The neutrophil: A key resourceful agent in immune-mediated vasculitis.

The term "vasculitis" refers to a group of rare immune-mediated diseases characterized by the dysregulated immune system attacking blood vessels located in any organ of the body, including the skin, lungs, and kidneys. Vasculitides are classified according to the size of the vessel that is affected. Although this observation is not specific to small-, medium-, or large-vessel vasculitides, patients show a high circulating neutrophil-to-lymphocyte ratio, suggesting the direct or indirect involvement of neutrophils in these diseases. As first responders to infection or inflammation, neutrophils release cytotoxic mediators, including reactive oxygen species, proteases, and neutrophil extracellular traps. If not controlled, this dangerous arsenal can injure the vascular system, which acts as the main transport route for neutrophils, thereby amplifying the initial inflammatory stimulus and the recruitment of immune cells. This review highlights the ability of neutrophils to "set the tone" for immune cells and other cells in the vessel wall. Considering both their long-established and newly described roles, we extend their functions far beyond their direct host-damaging potential. We also review the roles of neutrophils in various types of primary vasculitis, including immune complex vasculitis, anti-neutrophil cytoplasmic antibody-associated vasculitis, polyarteritis nodosa, Kawasaki disease, giant cell arteritis, Takayasu arteritis, and Behçet's disease.

Exosomal miR-126-3p: Potential protection against vascular damage by regulating the SLC7A5/mTOR Signalling pathway in human umbilical vein endothelial cells.

Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease. Vascular damage is one of the important features of SSc, which affects the progression and prognosis of the disease. MiR-126-3p is an important microRNA (miRNA) that regulates vascular structure and function, which can be transported through exosomes. However, the role of miR-126-3p in vascular damage in SSc is still unclear. Therefore, we focused on the connection between miR-126-3p and vascular damage in SSc, as well as investigated the potential role of miR-126-3p in vascular damage in SSc. First, this study successfully extracted extracellular vesicles from clinical plasma samples and characterized the exosomes within them. Then, we predicted and screened the target pathway mammalian/mechanistic target of rapamycin (mTOR) and the target gene SLC7A5 of miR-126-3p through online databases. Next, we constructed SSc mice for in vivo studies. The results showed that the expression of miR-126-3p was decreased in the plasma exosomes, while the SLC7A5 expression, autophagy, and lipid peroxidation were increased in the aorta. Luciferase reporter gene assays demonstrated that miR-126-3p can bind to SLC7A5, resulting in a decrease in its expression. In vitro experiments have shown that exosomal miR-126-3p can be internalized by human umbilical vein endothelial cells (HUVECs). The miR-126-3p group exhibited enhanced cell viability and tube formation ability, along with increased expression of the vascular formation marker CD31. Additionally, miR-126-3p downregulated the protein expression of SLC7A5 and LC3 in HUVECs, while upregulating the protein expression of mTOR, P62, PPARγ, and CPT-1. However, the effects of miR-126-3p on HUVECs were counteracted by mTOR inhibitors and enhanced by mTOR activators. The results indicated that exosomal miR-126-3p has the potential to protect against vascular injury in SSc by regulating the SLC7A5/mTOR signalling pathway in HUVECs.

Integrin-linked kinase mRNA expression in circulating mononuclear cells as a biomarker of kidney and vascular damage in experimental chronic kidney disease.

