Unravelling the impact of intrauterine growth restriction on heart development: insights into mitochondria and sexual dimorphism from a non-hominoid primate

2021 ◽  
Vol 135 (14) ◽  
pp. 1767-1772
Author(s):  
George W. Booz ◽  
Gaelle P. Massoud ◽  
Raffaele Altara ◽  
Fouad A. Zouein
Keyword(s):  
Heart Development ◽  
In Utero ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Primate Model ◽  
Mitochondrial Ros ◽  
Mitochondrial Functions ◽  
Mitochondrial Transcripts ◽  
The Impact

Abstract Fetal exposure to an unfavorable intrauterine environment programs an individual to have a greater susceptibility later in life to non-communicable diseases, such as coronary heart disease, but the molecular processes are poorly understood. An article in Clinical Science recently reported novel details on the effects of maternal nutrient reduction (MNR) on fetal heart development using a primate model that is about 94% genetically similar to humans and is also mostly monotocous. MNR adversely impacted fetal left ventricular (LV) mitochondria in a sex-dependent fashion with a greater effect on male fetuses, although mitochondrial transcripts increased more so in females. Increased expression for several respiratory chain and adenosine triphosphate (ATP) synthase proteins were observed. However, fetal LV mitochondrial complex I and complex II/III activities were significantly decreased, likely contributing to a 73% decreased LV ATP content and increased LV lipid peroxidation. Moreover, MNR fetal LV mitochondria showed sparse and disarranged cristae. This study indicates that mitochondria are targets of the remodeling and imprinting processes in a sex-dependent manner. Mitochondrial ROS production and inadequate energy production add another layer of complexity. Altogether these observations raise the possibility that dysfunctional mitochondria in the fetus may contribute in turn to epigenetic memory of in utero stress in the adult. The role of mitoepigenetics and involvement of mitochondrial and genomic non-coding RNAs in mitochondrial functions and nuclei–mitochondria crosstalk with in utero stress awaits further investigation.

scholarly journals Neonatal Immune System Ontogeny: The Role of Maternal Microbiota and Associated Factors. How Might the Non-Human Primate Model Enlighten the Path?

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 584
Author(s):  
Natalia Nunez ◽  
Louis Réot ◽  
Elisabeth Menu
Keyword(s):  
Immune System ◽  
Mode Of Delivery ◽  
Microbial Colonization ◽  
Therapeutic Interventions ◽  
Primate Model ◽  
Neonatal Immune System ◽  
Gastrointestinal Colonization ◽  
The Impact ◽  
Human Primate

Interactions between the immune system and the microbiome play a crucial role on the human health. These interactions start in the prenatal period and are critical for the maturation of the immune system in newborns and infants. Several factors influence the composition of the infant’s microbiota and subsequently the development of the immune system. They include maternal infection, antibiotic treatment, environmental exposure, mode of delivery, breastfeeding, and food introduction. In this review, we focus on the ontogeny of the immune system and its association to microbial colonization from conception to food diversification. In this context, we give an overview of the mother–fetus interactions during pregnancy, the impact of the time of birth and the mode of delivery, the neonate gastrointestinal colonization and the role of breastfeeding, weaning, and food diversification. We further review the impact of the vaccination on the infant’s microbiota and the reciprocal case. Finally, we discuss several potential therapeutic interventions that might help to improve the newborn and infant’s health and their responses to vaccination. Throughout the review, we underline the main scientific questions that are left to be answered and how the non-human primate model could help enlighten the path.

Impact of extracellular buffer composition on cardioprotective efficacy of Na+/H+ exchanger inhibitors

1996 ◽  
Vol 270 (2) ◽  
pp. H692-H700 ◽  
Author(s):  
Y. Shimada ◽  
D. J. Hearse ◽  
M. Avkiran
Keyword(s):  
Complete Recovery ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Experimental Conditions ◽  
Degree Of Protection ◽  
Buffer Composition ◽  
Ethanesulfonic Acid ◽  
Developed Pressure ◽  
The Impact ◽  
Postischemic Recovery

