Aberrant Angiogenesis Research Articles

Efficacy of stem cell secretome loaded in hyaluronate sponge for topical treatment of psoriasis.

Psoriasis vulgaris is an inflammatory disease characterized by distinctive skin lesions and dysregulated angiogenesis. Recent research uses stem cell secretion products (CM); a set of bioactive factors with therapeutic properties that regulate several cellular processes, including tissue repair and angiogenesis. The aim of this work was to evaluate the effect of CM of Wharton's gelatin MSC (hWJCM) in a treatment based on the bioactivation of a hyaluronic acid matrix (HA hWJCM) in a psoriasiform-like dermatitis (PD) mouse model. A preclinical study was conducted on PD mice. The effect of hWJCM, Clobetasol (Clob) gold standard, HA Ctrl, and HA hWJCM was tested topically evaluating severity of PD, mice weight as well as skin, liver, and spleen appearance. Treatment with either hWJCM, HA Ctrl or HA hWJCM, resulted in significant improvement of the PD phenotype. Moreover, treatment with HA hWJCM reduced the Psoriasis Area Severity Index (PASI), aberrant angiogenesis, and discomfort associated with the disease, leading to total recovery of body weight. We suggest that the topical application of HA hWJCM can be an effective noninvasive therapeutic solution for psoriasis, in addition to other skin diseases, laying the groundwork for future studies in human patients.

Real-World Data on Cabozantinib in Advanced Osteosarcoma and Ewing Sarcoma Patients: A Study from the Hellenic Group of Sarcoma and Rare Cancers.

Advanced osteosarcomas (OSs) and Ewing sarcomas (ESs) tend to have poor prognosis with limited therapeutic options beyond first-line therapy. Aberrant angiogenesis and MET signaling play an important role in preclinical models. The anti-angiogenic drug cabozantinib was tested in a phase 2 trial of advanced OS and ES and was associated with clinical benefits. We retrospectively analyzed the off-label use of cabozantinib in adult patients with advanced OS and ES/primitive neuroectodermal tumors (PNETs) in three centers of the Hellenic Group of Sarcoma and Rare Cancers (HGSRC). Between April 2019 and January 2022, 16 patients started taking 60 mg of cabozantinib for advanced bone sarcoma or PNET. Median age at cabozantinib initiation was 31 years (17-83). All patients had received peri-operative chemotherapy for primary sarcoma and between 0 and 4 lines of treatment (median; 2.5) for advanced disease. The most common adverse effects included fatigue, anorexia, hypertransaminasemia, weight loss, and diarrhea. One toxic death was noted (cerebral hemorrhage). Dose reduction to 40 mg was required in 31.3% of the patients. No objective response was noted, and 9/16 patients exhibited stable disease outcomes. Progression-free survival varied from 1 to 8 (median; 5) months. Our study demonstrates that cabozantinib has antitumor activity in this population. In the real-life setting, we observed similar adverse events as in the CABONE study and in other neoplasms.

A placenta-on-a-chip model to determine the regulation of FKBPL and galectin-3 in preeclampsia

Preeclampsia is a pregnancy-specific cardiovascular disorder, involving significant maternal endothelial dysfunction. Although inappropriate placentation due to aberrant angiogenesis, inflammation and shallow trophoblast invasion are the root causes of preeclampsia, pathogenic mechanisms are poorly understood, particularly in early pregnancy. Here, we first confirm the abnormal expression of important vascular and inflammatory proteins, FK506-binding protein-like (FKBPL) and galectin-3 (Gal-3), in human plasma and placental tissues from women with preeclampsia and normotensive controls. We then employ a three-dimensional microfluidic placental model incorporating human umbilical vein endothelial cells (HUVECs) and a first trimester trophoblast cell line (ACH-3P) to investigate FKBPL and Gal-3 signaling in inflammatory conditions. In human samples, both circulating (n = 17 controls; n = 30 preeclampsia) and placental (n ≥ 6) FKBPL and Gal-3 levels were increased in preeclampsia compared to controls (plasma: FKBPL, p < 0.0001; Gal-3, p < 0.01; placenta: FKBPL, p < 0.05; Gal-3, p < 0.01), indicative of vascular dysfunction in preeclampsia. In our placenta-on-a-chip model, we show that endothelial cells are critical for trophoblast-mediated migration and that trophoblasts effectively remodel endothelial vascular networks. Inflammatory cytokine tumour necrosis factor-α (10 ng/mL) modulates both FKBPL and Gal-3 signaling in conjunction with trophoblast migration and impairs vascular network formation (p < 0.005). Our placenta-on-a-chip recapitulates aspects of inappropriate placental development and vascular dysfunction in preeclampsia.