BACKGROUND: Traditional biomarkers of chronic kidney disease (CKD) detect the disease in its late stages and hardly predict associated vascular damage. Integrin-linked kinase (ILK) is a scaffolding protein and a serine/threonine protein kinase that plays multiple roles in several pathophysiological processes during renal damage. However, the involvement of ILK as a biomarker of CKD and its associated vascular problems remains to be fully elucidated. METHODS: CKD was induced by an adenine-rich diet for 6 weeks in mice. We used an inducible ILK knockdown mice (cKD-ILK) model to decrease ILK expression. ILK content in mice's peripheral blood mononuclear cells (PBMCs) was determined and correlated with renal function parameters and with the expression of ILK and fibrosis and inflammation markers in renal and aortic tissues. Also, the expression of five miRNAs that target ILK was analyzed in whole blood of mice. RESULTS: The adenine diet increased ILK expression in PBMCs, renal cortex, and aortas, and creatinine and urea nitrogen concentrations in the plasma of WT mice, while these increases were not observed in cKD-ILK mice. Furthermore, ILK content in PBMCs directly correlated with renal function parameters and with the expression of renal and vascular ILK and fibrosis and inflammation markers. Finally, the expression of the five miRNAs increased in the whole blood of adenine-fed mice, although only four correlated with plasma urea nitrogen, and of those, three were downregulated in cKD-ILK mice. CONCLUSIONS: ILK, in circulating mononuclear cells, could be a potential biomarker of CKD and CKD-associated renal and vascular damage.

Serum biomarkers of inflammation and vascular damage upon SARS-Cov-2 mRNA vaccine in patients with thymic epithelial tumors.

OBJECTIVES: Thymic epithelial tumors (TET) patients are at high risk of autoimmune and hypoimmune complications. Limited evidence is available on the potential risk of immune-related and inflammatory reactions induced by SARS-Cov-2 vaccine in this patient population. METHODS: In order to identify subjects at higher risk for vaccine complications, we prospectively evaluated a panel of serum biomarkers related to inflammation (TNF-α, IL-1ß, -6, -10, -12, and -17A, IFN-α, ß and γ, MPO, MMP-9), and vascular damage (E- and P-selectin, VEGF-A, P-ANCA and MCP-1) in 44 TET patients and in 30 healthy controls along the whole SARS-Cov-2 vaccine cycle. RESULTS: About 50 % of subjects (either TET and controls) showed an increase of serum biochemical markers of inflammation and endothelial damage with a large heterogeneity of values. Such increase appeared early, after the first dose in control subjects and later, after the second dose in TET patients (in which we observed mainly an increase of inflammatory biomarkers). The values normalized after about 3 months and did not increase after the third, booster dose. No autoimmune or vascular complications were observed in the study subjects and no difference was observed in terms of vaccine response among subjects showing serum biomarkers increase and those who experienced no changes. CONCLUSIONS: Our data highlight the relevance of Sars-Cov-2 vaccine in TET patients, as it resulted safe and prevented severe COVID-19. However, further studies are awaited to explore the mechanisms and the potential consequences of the observed increase of serum inflammatory and vascular damage biomarkers.

Genetically proxied appendicular lean mass and stroke risk: A two-step mendelian randomization study.

BACKGROUND AND PURPOSE: Prior observational studies have suggested a strong correlation between sarcopenia and stroke, but the causal link between them remains uncertain. This study aims to investigate the associations between genetically predicted sarcopenia-related traits and stroke using a two-step Mendelian randomization (MR) approach. METHODS: Genome-wide association study (GWAS) summary data for sarcopenia-related traits were acquired from the UK Biobank. Genetic associations for ischemic stroke (IS) and its subtypes were selected from the MEGASTROKE consortium comprising European ancestry participants. GWAS summary data for cerebral hemorrhage were obtained from the FinnGen consortium, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). MR estimates were calculated using the inverse-variance weighted (IVW) method. The robustness of results was assessed for heterogeneity and pleiotropy of individual single nucleotide polymorphisms (SNPs). RESULTS: Higher appendicular lean mass (ALM) exhibited a potential causal association with a reduced incidence of large artery atherosclerosis (LAA) (odds ratio [OR] = 0.81, 95% confidence interval [CI]:0.71-0.93; P = 0.003) and small vessel disease (SVD) (OR = 0.83, 95% CI:0.74-0.94; P = 0.002). The associations of ALM with IS and ICH were compromised after adjusting for body fat and physical activity with multivariable MR. Two-step MR mediation analysis explored 33 candidate mediators, among which hypertension and SBP accounted for more than 10% of the mediation proportion in the relationship between ALM and stroke and its subtypes. CONCLUSION: Our research findings indicate that lower ALM is associated with a increased risk of stroke . It is necessary to explore the specific protective mechanisms of higher ALM for preventing stroke occurrence.

Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review.

Systemic sclerosis (SSc, scleroderma) is a multifaceted rare connective tissue disease whose pathogenesis is dominated by immune dysregulation, small vessel vasculopathy, impaired angiogenesis, and both cutaneous and visceral fibrosis. Microvascular impairment represents the initial event of the disease, preceding fibrosis by months or years and accounting for the main disabling and/or life-threatening clinical manifestations, including telangiectasias, pitting scars, periungual microvascular abnormalities (e.g., giant capillaries, hemorrhages, avascular areas, ramified/bushy capillaries) clinically detectable by nailfold videocapillaroscopy, ischemic digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. Despite a variety of available treatment options, treatment of SSc-related vascular disease remains problematic, even considering SSc etherogenity and the quite narrow therapeutic window. In this context, plenty of studies have highlighted the great usefulness in clinical practice of vascular biomarkers allowing clinicians to assess the evolution of the pathological process affecting the vessels, as well as to predict the prognosis and the response to therapy. The current narrative review provides an up-to-date overview of the main candidate vascular biomarkers that have been proposed for SSc, focusing on their main reported associations with characteristic clinical vascular features of the disease.

Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage.

Both progression from the early pathogenic events to clinically manifest cardiovascular diseases (CVD) and cancer impact the integrity of the vascular system. Pathological vascular modifications are affected by interplay between endothelial cells and their microenvironment. Soluble factors, extracellular matrix molecules and extracellular vesicles (EVs) are emerging determinants of this network that trigger specific signals in target cells. EVs have gained attention as package of molecules with epigenetic reversible activity causing functional vascular changes, but their mechanisms are not well understood. Valuable insights have been provided by recent clinical studies, including the investigation of EVs as potential biomarkers of these diseases. In this paper, we review the role and the mechanism of exosomal epigenetic molecules during the vascular remodeling in coronary heart disease as well as in cancer-associated neoangiogenesis.

NAFLD as a continuous driver in the whole spectrum of vascular disease.

Vascular disease is the prime determinant to cardiovascular morbidities and mortalities, which comprises the early vascular damage and subsequent cardiovascular events. Non-alcohol Fatty Liver Disease (NAFLD) is a systemic metabolic disorder that drives the progression of vascular disease through complex interactions. Although a causal relationship between NAFLD and cardiovascular disease (CVD) has not been established, a growing number of epidemiological studies have demonstrated an independent association between NAFLD and early vascular disease and subsequent cardiovascular events. In addition, mechanistic studies suggest that NAFLD initiates and accelerates vascular injury by increasing systemic inflammation and oxidative stress, impairing insulin sensitivity and lipid metabolism, and modulating epigenetics, the intestinal flora and hepatic autonomic nervous system; thus, NAFLD is a putative driving force for CVD progression. In this review, we summarize the clinical evidence supporting the association of NAFLD with subclinical vascular disease and cardiovascular events and discuss the potential mechanisms by which NAFLD promotes the progression of vascular disease.

Far-infrared radiation alleviates cisplatin-induced vascular damage and impaired circulation via activation of HIF-1α.

