Expression Of Cellular Adhesion Molecules Research Articles

A systematic review of normal tissue neurovascular unit damage following brain irradiation-Factors affecting damage severity and timing of effects.

Radiotherapy is key in the treatment of primary and secondary brain tumors. However, normal tissue is inevitably irradiated, causing toxicity and contributing to cognitive dysfunction. The relative importance of vascular damage to cognitive decline is poorly understood. Here, we systematically review the evidence for radiation-induced damage to the entire neurovascular unit (NVU), particularly focusing on establishing the factors that influence damage severity, and timing and duration of vascular effects relative to effects on neural tissue. Using PubMed and Web of Science, we searched preclinical and clinical literature published between January 1, 1970 and December 1, 2022 and evaluated factors influencing NVU damage severity and timing of NVU effects resulting from ionizing radiation. Seventy-two rodents, 4 canines, 1 rabbit, and 5 human studies met inclusion criteria. Radiation increased blood-brain barrier (BBB) permeability, reduced endothelial cell number and extracellular matrix proteoglycans, reduced tight junction proteins, upregulated cellular adhesion molecule expression, reduced activity of glucose and BBB efflux transporters and activated glial cells. In the brain parenchyma, increased metalloproteinases 2 and 9 levels, demyelination, cell death, and inhibited differentiation were observed. Effects on the vasculature and neural compartment were observed across acute, delayed, and late timepoints, and damage extent was higher with low linear energy transfer radiation, higher doses, lower dose rates, broader beams, and in the presence of a tumor. Irradiation of normal brain tissue leads to widespread and varied impacts on the NVU. Data indicate that vascular damage is in most cases an early effect that does not quickly resolve. More studies are needed to confirm sequence of damages, and mechanisms that lead to cognitive dysfunction.

Endothelial dysfunction in neurodegenerative disease: Is endothelial inflammation an overlooked druggable target?

Neurological diseases with a neurodegenerative component have been associated with alterations in the cerebrovasculature. At the anatomical level, these are centred around changes in cerebral blood flow and vessel organisation. At the molecular level, there is extensive expression of cellular adhesion molecules and increased release of pro-inflammatory mediators. Together, these has been found to negatively impact blood-brain barrier integrity. Systemic inflammation has been found to accelerate and exacerbate endothelial dysfunction, neuroinflammation and degeneration. Here, we review the role of cerebrovasculature dysfunction in neurodegenerative disease and discuss the potential contribution of intermittent pro-inflammatory systemic disease in causing endothelial pathology, highlighting a possible mechanism that may allow broad-spectrum therapeutic targeting in the future.

Curcumin Improves Functional Recovery of Ruptured Tendon by Promoting Tenogenesis via PI3K/Akt Signaling.

In our previous study, we found that local release of curcumin from nanomicelles prevents peritendinous adhesion during Achilles tendon healing. The aim of this study is to further investigate the signaling integrated by curcumin to direct the tenogenetic program of tendon stem cells contributing to tendon healing. A surgical model of tendon rupture and repair (TRR) was established in rats. Peritendinous adhesion and inflammation, biomechanical function, and expression of β-catenin and epithelial cellular adhesion molecule (EpCAM) were determined. A dataset was analyzed to investigate differentially expressed genes and enriched genes related to the signaling pathways. Tendon stem cells were treated with curcumin to investigate the cellular and molecular events as well as the signaling pathway. In rat TRR model, curcumin treatment resulted in not only significantly decreased peritendinous inflammatory but also improved tendon functional recovery along with significantly increased expressions of EpCAM and β-catenin. Analysis of the dataset indicated that the enriched genes were positively related to differentiation pathways but negatively related to proliferation pathways. In rat tendon stem cells, curcumin treatment inhibited proliferation but promoted differentiation. Curcumin's antioxidative activity was associated with tenogenesis. The upregulated expression of tendon lineage-specific markers was dependent on phosphatidylinositol 3'-kinase/Akt (PI3K/Akt) pathway which could be a potential mechanism of tenogenesis of curcumin treatment. Curcumin could improve tendon functional recovery via promoting tenogenesis in addition to its antioxidant and anti-inflammatory activities. Curcumin induced differentiation of tendon stem/progenitor cell into tenocytes via PI3K/Akt signaling pathway. This finding provided evidence for the application of curcumin to prevent adhesion during tendon repair.

