). Moreover, multivariate Cox regression analysis showed that STOX1 expression may serve as a novel independent prognostic biomarker in glioma patients. Bioinformatic functional analysis (GSEA) predicted that STOX1 was related to many key cancer pathways including P53 signaling pathway (P < 0.01), DNA replication (P < 0.05), homologous recombination (P < 0.05), and Wnt signaling pathway (P < 0.05). Taken together, these findings suggested that STOX1 may be used as a novel predictive molecular biomarker for glioma grading and overall patient survival. Further investigations on the functional roles and therapeutic value of STOX1 in glioma are warranted.

2.
Invest Ophthalmol Vis Sci ; 62(14): 7, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34757418

RESUMO

Purpose: To examine the morphological and hemodynamic changes of the ophthalmic artery (OA) in patients with acute coronary syndrome (ACS). Methods: This cross-sectional observational study included 31 patients with ACS and 10 healthy controls (HCs). The ACS subgroups were ST-segment elevation myocardial infarction (STEMI; n = 10), non-STEMI (n = 10), and unstable angina (n = 11). OA three-dimensional (3D) models were reconstructed based on computed tomographic angiography, and morphological aspects of the OA were measured quantitatively. Moreover, numerical simulation by computational fluid dynamics was used to obtain hemodynamic information of the OA. Results: The study reconstructed 41 OA models. Hemodynamic simulation revealed a significant decrease in OA blood velocity in patients with ACS compared with the HCs (median velocity, 0.046 vs. 0.147 m/s; P < 0.001). No differences in the morphological data for the OA were observed. Also, no differences in the mass flow ratio of OA to the ipsilateral internal carotid artery was found. Similar differences were observed between the ACS subgroups and HCs. OA blood velocity was negatively correlated with body mass index, abdominal circumference, left ventricular ejection fraction, and triacylglycerol and was positively correlated with early to late transmitral flow velocity, N-terminal pro-brain natriuretic peptide, serum creatinine, and potassium. Conclusions: The initial OA blood velocity was slower in patients with ACS and was associated with ACS-related clinical parameters. To our knowledge, this is the first study to analyze OA characteristics in ACS using 3D model reconstruction and hemodynamic simulation, providing new perspectives on the relationship between ischemic heart disease and ocular manifestations.


Assuntos
Síndrome Coronariana Aguda/fisiopatologia , Artéria Oftálmica/fisiopatologia , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico por imagem , Idoso , Velocidade do Fluxo Sanguíneo/fisiologia , Artéria Carótida Interna/fisiopatologia , Angiografia por Tomografia Computadorizada , Creatinina/sangue , Estudos Transversais , Feminino , Hemodinâmica/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Artéria Oftálmica/diagnóstico por imagem , Fragmentos de Peptídeos/sangue , Potássio/sangue , Fluxo Sanguíneo Regional/fisiologia , Volume Sistólico , Triglicerídeos/sangue , Função Ventricular Esquerda
3.
Cell Prolif ; : e13145, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34668606

RESUMO

OBJECTIVES: Success in pregnancy in mammals predominantly depends on a well-developed placenta. The differentiation of invasive trophoblasts is a fundamental process of placentation, the abnormalities of which are tightly associated with pregnancy disorders including preeclampsia (PE). Monoclonal nonspecific suppressor factor beta (MNSFß) is an immunosuppressive factor. Its conventional knockout in mice induced embryonic lethality, whereas the underlying mechanism of MNSFß in regulating placentation and pregnancy maintenance remains to be elucidated. METHODS: Trophoblast-specific knockout of MNSFß was generated using Cyp19-Cre mice. In situ hybridization (ISH), haematoxylin and eosin (HE), immunohistochemistry (IHC) and immunofluorescence (IF) were performed to examine the distribution of MNSFß and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) at the foeto-maternal interface. The interaction and expression of MNSFß, IGF2BP2 and invasion-related molecules were detected by immunoprecipitation (IP), immunoblotting and quantitative real-time polymerase chain reaction (qRT-PCR). The cell invasion ability was measured by the Transwell insert assay. RESULTS: We found that deficiency of MNSFß in trophoblasts led to embryonic growth retardation by mid-gestation and subsequent foetal loss, primarily shown as apparently limited trophoblast invasion. In vitro experiments in human trophoblasts demonstrated that the conjugation of MNSFß with IGF2BP2 and thus the stabilization of IGF2BP2 essentially mediated the invasion-promoting effect of MNSFß. In the placentas from MNSFß-deficient mice and severe preeclamptic (PE) patients, downregulation of MNSFß was evidently associated with the repressed IGF2BP2 expression. CONCLUSIONS: The findings reveal the crucial role of MNSFß in governing the trophoblast invasion and therefore foetal development, and add novel hints to reveal the placental pathology of PE.

