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Polyethylene glycol (PEG) coating of gold nanoparticles (AuNPs) improves AuNP distribution via blood circulation. The use of PEG-coated AuNPs was shown to result in acute injuries to the liver, kidney, and spleen, but long-term toxicity has not been well studied. In this study, we investigated reporter induction for up to 90 days in NF-κB transgenic reporter mice following intravenous injection of PEG-coated AuNPs. The results of different doses (1 and 4 μg AuNPs per gram of body weight), particle sizes (13 nm and 30 nm), and PEG surfaces (methoxyl- or carboxymethyl-PEG 5 kDa) were compared. The data showed up to 7-fold NF-κB reporter induction in mouse liver from 3 h to 7 d post PEG-AuNP injection compared to saline-injected control mice, and gradual reduction to a level similar to control by 90 days. Agglomerates of PEG-AuNPs were detected in liver Kupffer cells, but neither gross pathological abnormality in liver sections nor increased activity of liver enzymes were found at 90 days. Injection of PEG-AuNPs led to an increase in collagen in liver sections and elevated total serum cholesterol, although still within the normal range, suggesting that inflammation resulted in mild fibrosis and affected hepatic function. Administrating PEG-AuNPs inevitably results in nanoparticles entrapped in the liver; thus, further investigation is required to fully assess the long-term impacts by PEG-AuNPs on liver health.

Ethnopharmacological Relevance: Poria cocos is a medicinal mushroom of the Polyporaceae family with antioxidant and anti-inflammatory activities, which has been used for its sedative, diuretic and tonic effects in traditional medicine for several hundred years., Aim of Study: Considering that depression is an inflammatory related mental disease, this study investigated the antidepressant-like effects of water extract of P. cocos in a rodent animal model., Materials and Methods: Rats that were exposed to a forced swimming test (FST) for 28 consecutive days, and unpredictable chronic mild stress (UCMS) for five weeks underwent treatment with P. cocos water extract (PCW) (doses: 100, 300 and 900 mg/kg body weight [bw]; administered by gavage). Dopamine (DA), serotonin (5-HT) and their metabolites in the frontal cortex of rats were measured., Results: Our results firstly showed that sucrose preference during the UCMS paradigm was increased and immobility time in the FST was reduced with administration of PCW. In addition, PCW significantly attenuated UCMS-induced turnover rate of DA and 5-HT in the frontal cortex. Moreover, PCW inhibited UCMS-induced activated inflammatory response, reflected by reduced expression in the frontal cortex of p38, NF-κB and TNF-α., Conclusions: Our results strongly suggest that PCW exhibits a potent antidepressant-like effect via regulation of monoaminergic neurotransmission and inactivation of inflammation, and that P. cocos may be considered as a traditional herbal potential medicine for the treatment of depression., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective To investigate the relationship between inflammatory factors, oxidative stress and type 1 deiodinase (DIO-1) concentration in patients with chronic renal failure (CRF) with or without euthyroid sick syndrome (ESS). Methods This study recruited patients with CRF and divided them into two groups: group 1 had low free triiodothyronine (FT3) levels; and group 2 had normal FT3 levels. Group 3 consisted of healthy volunteers. Serum levels of interleukin (IL)-6, IL-1β, tumour necrosis factor (TNF)-α, 8-isoprostane and DIO-1 were measured using enzyme-linked immunosorbent assays. Multiple regression analysis was used to analyse correlations between parameters. Results Sixty patients were enrolled into each group and the groups were comparable in terms of vital signs, white blood cell count, free thyroxine and thyroid stimulating hormone concentrations. The serum DIO-1 concentration was significantly higher in group 2 than in groups 1 and 3. Multivariate regression analysis revealed that the DIO-1 concentration was inversely correlated with the TNF-α concentration. Conclusions Patients with CRF without ESS showed higher concentrations of DIO-1 than patients with ESS. The DIO-1 concentration was inversely correlated with the TNF-α concentration, which might indicate that the inflammatory response was milder in the patients with CRF without ESS than in those with ESS.

Prenatal exposure to nonylphenol (NP) and/or bisphenol A (BPA) has been reported to be associated with adverse birth outcomes; however, the underlying mechanisms remain unclear. The primary mechanism is endocrine disruption of the binding affinity for the estrogen receptor, but oxidative stress and inflammation might also play a contributory role. We aimed to investigate urinary NP and BPA levels in relation to biomarkers of oxidative/nitrative stress and inflammation and to explore whether changes in oxidative/nitrative stress are a function of prenatal exposure to NP/BPA and inflammation in 241 mother-fetus pairs. Third-trimester urinary biomarkers of oxidative/nitrative stress were simultaneously measured, including products of oxidatively and nitratively damaged DNA (8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-nitroguanine (8-NO 2 Gua)) as well as products of lipid peroxidation (8-iso-prostaglandin F 2α (8-isoPF 2α ) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)). The antioxidant glutathione peroxidase (GPx) and inflammation biomarkers, including C-reactive protein (CRP) and a panel of cytokines (interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)), were analyzed in maternal and umbilical cord plasma samples. In adjusted models, we observed significant positive associations between NP exposure and 8-OHdG and 8-NO 2 Gua levels, between BPA and 8-isoPF 2α levels, and between maternal CRP levels and HNE-MA levels. Additionally, BPA and TNF-α levels in cord blood were inversely associated with maternal and GPx levels in cord blood as well as maternal TNF-α levels were inversely associated with maternal GPx levels. These results support a role for exposure to NP and BPA and possibly inflammation in increasing oxidative/nitrative stress and decreasing antioxidant activity during pregnancy.

