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1.
J Mol Endocrinol ; 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32197234

RESUMO

Decidualization is a critical process for embryo implantation and pregnancy maintenance in humans. The homeobox gene HOXA10 has been widely studied in endometrial receptivity establishment and decidualization. MEIS1, a three-amino-acid loop extension (TALE) family homeobox gene, has been proven to be a co-factor for HOXA10 in mouse uterus. However, the interaction between MEIS1 and HOXA10 in the human decidual cells remains to be elucidated. siRNA and CRISPR-Cas9 were employed to knockdown and knockout MEIS1 in the cultured human endometrial stromal cells, and it was found that MEIS1 deficiency leads to impaired decidualization. The physical interaction between the MEIS1 and HOXA10 in human endometrium stromal cell was confirmed by immunoprecipitation. Moreover, KAT2B and ETA were proved to be downregulated in the absence of MEIS1, and Luciferase reporter and ChIP assays demonstrated that MEIS1-HOXA10 complex binds to the promoters of KAT2B and ETA and regulates their activity. Overexpression of KAT2B and ETA can partially rescue the decidualization defects in MEIS1 knockout HESCs. Taken together, these data suggest that MEIS1 plays an indispensable role in decidualization in human endometrial stromal cells, and MEIS1 interacts with HOXA10 to regulate the downstream genes, such as KAT2B and ETA. These findings will contribute to our understanding about the regulatory network in the process of decidualization in humans.

2.
J Pediatr ; 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32093929

RESUMO

OBJECTIVES: To investigate the association of birthweight percentile with cord blood glucose, lipids, and insulin levels. STUDY DESIGN: Data obtained from 1522 newborns were included in the Born in Guangzhou Cohort study. The generalized additive model and multivariable linear regression model were used to explore the nonlinear and linear relationships between birthweight and cord blood metabolic measures, and to evaluate the differences of metabolic measures Z-scores among small for gestational age, appropriate for gestational age, and large for gestational age babies. RESULTS: Birthweight Z-score was linearly associated with increased cord blood insulin Z-score (adjusted ß = 0.30; 95% CI, 0.22-0.37). Compared with appropriate for gestational age babies, neonates born small for gestational age had significantly higher cord blood triglycerides Z-score (adjusted mean difference [MDadj], 0.60; 95% CI, 0.40-0.79) and lower cord blood insulin (MDadj, -0.37; 95% CI, -0.57 to -0.16), high-density lipoprotein cholesterol (MDadj, -0.34; 95% CI, -0.55 to -0.13), total cholesterol (MDadj, -0.26; 95% CI, -0.47 to -0.05), and low-density lipoprotein (MDadj, -0.23; 95% CI, -0.43 to -0.02) Z-scores, and neonates born large for gestational age had higher cord blood insulin Z-score (MDadj, 0.31; 95% CI, 0.09 to 0.52). CONCLUSIONS: Our findings support the hypothesis that babies born small for gestational age and large for gestational age are exposed to different intrauterine environments, which may contribute to altered fat accumulation patterns with implications for the risk of metabolic dysfunction later in life. There is a need to consider the development of tailored intervention strategies to prevent metabolic dysfunction in adult life for these babies.

3.
Diabetes Res Clin Pract ; 161: 108041, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006645

RESUMO

AIMS: To evaluate the difference in maternal circulating leptin profile between pregnant women with and without gestational diabetes mellitus (GDM). METHODS: This is a nested case-control study embedded in the Born in Guangzhou Cohort Study in Guangzhou Women and Children's Medical Center, with 198 GDM cases and 192 controls included. Maternal plasma leptin profile was defined as leptin concentrations measured at early (baseline) and late pregnancy, as well as a ratio of concentration at late to that at early pregnancy (RL1L0). General linear regression was used to assess the associations between GDM and log-transformed leptin measurements. RESULTS: Women with GDM had a higher baseline leptin concentration and lower RL1L0 compared to those without GDM. The log leptin concentration at baseline (ß: 0.19, 95%CI: 0.04, 0.34) and the log RL1L0 (ß: -0.22, 95%CI: -0.41, -0.03) were associated with GDM status. The RL1L0 decreased significantly along with the increase of 1-hour glucose and the difference between 1-hour and fasting glucose levels in both GDM and non-GDM women. CONCLUSIONS: Women with GDM had a certain profile of circulating leptin, with higher baseline concentration but less increase during pregnancy, suggesting an impaired compensatory response to increasing insulin resistance along with the progress of pregnancy.

