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a) Representative nitric oxide pathway.b) Effects of aging on nitric oxide pathway. BH4 = tetrahydrobiopterin; Ca2+ = calcium ion; cGMP = cyclic guanosine monophosphate; eNOS = endothelial nitric oxide synthase; GTP = guanosine triphosphate; NADPH = nicotinamide adenine dinucleotide phosphate; NO = nitric oxide; ONOO- = Peroxynitrite; ADMA = Dimethylarginine; ROS = reactive oxygen species.
Source publication
Aging is the sum of the deleterious changes that occur as time goes by. It is the main risk factor for the development of cardiovascular disease, and aging of the vasculature is the event that most often impacts on the health of elderly people. The "free-radical theory of aging" was proposed to explain aging as a consequence of the accumulation of...
Contexts in source publication
Context 1
... dysfunction is the hallmark of vascular damage in advancing age [37][38][39][40][41]. Many functions of the vascular endothelium are modulated by NO, which is able to induce smooth muscle relaxation [42][43][44], the inhibition of platelet aggregation [45], leukocyte adhe- sion to endothelial cells [46,47] and preservation of endothelial progenitor cell function [48] (Figure 1a). The crucial role of NO in protecting the cardiovascular system during aging was revealed by studies demon- strating that eNOS knockout mice have a premature cardiac-aging phenotype and early mortality [49]. ...Context 2
... of NO availability alters vascular homeosta- sis [50] and is a phenomenon involved in the de- velopment of hypertension [50,51], atherosclerosis and thrombosis leading to heart attack and stroke [52][53][54]. The mechanisms underlying vascular aging are complex and involve multiple pathways [41,55,56] (Figure 1b). During aging, there is a progressive misbalance between NO production − which becomes increasingly reduced − and oxidative stress − which increases without a com- pensatory enhancement of antioxidant defences [57][58][59]. ...Similar publications
BPIFB4 is associated with exceptional longevity: four single-nucleotide polymorphisms distinguish the wild-type form from a longevity-associated variant conferring positive effects on blood pressure. The effect of a rare variant (RV; allele frequency, 4%) on blood pressure is unknown. Here, we show that overexpression of RV-BPIFB4 in ex-vivo mouse...
Citations
... In addition, maintaining blood flow and vascular integrity during surgical procedures may help maintain the anticoagulant balance of endothelial nitric oxide and prostacyclin, thereby preventing aberrant endothelial cell activation and coagulation amplification [95]. For example, one specific study found a 50% reduction in levels of the catecholamine norepinephrine after robotic-assisted prostatectomy compared to open radical prostatectomy [96]. ...
Robotic surgеry rеprеsеnts a milеstonе in surgical procеdurеs, offering advantages such as lеss invasivе mеthods, еlimination of trеmors, scalеd motion, and 3D visualization. This in-dеpth analysis еxplorеs thе complеx biochеmical еffеcts of robotic mеthods. Thе usе of pnеumopеritonеum and stееp Trеndеlеnburg positioning can dеcrеasе pulmonary compliancе and splanchnic pеrfusion whilе incrеasing hypеrcarbia. Howеvеr, robotic surgеry rеducеs surgical strеss and inflammation by minimizing tissuе trauma. This contributеs to fastеr rеcovеry but may limit immunе function. Robotic procеdurеs also limit ischеmia-rеpеrfusion injury and oxidativе damagе comparеd to opеn surgеry. Thеy also hеlp prеsеrvе nativе antioxidant dеfеnsеs and coagulation. In a clinical sеtting, robotic procеdurеs rеducе blood loss, pain, complications, and lеngth of stay compared to traditional procеdurеs. Howеvеr, risks rеmain, including dеvicе failurе, thе nееd for convеrsion to opеn surgеry and incrеasеd costs. On thе oncology sidе, thеrе is still dеbatе about margins, rеcurrеncе, and long-term survival. Thе advеnt of advancеd tеchnologiеs, such as intraopеrativе biosеnsors, localizеd drug dеlivеry systеms, and thе incorporation of artificial intеlligеncе, may furthеr improvе thе еfficiеncy of robotic surgеry. Howеvеr, еthical dilеmmas rеgarding patiеnt consеnt, privacy, accеss, and rеgulation of this disruptivе innovation nееd to bе addrеssеd. Ovеrall, this rеviеw shеds light on thе complеx biochеmical implications of robotic surgеry and highlights arеas that rеquirе additional mеchanistic invеstigation. It prеsеnts a comprеhеnsivе approach to rеsponsibly maximizе thе potеntial of robotic surgеry to improvе patiеnt outcomеs, intеgrating tеchnical skill with carеful considеration of physiological and еthical issuеs.