4.
Front Immunol ; 12: 691908, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34589082

RESUMO

Decidual macrophages (dMϕ) are the second largest population of leukocytes at the maternal-fetal interface and play critical roles in maintaining pregnancy. Our previous studies demonstrated the active involvement of monoclonal nonspecific suppressor factor-ß (MNSFß) in embryonic implantation and pregnancy success. MNSFß is a ubiquitously expressed ubiquitin-like protein that also exhibits immune regulatory potential, but its function in human dMϕ remains unknown. Here, we observed that the proportion of CD11chigh (CD11cHI) dMϕ was significantly increased in dMϕ derived from patients with recurrent pregnancy loss (RPL dMϕ) compared to those derived from normal pregnant women (Control dMϕ). The production of MNSFß and TNFα by RPL dMϕ was also significantly increased compared to that by Control dMϕ. Conditioned medium from RPL dMϕ exerted an inhibitory effect on the invasiveness of human trophoblastic HTR8/SVneo cells, and this effect could be partially reversed by a neutralizing antibody against TNFα. Bioinformatics analysis indicated a potential interaction between MNSFß and RC3H1, a suppressor of TNFα transcription. Immunoprecipitation experiments with human Mϕ differentiated from the human monocyte cell line Thp1 (Thp1-derived Mϕ) proved the binding of MNSFß to RC3H1. Specific knockdown of MNSFß in Thp1-derived Mϕ led to a marked decrease in TNFα production, which could be reversed by inhibiting RC3H1 expression. Interestingly, a significant decrease in the protein level of RC3H1 was observed in RPL dMϕ. Together, our findings indicate that aberrantly increased MNSFß expression in dMϕ may promote TNFα production via its interaction with RC3H1, and these phenomena could result in the disruption of the immune balance at the maternal-fetal interface and thus pregnancy loss.


Assuntos
Aborto Habitual/imunologia , Decídua/imunologia , Macrófagos/imunologia , Proteínas de Ligação a RNA/imunologia , Fatores Supressores Imunológicos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Ubiquitina-Proteína Ligases/imunologia , Adulto , Células Cultivadas , Feminino , Humanos , Gravidez , Fatores Supressores Imunológicos/genética
5.
Zhongguo Zhen Jiu ; 41(8): 937-40, 2021 Aug 12.
Artigo em Chinês | MEDLINE | ID: mdl-34369709

RESUMO

Focusing on the original text record in Huangdi Neijing (Inner Canon of Yellow Emperor), the relevant theories of "Tianyou (TE 16) and five regions" are explored, e.g. acupoint names, meridians and acupoint features, and the clinical application of these acupoints has been analyzed. It is discovered that "Tianyou (TE 16) and five regions" are mainly used in treatment of the disorders in the nervous system, five sensory organs and motor system. Besides, in terms of the relevant theories, "Tianyou (TE 16) and five regions" has been compared with "root and knot" and "twelve divergent meridians". It is found that "Tianyou (TE 16) and five regions" communicates the externally-internally related meridians and is applicable in treatment of the disorders with both exterior and interior involved. It is the essential acupoint composition of the human body.


