Expression Of Adhesion Molecules Research Articles

Inhibitory neurons marked by a connectivity molecule regulate memory precision.

The CA3 region is central to hippocampal function during learning and memory and has a unique connectivity. CA3 pyramidal neurons are the targets of huge, excitatory mossy fiber synapses from DG axons and have a high degree of excitatory recurrent connectivity. Thus, inhibition likely plays an outsized importance in constraining excitation and shaping CA3 ensembles during learning and memory. Here, we investigate the function of a never-before studied set of dendrite-targeting, GABAergic neurons defined by expression of the synaptic adhesion molecule, Kirrel3. We discovered that activating Kirrel3-expressing GABAergic neurons specifically impairs memory discrimination and inhibits CA3 pyramidal neurons in novel contexts. Kirrel3 is required for DG-to-GABA synapse formation and variants in Kirrel3 are strong risk factors for neurodevelopmental disorders. Thus, our work suggests that Kirrel3-GABA neurons are a critical source of feed-forward inhibition from DG to CA3 during the encoding and retrieval of contextual memories, a function which may be specifically disrupted in some brain disorders.

CST3 alleviates retinal vascular leakage by regulating the Rap1 signaling pathway

Retinal vascular leakage is a major event in several retinal diseases, including diabetic retinopathy (DR). In a previous study, we demonstrated that the aqueous humor concentration of Cystatin C (CST3), a physiological inhibitor of cysteine protease, is negatively correlated with the severity of diabetic macular edema. However, its function in the retina has not been clearly elucidated. In this study, we found a significant decrease in the aqueous humor concentration of CST3 with DR progression. Furthermore, we found that CST3 was expressed in retinal endothelial cells and that its expression was significantly downregulated in high glucose-treated human retinal microvascular endothelial cells (HRMECs) and the retinal vessels of oxygen-induced retinopathy (OIR) mice. Silencing CST3 expression resulted in decreased HRMEC migration and tubule formation ability. Exogenous addition of the CST3 protein significantly improved HRMEC migration and tubular formation. In-vivo experiments demonstrated that CST3 silencing induced retinal vascular leakage in WT mice, while its intravitreal injection significantly reduced retinal leakage in OIR mice. Mechanistically, CST3 promoted the expression of the downstream adhesion molecules, claudin5, VE-cadherin, and ZO-1, in retinal vascular cells by regulating the Rap1 signaling pathway. Therefore, this study revealed a novel mechanism by which CST3 improves retinal vascular function and provided evidence that it is a potential therapeutic target for retinal vascular leakage.

TNF Induces Laminin-332-Encoding Genes in Endothelial Cells and Laminin-332 Promotes an Atherogenic Endothelial Phenotype.

Laminins are essential components of the basement membranes, expressed in a tissue- and cell-specific manner under physiological conditions. During inflammatory circumstances, such as atherosclerosis, alterations in laminin composition within vessels have been observed. Our study aimed to assess the influence of tumor necrosis factor-alpha (TNF), a proinflammatory cytokine abundantly found in atherosclerotic lesions, on endothelial laminin gene expression and the effects of laminin-332 (LN332) on endothelial cells' behavior. We also evaluated the expression of LN332-encoding genes in human carotid atherosclerotic plaques. Our findings demonstrate that TNF induces upregulation of LAMB3 and LAMC2, which, along with LAMA3, encode the LN332 isoform. Endothelial cells cultured on recombinant LN332 exhibit decreased claudin-5 expression and display a loosely connected phenotype, with an elevated expression of chemokines and leukocyte adhesion molecules, enhancing their attractiveness and adhesion to leukocytes in vitro. Furthermore, LAMB3 and LAMC2 are upregulated in human carotid plaques and show a positive correlation with TNF expression. In summary, TNF stimulates the expression of LN332-encoding genes in human endothelial cells and LN332 promotes an endothelial phenotype characterized by compromised junctional integrity and increased leukocyte interaction. These findings highlight the importance of basement membrane proteins for endothelial integrity and the potential role of LN332 in atherosclerosis.

Protective Effect of Hibifolin on Lipopolysaccharide-Induced Acute Lung Injury Through Akt Phosphorylation and NFκB Pathway.