4.
J Colloid Interface Sci ; 557: 112-123, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518833

RESUMO

Direct assembling 2D zeolitic imidazolate frameworks-derived (ZIFs)-derived Ni-Co oxide on Ni foam (NixCo3-xO4/Ni foam) is a very attractive way to obtain high performance for electrochemical energy storage device. In this work, the highly optimized NixCo3-xO4/Ni foam was prepared via facile co-precipitation, ion-exchange method and subsequently composited with rGO, acting as binder-less electrode for high properties hybrid supercapacitors. As electrode materials, the pure Co3O4/Ni foam shows 94.40 C g-1 (209.78 F g-1) at 1 A g-1, while the highly optimized NixCo3-xO4/Ni foam exhibits a high capacity of 870.3 C g-1 (1934F g-1) at 1 A g-1. Compared with NixCo3-xO4/Ni foam, the reduced graphene oxides (rGO) modified NixCo3-xO4/Ni foam electrodes possess a porous conductive structure, displaying more superior capacity of 1440.99 C g-1 (3202.22F g-1) at 1 A g-1 and a higher cycling stability of 76.10% retention value after 1000 cycles. Subsequently, the NixCo3-xO4/rGO/Ni foam electrodes were assembled as a hybrid supercapacitor, exhibiting a maximum energy density of 36.31 Wh kg-1, a maximum power density of 8000 W kg-1 and a good cycling stability of 76.29% retention value after 3000 cycles. The NixCo3-xO4/rGO/Ni foam also could light the blue LED device. Thereby, it is proved that NixCo3-xO4/rGO/Ni foam is a promising materials for hybrid supercapacitors.

5.
Reprod Toxicol ; 90: 109-117, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31520687

RESUMO

Our understanding of the relationship between stress-derived epinephrine and early pregnancy failure remains incomplete. Here, we explored the effect of epinephrine exposure on early pregnancy and pseudopregnancy in mice. Increased expression of adrenergic receptors Adra1b, Adra2b and Adrb2 was observed during decidualization and post-implantation embryogenesis was delayed or survival impaired. Epinephrine treatment also impaired decidualization in both the gravid and pseudopregnant uterus, suggesting the effect on decidualization was independent of the conceptus. This included a suppression of endometrial stroma cell proliferation and of key decidualization regulators, including COX2, BMP2 and WNT4. Collectively, these data demonstrate that maternal epinephrine exposure during early pregnancy impairs uterine decidualization and embryo development, underlying early pregnancy failure.

6.
Front Immunol ; 10: 2064, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31543879

RESUMO

T cells recognize antigens as peptides bound to major histocompatibility complex (MHC) proteins through T cell receptors (TCRs) on their surface. To recognize a wide range of pathogens, each individual possesses a substantial number of TCRs with an extremely high degree of variability. It remains controversial whether germline-encoded TCR repertoire is shaped by MHC polymorphism and, if so, what is the preference between MHC genetic variants and TCR V gene compatibility. To investigate the "net" genetic association between MHC variations and TRBV genes, we applied quantitative trait locus (QTL) mapping to test the associations between MHC polymorphism and TCR ß chain V (TRBV) genes usage using umbilical cord blood (UCB) samples of 201 Chinese newborns. We found TRBV gene and MHC loci that are predisposed to interact with one another differ from previous conclusions. The majority of MHC amino acid residues associated with the TRBV gene usage show spatial proximities in known structures of TCR-pMHC complexes. These results show for the first time that MHC variants bias TRBV gene usage in UCB of Chinese ancestry and indicate that germline-encoded contacts influence TCR-MHC interactions in intact T cell repertoires.

