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1.
Placenta ; 158: 165-174, 2024 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-39476475

RESUMO

BACKGROUND: Placenta plays a vital role in preeclampsia. The present study investigated the role of endothelin-1 (ET-1) and its receptors in preeclampsia placenta. METHOD: Placenta samples were collected from normal and preeclampsia pregnancies, with one single fetus. Placental chorionic plate vessel tone was measured with DMT using vasoactive agents with or without antagonists. Role of L-type voltage-dependent calcium channels (CaV1.2) in single smooth muscle cell was detected using whole-cell patch clamp. PCR, Western blot, and ELISA was used to detect molecule expressions. Placental vessel explants and human umbilical vein smooth muscle cell (HUVSMC) were exposed to ET-1 treatment with or without antagonists. Human umbilical vein endothelial cell (HUVEC) and pregnant sheep was exposed to hypoxic condition, simulating preeclampsia. RESULTS: ET-1 and IRL1620 mediated stronger contractions in preeclampsia placental veins, despite unchanged ETAR and decreased ETBR expression. Comparing with control, there was higher ET-1 in umbilical plasma, maternal plasma, and placental vessels from preeclampsia. In utero hypoxia increased plasma ET-1 in fetal lambs and ewes. Hypoxia promoted ET-1 production in HUVEC. Role and expression of CaV1.2 was decreased in preeclampsia placental vessels, while high-molecular-weight caldesmon (CALD1), the marker of contractile phenotype of smooth muscle cells, was significantly increased. ET-1 treatment increased CALD1 in placental explants and in HUVSMC via ETAR/ETBR. CONCLUSION: The present study firstly demonstrated ET-1 induced greater contraction in preeclampsia placental chorionic plate veins via ETAR/ETBR, instead of via weaker CaV1.2. In utero hypoxia promoted plasma ET-1 in fetal lambs and ewe, similar to that in preeclampsia. ET-1, binding with ETAR/ETBR increased CALD1, which was associated with stronger contraction in preeclampsia. The data provided important information in preeclampsia onset.

2.
J Nutr Sci ; 13: e67, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39473435

RESUMO

Perinatal malnutrition is a critical cause of diseases in offspring. Based on the different rates of organ development, we hypothesised that malnutrition at varying early life stages would have a differential impact on cardiovascular disease in middle-aged and older adults. This study sought to assess the long-term impact of exposure to the 1959-1961 Great Chinese Famine (GCF) during early developmental periods on risks of cardiovascular diseases in the late middle-aged offspring. A total 6, 662 individuals, born between 1958 and 1964, were divided into six groups according to the birth date. The generalised line model was used to control age and estimate differences with 95% confidence interval (CI) in blood pressure. Binary logistic regression was applied to evaluate the association between famine exposure and cardiovascular diseases. Compared to the unexposed late middle-aged persons, blood pressure was elevated in the entire gestation exposure group, regardless of postnatal exposure to GCF. Increased blood pressure was also found in the female offspring exposed to GCF during early and middle gestation. The early-childhood exposure was associated with the risk of bradycardia in the offspring. The risks of vertebral artery atherosclerosis were elevated in GCF famine-exposed groups except first trimester exposed group. The chronic influence of GCF in early life periods was specific to the developmental timing window, sexesand organs, suggesting an essential role of interactions among multiple factors and prenatal malnutrition in developmentally "programming" cardiovascular diseases.


Assuntos
Pressão Sanguínea , Doenças Cardiovasculares , Fome Epidêmica , Efeitos Tardios da Exposição Pré-Natal , Humanos , Feminino , Doenças Cardiovasculares/epidemiologia , Gravidez , Masculino , China/epidemiologia , Pessoa de Meia-Idade , Fatores de Risco , Lactente , Bradicardia/epidemiologia , Desnutrição , Modelos Logísticos , Hipertensão/epidemiologia , População do Leste Asiático
3.
Hypertension ; 81(11): 2368-2382, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39291377

