A role of macrophage complement receptor CRIg in immune clearance and inflammation

Complement receptor of the immunoglobulin superfamily (CRIg), also referred to as Z39Ig and V-set and Ig domain-containing 4 (VSIG4), has recently been implicated in the clearance of systemic pathogens and autologous cells. CRIg is exclusively expressed on tissue resident macrophages and binds to multimers of C3b and iC3b that are covalently attached to particle surfaces. Next to functioning as an important clearance receptor, CRIg's extracellular domain inhibits complement activation through the alternative, but not the classical, pathway, providing a novel tool to selectively block this pathway in vivo. Here, we review a role for CRIg in immune clearance, T-cell responses and complement regulation, and discuss the implications for disease manifestation.     

Safety but Limited Efficacy of Ensartinib in ROS1-Positive NSCLC: A Single-Arm,Multicenter Phase 2 Study

IntroductionSome ALK inhibitors with good inhibition of ROS1 in preclinical studies have been reported to be possibly beneficial in ROS1-positive NSCLC. In this work, we studied the efficacy and safety of ensartinib in the treatment of patients with ROS1-positive NSCLC.MethodsThe exploratory study was a phase 2, single-arm, multicenter design (NCT03608007). Patients with ROS1-positive NSCLC with a previous chemotherapy line number of less than or equal to 1 who received ensartinib at the dose of 225 mg once daily were enrolled. The primary end point was objective response rate evaluated by an investigator per Response Evaluation Criteria in Solid Tumors version 1.1.ResultsFrom June 2018 to July 2019, a total of 59 patients were enrolled at 23 centers in the People’s Republic of China. At the time of data cutoff, the median follow-up was 19.8 months (range: 0.8–22.5). The median objective response rate was 27.0 % (95 % confidence interval [CI]: 13.8–44.1) with 10 partial responses. Median duration of response was 4.8 months (95 % CI: 1.8–10.8). The median progression-free survival was 4.6 months (95 % CI: 4.0–6.4). The median overall survival was not estimable (95 % CI: 14.9–not estimable). Of four patients with brain metastases, intracranial disease control was reported in three (75.0 %, 95 % CI: 19.4–99.4). The most common treatment-related adverse events (TRAEs) were rash and liver enzyme abnormalities, with good prognosis after adjustment for dosage and concomitant medication. Most of the TRAEs were of grades 1 to 2, and incidence of grade greater than or equal to 3 TRAEs was 25.4 %.ConclusionsEnsartinib had a modest efficacy in patients with ROS1-positive NSCLC with an acceptable safety profile.     

Human papillomavirus in tonsillectomy specimen from China and Pakistan — Prevalence and genotype distribution

Background

The expected corresponding increase in tonsillar human papillomavirus (HPV) infection associated with increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) substantiate the evaluation of normal tonsillar tissue in different population. The epidemiology of HPV in tonsillar tissue varies geographically. This study evaluated samples from two countries to determine the prevalence in respective samples.

高脂饮食对自发性高血压大鼠中心动脉弹性的影响及鱼油的干预作用

目的观察高饱和脂肪酸及富含鱼油(n-3多不饱和脂肪酸)饮食对自发性高血压大鼠(SHR)大动脉弹性的影响。方法选择8周龄雄性SHR 30只,适应性喂养至14周龄后,按体重随机分为3组,每组10只,分别给予普通饲料、高脂饲料、高脂加鱼油饲料,持续喂养至36周龄,共干预22周。同龄对照大鼠(WKY)30只同前分组。干预后测定血压、体重、血浆游离脂肪酸谱、生化指标,喂养结束后,应用组织多普勒超声法测定中心动脉脉搏波传导速度(APWV),应用组织化学和免疫组织化学法测定中心动脉管壁的病理改变和基质金属蛋白酶9(MMP-9)的表达水平。结果 SHR高脂饮食组血压较普食组和高脂加鱼油组升高(160.5±5.5 mm Hg比153.1±1.0mm Hg、155.1±6.7 mm Hg,P0.01);HE染色显示高脂饮食组动脉管壁中膜横截面积(MCSA)较普食组增加(35500±8536μm2比28348±3956μm2,P0.05),高脂加鱼油组胸主动脉MCSA较高脂饮食组减小(16865±7235μm2,P0.05)。WKY大鼠MCSA无明显变化。SHR大鼠高脂饮食组主动脉弹力纤维占中膜面积百分比较普食组减少(21.1%±2.3%比30.7%±2.3%,P0.05),高脂加鱼油组较高脂饮食组升高(34.5%±4.1%,P0.05)。SHR大鼠高脂饮食组中心动脉APWV较普食组增加,而高脂加鱼油组APWV较高脂饮食组减小(P0.05)。SHR大鼠高脂饮食组的主动脉壁中MMP-9表达较普食组、高脂加鱼油组升高。结论高饱和脂肪酸饮食具有刺激SHR大鼠大动脉血管壁增厚、上调MMP-9在动脉壁表达及增加动脉僵硬度的作用,而富含n-3多不饱和脂肪酸的饮食可能通过逆转这一作用发挥预防及控制血压的作用。     

Urinary biomarkers of oxidative stress and plasmatic inflammatory profile in phenylketonuric treated patients