7.
Mol Genet Genomic Med ; 7(8): e807, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268247

RESUMO

BACKGROUND: Asthenozoospermia (AZS), also known as asthenospermia, is characterized by reduced motility of ejaculated spermatozoa and is detected in more than 40% of infertile patients. Because the proportion of progressive spermatozoa in severe AZS is <1%, severe AZS is an urgent challenge in reproductive medicine. Several genes have been reported to be relevant to severe asthenospermia. However, these gene mutations are found only in sporadic cases and can explain only a small fraction of severe AZS, so additional genetic pathogenies need to be explored. METHODS AND RESULTS: By screening the variant genes in a patient with severe AZS using whole exome sequencing, we identified biallelic mutations c.2521C>T: p.(Pro841Ser) (NC_000003.11: g.184043412C>T) in exon13 and c.2957C>G: p.(Ala986Gly) (NC_000003.11: g.184045117C>G) in exon17 in the eukaryotic translation initiation factor 4 gamma 1 gene (EIF4G1, RefSeq: NM_004953.4, OMIM: 600495) of the patient. Both of the mutation sites are rare and potentially deleterious. Transmission electron microscopy analysis showed a disrupted axonemal structure with mitochondrial sheath defects. The EIF4G1 protein level was extremely low, and the mitochondrial marker cytochrome c oxidase subunit 4I1 (COXIV, OMIM: 123864) and mitochondrially encoded ATP synthase 6 (ATP6, OMIM: 516060) protein levels were also decreased in the patient's spermatozoa as revealed by WB and IF analysis. This infertility associated with this condition was overcome by intracytoplasmic sperm injections, as his wife became pregnant successfully. CONCLUSION: Our experimental findings indicate that the EIF4G1 gene is a novel candidate gene that may be relevant to severe AZS.

8.
World J Pediatr ; 15(5): 483-491, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31286424

RESUMO

BACKGROUND: Birth weight is a strong determinant of infant short- and long-term health outcomes. Family socioeconomic position (SEP) is usually positively associated with birth weight. Whether this association extends to abnormal birth weight or there exists potential mediator is unclear. METHODS: We analyzed data from 14,984 mother-infant dyads from the Born in Guangzhou Cohort Study. We used multivariable logistic regression to assess the associations of a composite family SEP score quartile with macrosomia and low birth weight (LBW), and examined the potential mediation effect of maternal pre-pregnancy body mass index (BMI) using causal mediation analysis. RESULTS: The prevalence of macrosomia and LBW was 2.62% (n = 392) and 4.26% (n = 638). Higher family SEP was associated with a higher risk of macrosomia (OR 1.30, 95% CI 0.93-1.82; OR 1.53, 95% CI 1.11-2.11; and OR 1.59, 95% CI 1.15-2.20 for the 2nd, 3rd, and 4th SEP quartile respectively) and a lower risk of LBW (OR 0.69, 95% CI 0.55-0.86; OR 0.76, 95% CI 0.61-0.94; and OR 0.61, 95% CI 0.48-0.77 for the 2nd, 3rd, and 4th SEP quartile respectively), compared to the 1st SEP quartile. We found that pre-pregnancy BMI did not mediate the associations of SEP with macrosomia and LBW. CONCLUSIONS: Socioeconomic disparities in fetal macrosomia and LBW exist in Southern China. Whether the results can be applied to other populations should be further investigated.

9.
Sci Rep ; 9(1): 9998, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292492

RESUMO

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that has been linked with the development of systemic lupus erythematosus (SLE). Thus far, molecular mimicry has been implicated as the principal mechanism that explains this association. In this study, we characterise a potential alternative process whereby HCMV contributes to SLE. In a cohort of SLE patients, we show a significant association between HCMV infection and SLE through a human antibody response that targets UL44. UL44 is an obligate nuclear-resident, non-structural viral protein vital for HCMV DNA replication. The intracellular nature of this viral protein complicates its targeting by the humoral response - the mechanism remains unresolved. To characterise this response, we present a thorough molecular analysis of the first human monoclonal antibody specific for UL44 derived from a HCMV seropositive donor. This human antibody immunoprecipitates UL44 from HCMV-infected cells together with known nuclear-resident SLE autoantigens - namely, nucleolin, dsDNA and ku70. We also show that UL44 is redistributed to the cell surface during virus-induced apoptosis as part of a complex with these autoantigens. This phenomenon represents a potential mechanism for the bystander presentation of SLE autoantigens to the humoral arm of our immune system under circumstances that favour a break in peripheral tolerance.