Assuntos
Terapia por Acupuntura , Meridianos , Pontos de Acupuntura , Corpo Humano , Humanos
6.
PLoS Genet ; 17(8): e1009786, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34460816

RESUMO

The maternal recognition of pregnancy is a necessary prerequisite for gestation maintenance through prolonging the corpus luteum lifespan and ensuring progesterone production. In addition to pituitary prolactin and placental lactogens, decidual derived prolactin family members have been presumed to possess luteotropic effect. However, there was a lack of convincing evidence to support this hypothesis. Here, we unveiled an essential role of uterine Notch2 in pregnancy recognition and corpus luteum maintenance. Uterine-specific deletion of Notch2 did not affect female fertility. Nevertheless, the expression of decidual Prl8a2, a member of the prolactin family, was downregulated due to Notch2 ablation. Subsequently, we interrupted pituitary prolactin function to determine the luteotropic role of the decidua by employing the lipopolysaccharide-induced prolactin resistance model, or blocking the prolactin signaling by prolactin receptor-Fc fusion protein, or repressing pituitary prolactin release by dopamine receptor agonist bromocriptine, and found that Notch2-deficient females were more sensitive to these stresses and ended up in pregnancy loss resulting from abnormal corpus luteum function and insufficient serum progesterone level. Overexpression of Prl8a2 in Notch2 knockout mice rescued lipopolysaccharide-induced abortion, highlighting its luteotropic function. Further investigation adopting Rbpj knockout and DNMAML overexpression mouse models along with chromatin immunoprecipitation assay and luciferase analysis confirmed that Prl8a2 was regulated by the canonical Notch signaling. Collectively, our findings demonstrated that decidual prolactin members, under the control of uterine Notch signaling, assisted pituitary prolactin to sustain corpus luteum function and serum progesterone level during post-implantation phase, which was conducive to pregnancy recognition and maintenance.

7.
Ocul Immunol Inflamm ; : 1-11, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33970759

RESUMO

Background: Immune checkpoint inhibitors (ICIs) -induced adverse events (AEs) have been reported affecting almost all human organs. However, studies about ocular AEs are few. A meta-analysis was performed to evaluate the risks of ICI-related ophthalmic AEs compare to chemotherapy.Methods: Eligible studies were selected from phase II/III randomized controlled trials investigating ICIs. The data were analyzed by R software and Stata.Results: Odds ratio of treatment-related AE (trAEs) and nonspecific ophthalmic trAEs (NS-trAEs) were lower for PD-1/PD-L1 inhibitors than chemotherapy (OR 0.44, p < .05; OR 0.28, p < .001; OR 0.18, p < . 05; OR: 0.18, p < .001respectively). Compared with monotherapy, PD-1 plus CTLA-4 inhibitors increased the risks of immune-related AEs (irAEs) (OR 4.52, p < .01); ICIs plus chemotherapy increased the risks of trAEs and irAEs (OR 2.82, p < .001; OR 3.63, p < .05 respectively).Conclusions: PD-L1/PD-1 inhibitors had lower risks of trAEs and NS-trAEs than chemotherapy; Compared with monotherapy, combination therapy had higher risks of ophthalmic trAEs and irAEs.Abbreviation PD-1: programmed cell death protein 1; PD-L1: programmed cell death protein ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; ICI: immune checkpoint inhibitor; AE: adverse event; trAE: treatment-related adverse event;irAE: immune-related adverse events; NS-trAE: nonspecific ophthalmic treatment-related adverse event; RCT: randomized controlled trials; PFS: progression-free survival; OS: overall survival; ORR: objective response rate; MM: melanoma; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer; HNSCC: head-neck squamous cell carcinoma; PICOL: patient, intervention, comparison, and outcome; Versus: VS; Chem: chemotherapy; 95%CI: 95% confidence interval; FEM: fixed-effects model; REM: random-effects model; NA: not applicable; MeSH: medical subject heading.