Controlling cellular packing and hypoxia in 3D tumor spheroids via DNA interactions.

Tumor spheroids represent valuable in vitro models for studying cancer biology and evaluating therapeutic strategies. In this study, we investigated the impact of varying lengths of DNA-modified cell surfaces on spheroid formation, cellular adhesion molecule expression, and hypoxia levels within 4T1 mouse breast cancer spheroids. Through a series of experiments, we demonstrated that modifying cell surfaces with biotinylated DNA strands of different lengths facilitated spheroid formation without significantly altering the expression of fibronectin and e-cadherin, key cellular adhesion molecules. However, our findings revealed a notable influence of DNA length on hypoxia levels within the spheroids. As DNA length increased, hypoxia levels decreased, indicating enhanced intercellular spacing and porosity within the spheroid structure. These results contribute to a better understanding of how DNA modification of cell surfaces can modulate spheroid architecture and microenvironmental conditions. Such insights may have implications for developing therapeutic interventions targeting the tumor microenvironment to improve cancer treatment efficacy.

Trophoblast cellular adhesion molecule expression regulated by different genes and their correlation with pregnancy-induced hypertension

Trophoblast cellular adhesion molecule expression regulated by different genes and their correlation with pregnancy-induced hypertension

Endothelial junctional protein associated with coronary artery disease (JCAD) as a potential therapeutic target for acute ischemic stroke

Abstract Introduction Acute ischemic stroke (AIS) is a leading cause of mortality and long-time disability worldwide. Despite the increasing availability of early reperfusion, the neurological outcome of patients with AIS is still poor. Junctional protein associated with Coronary Artery Disease (JCAD) is a novel protein, associated to coronary artery disease, arterial thrombosis, atherosclerosis and inflammation. Yet, its role in acute ischemic stroke is unclear. Purpose To investigate the role of JCAD in the pathophysiology of brain acute ischemia and to explore its potential as a pharmacological target in AIS. Methods Transient Middle Cerebral Artery Occlusion (tMCAO) was inducede in mice with either global or endothelial-specific JCAD deletion, and in littermate controls. Stroke size was assessed ex-vivo 48 hours after reperfusion. For neurological assessment, RotaRod Test and Bederson score were recorded 24 and 48 hours after reperfusion. In vivo silencing of JCAD was achieved by intravenous injection of a JCAD small interfering RNA (siRNA) after tMCAO. JCAD silencing was performed in vitro in human brain microvascular endothelial cells (HBMVECs) using siRNA transfection, followed by hypoxia/reoxygenation (H/R) injury. Cell death and monolayer integrity were measured by LDH assay and trans-endothelial electrical resistance (TEER), respectively. Molecular mechanisms were investigated in vivo by immunohistochemistry and in vitro by Western blot, respectively. JCAD plasma levels were measured by ELISA in two independent cohorts of patients with AIS. Results The expression of JCAD was up-regulated in the ipsilateral hemisphere of stroke in wild-type mice. Both global and endothelial-specific JCAD knockout mice displayed reduced stroke size after tMCAO and an improved neurological outcome, similar to mice treated with post-ischemic JCAD silencing (Figure 1). In vitro, JCADsilenced HBMVECs showed a reduced cell death and an improved monolayer integrity after H/R injury, paralleled by a reduced expression of cellular adhesion molecules (CAMs). The intracellular messenger Akt was hyperphosphorylated in JCAD-silenced HBMVECs (Figure 2). The treatment with the Akt/PI3K inhibitor Wortmannin, retrieved the non-silenced phenotype in HBMVECs, following H/R. Circulating levels of JCAD were persistently increased in patients with AIS and higher levels of JCAD at the time of hospitalization were associated with higher inflammation and an increased risk of death 90 days after the event. Conclusions JCAD expression is associated with a larger brain damage in mice in vivo and with a higher mortality in patients. Mechanistic results suggest that JCAD plays a pivotal role in regulating the integrity of endothelium after a H/R injury, inducing cellular death and inflammation through the inhibition of the Akt/PI3K pathway. Thus, in vivo silencing of JCAD may represent a therapeutic target for the treatment of acute ischemic stroke, on top of early reperfusion.Figure 1Figure 2

Increased expression of cell adhesion molecules in myofasciitis.