10.
Chem Commun (Camb) ; 55(61): 9031-9034, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292574

RESUMO

A Cu-NWs paper synthesized by a one-step method is first presented. Owing to its good conductivity, it is an effective framework to interlink TMOs and prevent aggregation. For a practical application, the core-shell Cu NWs@ultrathin CoOx delivers good performance for the catalytic oxidation of glucose and energy storage, with a sensitivity of 396.57 µA mM-1 cm-2 and a capacitance of 797.7 F g-1 (1 A g-1).

11.
Proc Natl Acad Sci U S A ; 116(33): 16621-16630, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31346081

RESUMO

Implantation of the blastocyst into the uterus is the gateway for further embryonic development in mammals. Programming of blastocyst to an implantation-competent state known as blastocyst activation is the determining factor for implantation into the receptive uterus. However, it remains largely unclear how the blastocyst is globally programmed for implantation. Employing a delayed implantation mouse model, we show here that the blastocyst undergoes extensive programming essential for implantation. By analyzing the transcriptional profile of blastocysts with different implantation competency, we reveal the dynamic change in the biosynthesis, metabolism, and proliferation during blastocyst reactivation from diapause. We also demonstrate that reactivation of the X chromosome, one of the most important events during periimplantation of female embryonic development, is not completed even in blastocysts under conditions of dormancy, despite long term suspension in the uterus. Moreover, the mural trophectoderm (TE), but not the polar TE, differentiates to be more invasive through the weakened cell-cell tight junctions and extracellular matrices (ECMs). By analyzing the differentially expressed profile of secretory proteins, we further demonstrate that the blastocyst functions as a proinflammatory body to secrete proinflammatory signals, such as TNFα and S100A9, thereby triggering embryo-uterine attachment reaction during implantation. Collectively, our data systematically and comprehensively disclose the programming of blastocyst reactivation from diapause for implantation and uncover previously undefined roles of blastocyst during implantation.

12.
Cell Mol Life Sci ; 76(24): 4813-4828, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31352535

RESUMO

Embryo implantation is one of the pivotal steps during mammalian pregnancy, since the quality of embryo implantation determines the outcome of ongoing pregnancy and fetal development. A large number of factors, including transcription factors, signalling transduction components, and lipids, have been shown to be indispensable for embryo implantation. Increasing evidence also suggests the important roles of epigenetic factors in this critical event. This review focuses on recent findings about the involvement of epigenetic regulators during embryo implantation.


Assuntos
Implantação do Embrião/genética , Epigênese Genética/genética , Fatores de Transcrição/genética , Útero/metabolismo , Animais , Blastocisto/metabolismo , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Feminino , Humanos , Gravidez , Transdução de Sinais/genética , Útero/crescimento & desenvolvimento
13.
PLoS Med ; 16(7): e1002846, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31283770

