RESUMO
Placentas control the maternal-fetal transport of nutrients and gases. Placental reactions to adverse intrauterine conditions affect fetal development. Such adverse conditions occur in pregnancies complicated by diabetes, leading to alterations in placental anatomy and physiology. In this study, streptozocin (STZ) injection produced sustained hyperglycemia during pregnancy in rats. Hyperglycemic pregnant rats had gained significantly less weight than normal pregnant rats on embryonic day 15.5. We investigated the influence of diabetes on placental anatomy and physiology. Compared with controls, the diabetic group had a markedly thicker junctional zone at embryonic day 15.5. To explore a mechanism for this abnormality, we examined Nodal expression in the junctional zone of control and diabetic groups. We found lower expression of Nodal in the diabetic group. We then investigated the expression of its target gene p27Kip1 (p27), which is related to cell proliferation. In vitro, Nodal overexpression up-regulated p27 protein levels while interfered EBAF up-regulated p27. In vivo, the expression of p27 was lower in diabetic compared with normal rats, and localization was similar between the two groups. In contrast, a higher expression of PCNA was found in diabetic versus normal placenta. Endometrial bleeding associated factor (EBAF), an up-stream molecular regulator of Nodal, was expressed at higher levels in placenta from diabetic versus normal rats. Based on these results, we speculate that the EBAF/Nodal/p27 signaling pathway plays a role in morphological change of diabetic placenta.
Assuntos
Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Diabetes Mellitus Experimental/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Determinação Direita-Esquerda/metabolismo , Proteína Nodal/metabolismo , Placenta/metabolismo , Gravidez em Diabéticas/metabolismo , Transdução de Sinais , Animais , Feminino , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Gestational diabetes mellitus is a risk factor for congenital heart defects. The article aimed to investigate the expression and roles of MST1, YAP1, Last1/2 and Survivin in modulating HG-induced cardiomyocyte apoptosis and maternal diabetes-induced heart abnormality. METHODS: Diabetes mellitus was induced in rats using streptozotocin. The protein expression and phosphorylation analysis in fetal heart tissue was assessed by western blot and immunohistochemical staining. Hoechst 33342 staining assay was performed to explore H9C2 apoptosis. The gene and protein expression in H9C2 cells was assessed by quantitative PCR and western blot. Knockdown of gene expression was assessed by RNA interference. RESULTS: Our results revealed that increased MST1 protein levels in the heart tissues of the offspring of diabetic rats in vivo and in H9C2 cardiomyocytes under HG treatment in vitro, respectively. Knockdown and overexpression experiments showed that MST1 played a key role in mediating HG-induced apoptosis in cardiomyocytes. Downregulation of YAP1 was associated with HG-induced, MST1-mediated cardiomyocyte apoptosis. Further study showed that MST1 downregulated the protein level of YAP1 through mediation of YAP1 phosphorylation on Ser127 and Ser397; this process also required LATS1/2 participation. MST1 overexpression increased the phosphorylation levels of LATS1/2, which were also shown to be increased in the heart tissues of diabetic offspring. We also found that YAP1 mediated the expression of Survivin during HG-induced apoptosis, and the Survivin-inhibitor YM155 partially inhibited the role of YAP1 in suppressing apoptosis induced by HG in cardiomyocytes. CONCLUSION: These findings reveal a regulatory mechanism of MST1/YAP1/Survivin signaling in modulating cardiomyocyte apoptosis in vitro and maternal diabetes-induced congenital heart defects in vivo.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Glucose/efeitos adversos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Miócitos Cardíacos/citologia , Proteínas Serina-Treonina Quinases/metabolismo , Survivina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Regulação para Baixo , Imidazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/química , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Naftoquinonas/farmacologia , Fosforilação , Ratos , Estreptozocina , Proteínas de Sinalização YAPRESUMO
Gestational diabetes mellitus is one of the causes of abnormal embryonic heart development, but the mechanism is still poor. This study investigated the regulatory mechanism and role of SOX11 in congenital heart abnormality in a hyperglycemic environment. Immunohistochemistry, Western blotting, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) showed decreased SOX11 protein and messenger RNA (mRNA) levels in the heart tissue of diabetic offspring compared with the control group. A Sequenom EpiTYPER MassArray showed that methylation sites upstream in SOX11 region 1 were increased in the diabetic group compared with the control group. Luciferase reporter assays and qRT-PCR showed that Dnmt3b overexpression decreased SOX11 promoter activity and its mRNA level, whereas Dnmt3a had little effect on regulating SOX11 expression. Furthermore, we found that Dnmt3L cooperated with Dnmt3b to regulate SOX11 gene expression. Additionally, the function of SOX11 silencing was analyzed by using small interfering RNA-mediated knockdown. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and apoptotic assays showed that SOX11 downregulation inhibited cell viability and induced apoptosis in cardiomyocytes. Overexpression of the SOX11 gene suppressed cardiomyocytes apoptosis after high glucose treatment. We identified a novel epigenetic regulatory mechanism of SOX11 during heart development in a hyperglycemic environment and revealed a distinct role of SOX11 in mediating cardiomyocytes viability and apoptosis.