RESUMO

BACKGROUND: Calcium deficiency in women is strongly linked to an increased risk of developing preeclampsia. Mitochondrial calcium ([Ca2+]m) homeostasis is essential to regulate vascular smooth muscle cell (VSMC) function. However, the role of [Ca2+]m in preeclampsia development remains largely unknown. METHODS: To investigate this, human spiral arteries obtained from normotensive and preeclamptic women were collected for vascular function, RNA sequencing, and VSMC studies. N(ω)-nitro-L-arginine methyl ester-induced preeclampsia animal experiments were established to investigate the effects of intervening in [Ca2+]m to improve the outcome for preeclamptic mothers or their infants. RESULTS: Our initial findings revealed compromised vessel function in spiral arteries derived from patients with preeclampsia, as evidenced by diminished vasoconstriction and vasodilation responses to angiotensin II and sodium nitroprusside, respectively. Moreover, the spiral artery VSMCs from patients with preeclampsia exhibited phenotypic transformation and proliferation associated with the disrupted regulatory mechanisms of [Ca2+]m uptake. Subsequent in vitro experiments employing gain- and loss-of-function approaches demonstrated that the mitochondrial Na+/Ca2+ exchanger played a role in promoting phenotypic switching and impaired mitochondrial functions in VSMCs. Furthermore, mtNCLX (mitochondrial Na+/Ca2+ exchanger) inhibitor CGP37157 significantly improved VSMC phenotypic changes and restored mitochondrial function in both patients with preeclampsia-derived VSMCs and the preeclampsia rat model. CONCLUSIONS: This study provides comprehensive evidence supporting the disrupted regulatory mechanisms of [Ca2+]m uptake in VSMCs of spiral arteries of patients with preeclampsia and further elucidates its correlation with VSMC phenotypic switching and defective spiral artery remodeling. The findings suggest that targeting mtNCLX holds promise as a novel therapeutic approach for managing preeclampsia.


Assuntos
Cálcio , Mitocôndrias , Músculo Liso Vascular , Pré-Eclâmpsia , Remodelação Vascular , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/metabolismo , Feminino , Gravidez , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Animais , Cálcio/metabolismo , Mitocôndrias/metabolismo , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/fisiologia , Ratos , Adulto , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Artérias/metabolismo , Artérias/fisiopatologia , Artérias/efeitos dos fármacos , Artérias/patologia , Modelos Animais de Doenças , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Trocador de Sódio e Cálcio/metabolismo
4.
Toxicol Appl Pharmacol ; 489: 117019, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38950736

RESUMO

Maternal hypoxia is strongly linked to insulin resistance (IR) in adult offspring, and altered insulin signaling for muscle glucose uptake is thought to play a central role. However, whether the SIRT3/GSK-3ß/GLUT4 axis is involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring has not been investigated. Maternal hypoxia was established from Days 5 to 21 of pregnancy by continuous infusion of nitrogen and air. The biochemical parameters and levels of key insulin signaling molecules of old male rat offspring were determined through a series of experiments. Compared to the control (Ctrl) old male rat offspring group, the hypoxic (HY) group exhibited elevated fasting blood glucose (FBG) (∼30%), fasting blood insulin (FBI) (∼35%), total triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), as well as results showing impairment in the glucose tolerance test (GTT) and insulin tolerance test (ITT). In addition, hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) revealed impaired cellular structures and mitochondria in the longitudinal sections of skeletal muscle from HY group mice, which might be associated with decreased SIRT3 expression. Furthermore, the expression of insulin signaling molecules, such as GSK-3ß and GLUT4, was also altered. In conclusion, the present results indicate that the SIRT3/GSK-3ß/GLUT4 axis might be involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring.


Assuntos
Transportador de Glucose Tipo 4 , Glicogênio Sintase Quinase 3 beta , Hipóxia , Resistência à Insulina , Músculo Esquelético , Sirtuína 3 , Animais , Masculino , Glicogênio Sintase Quinase 3 beta/metabolismo , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Feminino , Transportador de Glucose Tipo 4/metabolismo , Gravidez , Sirtuína 3/metabolismo , Ratos , Hipóxia/metabolismo , Transdução de Sinais , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos Sprague-Dawley , Insulina/sangue , Insulina/metabolismo , Glicemia/metabolismo , Sirtuínas
5.
Front Immunol ; 15: 1357378, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38720885

RESUMO

Exosomes carry proteins, metabolites, nucleic acids and lipids from their parent cell of origin. They are derived from cells through exocytosis, are ingested by target cells, and can transfer biological signals between local or distant cells. Therefore, exosomes are often modified in reaction to pathological processes, including infection, cancer, cardiovascular diseases and in response to metabolic perturbations such as obesity and diabetes, all of which involve a significant inflammatory aspect. Here, we discuss how immune cell-derived exosomes origin from neutrophils, T lymphocytes, macrophages impact on the immune reprogramming of diabetes and the associated complications. Besides, exosomes derived from stem cells and their immunomodulatory properties and anti-inflammation effect in diabetes are also reviewed. Moreover, As an important addition to previous reviews, we describes promising directions involving engineered exosomes as well as current challenges of clinical applications in diabetic therapy. Further research on exosomes will explore their potential in translational medicine and provide new avenues for the development of effective clinical diagnostics and therapeutic strategies for immunoregulation of diabetes.