Myofasciitis is a heterogeneous group of diseases pathologically characterized by inflammatory cell infiltration into the fascia. Endothelial activation plays a critical role in the pathogenesis of the inflammatory response. However, the expression of cellular adhesion molecules (CAMs) in myofasciitis has not been investigated. Data on clinical features, thigh magnetic resonance imaging, and muscle pathology were collected from five patients with myofasciitis. Immunohistochemical (IHC) staining and Western blot (WB) of the muscle biopsies from patients and healthy controls were performed. Increased levels of serum pro-inflammatory cytokines, including IL-6, TNF-α, and IL-2R, were detected in four patients. IHC staining and WB indicated significantly increased expression of cell adhesion molecules in blood vessels or inflammatory cells within the perimysium in muscle and fascia tissues of patients with myofasciitis compared to controls. The up-regulation of CAMs in myofasciitis indicates endothelial activation, which may be potential therapy targets for the treatment of myofasciitis.

Effect of remote ischemic conditioning on the immune-inflammatory profile in patients with traumatic hemorrhagic shock in a randomized controlled trial

Resuscitation induced ischemia/reperfusion predisposes trauma patients to systemic inflammation and organ dysfunction. We investigated the effect of remote ischemic conditioning (RIC), a treatment shown to prevent ischemia/reperfusion injury in experimental models of hemorrhagic shock/resuscitation, on the systemic immune-inflammatory profile in trauma patients in a randomized trial. We conducted a prospective, single-centre, double-blind, randomized, controlled trial involving trauma patients sustaining blunt or penetrating trauma in hemorrhagic shock admitted to a Level 1 trauma centre. Patients were randomized to receive RIC (four cycles of 5-min pressure cuff inflation at 250 mmHg and deflation on the thigh) or a Sham intervention. The primary outcomes were neutrophil oxidative burst activity, cellular adhesion molecule expression, and plasma levels of myeloperoxidase, cytokines and chemokines in peripheral blood samples, drawn at admission (pre-intervention), 1 h, 3 h, and 24 h post-admission. Secondary outcomes included ventilator, ICU and hospital free days, incidence of nosocomial infections, 24 h and 28 day mortality. 50 eligible patients were randomized; of which 21 in the Sham group and 18 in the RIC group were included in the full analysis. No treatment effect was observed between Sham and RIC groups for neutrophil oxidative burst activity, adhesion molecule expression, and plasma levels of myeloperoxidase and cytokines. RIC prevented significant increases in Th2 chemokines TARC/CCL17 (P < 0.01) and MDC/CCL22 (P < 0.05) at 24 h post-intervention in comparison to the Sham group. Secondary clinical outcomes were not different between groups. No adverse events in relation to the RIC intervention were observed. Administration of RIC was safe and did not adversely affect clinical outcomes. While trauma itself modified several immunoregulatory markers, RIC failed to alter expression of the majority of markers. However, RIC may influence Th2 chemokine expression in the post resuscitation period. Further investigation into the immunomodulatory effects of RIC in traumatic injuries and their impact on clinical outcomes is warranted.ClinicalTrials.gov number: NCT02071290.

Compulsive methamphetamine self-administration in the presence of adverse consequences is associated with increased hippocampal mRNA expression of cellular adhesion molecules.

Methamphetamine (METH) is a popular but harmful psychostimulant. METH use disorder (MUD) is characterized by compulsive and continued use despite adverse life consequences. METH users experience impairments in learning and memory functions that are thought to be secondary to METH-induced abnormalities in the hippocampus. Recent studies have reported that about 50% of METH users develop MUD, suggesting that there may be differential molecular effects of METH between the brains of individuals who met criteria for addiction and those who did not after being exposed to the drug. The present study aimed at identifying potential transcriptional differences between compulsive and non-compulsive METH self-administering male rats by measuring global gene expression changes in the hippocampus using RNA sequencing. Herein, we used a model of METH self-administration (SA) accompanied by contingent foot-shock punishment. This approach led to the separation of animals into shock-resistant rats (compulsive) that continued to take METH and shock-sensitive rats (non-compulsive) that suppressed their METH intake in the presence of punished METH taking. Rats were euthanized 2 h after the last METH SA plus foot-shock session. Their hippocampi were immediately removed, frozen, and used later for RNA sequencing and qRT-PCR analyses. RNA sequencing analyses revealed differential expression of mRNAs encoding cell adhesion molecules (CAMs) between the two rat phenotypes. qRT-PCR analyses showed significant higher levels of Cdh1, Glycam1, and Mpzl2 mRNAs in the compulsive rats in comparison to non-compulsive rats. The present results implicate altered CAM expression in the hippocampus in the behavioral manifestations of continuous compulsive METH taking in the presence of adverse consequences. Our results raise the novel possibility that altered CAM expression might play a role in compulsive METH taking and the cognitive impairments observed in MUD patients.

