Search Results (14)

Hepatocellular carcinoma (HCC) represents the sixth most diagnosed cancer worldwide and is the second leading cause of cancer-related death in the world. The association of HCC and portal vein thrombosis (PVT) represents an advanced stage of the tumor. PVT has a prevalence of about 25–50% in HCC, determining poor prognosis and a remarkable reduction in therapeutic perspectives in these patients, leading to severe complications such as ascites, metastasis, an increase in portal hypertension and potentially fatal gastrointestinal bleeding. The aim of this review is to evaluate the molecular mechanisms that are at the basis of PVT development, trying to evaluate possible strategies in the early detection of patients at high risk of PVT. Full article

Mitomycin C (MMC)-induced genotoxic stress can be considered to be a novel trigger of endothelial dysfunction and atherosclerosis—a leading cause of cardiovascular morbidity and mortality worldwide. Given the increasing genotoxic load on the human organism, the decryption of the molecular pathways underlying genotoxic stress-induced endothelial dysfunction could improve our understanding of the role of genotoxic stress in atherogenesis. Here, we performed a proteomic profiling of human coronary artery endothelial cells (HCAECs) and human internal thoracic endothelial cells (HITAECs) in vitro that were exposed to MMC to identify the biochemical pathways and proteins underlying genotoxic stress-induced endothelial dysfunction. We denoted 198 and 71 unique, differentially expressed proteins (DEPs) in the MMC-treated HCAECs and HITAECs, respectively; only 4 DEPs were identified in both the HCAECs and HITAECs. In the MMC-treated HCAECs, 44.5% of the DEPs were upregulated and 55.5% of the DEPs were downregulated, while in HITAECs, these percentages were 72% and 28%, respectively. The denoted DEPs are involved in the processes of nucleotides and RNA metabolism, vesicle-mediated transport, post-translation protein modification, cell cycle control, the transport of small molecules, transcription and signal transduction. The obtained results could improve our understanding of the fundamental basis of atherogenesis and help in the justification of genotoxic stress as a risk factor for atherosclerosis. Full article

The pathogenesis of cerebral small vessel disease (CSVD) is largely unknown. Endothelial disfunction has been suggested as the turning point in CSVD development. In this study, we tested the effect of plasma from CSVD patients on human cerebral microvascular endothelial cells with the aim of describing the pattern of endothelial activation. Plasma samples from three groups of young subjects have been tested: PTs (subjects affected by early stage CSVD); CTRLs (control subjects without abnormalities at MRI scanning); BDs (blood donors). Human Brain Endothelial Cells 5i (HBEC5i) were treated with plasma and total RNA was extracted. RNAs were pooled to reduce gene expression-based variability and NGS analysis was performed. Differentially expressed genes were highlighted comparing PTs, CTRLs and BDs with HBEC5i untreated cells. No significantly altered pathway was evaluated in BD-related treatment. Regulation of p38 MAPK cascade (GO:1900744) was the only pathway altered in CTRL-related treatment. Indeed, 36 different biological processes turned out to be deregulated after PT treatment of HBEC5i, i.e., the cytokine-mediated signaling pathway (GO:0019221). Endothelial cells activate inflammatory pathways in response to stimuli from CSVD patients’ plasma, suggesting the pathogenetic role of neuroinflammation from the early asymptomatic phases of cerebrovascular disease. Full article

Diabetic retinopathy is one of the major causes of blindness today, despite important achievements in diagnosis and therapy. The involvement of a gut–retina axis is thought to be a possible risk factor for several chronic eye disease, such as glaucoma, age-related macular degeneration, uveitis, and, recently, diabetic retinopathy. Dysbiosis may cause endothelial disfunction and alter retinal metabolism. This review analyzes the evidence regarding changes in gut microbiota in patients with DR compared with diabetics and healthy controls (HCs). A systematic review was performed on PubMed, Web of Science, and Google Scholar for the following terms: “gut microbiota” OR “gut microbiome” AND “diabetic retinopathy”. Ultimately, 9 articles published between 2020 and 2022 presenting comparative data on a total of 228 T2DM patients with DR, 220 patients with T2DM, and 118 HCs were analyzed. All of the studies found a distinctive microbial beta diversity in DR vs. T2DM and HC, characterized by an altered Firmicutes/Bacteroidetes ratio, a decrease in butyrate producers, and an increase in LPS-expressing and pro-inflammatory species in the Bacteroidetes and Proteobacteria phyla. The probiotic species Bifidobacterium and Lactobacillus were decreased when compared with T2DM. Gut microbiota influence retinal health in multiple ways and may represent a future therapeutic target in DR. Full article

