Intracellular Adhesion Molecule-1 Research Articles

894-P: Monophasic Glucose Response Curve Is Associated with Increased C-Reactive Protein in Obese Adolescents

Three distinct glucose response curves, biphasic, monophasic and incessant increase, have been demonstrated in adults and adolescents during OGTT. Individuals with incessant increase and monophasic curves have increased risk of type 2 diabetes and decreased insulin sensitivity and secretion and thus are likely at increased risk for other cardiometabolic diseases. We, therefore, examined differences in traditional, and nontraditional cardiometabolic risk factors between obese adolescents with biphasic (n=9; age=12.6±0.9 yr, BMI=31.8±5.9 kg/m2; mean±SD) and monophasic (n=6; age=13.1±0.9; BMI=35.3±6.9) glucose response curves. Traditional risk factors were blood pressure and lipids while non-traditional risk factors included reactive hyperemia (RH), inflammatory markers [c-reactive protein (CRP), interleukin-6 (IL-6)], adiponectin, soluble intracellular adhesion molecule 1 (SICAM1), and insulin sensitivity and secretion (OGTT, Matsuda and insulinogenic indices). Systolic and diastolic blood pressure, triglycerides, HDL and LDL did not differ between groups. RH, Il-6 and Matsuda index also did not differ. Subjects with monophasic curves tended to have increased SICAM1 (260±33 vs. 184±21; mean±SE; p=0.087) and had significantly increased CRP levels (4.40±1.03 vs. 1.66±0.28 ng/ml; p=0.009) compared to subjects with biphasic curves. Adiponection (3570±450 vs. 2350±440 ng/ml; p=0.089) and insulin secretion (4.31±0.52 vs. 2.89±0.53 µU dl/mg ml; p=0.089) tended to be lower in subjects with monophasic curves. The difference in CRP remained significant when BMI was included as a covariate (p=0.02). Obese adolescents with monophasic glucose response curves to OGTT have increased inflammation compared to subjects with biphasic curves. Longitudinal studies are needed to determine whether this early phase of glucose intolerance causes increased inflammation or whether early inflammation reduces insulin secretion and causes early glucose intolerance. Disclosure R. P. Hoffman: Consultant; Self; Provention Bio, Inc., Other Relationship; Self; Medscape, Research Support; Self; Provention Bio, Inc. R. Cazeau: None. L. Rauch: None. J. A. Bauer: None. Funding National Center for Research Resources (UL1RR05755)

Insight into the LFA-1/SARS-CoV-2 Orf7a Complex by Protein-Protein Docking, Molecular Dynamics, and MM-GBSA Calculations.

In the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) genome, open reading frames (ORFs) encode for viral accessory proteins. Among these, Orf7a structurally resembles the members of the immunoglobulin (Ig) superfamily and intracellular adhesion molecules (ICAMs), in particular. ICAMs are involved in integrin binding through lymphocyte function-associated antigen 1 (LFA-1). Based on such considerations and on previous findings on SARS-CoV, it has been postulated that the formation of the LFA-1/Orf7a complex could contribute to SARS-CoV-2 infectivity and pathogenicity. With the current work, we aim at providing insight into this macromolecular assembly, taking advantage of the recently reported SARS-CoV-2 Orf7a structure. Protein–protein docking, molecular dynamics (MD) simulations, and a Molecular Mechanical-Generalized Born Surface Area (MM-GBSA)-based stage were enrolled to provide refined models.

Correlation of adhesion molecules and non-typeable haemophilus influenzae growth in a mice coinfected model of acute inflammation

Primary influenza virus (IV) infection can predispose hosts to secondary infection with Haemophilus influenzae (H. influenzae), which further increases the severity and mortality of the disease. While adhesion molecules play a key role in the host inflammatory response and H. influenzae colonization, it remains to be clarified which types of adhesion molecules are associated with H. influenzae colonization and invasion following IV infection. In this study, we established a mouse model of co-infection with influenza A virus (A/Puerto Rico/8/34, H1N1) (PR8) and non-typeable H. influenzae (NTHi) and found that sequential infection with PR8 and NTHi induced a lethal synergy in mice. This outcome may be possibly due to increased NTHi loads, greater lung damage and higher levels of cytokines. Furthermore, the protein levels of intracellular adhesion molecules-1 (ICAM-1) and Fibronectin (Fn) were significantly increased in the lungs of coinfected mice, but the levels of carcinoembryonic adhesion molecule (CEACAM)-1, CEACAM-5 and platelet-activating factor receptor (PAFr) were unaffected. Both the protein levels of ICAM-1 and Fn were positively correlated with NTHi growth. These results indicate the correlation between adhesion molecules, including ICAM-1 and Fn, and NTHi growth in secondary NTHi pneumonia following primary IV infection.