Nearly all genetic crosses generated from Apoe -/- or Lldlr -/- mice for genetic analysis of atherosclerosis have used C57BL/6 J (B6) mice as one parental strain, thus limiting their mapping power and coverage of allelic diversity. SM/J-Apoe -/- and BALB/cJ-Apoe -/- mice differ significantly in atherosclerosis susceptibility. 224 male F 2 mice were generated from the two Apoe -/- strains to perform quantitative trait locus (QTL) analysis of atherosclerosis. F 2 mice were fed 5 weeks of Western diet and analyzed for atherosclerotic lesions in the aortic root. Genome-wide scans with 144 informative SNP markers identified a significant locus near 20.2 Mb on chromosome 10 (LOD score: 6.03), named Ath48, and a suggestive locus near 49.5 Mb on chromosome 9 (LOD: 2.29; Ath29) affecting atherosclerotic lesion sizes. Using bioinformatics tools, we prioritized 12 candidate genes for Ath48. Of them, Tnfaip3, an anti-inflammatory gene, is located precisely underneath the linkage peak and contains two non-synonymous SNPs leading to conservative amino acid substitutions. Thus, this study demonstrates the power of forward genetics involving the use of a different susceptible strain and bioinformatics tools in finding atherosclerosis susceptibility genes.

Background: Patients undergoing maintenance hemodialysis (MHD) have a significantly higher prevalence of hepatitis C virus (HCV) infection and malnutrition-inflammation complex syndrome (MICS). In the present study of Taiwanese MHD patients, we determined the clinical characteristics and influence of HCV infection on MICS by calculation of the malnutrition-inflammation score (MIS)., Methods: This was a prospective longitudinal study performed at a single hemodialysis (HD) center in Taiwan from September 2007 through March 2008. The study enrolled 58 patients (38%) in the active HCV group and 95 patients (62%) in the non-HCV group. The two or three weekly HD sessions of all patients were followed for 7 months. The MIS was assessed using 10 components, 7 from the conventional subjective global assessment of nutrition and 3 additional elements, body mass index, serum albumin and total iron-binding capacity., Results: HD vintage and total MIS score were greater in patients with active HCV. The active HCV group had significantly longer dialysis vintage and lower total cholesterol but higher total MIS score than the non-HCV group. The MIS 5 score, a measure of major comorbid conditions (including number of years on dialysis), was also significantly higher in the active HCV group., Conclusion: MHD patients with active HCV infections have more severe MICS-associated metabolic and physiological disease than MHD patients without active HCV infection.

Fibroblasts are important participants in inflammation. Although not leukocytes, their capacity to produce cytokines, chemokines, and other inflammatory factors locally in tissues suggests that they can contribute to inflammatory diseases. For example, fibroblasts in a rheumatoid arthritis (RA) joint are a dominant source of IL-6 and RANKL in the synovium, both of which are therapeutic targets for inflammation and bone erosion. Previously, we found that fibroblasts can be targeted by mAb directed against cadherin-11 (cad-11), a mesenchymal cadherin that fibroblasts selectively express. Targeting cad-11 significantly reduced inflammation as assessed by joint swelling and clinical inflammation scores. However, the mechanism by which anti-cad-11 reduced inflammation was not known. Here, we show that cad-11 engagement induces synovial fibroblasts to secret proinflammatory cytokines including IL-6. Cad-11 engagement strongly synergized with TNF-α and IL-1β in the induction of IL-6. Importantly, cad-11 activated MAP kinases and NF-κB for IL-6 induction. IL-6 levels in ankles of inflamed joints were reduced in cad-11 mutant mice compared to wild-type mice with inflammatory arthritis. Thus, we suggest that cad-11 modulates synovial fibroblasts to evoke inflammatory factors that may contribute to the inflammatory process in RA.