Background: Systemic sclerosis (SSc) is a connective tissue disease manifesting with progressive fibrosis of the skin and internal organs. Its pathogenesis is strictly associated with vascular disfunction and damage. Salusin-α and salusin-β, endogenous peptides regulating secretion of pro-inflammatory cytokines and vascular smooth muscle proliferation, may potentially play a role in SSc pathogenesis. Objectives: The aim of this study was to assess the concentration of salusins in sera of patients with SSc and healthy controls and to evaluate correlations between the salusins levels and selected clinical parameters within the study group. Materials and methods: 48 patients with SSc (44 women; mean age, 56.4, standard deviation, 11.4) and 25 adult healthy volunteers (25 women; mean age, 55.2, standard deviation, 11.2) were enrolled. All patients with SSc were treated with vasodilators and twenty-seven of them (56%) also received immunosuppressive therapy. Results: Circulating salusin-α was significantly elevated in patients with SSc in comparison to healthy controls (U = 350.5, p = 0.004). Patients with SSc receiving immunosuppression had higher serum salusin-α concentrations compared with those without immunosuppressive therapy (U = 176.0, p = 0.026). No correlation was observed between salusins concentrations and skin or internal organ involvement parameters. Conclusions: Salusin-α, a bioactive peptide mitigating the endothelial disfunction, was elevated in patients with systemic sclerosis receiving vasodilators and immunosuppressants. Increased salusin-α concertation may be associated with the initiation of atheroprotective processes in patients with SSc managed pharmacologically, which requires verification in future studies. Full article

Atherosclerosis is a leading cause of cardiovascular morbidity and mortality worldwide. Endothelial disfunction underlying the atherogenesis can be triggered by genotoxic stress in endothelial cells. In the presented research whole transcriptome sequencing (RNA-seq) of human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells in vitro exposed to 500 ng/mL mitomycin C (treatment group) or 0.9% NaCl (control group) was performed. Resulting to bioinformatic analysis, 56 upregulated differentially expressed genes (DEGs) and 6 downregulated DEGs with absolute fold change ≥ 2 and FDR p-value < 0.05 were selected in HCAEC exposed to mitomycin C compared to the control group; in HITAEC only one upregulated DEG was found. According to Gene Ontology enrichment analysis, DEGs in HCAEC were classified into 25 functional groups of biological processes, while in HITAEC we found no statistically significant (FDR p-value < 0.05) groups. The four largest groups containing more than 50% DEGs (“signal transduction”, “response to stimulus”, “biological regulation”, and “regulation of biological process”) were identified. Finally, candidate DEGs and pathways underlying the genotoxic stress induced endothelial disfunction have been discovered that could improve our understanding of fundamental basis of atherogenesis and help to justification of genotoxic stress as a novel risk factor for atherosclerosis. Full article

Intensive cancer chemotherapy is well known to cause bone vasculature disfunction and damage, but the mechanism is poorly understood and there is a lack of treatment. Using a rat model of methotrexate (MTX) chemotherapy (five once-daily dosses at 0.75 mg/kg), this study investigated the roles of the Notch2 signalling pathway in MTX chemotherapy-induced bone micro-vasculature impairment. Gene expression, histological and micro-computed tomography (micro-CT) analyses revealed that MTX-induced micro-vasculature dilation and regression is associated with the induction of Notch2 activity in endothelial cells and increased production of inflammatory cytokine tumour necrosis factor alpha (TNFα) from osteoblasts (bone forming cells) and bone marrow cells. Blockade of Notch2 by a neutralising antibody ameliorated MTX adverse effects on bone micro-vasculature, both directly by supressing Notch2 signalling in endothelial cells and indirectly via reducing TNFα production. Furthermore, in vitro studies using rat bone marrow-derived endothelial cell revealed that MTX treatment induces Notch2/Hey1 pathway and negatively affects their ability in migration and tube formation, and Notch2 blockade can partially protect endothelial cell functions from MTX damage. Full article