Effects of Vitex Agnus Castus Leave Extract on Induced Retinal Angiogenesis in Rabbit

Retinal pathologic angiogenesis is the leading cause of blindness in human generate from age-relatedmacular degeneration (AMD), diabetic retinopathy and premature retinopathy (ROP).The aim of this studyis to investigate the effect of vitex agnus castus leave extract on induced retinal angiogenesis in rabbitsby intravitreal injection of VEGF. Alcoholic extract of vitex agnus castus prepared and formulated forintravitreal injection. Twenty four pigmented rabbits included in this study and allocated into four equalgroups(6 rabbits in each group): Retinal angiogenesis induced group, group treated by bevacizumab, grouptreated by 100mcg of Vitex agnus castus leave extract, and group treated by 50mcg of Vitex agnus castusleave extract as intravitreal injection. Parameters include matrixmetalloproteinase-9, intracellular adhesionmolecule-1. The result of the current study revealed that intravitreal injection of Vitex agnus castus leaveextract was reduced the level of MMP-9 and ICAM-1 in comparison with retinal angiogenesis inducedgroup after one week of retinal angiogenesis induction , although it was non-significant (P>0.05).

Heart rate variability and circulating inflammatory markers in midlife

Theoretical perspectives and empirical evidence suggest that the parasympathetic nervous system engages in active monitoring and moderating of inflammatory processes. A clearer understanding of the bidirectional communication between the parasympathetic nervous system and the immune system could lead to novel clinical interventions for inflammatory illnesses. The current study used a large (N ​= ​836) nationally representative sample of adults in the United States to investigate the associations between resting parasympathetic modulation of the heart, indexed through both high frequency heart rate variability (HF-HRV) and low frequency heart rate variability (LF-HRV), and six circulating markers of inflammation. Statistical analyses revealed robust inverse associations of HF-HRV with interleukin-6 (IL6), C-reactive protein (CRP), and fibrinogen, with or without covariate adjustment. Similar inverse associations were observed between LF-HRV and IL6 and CRP. No significant associations were observed between HRV and either inflammatory adhesion molecules (E-selectin, intracellular adhesion molecule-1) or soluble IL6 receptor. Results are consistent with the cholinergic anti-inflammatory pathway and suggest that parasympathetic modulation of inflammation through the vagus nerve may act on specific inflammatory molecules more than others.

Effects of intermittent negative pressure treatment on circulating vascular biomarkers in patients with intermittent claudication.

The aim of this study was to investigate the effects of lower extremity intermittent negative pressure (INP) treatment for 1 hour twice daily for 12 weeks, on circulating vascular biomarkers in patients with intermittent claudication. Patients were randomized to treatment with –40 mmHg INP (treatment group), or –10 mmHg INP (sham control group). Venous blood samples were collected at baseline and after 12 weeks, and concentrations of vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin, P-selectin, von Willebrand factor (vWF), l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were analyzed. A larger proportion of the patients in the treatment group (25/31) had a reduction in vWF levels after 12 weeks, compared to the sham control group (17/30) (p = 0.043). Within the treatment group there was a significant mean (SEM) reduction in the concentration of vWF of –11% (4) (p = 0.019), whereas there was no significant change in the levels of vWF in the sham control group (1% (6); p = 0.85). There were no significant differences in the change of any of the biomarker levels between the groups after 12 weeks of treatment. In conclusion, there were no differences in the change of the circulating levels of the measured biomarkers between the treatment group and the sham control group after 12 weeks of INP treatment. However, the observed changes in vWF might indicate a beneficial effect of INP treatment on endothelial activation and endothelial injury. Clinicaltrials.gov Identifier: NCT03640676

The protective effects of topiramate on intestinal injury induced with infrarenal aortic occlusion via oxidative stress and apoptosis