Assuntos
Diabetes Mellitus , Exossomos , Imunomodulação , Exossomos/imunologia , Exossomos/metabolismo , Humanos , Diabetes Mellitus/imunologia , Diabetes Mellitus/terapia , Animais , Macrófagos/imunologia , Macrófagos/metabolismo
6.
Addict Biol ; 29(3): e13385, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38488472

RESUMO

Alcohol consumption is popular worldwidely and closely associated with cardiovascular diseases. Influences of paternal preconception alcohol consumption on offspring cerebral arteries are largely unknown. Male rats were randomly given alcohol or water before being mated with alcohol-naive females to produce alcohol- and control-sired offspring. Middle cerebral artery (MCA) was tested with a Danish Myo Technology wire myograph, patch-clamp, IONOPTIX, immunofluorescence and quantitative PCR. Alcohol consumption enhanced angiotensin II (AngII)-mediated constriction in male offspring MCA mainly via AT1R. PD123,319 only augmented AngII-induced constriction in control offspring. AngII and Bay K8644 induced stronger intracellular calcium transient in vascular smooth muscle cells (VSMCs) from MCA of alcohol offspring. L-type voltage-dependent calcium channel (L-Ca2+ ) current at baseline and after AngII-stimulation was higher in VSMCs. Influence of large-conductance calcium-activated potassium channel (BKC a ) was lower. Caffeine induced stronger constriction and intracellular calcium release in alcohol offspring. Superoxide anion was higher in alcohol MCA than control. Tempol and thenoyltrifluoroacetone alleviated AngII-mediated contractions, while inhibition was significantly higher in alcohol group. The mitochondria were swollen in alcohol MCA. Despite lower Kcnma1 and Prkce expression, many genes expressions were higher in alcohol group. Hypoxia induced reactive oxygen species production and increased AT1R expression in control MCA and rat aorta smooth muscle cell line. In conclusion, this study firstly demonstrated paternal preconception alcohol potentiated AngII-mediated vasoconstriction in offspring MCA via ROS-AT1R. Alcohol consumption increased intracellular calcium via L-Ca2+ channel and endoplasmic reticulum and decreased BKCa function. The present study provided new information for male reproductive health and developmental origin of cerebrovascular diseases.


Assuntos
Angiotensina II , Vasoconstrição , Feminino , Ratos , Masculino , Animais , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Cálcio/metabolismo , Artérias Cerebrais/metabolismo , Consumo de Bebidas Alcoólicas , Estresse Oxidativo
7.
Hypertension ; 81(2): 240-251, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37795601

RESUMO

BACKGROUND: Cigarette smoking/nicotine exposure in pregnancy shows an increased risk of hypertension in offspring, but the mechanisms are unclear. This study tested the hypothesis that m6A RNA hypomethylation epigenetically regulates vascular NOX (NADPH oxidase) and reactive oxygen species production, contributing to the fetal programming of a hypertensive phenotype in nicotine-exposed offspring. METHODS: Pregnant rats were exposed to episodic chronic intermittent nicotine aerosol (CINA) or saline aerosol control from gestational day 4 to day 21, and experiments were performed in 6-month-old adult offspring. RESULTS: Antenatal CINA exposure augmented Ang II (angiotensin II)-stimulated blood pressure response in male, but not female offspring. Moreover, CINA increased vascular NOX2 expression and superoxide production exclusively in male offspring. Inhibition of NOX2 with gp91ds-tat, both ex vivo and in vivo, mitigated the CINA-induced elevation in superoxide production and blood pressure response. Notably, CINA enhanced the expression of vascular m6A demethylase FTO (fat mass and obesity-associated protein), while reducing the total vascular m6A abundance and specific m6A methylation of the NOX2 gene. Additionally, ex vivo inhibition of FTO with FB23-2 attenuated CINA-induced increases in vascular NOX2 expression. In vitro experiments using human umbilical vein endothelial cells demonstrated that nicotine dose-dependently upregulated FTO and NOX2 protein abundance, which were reversed by treatment with the FTO inhibitor FB23-2 or FTO knockdown using siRNAs. CONCLUSIONS: This study uncovers a new mechanism: m6A demethylase FTO-mediated epigenetic upregulation of vascular NOX2 signaling in CINA-induced hypertensive phenotype. This insight could lead to a therapeutic target for preventing and treating developmental hypertension programming.