Assuntos
Apoptose , Regulação para Baixo , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Hiperglicemia/embriologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Fatores de Transcrição SOXC/biossíntese , Animais , Feminino , Feto/patologia , Hiperglicemia/patologia , Masculino , Miocárdio/patologia , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-DawleyRESUMO
The pathogenesis of atherosclerosis (AS) and abnormal endothelial cells apoptosis is a multifactorial biological process. Oxidized low density lipoprotein (ox-LDL) is a critical factor in the formation of AS. However, the exact mechanism is still not clear. Therefore, the aim of this study was to investigate some genes and biological pathways in endothelial cells apoptosis in response to ox-LDL. First, our results has validated that ox-LDL is an effective inducer of endothelial cells apoptosis, then, transcriptome sequencing was used to detect differential expression genes. In total, 71 differentially expressed genes (DEGs) were identified, including 32 upregulated genes and 39 downregulated genes. GO analysis showed that DEGs were mainly enriched in cytokine-mediated signaling pathway, gene expression, external side of plasma membrane, steroid binding, and signaling receptor binding. After KEGG analysis, the DEGs mainly focused on the following biochemical signaling pathways, including Signaling molecules and interaction (such as ICOSLG, IL6, ITGAM, TNFRSF13C and VTCN1), Signal transduction (such as IL13RA2, IL6, ITGAM, PDE5A, SGK3 and TNFRSF13C), Immune system (such as FCGR2A, ICOSLG, IL6, ITGAM and TNFRSF13C), and so on. These genes may play a dominant role in HAECs apoptosis and AS genesis. The above prediction and analysis provide an important basis for our follow-up study of the mechanism of these genes, which might be used as molecular targets or diagnostic biomarkers for AS.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , RNA Mensageiro/genética , Apoptose/efeitos dos fármacos , Aterosclerose/genética , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , TranscriptomaRESUMO
BACKGROUND: Age-related cataract (ARC) is a serious visual impairment disease, and its pathogenesis is unclear. This article aims to investigate the role of ROCK1 in the apoptosis of lens epithelial cells (LECs) in age-related cataracts. METHODS: We collect anterior capsule samples from normal people, patients with age-related cataracts, young mice and naturally aging cataract mice. The oxidative stress-induced apoptosis model was constructed by cultivating HLE-B3 cells with H2O2. MTT, Hoechst 33342, and TUNEL assay were performed to explore proliferation and apoptosis. HE assay was used to observe cell morphology. The gene and protein expression were assessed by quantitative real-time PCR, western blot, immunofluorescence, and immunohistochemical staining. RESULT: The results from the clinic and mice experiments showed that the numbers of lens epithelial cells from cataract individuals were less than the control individuals. In vitro, the apoptotic cells were increased in lens epithelial cells under H2O2 treatment. The ROCK1 protein level increased in the lens epithelial cells from age-related cataract patients and the old mice, respectively. Meanwhile, the up-regulation of the ROCK1 gene was associated with H2O2-induced HLE-B3 cells apoptosis. MTT and apoptosis assay showed ROCK1 was necessary in mediating H2O2-induced lens epithelial cells apoptosis through ROCK1 over-expression and knockdown experiment, respectively. Further investigation showed that p53 protein levels had been increased during ROCK1-mediated apoptosis in response to H2O2. Besides, ROCK1 phosphorylated p53 at ser15 to up-regulate its protein level. CONCLUSIONS: This study established the novel association of ROCK1/p53 signaling with lens epithelial cells apoptosis and age-related cataract genesis.