There is controversy over whether the cardioprotective effects of Na+/H+ exchanger inhibitors are exerted primarily during ischemia or during subsequent reperfusion, possibly because of interstudy differences in experimental conditions. We studied the impact of perfusate buffer composition on the relative degree of protection afforded by Na+/H+ exchanger inhibition during ischemia vs. reperfusion. Isolated rat hearts (n = 8/group) were perfused (37 degrees C, 75 mmHg) with bicarbonate- or N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered medium and subjected to 20 min of global zero-flow ischemia and 45 min of reperfusion. One of two structurally distinct Na+/H+ exchanger inhibitors [5-(N,N-dimethyl)amiloride (DMA) or (3-methylsulfonyl-4-piperidinobenzoyl)guanidine methanesulfonate (HOE-694), 10 mumol/l] was transiently (5 min) infused 1) immediately before ischemia, 2) during initial reperfusion, or 3) during both of these periods. With bicarbonate-buffered medium, neither drug improved the postischemic recovery of left ventricular developed pressure (LVDP) when given only during reperfusion. In contrast, HOE-694 improved the postischemic recovery of LVDP from 39 +/- 5% in control to 66 +/- 6% (P < 0.05) when given before ischemia and from 33 +/- 4% in control to 65 +/- 4% (P < 0.05) when given before ischemia plus during reperfusion. With the latter protocol, the cardioprotective effect of HOE-694 occurred in a dose-dependent manner at 0.1-10 mumol/l. In contrast to the results with bicarbonate-buffered medium, in the presence of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered medium, DMA and HOE-694 significantly improved recovery of LVDP (from 34 +/- 5% in controls to 56 +/- 3 and 71 +/- 8%, both P < 0.05) when given only during reperfusion. They also provided significant protection when given before ischemia or before ischemia plus during reperfusion; with the latter protocol, HOE-694 produced an almost complete recovery of LVDP (88 +/- 9 vs. 30 +/- 7% in controls, P < 0.05). In conclusion, our results suggest that the influence of Na+/H+ exchanger activity during reperfusion on the extent of functional recovery is modulated significantly by perfusate buffer composition. As a consequence, the cardioprotective efficacy of Na+/H+ exchanger inhibitors may be overestimated under bicarbonate-free conditions.

scholarly journals Atherothrombosis and Thromboembolism: Position Paper from the Second Maastricht Consensus Conference on Thrombosis

2018 ◽  
Vol 118 (02) ◽  
pp. 229-250 ◽  
Author(s):  
H. Spronk ◽  
T. Padro ◽  
J. Siland ◽  
J. Prochaska ◽  
J. Winters ◽  
...  
Keyword(s):  
Risk Factors ◽  
Antithrombotic Therapy ◽  
Thrombus Formation ◽  
Consensus Conference ◽  
Risk Scores ◽  
Dependent Manner ◽  
Metabolomics Data ◽  
Circulating Cells ◽  
The Impact

AbstractAtherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in)stability; proteomic and metabolomics data are to be added to genetic information. 2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; disease mechanism-based biomarkers need to be identified; experimental systems are needed that incorporate whole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation. 3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin–angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet–fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences. 4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis à vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time. 5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia–reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novel modified activated protein C–based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.

scholarly journals The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases

2018 ◽  
Vol 19 (12) ◽  
pp. 3711 ◽  
Author(s):  
Ovidiu Balacescu ◽  
Daniel Sur ◽  
Calin Cainap ◽  
Simona Visan ◽  
Daniel Cruceriu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Cancer Progression ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Cancer Management ◽  
Incidence And Mortality ◽  
The Impact

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial–mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

scholarly journals The Modulatory Effect of Ischemia and Reperfusion on Arginine Vasopressin-Induced Arterial Reactions

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Katarzyna Szadujkis-Szadurska ◽  
Bartosz Malinowski ◽  
Małgorzata Piotrowska ◽  
Grzegorz Grześk ◽  
Michał Wiciński ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Arginine Vasopressin ◽  
Muscle Cells ◽  
Signalling Pathway ◽  
Ischemia And Reperfusion ◽  
Dependent Manner ◽  
Male Wistar Rats ◽  
The Impact

Aim of the Study.The purpose of this study was to investigate the impact of ischemia and reperfusion on the resistance of arteries to AVP (arginine vasopressin), with a particular emphasis on the role of smooth muscle cells in the action of vasopressin receptors and the role of the cGMP-associated signalling pathway.Materials and Methods.Experiment was performed on the perfunded tail arteries from male Wistar rats. The constriction triggered by AVP after 30 minutes of ischemia and 30 and 90 minutes of reperfusion was analysed. Analogous experiments were also carried out in the presence of 8Br-cGMP.Results.Ischemia reduces and reperfusion increases in a time-dependent manner the arterial reaction to AVP. The presence of 8Br-cGMP causes a significant decrease of arterial reactivity under study conditions.Conclusions.Ischemia and reperfusion modulate arterial contraction triggered by AVP. The effect of 8Br-cGMP on reactions, induced by AVP after ischemia and reperfusion, indicates that signalling pathway associated with nitric oxide (NO) and cGMP regulates the tension of the vascular smooth muscle cells.

scholarly journals Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

2021 ◽  
Author(s):  
Zhiyu Dai ◽  
Jianding Cheng ◽  
Bin Liu ◽  
Dan Yi ◽  
Anlin Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Adaptive Responses ◽  
Genetic Ablation ◽  
Pathological Cardiac Hypertrophy ◽  
And Function

Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. We observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Mice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) or tamoxifen-induced endothelial Egln1 deletion exhibited left ventricular hypertrophy and cardiac fibrosis. Genetic ablation and pharmacological inhibition of Hif2a but not Hif1a in endothelial Egln1 deficient mice normalized cardiac size and function. The present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2α dependent manner. Targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

scholarly journals Stent strut streamlining and thickness reduction promote endothelialization