Angiogenesis in hepatocellular carcinoma: mechanisms and anti-angiogenic therapies.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Angiogenesis, the process of formation of new blood vessels, is required for cancer cells to obtain nutrients and oxygen. HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth, progression, invasion, and metastasis. Current anti-angiogenic therapies target mainly tyrosine kinases, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), and are considered effective strategies for HCC, particularly advanced HCC. However, because the survival benefits conferred by these anti-angiogenic therapies are modest, new anti-angiogenic targets must be identified. Several recent studies have determined the underlying molecular mechanisms, including pro-angiogenic factors secreted by HCC cells, the tumor microenvironment, and cancer stem cells. In this review, we summarize the roles of pro-angiogenic factors; the involvement of endothelial cells, hepatic stellate cells, tumor-associated macrophages, and tumor-associated neutrophils present in the tumor microenvironment; and the regulatory influence of cancer stem cells on angiogenesis in HCC. Furthermore, we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC. A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.

Meet the First Authors.

Meet the First Authors.

The role of superb micr ole of superb microvascular imaging in detecting low-gr ascular imaging in detecting low-grade inflammation among adults and those with chronic kidney disease: A preliminary study.

Pathophysiologic changes associated with chronic inflammation occur with aging and more prominently in patients with chronic kidney disease (CKD), and an association between chronic inflammation and muscle wasting has been identified. The microcirculation is extremely sensitive to the inflammatory process and actively participates in it. In a healthy adult, angiogenesis is a strictly controlled and rare occurrence. However, aberrant angiogenesis and the development of new tiny blood vessels are known in chronic inflammatory diseases. Superb microvascular imaging (SMI) is a noninvasive technique that can evaluate tiny vessels with low blood flow and provide quantitative data. Our goal was to detect increased blood flow secondary to low-grade chronic inflammation in micro-circulation in the rectus femoris (RF) muscle using SMI. This cross-sectional study involved 30 patients with CKD, 30 adults without CKD or other chronic illnesses, and 32 young healthy volunteers. This study was conducted in our university hospital between March and December 2021. The RF cross-sectional area (CSA) was measured, and vascular index (VI) values were obtained using SMI. All three groups' RF-CSA and VI values were compared. Although there was no statistically significant difference in RF-CSAs between the groups, the VI values of all three groups were statistically different (p < 0.001). The median (min-max) VI values were 0.90 (0.60-1.30), 0.50 (0.20-1.0), and 0.30 (0.10-0.50) for the CKD, adult control, and young healthy groups, respectively. The VI significantly differentiated patients with CKD from all other patients and the adult control group. When a cutoff value of 6.5 was used for the VI in detecting increased blood supply in RF muscle in patients with CKD, the accuracy, positive predictive value, and negative predictive value were 93.5%, 85.3%, and 98.3%, respectively. SMI can detect increased blood supply caused by low-grade inflammation in the RF muscle.

Thrombosis in hereditary hemorrhagic telangiectasia

Thrombosis in hereditary hemorrhagic telangiectasia

The role of extracellular matrix proteins on placental angiogenesis in severe fetal growth restriction