Acute lung injury (ALI) is a difficult condition to manage, especially when it is complicated by bacterial sepsis. Hibifolin, a flavonoid glycoside, has anti-inflammatory properties that make it a potential treatment for ALI. However, more research is needed to determine its effectiveness in LPS-induced ALI. In this study, male ICR mice were treated with hibifolin before LPS-induced ALI. Protein content and neutrophil count in bronchoalveolar lavage (BAL) fluid were measured by BCA assay and Giemsa staining method, respectively. The levels of proinflammatory cytokines and adhesive molecules were detected by ELISA assay. The expression of NFκB p65 phosphorylation, IκB degradation, and Akt phosphorylation was assessed by western blot assay. Hibifolin pre-treatment significantly reduced pulmonary vascular barrier dysfunction and neutrophil infiltration into the BAL fluid in LPS-induced ALI mice. In addition, LPS-induced expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α) and adhesive molecules (ICAM-1, VCAM-1) within the BAL fluid were markedly reduced by hibifolin in LPS-induced ALI mice. More, hibifolin inhibited LPS-induced phosphorylation of NFκB p65, degradation of IκB, and phosphorylation of Akt in lungs with ALI mice. In conclusion, hibifolin shows promise in improving the pathophysiological features and proinflammatory responses of LPS-induced ALI in mice through the NFκB pathway and its upstream factor, Akt phosphorylation.

Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin.

Inflammation is activated by diverse triggers that induce the expression of cytokines and adhesion molecules, which permit a succession of molecules and cells to deliver stimuli and functions that help the immune system clear the primary cause of tissue damage, whether this is an infection, a tumor, or a trauma. During inflammation, short-term changes in the expression and secretion of strong mediators of inflammation occur, while long-term changes occur to specific groups of cells. Long-term changes include cellular transdifferentiation for some types of cells that need to regenerate damaged tissue, as well as death for specific immune cells that can be detrimental to tissue integrity if they remain active beyond the boundaries of essential function. The transcriptional regulator NFκB enables some of the fundamental gene expression changes during inflammation, as well as during tissue development. During recurrence of malignant disease, cell stress-induced alterations enable the growth of cancer cell clones that are substantially resistant to therapeutic intervention and to the immune system. A number of those alterations occur due to significant defects in feedback signal cascades that control the activity of NFκB. Specifically, cell stress contributes to feedback defects as it overrides modules that otherwise control inflammation to protect host tissue. NFκB is involved in both the suppression and promotion of cancer, and the key distinctive feature that determines its net effect remains unclear. This paper aims to provide a clear answer to at least one aspect of this question, namely the mechanism that enables a divergent response of cancer cells to critical inflammatory stimuli and to cell stress in general.

Avapritinib efficacy in primary hepatic neuroendocrine carcinoma with elevated PDGFRA expression: Insights from a PDX model study

Background & aimsPrimary Hepatic Neuroendocrine Carcinoma (PHNEC) is a rare and aggressive tumor with high recurrence rates. Surgical resection remains the only therapeutic strategy. The effectiveness of tyrosine kinase inhibitors (TKIs) for PHNEC remains unclear due to limited research. MethodsWe employed immunohistochemical staining to diagnose PHNEC and assess the expression of eight tyrosine kinase receptors in tumor tissues, including VEGFRs, PDGFRA, EGFR, FGFRs et al. A patient-derived xenograft (PDX) model was established using PHNEC tumor tissues to test the efficacy of TKIs. PDX mice bearing tumors were treated with Avapritinib, an FDA-approved PDGFRA-targeting drug, at a daily oral dose of 10 mg/kg for 2 weeks. ResultsPathological analysis confirmed the diagnosis of PHNEC with positive expression of Neural cell adhesion molecule (NCAM/CD56), Synaptophysin (Syn), and Somatostatin receptor 2 (SSTR-2), and negative expression of Hep (Hepatocyte Paraffin 1), a biomarker for Hepatocellular carcinoma. Notably, PDGFRA was significantly overexpressed in PHNEC tumor tissues compared to other tyrosine kinases. Avapritinib treatment significantly reduced tumor growth in PDX mice by 73.9 % (p = 0.008). Additionally, Avapritinib treatment led to a marked decrease in PDGFRA and Ki-67 expression, suggesting that it inhibits tumor cell proliferation by suppressing PDGFRA. ConclusionOur findings suggest that PDGFRA is a potential therapeutic target for PHNEC, and its inhibition with Avapritinib may offer clinical benefits to patients with this rare malignancy.

