Cerebrovascular Systems Research Articles

Sequelae and Comorbidities of COVID-19 Manifestations on the Cardiac and the Vascular Systems.

COVID-19 patients with pre-existing cardiovascular conditions are at greater risk of severe illness due to the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus. This review evaluates the highest risk factors for these patients, not limited to pre-existing hypertension, cardiac arrhythmias, hypercoagulation, ischemic heart disease, and a history of underlying heart conditions. SARS-CoV-2 may also precipitate de novo cardiac complications. The interplay between existing cardiac conditions and de novo cardiac complications is the focus of this review. In particular, SARS-CoV-2 patients present with hypercoagulation conditions, cardiac arrhythmias, as significant complications. Also, cardiac arrhythmias are another well-known cardiovascular-related complication seen in COVID-19 infections and merit discussion in this review. Amid the pandemic, myocardial infarction (MI) has been reported to a high degree in SARS-CoV-2 patients. Currently, the specific causative mechanism of the increased incidence of MI is unclear. However, studies suggest several links to high angiotensin-converting enzyme 2 (ACE2) expression in myocardial and endothelial cells, systemic hyper-inflammation, an imbalance between myocardial oxygen supply and demand, and loss of ACE2-mediated cardio-protection. Furthermore, hypertension and SARS-CoV-2 infection patients’ prognosis has shown mixed results across current studies. For this reason, an in-depth analysis of the interactions between SARS-CoV2 and the ACE2 cardio-protective mechanism is warranted. Similarly, ACE2 receptors are also expressed in the cerebral cortex tissue, both in neurons and glia. Therefore, it seems very possible for both cardiovascular and cerebrovascular systems to be damaged leading to further dysregulation and increased risk of mortality risk. This review aims to discuss the current literature related to potential complications of COVID-19 infection with hypertension and the vasculature, including the cervical one. Finally, age is a significant prognostic indicator among COVID-19 patients. For a mean age group of 70 years, the main presenting symptoms include fever, shortness of breath, and a persistent cough. Elderly patients with cardiovascular comorbidities, particularly hypertension and diabetes, represent a significant group of critical cases with increased case fatality rates. With the current understanding of COVID-19, it is essential to explore the mechanisms by which SARS-CoV-2 operates to improve clinical outcomes for patients suffering from underlying cardiovascular diseases and reduce the risk of such conditions de novo.

Relation of post-stroke headachto cerebrovascular pathology and hemodynamics.

Despite high prevalence of cerebrovascular stroke, headache attributed to ischemic strokes is often undertreated and overlooked. The aim is to detect the relation of a post-stroke headache to cerebrovascular pathology and changes in hemodynamics through a high-resolution duplex ultrasound examination. The present study was a case-control study conducted among 239 patients, who presented with an acute ischemic stroke. Patients were sub-divided into two groups: group I included patients with headache attributed to ischemic stroke (cases) and group II included headache-free stroke patients (controls). History consisted of headache characteristics and risk factors. Clinical and radiological examination were preformed to detect the type of stroke. Ultrasound duplex examination of extra-cranial and intra-cranial cerebrovascular system was carried for both groups. Group I included 112 patients (mean age, 57.66 ±6.59 years), and group II included 127 patients (mean age 57.73 ±7.89 years). Post-stroke headache was more frequent in patients with posterior circulation infarction (58%). Post-stroke headache was reported within 7 days post-stroke in 61.6% of patients. Pre-stroke headache was an independent predictor for post-stroke headache occurrence (OR = 28.187, 95% CI: 6.612-120.158%, p < 0.001). Collateral opening and various degrees of intra-cranial vascular stenosis were strong predictors of headache occurrence (OR = 25.071, 95% CI: 6.498-96.722%, p < 0.001). In conclusion, post-stroke headache is a common phenomenon, especially in patients with pre-stroke headache, history of old stroke, posterior circulation infarction, and large artery disease. This headache was of moderate-intensity with clinical characteristics of tension-type. Intra-cranial cerebrovascular pathological changes including opening of collateral channels and variable degrees of stenosis of cerebrovascular systems were implicated in the production of that headache.