Assuntos
Hipertensão , Nicotina , Gravidez , Ratos , Masculino , Feminino , Animais , Humanos , Lactente , Nicotina/farmacologia , Pressão Sanguínea , Espécies Reativas de Oxigênio/metabolismo , Superóxidos , Células Endoteliais/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Aerossóis/efeitos adversos , Dioxigenase FTO Dependente de alfa-Cetoglutarato
9.
Mol Nutr Food Res ; 67(23): e2300401, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37863820

RESUMO

SCOPE: High salinity has been reported to induce many human disorders in tissues and organs to interfere with their normal physiological functions. However, it is unknown how salinity affects the development of female germ cells. This study suggests that a high-salt diet (HSD) may weaken oocyte quality to impair female fertility in mice and investigates the underlying mechanisms. METHODS AND RESULTS: C57BL/6 female mice are fed with a regular diet (Control) or a high-salt diet (HSD). Oocyte maturation, fertilization rate, embryonic development, and female fertility are evaluated. In addition, the spindle organization, actin polymerization, and kinetochore-microtubule attachment of oocytes are examined in both groups. Moreover, single-cell transcriptome data are used to demonstrate how HSD alters the transcript levels of genes. The observations confirm that HSD leads to female subfertility due to the deterioration of oocyte and embryo quality. The mechanism underlying reveals HSD compromises the oocytes' autophagy, apoptosis level, and mitochondrial function. CONCLUSION: The work illustrates that a high concentration of salt diet results in oocyte meiotic arrest, fertilization failure, and early developmental defection that embryos undergo to reduce female fertility in mice by perturbing the level of autophagy and apoptosis, mitochondrial function in oocytes.


Assuntos
Desenvolvimento Embrionário , Oócitos , Gravidez , Feminino , Humanos , Animais , Camundongos , Camundongos Endogâmicos C57BL , Dieta , Fertilidade
10.
Methods Mol Biol ; 2695: 263-277, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37450125

RESUMO

Preeclampsia (PE) remains a leading cause of maternal and fetal mortality, due to ineffective treatment and diagnostic strategies, compounded by the lack of clarity on the etiology of the disorder. The early prediction or accurate diagnosis of PE is a concern of researchers. Liquid biopsy can be analyzed for cell-free nucleic acids and exosomes. Because circulating non-coding RNAs (ncRNAs) and peripheral blood exosomes can be detected in the peripheral blood of women in early pregnancy, these vesicles and their contents have become the focus of research on early predictive and diagnostic biomarkers for preeclampsia. In this review, we focus on recent studies addressing the roles of circulating ncRNAs and exosomes in PE, with particular attention paid to the potential application value of placenta-derived exosomes and circulating ncRNAs as PE-specific biomarkers.


Assuntos
Ácidos Nucleicos Livres , Exossomos , Pré-Eclâmpsia , Gravidez , Humanos , Feminino , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/genética , Exossomos/genética , Exossomos/patologia , Biópsia Líquida , Biomarcadores , Ácidos Nucleicos Livres/genética
11.
Reprod Biol Endocrinol ; 21(1): 54, 2023 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-37312191

RESUMO

OBJECTIVE: In vitro fertilization-embryo transfer (IVF-ET) technologies (especially frozen ET) have been widely used, which might affect maternal and fetal health. Information regarding influence of IVF-ET on the vasoconstriction of human umbilical vein (HUV) is limited. This study determined effects of frozen ET on histamine-mediated vascular responses in HUV and related mechanisms. METHODS AND RESULTS: HUVs were collected from frozen ET conceived pregnancy and spontaneously conceived pregnancy (control). Histamine concentration in umbilical plasma was higher in frozen ET group than the control. Histamine-mediated contractile response curve was left-shifted in the frozen ET group when comparing with the control. In isolated HUV rings, H1R showed a critical role in regulating vascular constriction, while H2R played little roles in regulating vessel tone. Iberiotoxin and 4-aminopyridine didn't significantly change histamine-mediated constriction in HUVs. Histamine-induced vasoconstrictions were significantly decreased by nifedipine, KN93, or GF109203X, while the inhibitory effects were significantly greater in the frozen ET group in comparison to the control. The constrictions by Bay K8644, phenylephrine, or PDBu were stronger in frozen ET, respectively. There was a decrease in the protein expressions of H1R and H2R, an increase in protein expressions of BKCaα and PKCß. CONCLUSIONS: Histamine-induced constriction in HUV was mainly via H1R. The increased sensitivity to histamine in HUV following frozen ET cycles were linked to the enhanced PKCß protein expression and function. The new data and findings in this study provide important insight into influences of frozen ET on fetal vessel development and potential influence in long-term.