Persicaria minor (Huds.) Opiz Prevents In Vitro Atherogenesis by Attenuating Tumor Necrosis Factor-α-Induced Monocyte Adhesion to Human Umbilical Vein Endothelial Cells.

Persicaria minor (Huds.) Opiz is an herb with anti-inflammatory, antioxidant, and anti-atherosclerosis effects. Nevertheless, the mechanism underlying its anti-atherosclerosis effect is poorly comprehended. This in vitro study assessed the protective effects of standardized aqueous extract of P. minor leaves (PM) on tumor necrosis factor-α (TNF-α)-induced monocyte adhesion to human umbilical vein endothelial cells (HUVEC), which is one of the pivotal early steps in atherogenesis. The results showed that PM decreased the mRNA and protein expression of cellular adhesion molecules, vascular adhesion molecule-1 and intercellular adhesion molecule-1, resulting in reduced adhesion of monocytes to HUVEC. Additionally, PM inhibited nuclear factor kappaB (NF-κB) activation as indicated by reduced NF-κB p65 levels in TNF-α-induced HUVEC. Overall, PM could prevent in vitro atherogenesis by inhibiting NF-κB activation and adhesion of monocytes to HUVEC. The effects of PM are probably mediated by its bioactive compound, quercetin-3-O-glucuronide. The findings may provide a rationale for the in vivo anti-atherosclerosis effect of PM, and support its potential use in atherosclerosis.

Dextran sulfate prevents excess aggregation of human pluripotent stem cells in 3D culture by inhibiting ICAM1 expression coupled with down-regulating E-cadherin through activating the Wnt signaling pathway

BackgroundHuman pluripotent stem cells (hPSCs) have great potential in applications for regenerative medicine and drug development. However, 3D suspension culture systems for clinical-grade hPSC large-scale production have been a major challenge. Accumulating evidence has demonstrated that the addition of dextran sulfate (DS) could prevent excessive adhesion of hPSCs from forming larger aggregates in 3D suspension culture. However, the signaling and molecular mechanisms underlying this phenomenon remain elusive.MethodsBy using a cell aggregate culture assay and separating big and small aggregates in suspension culture systems, the potential mechanism and downstream target genes of DS were investigated by mRNA sequence analysis, qRT-PCR validation, colony formation assay, and interference assay.ResultsSince cellular adhesion molecules (CAMs) play important roles in hPSC adhesion and aggregation, we assumed that DS might prevent excess adhesion through affecting the expression of CAMs in hPSCs. As expected, after DS treatment, we found that the expression of CAMs was significantly down-regulated, especially E-cadherin (E-cad) and intercellular adhesion molecule 1 (ICAM1), two highly expressed CAMs in hPSCs. The role of E-cad in the adhesion of hPSCs has been widely investigated, but the function of ICAM1 in hPSCs is hardly understood. In the present study, we demonstrated that ICAM1 exhibited the capacity to promote the adhesion in hPSCs, and this adhesion was suppressed by the treatment with DS. Furthermore, transcriptomic analysis of RNA-seq revealed that DS treatment up-regulated genes related to Wnt signaling resulting in the activation of Wnt signaling in which SLUG, TWIST, and MMP3/7 were highly expressed, and further inhibited the expression of E-cad.ConclusionOur results demonstrated that DS played an important role in controlling the size of hPSC aggregates in 3D suspension culture by inhibiting the expression of ICAM1 coupled with the down-regulation of E-cad through the activation of the Wnt signaling pathway. These results represent a significant step toward developing the expansion of hPSCs under 3D suspension condition in large-scale cultures.

Serum levels of VCAM-1 are associated with survival in patients treated with nivolumab for NSCLC.