... The major factor in senescent-associated endothelial dysfunction is the insufficient production of nitric oxide (NO), a key regulator of vascular tone (El Assar et al., 2012;Bourdrel et al., 2017). FD-induced endothelial dysfunction is primarily associated with reduction in NO bioavailability (Finch and Conklin, 2016), whereas, enhanced endothelial NO synthase (eNOS) activity delays EC senescence, preventing endothelial dysfunction (Puca et al., 2012). In this study, the eNOS expression was assessed in ECs treated with FD alone or in combination with different concentrations of γ-Ory to investigate whether γ-Ory ameliorates FD-induced NO insufficiency. ...
Various cardiovascular diseases are associated with endothelial senescence, and a recent study showed that fine dust (FD)-induced premature endothelial senescence and dysfunction is associated with increased oxidative stress. The aim of the present study was to investigate protective effect of rice bran extract (RBE) and its major component of γ-Oryzanol (γ-Ory) against FD-induced premature endothelial senescence. Porcine coronary artery endothelial cells (PCAECs) were treated with FD alone or with RBE or γ-Ory. Senescence-associated β-galactosidase (SA-β-gal) activity, expression of cell cycle regulatory proteins, and oxidative stress levels were evaluated. The results indicated that SA-β-gal activity in the FD-treated PCAECs was attenuated by RBE and γ-Ory. Additionally, γ-Ory inhibited FD-induced cell cycle arrest, restored cell proliferation, and reduced the expression of cell cycle regulatory proteins. γ-Ory also inhibited oxidative stress and prevented senescence-associated NADPH oxidase and LAS activity in FD-exposed ECs suggesting that γ-Ory could protect against FD-induced ECs senescence and dysfunction.
... A correlation between delayed aging and preservation of NO-dependent vasodilation has already been established [50]. Although in vitro study using carotid reported that longevity and endothelial function preservation does not correlate with maximal sensitivity to Ach [51], many studies on various organisms ranging from yeasts to mammals have shown that longevity is correlated to NO pathway preservation [14,52] and eNOS function [53,54]. In BN rats, the NO pathway preservation is, therefore, in accordance with their high longevity. ...
... Indeed, PIV relies not only on vascular function but also requires intact functional integrity of sensory nervous system, especially capsaicin-sensitive nerve endings [11,27] following the activation of acid-sensing ion channel 3 (ASIC3) [13], a mechanoreceptor residing in cutaneous sensory nerve endings. Interestingly, ASIC3 deletion (Asic3 knockout mice) and ASIC3 inhibitors in human and rat skin abolished PIV, without affecting Achmediated vasodilation [14], strengthening the crucial role of the sensory nerve endings in PIV. At 6 months, the Wistar strain has an overall lower skin sensitivity than the BN strain (excluding the Randall-Selitto test) associated with lower PIV capacities but equivalent Ach-mediated vasodilation. ...
Many changes characterize skin aging, and the resulting dysfunctions still constitute a real challenge for our society. The aim of this study was to compare the skin aging of two rat strains, Wistar and Brown Norway (BN), considered as “poorly aging” and “healthy aging” models, respectively, and to assess the effect of alpha-lipoic acid (LPA), especially on skin microcirculation. To this purpose, various skin characteristics were studied at 6, 12, and 24 months and compared to the results of LPA treatment performed at 12 or 24 months. Skin aging occurred in both strains, but we showed an early occurrence of different age-related disorders in the Wistar strain compared to BN strain, especially regarding weight gain, glycemia dysregulation, basal skin perfusion, endothelial function, and skin resistance to low pressure. LPA treatment tended to improve skin resistance to low pressure in BN but not in Wistar despite the improvement of basal skin perfusion, endothelial function, and skin sensory sensitivity. Overall, this study confirmed the healthier aging of BN compared to Wistar strain and the positive effect of LPA on both general state and skin microcirculation.
... Impaired endothelial NOS activity and enhanced ROS production in DM result in diminished NO bioavailability and vascular damage [83]. Therefore, NO is considered an important anti-atherogenic molecule that is necessary to contain diabetic endothelial alterations [84,85]. Inflammation is widely considered a key etiological factor that plays a vital role in the development of diabetic complications [86]. ...