Assuntos
Fertilização in vitro , Histamina , Feminino , Gravidez , Humanos , Histamina/farmacologia , Veias Umbilicais , Transferência Embrionária , 4-Aminopiridina
12.
Mol Nutr Food Res ; 67(17): e2200722, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37366318

RESUMO

SCOPE: Perinatal high-fat diets (PHF) can influence fetal/neonate development, resulting in cardiovascular pathogenesis, but precise mechanisms remain unclear. This study tests aldosterone receptor-mediated Ca2+ influx and the underlying mechanisms influenced by PHF. METHODS AND RESULTS: Maternal S.D. rats receive PHF during pregnancy and lactation periods. Their male offspring are fed normal diets after weaning for four months. Mesenteric arteries (MA) are for electrophysiological testing, Ca2+ imaging, target gene expression, and promotor methylation. PHF increases aldosterone receptor gene Nr3c2-mediated Ca2+ currents in the smooth muscle cells (SMCs) of the MA via L-type Ca2+ channels (LTCC) in the offspring. The increased expression of aldosterone-receptors and LTCC are responsible for an activated Nr3c2-LTCC pathway in the vasculature, eventually predisposes an increase of Ca2+ influx in the myocytes of resistance arteries. The inhibitor of aldosterone-receptors suppresses the increased Ca2+ currents in the SMCs. Nr3c2 and LTCC are upregulated through the transcriptional mechanism in methylation, which can be reversed in the functional changes by methylation inhibitor 5AZA. CONCLUSION: The results firstly demonstrate that aldosterone-receptor activation can stimulate Ca2+ currents via LTCC in vascular myocytes, which can be altered by perinatal foods via epigenetic changes of DNA methylation in the promoters of Nr3c2 and LTCC.


Assuntos
Aldosterona , Receptores de Mineralocorticoides , Gravidez , Feminino , Ratos , Masculino , Animais , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Aldosterona/farmacologia , Aldosterona/metabolismo , Artérias Mesentéricas/fisiologia , Metilação de DNA , Dieta , Miócitos de Músculo Liso/metabolismo
13.
Front Endocrinol (Lausanne) ; 14: 1182636, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37293496

RESUMO

Objective: Endothelial functions in controlling blood flow in placental circulation are still unclear. The present study compares vascular dilations between placental circulation and other vessels, as well as between normal and preeclampsia placental vessels. Methods: Placental, umbilical, and other vessels (cerebral and mesenteric arteries) were collected from humans, sheep, and rats. Vasodilation was tested by JZ101 and DMT. Q-PCR, Western blot, and Elisa were used for molecular experiments. Results: Endothelium-dependent/derived vasodilators, including acetylcholine, bradykinin, prostacyclin, and histamine, mediated no or minimal dilation in placental circulation, which was different from that in other vessels in sheep and rats. There were lower mRNA expressions of muscarinic receptors, histamine receptors, bradykinin receptor 2, endothelial nitric oxide synthesis (eNOS), and less nitric oxide (NO) in human umbilical vessels when compared with placental vessels. Exogenous NO donors (sodium nitroprusside, SNP) and soluble guanylate cyclase (sGC) activators (Bay41-2272) decreased the baseline of vessel tone in placental circulation in humans, sheep, and rats, but not in other arteries. The sGC inhibitor ODQ suppressed the reduced baseline caused by the SNP. The decreased baseline by SNP or Bay41-2272 was higher in placental vessels than in umbilical vessels, suggesting that the role of NO/sGC is more important in the placenta. NO concentrations in preeclampsia placental vessels were lower than those in control, while no significant change was found in umbilical plasma between the two groups. eNOS expression was similar between normal and preeclampsia placental vessels, but phosphorylated eNOS levels were significantly lower in preeclampsia. Following serotonin, SNP or Bay41-2272-mediated dilations were weaker in preeclampsia placental vessels. The decreased amplitude of SNP- or Bay41-2272 at baseline was smaller in preeclampsia. The decreased amplitudes of ODQ + SNP were comparable between the two groups. Despite higher beta sGC expression, sGC activity in the preeclampsia placenta was lower. Conclusion: This study demonstrated that receptor-mediated endothelium-dependent dilation in placental circulation was significantly weaker than other vessels in various species. The results, showed firstly, that exogenous NO played a role in regulating the baseline tone of placental circulation via sGC. Lower NO production and decreased NO/sGC could be one of the reasons for preeclampsia. The findings contribute to understanding specific features of placental circulation and provide information about preeclampsia in placental vessels.