Hypertension and Stroke Cardiovascular Control Evaluation by Analyzing Blood Pressure, Cerebral Blood Flow, Blood Vessel Resistance and Baroreflex.

Cardiovascular diseases have been the leading causes of mortality in Taiwan and the world at large for decades. The composition of cardiovascular and cerebrovascular systems is quite complicated. Therefore, it is difficult to detect or trace the related signs of cardiovascular and cerebrovascular diseases. The characteristics and changes in cardiopulmonary system disease can be used to track cardiovascular and cerebrovascular disease prevention and diagnosis. This can effectively reduce the occurrence of cardiovascular and cerebrovascular diseases. This study analyzes the variability in blood pressure, cerebral blood flow velocity and the interaction characteristics using linear and nonlinear approaches in stroke, hypertension and healthy groups to identify the differences in cardiovascular control in these groups. The results showed that the blood pressure and cerebral blood flow of stroke patients and hypertensive patients were significantly higher than those of healthy people (statistical differences (p < 0.05). The cerebrovascular resistance (CVR) shows that the CVR of hypertensive patients is higher than that of healthy people and stroke patients (p < 0.1), indicating that the cerebral vascular resistance of hypertensive patients is slightly higher. From the patient’s blood flow and vascular characteristics, it can be observed that the cardiovascular system is different from those in healthy people. Baroreflex sensitivity (BRS) decreased in stroke patients (p < 0.05). Chaotic analysis revealed that the blood pressure disturbance in hypertensive patients has a higher chaotic behavior change and the difference in initial state sensitivity. Cross-correlation (CCF) analysis shows that as the course of healthy→hypertension→stroke progresses, the maximum CCF value decreases significantly (p < 0.05). That means that blood pressure and cerebral blood flow are gradually not well controlled by the self-regulation mechanism. In conclusion, cardiovascular control performance in hypertensive and stroke patients displays greater variation. This can be observed by the bio-signal analysis. This analysis could identify a measure for detecting and preventing the risk for hypertension and stroke in clinical practice. This is a pilot study to analyze cardiovascular control variation in healthy, hypertensive and stroke groups.

Effects of puerarin on chronic inflammation: Focus on the heart, brain, and arteries.

Age‐associated increases in physical and mental stress, known as allostatic load, could lead to a chronic low‐grade inflammation in the heart, brain, and arteries. This low‐grade inflammation potentially contributes to adverse structural and functional remodeling, such as intimal medial thickening, endothelial dysfunction, arterial stiffening, cardiac hypertrophy and ischemia, and cognitive decline. These cellular and tissue remodeling is the fertile soil for the development of age‐associated structural and functional disorders in the cardiovascular and cerebrovascular systems in the pathogenesis of obesity, type II diabetes, hypertension, atherosclerosis, heart dysfunction, and cognitive decline. Growing evidence indicates that puerarin, a polyphenol, extracted from Puerara Labota, efficiently alleviates the initiation and progression of obesity, type II diabetes, hypertension, atherosclerosis, cardiac ischemia, cardiac arrythmia, cardiac hypertrophy, ischemic stroke, and cognition decline via suppression of oxidative stress and inflammation. This mini review focuses on recent advances in the effects of puerarin on the oxidative and inflammatory molecular, cellular, tissue events in the heart, brain, and arteries.