The development and progression of the complications of chronic diabetes mellitus are attributed not only to increased blood glucose levels but also to glycemic variability. Therefore, a deeper understanding of the role of glycemic variability in the development of diabetic complications may provide more insight into targeted clinical treatment strategies in the future. Previously, the mechanisms implicated in glycemic variability-induced diabetic complications have been comprehensively discussed. However, endothelial dysfunction and platelet hyperactivation, which are two newly recognized critical pathogenic factors, have not been fully elucidated yet. In this review, we first evaluate the assessment of glycemic variability and then summarise the roles of endothelial dysfunction and platelet hyperactivation in glycemic variability-induced complications of diabetes, highlighting the molecular mechanisms involved and their interconnections.
... Soon after, the other relevant alteration in brain SVD is a compromised response to the endothelium vasodilators, such as NO [66], prostacyclin [67], and endothelium-derived hyperpolarizing factors (EDHF) [68]. Mitochondrial dysfunction, associated with reactive-oxygen-species (ROS) overproduction, decreased endothelial NO synthase (eNOS) activity, and consequent low-NO bioavailability, contributes to the disruption of the cerebral endothelial cells and endothelial walls [69][70][71][72]. Decreased NO concentration in SVD represents a marker of compromised endothelial regulatory response against external factors such as hypercapnia, reducing the ability of the endothelium to properly proceed with neurovascular coupling to potentiate the correct metabolic requirement of cortical areas of the brain [70,73,74]. ...
Small-vessel disease (SVD), also known as microvascular endothelial dysfunction, is a disorder with negative consequences for various organs such as the heart and brain. Impaired dilatation and constriction of small vessels in the heart lead to reduced blood flow and ischemia independently of coronary artery disease (CAD) and are associated with major cardiac events. SVD is usually a silent form of subcortical vascular burden in the brain with various clinical manifestations, such as silent-lacunar-ischemic events and confluent white-matter hyperintensities. Imaging techniques are the main help for clinicians to diagnose cardiac and brain SVD correctly. Markers of inflammation, such as C-reactive protein, tumor-necrosis-factor α, and interleukin 6, provide insight into the disease and markers that negatively influence nitric-oxide bioavailability and promote oxidative stress. Unfortunately, the therapeutic approach against SVD is still not well-defined. In the last decades, various antioxidants, oxidative stress inhibitors, and superoxide scavengers have been the target of extensive investigations due to their potential therapeutic effect, but with unsatisfactory results. In clinical practice, traditional anti-ischemic and risk-reduction therapies for CAD are currently in use for SVD treatment.
... E attenuated arginase activity in the brain of DOX-induced rats. According to the report of Puca et al., [2012], inhibition of arginase activity reversed cognitive impairment, β-amyloid production, and immunosuppression. The reduction of arginase activity observed in DOX + P.A (200 and 400 mg/kg), and DOX + M.C (200 and 400 mg/kg) rats groups could be attributed to the phenolic constituents (Table 1) Angiotensin-I converting enzyme (ACE) is an essential target in the treatment of renal and cardiovascular disorders, but recent reports have shown its involvement as a therapeutic target in the treatment/management of neurodegeneration [Puca et al., 2012;Tota et al., 2012;Oboh et al., 2018]. ...
... According to the report of Puca et al., [2012], inhibition of arginase activity reversed cognitive impairment, β-amyloid production, and immunosuppression. The reduction of arginase activity observed in DOX + P.A (200 and 400 mg/kg), and DOX + M.C (200 and 400 mg/kg) rats groups could be attributed to the phenolic constituents (Table 1) Angiotensin-I converting enzyme (ACE) is an essential target in the treatment of renal and cardiovascular disorders, but recent reports have shown its involvement as a therapeutic target in the treatment/management of neurodegeneration [Puca et al., 2012;Tota et al., 2012;Oboh et al., 2018]. The overexpression of this enzyme has been reported to result in overproduction of angiotensin-II, which causes blockage of acetylcholine production and utilization, anxiety, behavioral disturbances, oxidative stress, and ultimately memory loss [Tota et al., 2012;Aziriova et al., 2014]. ...
Background
Phyllanthus amarus (P.A) and Momordica charantia (M.C) are common herbs known for their various pharmacological importance. However, limited studies have been done regarding their neuroactive effect. This study investigates the role of Phyllanthus amarus (P.A) and Momordica charantia (M.C) extracts on cognitive behavior and some neurochemicals associated with memory function in rats administered with doxorubicin (DOX).