Assuntos
Óxido Nítrico , Pré-Eclâmpsia , Feminino , Ratos , Humanos , Gravidez , Ovinos , Animais , Óxido Nítrico/metabolismo , Placenta/metabolismo , Circulação Placentária , Dilatação , Guanilato Ciclase/metabolismo , Histamina
14.
Molecules ; 28(9)2023 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-37175308

RESUMO

A novel dual-response fluorescence probe (XBT-CN) was developed by using a fluorescence priming strategy for quantitative monitoring and visualization of hydrazine (N2H4) and hypochlorite (ClO-). With the addition of N2H4/ClO-, the cleavage reaction of C=C bond initiated by N2H4/ClO- was transformed into corresponding hydrazone and aldehyde derivatives, inducing the probe XBT-CN appeared a fluorescence "off-on" response, which was verified by DFT calculation. HRMS spectra were also conducted to confirm the sensitive mechanism of XBT-CN to N2H4 and ClO-. The probe XBT-CN had an obvious fluorescence response to N2H4 and ClO-, which caused a significant color change in unprotected eyes. In addition, the detection limits of XBT-CN for N2H4 and ClO- were 27 nM and 34 nM, respectively. Interference tests showed that other competitive analytes could hardly interfere with the detection of N2H4 and ClO- in a complex environment. In order to realize the point-of-care detection of N2H4 and ClO-, an XBT-CN@hydrogel test kit combined with a portable smartphone was developed. Furthermore, the portable test kit has been applied to the detection of N2H4 and ClO- in a real-world environment and food samples, and a series of good results have been achieved. Attractively, we demonstrated that XBT-CN@hydrogel was successfully applied as an encryption ink in the field of information security. Finally, the probe can also be used to monitor and distinguish N2H4 and ClO- in living cells, exhibiting excellent biocompatibility and low cytotoxicity.


Assuntos
Hidrogéis , Ácido Hipocloroso , Ácido Hipocloroso/química , Sistemas Automatizados de Assistência Junto ao Leito , Espectrometria de Fluorescência/métodos , Corantes Fluorescentes/química , Hidrazinas
15.
J Pers Med ; 13(2)2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36836398

RESUMO

Perinatal malnutrition affects postnatal cardiovascular functions. This study used the Great Chinese Famine (GCF) to determine the long-term impact of perinatal undernutrition on hypertension and arrhythmias in older offspring. Subjects (n = 10,065) were divided into an exposed group whose fetal life was in the GCF and an unexposed group. The exposed group showed higher systolic/diastolic pressure, heart rate, and total cholesterol. Perinatal exposure to the GCF was a significant risk to Grade 2 and Grade 3 hypertension (OR = 1.724, 95%CI: 1.441-2.064, p < 0.001; OR = 1.480, 95%CI: 1.050-2.086, p < 0.05) compared to the control. The GCF also increased risks for myocardial ischemia (OR = 1.301, 95%CI: 1.135-1.490, p < 0.001), bradycardia (OR = 1.383, 95%CI: 1.154-1.657, p < 0.001), atrial fibrillation (OR = 1.931, 95%CI: 1.033-3.610, p < 0.05), and atrioventricular block (OR = 1.333, 95%CI: 1.034-1.719, p < 0.05). Total cholesterol, diabetes, and metabolic syndrome were associated with Grade 2 or Grade 3 hypertension after exposure to the GCF; high cholesterol, high BMI, diabetes, metabolic syndrome, and elevated blood pressure were linked to certain types of arrhythmias in exposed offspring. The results first demonstrated perinatal undernutrition was a significant risk factor for the development of Grade 2-3 hypertension and certain arrhythmias in humans. Perinatal undernutrition still significantly impacted cardiovascular systems of the aged offspring even 50 years after the GCF. The results also provided information to a specific population with a history of prenatal undernutrition for early prevention against cardiovascular diseases before aging.