Luteolin Inhibits Indoxyl Sulfate-Induced ICAM-1 and MCP-1 Expression by Inducing HO-1 Expression in EA.hy926 Human Endothelial Cells.

In patients with chronic kidney disease, the uremic toxin indoxyl sulfate (IS) accelerates kidney damage and the progression of cardiovascular disease. IS may contribute to vascular diseases by inducing inflammation in endothelial cells. Luteolin has documented antioxidant and anti-inflammatory properties. This study aimed to investigate the effect of luteolin on IS-mediated reactive oxygen species (ROS) production and intercellular adhesion molecule (ICAM-1) and monocyte chemoattractant protein (MCP-1) expression in EA.hy926 cells and the possible mechanisms involved. IS significantly induced ROS production (by 6.03-fold, p < 0.05), ICAM-1 (by 2.19-fold, p < 0.05) and MCP-1 protein expression (by 2.18-fold, p < 0.05), and HL-60 cell adhesion (by 31%, p < 0.05), whereas, luteolin significantly decreased IS-induced ROS production, ICAM-1 and MCP-1 protein expression, and HL-60 cell adhesion. Moreover, luteolin attenuated IS-induced nuclear accumulation of p65 and c-jun. Luteolin dose-dependently increased heme oxygenase-1 (HO-1) expression and the maximum fold induction of HO-1 by luteolin was 3.68-fold (p < 0.05), whereas, HO-1 knockdown abolished the suppression of ICAM-1 and MCP-1 expression by luteolin. Luteolin may protect against IS-induced vessel damage by inducing HO-1 expression in vascular endothelial cells, which suppresses nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) mediated ICAM-1 and MCP-1 expression.

Abstract Tu043: Gut Microbial Metabolite Phenylacetylglutamine Leads to Cardiomyocyte Hypercontractility and Vascular Endothelial Cell Activation

Background: Numerous gut microbial metabolites including phenylacetylglutamine (PAGln) are associated with increased cardiovascular disease risk and mortality. However, little is known about the cellular-specific perturbations by which PAGln may drive cardiovascular dysfunction. Aims: To understand if elevated PAGln leads to cardiovascular dysfunction and what direct cardiac- and vascular-specific pathophysiology is occurring. Methods: Herein, we subject C57Bl/6N male mice to pharmacological increases in circulating PAGln (50mg/kg) or vehicle twice daily for 20 days. We performed echocardiography, invasive hemodynamics, and vascular reactivity assays. We also performed ex vivo cardiomyocyte cell physiology experiments in the presence or absence of PAGln. Moreover, to understand vascular effects we subjected endothelial cells to PAGln and looked at expression of proinflammatory and cell adhesion molecules. Results: We first performed LC-MS/MS analysis demonstrating significant elevation in PAGln levels in multiple tissues compared to vehicle. There was no significant alteration in cardiac structure and function through echocardiographic analysis. Invasive hemodynamic assessment of systemic blood pressure showed no change, however left ventricular filling pressures were significantly elevated in PAGln group. Aortic rings subjected to varying concentrations of acetylcholine in the PAGln-treated animals were significantly impaired compared to vehicle controls. Given the elevated filling pressures and aberrant vascular endothelial relaxation we measured nitrite levels. Nitrite was significantly reduced in the plasma, cardiac, and liver tissue in PAGln group. Cardiomyocyte fractional shortening was significantly increased compared to baseline and equivalent to b-adrenergic agonism. PAGln hypercontractility was not inhibited with adrenergic antagonism. Vascular endothelial cells which were exposed to PAGln had an increase in expression of proinflammatory and cell adhesion molecules versus vehicle. Conclusion: Our data demonstrates that PAGln drives cardiovascular dysfunction through cardiomyocyte hypercontractility and inducing vascular coronary endothelial cell activation in vitro .