Assuntos
Apoptose/genética , Catarata/etiologia , Células Epiteliais/metabolismo , Proteína Supressora de Tumor p53/genética , Quinases Associadas a rho/genética , Animais , Apoptose/efeitos dos fármacos , Catarata/metabolismo , Catarata/patologia , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Imuno-Histoquímica , Camundongos , Fosforilação , Proteína Supressora de Tumor p53/metabolismo , Quinases Associadas a rho/metabolismoRESUMO
BACKGROUND: Iodine intake is essential in the production of thyroid hormone but very few foods are rich in it. Iodine deficiency or excess iodine level may both lead to thyroid disorders, which further affects human fertility function. The objective of this study is to investigate the relationship between iodine intake and seminal parameters among fertile men in China. METHODS: A total of 1098 couples were recruited by trained physicians at different family planning service stations in 2015. Semen and iodine samples were obtained from male respondents. A questionnaire survey inquired about demographic information from couples. The main outcome variables of semen quality were semen volume, semen concentration, semen motility, and sperm count, and time to pregnancy. Urinary iodine concentration (UIC) was used to measure iodine levels for male respondents. Ordinary least squared regressions and logistic regressions were performed to estimate the association between iodine intake level and semen quality parameters. RESULTS: Male respondents with deficient or excess iodine levels had a 5% higher semen volume relative to those with optimal iodine intake (p < 0.1). Suboptimal iodine intake was negatively associated with semen concentration and semen counts (p < 0.01). Longer time of pregnancy was observed in iodine deficiency and excess group than those in the optimal group (p < 0.01). CONCLUSION: In general, iodine deficiency and excess were both associated with decreasing semen quality parameters in male respondents.
Assuntos
Ingestão de Alimentos/fisiologia , Fertilidade/efeitos dos fármacos , Iodo/urina , Análise do Sêmen , Adulto , China , Dieta/efeitos adversos , Feminino , Humanos , Infertilidade Masculina/etiologia , Iodo/deficiência , Análise dos Mínimos Quadrados , Modelos Logísticos , Masculino , Estado Nutricional , GravidezRESUMO
Gestational diabetes mellitus is a risk factor for congenital heart defects. Our previous results indicated that a decrease in myocardial cells and an increase in apoptotic cells leads to heart defects under hyperglycemia, but much work remains to elucidate this important mechanism of myocardial cell apoptosis induced by high glucose (HG). In this study, we found that a decrease in GSK3ß phosphorylation on Ser9 occurred concomitantly with HG-induced cardiomyocyte apoptosis and in the heart tissues of the offspring of diabetic rats in vitro and in vivo. Decreases in GSK3ß (Ser9) phosphorylation in response to HG were remarkably restored after treatment with SC79, an activator of the Akt signaling pathway. SB216763, an effective inhibitor of the GSK3ß signaling pathway, suppressed HG-induced apoptosis in cardiomyocytes. Further studies showed a decrease in the expression of the anti-apoptotic protein MCL-1 was associated with GSK3ß-mediated apoptosis. MCL-1 overexpression partly inhibits HG-induced apoptosis in cardiomyocytes. Herein, this study revealed the roles of GSK3ß and MCL-1 in modulating HG-induced cardiomyocyte apoptosis and maternal diabetes-induced abnormalities.