Severe vascular damage and complications are often observed in cancer patients during treatment with chemotherapeutic drugs such as cisplatin. Thus, development of potential options to ameliorate the vascular side effects is urgently needed. In this study, the effects and the underlying mechanisms of far-infrared radiation (FIR) on cisplatin-induced vascular injury and endothelial cytotoxicity/dysfunction in mice and human umbilical vein endothelial cells (HUVECs) were investigated. An important finding is that the severe vascular stenosis and poor blood flow seen in cisplatin-treated mice were greatly mitigated by FIR irradiation (30 minutes/day) for 1-3 days. Moreover, FIR markedly increased the levels of phosphorylation of PI3K and Akt, and VEGF secretion, as well as the expression and the activity of hypoxia-inducible factor 1α (HIF-1α) in cisplatin-treated HUVECs in a promyelocytic leukemia zinc finger protein (PLZF)-dependent manner. However, FIR-stimulated endothelial angiogenesis and VEGF release were significantly diminished by transfection with HIF-1α siRNA. We also confirmed that HIF-1α, PI3K, and PLZF contribute to the inhibitory effect of FIR on cisplatin-induced apoptosis in HUVECs. Notably, FIR did not affect the anticancer activity and the HIF-1α/VEGF cascade in cisplatin-treated cancer cells under normoxic or hypoxic condition, indicating that the actions of FIR may specifically target endothelial cells. It is the first study to demonstrate that FIR effectively attenuates cisplatin-induced vascular damage and impaired angiogenesis through activation of HIF-1α-dependent processes via regulation of PLZF and PI3K/Akt. Taken together, cotreatment with the noninvasive and easily performed FIR has a therapeutic potential to prevent the pathogenesis of vascular complications in cancer patients during cisplatin treatment.

Plasma microparticles of intubated COVID-19 patients cause endothelial cell death, neutrophil adhesion and netosis, in a phosphatidylserine-dependent manner.

COVID-19 has compelled scientists to better describe its pathophysiology to find new therapeutic approaches. While risk factors, such as older age, obesity, and diabetes mellitus, suggest a central role of endothelial cells (ECs), autopsies have revealed clots in the pulmonary microvasculature that are rich in neutrophils and DNA traps produced by these cells, called neutrophil extracellular traps (NETs.) Submicron extracellular vesicles, called microparticles (MPs), are described in several diseases as being involved in pro-inflammatory pathways. Therefore, in this study, we analyzed three patient groups: one for which intubation was not necessary, an intubated group, and one group after extubation. In the most severe group, the intubated group, platelet-derived MPs and endothelial cell (EC)-derived MPs exhibited increased concentration and size, when compared to uninfected controls. MPs of intubated COVID-19 patients triggered EC death and overexpression of two adhesion molecules: P-selectin and vascular cell adhesion molecule-1 (VCAM-1). Strikingly, neutrophil adhesion and NET production were increased following incubation with these ECs. Importantly, we also found that preincubation of these COVID-19 MPs with the phosphatidylserine capping endogenous protein, annexin A5, abolished cytotoxicity, P-selectin and VCAM-1 induction, all like increases in neutrophil adhesion and NET release. Taken together, our results reveal that MPs play a key role in COVID-19 pathophysiology and point to a potential therapeutic: annexin A5.

P75 neurotrophin receptor controls subventricular zone neural stem cell migration after stroke.

Stroke is the leading cause of adult disability. Endogenous neural stem/progenitor cells (NSPCs) originating from the subventricular zone (SVZ) contribute to the brain repair process. However, molecular mechanisms underlying CNS disease-induced SVZ NSPC-redirected migration to the lesion area are poorly understood. Here, we show that genetic depletion of the p75 neurotrophin receptor (p75NTR-/-) in mice reduced SVZ NSPC migration towards the lesion area after cortical injury and that p75NTR-/- NSPCs failed to migrate upon BDNF stimulation in vitro. Cortical injury rapidly increased p75NTR abundance in SVZ NSPCs via bone morphogenetic protein (BMP) receptor signaling. SVZ-derived p75NTR-/- NSPCs revealed an altered cytoskeletal network- and small GTPase family-related gene and protein expression. In accordance, BMP-treated non-migrating p75NTR-/- NSPCs revealed an altered morphology and α-tubulin expression compared to BMP-treated migrating wild-type NSPCs. We propose that BMP-induced p75NTR abundance in NSPCs is a regulator of SVZ NSPC migration to the lesion area via regulation of the cytoskeleton following cortical injury.