Коронавирусная болезнь-2019 (COVID-19): течение и отдаленные последствия

A new strain of coronavirus — SARS-CoV-2 (Severe Acute Respiratory Syndrome CorOnaVirus-2) has caused an increase in the number of cases and high mortality worldwide. In patients with coronavirus disease 2019 (COVID-19, Corona Virus Disease 19), in addition to lung damage, there is a high risk of developing multiple organ failure. Concomitant cardiovascular diseases are independent risk factors for the development of severe forms of COVID-19. Acute COVID-19 is manifested by polysegmental pneumonia, pulmonary edema, sepsis, atrial or ventricular fibrillation, acute myocardial injury, myocarditis, pericardial effusion, cardiac tamponade, and various thromboembolic disorders. COVID-19 can provoke chronic damage to the cardiovascular, nephro- and cerebrovascular systems, which worsen the patient's life prognosis. In persons who have undergone COVID-19, in the future, an increase in various cardiovascular complications, disorders of carbohydrate and purine metabolism, etc. can be expected. The article discusses the course and long-term consequences of Coronavirus Disease 2019 (COVID-19) based on the presented case series. The above observations of cases of coronavirus disease (COVID-19) demonstrate a variety of its clinical manifestations and outcomes, in which, along with damage to the lungs, there are also lesions of the cardiovascular, endocrine and urinary systems. Based on the accumulated experience in the management of patients, it is proposed to distinguish between acute (from 1 to 4 weeks), subacute (from 4 to 12 weeks) and chronic (from 12 weeks or more) forms. The use of this approach in real clinical practice facilitates the work of doctors in the outpatient-polyclinic stage of observation, reducing the social burden of the disease, routing patients, as well as stratification of persons suffering from COVID-19 for the development of pulmonary fibrosis.

Cardiovascular and Cerebrovascular Implications of Growth Restriction: Mechanisms and Potential Treatments.

Fetal growth restriction (FGR) is a common complication of pregnancy, resulting in a fetus that fails to reach its genetically determined growth potential. Whilst the fetal cardiovascular response to acute hypoxia is well established, the fetal defence to chronic hypoxia is not well understood due to experiment constraints. Growth restriction results primarily from reduced oxygen and nutrient supply to the developing fetus, resulting in chronic hypoxia. The fetus adapts to chronic hypoxia by redistributing cardiac output via brain sparing in an attempt to preserve function in the developing brain. This review highlights the impact of brain sparing on the developing fetal cardiovascular and cerebrovascular systems, as well as emerging long-term effects in offspring that were growth restricted at birth. Here, we explore the pathogenesis associated with brain sparing within the cerebrovascular system. An increased understanding of the mechanistic pathways will be critical to preventing neuropathological outcomes, including motor dysfunction such as cerebral palsy, or behaviour dysfunctions including autism and attention-deficit/hyperactivity disorder (ADHD).

The "Angiogenic Switch" and Functional Resources in Cyclic Sports Athletes.

Regular physical activity in cyclic sports can influence the so-called “angiogenic switch”, which is considered as an imbalance between proangiogenic and anti-angiogenic molecules. Disruption of the synthesis of angiogenic molecules can be caused by local changes in tissues under the influence of excessive physical exertion and its consequences, such as chronic oxidative stress and associated hypoxia, metabolic acidosis, sports injuries, etc. A review of publications on signaling pathways that activate and inhibit angiogenesis in skeletal muscles, myocardium, lung, and nervous tissue under the influence of intense physical activity in cyclic sports. Materials: We searched PubMed, SCOPUS, Web of Science, Google Scholar, Clinical keys, and e-LIBRARY databases for full-text articles published from 2000 to 2020, using keywords and their combinations. Results: An important aspect of adaptation to training loads in cyclic sports is an increase in the number of capillaries in muscle fibers, which improves the metabolism of skeletal muscles and myocardium, as well as nervous and lung tissue. Recent studies have shown that myocardial endothelial cells not only respond to hemodynamic forces and paracrine signals from neighboring cells, but also take an active part in heart remodeling processes, stimulating the growth and contractility of cardiomyocytes or the production of extracellular matrix proteins in myofibroblasts. As myocardial vascularization plays a central role in the transition from adaptive heart hypertrophy to heart failure, further study of the signaling mechanisms involved in the regulation of angiogenesis in the myocardium is important in sports practice. The study of the “angiogenic switch” problem in the cerebrovascular and cardiovascular systems allows us to claim that the formation of new vessels is mediated by a complex interaction of all growth factors. Although the lungs are one of the limiting systems of the body in cyclic sports, their response to high-intensity loads and other environmental stresses is often overlooked. Airway epithelial cells are the predominant source of several growth factors throughout lung organogenesis and appear to be critical for normal alveolarization, rapid alveolar proliferation, and normal vascular development. There are many controversial questions about the role of growth factors in the physiology and pathology of the lungs. The presented review has demonstrated that when doing sports, it is necessary to give a careful consideration to the possible positive and negative effects of growth factors on muscles, myocardium, lung tissue, and brain. Primarily, the “angiogenic switch” is important in aerobic sports (long distance running). Conclusions: Angiogenesis is a physiological process of the formation of new blood capillaries, which play an important role in the functioning of skeletal muscles, myocardium, lung, and nervous tissue in athletes. Violation of the “angiogenic switch” as a balance between proangiogenic and anti-angiogenic molecules can lead to a decrease in the functional resources of the nervous, musculoskeletal, cardiovascular, and respiratory systems in athletes and, as a consequence, to a decrease in sports performance.

