The Role of the Inflammatory and the Vascular Pathogenesis in a Model of Streptozotocin Induced Diabetic Neuropathy in Rats

Background Peripheral diabetic neuropathy (DN) is one of the major health problems facing the whole world. There is no treatment that could completely reverse or prevent progression of DN except for good glycemic control. The inflammatory and vascular pathways are two main domains that are incorporated in the pathogenesis of diabetic neuropathic pain (DNP) and DN. Thus, targeting both of them could be an appropriate way to delay progression of DN. Aim To investigate the role of the inflammatory and the vascular pathogenesis in diabetic mechanical allodynia. Method Twenty male Wistar rats were divided randomly into naïve and diabetic groups (n = 10). Diabetes was induced through i.p injection of single dose of streptozotocin (STZ) (50mg/kg), then 8 weeks after induction of diabetes, the sciatic content of tumor necrosis factor alpha (TNFα) and vascular endothelial growth factor (VEGF) was assessed using ELISA technique. Additionally, the number of intercellular adhesion molecule-1 (ICAM-1) as well as CD31, the most specific vascular marker, positively stained vessels was counted manually in sciatic nerves cross sections. Whereas, DNP was assessed weekly throughout the experiment using 60%mechanical threshold of paw withdrawal test. Results There was a significant increase in the sciatic content of TNFα, VEGF and ICAM-1 positively stained vessels and a significant decrease in CD31 positively stained vessels in the diabetic group as compared to the naïve group. There was a correlation between TNFα, VEGF, ICAM-1, CD31 positively stained vessels in one side and the 60% mechanical threshold on the other side (r=-0.8, -0.9, -0.8 and 0.7 respectively). Conclusion The diabetic mechanical allodynia is negatively correlated to the sciatic nerve content TNFα, VEGF, ICAM-1 and positively correlated to the CD31.

The Significance of Vascular Pathogenesis in the Examination of Corticobasal Syndrome

Corticobasal syndrome (CBS) is a clinical entity, classified as an atypical Parkinsonism, characterized by both motor and higher cortical dysfunctions. The clinical manifestation of CBS is associated with several pathologies, among which corticobasal degeneration (CBD) is the most common. The aim of our study was to elaborate on the possible vascular pathogenesis of CBS and consider types of vascular lesions in these cases. Several cases of vascular CBS are described in the literature. The majority of presented patients were affected by internal carotid artery (ICA) stenosis and ischemic strokes; few cases were associated with vascular malformations or autoimmune diseases. Vascular CBS is preceded by an abrupt onset. The clinical manifestation does not significantly differ with non-vascular CBS. Patients with vascular CBS are usually elderly; often with coexistent hypertension, dyslipidemia and diabetes mellitus. Inferring from our observations, cerebral hypoperfusion can play a significant role in neuropathological changes in neurodegenerative diseases. To the best of our knowledge paper is the first comprehensive review of vascular CBS and we are positive that our observations show that further research concerning the vascular pathogenesis of tauopathy atypical Parkinsonism is required.

Validity of endocan as a biomarker in systemic sclerosis: relation to pathogenesis and disease activity

Background Systemic sclerosis (SSc), an autoimmune disease, has endothelial dysfunction and tissue fibrosis. The lack of its specific activity markers urges the research. Endocan is an immunomodulatory protein associated with endothelial dysfunction. We aimed to measure of the endocan level in systemic sclerosis (SSc) patients’ sera to test its relation to disease activity and treatment responses. Also, to evaluate its specificity by comparing these data with Behçet’s disease (BD) and rheumatoid arthritis (RA) patients’ data. Results SSc and RA patients were in activity but in the BD group; eight were active and seven were inactive. The endocan level was higher in the three groups in comparison to the controls without statistically significant differences (p value RA 0.697, SSc 0.063, and BD 0.196). A statistically significant difference in endocan levels between SSc patients with and without vascular manifestations (pulmonary hypertension and finger pitting ulcers, p < 0.0001, p = 0.0097, respectively). There were no significant correlations between endocan level and the erythrocyte sedimentation rate and C-reactive protein (positive rheumatoid factor for RA) in the three groups (p > 0.05). There were no significant correlations between endocan level and activity scores in the three groups (p > 0.05). The cut-off value of endocan was 1.3 ng/ml. Conclusion Endocan is a non-specific marker for the vascular pathogenesis in systemic sclerosis but not a good predictor for its activity.

Repeated gain and loss of a single gene modulates the evolution of vascular plant pathogen lifestyles

Vascular plant pathogens travel long distances through host veins, leading to life-threatening, systemic infections. In contrast, nonvascular pathogens remain restricted to infection sites, triggering localized symptom development. The contrasting features of vascular and nonvascular diseases suggest distinct etiologies, but the basis for each remains unclear. Here, we show that the hydrolase CbsA acts as a phenotypic switch between vascular and nonvascular plant pathogenesis. cbsA was enriched in genomes of vascular phytopathogenic bacteria in the family Xanthomonadaceae and absent in most nonvascular species. CbsA expression allowed nonvascular Xanthomonas to cause vascular blight, while cbsA mutagenesis resulted in reduction of vascular or enhanced nonvascular symptom development. Phylogenetic hypothesis testing further revealed that cbsA was lost in multiple nonvascular lineages and more recently gained by some vascular subgroups, suggesting that vascular pathogenesis is ancestral. Our results overall demonstrate how the gain and loss of single loci can facilitate the evolution of complex ecological traits.