ABSTRACT Purpose: Prolonged surgical procedures and some clinical conditions such as surgeries of thoracoabdominal aorta, mesenteric ischemia, cardiopulmonary bypass, strangulated hernias and neonatal necrotizing enterocolitis may cause decreased perfusion and injury of relevant organs and tissues. After reperfusion, injuries may get worse, leading to ischemia–reperfusion (I/R) injury. Reperfusion following arterial clamping allows oxygen to ischemic tissues and produce injury by multiple mechanisms, including neutrophilic infiltration, intracellular adhesion molecules, and generation of reactive oxygen radicals. In this study with the analysis of SOD, MDA and Caspase-3 levels, we aimed to investigate the effect of topiramate on the outcome of I/R occured after abdominal aorta clamping on rats. Materials and Methods: Totaly 24 Sprague–Dawley male rats were randomly divided into three experimental groups; the control group (n = 8), I/R (n = 8) and I/R+ topiramate (n = 8). Topiramate (100 mg/kg/day); 50 mg/kg (single dose) was administered intraperitoneally after being diluted with saline 5 days before I/R. Results: The intestinal tissue of the ischemia group displayed hemorrhage, Crypts of Lieberkuhn degeneration, ulceration, vascular congestion and edematous fields as a result of aortic occlusion. We also observed that MDA levels and Caspase-3 positivity increased and SOD levels decreased in the small intestine. However, topiramate administration decreased Crypts of Lieberkuhn degeneration, ulceration, vascular congestion and edematous fields, Caspase-3 positivity, and MDA levels. Conclusion: Our findings suggest that topiramate is effective against aortic occlusion-induced intestinal injury by reducing oxidative stress and apoptosis.

Progression of Metabolic Syndrome Components along with Depression Symptoms and High Sensitivity C-Reactive Protein: The Bogalusa Heart Study.

This study examined the association between depression symptoms and metabolic syndrome (MetS) or its components prospectively. It assessed the mediator role of high-sensitivity C-reactive protein (hs-CRP) and intracellular adhesion molecule-1 (ICAM-1). Self-reported depression symptoms were assessed using the Center for Epidemiologic Studies-Depression scale. MetS was defined as having at least three of the following five criteria: (1) waist circumference >102 centimeters (cm) in men or >88 cm in women; (2) triglycerides ≥ 50 milligrams per deciliter (mg/dL); (3) high-density lipoprotein cholesterol <40 mg/dL in men or <50 mg/dL in women; (4) blood pressure: systolic ≥ 30 and diastolic ≥85 mm of mercury or on antihypertensive medication; and (5) fasting glucose ≥110 mg/dL. The risk ratios (RR) with 95% confidence interval (CI) were estimated using multivariate Poisson regression models. A total of 419 White and 180 Black individuals with a mean age of 36 years were followed for 6.9 years. The findings demonstrated that hs-CRP mediated the influence of depression symptoms on central obesity in White young adults. The adjusted RR for central obesity was 1.08 with 95% CI of 0.88–1.32, and the value for hs-CRP was 1.12 with 95% CI of 1.02–1.23. Although depression did not influence MetS in this study cohort, the complete mediator role of hs-CRP was established for central obesity, a component of MetS in White young adults.

ROC1 promotes the malignant progression of bladder cancer by regulating p-I\u03baB\u03b1/NF-\u03baB signaling

BackgroundRegulator of cullins 1 (ROC1) is an important catalytic subunit of cullin–RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa). However, it is unclear whether ROC1 is involved in the NF-κB signaling associated with malignant BCa progression.MethodsThe expression of ROC1 and p65 in bladder cancer and paracancerous tissues were detected by immunohistochemistry (IHC). Pearson correlation was used to assess correlation between ROC1 and p65 protein expressions. The wound-healing and transwell assays were used to monitor cell invasion and migration. The effect of ROC1 on the expression of key proteins in the NF-κB signaling was determined by immunofluorescence and western blot (WB). Cycloheximide (CHX), MG132 and immunoprecipitation assays were used to evaluate the effect of ROC1 on the ubiquitination of phosphorylated inhibitor of kappa B alpha (p-IκBα). A lung metastasis mouse model was generated to detect the role of ROC1 in tumor metastasis.ResultsWe found that ROC1 was up-regulated in BCa tissues and cell lines, and high ROC1 levels were positively correlated with higher tumour grade, lymph node metastasis, distant metastasis and poor prognosis. Linear-regression analysis showed significant a Pearson correlation between ROC1 and nuclear p65 expression in BCa tissue microarray (TMA) samples. Functional studies demonstrated that ROC1 promoted BCa cell invasion and migration. In vitro and in vivo experiments showed that ROC1 activated NF-κB signaling by enhancing the ubiquitination of p-IκBα, which caused p65 nuclear translocation and promoted the transcription of some metastasis-related target genes, such as urokinase-type plasminogen activator receptor (uPAR), intracellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and matrix metalloproteinase 9 (MMP9), resulting in promoting BCa metastasis.ConclusionROC1 plays an important role in the progression of BCa and serves as a potential diagnostic and therapeutic target for patients with BCa.