BackgroundHigh circulating levels of cellular adhesion molecules (CAMs) in non‐small cell lung cancer (NSCLC) have been supposed to act as a negative prognostic factor. Here, we explored the predictive role of pre‐treatment levels of CAMs in previously treated patients receiving nivolumab for NSCLC.Materials and methodsSeventy one patients with advanced NSCLC, treated with nivolumab at the dose of 3 mg/kg every 14 days, were enrolled. Maximum follow‐up time was 3 years. Serum levels of Vascular Cell Adhesion Molecule‐1 (VCAM‐1) and Intracellular Adhesion Molecule‐1 (ICAM‐1) were measured at baseline and before each nivolumab administration. Endpoints of the study were a composite outcome of survival ≥2 years or absence of disease progression at the end of the follow‐up, and the overall survival.ResultsComposite outcome and overall survival were positively associated with VCAM‐1 baseline levels and with the reduction of VCAM‐1 during the treatment. After adjustment for potential confounders, the change in VCAM‐1 serum levels during the treatment was an independent predictor of overall survival.ConclusionsHigh baseline serum levels of VCAM‐1 are associated with a longer survival in patients treated with nivolumab as second line treatment for NSCLC. Surviving patients experience also a significant reduction in CAMs expression during the treatment. Hence, CAMs might be promising prognostic factors in patients with NSCLC underoing immunotherapy.

Metformin inhibits cholesterol‑induced adhesion molecule expression via activating the AMPK signaling pathway in vascular smooth muscle cells.

Recruitment of lymphocytes to the vascular wall contributes to the pathogenesis of atherosclerosis (AS). The expression of cellular adhesion molecules, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, serves a critical role in mediating lymphocyte adhesion to the vascular wall. Cholesterol loading induces the expression of adhesion molecules in vascular smooth muscle cells (VSMCs), but the underlying mechanism is not completely understood. The present study aimed to investigate the mechanism underlying the effects of cholesterol on adhesion molecule expression, and whether metformin protected VSMCs against cholesterol-induced functional alterations. Human VSMCs were loaded with cholesterol and different concentrations of metformin. The expression levels of adhesion molecules were assessed via reverse transcription-quantitative PCR and western blotting. Reactive oxygen species (ROS) accumulation and levels were quantified via fluorescence assays and spectrophotometry, respectively. AMP-activated protein kinase (AMPK), p38 MAPK and NF-κB signaling pathway-related protein expression levels were evaluated via western blotting. Compared with the control group, cholesterol loading significantly upregulated adhesion molecule expression levels on VSMCs by increasing intracellular ROS levels and activating the p38 MAPK and NF-κB signaling pathways. Metformin decreased cholesterol-induced VSMC damage by activating the AMPK signaling pathway, and suppressing p38 MAPK and NF-κB signaling. The present study indicated the therapeutic potential of metformin for VSMC protection, reduction of monocyte adhesion, and ultimately, the prevention and treatment of AS.

Autoimmune susceptibility gene PTPN2 is required for clearance of adherent-invasive Escherichia coli by integrating bacterial uptake and lysosomal defence

ObjectivesAlterations in the intestinal microbiota are linked with a wide range of autoimmune and inflammatory conditions, including inflammatory bowel diseases (IBD), where pathobionts penetrate the intestinal barrier and promote inflammatory...

Ginsenoside Rb1 attenuates age-associated vascular impairment by modulating the Gas6 pathway

Context Ginsenoside Rb1 (Rb1) exerts many beneficial effects and protects against cardiovascular disease. Objective To investigate whether Rb1 could attenuate age-related vascular impairment and identify the mechanism. Materials and methods Female C57BL/6J mice aged 2 and 18 months, randomly assigned to Young, Young + 20 mg/kg Rb1, Old + vehicle, Old + 10 mg/kg Rb1 and Old + 20 mg/kg Rb1 groups, were daily intraperitoneal injected with vehicle or Rb1 for 3 months. The thoracic aorta segments were used to inspect the endothelium-dependent vasorelaxation. Left thoracic aorta tissues were collected for histological or molecular expression analyses, including ageing-related proteins, markers relevant to calcification and fibrosis, and expression of Gas6/Axl. Results We found that in Old + vehicle group, the expression of senescence proteins and cellular adhesion molecules were significantly increased, with worse endothelium-dependent thoracic aorta relaxation (58.35% ± 2.50%) than in Young group (88.84% ± 1.20%). However, Rb1 treatment significantly decreased the expression levels of these proteins and preserved endothelium-dependent relaxation in aged mice. Moreover, Rb1 treatment also reduced calcium deposition, collagen deposition, and the protein expression levels of collagen I and collagen III in aged mice. Furthermore, we found that the downregulation of Gas6 protein expression by 41.72% and mRNA expression by 52.73% in aged mice compared with young mice was abrogated by Rb1 treatment. But there was no significant difference on Axl expression among the groups. Conclusions Our study confirms that Rb1 could ameliorate vascular injury, suggesting that Rb1 might be a potential anti-ageing related vascular impairment agent.