Neurovascular-glymphatic dysfunction and white matter lesions.

Cerebral white matter lesions (WML) represent a spectrum of age-related structural changes that are identified as areas of white matter high signal intensity on brain magnetic resonance imaging (MRI). Preservation of white matter requires proper functioning of both the cerebrovascular and glymphatic systems. The cerebrovascular safeguards adequate cerebral blood flow to supply oxygen, energy, and nutrients through a dynamic process of cerebral autoregulation and neurovascular coupling to keep up with global and regional demands of the brain. The glymphatic system maintains white matter integrity by preserving flow of interstitial fluid, exchanging metabolic waste and eventually its clearance into the venous circulation. Here, we argue that these two systems should not be considered separate entities but as one single physiologically integrated unit to preserve brain health. Due to the process of aging, damage to the neurovascular-glymphatic system accumulates over the life course. It is an insidious process that ultimately leads to the disruption of cerebral autoregulation, to the neurovascular uncoupling, and to the accumulation of metabolic waste products. As cerebral white matter is particularly vulnerable to hypoxic, inflammatory, and metabolic insults, WML are the first recognized pathologies of neurovascular-glymphatic dysfunction. A better understanding of the underlying pathophysiology will provide starting points for developing effective strategies to prevent a wide range of clinical disorders among which there are gait disturbances, functional dependence, cognitive impairment, and dementia.

Prospects for Proanthocyanidins from Grape Seed: Extraction Technologies and Diverse Bioactivity

ABSTRACT Grape seed extract is a highly efficient natural antioxidant, mainly due to proanthocyanidin. Grape seed proanthocyanidin (GSP) confers antitumor, antiradiation, antibacterial and anti-inflammatory activities, protection of cardiovascular and cerebrovascular systems, and visual function improvement, among other biological activities. However, GSP is sensitive to light and heat, and is easily affected by pH, oxygen levels, etc., complicating its extraction and application. This article analyzes the advantages and disadvantages of different extraction processes, summarizes the applicable extraction methods under different conditions, and provides a theoretical basis for GSP processing, while emphasizing GSP’s excellent biological activity and the current status of its development and utilization in food industry.

Large Vessel Stroke Following Multiple Other Strokes and Cardiomyopathy in a Forty-Nine-Year-Old COVID-19 Patient

The novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made its presence known on the centerstage of worldwide healthcare in 2020. Although it is widely known about its pulmonary presence and ensuing complications, evidence is emerging that there are other organ systems including the cardiovascular and cerebrovascular systems that may be damaged by this virus. There have been reports of large vessel stroke occurring in coronavirus disease 2019 (COVID-19) positive patients, with very few reported in the age group less than 50 years. In this case, we describe a previously healthy 49-year-old male who presented with signs of stroke, and was found to have the novel coronavirus as he had been suffering from upper respiratory tract symptoms for 3 weeks. He subsequently developed further large vessel stroke while in the hospital despite being started on antiplatelet therapy. He was also found to have new onset cardiomyopathy. He was started on anticoagulation and discharged with follow-up for cardiomyopathy testing outpatient. This case begs the question on which anticoagulation to utilize in COVID-19 positive patients to be effective in preventing thrombotic events. It is postulated that a pro-inflammatory state induced by the virus and the virus’ affinity for angiotensin converting enzyme-2 receptors in the cerebral vasculature are predispositions to cause a stroke. The virus also directly damages cardiac myocytes causing a number of cardiac complications including cardiomyopathy. It is crucial that guidelines on anticoagulation choice and indications for when to start anticoagulation be developed in order to prevent the more devastating consequences of thrombosis and embolism and their subsequent clinical sequelae. J Med Cases. 2021;12(6):238-242 doi: https://doi.org/10.14740/jmc3682

Zingiberis Rhizoma Recens: A Review of Its Traditional Uses, Phytochemistry, Pharmacology, and Toxicology.