Impaired vascular development is a central finding in severe fetal growth restriction (FGR) with abnormal Doppler velocimetry. Angiogenesis involves complex interactions between endothelial cells (ECs) and extracellular matrix (ECM). Our laboratory previously found that FGR ECs exhibit deficient angiogenic properties, a deficit that is further worsened in the presence of ECM generated from FGR placentae but partially rescued by control ECM. Our objective was to identify the effects of individual ECM substrates on EC function to better characterize the impaired angiogenic pathway characteristic of FGR. ECs were isolated from term control (n=8) or severe FGR (n=8) human placentae and plated on six individual ECM proteins: fibronectin; collagens I, III, and IV; laminin; and thrombospondin. Adhesion was assessed by colorimetric staining. Live cell microscopy was used to determine proliferation. Migration was analyzed via relative wound density following wound scratch. Apoptosis was evaluated by immunoblotting for cleaved caspase 3. T tests, ANOVAs, and nonlinear regressions were performed. There was no difference between adhesion of control and FGR ECs to individual ECM substrates. Control ECs proliferated more rapidly than FGR ECs (p< 0.01; figure 1). Deficient growth of FGR ECs was not rescued by any ECM substrate. Migration of FGR ECs was impaired relative to control ECs when accounting for all substrates (p=0.02). This finding persisted specifically in the presence of collagen I (p=0.03; figure 2) but not other substrates. Apoptosis was not detected for either type of ECs on any substrate. ECs from placentae affected by severe FGR display impaired proliferation and migration. This growth deficit appears to be independent of individual ECM substrates. FGR migratory defects persist on collagen I but not other substrates. Our data suggest that no singular ECM protein is responsible for the aberrant angiogenesis seen in severe FGR and rather there are likely multiple mechanisms underlying this pathology.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

RNF213 Loss-of-Function Promotes Angiogenesis of Cerebral Microvascular Endothelial Cells in a Cellular State Dependent Manner.

Enhanced and aberrant angiogenesis is one of the main features of Moyamoya disease (MMD) pathogenesis. The ring finger protein 213 (RNF213) and the variant p.R4810K have been linked with higher risks of MMD and intracranial arterial occlusion development in east Asian populations. The role of RNF213 in diverse aspects of the angiogenic process, such as proliferation, migration and capillary-like formation, is well-known but has been difficult to model in vitro. To evaluate the effect of the RNF213 MMD-associated gene on the angiogenic activity, we have generated RNF213 knockout in human cerebral microvascular endothelial cells (hCMEC/D3-RNF213-/-) using the CRISPR-Cas9 system. Matrigel-based assay and a tri-dimensional (3D) vascularized model using the self-assembly approach of tissue engineering were used to assess the formation of capillary-like structures. Quite interestingly, this innovative in vitro model of MMD recapitulated, for the first time, disease-associated pathophysiological features such as significant increase in angiogenesis in confluent endothelial cells devoid of RNF213 expression. These cells, grown to confluence, also showed a pro-angiogenic signature, i.e., increased secretion of soluble pro-angiogenic factors, that could be eventually used as biomarkers. Interestingly, we demonstrated that that these MMD-associated phenotypes are dependent of the cellular state, as only noted in confluent cells and not in proliferative RNF213-deficient cells.

TAK1 blockade as a therapy for retinal neovascularization

Retinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Transforming growth factor-β-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-β1 and other proinflammatory cytokines. TAK1 is also a key mediator of proinflammatory signals and plays an important role in maintaining vascular integrity upon proinflammatory cytokine stimulation such as TNFα. However, its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. Here, we investigate the regulatory role of TAK1 in human endothelial cells responding to inflammatory stimuli and in a rat model of oxygen-induced retinopathy (OIR) featured retinal neovascularization. Using TAK1 knockout human endothelial cells that subjected to inflammatory stimuli, transcriptome analysis revealed that TAK1 is required for activation of NFκB signaling and mediates its downstream gene expression related to endothelial activation and angiogenesis. Moreover, pharmacological inhibition of TAK1 by 5Z-7-oxozeaenol attenuated angiogenic activities of endothelial cells. Transcriptome analysis also revealed enrichment of TAK1-mediated NFκB signaling pathway in the retina of OIR rats and retinal neovascular membrane from patients with proliferative diabetic retinopathy. Intravitreal injection of 5Z-7-oxozeaenol significantly reduced hypoxia-induced inflammation and microglial activation, thus attenuating aberrant retinal angiogenesis in OIR rats. Our data suggest that inhibition of TAK1 may have therapeutic potential for the treatment of retinal neovascular pathologies.

Single-cell transcriptome analyses reveal microglia types associated with proliferative retinopathy.