Mycoplasma pneumoniae-induced Kawasaki disease via PINK1/Parkin-mediated mitophagy

Kawasaki disease (KD) is a systemic vasculitis with an unknown cause that primarily affects children. The objective of this study was to explore the function and underlying mechanism of mitophagy in Mycoplasma pneumoniae (MP)-induced KD.To create MP-induced KD models, Human coronary endothelial cells (HCAECs) and DBA/2 mice were employed and treated with Mp-Lipid-associated membrane proteins （LAMPs）. Lactate dehydrogenase (LDH) levels were tested to determine cellular damage or death. The inflammatory cytokines tumor necrosis factor (TNF)--α and interleukin (IL)-6 were measured using the Enzyme-Linked Immunosorbent Assay (ELISA) method. RT-qPCR and Western blotting were used to determine the expression of Intercellular Adhesion Molecule(ICAM)-1, vascular cell adhesion molecule (VCAM)-1, inducible nitric oxide synthase(iNOS), LC3, p62, PINK1(a mitochondrial serine/threonine-protein kinase), and PARKIN(a cytosolic E3-ubiquitin ligase). The adenosine triphosphate （ATP）, reactive oxygen species （ROS）, and mitochondrial membrane potential（MMP） levels were measured to determine mitochondrial function. Mitophagy was investigated using immunofluorescence and a mitophagy detection test. Autophagosome and mitochondrial morphology were examined using transmission electron microscopy. To identify inflammatory cell infiltration, hematoxylin and eosin staining was utilized. Mp-LAMPs increased the levels of TNF-α, IL-6, ICAM-1, VCAM-1, and iNOS in an HCAEC cell model, along with LDH release. After Mp-LAMPs exposure, there was a rise in LC3 and a reduction in p62. Meanwhile, the expression of PINK1 and Parkin was increased. Cyclosporin A dramatically increased ATP synthesis and MMP in HCAEC cells treated with Mp-LAMPs, while suppressing ROS generation, demonstrating excessive mitophagy-related mitochondrial dysfunction. Additionally, neither body weight nor artery tissue were affected due to PINK1 and Parkin suppression Cyclosporin A in Mp-LAMPs-treated mice. These findings indicated that PINK1/Parkin-mediated mitophagy inhibition may be a therapeutic target for MP-induced KD.

Immunohistochemistry identifies E-cadherin, N-cadherin and focal adhesion kinase (FAK) as predictors of stage I non-small cell lung carcinoma spread through the air spaces (STAS), and the combinations as prognostic factors.

Spread through air spaces (STAS) is one of the multiple modes of lung cancer dissemination, yet its molecular and clinicopathological characterization remains poorly studied. This study aimed to investigate the effect of adhesion molecule expression levels on the incidence of STAS and postoperative recurrence in stage I lung cancer patients undergoing radical resection. E-cadherin, P-cadherin, N-cadherin, focal adhesion kinase (FAK), epithelial cell adhesion molecule (EpCAM), neural cell adhesion molecule 1 (NCAM1), vascular cell adhesion molecule 1 (VCAM1), intercellular cell adhesion molecule-1 (ICAM-1) were analyzed retrospectively using immunohistochemistry in patients undergoing radical resection for stage I non-small cell lung cancer (NSCLC). Patients were categorized into four groups based on adhesion molecule expression levels: "low/low", "high/low", "low/high", and "high/high", and the group with the lowest recurrence-free probability (RFP) was defined as high risk. Associations between those adhesion molecules' expression levels and STAS were determined by using the Chi-squared test and logistic regression model. RFP was analyzed by using the log-rank test and Cox proportional risk model. As of January 1, 2024, 12 of 60 patients undergoing radical resection for stage I lung carcinoma had a disease recurrence. All 60 patients' tissue specimens were retrospectively analyzed, and there were no significant differences between patients with STAS-positive (n=30) and STAS-negative (n=30) in baseline clinicopathologic features, except for histological growth patterns. We found that low expression of E-cadherin, high expression of N-cadherin and FAK, and males were independent predictors of higher incidence of STAS. Multivariate Cox analysis showed that tumors with low E-cadherin/high N-cadherin, low E-cadherin/high FAK, and high N-cadherin/high FAK expression were important predictors of recurrence in patients with stage I lung carcinoma. In addition, females and high N-cadherin/high FAK were associated with a high risk of recurrence in patients with STAS. E-cadherin, N-cadherin, and FAK are predictors of STAS occurrence in stage I NSCLC, and their combinations are prognostic factors. The discovery of these molecular markers provides clinicians with a reliable means that may help in the early identification of individuals with a higher risk of recurrence in lung cancer patients, targeting personalized treatment plans such as aggressive adjuvant therapy or closer follow-up.