8.
Ann Transl Med ; 9(6): 451, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33850848

RESUMO

Background: The ophthalmic artery (OA) was first reconstructed using computer software. The structural differences of ophthalmic arteries in non-arteritic anterior ischemic optic neuropathy (NAION) and normal eyes, in addition to hemodynamic alterations, were assessed. Methods: Thirty-one NAION eyes, 19 uninvolved eyes with NAION, and a control group of 26 healthy eyes were retrospectively included. Computed tomographic angiography data were recorded, and corresponding three-dimensional OA models were constructed. Initial OA and internal carotid artery (ICA) diameters and the angle between them were analyzed. Three different OA models were used to evaluate hemodynamic performance. The statistical relationships between the initial diameters of the OA and ICA and the angle between the OA and ICA were described. Results: OA diameters in NAION eyes were significantly smaller than those in both uninvolved and healthy eyes (P<0.05). There was no significant difference between uninvolved and healthy eyes (P=0.31). The initial ICA diameter and the angle between the OA and ICA did not significantly differ among the three groups. In the three models, the blood flow velocity in the initial ophthalmic arteries of uninvolved eyes was higher than that in the NAION eyes. The mass flows of the right and left ophthalmic arteries, accounting for the ipsilateral ICA in the control model, were 0.57%. However, these values in uninvolved and NAION eyes were 1.36% and 0.25%, respectively. Conclusions: NAION is associated with a smaller initial OA diameter, which may be related to hypoperfusion. To our knowledge, this is the first pilot study to analyze hemodynamic alterations using OA models.

9.
Front Cell Dev Biol ; 9: 646326, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777951

RESUMO

In placental mammals, reproductive success, and maternal-fetal health substantially depend on a well-being placenta, the interface between the fetus and the mother. Disorders in placental cells are tightly associated with adverse pregnancy outcomes including preeclampsia (PE), fetal growth restriction, etc. MicroRNAs (miRNAs) represent small non-coding RNAs that regulate post-transcriptional gene expression and are integral to a wide range of healthy or diseased cellular proceedings. Numerous miRNAs have been detected in human placenta and increasing evidence is revealing their important roles in regulating placental cell behaviors. Recent studies indicate that placenta-derived miRNAs can be released to the maternal circulation via encapsulating into the exosomes, and they potentially target various maternal cells to provide a hormone-like means of intercellular communication between the mother and the fetus. These placental exosome miRNAs are attracting more and more attention due to their differential expression in pregnant complications, which may provide novel biomarkers for prediction of the diseases. In this review, we briefly summarize the current knowledge and the perspectives of the placenta-derived miRNAs, especially the exosomal transfer of placental miRNAs and their pathophysiological relevance to PE. The possible exosomal-miRNA-targeted strategies for diagnosis, prognosis or therapy of PE are highlighted.

11.
Cell Chem Biol ; 28(6): 788-801.e5, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33626323

RESUMO

Emerging evidence indicates the involvement of O-GlcNAc modification in placental development and pregnant health through mechanisms that are not well understood. Herein, by applying the quantitative O-GlcNAc proteomics, we established a database of O-GlcNAcylated proteins in human placental trophoblasts. Hundreds of proteins that were dynamically O-GlcNAcylated during trophoblast differentiation were identified, among which cystathionine γ-lyase (CSE) exhibited the most significant change. Site-specific analysis by mass spectrometry revealed Ser138 as the core O-GlcNAc site in CSE, and its O-GlcNAcylation promoted the enzymatic activity to produce H2S, which in turn repressed trophoblast differentiation via inhibiting androgen receptor dimerization. Consistently, in preeclamptic placentas, remarkably enhanced CSE O-GlcNAcylation and H2S production were associated with restricted trophoblast differentiation. The findings establish a resource of O-GlcNAc dynamics in human placenta, and provide a deeper insight into the biological significance of O-GlcNAcylation in placental development as well as potential therapeutic targets for the relevant pregnant complications.