Pathological angiogenesis is a major cause of irreversible blindness in individuals of all age groups with proliferative retinopathy (PR). Mononuclear phagocytes (MPs) within neovascular areas contribute to aberrant retinal angiogenesis. Due to their cellular heterogeneity, defining the roles of MP subsets in PR onset and progression has been challenging. Here, we aimed to investigate the heterogeneity of microglia associated with neovascularization and to characterize the transcriptional profiles and metabolic pathways of proangiogenic microglia in a mouse model of oxygen-induced PR (OIR). Using transcriptional single-cell sorting, we comprehensively mapped all microglia populations in retinas of room air (RA) and OIR mice. We have unveiled several unique types of PR-associated microglia (PRAM) and identified markers, signaling pathways, and regulons associated with these cells. Among these microglia subpopulations, we found a highly proliferative microglia subset with high self-renewal capacity and a hypermetabolic microglia subset that expresses high levels of activating microglia markers, glycolytic enzymes, and proangiogenic Igf1. IHC staining shows that these PRAM were spatially located within or around neovascular tufts. These unique types of microglia have the potential to promote retinal angiogenesis, which may have important implications for future treatment of PR and other pathological ocular angiogenesis-related diseases.

STAT3 signaling induced by the IL-6 family of cytokines modulates angiogenesis.

Aberrant angiogenesis is a hallmark of cardiovascular and retinal neovascular disease. The STAT3 signaling pathway represents a potential pharmacological target for these diseases due to its impact on angiogenesis. Surprisingly, some STAT3 activators, such as the IL-6 cytokine family member oncostatin M (OSM), enhance angiogenesis, whereas others, such as ciliary neurotropic factor (CNTF), reduce it. This study aimed to clarify these conflicting effects. In contrast to the anti-angiogenic cytokine CNTF, the pro-angiogenic cytokine OSM was able to activate intracellular signaling pathways beyond the STAT3 pathway, including the ERK and AKT pathways. These differences translated into transcriptomic and metabolic shifts. siRNA-mediated STAT3 knockdown experiments showed a decrease in VEGF-induced endothelial migration and sprouting, enhancing the pro-angiogenic drive of OSM and switching the CNTF response from anti-angiogenic to pro-angiogenic. These effects correlated with a transcriptomic shift representing enhanced STAT1 and ERK activity following STAT3 knockdown, including a compensatory prolonged phosphorylated STAT1 activity. In conclusion, the angiogenic effect of STAT3 appears to be determined by cytokine-induced STAT3 specificity and simultaneous activity of other intracellular signaling pathways, whereas the STAT3 pathway, predominantly recognized for its pro-angiogenic phenotypes, reveals novel anti-angiogenic potential.

Transcriptomic Differences in Endothelial Cells Across Five Brain Regions in Normal Aging and Alzheimer's Disease

AbstractBackgroundAltered cerebral vasculature is recognized as a key feature of Alzheimer’s disease (AD) neuropathology, with current evidence suggesting a diverse collection of changes including aberrant angiogenesis, vascular pruning, inflammation, senescence, and other remodeling events. Previous studies examining the endothelial cell transcriptome in AD have been limited to 1‐2 brain regions and hampered by low numbers of isolated endothelial cell nuclei, potentially missing relevant regional heterogeneity. We hypothesized that such regional heterogeneity in endothelial cell gene expression in the normal aging brain may contribute to the varied vascular responses to AD neuropathology.MethodNuclei were isolated from five brain areas in subjects with increasing AD pathology (n=32 donors). The five brain areas chosen represent the hierarchical accumulation of tau pathology in AD: entorhinal cortex &gt; inferior temporal gyrus &gt; prefrontal cortex &gt; secondary visual cortex &gt; primary visual cortex. All subjects had detailed p‐tau, in vitro tau seeding, and amyloid‐beta plaque measurements available. Nuclei were FACS sorted to exclude NeuN+ and Olig2+ cells, and the resulting neuron‐ and oligodendrocyte‐depleted fraction was subject to single‐nucleus RNAseq. Endothelial cell nuclei were identified based on high von Willebrand factor expression and filtered to exclude contaminating glia, yielding a dataset comprised of 51,586 total nuclei.ResultTranscriptomic analysis confirmed that endothelial cells share a core set of commonly upregulated genes across the five brain regions compared to other cell types. However, there is also regional heterogeneity with 193‐311 differentially upregulated genes expressed in endothelial cells within each brain area relative to all other areas. Compared to normal aging brain, endothelial cells from AD donors downregulated 962 genes and upregulated 936 genes that are enriched in vasculogenesis, blood‐brain barrier maintenance, senescence, and leukocyte interactions. Further analysis indicates regional differences in upregulation of these pathways and highlights the relationship to disease burden.ConclusionThis dataset demonstrates a previously unrecognized regional heterogeneity in endothelial cell transcriptome in the normal aging human brain. These regional differences may impact the endothelial cell response to the local AD pathology. This dataset will inform ongoing research efforts to unravel the molecular underpinnings of AD‐induced endothelial cell dysfunction.