Zingiberis Rhizoma Recens (ZRR, the fresh rhizoma of Zingiber officinale Roscoe) is a widely used traditional Chinese medicine (TCM). It is also a traditional spice, widely used around the world. The present paper reviews advances in research relating to the botany, ethnopharmacology, phytochemistry, pharmacology, and toxicology of Zingiberis Rhizoma Recens. In addition, this review also discusses some significant issues and the potential direction of future research on Zingiberis Rhizoma Recens. More than 100 chemical compounds have been isolated from Zingiberis Rhizoma Recens, including gingerols, essential oils, diarylheptanoids, and other compounds. Modern studies have confirmed that Zingiberis Rhizoma Recens has pharmacological effects on the nervous system and cardiovascular and cerebrovascular systems, as well as antiemetic, antibacterial, antitumor, anti-inflammatory, and antioxidant effects. However, the modern studies of Zingiberis Rhizoma Recens are still not complete and more bioactive components and potential pharmacological effects need to be explored in the future. There is no unified standard to evaluate the quality and clinical efficacy of Zingiberis Rhizoma Recens. Therefore, we should establish reasonable, accurate, and reliable quality control standards to make better use of Zingiberis Rhizoma Recens.

Large Vessel Stroke Following Multiple Other Strokes and Cardiomyopathy in a Forty-Nine-Year-Old COVID-19 Patient

The novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made its presence known on the centerstage of worldwide healthcare in 2020. Although it is widely known about its pulmonary presence and ensuing complications, evidence is emerging that there are other organ systems including the cardiovascular and cerebrovascular systems that may be damaged by this virus. There have been reports of large vessel stroke occurring in coronavirus disease 2019 (COVID-19) positive patients, with very few reported in the age group less than 50 years. In this case, we describe a previously healthy 49-year-old male who presented with signs of stroke, and was found to have the novel coronavirus as he had been suffering from upper respiratory tract symptoms for 3 weeks. He subsequently developed further large vessel stroke while in the hospital despite being started on antiplatelet therapy. He was also found to have new onset cardiomyopathy. He was started on anticoagulation and discharged with follow-up for cardiomyopathy testing outpatient. This case begs the question on which anticoagulation to utilize in COVID-19 positive patients to be effective in preventing thrombotic events. It is postulated that a pro-inflammatory state induced by the virus and the virus’ affinity for angiotensin converting enzyme-2 receptors in the cerebral vasculature are predispositions to cause a stroke. The virus also directly damages cardiac myocytes causing a number of cardiac complications including cardiomyopathy. It is crucial that guidelines on anticoagulation choice and indications for when to start anticoagulation be developed in order to prevent the more devastating consequences of thrombosis and embolism and their subsequent clinical sequelae.

Respiratory alkalinization and posterior cerebral artery dilatation predict acute mountain sickness severity during 10h normobaric hypoxia.