16.
Nutrients ; 15(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36615902

RESUMO

Perinatal malnutrition affects vascular functions, and calcium is important in vascular regulations. It is unknown whether and how perinatal maternal high-fat diets (MHF)-mediated vascular dysfunction occurs via the angiotensin-PKC-L-type-calcium-channels (LTCC) axis. This study determined angiotensin II (AII) roles in the PKC-LTCC axis in controlling calcium influx in the arteries of offspring after perinatal MHF. Mesenteric arteries (MA) and smooth muscle cells (SMCs) from 5-month-old offspring rats were studied using physiological, ion channel, molecular, and epigenetic analysis. Pressor responses to AII were significantly increased in the free-moving MHF offspring rats. In cell experiments, MA-SMC proliferation was enhanced, and associated with thicker vascular wall in the obese offspring. Imaging analysis showed increase of fluorescence Ca2+ intensity in the SMCs of the MHF group. Angiotensin II receptor (AT1R)-mediated PKC-LTCC axis in vasoconstrictions was altered by perinatal MHF via reduced DNA methylation at specific CpG sites of Agtr1a and Prkcb gene promoters at the transcription level. Accordingly, mRNA and protein expression of AT1R and PKCß in the offspring MA were increased, contributing to enhanced Ca2+ currents and vascular tone. The results showed that DNA methylation resulted in perinatal MHF-induced vascular disorders via altered AT1-PKC-LTCC pathway in resistance arteries of the offspring, providing new insights into the pathogenesis and early prevention/treatments for hypertension in developmental origins.


Assuntos
Angiotensina II , Canais de Cálcio Tipo L , Gravidez , Feminino , Ratos , Animais , Angiotensina II/metabolismo , Canais de Cálcio Tipo L/metabolismo , Cálcio/metabolismo , Metilação de DNA , Artérias Mesentéricas , Dieta , Receptor Tipo 1 de Angiotensina/genética
17.
Curr Med Chem ; 30(27): 3090-3118, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36200146

RESUMO

Melatonin, mainly released from the pineal gland, also produced in the reproductive organs and cells, plays important roles in rhythms of the sleep-wake cycle, retardation of ageing processes, and antioxidant/anti-inflammatory functions. As a key mediator in reproductive systems, melatonin is participated in the reproductive process via regulating gamete and embryo development and influences reproductive diseases and pregnancy outcomes. The underlying mechanisms include epigenetic and other regulations, which are interesting for exploring new targets in the prevention and treatment of reproductive diseases. This review discusses the relationship between melatonin and reproductive functions and dysfunction, as well as potential clinical applications of melatonin in reproductive medicine. Notably, Developmental Origins of Health and Diseases (DOHaD) is closely linked to reproduction, this article is the first to review the new progress in studies on the possible relationship between melatonin and DOHaD.


Assuntos
Melatonina , Glândula Pineal , Medicina Reprodutiva , Gravidez , Feminino , Humanos , Melatonina/farmacologia , Melatonina/uso terapêutico , Melatonina/fisiologia , Glândula Pineal/fisiologia , Reprodução/fisiologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ritmo Circadiano/fisiologia
18.
Front Nutr ; 9: 913966, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35811949

RESUMO

Background: About 50 years ago, Chinese Great Famine (CGF) affected the entire population in China, and its long-term influence on the offspring has attracted significant attention for research. However, information on possible metabolic differences between sexes is limited. This study explored whether there might be sex differences in the risks of development of glucolipid metabolic dysfunction and fatty liver following prenatal exposure to CGF. Materials and Methods: There were 11,417 subjects around 55 years of age (6,661 women and 4,756 men). They were divided as the exposed group in which the fetal stage was in CGF, and the unexposed group included those born after CGF. Analysis focused on comparisons between sexes. Results: Compared to the unexposed group, the BMI and triglyceride (P < 0.05) in men were higher in exposed group, while waist circumference and blood sugar (P < 0.05) in the exposed women were significantly higher. With the ages being properly balanced, the risks of glycolipid metabolic dysfunction were significantly higher in both men and women in the exposed than in the unexposed group (P < 0.001). Prenatal exposure to CGF significantly increased risks of abnormal BMI (P < 0.001, 95% CI: 2.305-2.93), blood sugar (P < 0.05, 95% CI: 1.050-1.401), triglycerides (P < 0.05, 95% CI: 1.006-1.245), and fatty liver (P < 0.001, 95% CI: 1.121-1.390) in men, and increased risks of abnormal blood sugar (P < 0.05, 95% CI: 1.024-1.689) and positive urine sugar (P < 0.05, 95% CI: 1.062-6.211) in women. Height and body weight were either the same or higher in the exposed subjects compared with the unexposed ones, regardless of sexes. Conclusion: This study is the first to identify sex differences in the long-term effects of CGF on metabolism and fatty liver. Importance of the findings include the benefits of prescribing medicine for the early prevention of certain diseases for each sex before aging based on the differences revealed. This study also shows "catch-up growth" in the offspring prenatally exposed to CGF as possible mechanisms underlying the long-term effects.