Brain AVMs-Related microRNAs: Machine Learning Algorithm for Expression Profiles of Target Genes.

microRNAs (miRNAs) are a class of non-coding RNAs playing a myriad of important roles in regulating gene expression. Of note, recent work demonstrated a critical role of miRNAs in the genesis and progression of brain arteriovenous malformations (bAVMs). Accordingly, here we examine miRNA signatures related to bAVMs and associated gene expression. In so doing we expound on the potential prognostic, diagnostic, and therapeutic significance of miRNAs in the clinical management of bAVMs. A PRISMA-based literature review was performed using PubMed/Medline database with the following search terms: "brain arteriovenous malformations", "cerebral arteriovenous malformations", "microRNA", and "miRNA". All preclinical and clinical studies written in English, regardless of date, were selected. For our bioinformatic analyses, miRWalk and miRTarBase machine learning algorithms were employed; the Kyoto Encyclopedia of Genes and Genomes (KEGG) database was quired for associated pathways/functions. four studies were ultimately included in the final analyses. Sequencing data consistently revealed the decreased expression of miR-18a in bAVM-endothelial cells, resulting in increased levels of vascular endodermal growth factor (VEGF), Id-1, matrix metalloproteinase, and growth signals. Our analyses also suggest that the downregulation of miR-137 and miR-195* within vascular smooth muscle cells (VSMCs) may foster the activation of inflammation, aberrant angiogenesis, and phenotypic switching. In the peripheral blood, the overexpression of miR-7-5p, miR-629-5p, miR-199a-5p, miR-200b-3p, and let-7b-5p may contribute to endothelial proliferation and nidus development. The machine learning algorithms employed confirmed associations between miRNA-related target networks, vascular rearrangement, and bAVM progression. miRNAs expression appears to be critical in managing bAVMs' post-transcriptional signals. Targets of microRNAs regulate canonical vascular proliferation and reshaping. Although additional scientific evidence is needed, the identification of bAVM miRNA signatures may facilitate the development of novel prognostic/diagnostic tools and molecular therapies for bAVMs.

Study of Angiogenic Potential and Oxidative Metabolism in Mesenchymal Stromal Cells Derived from Shwachman-Diamond Syndrome Patients