Arterial structure and function in Africans with HIV for &gt; 5 years: longitudinal relationship with endothelial activation and cardiovascular risk markers

We aimed to determine whether people with human immunodeficiency virus (PWHIV) have increased measures of arterial injury [carotid intima-media thickness (cIMT)] and large artery stiffness [carotid-femoral pulse wave velocity (cfPWV)] when compared with their counterparts without HIV, and whether baseline markers of endothelial activation and cardiovascular risk are associated with cIMT and cfPWV after 5years. We matched 126 PWHIV from North West Province, South Africa, to 126 without HIV according to age, sex and locality. Cardiovascular risk and endothelial function markers [soluble intracellular adhesion molecule (ICAM-1) and soluble vascular cell adhesion molecule (VCAM-1)] were measured at baseline and cIMT and cfPWV at follow-up. This study included 21.4% men. The use of antiretroviral therapy (ART) increased from 44.1% at baseline to 81.4% at follow-up. At follow-up, cIMT (P=0.90) and cfPWV (P=0.35) were similar in the groups. Despite elevated ICAM-1 and VCAM-1 in the PWHIV (all P<0.001) at baseline, these markers did not associate with cIMT and cfPWV after 5years. In multivariable-adjusted regression analysis, cIMT associated positively with age (β=0.31, P=0.002) and triglyceride: high-density lipoprotein-cholesterol (β=0.23, P=0.016) in PWHIV. Mean arterial pressure (MAP) (β=0.28, P=0.010) associated positively with cfPWV in the PWHIV. In the people without HIV, sex (β=0.31, P=0.004) and glycated haemoglobin (HbA1c) (β=0.24, P=0.026) associated with cIMT while age (β=0.17, P=0.049), sex (β=0.29, P=0.003), MAP (β=0.31, P=0.001) and HbA1c (β=0.21, P=0.041) associated positively with cfPWV. Measures of arterial structure and function were similar in Africans with HIV and their age, sex and locality matched controls. Traditional cardiovascular risk markers rather than elevated endothelial activation at baseline were independently associated with cIMT and cfPWV over 5years.

Inhibitory effect of HTLV-1 infection on the production of B-cell activating factors in established follicular dendritic cell-like cells.

IntroductionThe low frequency of ectopic germinal center in labial salivary glands of patients with human T‐cell leukemia virus type 1 (HTLV‐1) antibody‐positive Sjögren's syndrome (SS) suggests that HTLV‐1 has some effects on follicular dendritic cells (FDCs).MethodsWe used flow cytometry, immunofluorescence, and enzyme‐linked immunosorbent assays (ELISAs) to investigate the direct effect of HTLV‐1 on B‐cell activating factors produced by established FDC like cells obtained from excised human tonsils. We then measured the serum B‐cell activating factor (BAFF) and C‐X‐C motif ligand (CXCL) 13 concentrations of the HTLV‐1‐seropositive SS patients and the HTLV‐1‐seronegative SS patients by ELISA.ResultsAmong the 31 isolated specimens, 22 showed morphological characteristics of FDCs. Day 2‐cultured specimens showed expressions of CD14, CD23, CD40, intracellular adhesion molecule‐1 (ICAM‐1), and vascular cell adhesion molecule‐1. After 2 weeks, 12 of these specimens expressed ICAM‐1, FDC, and fibroblast cell marker. Intracellular BAFF and CXCL13 were constitutively expressed regardless of stimulation. After direct coculture with the HTLV‐1‐infected T‐cell line HCT‐5 or MT‐2, the BAFF and CXCL13 expressions on the FDC‐like cells were decreased in accord with the increased number of HCT‐5 and MT‐2 cells with styliform change and without HTLV‐1 Gag protein expression. Interferons upregulated the concentration of BAFF (but not CXCL13) in the culture supernatant, which showed a declining trend under the presence of HCT‐5 or MT‐2. The serum concentrations of BAFF and CXCL13 in the HTLV‐1‐seropositive SS patients were lower than those of the HTLV‐1 seronegative SS patients.ConclusionsHTLV‐1 partially inhibited the BAFF and CXCL13 expressions of established FDC‐like cells.