Dietary sugars and subclinical vascular damage in moderate-to-high cardiovascular risk adults.

BACKGROUND AND AIMS: The association between dietary sugars and vascular damage has been scarcely examined out of the context of established cardiovascular disease. We aimed to investigate the association between different types of sugars with subclinical atheromatosis and arteriosclerosis, in individuals free of cardiovascular disease being, however, at moderate-to-high cardiovascular risk. METHODS AND RESULTS: Two 24-h dietary recalls were conducted to estimate sugars intake. Subclinical atheromatosis was assessed by B-mode ultrasonography and arteriosclerosis (arterial stiffness) via tonometry (carotid-to-femoral pulse wave velocity). Multiple logistic regression analysis was performed to determine the relationship of quartiles of total sugars, monosaccharides and disaccharides with atheromatosis and arteriosclerosis, adjusting for potential confounders [Odds Ratio (95%Confidence Interval)]. In 901 participants (52.4 ± 13.8 years, 45.2% males), total sugars intake was not associated with any type of subclinical vascular damage. Subjects at 4th quartile of lactose intake (15.3 ± 5.5 g/day) had lower probability to present atheromatosis compared to those at 1st quartile (0.00 ± 0.01 g/day) even in the fully adjusted model [0.586 (0.353-0.974)]. Subjects at 3rd quartile of total disaccharides intake and particularly sucrose (15.1 ± 2.2 g/day) had higher probability to present arteriosclerosis compared to those at 1st quartile (3.0 ± 1.9 g/day) even after adjustment for all potential confounders [2.213 (1.110-4.409)]. CONCLUSIONS: Overall, the present data suggest a distinct role of each type of sugars on vascular damage. These observations highlight the need for further studies investigating not only foods rich in sugars, but sugars as separate components of food as they probably contribute via different ways on the development of arterial pathologies.

Right atrium enlargement is related to increased heart damage and mortality in well-controlled hypertension.

BACKGROUND AND AIM: Left heart remodeling is a well-known pathophysiological effect of arterial hypertension. Right Heart status is not considered in its evaluation. No data are available on right atrium (RA) and its impact on the outcome in hypertension. We wondering to understand whether RA may play a role as a marker of an increased risk for organ damage in well-controlled hypertensives, to probe the clinical significance and whether it could indicate an increased risk. METHODS AND RESULTS: We studied well-controlled hypertensive patients. Heart damage was assessed by echocardiography. Patients were subdivided into those with RA area ≤18 cm2 (normal RA - Group 1) (554 pts, 227 M, aged 60.35 ± 10.48 years) and those >18 cm2 (Increased RA - Group 2) (101 pts, 71 M, age 61.65 ± 9.46 years). Group 2 had a higher left ventricle mass (LVM) and left atrium volume (LAV) both as absolute value (both p < 0.0001) and indexed for body surface area (LVMi p < 0.013; LAVi p = 0.0013). Group 2 showed an increased vascular stiffness (p < 0.0001) and carotid stenosis percentage (p = 0.011). TAPSE (p < 0.0001) resulted significantly increased. In The RA area was significantly correlated directly to LVM and LAV in both groups, but these correlations persisted in indexed values only in Group 2. Moreover, in this group there was a significant direct correlation between RA area and Tricuspid s'wave at echocardiography TDI analysis. Finally, Group 2 had an increased mortality rate compared to Group 1 (Log-Rank p = 0.0006). CONCLUSION: Group 2 hypertensive patients showed more alterations in dimensional and volumetric left heart parameters, and an increased mortality.

Comparison of Carotid Intima-Media Thickness in Children and Adults With and Without Obesity: A Hysteresis Model.