Assuntos
Acetilglucosamina/metabolismo , Cistationina gama-Liase/metabolismo , Proteômica , Trofoblastos/metabolismo , Adulto , Diferenciação Celular , Feminino , Glicosilação , Humanos , Sulfeto de Hidrogênio/metabolismo , Gravidez , Células Tumorais Cultivadas
12.
Int Ophthalmol ; 41(3): 1129-1140, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33392941

RESUMO

PURPOSE: Pars plana vitrectomy is the gold standard for the treatment of idiopathic macular hole. Several chromovitrectomy dyes have been used to improve the visualization of the internal limiting membrane (ILM), including indocyanine green, trypan blue (TB), brilliant blue G (BBG), and triamcinolone acetonide (TA). We conducted a network meta-analysis (NMA) to establish the optimum concentration of chromovitrectomy dye-assisted ILM peeling for IMH. METHODS: We searched PubMed, Embase, and Cochrane Library for relevant studies before January 2020. We performed a random-effects NMA using STATA version 15.1 to assess mean difference and odds ratios with 95% confidence intervals. RESULTS: We identified twelve retrospective trails and five randomized controlled trials (RCTs), comprising 1 492 patients of IMH on stage II-IV for ILM peeling. The results of IMH closure rate show that the effect of ILM peeling without dye was better than 0.25% ICG, the effects of ILM peeling with 0.5% ICG or TA were better than without dye, and the effects of ILM peeling with 0.05% BBG, 0.15% TB, 0.5% ICG or 0.05% ICG were better than 0.25% ICG. Ranking probability analysis shows that the rates of IMH closure after ILM peeling with 0.15% TB or 0.05% BBG were better than nine other concentrations of chromovitrectomy dyes. CONCLUSION: The 0.15% TB and 0.05% BBG were recommended as the better efficient treatment-assisted ILM peeling for IMH closure. For retina specialists who prefer to use ICG to assist ILM peeling, 0.05% ICG may be a good choice. However, high-quality large-scale RCTs are recommended to confirm the NMA results.


Assuntos
Membrana Epirretiniana , Perfurações Retinianas , Membrana Basal/cirurgia , Corantes , Membrana Epirretiniana/diagnóstico , Membrana Epirretiniana/cirurgia , Humanos , Verde de Indocianina , Metanálise em Rede , Retina , Perfurações Retinianas/diagnóstico , Perfurações Retinianas/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Acuidade Visual , Vitrectomia
13.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33402432

RESUMO

During pregnancy, the appropriate allocation of nutrients between the mother and the fetus is dominated by maternal-fetal interactions, which is primarily governed by the placenta. The syncytiotrophoblast (STB) lining at the outer surface of the placental villi is directly bathed in maternal blood and controls feto-maternal exchange. The STB is the largest multinucleated cell type in the human body, and is formed through syncytialization of the mononucleated cytotrophoblast. However, the physiological advantage of forming such an extensively multinucleated cellular structure remains poorly understood. Here, we discover that the STB uniquely adapts to nutrient stress by inducing the macropinocytosis machinery through repression of mammalian target of rapamycin (mTOR) signaling. In primary human trophoblasts and in trophoblast cell lines, differentiation toward a syncytium triggers macropinocytosis, which is greatly enhanced during amino acid shortage, induced by inhibiting mTOR signaling. Moreover, inhibiting mTOR in pregnant mice markedly stimulates macropinocytosis in the syncytium. Blocking macropinocytosis worsens the phenotypes of fetal growth restriction caused by mTOR-inhibition. Consistently, placentas derived from fetal growth restriction patients display: 1) Repressed mTOR signaling, 2) increased syncytialization, and 3) enhanced macropinocytosis. Together, our findings suggest that the unique ability of STB to undergo macropinocytosis serves as an essential adaptation to the cellular nutrient status, and support fetal survival and growth under nutrient deprivation.