RESUMO

BACKGROUND: The cesarean section (CS) rate has risen globally during the last two decades. Effective and feasible strategies are needed to reduce it. The aim of this study was to assess the CS rate change after a two-stage intervention package that was designed to reduce the overall CS rate in Guangzhou, China. METHODS AND FINDINGS: This intervention package was implemented by the Health Commission of Guangzhou Municipality in 2 stages (October 2010-September 2014 and October 2014-December 2016) and included programs for population health education, skills training for healthcare professionals, equipment and technical support for local healthcare facilities, and capacity building for the maternal near-miss care system. A retrospective repeated cross-sectional study was conducted to evaluate influences of the intervention on CS rates. A pre-intervention period from January 2008 to September 2010 served as the baseline. The primary outcome was the CS rate, and the secondary outcomes included maternal mortality ratio (MMR) and perinatal mortality rate (PMR), all obtained from the Guangzhou Perinatal Health Care and Delivery Surveillance System (GPHCDSS). The Cochran-Armitage test was used to examine the trends of the overall CS rate, MMR, and PMR across different stages. Segmented linear regression analysis was used to assess the change of the CS rate over the intervention period. A total of 1,921,932 records of births and 108 monthly CS rates from 2008 to 2016 were analyzed. The monthly CS rate declined across the intervention stages (Z = 75.067, p < 0.001), with an average rate of 42.4% at baseline, 39.8% at Stage 1, and 35.0% at Stage 2. The CS rate declined substantially among nulliparous women who delivered term singletons, with an accelerating decreasing trend observed across Stage 1 and Stage 2 (the difference in slopes: -0.09 [95% CI -0.16 to -0.02] between Stage 1 and baseline, p = 0.014; -0.11 [95% CI -0.20 to -0.02] between Stage 1 and Stage 2, p = 0.017). The CS rate in the remaining population increased during baseline and Stage 1 and subsequently decreased during Stage 2. The sensitivity analysis suggested no immediate impact of the universal two-child policy on the trend of the CS rate. The MMR (Z = -4.368, p < 0.001) and PMR (Z = -13.142, p < 0.001) declined by stage over the intervention period. One of the main limitations of the study is the lack of a parallel control group. Moreover, the influence of temporal changes in the study population on the CS rate was unknown. Given the observational nature of the present study, causality cannot be confirmed. CONCLUSIONS: Apparent decline in the overall CS rate was observed in Guangzhou, China, after the implementation of a two-stage intervention package. The decline was most evident among nulliparous women who delivered term singletons. Despite some limitations for causal inference, Guangzhou's experience in controlling the CS rate by implementing composite interventions with public health education and perinatal healthcare service improvement could have implications for other similar areas with high rates of CS.


Assuntos
Cesárea/tendências , Educação em Saúde/tendências , Assistência Perinatal/tendências , Padrões de Prática Médica/tendências , Adulto , Fortalecimento Institucional/tendências , Cesárea/efeitos adversos , Cesárea/mortalidade , China , Estudos Transversais , Feminino , Pessoal de Saúde/educação , Humanos , Recém-Nascido , Capacitação em Serviço/tendências , Mortalidade Materna/tendências , Educação de Pacientes como Assunto/tendências , Mortalidade Perinatal/tendências , Gravidez , Avaliação de Programas e Projetos de Saúde , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
14.
J Med Genet ; 56(10): 678-684, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31151990

RESUMO

BACKGROUND: Multiple morphological abnormalities of the sperm flagella (MMAF) is a kind of severe teratozoospermia. Patients with the MMAF phenotype are infertile and present aberrant spermatozoa with absent, short, coiled, bent and/or irregular flagella. Mutations in several genes can explain approximately 30%-50% of MMAF cases and more genetic pathogenies need to be explored. SPEF2 was previously demonstrated to play an essential role in sperm tail development in mice and pig. Dysfunctional mutations in SPEF2 impair sperm motility and cause a short-tail phenotype in both animal models. OBJECTIVE: Based on 42 patients with severe infertility and MMAF phenotype, we explored the new genetic cause of human MMAF phenotype. METHODS AND RESULTS: By screening gene variants in 42 patients with MMAF using whole exome sequencing, we identified the c. 12delC, c. 1745-2A > G, c. 4102 G > T and c. 4323dupA mutations in the SPEF2 gene from two patients. Both of these mutations are rare and potentially deleterious. Transmission electron microscope (TEM) analysis showed a disrupted axonemal structure with mitochondrial sheath defects in the patients' spermatozoa. The SPEF2 protein level was significantly decreased in the spermatozoa of the patients revealed by Western blot (WB) and immunofluorescence (IF) analyses. CONCLUSION: Our experimental findings indicate that loss-of-function mutations in the SPEF2 gene can cause the MMAF phenotype in human.