Expression of cellular adherent and invasive molecules in recurrent ovarian endometriosis.

ObjectiveThis study aimed to examine expression of cellular adhesion molecules and metalloproteinases of the extracellular matrix in ectopic endometrium for evaluating their roles in recurrence of endometriosis.MethodsThis study retrospectively analyzed 49 female patients (mean age: 30.1±5.5 years) with endometriomas who had undergone two separate operations. After a maximum follow-up of 80 months, all participants were divided into the recurrent group or nonrecurrent (control) group. Samples were immunostained for epithelial cadherin (E-cadherin), β-catenin, urokinase plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-2, and extracellular matrix metalloproteinase inducer (EMMPRIN).ResultsIn the recurrent group, E-cadherin concentrations in the membrane and cytoplasm of ectopic endometrial glandular cells were significantly reduced, while those of MMP-9 and EMMPRIN were higher than those in the control group. Additionally, uPA concentrations in the membrane and cytoplasm of ectopic endometrial glandular, stromal, and vascular endothelial cells were significantly higher in the recurrent group than in the control group. Tissue inhibitor of matrix metalloproteinase-2 and β-catenin concentrations were similar between the groups.ConclusionE-cadherin, MMP-9, and associated factors may contribute to development of endometriosis. E-cadherin, MMP-9, and uPA may act as potential markers for detection of recurrence of endometriosis.

Biological effects of chronic and acute exposure of human endothelial cell line EA.hy926 to bisphenol A: New tricks from an old dog

Although epidemiological and animal studies suggest a possible correlation between bisphenol A (BPA) exposure and atherosclerosis, very few in vitro mechanistic and functional studies regarding the effect of BPA on vascular cells have been conducted. Here, we applied a “real-life” exposure scenario by continuously exposing human endothelial cell (EC) line EA.hy926 to environmentally relevant concentrations of BPA (10−9, 10−8, and 10−7 M) during 14 weeks. We also exposed EA.hy926 cells to higher concentrations of BPA (10−7, 10−6, and 10−5 M) for up to 48 h to gain mechanistic insight into the BPA’s action in ECs. Chronic exposure to BPA produced some unexpected effects in EA.hy926 cells including a transient decrease in the adhesion of monocytes to the EC monolayer and decrease in the expression of cellular adhesion molecules, improvement in endothelial barrier function and elevated expression of tight junction proteins occludin and zonula occludens-1 (ZO-1), increased adhesion of ECs, and increased nitric oxide (NO) production. Some of these effects, such as diminished adhesion of monocytes to the EC monolayer and elevated NO production have also been replicated during acute exposure experiments. Using Western blotting and specific pharmacological inhibitors in the acute study, we have shown that direct BPA’s action in EA.hy926 cells involves activation of estrogen receptor (ER), phosphorylation of protein kinase B (PKB/Akt) and endothelial nitric oxide synthase (eNOS)-mediated production of NO. Collectively, these data indicate that BPA induces functional and molecular changes in EA.hy926 cells associated with the promotion of endothelial integrity through activation of the ER/Akt/eNOS pathway.