Assuntos
Apoptose , Glicemia/metabolismo , Diabetes Gestacional/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Cardiopatias Congênitas/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Gestacional/patologia , Feminino , Cardiopatias Congênitas/patologia , Masculino , Miócitos Cardíacos/patologia , Fosforilação , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Accumulated evidences show that neuroinflammation play a pivotal role in the pathogenesis of depression. Neuropeptide Y (NPY) and its receptors have been demonstrated to have anti-inflammative as well as antidepressant effects. In the present study, the ability of NPY to modulate depressive-like behaviors induced by lipopolysaccharides (LPS) in rats and the receptors and signaling mechanisms involved were investigated. Continuous injection LPS (i.p) for 4 days led to development of depressive-like behaviors in rats, accompanied with M1-type microglia activation and increased levels of IL-1ß as well as decreased levels of NPY and Y2R expression in the mPFC selectively. Local injection of NPY into the medial prefrontal cortex (mPFC) ameliorated the depression-like behaviors and suppressed the NLRP3 inflammasome signaling pathway. Y2R agonist PYY (3-36) mimicked and Y2R antagonist BIIE0246 abolished the NPY effects in the mPFC. All these results suggest that NPY and Y2R in the mPFC are involved in the pathophysiology of depression and NPY plays an antidepressant role in the mPFC mainly via Y2R, which suppresses the NLRP3 signaling pathway, in LPS-induced depression model rats.
Assuntos
Lipopolissacarídeos/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Animais , Western Blotting , Depressão/metabolismo , Interleucina-1beta/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacosRESUMO
Lens epithelial cell apoptosis is regarded as the common molecular basis of the initiation and subsequent progression of cataract. Recent studies have shown that Oxidative radicals derived from H2O2 causes lens epithelial cell apoptosis, While much work still needs to be done to elucidate this important mechanism of lens epithelial cell apoptosis induced by H2O2. The present study investigated the effect of human lens epithelial cell (SRA01/04) apoptosis induced by H2O2 and the possible molecular mechanism involved. Our data in this report has validated that H2O2 is an effective inducer of lens epithelial cells apoptosis, with the concentrations of H2O2 (100 µM). Moreover, we revealed that the down regulation of the GJA3 gene was associated with H2O2-induced lens epithelial cells apoptosis. Over-expression of GJA3 gene restrained the lens epithelial cells apoptosis induced by H2O2. Furthermore, GJA3 V44 M mutation partly inhibited the capacity of GJA3 to suppress apoptosis induced by H2O2 in SRA01/04 cells, eliciting the critical role of GJA3 in H2O2-induced lens epithelial cells apoptosis. The in vivo results indicated that down-regulation of GJA3 in lens epithelial cells was associated with age-related cataract genesis. Data from this study established the association of GJA3 down regulation with lens epithelial cells apoptosis and age-related cataract genesis.
Assuntos
Envelhecimento/patologia , Apoptose , Catarata/metabolismo , Conexinas/metabolismo , Regulação para Baixo , Cristalino/patologia , Animais , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Peróxido de Hidrogênio/metabolismo , Cristalino/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Gestational diabetes mellitus is a risk factor for congenital heart defects; however, the molecular basis of the congenital heart anomalies remains obscure. Previous reports showed a positive correlation between abnormal cardiomyocyte apoptosis and ventricular wall thinness, one type of congenital heart anomaly. This work explored the expression pattern and molecular mechanism of the Rho-associated coiled-coil containing protein kinase 1 (ROCK1) gene in cardiomyocyte apoptosis and genesis of ventricular wall thinness. In this report, we found a marked increase in the number of apoptotic cardiomyocytes in response to high glucose (HG) treatment. Moreover, up-regulation of ROCK1 expression observed in diabetic offspring compared with controls was potentially associated with cardiomyocyte apoptosis and the ventricular wall thinness. Further investigation showed that p53 and NOXA protein levels increased during ROCK1-meidated apoptosis in response to HG. In response to HG, whereby ROCK1 phosphorylated p53 at Ser15 to up-regulate its protein level. Furthermore, we found that p53 mediated the expression of NOXA during HG-induced apoptosis, and histone acetyltransferase p300 participated in this process. These findings reveal a novel regulatory mechanism of ROCK1/p53/NOXA signaling in modulating cardiomyocyte apoptosis in vitro and maternal diabetes-induced congenital heart defects in vivo.