Heterogeneous Patterns of Endothelial NF-κB p65 and MAPK c-Jun Activation, Adhesion Molecule Expression, and Leukocyte Recruitment in Lung Microvasculature of Mice with Sepsis.

Sepsis is an uncontrolled systemic inflammatory response to an infection that can result in acute failure of the function of the lung called acute respiratory distress syndrome. Leukocyte recruitment is an important hallmark of acute lung failure in patients with sepsis. Endothelial cells (EC) participate in this process by facilitating tethering, rolling, adhesion, and transmigration of leukocytes via adhesion molecules on their cell surface. In in vivo studies, endothelial nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 and mitogen-activated protein kinase (MAPK) c-Jun intracellular signal transduction pathways were reported to regulate the expression of adhesion molecules. Mice underwent cecal ligation and puncture (CLP) to induce polymicrobial sepsis and were sacrificed at different time points up to 72 h after sepsis onset. Immunohistochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses were used to determine the kinetics of nuclear localization of p65 and c-Jun in EC, expression and location of adhesion molecules E-selectin and vascular cell adhesion molecule 1 (VCAM-1). Furthermore, the extent and location of leukocyte recruitment were assessed based on Ly6G staining of neutrophils, cluster determinant (CD) 3 staining of T lymphocytes, and CD68 staining of macrophages. In all pulmonary microvascular beds, we identified p65 and c-Jun nuclear accumulation in a subset of endothelial cells within the first 24 h after CLP-sepsis initiation. E-selectin protein was expressed in a subset of microvessels at 4 and 7 h after sepsis initiation, while VCAM-1 was expressed in a scattered pattern in alveolar tissue and microvessels, without discernible changes during sepsis development. CLP-induced sepsis predominantly promoted the accumulation of neutrophils and T lymphocytes 4 and 7 h after disease onset. Neutrophil accumulation occurred in all pulmonary microvascular beds, while T lymphocytes were present in alveolar tissue and postcapillary venules. Taken together, nuclear localization of p65 and c-Jun in EC and neutrophil recruitment could be associated with induced E-selectin expression in the pulmonary microvessels in CLP-septic mice at the early stage of the disease. In alveolar capillaries, on the other hand, activation of these molecular pathways and leukocyte accumulation occurred in the absence of E-selectin or VCAM-1. Endothelial activation and leukocyte recruitment in sepsis-induced lung injury are regulated by multiple, heterogeneously controlled mechanisms, which vary depending on the type of microvascular bed involved.

Fabrication of heterocellular spheroids with controllable core-shell structure using inertial focusing effect for scaffold-free 3D cell culture models

Three-dimensional (3D) cell culture models capable of emulating the biological functions of natural tissues are pivotal in tissue engineering and regenerative medicine. Despite progress, the fabrication ofin vitroheterocellular models that mimic the intricate structures of natural tissues remains a significant challenge. In this study, we introduce a novel, scaffold-free approach leveraging the inertial focusing effect in rotating hanging droplets for the reliable production of heterocellular spheroids with controllable core-shell structures. Our method offers precise control over the core-shell spheroid's size and geometry by adjusting the cell suspension density and droplet morphology. We successfully applied this technique to create hair follicle organoids, integrating dermal papilla cells within the core and epidermal cells in the shell, thereby achieving markedly enhanced hair inducibility compared to mixed-structure models. Furthermore, we have developed melanoma tumor spheroids that accurately mimic the dynamic interactions between tumor and stromal cells, showing increased invasion capabilities and altered expressions of cellular adhesion molecules and proteolytic enzymes. These findings underscore the critical role of cellular spatial organization in replicating tissue functionalityin vitro. Our method represents a significant advancement towards generating heterocellular spheroids with well-defined architectures, offering broad implications for biological research and applications in tissue engineering.