Hedgehog signaling modulates cigarette-induced COPD development.

Hedgehog (Hh) signaling is involved in early embryogenesis and maintains quiescence in the adult lungs. The interruption of Hh signaling may lead to the development of chronic obstructive pulmonary disease (COPD). The current study aimed to assess whether the Hh pathway affects cigarette-induced emphysema and airway inflammation by regulating inflammatory cytokines. C57BL/6J mice were randomized into control, cigarette smoke (CS) or CS + cyclopamine (CSC) groups. Control mice were exposed to normal room air, CS mice were exposed to tobacco smoke and CSC mice were exposed to CS and received cyclopamine treatment. Histopathological examination of lung tissues was performed, and the expression of sonic hedgehog (HH), glioma-associated oncogene homolog 1 (Gli1), hedgehog-interacting protein (HIP) and several inflammatory mediators (intracellular adhesion molecule-1, IL-6, IL-8 and TNF-α) were compared using reverse transcription-quantitative PCR and western blotting. The emphysema of lung tissues by histopathological examination demonstrated partial amelioration in the CSC group compared with that in the CS group. Additionally, expression levels of SHH, Gli1 and inflammatory mediators were significantly higher in the CS group compared with the control group but were significantly decreased in the CSC group. The expression of HIP was decreased in the CS group, but significantly increased in the CSC group. Hh signaling may serve an important role in cigarette-induced emphysema and airway inflammation by regulating inflammatory cytokines in animal models. Therefore, diminishing the activation of the Hh signal may serve as a novel therapeutic strategy for patients suffering from smoking-related COPD.

Inhibitory Effect of Ethanol Extract from Folium et Ramulus Securinegae on TNF‐α induced vascular inflammation in Human Umbilical Vein Endothelial Cells

Folium et Ramulus Securinegae (FRS) is known as a drug that protects and strengthen kidney and spleen by improving the blood circulation and relaxing muscles and tendons. This study investigated whether FRS has protective effect of inhibiting the vascular inflammation in human umbilical vein endothelial cells (HUVECs) by inducing nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) coupling pathway. Results showed that FRS suppressed TNF-α (Tumor necrosis factor–α) induced protein and mRNA levels of cell adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and Interleukin-6 (IL-6). Pretreatment of HUVEC with FRS decreased the adhesion of HL-60 cells to Ox-LDL (Oxidized Low-Density-Lipoprotein)-induced HUVEC. Moreover, FRS inhibited TNF-α induced intracellular reactive oxygen species (ROS) production. FRS also inhibited phosphorylation of IκB-α in cytoplasm and translocation of NF-κB (Nuclear factor-kappa B) p65 to the nucleus. FRS increased NO production, as well increased the phosphorylation of eNOS and Akt (protein kinase B) which are related with NO production. In addition, FRS increased the protein expression of GTPCH (Guanosine triphosphate cyclohydrolase Ⅰ) and the production of BH4 in HUVEC which are related with eNOS coupling pathway. Overall, the present data suggest that FRS has a protective effect against vascular inflammation and can be a potential therapeutic agent for early atherosclerosis.

Brief Report: Youth Living With Perinatally Acquired HIV Have Lower Physical Activity Levels as They Age Compared With HIV-Exposed Uninfected Youth.