Assuntos
Apoptose/efeitos dos fármacos , Glucose/farmacologia , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/biossíntese , Regulação para Cima/efeitos dos fármacos , Quinases Associadas a rho/biossíntese , Animais , Feminino , Glucose/metabolismo , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Masculino , Miócitos Cardíacos/patologia , Gravidez , Gravidez em Diabéticas/metabolismo , Gravidez em Diabéticas/patologia , RatosRESUMO
Gestational diabetes mellitus is a risk factor for abnormal heart development, but the molecular basis remains obscure. To further analyze this, the hyperglycemia rat and cell model were established in this study. The results showed that hyperglycemic rats gained significantly less weight during gestation than controls. The number of embryos per litter was significantly reduced in diabetic mothers compared to controls. Ventricular wall thickness was often decreased in the diabetic offspring and cardiomyocyte apoptosis participated in ventricular wall thinness. Our results also indicated that Cited2 expression decreased in the heart tissues of diabetic-exposed embryos comparing with the control. The vitro results showed that down-regulation of Cited2 was associated with high glucose-induced apoptosis in cardiomyocytes in vitro. Over-expression of Cited2 gene restrained the cardiomyocyte apoptosis induced by high glucose. Furthermore, Cited2 S192G mutation partly inhibited the capacity of Cited2 to suppress apoptosis induced by high glucose in cardiomyocytes. This showed the critical role of Cited2 in high glucose-induced cardiomyocytes apoptosis. Data from this study found the association of Cited2 down regulation with cardiomyocytes apoptosis and maternal diabetes-induced ventricular wall thinness genesis.
Assuntos
Diabetes Gestacional/metabolismo , Cardiopatias Congênitas/etiologia , Cardiopatias Congênitas/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Repressoras/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/fisiologia , Linhagem Celular , Células Cultivadas , Feminino , Cardiopatias Congênitas/patologia , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Masculino , Troca Materno-Fetal , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Proteínas Repressoras/genética , Fatores de Risco , Transativadores/genética , Fatores de Transcrição/genéticaRESUMO
Nerve growth factor (NGF) was first found in the central nervous system and is now well known for its multiple pivotal roles in the nervous system and immune system. However, more and more evidences showed that NGF and its receptors TrkA and p75 were also found in the head and tail of spermatozoa, which indicate the possible effect of NGF on the sperm motility. Nevertheless, the exact role of NGF in the human sperm motility remains unclear until now. In this study, we investigated the effect of NGF on human sperm motility, and the results showed that NGF could promote human sperm motility in vitro by increasing the movement distance and the number of A grade spermatozoa. Further analysis demonstrated that NGF promoted the sperm motility in a dose-dependent manner in vitro. These results may facilitate the further studies on human fertility and assisted reproduction techniques.
Assuntos
Fator de Crescimento Neural/farmacologia , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Humanos , Técnicas In Vitro , MasculinoRESUMO
Tanshinol (3-(3',4'-dihydroxyphenyl)-(2R)-lactic acid, TSL) is widely used in traditional Chinese medicine for the treatment of cardiovascular and cerebrovascular diseases. Here, we assessed whether TSL protected hippocampus and attenuated vascular dementia (VD) development in rats. The behavioral analysis showed that TSL could decrease the distance and latency time, and increase the swim speed in water maze in rats subjected to VD. TSL remarkably increased acetylcholine level and decreased acetylcholinesterase activity in rats subjected to VD. Likewise, TSL remarkably decreased malondialdehyde and increased superoxide dismutase levels in rats subjected to VD. Furthermore, treatment with TSL reduced the level of dead neurons in dentate gyrus. In addition, TSL upregulated growth-associated protein 43 (GAP43) and vascular endothelial growth factor (VEGF) expression and downregulated phosphorylated Akt (p-AKt) and phosphorylated glycogen synthase kinase (p-GSK3ß) expression in hippocampus in rats subjected to VD. These results suggest that TSL may be a potential compound in VD model.