What is the central question of this study? The pathophysiology of acute mountain sickness (AMS), involving the respiratory, renal and cerebrovascular systems, remains poorly understood. How do the early adaptations in these systems during a simulated altitude of 5000m relate to AMS risk? What is the main finding and its importance? The rate of blood alkalosis and cerebral artery dilatation predict AMS severity during the first 10 h of exposure to a simulated altitude of 5000m. Slow metabolic compensation by the kidneys of respiratory alkalosis attributable to a brisk breathing response together with excessive brain blood vessel dilatation might be involved in early development of AMS. The complex pathophysiology of acute mountain sickness (AMS) remains poorly understood and is likely to involve maladaptive responses of the respiratory, renal and cerebrovascular systems to hypoxia. Using stepwise linear regression, we tested the hypothesis that exacerbated respiratory alkalosis, as a result of a brisk ventilatory response, sluggish renal compensation in acute hypoxia and dysregulation of cerebral perfusion predict AMS severity. We assessed the Lake Louise score (LLS, an index of AMS severity), fluid balance, ventilation, venous pH, bicarbonate, sodium and creatinine concentrations, body weight, urinary pH and cerebral blood flow [internal carotid artery (ICA) and vertebral artery (VA) blood flow and diameter], in 27 healthy individuals (13 women) throughout 10h exposures to normobaric normoxia (fraction of inspired O2 = 0.21) and normobaric hypoxia (fraction of inspired O2 = 0.117, simulated 5000m) in a randomized, single-blinded manner. In comparison to normoxia, hypoxia increased the LLS, ventilation, venous and urinary pH, and blood flow and diameter in the ICA and VA, while venous concentrations of both bicarbonate and creatinine were decreased (P<0.001 for all). There were significant correlations between AMS severity and the rates of change in blood pH, sodium concentration and VA diameter and more positive fluid balance (P<0.05). Stepwise regression found increased blood pH [beta coefficient (β) = 0.589, P<0.001] and VA diameter (β = 0.418, P = 0.008) to be significant predictors of AMS severity in our cohort [F(2, 20) = 16.1, R2 = 0.617, P<0.001, n = 24], accounting for 62% of the variance in peak LLS. Using classic regression variable selection, our data implicate the degree of respiratory alkalosis and cerebrovascular dilatation in the early stages of AMS development.

From Preclinical Stroke Models to Humans: Polyphenols in the Prevention and Treatment of Stroke.

Polyphenols are an important family of molecules of vegetal origin present in many medicinal and edible plants, which represent important alimentary sources in the human diet. Polyphenols are known for their beneficial health effects and have been investigated for their potential protective role against various pathologies, including cancer, brain dysfunctions, cardiovascular diseases and stroke. The prevention of stroke promoted by polyphenols relies mainly on their effect on cardio- and cerebrovascular systems. However, a growing body of evidence from preclinical models of stroke points out a neuroprotective role of these molecules. Notably, in many preclinical studies, the polyphenolic compounds were effective also when administered after the stroke onset, suggesting their possible use in promoting recovery of patients suffering from stroke. Here, we review the effects of the major polyphenols in cellular and in vivo models of both ischemic and hemorrhagic stroke in immature and adult brains. The results from human studies are also reported.

Small molecules targeting cyclooxygenase/prostanoid cascade in experimental brain ischemia: Do they translate?

Acute brain ischemia accounts for most of stroke cases and constitutes a leading cause of deaths among adults and permanent disabilities in survivors. Currently, the intravenous thrombolysis is the only available medication for ischemic stroke; mechanical thrombectomy is an emerging alternative treatment for occlusion of large arteries and has shown some promise in selected subsets of patients. However, the overall narrow treatment window and potential risks largely limit the patient eligibility. New druggable targets are needed to innovate the treatment of brain ischemia. As the rate-limiting enzyme in the biosyntheses of prostanoids, cyclooxygenase (COX), particularly the inducible isoform COX-2, has long been implicated in mechanisms of acute stroke-induced brain injury and inflammation. However, the notion of therapeutically targeting COX has been diminished over the past two decades due to significant complications of the cardiovascular and cerebrovascular systems caused by long-term use of COX-2 inhibitor drugs. New treatment strategies targeting the downstream prostanoid signaling receptors regulating the deleterious effects of COX cascade have been proposed. As such, a large number of selective small molecules that negatively or positively modulate these important inflammatory regulators have been evaluated for neuroprotection and other beneficial effects in various animal models of brain ischemia. These timely preclinical studies, though not yet led to clinical innovation, provided new insights into the regulation of inflammatory reactions in the ischemic brain and could guide drug discovery efforts aiming for novel adjunctive strategies, along with current reperfusion therapy, to treat acute brain ischemia with higher specificity and longer therapeutic window.

Regulation of the parental gene GRM4 by circGrm4 RNA transcript and glutamate-mediated neurovascular toxicity in eyes.