Few studies have evaluated physical activity patterns or their association with vascular inflammation among youth living with perinatally acquired HIV (YPHIV). We assessed YPHIV and youth perinatally HIV-exposed but uninfected (YPHEU) in the PHACS Adolescent Master Protocol with at least one Block physical activity questionnaire (PAQ) completed between ages 7-19 years. Physical activity metrics were as follows: (1) daily total energy expenditure (TEE) and (2) physical activity duration (PAD) defined as the minutes of daily moderate and vigorous activities. In a subgroup, we measured serum biomarkers of coagulation (fibrinogen and P-selectin) and endothelial dysfunction (soluble intracellular cell adhesion molecule-1, soluble vascular cell adhesion molecule-1, and E-selectin) obtained within 3 months of a single PAQ. Repeated measures linear regression models were used to compare the trajectories of log-transformed TEE and PAD by HIV status, adjusting for confounders. Spearman correlations were calculated to assess the relationship of TEE and PAD with vascular biomarkers. Five hundred ninety-six youth (387 YPHIV and 209 YPHEU) completed 1552 PAQs (median PAQs completed = 3). The median age at enrollment (Q1, Q3) was 11 (9, 13) years. TEE and PAD increased with age in both YPHIV and YPHEU. However, even after adjusting for confounders, YPHIV had significantly less increase per year than YPHEU for TEE (5.7% [95% confidence interval (CI): -9.9% to -1.4%, P = 0.010] less) and PAD (5.2% [95% CI: -9.2% to -1.1%, P = 0.016] less). Among 302 youth with biomarker measures (187 YPHIV and 114 YPHEU), we observed little correlation with TEE or PAD. Both groups had increases in physical activity levels as they aged, but YPHIV had smaller increases throughout adolescence compared with YPHEU, which may impact long-term health.

Cytokine Levels in Human Vitreous in Proliferative Diabetic Retinopathy.

In this study, we compare the vitreous cytokine profile in patients with proliferative diabetic retinopathy (PDR) to that of patients without PDR. The identification of novel cytokines involved in the pathogenesis of PDR provides candidate therapeutic targets that may stand alone or work synergistically with current therapies in the management of diabetic retinopathy. Undiluted vitreous humor specimens were collected from 74 patients undergoing vitrectomy for various vitreoretinal disorders. Quantitative immunoassay was performed for a panel of 36 neuroinflammatory cytokines in each specimen and assessed to identify differences between PDR (n = 35) and non-PDR (n = 39) patients. Levels of interleukin-8 (IL-8), IL-15, IL-16, vascular endothelial growth factor (VEGF), VEGF-D, c-reactive protein (CRP), serum amyloid-A (SAA), and intracellular adhesion molecule-1 (ICAM1) were significantly increased in the vitreous of PDR patients compared to non-PDR patients (p < 0.05). We report novel increases in IL-15 and IL-16, in addition to the expected VEGF, in the human vitreous humor of patients with PDR. Additionally, we confirm the elevation of ICAM-1, VCAM-1, SAA, IL-8 and CRP in the vitreous of patients with PDR, which has previously been described.

Heme oxygenase-1 induction mitigates burn-associated early acute kidney injury via the TLR4 signaling pathway

ObjectivesEarly acute kidney injury (AKI) after burn contributes to disastrous prognoses for severely burned patients. Burn-induced renal oxidative stress and secondary proinflammatory mediator release contribute to early AKI development, and Toll-like receptor (TLR) 4 regulates inflammation. Heme oxygenase-1 (HO-1) is a stress-responsive enzyme that plays a vital role in protecting against ischemia-induced organ injury via its antioxidant properties and regulation of inflammation. We investigated the potential effect of HO-1 induction in preventing burn-induced early AKI and its related mechanism. MethodsA classic major-burn rat model was established using a 100 °C water bath, and hemin was injected intraperitoneally immediately after the injury to induce HO-1. Histological staining and blood tests were used to assess AKI progression based on structural changes and function. Renal levels of HO-1, oxidative stress, proinflammatory mediators and TLR4-related signals were detected using ELISA, immunostaining, qRT-PCR, and western blotting. The selective TLR4 inhibitor TAK242 and TLR4 inducer LPS were introduced to determine the roles of HO-1 in burn-related renal inflammation and the TLR4 pathway. ResultsHemin improved burn-induced renal histological damage and dysfunction, and this beneficial effect was related to reduced renal oxidative stress and the release of proinflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and intracellular adhesion molecule-1 (ICAM-1). Hemin downregulated the expression of TLR4 and the subsequent phosphorylation of IKKα/β, IκBα, and NF-κB p65;. TAK242 exerted an effect similar to but weaker than hemin; and LPS reversed the antiinflammatory effect of hemin and the regulation of TLR4 signals. These results suggested that the TLR4 signaling pathway mediated the HO-1-facilitated regulation of renal inflammation after burn. ConclusionThe present study demonstrated that HO-1 induction prevented burn-induced early AKI by targeting renal inflammation, which was mediated via regulation of the TLR4/NF-κB signaling pathway.