Assuntos
Adaptação Fisiológica , Retardo do Crescimento Fetal/metabolismo , Troca Materno-Fetal/fisiologia , Pinocitose/genética , Proteínas da Gravidez/genética , Serina-Treonina Quinases TOR/genética , Trofoblastos/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Aminoácidos/deficiência , Animais , Linhagem Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , Vilosidades Coriônicas/metabolismo , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Regulação da Expressão Gênica , Humanos , Camundongos , Gravidez , Proteínas da Gravidez/metabolismo , Cultura Primária de Células , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Trofoblastos/citologia
14.
J Reprod Dev ; 67(2): 89-97, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33455972

RESUMO

Depletion of hepatocyte growth factor (HGF) or mesenchymal-epithelial transition factor (c-Met) in mice leads to fetal lethality and placental maldevelopment. However, the dynamic change pattern of HGF/c-Met signaling during placental development and its involvement in the early differentiation of trophoblasts remain to be elucidated. In this study, using in situ hybridization assay, we elaborately demonstrated the spatial-temporal expression of Hgf and c-Met in mouse placenta from E5.5, the very early stage after embryonic implantation, to E12.5, when the placental structure is well developed. The concentration of the soluble form of c-Met (sMet) in maternal circulation peaked at E10.5. By utilizing the induced differentiation model of mouse trophoblast stem cells (mTSCs), we found that HGF significantly promoted mTSC differentiation into syncytiotrophoblasts (STBs) and invasive parietal trophoblast giant cells (PTGCs). Interestingly, sMet efficiently reversed the effect of HGF on mTSC differentiation. These findings indicate that HGF/c-Met signaling participates in regulating placental trophoblast cell fate at the early differentiation stage and that sMet acts as an endogenous antagonist in this aspect.

15.
Genomics Proteomics Bioinformatics ; 19(2): 208-222, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33482359

RESUMO

Successful pregnancy in placental mammals substantially depends on the establishment of maternal immune tolerance to the semi-allogenic fetus. Disorders in this process are tightly associated with adverse pregnancy outcomes including recurrent miscarriage (RM). However, an in-depth understanding of the systematic and decidual immune environment in RM remains largely lacking. In this study, we utilized single-cell RNA-sequencing (scRNA-seq) to comparably analyze the cellular and molecular signatures of decidual and peripheral leukocytes in normal and unexplained RM pregnancies at the early stage of gestation. Integrative analysis identifies 22 distinct cell clusters in total, and a dramatic difference in leukocyte subsets and molecular properties in RM cases is revealed. Specifically, the cytotoxic properties of CD8+ effector T cells, nature killer (NK), and mucosal-associated invariant T (MAIT) cells in peripheral blood indicates apparently enhanced pro-inflammatory status, and the population proportions and ligand-receptor interactions of the decidual leukocyte subsets demonstrate preferential immune activation in RM patients. The molecular features, spatial distribution, and the developmental trajectories of five decidual NK (dNK) subsets have been elaborately illustrated. In RM patients, a dNK subset that supports embryonic growth is diminished in proportion, while the ratio of another dNK subset with cytotoxic and immune-active signature is significantly increased. Notably, a unique pro-inflammatory CD56+CD16+ dNK subset substantially accumulates in RM decidua. These findings reveal a comprehensive cellular and molecular atlas of decidual and peripheral leukocytes in human early pregnancy and provide an in-depth insight into the immune pathogenesis for early pregnancy loss.

16.
Biol Reprod ; 104(2): 418-429, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33074310

RESUMO

MicroRNA (miR)-210 is a well-known hypoxia-inducible small RNA. Increasing in vitro evidence demonstrates its involvement in regulating multiple behaviors of placental trophoblasts. However, direct in vivo evidence remains lacking. In the present study, we generated a miR-210-deficient mouse strain using CRISPR/Cas9 technology, in which miR-210 expression was markedly deficient in various tissues. Little influence on fertility rate and litter size was observed after the deletion of miR-210 in mice. Continuous exposure of pregnant mice to hypoxia (10.5% O2) from E6.5 to E10.5 or to E18.5 led to reduction in fetal weight, and such fetal weight loss was markedly worsened in miR-210-knockout dams. Analysis of the placental structure demonstrated the reduced expansion of placental spongiotrophoblast layer and hampered development of labyrinth fetal blood vessels in knockout mice compared to the wild-type controls upon hypoxia stimulation. The findings indicate that miR-210 participates in regulating placental adaptation to hypoxic stress during pregnancy.