Introduction: Shwachman-Diamond Syndrome (SDS) is a rare autosomal recessive bone marrow (BM) failure disorder. SDS BM biopsies showed tortuous vessels with collapsed lumens, which might promote progression of malignant clones. Mesenchymal stromal cells (MSCs) are crucial elements in the BM niche homeostasis. Our group previously demonstrated that the in vivo ability of semi-cartilaginous pellets derived from SDS-MSCs to generate complete heterotopic ossicles was severely impaired in comparison with healthy donors (HDs). In addition, after specific angiogenic stimuli, SDS-MSCs showed an in vitro defective capability to form a well-defined tubular network. The aim of this study was to deeply investigate the cellular and molecular mechanisms underlying the SDS-MSCs impaired angiogenic potential. Methods: The angiogenic capability of BM derived SDS- and HD-MSCs was evaluated by performing in vitro Matrigel angiogenesis assay, by analysing cell viability and the expression of key angiogenic molecules before and after the angiogenic assay (RT-PCRs and/or ELISA). Concerning energy metabolism, oxidative phosphorylation (OxPhos) has been assayed by oximetry and bioluminescent ATP synthesis assay, and ATP/AMP ratio, malondialdehyde (MDA) level, and complex IV and lactate dehydrogenase (LDH) activity have been evaluated by spectrophotometric analyses. Results: We confirmed the impaired angiogenic potential of SDS-MSCs, previously observed in a restricted cohort of patients (n=6), in 13 SDS- compared to 14 HD-MSCs. In detail, after 3h of angiogenic stimuli, SDS-MSCs showed a defective capability to recreate a defined capillary-like network compared to HD-MSCs in a Matrigel-based assay. Accordingly, ImageJ Angiogenesis Analyzer showed that several angiogenic elements, including branches and meshes, were significantly reduced in SDS-MSCs. Furthermore, we demonstrated that the angiogenic defect of SDS-MSCs was correlated neither to a lower cellular viability than HD-MSCs, nor to a different expression of the main angiogenic molecules. Different reports showed a close relationship between aberrant angiogenesis and oxidative stress. Based on previous studies that demonstrated a defective energy metabolism and an increased oxidative stress in SDS patient-derived lymphoblastoid cells, we performed metabolic analyses of 6 SDS- and 6 HD-MSCs from the cohort used for angiogenic assay. In detail, we assayed OxPhos metabolism, evaluating oxygen consumption and ATP production. Concerning the I, III, and IV complexes pathway, we demonstrated that SDS-MSCs consumed 54% less oxygen (p=0.009) and they produced 60% less ATP compared to HD-MSCs (p=0.004). Accordingly, the analysis of the II, III, and IV complexes pathway demonstrated that the oxygen consumption was reduced by 61% (p=0.002) and the ATP synthesis was 67% lower than HD-MSCs (p=0.002). In addition, the P/O ratio, an index of OxPhos efficiency, was significantly reduced in SDS-MSCs in both electron transport chain pathways (p=0.004 for both). Moreover, OxPhos defect of SDS-MSCs was associated to the decreased enzymatic activity of complex IV compared to HD-MSCs (mean=9.5mU of oxidated cytochrome c/mg protein, range=7.8-11.5mU/mg vs mean=25.6mU/mg, range=21.6-31.9mU/mg; p=0.002). Consequently, SDS-MSCs showed a low intracellular ATP/AMP ratio (mean=1.1, range=0.8-1.6 vs mean=3.6, range=3.1-4.0, in HDs; p=0.002). This decrease was accompanied by an increased LDH activity (mean=0.4mU/mg protein, range=0.4-0.6mU/mg vs mean=0.3mU/mg, range=0.27-0.32mU/mg, in HDs; p=0.0022) in SDS-MSCs, showing an attempt to compensate the mitochondrial defect by the anaerobic glycolysis enhancement. Finally, we demonstrated that the level of lipid peroxidation of SDS-MSCs was significantly increased compared to HDs (mean=11.8µM of MDA/mg protein, range=10.4-15.2µM/mg vs mean=6.5µM/mg, range=5.0-7.7µM/mg; p=0.0022), suggesting an oxidative stress production increment. Conclusions: We demonstrated that the angiogenic defect in SDS-MSCs coexists with metabolic alterations. In addition, we demonstrated for the first time to our knowledge, that SDS-MSCs showed a defective oxidative metabolism, characterized by a decreased energy production and a high level of oxidative damage. These results underline the key role of MSCs in SDS BM niche and provide new insights into the pathogenesis of this rare disease.

What's New in Musculoskeletal Basic Science.

What's New in Musculoskeletal Basic Science.

Tetrabromobisphenol a exacerbates the overall radioactive hazard to zebrafish (Danio rerio)

The major health risks of dual exposure to two hazardous factors of plastics and radioactive contamination are obscure. In the present study, we systematically evaluated the combinational toxic effects of tetrabromobisphenol A (TBBPA), one of the most influential plastic ingredients, mainly from electronic wastes, and γ-irradiation in zebrafish for the first time. TBBPA (0.25 μg/mL for embryos and larvae, 300 μg/L for adults) contamination aggravated the radiation (6 Gy for embryos and larvae, 20 Gy for adults)-induced early dysplasia and aberrant angiogenesis of embryos, further impaired the locomotor vitality of irradiated larvae, and worsened the radioactive multiorganic histologic injury, neurobehavioural disturbances and dysgenesis of zebrafish adults as well as the inter-generational neurotoxicity in offspring. TBBPA exaggerated the radiative toxic effects not only by enhancing the inflammatory and apoptotic response but also by further unbalancing the endocrine system and disrupting the underlying gene expression profiles. In conclusion, TBBPA exacerbates radiation-induced injury in zebrafish, including embryos, larvae, adults and even the next generation. Our findings provide new insights into the toxicology of TBBPA and γ-irradiation, shedding light on the severity of cocontamination of MP components and radioactive substances and thereby inspiring novel remediation and rehabilitation strategies for radiation-injured aqueous organisms and radiotherapy patients.