Lianhuaqingwen capsule inhibits influenza-induced bacterial adhesion to respiratory epithelial cells through down-regulation of cell adhesion molecules

Ethnopharmacological relevanceInfluenza virus infection is widely believed to cause mild symptoms, but can lead to high mortality and severe disease complicated by secondary bacterial pneumonia. Traditional Chinese medicine (TCM) has been proposed as a promising agent to treat respiratory viral infections. A herbal formula Lianhuaqingwen capsule (LHQW) comprising two prescriptions: Maxing Shigan decoction and Yinqiao San, has been used clinically to treat respiratory infection with immune regulatory effects. However, little is known about the capacity of LHQW against influenza-induced secondary bacterial pneumonia. Aim of studyThis study aimed to evaluate the efficacy and underlying mechanism of LHQW on influenza A virus A/PR/8/34 (PR8) secondary methicillin-resistant Staphy-lococcus aureus (MRSA) infection. MethodsThe anti-adhesion activity of LHQW against PR8-induced MRSA infection was assessed in human lung epithelial (A549) cells and the effect of LHQW on the expression of intracellular adhesion molecule 1 (ICAM-1) was detected. Also, the mRNA expression levels of inflammatory cytokines upon lipopolysaccharide (LPS) stimulation in PR8-infected A549 cells were determined. The body weight change, survivals, viral titers, colonies and the pathological parameters after LHQW treatment in severe pneumonia model have all been systematically determined. ResultsLHQW significantly reduced the adhesion of MRSA to PR8-infected A549 cells in a dose-dependent manner by suppressing the up-regulation of bacterial receptors. LHQW also markedly declined the overexpression of IL-6, IL-8, and TNF-α induced by LPS stimulated-A549 cells following influenza virus infection. Furthermore, the abnormal changes of lung index in dual-infection mice were relieved after administered with LHQW in preventive and therapeutic mode, but with no significantly difference (P > 0.05). LHQW could not effectively improve survival rate or prolong the survival time of mice (P > 0.05). LHQW (1000 mg/kg/d) administered prophylactically significantly decreased the lung viral titers (P < 0.05), slightly downregulated IL-6 but TNF-α, IL-1β levels and improved lung pathological inflammation including neutrophil infiltration, necrosis, which is consistent with the expression of inflammatory factors. ConclusionsLHQW inhibited influenza-induced bacterial adhesion by down-regulating the adhesion molecules with the improvement trend on severe pneumonia, indicating that it can be used as an adjuvant medication in severe viral-bacterial pneumonia therapy rather than as a single medication.

Limited utility of novel serological biomarkers in patients newly suspected of having giant cell arteritis.

Diagnosing and monitoring vascular activity in giant cell arteritis (GCA) is difficult due to the paucity of specific serological biomarkers. We assessed the utility of 8 novel biomarkers in an inception cohort of newly suspected GCA patients. Consecutive patients were enrolled between May 2016 and December 2017. Serum was collected within 72hours of commencing corticosteroids and at 6months. It was analyzed for levels of intra-cellular adhesion molecule 1, vascular endothelial growth factor (VEGF), pentraxin 3, von Willebrand factor and procalcitonin (5-plex R&D Systems multiplex assay) and interleukin (IL)6, IL12 and interferon-γ (high-sensitivity 3-plex ProcartaPlex multiplex assay). A GCA specific positron emission tomography / computed tomography (PET/CT) scan was performed at enrolment with uptake in each vascular territory graded and summed to derive a total vascular score (TVS). For the 63 patients enrolled, 12 (19%) had a final diagnosis of biopsy-positive GCA and a further 9 had a clinical diagnosis of biopsy-negative GCA. None of the 8 biomarkers was significantly higher in GCA patients compared with those with alternative diagnoses, or demonstrated a positive correlation with the PET/CT TVS. This was in contrast to the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) which were higher in the biopsy-positive GCA cohort (P<.04) and showed weak positive correlations with the TVS (correlation coefficient 0.34, P<.01). Procalcitonin did not distinguish between GCA and infection. Concentrations of CRP, ESR, VEGF and pentraxin 3 decreased between diagnosis and 6months in GCA patients. This study did not identify new serological biomarkers to assist in diagnosing or assessing the vasculitis burden in GCA.