Assuntos
Ácidos Cafeicos/farmacologia , Demência Vascular/tratamento farmacológico , Hipocampo/metabolismo , Animais , Apoptose/fisiologia , Ácidos Cafeicos/química , Modelos Animais de Doenças , Masculino , Malondialdeído/análise , Malondialdeído/sangue , Malondialdeído/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Medicina Tradicional Chinesa , Memória/efeitos dos fármacos , Estrutura Molecular , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/análise , Superóxido Dismutase/sangue , Superóxido Dismutase/metabolismoRESUMO
The normal aging process is accompanied by cognitive decline, and previous studies have indicated the crucial role of the hypothalamus in regulating both aging and cognition. However, the precise molecular mechanism underlying this relationship remains unclear. Therefore, this present study aimed to identify potential predictors of cognitive decline associated with aging specifically within the hypothalamus. To achieve this, we employed Morris water maze (MWM) testing to assess learning and memory differences between young and aged mice. Additionally, transcriptome sequencing was conducted on the hypothalamus of young and aged mice to identify potential genes. Subsequently, GO and KEGG analyses were performed to investigate the functions of differentially expressed genes (DEGs) and their associated biological pathways. Finally, the results obtained from sequencing analysis were further validated using qRT-PCR. Notably, MWM testing revealed a significant decrease in spatial learning and memory ability among aged mice. According to KEGG analysis, the DEGs primarily encompassed various biochemical signaling pathways related to immune system (e.g., C3; C4b; Ccl2; Ccl7; Cebpb; Clec7a; Col3a1; Cxcl10; Cxcl2; Fosb; Fosl1; Gbp5; H2-Ab1; Hspa1a; Hspa1b; Icam1; Il1b; Itga5; Itgax; Lilrb4a; Plaur; Ptprc; Serpine1; Tnfrsf10b; Tnfsf10), neurodegenerative disease (e.g., Atp2a1; Creb5; Fzd10; Hspa1a; Hspa1b; Il1b; Kcnj10; Nxf3; Slc6a3; Tubb6; Uba1y; Wnt9b), nervous system function (e.g., Chrna4; Chrna6; Creb5; Slc6a3),and aging (e.g., Creb5; Hspa1a; Hspa1b) among others. These identified genes may serve as potential predictors for cognitive function in elderly individuals and will provide a crucial foundation for further exploration into the underlying molecular mechanisms.
Assuntos
Disfunção Cognitiva , Doenças Neurodegenerativas , Humanos , Camundongos , Animais , Idoso , Perfilação da Expressão Gênica , Envelhecimento/genética , Disfunção Cognitiva/genética , Hipotálamo , TranscriptomaRESUMO
PURPOSE: We assessed whether tetramethylpyrazine (TMP), an active ingredient of Ligusticum wallichii Franchat, attenuates atherosclerosis (AS) development in rabbits and protects endothelial cells injured by ox-LDL. METHODS: In vivo, rabbits subjected to atherosclerosis were treated with TMP (75 and 150 mg/kg) by oral gavage for 12 weeks. In vitro, rat aortic endothelial cells (RAECs) were stimulated by ox-LDL. RESULTS: TMP treatment with 75 and 150 mg/kg significantly reduced the relative atherosclerosis area ratio in the aorta (0.41 ± 0.042, 0.27 ± 0.047 vs. 0.66 ± 0.058 in AS), the ratio of intimal/medial thickness (0.54 ± 0.09, 0.39 ± 0.07 vs. 1.1 ± 0.3 in AS) and the number of monocytes in intimal (10.1 ± 2.8, 8.2 ± 2.0 vs. 14.1 ± 4.9 counts/mm(2) in AS). TMP also decreased levels of TC (15 ± 4.2 to 6.1 ± 1.2 mmol/L), TG (1.8 ± 0.3 to 1.08 ± 0.24 mmol/L), LDL-C (20.1 ± 4.3 to 10.2 ± 1.6 mmol/L) and increased HDL-C levels (0.40 ± 0.08 to 0.85 ± 0.17 mmol/L) in atherosclerosis rabbit plasma. TMP decreased the MCP-1 (187.3 ± 38.4 to 86.1 ± 17.2 pg/ml) and ICAM-1 (350.6 ± 43.7 to 260.6 ± 46.1 pg/ml) levels in plasma and inhibited LOX-1 expression in the rabbit aortas. Moreover, our in vitro study revealed that TMP suppressed monocyte adhesion to RAECs, inhibited RAEC migration, and down-regulated MCP-1 and ICAM-1 expression in ox-LDL-injured RAECs. Likewise, TMP inhibited LOX-1 and 5-LOX expression, and prevented nuclear accumulation of RelA/p65 and IκB degradation in ox-LDL-injured RAECs. Furthermore, TMP suppressed ox-LDL-induced activations of p-ERK, p-p38, and p-JNK MAPK. CONCLUSION: TMP produces a tangible protection in atherosclerosis and endothelial cells. TMP might be a potential protective agent for atherosclerosis.