Assuntos
Hipóxia/metabolismo , MicroRNAs/metabolismo , Oxigênio/administração & dosagem , Placenta/fisiologia , Adaptação Fisiológica , Animais , Sequência de Bases , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Tamanho da Ninhada de Vivíparos , Masculino , Troca Materno-Fetal , Camundongos , Camundongos Knockout , MicroRNAs/genética , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Distribuição Aleatória , Distribuição Tecidual
17.
Biol Reprod ; 104(3): 624-637, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33336235

RESUMO

Uterine spiral artery (SPA) remodeling is a crucial event during pregnancy to provide enough blood supply to maternal-fetal interface and meet the demands of the growing fetus. Along this process, the dynamic change and the fate of spiral artery vascular smooth muscle cells (SPA-VSMCs) have long been debatable. In the present study, we analyzed the cell features of SPA-VSMCs at different stages of vascular remodeling in human early pregnancy, and we demonstrated the progressively morphological change of SPA-VSMCs at un-remodeled (Un-Rem), remodeling, and fully remodeled (Fully-Rem) stages, indicating the extravillous trophoblast (EVT)-independent and EVT-dependent phases of SPA-VSMC dedifferentiation. In vitro experiments in VSMC cell line revealed the efficient roles of decidual stromal cells, decidual natural killer cells (dNK), decidual macrophages, and EVTs in inducing VSMCs dedifferentiation. Importantly, the potential transformation of VSMC toward CD56+ dNKs was displayed by immunofluorescence-DNA in-situ hybridization-proximity ligation and chromatin immunoprecipitation assays for H3K4dime modification in the myosin heavy chain 11 (MYH11) promoter region. The findings clearly illustrate a cascade regulation of the progressive dedifferentiation of SPA-VSMCs by multiple cell types in uterine decidual niche and provide new evidences to reveal the destination of SPA-VSMCs during vascular remodeling.

18.
Int J Ophthalmol ; 13(12): 1941-1947, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33344194

RESUMO

AIM: To evaluate whether narrowing of internal carotid artery siphon (ICAS) may increase the risk of developing non-arteritic anterior ischaemic optic neuropathy (NAION). METHODS: Totally 30 consecutive patients who had unilateral NAION and 30 gender-matched control subjects were recruited in the present study. The diameter of ICAS of all the participants were measured using head-and-neck computed tomographic angiography (CTA). Color doppler flow imaging (CDI) was used to measure the haemodynamics parameters of ICAS and short posterior ciliary arteries (SPCAs) in all subjects. Comparison of parameters between the NAION patients and controls as well as between the two sides within the patients were performed. The correlation between the diameter of ICAS and NAION was analyzed. RESULTS: A comparison of parameters between the affected side of the NAION patients and the controls, including the diameter of ICAS, the resistance index (RI) of ICAS, the blood flow velocities of SPCAs and RI of SPCAs, showed significantly difference (P<0.01), while there was no significant difference in terms of the mean blood flow velocity (Vm) of ICAS; Similar results were found while comparing all the measurements of the affected and unaffected side of patients (P for RI of SPCAs <0.05). No marked difference was detected in nearly all parameters except for RI of ICAS and SPCAs between the unaffected side of the NAION patients and the controls (P<0.05). The diameter of ICAS were significantly positive correlated with both peak systolic velocity (PSV) of SPCAs and end diastolic velocity (EDV) of SPCAs in patients with NAION (r=0.514, P<0.01 and r=0.418, P<0.05, respectively). CONCLUSION: Narrowing of ICAS may increase the risk of developing NAION.