15.
Pediatr Res ; 86(4): 529-536, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31158843

RESUMO

BACKGROUND: Previous studies proposed that there were racial or ethnic disparities in fetal growth, challenging the use of international standards in specific populations. This study was to evaluate the validity of applying the INTERGROWTH-21st standard to a Chinese population for identifying abnormal head circumference (HC), in comparison with a newly generated local reference. METHODS: There were 24,257 singletons delivered by low-risk mothers in four perinatal health-care centers in Southern China. New HC reference was constructed and comparison in distribution of HC categories was performed between the INTERGROWTH-21st standard and new reference after applying these two tools in study population. Logistic regression was used to examine the association between abnormal HC and adverse neonatal outcomes. RESULTS: There were 4.40% of the newborns identified with microcephaly (HC > 2 standard deviation below the mean) using the INTERGROWTH-21st standard, comparing to the proportion of 2.83% using new reference. The newborns identified with microcephaly only by the INTERGROWTH-21st standard were not at a higher risk of adverse neonatal outcome, compared with those identified as non-microcephaly by both tools (OR 0.73, 95% CI 0.47-1.13). CONCLUSION: The new HC reference may be more appropriate for newborn assessment in Chinese populations than the INTERGROWTH-21st standard.

16.
Cell Death Dis ; 10(6): 438, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31165749

RESUMO

The placenta, responsible for the nutrient and gas exchange between the mother and fetus, is pivotal for successful pregnancy. It has been shown that Rbpj, the core transcriptional mediator of Notch signaling pathway, is required for normal placentation in mice. However, it remains largely unclear how Rbpj signaling in different placental compartments coordinates with other important regulators to ensure normal placental morphogenesis. In this study, we found that systemic deletion of Rbpj led to abnormal chorioallantoic morphogenesis and defective trophoblast differentiation in the ectoplacental cone (EPC). Employing mouse models with selective deletion of Rbpj in the allantois versus trophoblast, combining tetraploid aggregation assay, we demonstrated that allantois-expressed Rbpj is essential for chorioallantoic attachment and subsequent invagination of allantoic blood vessels into the chorionic ectoderm. Further studies uncovered that allantoic Rbpj regulates chorioallantoic fusion and morphogenesis via targeting Vcam1 in a Notch-dependent manner. Meanwhile, we also revealed that trophoblast-expressed Rbpj in EPC facilitates Mash2's transcriptional activity, promoting the specification of Tpbpα-positive trophoblasts, which differentiate into trophoblast subtypes responsible for interstitial and endovascular invasion at the later stage of placental development. Collectively, our study further shed light on the molecular network governing placental development and functions, highlighting the necessity of a spatiotemporal coordination of Rbpj signaling for normal placental morphogenesis.

17.
Intern Med J ; 49(10): 1299-1306, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30985051

RESUMO

BACKGROUND: Elevated D-dimer levels have been associated with poor outcomes in patients with cardiovascular disease. AIM: To study this association in elderly patients with chronic heart failure (CHF). METHODS: We analysed 1355 elderly patients who were admitted with CHF. All patients had D-dimer levels measured within the first 24 h following admission. A multivariate logistic regression model was used to assess the variables associated with chronic kidney disease. We used Cox regression analysis to assess the multivariable relationship between the D-dimer and subsequent all-cause death. RESULTS: In the multiple logistic regression analysis, the D-dimer was identified as a risk factor for chronic kidney disease (odds ratio = 1.278, 95% confidence interval 1.138 to 1.436, P < 0.001). The optimal cut-off level for D-dimer to predict all-cause death was found to be >885 ng/mL. In the multivariate Cox proportional-hazards model, a D-dimer level >885 ng/mL remained significantly associated with all-cause death (hazard ratio = 2.003, 95% confidence interval 1.334 to 3.010, P = 0.001). Additional analyses revealed that higher D-dimer levels were associated with an increased risk of all-cause death irrespective of the subtype of heart failure (including heart failure with reduced ejection fraction and heart failure with preserved ejection fraction). CONCLUSION: In elderly patients with CHF, measurement of D-dimer levels may help to risk stratify these patients, and high D-dimer levels might be regarded as a warning sign to intensify therapy.