Methodology
Normal rats were pre-treated with P.A and M.C (200 and 400 mg/kg bwt.) for 14 days, while on the last day, DOX (15 mg/kg bwt. i.p.) was administered in a single dose. The cognitive behavior was evaluated using Y-maze and Morris Water Maze Tests. Thereafter, the biochemical assays [acetylcholinesterase (AChE), butyrylcholinesterase (BChE), arginase, 5′- nucleotidase, adenosine deaminase (ADA), angiotensin-I converting enzyme (ACE), and catalase activities, thiobarbituric acid reactive species, and non-protein thiol levels] were determined in rats’ brains. The extracts were characterized using a high-performance liquid chromatography-diode array detector (HPLC-DAD).
Result
P.A and M.C extract restored cognitive behavior, nootropic-related enzyme activities, and improved antioxidant biomarkers altered by DOX. Furthermore, phenolic characterization of the extracts revealed gallic, chlorogenic, caffeic, and ellagic acids, catechin, epicatechin, rutin, quercitrin, isoquercitrin, quercetin, and kaempferol. Molecular docking analysis revealed that all the phenolic compounds detected in the studied plants had binding affinities for ACE, AChE, 5’-nucleotidase, and ADA proteins as the target proteins.
Conclusion
Extract from P.A and M.C effectively suppressed DOX-induced neurotoxicity by improving brain antioxidant status. Thus, they could play a significant role in restoring cognitive function altered by DOX treatment.
... However, it can also be reduced in its production, as it occurs in normal aging [117], in an accelerated way, in SVD, with a consistent down-regulation of endothelial NO synthase (eNOS). Moreover, in SVD, there is an evident dysfunction of the Rho-associated protein kinase (ROCK) [118] and the related ERM proteins (ezrin, radixin, and moesin), fundamental for barrier properties' integrity [118][119][120] and their induction of the downregulation of the vascular endothelium cadherins (VE-cadherins) [121]. ...
... However, it can also be reduced in its production, as it occurs in normal aging [117], in an accelerated way, in SVD, with a consistent down-regulation of endothelial NO synthase (eNOS). Moreover, in SVD, there is an evident dysfunction of the Rho-associated protein kinase (ROCK) [118] and the related ERM proteins (ezrin, radixin, and moesin), fundamental for barrier properties' integrity [118][119][120] and their induction of the downregulation of the vascular endothelium cadherins (VE-cadherins) [121]. ...
Small vessel disease (SVD) is one of the most frequent pathological conditions which lead to dementia. Biochemical and neuroimaging might help correctly identify the clinical diagnosis of this relevant brain disease. The microvascular alterations which underlie SVD have common origins, similar cognitive outcomes, and common vascular risk factors. Nevertheless, the arteriolosclerosis process, which underlines SVD development, is based on different mechanisms, not all completely understood, which start from a chronic hypoperfusion state and pass through a chronic brain inflammatory condition, inducing a significant endothelium activation and a consequent tissue remodeling action. In a recent review, we focused on the pathophysiology of SVD, which is complex, involving genetic conditions and different co-morbidities (i.e., diabetes, chronic hypoxia condition, and obesity). Currently, many points still remain unclear and discordant. In this paper, we wanted to focus on new biomarkers, which can be the expression of the endothelial dysfunction, or of the oxidative damage, which could be employed as markers of disease progression or for future targets of therapies. Therefore, we described the altered response to the endothelium-derived nitric oxide-vasodilators (ENOV), prostacyclin, C-reactive proteins, and endothelium-derived hyperpolarizing factors (EDHF). At the same time, due to the concomitant endothelial activation and chronic neuroinflammatory status, we described hypoxia-endothelial-related markers, such as HIF 1 alpha, VEGFR2, and neuroglobin, and MMPs. We also described blood–brain barrier disruption biomarkers and imaging techniques, which can also describe perivascular spaces enlargement and dysfunction. More studies should be necessary, in order to implement these results and give them a clinical benefit.
... Consistent with our proposed mechanism, eNOS knockout (KO) mice show impaired physical performance (33,34) as well as vessel rarefaction (35,36) and reduced angiogenesis and arteriogenesis (37)(38)(39). eNOS is considered to have a key role in maintaining vascular integrity with ageing (40). ...