2021 ◽  
Vol 18 (181) ◽  
pp. 20210023
Author(s):  
Duy T. Nguyen ◽  
Alexander F. Smith ◽  
Juan M. Jiménez
Keyword(s):  
Stent Thrombosis ◽  
Critical Factor ◽  
Prognostic Indicator ◽  
Dependent Manner ◽  
Wound Healing Assay ◽  
Strut Thickness ◽  
Stent Strut ◽  
Static Conditions ◽  
The Impact

Stent thrombosis (ST) carries a high risk of myocardial infarction and death. Lack of endothelial coverage is an important prognostic indicator of ST after stenting. While stent strut thickness is a critical factor in ST, a mechanistic understanding of its effect is limited and the role of haemodynamics is unclear. Endothelialization was tested using a wound-healing assay and five different stent strut models ranging in height between 50 and 150 µm for circular arc (CA) and rectangular (RT) geometries and a control without struts. Under static conditions, all stent strut surfaces were completely endothelialized. Reversing pulsatile disturbed flow caused full endothelialization, except for the stent strut surfaces of the 100 and 150 µm RT geometries, while fully antegrade pulsatile undisturbed flow with a higher mean wall shear stress caused only the control and the 50 µm CA geometries to be fully endothelialized. Modest streamlining and decrease in height of the stent struts improved endothelial coverage of the peri-strut and stent strut surfaces in a haemodynamics dependent manner. This study highlights the impact of the stent strut height (thickness) and geometry (shape) on the local haemodynamics, modulating reendothelialization after stenting, an important factor in reducing the risk of stent thrombosis.

Role of pulmonary C fibers in adenosine-induced respiratory inhibition in anesthetized rats

1998 ◽  
Vol 84 (2) ◽  
pp. 417-424 ◽  
Author(s):  
Kevin Kwong ◽  
Ju-Lun Hong ◽  
Robert F. Morton ◽  
Lu-Yuan Lee
Keyword(s):  
Left Ventricular ◽  
Right Atrial ◽  
Dependent Manner ◽  
Sensory Afferents ◽  
C Fibers ◽  
Respiratory Inhibition ◽  
Anesthetized Rats ◽  
Long Latency ◽  
Therapeutic Doses

Kwong, Kevin, Ju-Lun Hong, Robert F. Morton, and Lu-Yuan Lee. Role of pulmonary C fibers in adenosine-induced respiratory inhibition in anesthetized rats. J. Appl. Physiol. 84(2): 417–424, 1998.—The clinical use of adenosine is commonly associated with pulmonary side effects, namely dyspnea, that suggest the possible involvement of bronchopulmonary sensory afferents. Our objective in this study was to characterize the effects of adenosine on breathing and to determine whether the vagal pulmonary afferents play a role in mediating these effects. We measured respiratory and cardiovascular changes in anesthetized, spontaneously breathing rats after bolus injections of adenosine at therapeutic doses. Right atrial injection of adenosine (0.04–0.6 mg/kg) elicits, in a dose-dependent manner, a pulmonary chemoreflex-like response consisting of a delayed apnea, bradycardia, and hypotension. In contrast, the classic capsaicin-elicited pulmonary chemoreflex occurs immediately after injection. Perineural capsaicin treatment of the cervical vagi blocked the adenosine-induced respiratory inhibition. Left ventricular administration of adenosine failed to elicit an apneic response. Pretreatment with the adenosine A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine attenuated the adenosine-induced apnea. These results indicate that adenosine elicits a respiratory inhibition via stimulation of pulmonary C fibers and that activation of the A1-receptor is probably involved. It is unclear, however, what accounts for the exceedingly long latency in this response.

scholarly journals The autophagy receptor p62/SQST-1 promotes proteostasis and longevity in C. elegans by inducing autophagy

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Caroline Kumsta ◽  
Jessica T. Chang ◽  
Reina Lee ◽  
Ee Phie Tan ◽  
Yongzhi Yang ◽  
...  
Keyword(s):  
Heat Shock ◽  
Stress Responses ◽  
Dependent Manner ◽  
Selective Autophagy ◽  
C Elegans ◽  
Proteotoxic Stress ◽  
Autophagy Induction ◽  
The Impact ◽  
Lifespan Regulation

AbstractAutophagy can degrade cargos with the help of selective autophagy receptors such as p62/SQSTM1, which facilitates the degradation of ubiquitinated cargo. While the process of autophagy has been linked to aging, the impact of selective autophagy in lifespan regulation remains unclear. We have recently shown in Caenorhabditis elegans that transcript levels of sqst-1/p62 increase upon a hormetic heat shock, suggesting a role of SQST-1/p62 in stress response and aging. Here, we find that sqst-1/p62 is required for hormetic benefits of heat shock, including longevity, improved neuronal proteostasis, and autophagy induction. Furthermore, overexpression of SQST-1/p62 is sufficient to induce autophagy in distinct tissues, extend lifespan, and improve the fitness of mutants with defects in proteostasis in an autophagy-dependent manner. Collectively, these findings illustrate that increased expression of a selective autophagy receptor is sufficient to induce autophagy, enhance proteostasis and extend longevity, and demonstrate an important role for sqst-1/p62 in proteotoxic stress responses.

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