P.336 Depression, diabetes and expression of cellular adhesion molecules

Regional anaesthesia is commonly utilised for foot and ankle surgery. Debate remains at to the level of regional anaesthesia that is required. The objective of this study was to evaluate whether surgeon-delivered “blind” local anaesthetic infiltration around the first ray (metatarsal block without ultrasound guidance) was as effective as an ultrasound guided ankle block in providing post-operative analgesia after osseous first ray surgery performed under general anaesthetic.50 patients were recruited to a single surgeon and anaesthetist double-blinded randomised controlled trial at a single-centre. 20 mls of 0.5% levobupivacaine was used to perform either an ankle or metatarsal nerve block.Forty-eight patients completed the study: 25 in the ankle block treatment arm and 23 in the metatarsal block arm. The demographics were comparable between groups. There was no statistical difference in visual analogue pain scores at two (21.3 vs 15.2), six (23.6 vs 20.8) and 24 (42.2 vs 50.4) hours following the procedure between the two groups (metatarsal block vs ankle block). Metatarsal block groups had a faster return of normal sensation (2.3 vs 2.8 h) but there was no difference in time to safe mobilisation (2.6 vs 2.8 h).This study demonstrates the efficacy and safety of surgeon delivered “blind” metatarsal block is comparable to an ultrasound guided ankle block for first ray surgery performed under general anaesthetic.1.

Siphonaxanthin, a carotenoid from green algae, suppresses advanced glycation end product-induced inflammatory responses.

Advanced glycation end products (AGEs) induce inflammation and contribute to the pathogenesis of atherosclerosis. Although many studies have demonstrated the protective effects of carotenoids against atherosclerosis, the effects of carotenoids on AGE-induced inflammation have not been characterized. As such, we aimed to identify carotenoids that provided protection against AGE-elicited inflammation. AGE-stimulated RAW264 macrophages were first evaluated for NO generation. Among 17 carotenoids tested, only siphonaxanthin significantly suppressed it. Next, mRNA expression levels were measured in RAW264 macrophages and human umbilical vascular endothelial cells following siphonaxanthin and AGE treatment. Siphonaxanthin significantly suppressed AGE-induced mRNA expression of interleukin-6 and cellular adhesion molecules, which are known to be important for the pathogenesis of atherosclerosis. Siphonaxanthin also significantly suppressed endoplasmic reticulum (ER) stress marker genes. A reporter gene assay revealed that siphonaxanthin, as well as an ER stress inhibitor, significantly inhibited AGE-induced nuclear factor-κB (NF-κB) activation. Altogether, mitigation of ER stress and subsequent NF-κB activation is one of the molecular mechanisms by which siphonaxanthin suppressed AGE-elicited inflammation. Siphonaxanthin is a carotenoid commonly found in standard diets and is considered relatively safe for human consumption, and hence, dietary intake of siphonaxanthin or siphonaxanthin-containing green algae could be beneficial in lowering the risk of developing atherosclerosis.

LOX-1: Regulation, Signaling and Its Role in Atherosclerosis.

Atherosclerosis has long been known to be a chronic inflammatory disease. In addition, there is intense oxidative stress in atherosclerosis resulting from an imbalance between the excess reactive oxygen species (ROS) generation and inadequate anti-oxidant defense forces. The excess of the oxidative forces results in the conversion of low-density lipoproteins (LDL) to oxidized LDL (ox-LDL), which is highly atherogenic. The sub-endothelial deposition of ox-LDL, formation of foamy macrophages, vascular smooth muscle cell (VSMC) proliferation and migration, and deposition of collagen are central pathophysiologic steps in the formation of atherosclerotic plaque. Ox-LDL exerts its action through several different scavenger receptors, the most important of which is LOX-1 in atherogenesis. LOX-1 is a transmembrane glycoprotein that binds to and internalizes ox-LDL. This interaction results in variable downstream effects based on the cell type. In endothelial cells, there is an increased expression of cellular adhesion molecules, resulting in the increased attachment and migration of inflammatory cells to intima, followed by their differentiation into macrophages. There is also a worsening endothelial dysfunction due to the increased production of vasoconstrictors, increased ROS, and depletion of endothelial nitric oxide (NO). In the macrophages and VSMCs, ox-LDL causes further upregulation of the LOX-1 gene, modulation of calpains, macrophage migration, VSMC proliferation and foam cell formation. Soluble LOX-1 (sLOX-1), a fragment of the main LOX-1 molecule, is being investigated as a diagnostic marker because it has been shown to be present in increased quantities in patients with hypertension, diabetes, metabolic syndrome and coronary artery disease. LOX-1 gene deletion in mice and anti-LOX-1 therapy has been shown to decrease inflammation, oxidative stress and atherosclerosis. LOX-1 deletion also results in damage from ischemia, making LOX-1 a promising target of therapy for atherosclerosis and related disorders. In this article we focus on the different mechanisms for regulation, signaling and the various effects of LOX-1 in contributing to atherosclerosis.