Epigenetic memory plays crucial roles in gene regulation. It not only modulates the expression of specific genes but also has ripple effects on transcription as well as translation of other genes. Very often an alteration in expression occurs either via methylation or demethylation. In this context, "1-carbon metabolism" assumes a special significance since its dysregulation by higher levels of homocysteine; Hcy (known as hyperhomocysteinemia; HHcy), a byproduct of "1-Carbon Metabolism" during methionine biosynthesis leads to serious implications in cardiovascular, renal, cerebrovascular systems, and a host of other conditions. Currently, the circular RNAs (circRNAs) generated via non-canonical back-splicing events from the pre-mRNA molecules are at the center stage for their essential roles in diseases via their epigenetic manifestations. We recently identified a circular RNA transcript (circGRM4) that is significantly upregulated in the eye of cystathionine β-synthase-deficient mice. We also discovered a concurrent over-expression of the mGLUR4 receptor in the eyes of these mice. In brief, circGRM4 is selectively transcribed from its parental mGLUR4 receptor gene (GRM4) functions as a "molecular-sponge" for the miRNAs and results into excessive turnover of the mGLUR4 receptor in the eye in response to extremely high circulating glutamate concentration. We opine that this epigenetic manifestation potentially predisposes HHcy people to retinovascular malfunctioning.

Homocysteine and Mitochondria in Cardiovascular and Cerebrovascular Systems.

Elevated concentration of homocysteine (Hcy) in the blood plasma, hyperhomocysteinemia (HHcy), has been implicated in various disorders, including cardiovascular and neurodegenerative diseases. Accumulating evidence indicates that pathophysiology of these diseases is linked with mitochondrial dysfunction. In this review, we discuss the current knowledge concerning the effects of HHcy on mitochondrial homeostasis, including energy metabolism, mitochondrial apoptotic pathway, and mitochondrial dynamics. The recent studies suggest that the interaction between Hcy and mitochondria is complex, and reactive oxygen species (ROS) are possible mediators of Hcy effects. We focus on mechanisms contributing to HHcy-associated oxidative stress, such as sources of ROS generation and alterations in antioxidant defense resulting from altered gene expression and post-translational modifications of proteins. Moreover, we discuss some recent findings suggesting that HHcy may have beneficial effects on mitochondrial ROS homeostasis and antioxidant defense. A better understanding of complex mechanisms through which Hcy affects mitochondrial functions could contribute to the development of more specific therapeutic strategies targeted at HHcy-associated disorders.

The impact of sex and gender on heart-brain axis dysfunction: current concepts and novel perspectives.

The heart-brain axis (HBA) recapitulates all the circuits that regulate bidirectional flow of communication between heart and brain. Several mechanisms may underlie the interdependent relationship involving heterogeneous tissues at rest and during specific target organ injury such as myocardial infarction, heart failure, arrhythmia, stroke, mood disorders, or dementia. In-depth translational studies of the HBA dysfunction under single-organ injury should include both male and female animals to develop sex- and gender-oriented prevention, diagnosis, and treatment strategies. Indeed, sex and gender are determining factors as females and males exhibit significant differences in terms of susceptibility to risk factors, age of onset, severity of symptoms, and outcome. Despite most studies having focused on the male population, we have conducted a careful appraisal of the literature investigating HBA in females. In particular, we have (i) analyzed sex-related heart and brain illnesses, (ii) recapitulated the most significant studies simultaneously conducted on cardio- and cerebro-vascular systems in female populations, and (iii) hypothesized future perspectives for the development of a gender-based approach to HBA dysfunction. Although sex- and gender-oriented research is at its infancy, the impact of sex on HBA dysfunction is opening unexpected new avenues for managing the health of female subjects exposed to risk of lifestyle multi-organ disease.