19.
Mol Ther Nucleic Acids ; 22: 542-556, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33230456

RESUMO

The study investigated the regulation of Smad2 by miR-18a and its role in preeclampsia (PE). Bioinformatics analysis showed that both Smad2 and Smad3 were the predicted targets for miR-18a. Mass spectrum analysis showed that two mature Smad2 isoforms existed in human placenta: full length, Smad2(FL), and that lacking exon3, Smad2(Δexon3). The protein level of Smad2(FL), but not Smad2(Δexon3) or Smad3, was significantly increased in severe PE (sPE) placenta, which was inversely correlated with the level of miR-18a. Elevated Smad2(FL) phosphorylation level appeared in sPE placenta, and Smad2 was colocalized with miR-18a in various subtypes of trophoblasts in human placenta. Smad2(FL) was validated as the direct target of miR-18a in HTR8/SVneo cells. miR-18a enhanced trophoblast cell invasion, which was blocked by the overexpression of Smad2(FL). Furthermore, overexpression of miR-18a repressed Smad2 activation and the inhibition of trophoblast cell invasion by transforming growth factor-ß (TGF-ß). In conclusion, our results suggest that miR-18a inhibits the expression of Smad2(FL), but not Smad2(Δexon3) or Smad3, which can reduce TGF-ß signaling, leading to the enhancement of trophoblast cell invasion. A lack of miR-18a, which results in the upregulation of Smad2(FL), contributes to the development of PE.

20.
Endocrinology ; 161(11)2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32976565

RESUMO

Uterine surgical scarring is an increasing risk factor for adverse pregnant consequences that threaten fetal-maternal health. The detailed molecular features of scar implantation remain largely unknown. We aim to study the pathologic features of uterine surgical scarring and the mechanisms of compromised pregnancy outcomes of scar implantation. We generated a mouse model of uterine surgical scarring with a uterine incision penetrating the myometrium to endometrium to examine the pathologic changes and transcriptome profiles of uterine scarring at various postsurgery (PS) time points, as well as features of the feto-maternal interface during scar implantation. We found that uterine surgical scar recovery was consistently poor at PS3 until PS90, as shown by a reduced number of endometrial glands, inhibition of myometrial smooth muscle cell growth but excessive collagen fiber deposition, and massive leukocyte infiltration. Transcriptome annotation indicated significant chronic inflammation at the scarring site. At the peri-implantation and postimplantation stages, abnormal expression of various steroid-responsive genes at the scarring site was in parallel with lumen epithelial cell hyperplasia, inappropriate luminal closure, and disorientation of the implanted embryo, restricted stromal cell proliferation, and defective decidualization. High embryonic lethality (around 70%) before E10.5 was observed, and the small amount of survival embryos at E10.5 exhibited restricted growth and aberrant placenta defects including overinvasion of trophoblast cells into the decidua and insufficient fetal blood vessel branching in the labyrinth. The findings indicate that chronic inflammation and compromised responses to steroids in uterine scar tissues are the pivotal molecular basis for adverse pregnancy consequences of scar implantation.


Assuntos
Cicatriz/complicações , Endométrio/efeitos dos fármacos , Hormônios Esteroides Gonadais/farmacologia , Complicações na Gravidez/etiologia , Útero/lesões , Animais , Cicatriz/genética , Cicatriz/metabolismo , Cicatriz/patologia , Decídua/efeitos dos fármacos , Decídua/metabolismo , Decídua/patologia , Modelos Animais de Doenças , Implantação do Embrião/efeitos dos fármacos , Implantação do Embrião/fisiologia , Endométrio/lesões , Endométrio/patologia , Endométrio/fisiologia , Feminino , Camundongos , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/patologia , Complicações na Gravidez/fisiopatologia , Gravidez Ectópica/etiologia , Gravidez Ectópica/genética , Gravidez Ectópica/metabolismo , Gravidez Ectópica/patologia , Ferida Cirúrgica/complicações , Ferida Cirúrgica/genética , Ferida Cirúrgica/metabolismo , Ferida Cirúrgica/patologia , Doenças Uterinas/etiologia , Doenças Uterinas/fisiopatologia , Útero/efeitos dos fármacos , Útero/patologia , Útero/fisiologia
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