Oxidative stress has been proposed as an important pathophysiologic feature of various inborn errors of metabolism, including phenylketonuria (PKU). Considering that there are few studies relating oxidative stress and inflammation directly in PKU disease, the aim of this study was to evaluate and correlate oxidative damage to biomolecules, antioxidant defenses, pro-inflammatory cytokines, phenylalanine (Phe) and its metabolites (phenyllactic acid—PLA and phenylacetic acid—PAA) levels in urine and plasma from patients with PKU under dietary treatment. We observed a marked increase of isoprostanes, which is a lipid peroxidation biomarker, in urine from these treated patients. Next, we demonstrated that protein oxidative damage, measured by di-tyrosine formation, was significantly increased in urine from PKU treated patients and that decreased urinary antioxidant capacity was also observed. Our findings concerning to the inflammatory cytokines interleukin-6 and interleukin-1β, both significantly increased in these patients, provide evidence that the pro-inflammatory state occurs. Besides, interleukin-1β was positively correlated with isoprostanes. We observed a negative correlation between interleukin-6 and interleukin-10, an anti-inflammatory cytokine. Di-tyrosine was positively correlated with Phe, which indicates oxidative damage to proteins, as well as with PAA. These findings may suggest that the protein damage may be induced by Phe and its metabolite PAA in PKU. Our results indicate that pro-oxidant and pro-inflammatory states occur and are, in part, correlated and protein oxidation seems to be induced by Phe and PPA in PKU patients.     

Short term exendin-4 treatment reduces markers of metabolic disorders in female offspring of obese rat dams

ObjectivesMaternal obesity imposes significant health risks in the offspring including diabetes and dyslipidemia. We previously showed that the hypoglycaemic agent exendin-4 (Ex-4) administered from weaning can reverse the maternal impact of ‘transmitted disorders’ in such offspring. However daily injection for six-weeks was required and the beneficial effect may lapse upon drug withdrawal. This study aimed to investigate whether short term Ex-4 treatment during suckling period in a rodent model can reverse transmitted metabolic disorders due to maternal obesity.MethodsMaternal obesity was induced in female Sprague Dawley rats by high-fat diet feeding for 6 weeks, throughout gestation and lactation. Female offspring were treated with Ex-4 (5 μg/kg/day) between postnatal day (P) 4 and 14. Female offspring were harvested at weaning (P20). Lipid and glucose metabolic markers were measured in the liver and fat. Appetite regulators were measured in the plasma and hypothalamus.ResultsMaternal obesity significantly increased body weight, fat mass, and liver weight in the offspring. There was an associated inhibition of peroxisomal proliferator activated receptor gamma coactivator 1α (PGC1α), increased fatty acid synthase (FASN) expression in the liver, and reduced adipocyte triglyceride lipase (ATGL) expression. It also increased the plasma gut hormone ghrelin and reduced glucagon-like peptide-1. Ex-4 treatment partially reversed the maternal impact on adiposity and impaired lipid metabolism in the offspring, with increased liver PGC1α and inhibition of FASN mRNA expression. Ex-4 treatment also increased the expression of a novel fat depletion gene a2-zinc-glycoprotein 1 in the fat tissue.ConclusionShort term Ex-4 treatment during the suckling period significantly improved the metabolic profile in the offspring from the obese mothers at weaning. Long-term studies are needed to follow such offspring to adulthood to examine the sustained effects of Ex-4 in preventing the development of metabolic disease.     

Reprint of: MicroRNA profiling of human intermediate monocytes

Among the three human monocyte subsets, intermediate CD14++CD16+ monocytes have been characterized as particularly proinflammatory cells in experimental studies and as potential biomarkers of cardiovascular risk in clinical cohorts. To further substantiate the distinct role of intermediate monocytes within human monocyte heterogeneity, we assessed subset-specific expression of miRNAs as central epigenetic regulators of gene expression. We hypothesized that intermediate monocytes have a distinct miRNA profile compared to classical and non-classical monocytes.By using small RNA-seq we analyzed 662 miRNAs in the three monocyte subsets. We identified 38 miRNAs that are differentially expressed in intermediate monocytes compared to both classical and non-classical monocytes with a p value of <10⁻¹⁰, of which two miRNAs – miR-6087 (upregulated) and miR-150-5p (downregulated) – differed in their expression more than ten-fold. Pathway analysis of the 38 differentially expressed miRNAs linked intermediate monocytes to distinct biological processes such as gene regulation, cell differentiation, toll-like receptor signaling as well as antigen processing and presentation. Moreover, differentially expressed miRNAs were connected to those genes that we previously identified as markers of intermediate monocytes.In aggregation, we provide first genome-wide miRNA data in the context of monocyte heterogeneity, which substantiate the concept of monocyte trichotomy in human immunity. The identification of miRNAs that are specific for intermediate monocytes may allow to develop strategies, which particularly target this cell population while sparing the other two subsets.     

An orally administrated nucleotide-delivery vehicle targeting colonic macrophages for the treatment of inflammatory bowel disease

Tumor necrosis factor-alpha (TNF-α) plays a central role in the pathogenesis of inflammatory bowel disease (IBD). Anti-TNF-α therapies have shown protective effects against colitis, but an efficient tool for target suppression of its secretion - ideally via oral administration - remains in urgent demand. In the colon tissue, TNF-α is mainly secreted by the colonic macrophages. Here, we report an orally-administrated microspheric vehicle that can target the colonic macrophages and suppress the local expression of TNF-α for IBD treatment. This vehicle is formed by cationic konjac glucomannan (cKGM), phytagel and an antisense oligonucleotide against TNF-α. It was given to dextran sodium sulfate (DSS) colitic mice via gastric perfusion. The unique swelling properties of cKGM enabled the spontaneous release of cKGM& antisense nucleotide (ASO) nano-complex from the phytagel scaffold into the colon lumen, where the ASO was transferred into colonic macrophages via receptor-mediated phagocytosis. The treatment significantly decreased the local level of TNF-α and alleviated the symptoms of colitis in the mice. In summary, our study demonstrates a convenient, orally-administrated drug delivery system that effectively targets colonic macrophages for suppression of TNF-α expression. It may represent a promising therapeutic approach in the treatment of IBD.