The Piper species are a recognized botanical source of a broad structural diversity of lignans and its derivatives. For the first time, Piper tectoniifolium Kunth is presented as a promising natural source of the bioactive (−)-grandisin. Phytochemical analyses of extracts from its leaves, branches and inflorescences showed the presence of the target compound in large amounts, with leaf extracts found to contain up to 52.78% in its composition. A new HPLC-DAD-UV method was developed and validated to be selective for the identification of (−)-grandisin being sensitive, linear, precise, exact, robust and with a recovery above 90%. The absolute configuration of the molecule was determined by X-ray diffraction. Despite the identification of several enantiomers in plant extracts, the major isolated substance was characterized to be the (−)-grandisin enantiomer. In vascular reactivity tests, it was shown that the grandisin purified from botanical extracts presented an endothelium-dependent vasorelaxant effect with an IC₅₀ of 9.8 ± 1.22 μM and around 80% relaxation at 30 μM. These results suggest that P. tectoniifolium has the potential to serve as a renewable source of grandisin on a large scale and the potential to serve as template for development of new drugs for vascular diseases with emphasis on disorders related to endothelial disfunction. Full article

Sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs. Despite significant morbidity and mortality throughout the world, its pathogenesis and mechanisms are not clearly understood. In this narrative review, we aimed to summarize the recent developments in our understanding of the hallmarks of sepsis pathogenesis (immune and adaptive immune response, the complement system, the endothelial disfunction, and autophagy) and highlight novel laboratory diagnostic approaches. Clinical management is also discussed with pivotal consideration for antimicrobic therapy management in particular settings, such as intensive care unit, altered renal function, obesity, and burn patients. Full article

The exact molecular pathways underlying the multifactorial natural history of intracranial aneurysms (IAs) are still largely unknown, to the point that their understanding represents an imperative challenge in neurovascular research. Wall shear stress (WSS) promotes the genesis of IAs through an endothelial dysfunction causing an inflammatory cascade, vessel remodeling, phenotypic switching of the smooth muscle cells, and myointimal hyperplasia. Aneurysm growth is supported by endothelial oxidative stress and inflammatory mediators, whereas low and high WSS determine the rupture in sidewall and endwall IAs, respectively. Angioarchitecture, age older than 60 years, female gender, hypertension, cigarette smoking, alcohol abuse, and hypercholesterolemia also contribute to growth and rupture. The improvements of aneurysm wall imaging techniques and the implementation of target therapies targeted against inflammatory cascade may contribute to significantly modify the natural history of IAs. This narrative review strives to summarize the recent advances in the comprehension of the mechanisms underlying the genesis, growth, and rupture of IAs. Full article

(1) Background: Chronic venous insufficiency (CVI) is a common disorder related to functional and morphological abnormalities of the venous system. Inflammatory processes and angiogenesis alterations greatly concur to the onset of varicose vein. KYP-2047 is a selective inhibitor of prolyl oligopeptidase (POP), a serine protease involved in the release of pro-angiogenic molecules. The aim of the present study is to evaluate the capacity of KYP-2047 to influence the angiogenic and inflammatory mechanisms involved in the pathophysiology of CVI. (2) Methods: An in vivo model of CVI-induced by saphene vein ligation (SVL) and a tissue block culture study were performed. Mice were subjected to SVL followed by KYP-2047 treatment (intraperitoneal, 10 mg/kg) for 7 days. Histological analysis, Masson’s trichrome, Van Gieson staining, and mast cells evaluation were performed. Release of cytokines, nitric oxide synthase production, TGF-beta, VEGF, α-smooth muscle actin, PREP, Endoglin, and IL-8 quantification were investigated. (3) Results: KYP-2047 treatment ameliorated the histological abnormalities of the venous wall, reduced the collagen increase and modulated elastin content, lowered cytokines levels and prevented mast degranulation. Moreover, a decreased expression of TGF-beta, eNOS, VEGF, α-smooth muscle actin, IL-8, and PREP was observed in in vivo study; also a reduction in VEGF and Endoglin expression was confirmed in tissue block culture study. (4) Conclusions: For the first time, this research, highlighting the importance of POP as new target for vascular disorders, revealed the therapeutic potential of KYP-2047 as a helpful treatment for the management of CVI. Full article