OBJECTIVE: To describe a third-degree polynomial function (hysteresis) of the effect size of age, obesity, and insulin sensitivity over the carotid intima-media thickness (c-IMT), in the pediatric and adult groups. METHODS: A quasi-experimental study with fixed factor analysis of age (children aged 8-12 years, n = 73; adults aged 21-45 years, n = 82) and obesity (yes, n = 76; no, n = 79) was conducted to analyze the effect on the c-IMT and Matsuda insulin sensitivity index values. This quasi-experimental design was analyzed with robust regression modeling. RESULTS: The additive effect of obesity, independent of age, was evident in the case of the c-IMT values. There was no interaction effect, but a significant difference between participants with normal weight and those with obesity was found (P < .0001). The difference between adults and children was also significant, but the effect size was smaller. A model was created based on age, Tanner stage, and obesity using the c-IMT and Matsuda insulin sensitivity index values. A linear function fit as R2, and the cubic function estimated parameters like a polynomial model. CONCLUSION: This practical study design showed that children with obesity displayed the same levels of carotid intima-media abnormalities as adults with obesity. The polynomial shape of the model suggests potentially poor outcomes that resemble the hysteresis process and may predict chronic cardiometabolic events during early adulthood.

Assessment of vascular damage in children and young adults with Familial Mediterranean Fever.

Familial Mediterranean Fever (FMF) is the most frequent autoinflammatory disease. This study aimed to evaluate the risk of subclinical vascular damage in FMF children, and young adults, using both imaging and laboratory tests. Forty-five FMF patients (mean age 14.3 ± 9.5 years, 33 children) and 44 healthy controls(mean age 13.3 ± 8.6 years, 36 children) were included in the study. The patients were diagnosed according to Tel-Hashomer criteria, were positive for MEFV gene mutation, were treated with colchicine and were evaluated during an attack free-period. The arterial stiffness parameters studied were carotid-femoral pulse wave velocity (PWV), Augmentation Index (Aix), subendocardial viability ratio (SEVR) and carotid intima-media thickness (cIMT). Laboratory parameters, inflammation markers and lipid profile were also evaluated for all participants. There were no significant differences between patients and healthy individuals, as well as in our children population regarding PWV, SEVR, Aix and cIMT. However, significantly higher ESR, CRP and fibrinogen levels were detected in the total population of FMF patients and higher amyloid levels in FMF children, compared to controls. Atherogenic Index of Plasma was significantly higher both in the total patient population and in the subgroup of children, compared to controls. Furthermore, a significant positive correlation between Aix and CRP and a negative correlation between SEVR and ESR became apparent in the pediatric subgroup. Our study demonstrated no significant differences in vascular measurements between FMF patients and controls. The above could be attributed to the regular colchicine treatment, which seems to have a cardioprotective role against vascular damage.

Application of Ultrasound Combined with Microbubbles for Cancer Therapy.

At present, cancer is one of the leading causes of death worldwide. Treatment failure remains one of the prime hurdles in cancer treatment due to the metastatic nature of cancer. Techniques have been developed to hinder the growth of tumours or at least to stop the metastasis process. In recent years, ultrasound therapy combined with microbubbles has gained immense success in cancer treatment. Ultrasound-stimulated microbubbles (USMB) combined with other cancer treatments including radiation therapy, chemotherapy or immunotherapy has demonstrated potential improved outcomes in various in vitro and in vivo studies. Studies have shown that low dose radiation administered with USMB can have similar effects as high dose radiation therapy. In addition, the use of USMB in conjunction with radiotherapy or chemotherapy can minimize the toxicity of high dose radiation or chemotherapeutic drugs, respectively. In this review, we discuss the biophysical properties of USMB treatment and its applicability in cancer therapy. In particular, we highlight important preclinical and early clinical findings that demonstrate the antitumour effect combining USMB and other cancer treatment modalities (radiotherapy and chemotherapy). Our review mainly focuses on the tumour vascular effects mediated by USMB and these cancer therapies. We also discuss several current limitations, in addition to ongoing and future efforts for applying USMB in cancer treatment.