Extracranial arteriovenous malformations demonstrate dysregulated TGF-β/BMP signaling and increased circulating TGF-β1

Extracranial arteriovenous malformations (AVMs) are characterized by anomalous arterial-to-venous connections, aberrant angiogenesis, local inflammation and hypoxia, and disorganized histological architecture; however, the precise molecular perturbations leading to this phenotype remain elusive. We hypothesized that extracranial AVM tissue would demonstrate deregulation of the TGF-β/BMP signaling pathway, which may serve as a potential target in the development of molecular-based therapies for AVMs. AVM tissue was harvested during resection from 10 patients with AVMs and compared to control tissue. Blood was collected from 14 AVM patients and 10 patients without AVMs as controls. Expression of TGF-β/BMP pathway components was analyzed using RT-PCR, western blotting, and immunohistochemistry. Circulating levels of TGF-β1 were analyzed by ELISA. Paired t tests were utilized to perform statistical analysis. The mRNA levels of TGF-β1, ALK1, Endoglin (ENG), Smad6, Smad7, and Smad8 were significantly elevated in AVM tissue when compared to controls. Protein levels of TGF-β1 and Smad3 were elevated in AVM tissue while protein levels of BMP-9, ALK1, Smad1, Smad6, and Smad8 were significantly decreased in AVMs. Immunohistochemistry demonstrated increased TGF-β1 in the perivascular cells of AVMs compared to normal controls, and circulating levels of TGF-β1 were significantly higher in AVM patients. Patients with AVMs demonstrate aberrant TGF-β/BMP expression in AVM tissue and blood compared to controls. Targeting aberrantly expressed components of the TGF-β/BMP pathway in extracranial AVMs may be a viable approach in the development of novel molecular therapies, and monitoring circulating TGF-β1 levels may be a useful indicator of treatment success.

Design, synthesis and biological evaluation of conformationnally-restricted analogues of E7010 as inhibitors of tubulin assembly (ITA) and vascular disrupting agents (VDA)

Vascular-disrupting agents (VDA) specifically target established neovasculature which results in vascular shutdown. This therapeutic strategy could improve the outcome of pathologies involving aberrant angiogenesis. Although several classes of VDA exist, inhibitors of tubulin assembly (ITA) represent the main category. A series of 21 conformationnally-restricted analogues of E7010, a known ITA-VDA, were designed and synthesised as novel inhibitors of tubulin assembly (ITA) and vascular-disrupting agents (VDA). Among them, indole 4j exhibited good potency against HUVEC and HIG-82 cell lines, as well as a good ability to inhibit tubulin assembly. Furthermore, indole 4j reduced HUVEC migration in a dose-dependent manner, indicating a vascular disrupting activity comparable to that of the gold standard, Combretastatin A4 (CA4).

Cell-Free Filtrates (CFF) as Vectors of a Transmissible Pathologic Tissue Memory Code: A Hypothetical and Narrative Review.

Cellular memory is a controversial concept representing the ability of cells to “write and memorize” stressful experiences via epigenetic operators. The progressive course of chronic, non-communicable diseases such as type 2 diabetes mellitus, cancer, and arteriosclerosis, is likely driven through an abnormal epigenetic reprogramming, fostering the hypothesis of a cellular pathologic memory. Accordingly, cultured diabetic and cancer patient-derived cells recall behavioral traits as when in the donor’s organism irrespective to culture time and conditions. Here, we analyze the data of studies conducted by our group and led by a cascade of hypothesis, in which we aimed to validate the hypothetical existence and transmissibility of a cellular pathologic memory in diabetes, arteriosclerotic peripheral arterial disease, and cancer. These experiments were based on the administration to otherwise healthy animals of cell-free filtrates prepared from human pathologic tissue samples representative of each disease condition. The administration of each pathologic tissue homogenate consistently induced the faithful recapitulation of: (1) Diabetic archetypical changes in cutaneous arterioles and nerves. (2) Non-thrombotic arteriosclerotic thickening, collagenous arterial encroachment, aberrant angiogenesis, and vascular remodeling. (3) Pre-malignant and malignant epithelial and mesenchymal tumors in different organs; all evocative of the donor’s tissue histopathology and with no barriers for interspecies transmission. We hypothesize that homogenates contain pathologic tissue memory codes represented in soluble drivers that “infiltrate” host’s animal cells, and ultimately impose their phenotypic signatures. The identification and validation of the actors in behind may pave the way for future therapies.