Apelin modulates inflammation and leukocyte recruitment in experimental autoimmune encephalomyelitis

Demyelination due to autoreactive T cells and inflammation in the central nervous system are principal features of multiple sclerosis (MS), a chronic and highly disabling human disease affecting brain and spinal cord. Here, we show that treatment with apelin, a secreted peptide ligand for the G protein-coupled receptor APJ/Aplnr, is protective in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Apelin reduces immune cell entry into the brain, delays the onset and reduces the severity of EAE. Apelin affects the trafficking of leukocytes through the lung by modulating the expression of cell adhesion molecules that mediate leukocyte recruitment. In addition, apelin induces the internalization and desensitization of its receptor in endothelial cells (ECs). Accordingly, protection against EAE major outcomes of apelin treatment are phenocopied by loss of APJ/Aplnr function, achieved by EC-specific gene inactivation in mice or knockdown experiments in cultured primary endothelial cells. Our findings highlight the importance of the lung-brain axis in neuroinflammation and indicate that apelin targets the transendothelial migration of immune cells into the lung during acute inflammation.

Vitexin Suppresses High-Glucose-upregulated Adhesion Molecule Expression in Endothelial Cells through Inhibiting NF-κB Signaling Pathway.

Vascular damage is one of the significant complications of diabetes mellitus (DM). Central to this damage is endothelial damage, especially under high-glucose conditions, which promotes inflammation via the NF-κB signaling pathway. Inflammatory processes in endothelial cells directly contribute to endothelial dysfunction, such as promoting inflammatory cytokine release and activation of adhesion molecules. Vitexin, a compound found in many medicinal plants, shows promise in countering oxidative stress in diabetic contexts and modulating blood glucose. However, its effect on high-glucose-induced endothelial cell activation has not yet been studied. This research explores vitexin's potential role in this process, focusing on its influence on the NF-κB pathway in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were stimulated with 30 mM glucose (high glucose, HG) with or without vitexin treatment for 24 h. Western blotting assay was conducted for the NF-κB pathway and p-p38. Adhesion molecules (ICAM-1, VCAM-1, E-selectin, and MCP-1) were studied using flow cytometry, while pro-inflammatory cytokines were investigated using ELISA. Monocyte adhesion and vascular permeability tests were conducted to confirm the protective effect of vitexin under HG exposure. This study confirms vitexin's capacity to suppress p38 MAPK and NF-κB activation under HG conditions, reducing HG-elevated adhesion molecules and pro-inflammatory cytokine secretion. Additionally, vitexin mitigates HG-stimulated vascular permeability and monocyte adhesion. In conclusion, this study shows the therapeutic potential of vitexin against hyperglycemia-related vascular complications via p38 MAPK/NF-κB inhibition.

Partners in health and disease: pineal gland and purinergic signalling.

In mammal's pineal glands, ATP interacts with the high-affinity P2Y1 and the low-affinity P2X7 receptors. ATP released from sympathetic nerve terminals potentiates noradrenaline-induced serotonin N-acetyltransferase (Snat) transcription, N-acetylserotonin (NAS), and melatonin (MLT) synthesis. Circulating melatonin impairs the expression of adhesion molecules in endothelial cells, blocking the migration of leukocytes. Acute defence response induced by pathogen- and danger/damage-associated molecular patterns (PAMPs and DAMPs) triggers the NF-κB pathway in pinealocytes and blocks the transcription of Snat. Therefore, the darkness hormone is not released, and neutrophils and monocytes migrate to the lesion sites. ATP released in high amounts from apoptotic and death cells was considered a DAMP, and the blockage of P2X7 receptors was tested as a new class of drugs for treating brain damage. However, this is not a simple equation. High ATP injected in a lateral ventricle blocked MLT, but not NAS, synthesis as it impairs the transcription of acetyl serotonin N-methyltransferase. NAS is released in the plasma and the cerebral spinal fluid. NAS also blocks the rolling and adhesion of leukocytes to endothelial cells. Otherwise, it is metabolised specifically in each brain area to provide the requested concentration of MLT as a neuroprotector. As observed in physiological conditions, high extracellular ATP, different from the other DAMPs, reports the environmental light/dark cycle rhythm because NAS substitutes MLT as the nocturnal chemical indicator, the darkness hormone. Thus, blocking the P2X7R should not be considered a universal therapy for improving acute strokes, as MLT and ATP are partners in health and disease.

MicroRNAs Associated with IgLON Cell Adhesion Molecule Expression.