Assuntos
Aterosclerose/prevenção & controle , Células Endoteliais/efeitos dos fármacos , Lipoproteínas LDL/efeitos adversos , Placa Aterosclerótica/prevenção & controle , Pirazinas/uso terapêutico , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/patologia , Aterosclerose/sangue , Aterosclerose/patologia , Adesão Celular/efeitos dos fármacos , Técnicas de Cultura de Células , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Colesterol/sangue , Colesterol na Dieta/administração & dosagem , Modelos Animais de Doenças , Imuno-Histoquímica , Ligusticum/química , Masculino , Placa Aterosclerótica/sangue , Placa Aterosclerótica/patologia , Pirazinas/administração & dosagem , Pirazinas/isolamento & purificação , Coelhos , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangueRESUMO
Diabetes mellitus causes an increased incidence of congenital heart malformations. However, the pathogenesis and potential epigenetic mechanism involved in this process are unclear. In this study, we used MethylRAD sequencing to compare changes in methylation levels in the genomic landscapes in the fetal heart in a rat model of hyperglycemia. Our results showed that methylation of CCGG/CCNGG sites were mostly enriched in intergenic regions, followed by intron, exon, upstream and the 5' and 3' untranslated regions. qRT-PCR results confirmed the MethylRAD sequencing findings, suggesting that abnormal CCGG/CCNGG methylation in the upstream region regulated gene expression. The differential methylation genes (DMGs) based on the CCGG and CCNGG sites in the upstream region were examined by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Gene Ontology indicated that the CCGG-based DMGs involved in biological process and function were mainly related to transcription and co-SMAD binding. The CCNGG-based DMGs were mainly related to transcription and cytokine-mediated signaling pathways. Kyoto Encyclopedia of Genes and Genomes analysis indicated that CCGG-based DMGs were mainly involved in the Wnt signaling and TGF-ß signaling pathways. CCNGG-based DMGs were involved in the TNF signaling and apoptosis pathways. These genes may play dominant roles in cardiomyocyte apoptosis and heart disease and require further study. These genes may also serve as potential molecular targets or diagnostic biomarkers for heart malformations under hyperglycemia.
Assuntos
Metilação de DNA , Hiperglicemia , Animais , Epigênese Genética , Coração Fetal , Hiperglicemia/genética , Ratos , Análise de Sequência de DNARESUMO
Objective: The objective of this study is to reduce the dimension of several indicators with a strong correlation when conducting semen quality analysis in a small number of comprehensive variables that could retain most of the information in the original variables. Methods: A total of 1132 subjects were recruited from the Maternal and Child Health Institutions of seven provinces in mainland China. They completed the questionnaire and provided semen samples. Visualization of the correlation between variables was realized by using a function chart and correlation in the PerformanceAnalytics package of the R programming language (version 3.6.3 [2020-02-29]). Factor analysis was conducted using the principal function in the psych package of R. Principal component analysis, combined with varimax rotation, was used in the operation of the model, and two common factors were selected and measured to provide values for the common factor. The score coefficient was estimated using the regression method. Results: The contribution rates of the two common factors to variable X were 43.7% and 33.98%, respectively. When the two common factors were selected, approximately 78% of the information of the original variables could be explained. The correlation coefficients between the first common factor (the quantitative factor) and sperm density, total sperm count, and semen volume were 0.824, 0.984, and 0.544, respectively. The correlation coefficients between the second common factor (the quality factor) and sperm motility and the percentage of forward-moving (progressive spermatozoa) sperm were 0.978 and 0.976, respectively. Conclusion: The correlation between the original variables of a semen quality analysis was strong and suitable for dimensionality reduction by factor analysis. Factor analysis and dimensionality reduction provide a fast and accurate assessment of semen quality. Patients with low fertility or infertility can be identified and provided with corresponding treatments.