19.
Hypertension ; 79(9): 1997-2007, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35762340

RESUMO

BACKGROUND: Administration of antenatal glucocorticoids remains common practice for treating preterm delivery. Antenatal glucocorticoid exposure increased the risk of developing vascular diseases in later life, but the precise mechanisms remain unclear. This study aimed to explore the effects and mechanisms of antenatal exposure to clinically relevant doses of dexamethasone (synthetic glucocorticoids) on vascular functions in adult male offspring. METHODS: Pregnant Sprague-Dawley rats received dexamethasone or vehicle during the last week of pregnancy. Male offspring were killed at gestational day 21 (Fetus) or postnatal day 120 (adult offspring). Mesenteric arteries were collected for vascular function, electrophysiology, target gene expression, and promotor methylation studies. RESULTS: Antenatal dexamethasone exposure increased phenylephrine-mediated vascular contractility in offspring, which was resulted by the activated inositol 1,4,5-trisphosphate (IP3) receptor and L-type Ca2+ channels. Specifically, increases of IP3R1 (IP3 receptor 1) and Cav1.2 (L-type Ca2+ channels subunit alpha1 C) were responsible for an activated IP3-Ca2+ pathway in the vasculature, and eventually predisposed the antenatal dexamethasone offspring to vascular hypercontractility. In addition, IP3R1 and Cav1.2 was upregulated through transcriptional mechanism; the overall changes in promotor histone modifications were consistent with the corresponding changes in transcriptional levels of the 2 genes, suggesting that antenatal dexamethasone exposure activated the transcription of IP3R1 and Cav1.2 via altering promotor histone modifications. CONCLUSIONS: Taken together, this study demonstrated that antenatal dexamethasone exposure resulted in vascular adverse outcomes in male offspring that is linked to the increases of IP3R1 and Cav1.2 mediated by epigenetic modifications in the vasculature.


Assuntos
Glucocorticoides , Efeitos Tardios da Exposição Pré-Natal , Animais , Dexametasona/metabolismo , Dexametasona/farmacologia , Feminino , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley
20.
Hypertens Res ; 45(7): 1168-1182, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35585170

RESUMO

Hypoxia can lead to adult middle cerebral artery (MCA) dysfunction and increase the risk of cerebrovascular diseases. It is largely unknown whether intrauterine hypoxia affects fetal MCA vasodilatation. This study investigated the effects and mechanisms of intrauterine hypoxia on fetal MCA vasodilatation. Near-term fetal sheep were exposed to intrauterine hypoxia. Human umbilical vein endothelial cells (HUVECs) were exposed to hypoxia in cellular experiments. Vascular tone measurement, molecular analysis, and transmission electron microscope (TEM) were utilized to determine vascular functions, tissue anatomy, and molecular pathways in fetal MCA. In fetal MCA, acetylcholine (ACh) induced reliable relaxation, which was markedly attenuated by intrauterine hypoxia. Atropine, P-F-HHSiD, L-NAME, and u0126 blocked most ACh-mediated dilation, while AF-DX 116 and tropicamide partially inhibited the dilation. Indomethacin and SB203580 did not significantly change ACh-mediated dilation. Tempol and PS-341 could restore the attenuated ACh-mediated vasodilatation following intrauterine hypoxia. The mRNA expression levels of CHRM2 and CHRM3 and the protein levels of CHRM3, p-NOS3, SOD2, ERK1/2, p-ERK1/2, MAPK14, and p-MAPK14 were significantly reduced by intrauterine hypoxia. The dihydroethidium assay showed that the production of ROS was increased under intrauterine hypoxia. TEM analysis revealed endothelial cells damaged by intrauterine hypoxia. In HUVECs, hypoxia increased ROS formation and decreased the expression of CHRM3, p-NOS3, SOD1, SOD2, SOD3, ERK1/2, p-ERK1/2, and p-MAPK14, while tempol and PS-341 potentiated p-NOS3 protein expression. In conclusion, in utero hypoxia reduced ACh-mediated vasodilatation in ovine MCA predominantly via decreased CHRM3 and p-NOS3, and the decreased NOS3 bioactivities might be attributed to ROS and ERK1/2.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno , Vasodilatação , Acetilcolina/farmacologia , Animais , Bortezomib/farmacologia , Feminino , Hipóxia Fetal , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipóxia , Sistema de Sinalização das MAP Quinases , Artéria Cerebral Média , Óxido Nítrico Sintase Tipo III/genética , Espécies Reativas de Oxigênio , Receptor Muscarínico M3 , Ovinos
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