Proteome-Wide Differential Effects of Peritoneal Dialysis Fluid Properties in an In Vitro Human Endothelial Cell Model.

To replace kidney function, peritoneal dialysis (PD) utilizes hyperosmotic PD fluids with specific physico-chemical properties. Their composition induces progressive damage of the peritoneum, leading to vasculopathies, decline of membrane function, and PD technique failure. Clinically used PD fluids differ in their composition but still remain bioincompatible. We mapped the molecular pathomechanisms in human endothelial cells induced by the different characteristics of widely used PD fluids by proteomics. Of 7894 identified proteins, 3871 were regulated at least by 1 and 49 by all tested PD fluids. The latter subset was enriched for cell junction-associated proteins. The different PD fluids individually perturbed proteins commonly related to cell stress, survival, and immune function pathways. Modeling two major bioincompatibility factors of PD fluids, acidosis, and glucose degradation products (GDPs) revealed distinct effects on endothelial cell function and regulation of cellular stress responses. Proteins and pathways most strongly affected were members of the oxidative stress response. Addition of the antioxidant and cytoprotective additive, alanyl-glutamine (AlaGln), to PD fluids led to upregulation of thioredoxin reductase-1, an antioxidant protein, potentially explaining the cytoprotective effect of AlaGln. In conclusion, we mapped out the molecular response of endothelial cells to PD fluids, and provided new evidence for their specific pathomechanisms, crucial for improvement of PD therapies.

Involvement of Ceramide Signalling in Radiation-Induced Tumour Vascular Effects and Vascular-Targeted Therapy.

Sphingolipids are well-recognized critical components in several biological processes. Ceramides constitute a class of sphingolipid metabolites that are involved in important signal transduction pathways that play key roles in determining the fate of cells to survive or die. Ceramide accumulated in cells causes apoptosis; however, ceramide metabolized to sphingosine promotes cell survival and angiogenesis. Studies suggest that vascular-targeted therapies increase endothelial cell ceramide resulting in apoptosis that leads to tumour cure. Specifically, ultrasound-stimulated microbubbles (USMB) used as vascular disrupting agents can perturb endothelial cells, eliciting acid sphingomyelinase (ASMase) activation accompanied by ceramide release. This phenomenon results in endothelial cell death and vascular collapse and is synergistic with other antitumour treatments such as radiation. In contrast, blocking the generation of ceramide using multiple approaches, including the conversion of ceramide to sphingosine-1-phosphate (S1P), abrogates this process. The ceramide-based cell survival "rheostat" between these opposing signalling metabolites is essential in the mechanotransductive vascular targeting following USMB treatment. In this review, we aim to summarize the past and latest findings on ceramide-based vascular-targeted strategies, including novel mechanotransductive methodologies.

Small Vessel Disease: Ancient Description, Novel Biomarkers.

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.

[Update on etiopathogenesis of small vessel vasculitis]. / Update Ätiopathogenese der Kleingefäßvaskulitis.

Small vessel vasculitis is characterized by a necrotizing inflammation of the vessel wall predominantly with involvement of small intraparenchymal arteries, arterioles, capillaries and venules. Medium-sized and occasionally large vessels can also be involved. Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis) are differentiated from immune complex vasculitides based on immunopathological and serological aspects. Immune complex vasculitides include IgA vasculitis, cryoglobulinemic vasculitis, hypocomplementemic urticarial vasculitis (anti-C1q vasculitis) and anti-glomerular basement membrane disease. Epidemiological and next-generation sequencing-based studies have significantly contributed to the identification of predisposing environmental factors and genetic risk factors in recent years. Under specific conditions ANCA and immune complexes can induce premature intravascular activation of neutrophilic granulocytes with degranulation and release of enzymes and reactive oxygen species, which leads to vascular damage. In granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis various factors, such as barrier dysfunction and dysbiosis of the microbiome contribute to extravascular granuloma formation predominantly affecting the respiratory tract.