RESUMO
Objective: To establish a system for evaluation of semen quality in fertile men by factor analysis (FA). Methods: The FA method was used to analyze five sperm test indicators for fertile men (sperm pH, sperm motility, sperm progressive motility, semen density, and total sperm number) to determine the evaluation standard of semen quality. Pearson analysis was adopted for correlation testing. Results: The comprehensive score formula for semen quality of normal fertile men was as follows: comprehensive score of semen quality = (0.38272 F1 + 0.36359 F2 + 0.20018 F 3)/94.699. Across the whole fertile population, semen quality was found to be correlated with abstinence period, age of first spermatorrhea, and frequency of intercourse. Smoking, drinking, and place of residence were correlated with semen quality in the high semen quality population. In the population with medium semen quality, only the abstinence period was associated with semen quality. Conclusion: It is feasible to evaluate the semen quality of fertile men using the FA method. The comprehensive indicators of semen volume, sperm motility, and semen pH can be used as evaluative measures. Across the whole fertile population, the abstinence period and age of first spermatorrhea were correlated with semen quality. In the high semen quality population, smoking and drinking were negatively correlated with semen quality, and participants living in rural areas had better semen quality.
RESUMO
Many works showed that nerve growth factor (NGF) injected into the brain of animal model emerges potential antidepressant effects. However, this route of administration significantly restricts the application of NGF clinically. Here, we reported that intranasal NGF could provide an alternative to intraventricular injection. The behavioral analysis showed that intranasal administration of NGF reduced the immobility time in forced swimming test (FST) and tail suspension test (TST) in mice. Likewise, intranasal NGF increased the sucrose intake and the locomotor activity in rats after unpredictable chronic mild stress (UCMS). Furthermore, intranasal NGF increased the levels of monoamine neurotransmitters (norepinephrine, dopamine) in the frontal cortex and hippocampus and affected the number of 5-bromodeoxyuridine (BrdU), c-fos and caspase-3 positive neurons in dentate gyrus of hippocampus in rats after UCMS. In summary, intranasal NGF had significant antidepressant effects on animal models of depression and this route of administration may provide a promising way to deliver NGF to brain in a therapeutic perspective.
Assuntos
Administração Intranasal , Antidepressivos , Comportamento Animal/efeitos dos fármacos , Fator de Crescimento Neural , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Monoaminas Biogênicas/análise , Química Encefálica , Caspase 3/metabolismo , Elevação dos Membros Posteriores , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Fator de Crescimento Neural/administração & dosagem , Fator de Crescimento Neural/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Testes Neuropsicológicos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Psicológico , SacaroseRESUMO
Background: Carotid artery stenosis (CAS), typically resulting from atherosclerotic progression, is more common than intracranial atherosclerotic disease in patients with cerebrovascular disease. Prior literature has incompletely established the relationship of Pentraxin 3 (PTX3) and CAS complexity and severity. This study aims to more thoroughly evaluate the association of plasma PTX3 levels and the prevalence and severity of CAS in patients with cerebrovascular disease. Methods: Two hundred and six patients with ischemic stroke underwent multiphase computerized tomography angiography (CTA) of the head and neck to assess the presence and severity of carotid artery stenosis. Patients were divided into groups with either no carotid artery stenosis (CAS-free) or carotid artery stenosis (CAS). The CAS group was further divided into groups based on the degree of stenosis and the number of involved vessels. The PTX3 and Tumor Necrosis Factor-alpha (TNF-α) concentration were measured by ELISA. Results: Plasma levels of PTX3, TNF-α, and low-density lipoprotein cholesterol (LDL-C) were increased significantly in the CAS group patients vs. the CAS-free group (p = 0.000, 0.002, 0.002, respectively). Within the CAS group, PTX3, TNF-α, and LDL-C were significantly elevated in stenosis of ≥50% group compared to <50% group (p = 0.001, 0.002, 0.049, respectively). The multivariate logistic binary regression analysis revealed that increased age, elevated levels of PTX3, LDL-C, and TNF-α were all independent risk factors for occurrence of carotid stenosis. PTX3 level correlated with the severity of carotid stenosis. Conclusions: High plasma PTX3 levels, TNF-α, and LDL-C are significantly correlated with the prevalence and severity of carotid artery stenosis. PTX3 may be a more powerful predictor for the severity of carotid artery stenosis.