Enterovirus Encephalitis in Newborns: Not-Periventricular Brain Involvement and Vascular Pathogenesis in a Novel Case

Neonatal encephalitis by either enteroviruses (EVs) or parechoviruses (PeVs) is often complicated by hemispheric periventricular white matter lesions. Although showing many similarities, the two types of encephalitis differ in some clinical and laboratory aspects, mostly because PeV encephalitis does not show any change of protein and white cell content in the cerebrospinal fluid, and clinically, the onset of PeV encephalitis is often marked by early seizures accompanying a fever of sepsis-like disease. Instead, no difference exists relative to the white matter lesions, which are constantly described as periventricular, even in rare detailed neuropathological studies. Herein, taking a cue from a neonate with EV encephalitis who showed occipital white matter lesions involving the overlying cortex, but completely sparing the periventricular area, we demonstrate that the brain lesions in EV encephalitis in newborns can be more extended than known. To our knowledge, the not-periventricular involvement of the white matter with EV encephalitis has never been described so far, as well as the potential of EV to injure the cortex. We confirm the pathogenetic role of a vascular mechanism for the tissue injury, but other proposed mechanisms are also discussed. It is noteworthy that the neurological outcome of this newborn remained favorable, and no epileptic seizures occurred in the first few days nor afterward.

Repeated gain and loss of a single gene modulates the evolution of vascular pathogen lifestyles

Vascular pathogens travel long distances through host veins leading to life-threatening, systemic infections. In contrast, non-vascular pathogens remain restricted to infection sites, triggering localized symptom development. The contrasting features of vascular and non-vascular diseases suggest distinct etiologies, but the basis for each remains unclear. Here, we show that the hydrolase CbsA acts as a phenotypic switch between vascular and non-vascular plant pathogenesis. cbsA was enriched in genomes of vascular phytopathogenic bacteria in the Xanthomonadaceae family and absent in most non-vascular species. CbsA expression allowed non-vascular Xanthomonas to cause vascular blight while cbsA mutagenesis resulted in reduction of vascular or enhanced non-vascular symptom development. Phylogenetic hypothesis testing further revealed that cbsA was lost in multiple non-vascular lineages and more recently gained by some vascular subgroups, suggesting that vascular pathogenesis is ancestral. Our results overall demonstrate how the gain and loss of single loci can facilitate the evolution of complex ecological traits.

Vascular Smooth Muscle Cell-Derived Exosomal MicroRNAs Regulate Endothelial Cell Migration Under PDGF Stimulation

Intercellular communication between vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) is essential for the maintenance of vascular homeostasis. The presence of exosomes, a recently discovered player in vascular cell communication, has been associated with vascular disease progression. However, the detailed mechanism of how the signal mediated by exosomes affects the function of vascular cells during vascular pathogenesis is yet to be further understood. In this study, we investigated the expression of exosomal microRNAs (miRNAs) secreted by VSMCs and their functional relevance to ECs in pathogenesis, including their role in processes such as platelet-derived growth factor (PDGF) stimulation. We observed that PDGF stimulation contributes to a change in exosomal miRNA release from VSMCs; specifically, miR-1246, miR-182, and miR-486 were deficient in exosomes derived from PDGF-stimulated VSMCs. The reduced miRNA expression in these exosomes is associated with an increase in EC migration. These findings increase our understanding of exosome-mediated crosstalk between vascular cells under a pathological condition.

Design and Fabrication of a Three-Dimensional In Vitro System for Modeling Vascular Stenosis

Vascular stenosis, the abnormal narrowing of blood vessels, arises from defective developmental processes or atherosclerosis-related adult pathologies. Stenosis triggers a series of adaptive cellular responses that induces adverse remodeling, which can progress to partial or complete vessel occlusion with numerous fatal outcomes. Despite its severity, the cellular interactions and biophysical cues that regulate this pathological progression are poorly understood. Here, we report the design and fabrication of a three-dimensional (3D) in vitro system to model vascular stenosis so that specific cellular interactions and responses to hemodynamic stimuli can be investigated. Tubular cellularized constructs (cytotubes) were produced, using a collagen casting system, to generate a stenotic arterial model. Fabrication methods were developed to create cytotubes containing co-cultured vascular cells, where cell viability, distribution, morphology, and contraction were examined. Fibroblasts, bone marrow primary cells, smooth muscle cells (SMCs), and endothelial cells (ECs) remained viable during culture and developed location- and time-dependent morphologies. We found cytotube contraction to depend on cellular composition, where SMC-EC co-cultures adopted intermediate contractile phenotypes between SMC- and EC-only cytotubes. Our fabrication approach and the resulting artery model can serve as an in vitro 3D culture system to investigate vascular pathogenesis and promote the tissue engineering field.