18.
J Cell Biochem ; 120(8): 12500-12507, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30834595

RESUMO

Radiation-induced lung injury (RILI) frequently occurs in patients with thoracic malignancies. In response to radiation, alveolar epithelial cells (AEC) undergo epithelial-mesenchymal transition (EMT) and contribute to the pathogenesis of RILI. Insulin-like growth factor binding protein 7 (IGFBP7) is reported as a downstream mediator of transforming growth factor-ß1 (TGF-ß1) pathway, which plays a crucial role in radiation-induced EMT. In the present study, the levels of IGFBP7 and TGF-ß1 were simultaneously increased in experimental RILI models and radiation-treated AEC (human pulmonary alveolar epithelial cells [HPAEpic]). The expression of IGFBP7 in radiation-treated HPAEpic cells was obviously inhibited by the specific inhibitor of TGF-ß receptor antagonist SB431542 and TGF-ß1 neutralizing antibody, and time-dependently enhanced by TGF-ß1 treatment. Moreover, IGFBP7 knockdown significantly attenuated the effects of radiation on morphology change, cell migration, expression of EMT-related markers (E-cadherin, α-SMA, and Vimentin), and phosphorylation of extracellular-signal-regulated kinase (ERK). The effects of IGFBP7 overexpression on the expression of EMT-related markers were partially reversed by the ERK inhibitor PD98059. In conclusion, IGFBP7, was enhanced by TGF-ß1, may be involved in radiation-induced EMT of AEC via the ERK signaling pathway, thus contributing to the pathogenesis of RILI.

19.
Am J Transl Res ; 11(2): 733-743, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30899375

RESUMO

Radiation-induced lung toxicity, including radiation pneumonitis and pulmonary fibrosis, often occurs in patients receiving radiation therapy. Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs) plays critical roles in radiation-induced lung toxicity. In the present study, RNA sequencing was applied to examine the whole transcriptomes of human pulmonary AEC cells (HPAEpiC) with or without radiation treatment. We found that cytokine, chemokine and cell adhesion signaling pathways were enriched in radiation-treated cells. CCL2 (C-C Motif Chemokine Ligand 2), CCL5 and CCR4 (C-C Motif Chemokine Receptor 4) were among the top enriched genes in chemokine signaling pathway. The upregulation of CCL2, CCL5 and CCR4 in response to irradiation was confirmed at both mRNA and protein levels by real-time PCR, western blotting and enzyme-linked immunosorbent assay analyses. Ophiopogonin B, a bioactive ingredient of Radix Ophiopogon japonicas, was found to attenuate radiation-induced EMT in HPAEpiC cells as demonstrated by the alteration in cell morphology, and the expression of E-cadherin and Vimentin. Ophiopogonin B could also reduce radiation-induced expression of CCL2, CCL5, CCR4 and phosphorylated ERK (p-ERK). Moreover, CCR4 knockdown, U0126 (a MEK/ERK inhibitor) or ophiopogonin B also partially blocked the EMT promoting effects of CCL2 and CCL5. Our data suggested CCL2, CCL5 and CCR4 may be potential therapeutic targets for radiation-induced lung toxicity. Ophiopogonin B, which could down-regulate CCL2, CCL5 and CCR4, may be a useful radioprotective agent.

20.
Clin Genet ; 95(5): 590-600, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30811583

RESUMO

Multiple morphological abnormalities of flagella (MMAF) is one kind of severe teratozoospermia. Gene mutations reported in previous works only revealed the pathogenesis of approximately half of the MMAF cases, and more genetic defects in MMAF need to be explored. In the present study, we performed a genetic analysis on Han Chinese men with MMAF using whole-exome sequencing. After filtering out the cases with known gene mutations, we identified five novel mutation sites in the DNAH2 gene in three cases from three families. These mutations were validated through Sanger sequencing and absent in all control individuals. In silico analysis revealed that these DNAH2 variations are deleterious. The spermatozoa with DNAH2 mutations showed severely disarranged axonemal structures with mitochondrial sheath defection. The DNAH2 protein level was significantly decreased and inner dynein arms were absent in the spermatozoa of patients. ICSI treatment was performed for two MMAF patients with DNAH2 mutations and the associated couples successfully achieved pregnancy, indicating good nuclear quality of the sperm from the DNAH2 mutant patients. Together, these data suggest that the DNAH2 mutation can cause severe sperm flagella defects that damage sperm motility. These results provide a novel genetic pathogeny for the human MMAF phenotype.

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