The Short-Term Effects of Remote Ischaemic Conditioning on Cerebral Haemodynamics and Cerebral Autoregulation in Healthy Individuals

Remote Ischaemic conditioning (RIC), where brief cycles of ischaemia and reperfusion are applied to the limbs, may improve neurological outcome in acute stroke and reduce recurrent stroke. The short-term effect of RIC on the regulation of cerebral blood flow (CBF), one possible mechanism for these benefits, was investigated. Healthy participants underwent 5-minute recordings in beat-to-beat blood pressure (BP), electrocardiogram (heart rate, HR), end-tidal CO2 and cerebral blood flow velocity (CBFV) with transcranial Doppler insonation of the middle cerebral arteries, before and after four cycles of RIC using 5-min inflation of bilateral thigh cuffs followed by 5-min deflation. Mean values were calculated together with estimates for cerebrovascular resistance, transfer function analysis (TFA) and autoregulation index (ARI). Twenty-five individuals (10 male), aged 28 ± 11 years, had increases in mean and diastolic BP after RIC (113 ± 13 vs. 116 ± 13, p = 0.046; 74 ± 8 vs. 76 ± 9 mmHg, p = 0.03; respectively). Systolic and mean CBFV decreased after RIC (94.5 ± 17.7 vs. 90.0 ± 15.5, p = 0.001; 63.9 ± 11.1 vs. 62.2 ± 10.5 cm s–1, p = 0.02; respectively), as well as pulsatility index (0.77 ± 0.11 vs 0.73 ± 0.11, p = 0.001). No changes occurred in ARI. TFA showed changes in very low frequency range with significantly increased power oscillations (BP and CBFV) and reduction in phase shift (1.04 ± 0.35 vs. 0.76 ± 0.34 radians, p < 0.01). RIC using bilateral thigh cuffs achieved short-term changes to the cerebrovascular and cardiovascular systems. Further evidence is required to establish the effects in a stroke population.

Polyunsaturated fatty acid supplement alleviates depression-incident cognitive dysfunction by protecting the cerebrovascular and glymphatic systems

IntroductionDepression, the most prevalent mood disorder, has high comorbidity with cerebrovascular disease and cognitive decline. However, there is little understanding of the cellular mechanisms involved in depression and its comorbid cerebrovascular damage and cognition impairment. Here, we tested the prediction that the chronic unpredictable mild stress (CUMS) mouse model would manifest in disturbed glymphatic function and that dietary supplementation with polyunsaturated fatty acids (PUFA) could ameliorate these deficits while alleviating the depression-associated cognitive decline. MethodsTo test the treatment effects of PUFA or Es on behaviours, we applied the tail suspension, open field, and sucrose preference tests to assess depressive symptoms, and applied the Morris water maze test to assess cognition in groups of control, chronic unpredictable mild stress (CUMS), PUFA, and escitalopram (Es) treatment. We measured the extracellular concentrations of dopamine (DA), 5-hydroxytryptamine (5-HT) and noradrenaline (NA) in microdialysates from prefrontal cortex (PFC) by liquid chromatography mass spectrometry. Glia cells and inflammatory factors were analysed with fluorescent immunochemistry and western blot, respectively. We tested brain vasomotor function with two-photon and laser speckle imaging in vivo, and measured glymphatic system function by two-photon imaging in vivo and fluorescence tracer imaging ex vivo, using awake and anesthetized mice. Besides, we monitored cortical spreading depression by laser speckle imaging system. AQP4 depolarization is analysed by fluorescent immunochemistry and western blot. ResultsWe confirmed that CUMS elicited depression-like and amnestic symptoms, accompanied by decreased monoamines neurotransmitter concentration in PFC and upregulated neuroinflammation markers. Moreover, CUMS mice showed reduced arterial pulsation and compliance in brain, and exhibited depolarized expression of AQP4, thus indicating glymphatic dysfunction both in awake and anesthetized states. PUFA supplementation rescued depression-like behaviours of CUMS mice, reduced neuroinflammation and cerebrovascular dysfunction, ultimately improved cognitive performance, all of which accompanied by restoring glymphatic system function. In contrast, Es treatment alleviated only the depression-like behavioural symptoms, while showing no effects on glymphatic function and depression-incident cognitive deficits. ConclusionsThe CUMS depression model entails suppression of the glymphatic system. PUFA supplementation rescued most behavioural signs of depression and the associated cognitive dysfunction by restoring the underlying glymphatic system disruption and protecting cerebral vascular function.