Meibomian gland dysfunction is suppressed via selective inhibition of immune responses by topical LFA-1/ICAM antagonism with lifitegrast in the allergic eye disease (AED) model

PurposeThe etiology of meibomian gland dysfunction (MGD) is incompletely understood, despite being a common ophthalmic condition and an area of unmet medical need. It is characterized by an insufficiency in glandular provision of specialized lipids (meibum) to the tear film and is a major cause of dry eye. Work in the allergic eye disease (AED) mouse model has revealed an immunopathogenic role in MGD causation, now raising interest in the applicability of immunomodulatory therapies. As such, we herein ask whether inhibition of lymphocyte function associated antigen (LFA)-1/intracellular adhesion molecules (ICAM)-1 signaling via topical lifitegrast administration has a therapeutic effect on MGD in AED mice. MethodsMice were induced with AED by i.p. injection of ovalbumin (OVA) mixed with alum and pertussis toxin, followed 2 weeks later by once daily topical OVA challenges for 7 days. Mice were treated topically with 5% lifitegrast ophthalmic solution or vehicle (PBS) 30 min prior to challenge. We developed a clinical ranking method to assess MGD severity, and also scored clinical allergy. Conjunctivae and draining lymph nodes were collected for flow cytometry. ResultsTopical lifitegrast significantly inhibited clinical MGD severity, which was associated with diminished pathogenic TH17 cell and neutrophil numbers in the conjunctiva. No significant change in conjunctival TH2 cells or eosinophils, and only marginal differences in ocular allergy were observed. ConclusionsIn AED mice, lifitegrast inhibited MGD severity marked by a reduction in select immune populations in the conjunctiva. Our findings warrant future examination of lifitegrast in the treatment of patients with forms of MGD.

Targeting macrophage liver X receptors by hydrogel-encapsulated T0901317 reduces atherosclerosis without effect on hepatic lipogenesis.

Targeting macrophage but not hepatocyte liver X receptors (LXRs) can reduce atherosclerosis without effect on hepatic lipogenesis. In this study, we encapsulated LXR ligands with D-Nap-GFFY to form a nanofibre hydrogel (D-Nap-GFFY-T0901317 or GFFY-T0901317) and determined its effect on atherosclerosis, hepatic lipogenesis and the underlying mechanisms involved. D-Nap-GFFY-T0901317 was subcutaneously injected to proatherogenic diet-fed apoE-deficient (Apoe-/- ) mice, followed by determination of the development of atherosclerosis, liver steatosis and the involved mechanisms, with comparison of T0901317 oral administration. Subcutaneous injection of D-Nap-GFFY-T0901317 to Apoe-/- mice inhibited atherosclerosis at a comparable level as T0901317 oral administration without effect on hepatic lipogenesis. More importantly, D-Nap-GFFY-T0901317 regressed the advanced lesions. In arterial wall, D-Nap-GFFY-T0901317 reduced macrophage/foam cells, necrotic cores and calcification and increased collagen content. It activated expression of ABCA1/G1 and smooth muscle α-actin, while inhibiting expression of intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). D-Nap-GFFY-T0901317 also reduced serum pro-inflammatory cytokines and facilitated Kupffer cell M2 polarization. Mechanistically, D-Nap-GFFY-T0901317 was selectively taken up by macrophages but not hepatocytes, resulting in activation of macrophage ABCA1/G1 expression, while having no effect on lipogenic genes in hepatocytes. Moreover, the selective uptake of D-Nap-GFFY-T0901317 by macrophages was mainly completed in a scavenger receptor class A-dependent manner. Our study demonstrates that D-Nap-GFFY-T0901317 reduces atherosclerosis without effect on hepatic lipogenesis by targeting macrophage LXRs selectively, indicating its potential application for atherosclerosis treatment.