The IgLON family of cell adhesion molecules consists of five members (LSAMP, OPCML, neurotrimin, NEGR1, and IgLON5) discovered as supporters of neuronal development, axon growth and guidance, and synapse formation and maintenance. Tumour suppression properties have recently been emerging based on antiproliferative effects through the modulation of oncogenic pathways. Available evidence endorses a role for non-coding RNAs or microRNAs as relevant controllers of IgLON molecule expression that can impact their critical physiological and pathological roles. Current findings support a function for long non-coding RNAs and microRNAs in the modulation of LSAMP expression in cell senescence, cancer biogenesis, addiction, and pulmonary hypertension. For OPCML, data point to a role for several microRNAs in the control of tumorigenesis. MicroRNAs were detected in neurotrimin-mediated functions in cancer biogenesis and in Schwann cell responses to peripheral nerve injury. For NEGR1, studies have mainly investigated microRNA involvement in neuronal responses to ischaemic injury, although data also exist about tumorigenesis and endothelial cell dysfunction. For IgLON5, information is only available about microRNA involved in myocardial infarction. In conclusion, despite much information being still missing and further research needed, the emerging picture favours a model in which non-coding RNAs exert a crucial role in modulating IgLON expression, ultimately affecting their important physiological functions.

The concentration of P-selectin in the blood serum of patients with chronic kidney disease

BACKGROUND. Endothelial dysfunction (ED) plays an important role in the development and progression of chronic kidney disease (CKD). However, there is insufficient information in the literature on changes in the expression of vascular wall endothelial adhesive molecules in patients with kidney disease.THE AIM: to study the content of P-selectin in the blood of patients with CKD and to evaluate its effect on the development of ED and atherosclerotic changes.PATIENTS AND METHODS. 128 patients with CKD (41% of men and 59% of women) were monitored, with an average age of 63.5±1.7 years. The diagnosis of CKD was made in accordance with the recommendations of KDIGO (2012). The concentration in serum of P-selectin was determined by solid-phase enzyme immunoassay using a set of reagents "Cloud-Clone Corp. P-selectin ELISA" (China).RESULTS. All patients were divided into 6 groups depending on the stage of CKD. In CKD C1 - C3a stage, an increase in the concentration of P-selectin in blood serum was revealed. Starting from the C3b stage of CKD, the values of P-selectin begin to decrease significantly, especially sharply at the C5d stage.CONCLUSION. An increase in the concentration of P-selectin in blood serum can serve as an indication for in-depth dynamic monitoring of coagulogram and lipidogram parameters, a decrease in the concentration of P-selectin in blood serum is highly likely to indicate adverse changes in the geometry of the arterial bed. In this regard, it is advisable to determine the pulse wave velocity and the Agatston index.

Effect of Diminazene Aceturate, an ACE2 activator, on platelet CD40L signaling induced glial activation in rat model of hypertension

Hypertension causes platelet activation and adhesion in the brain resulting in glial activation and neuroinflammation. Further, activation of Angiotensin-Converting Enzyme 2/Angiotensin (1–7)/Mas Receptor (ACE2/Ang (1–7)/MasR) axis of central Renin-Angiotensin System (RAS), is known to reduce glial activation and neuroinflammation, thereby exhibiting anti-hypertensive and anti-neuroinflammatory properties. Therefore, in the present study, the role of ACE2/Ang (1–7)/MasR axis was studied on platelet-induced glial activation and neuroinflammation using Diminazene Aceturate (DIZE), an ACE2 activator, in astrocytes and microglial cells as well as in rat model of hypertension. We found that the ACE2 activator DIZE, independently of its BP-lowering properties, efficiently prevented hypertension-induced glial activation, neuroinflammation, and platelet CD40-CD40L signaling via upregulation of ACE2/Ang (1–7)/MasR axis. Further, DIZE decreased platelet deposition in the brain by reducing the expression of adhesion molecules on the brain endothelium. Activation of ACE2 also reduced hypertension-induced endothelial dysfunction by increasing eNOS bioavailability. Interestingly, platelets isolated from hypertensive rats or activated with ADP had significantly increased sCD40L levels and induced significantly more glial activation than platelets from DIZE treated group. Therefore, injection of DIZE pre-treated ADP-activated platelets into normotensive rats strongly reduced glial activation compared to ADP-treated platelets. Moreover, CD40L-induced glial activation, CD40 expression, and NFкB-NLRP3 inflammatory signaling are reversed by DIZE. Furthermore, the beneficial effects of ACE2 activation, DIZE was found to be significantly blocked by MLN4760 (ACE2 inhibitor) as well as A779 (MasR antagonist) treatments. Hence, our study demonstrated that ACE2 activation reduced the platelet CD40-CD40L induced glial activation and neuroinflammation, hence imparted neuroprotection.