It is well accepted that the immune system and some cells from adaptive and innate immunity are necessary for the initiation/perpetuation of arterial hypertension (AH). However, whether neutrophils are part of this group remains debatable. There is evidence showing that the neutrophil/lymphocyte ratio correlates with AH and is higher in non-dipper patients. On the other hand, the experimental neutrophil depletion in mice reduces basal blood pressure. Nevertheless, their participation in AH is still controversial. Apparently, neutrophils may modulate the microenvironment in blood vessels by increasing oxidative stress, favoring endothelial disfunction. In addition, neutrophils may contribute to the tissue infiltration of immune cells, secreting chemoattractant chemokines/cytokines and promoting the proinflammatory phenotype, leading to AH development. In this work, we discuss the potential role of neutrophils in AH by analyzing different mechanisms proposed from clinical and basic studies, with a perspective on cardiovascular and renal damages relating to the hypertensive phenotype. Full article

The interplay between chronic constraint and advanced aging on blood flow, shear-rate, vascular function, nitric oxide (NO)-bioavailability, microcirculation, and vascular inflammation factors is still a matter of debate. Ninety-eight individuals (Young, n = 28, 23 ± 3 yrs; Old, n = 36, 85 ± 7 yrs; Bedridden, n = 34, 88 ± 6 yrs) were included in the study. The bedridden group included old individuals chronically confined to bed (3.8 ± 2.3 yrs). A blood sample was collected and analyzed for plasma nitrate, and vascular inflammatory markers. Hyperemic response (∆peak) during the single passive leg movement (sPLM) test was used to measure vascular function. Skeletal muscle total hemoglobin was measured at the vastus lateralis during the sPLM test, by means of near infrared spectroscopy (NIRS). Bedridden subjects revealed a depletion of plasma nitrates compared with Old (−23.8%) and Young (−31.1%). Blood flow was lower in the Bedridden in comparison to Old (−20.1%) and Young (−31.7%). Bedridden presented lower sPLM ∆peak compared Old (−72.5%) and the Young (−83.3%). ∆peak of NIRS total hemoglobin was lower in the Bedridden compared to that in the Young (−133%). All vascular inflammatory markers except IL-6 were significantly worse in the Bedridden compared to Old and Young. No differences were found between the Old and Young in inflammatory markers. Results of this study confirm that chronic physical constraint induces an exacerbation of vascular disfunction and differential regulation of vascular-related inflammatory markers. The mechanisms involved in these negative adaptations seems to be associated with endothelial dysfunction and consequent diminished NO-bioavailability likely caused by the reduced shear-rate consequential to long-term reduction of physical activity. Full article

The term of angiogenesis refers to the growth of new vessels from pre-existing capillaries. The phenomenon is necessary for physiological growth, repair and functioning of our organs. When occurring in a not regulated manner, it concurs to pathological conditions as tumors, eye diseases, chronic degenerative disorders. On the contrary insufficient neovascularization or endothelial disfunction accompanies ischemic and metabolic disorders. In both the cases an inflammatory and oxidative condition exists in supporting angiogenesis deregulation and endothelial dysfunction. The use of nutraceuticals with antioxidant and anti-inflammatory activities can be a therapeutic option to maintain an adequate vascularization and endothelial cell proper functioning or to blunt aberrant angiogenesis. A revision of the updated literature reports on nutraceuticals to guide endothelial cell wellness and to restore physiological tissue vascularization is the objective of this paper. The critical aspects as well as lacking data for human use will be explored from a pharmacological perspective. Full article