Piezo1 forms mechanically-activated non-selective cation channels that contribute to endothelial response to fluid flow. Here we reveal an important role in the control of capillary density. Conditional endothelial-specific deletion of Piezo1 in adult mice depressed physical performance. Muscle microvascular endothelial cell apoptosis and capillary rarefaction were evident and sufficient to account for the effect on performance. There was selective upregulation of thrombospondin-2 (TSP2), an inducer of endothelial apoptosis, with no effect on thrombospondin-1 (TSP1), a related important player in muscle physiology. TSP2 was poorly expressed in muscle endothelial cells but robustly expressed in muscle pericytes, in which nitric oxide (NO) repressed the Tsp2 gene without effect on Tsp1. In the endothelial cells, Piezo1 was required for normal expression of endothelial nitric oxide synthase (eNOS). The data suggest an endothelial-pericyte partnership of muscle in which endothelial Piezo1 senses blood flow to sustain capillary density and thereby maintain physical capability.
... Nitric oxide (NO), the most important endotheliumderived vasodilator for ECs, exerts powerful antiinflammation, anti-apoptosis, and pro-angiogenesis effects and modulates cellular metabolism, mitochondrial function, and synaptic transmission [125][126][127][128][129]. Senescence leads to increased mitochondrial production of superoxide [130], which reacts with NO to form peroxynitrite, resulting in reduced availability of NO and endothelial dysfunction [131][132][133]. The activity and expression of endothelial NO synthase is reduced during advanced aging [134,135], which directly inhibits the production of NO [136]. Thus, an age-related reduction in the production of endothelium-derived NO negatively affects the function of microvessels, neurons, astrocytes, and microglia. ...
An emerging concept termed the "neuro-glia-vascular unit" (NGVU) has been established in recent years to understand the complicated mechanism of multicellular interactions among vascular cells, glial cells, and neurons. It has been proverbially reported that the NGVU is significantly associated with neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Physiological aging is an inevitable progression associated with oxidative damage, bioenergetic alterations, mitochondrial dysfunction, and neuroinflammation, which is partially similar to the pathology of AD. Thus, senescence is regarded as the background for the development of neurodegenerative diseases. With the exacerbation of global aging, senescence is an increasingly serious problem in the medical field. In this review, the coupling of each component, including neurons, glial cells, and vascular cells, in the NGVU is described in detail. Then, various mechanisms of age-dependent impairment in each part of the NGVU are discussed. Moreover, the potential bioenergetic alterations between different cell types in the NGVU are highlighted, which seems to be an emerging physiopathology associated with the aged brain. Bioenergetic intervention in the NGVU may be a new direction for studies on delaying or diminishing aging in the future.
... The general neuroinflammation present in SVD determines a hyperproduction of peroxynitrite [81,82]. It depends on an altered redox response associated with a reduction of the activity of endothelial NO synthase (eNOS) and downregulation of the Rho-associated protein kinase (ROCK), which usually promotes the vascular endothelium growth factor (VEGF) in response to vascular injury [83][84][85][86][87][88][89][90][91][92]. ...
... Besides, NO-mediated signals trigger an increase in myosin light-chain phosphatase (MLCP) activity. ROCK inactivates MLCP via calcium desensitization [83,93] and therefore decreases the availability of NO [94,95]. ...
Homocysteine (Hcy) is a sulfur-containing amino acid generated during methionine metabolism, accumulation of which may be caused by genetic defects or the deficit of vitamin B12 and folate. A serum level greater than 15 micro-mols/L is defined as hyperhomocysteinemia (HHcy). Hcy has many roles, the most important being the active participation in the transmethylation reactions, fundamental for the brain. Many studies focused on the role of homocysteine accumulation in vascular or degenerative neurological diseases, but the results are still undefined. More is known in cardiovascular disease. HHcy is a determinant for the development and progression of inflammation, atherosclerotic plaque formation, endothelium, arteriolar damage, smooth muscle cell proliferation, and altered-oxidative stress response. Conversely, few studies focused on the relationship between HHcy and small vessel disease (SVD), despite the evidence that mice with HHcy showed a significant end-feet disruption of astrocytes with a diffuse SVD. A severe reduction of vascular aquaporin-4-water channels, lower levels of high-functioning potassium channels, and higher metalloproteinases are also observed. HHcy modulates the N-homocysteinylation process, promoting a pro-coagulative state and damage of the cellular protein integrity. This altered process could be directly involved in the altered endothelium activation, typical of SVD and protein quality, inhibiting the ubiquitin-proteasome system control. HHcy also promotes a constant enhancement of microglia activation, inducing the sustained pro-inflammatory status observed in SVD. This review article addresses the possible role of HHcy in small-vessel disease and understands its pathogenic impact.