Tagetes erecta L.: A traditional medicine effective in inflammatory process treatment

Ethnopharmacological relevanceTagetes erecta L. (Asteraceae), popularly known as Aztec Marigold, is used in folk medicine to treat several ailments including inflammatory processes. Despite its historical use, the specific mechanisms through which it may modulate inflammation, particularly its effects on neutrophils and macrophages activation, have not yet been completely investigated. Aim of the studyThis study aimed to elucidate the anti-inflammatory mechanism of the hydroalcoholic extract obtained from T. erecta flowers, focusing on its role in the regulation of neutrophil and macrophage functions. Material and methodsThe production of TNF, IL-6, CXCL-1, IL-1β, IL-10 (ELISA) and NO (Griess reaction), adhesion molecule expression (CD62L, CD49d and CD18, flow cytometry), and chemotaxis were analyzed in vitro using oyster glycogen-recruited peritoneal neutrophils or macrophages (RAW 264.7) stimulated with lipopolysaccharide (LPS) and treated with the extract (1, 10 or 100 μg/mL). The resolution of inflammation was accessed by efferocytosis assay. The in vivo anti-inflammatory activity was investigated using carrageenan-induced inflammation in the subcutaneous tissue of male Swiss mice orally treated with the T. erecta extract (30, 100 or 300 mg/kg). The leukocyte influx (optical microscopy), secretion of chemical mediators (TNF, IL-6 and IL-1β, ELISA) and protein exudation (Bradford reaction) were quantified in the inflamed exudate. ResultsIn vitro studies demonstrated that the extract inhibited neutrophil chemotaxis and reduced the production and/or release of cytokines (TNF, IL-1β, CXCL1, and IL-6) as well as nitric oxide (NO) by neutrophils and macrophages when stimulated with LPS. Neutrophils treated with LPS and incubated with the extract showed an increase in CD62L expression, which leads to the impairment of neutrophil adhesion. The extract also enhanced efferocytosis of apoptotic neutrophils by macrophages, which was accompanied by increased IL-10 secretion and decreased TNF levels. In vivo studies yielded similar results, showing reduction in neutrophil migration, protein exudation, and cytokine release (TNF, IL-6, and IL-1β). ConclusionsTogether, the data herein obtained shows that T. erecta flower extract has anti-inflammatory effects by regulating inflammatory mediators, limiting neutrophil migration, and promoting efferocytosis. The in vivo results suggest that an herbal medicine made with T. erecta could represent an interesting pharmacological tool for the treatment of acute inflammatory condition.

Prunus yedoensis Bark Downregulates the Expression of Cell Adhesion Molecules in Human Endothelial Cell Lines and Relaxes Blood Vessels in Rat Aortic Rings.

The incidence of cardiovascular diseases, such as high blood pressure, is increasing worldwide, owing to population aging and irregular lifestyle habits. Previous studies have reported the vasorelaxant effects of Prunus yedoensis bark methanol extract. However, various solvent extracts of P. yedoensis bark and their vascular relaxation mechanisms have not been sufficiently studied. We prepared extracts of P. yedoensis bark using various solvents (water, 30% ethanol, and 70% ethanol). P. yedoensis bark 30% ethanol extract (PYB-30E) decreased the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in human umbilical vein endothelial cells (HUVECs) activated with 200 ng/mL TNF-α. Additionally, PYB-30E showed vasodilatory effects on isolated rat aortic rings. This was confirmed to be the result of the activation of the NO/cGMP pathway, regulation of non-selective calcium-activated K+ channels, and calcium channel blockade. Additionally, PYB-30E significantly reduced systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR). Taken together, our results indicated that PYB-30E is a candidate functional material with preventive and therapeutic effects against hypertension.