Mechanisms by which mesenchymal-derived tissue lineages participate in amplifying and perpetuating synovial inflammation in arthritis have been relatively underinvestigated and are therefore poorly understood. Elucidating these processes is likely to provide new insights into the pathogenesis of multiple diseases. Leukotriene B(4) (LTB(4)) is a potent proinflammatory lipid mediator that initiates and amplifies synovial inflammation in the K/BxN model of arthritis. We sought to elucidate mechanisms by which mesenchymal-derived fibroblast-like synoviocytes (FLSs) perpetuate synovial inflammation. We focused on the abilities of FLSs to contribute to LTB(4) synthesis and to respond to LTB(4) within the joint. Using a series of bone marrow chimeras generated from 5-lipoxygenase(-/-) and leukotriene A(4) (LTA(4)) hydrolase(-/-) mice, we demonstrate that FLSs generate sufficient levels of LTB(4) production through transcellular metabolism in K/BxN serum-induced arthritis to drive inflammatory arthritis. FLSs-which comprise the predominant lineage populating the synovial lining-are competent to metabolize exogenous LTA(4) into LTB(4) ex vivo. Stimulation of FLSs with TNF increased their capacity to generate LTB(4) 3-fold without inducing the expression of LTA(4) hydrolase protein. Moreover, LTB(4) (acting via LTB(4) receptor 1) was found to modulate the migratory and invasive activity of FLSs in vitro and also promote joint erosion by pannus tissue in vivo. Our results identify novel roles for FLSs and LTB(4) in joints, placing LTB(4) regulation of FLS biology at the center of a previously unrecognized amplification loop for synovial inflammation and tissue pathology.

Neuroinflammation, caused by 6 days of intracerebroventricular infusion of a low dose of lipopolysaccharide (LPS; 0.5 ng/h), stimulates brain arachidonic acid (AA) metabolism in rats, but 6 weeks of lithium pretreatment reduces this effect. To further understand this action of lithium, we measured concentrations of eicosanoids and docosanoids generated from AA and docosahexaenoic acid (DHA), respectively, in high-energy microwaved rat brain using LC/MS/MS and two doses of LPS. In rats fed a lithium-free diet, low (0.5 ng/h)- or high (250 ng/h)-dose LPS compared with artificial cerebrospinal fluid increased brain unesterified AA and prostaglandin E(2) concentrations and activities of AA-selective Ca(2+)-dependent cytosolic phospholipase A(2) (cPLA(2))-IV and Ca(2+)-dependent secretory sPLA(2). LiCl feeding prevented these increments. Lithium had a significant main effect by increasing brain concentrations of lipoxygenase-derived AA metabolites, 5- hydroxyeicosatetraenoic acid (HETE), 5-oxo-eicosatetranoic acid, and 17-hydroxy-DHA by 1.8-, 4.3- and 1.9-fold compared with control diet. Lithium also increased 15-HETE in high-dose LPS-infused rats. Ca(2+)-independent iPLA(2)-VI activity and unesterified DHA and docosapentaenoic acid (22:5n-3) concentrations were unaffected by LPS or lithium. This study demonstrates, for the first time, that lithium can increase brain 17-hydroxy-DHA formation, indicating a new and potentially important therapeutic action of lithium.

Bile acids are lipid-emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine1. As detergents, bile acids can cause toxicity and inflammation in enterohepatic tissues2. Nuclear receptors maintain bile acid homeostasis in hepatocytes and enterocytes3, but it is unclear how mucosal immune cells tolerate high concentrations of bile acids in the small intestine lamina propria (siLP). CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter MDR1 (encoded by Abcb1a) in the siLP to prevent bile acid toxicity and suppress Crohn's disease-like small bowel inflammation4. Here we identify the nuclear xenobiotic receptor CAR (encoded by Nr1i3) as a regulator of MDR1 expression in T cells that can safeguard against bile acid toxicity and inflammation in the mouse small intestine. Activation of CAR induced large-scale transcriptional reprogramming in Teff cells that infiltrated the siLP, but not the colon. CAR induced the expression of not only detoxifying enzymes and transporters in siLP Teff cells, as in hepatocytes, but also the key anti-inflammatory cytokine IL-10. Accordingly, CAR deficiency in T cells exacerbated bile acid-driven ileitis in T cell-reconstituted Rag1-/- or Rag2-/- mice, whereas pharmacological activation of CAR suppressed it. These data suggest that CAR acts locally in T cells that infiltrate the small intestine to detoxify bile acids and resolve inflammation. Activation of this program offers an unexpected strategy to treat small bowel Crohn's disease and defines lymphocyte sub-specialization in the small intestine.

CA is a plant derivative with antibacterial and antiviral pharmacological effects, however, the therapeutic effect of CA on Klebsiella pneumonia and its mechanism study is still unclear. A rat KP model was established in vitro, a pneumonia cell model was established in vivo, the histopathological changes in the lungs were observed by HE staining after CA treatment, the expression of relevant inflammatory factors was detected by ELISA, the changes in the expression of proteins related to the AhR‐Src‐STAT3‐IL‐10 signaling pathway were detected by Western blot and immunofluorescence in the lungs, and the interactions between the proteins were verified by COIP relationship. The results showed that CA was able to attenuate the injury and inflammatory response of lung tissues, and molecular docking showed that there were binding sites between CA and AhR, and COIP demonstrated that AhR interacted with both STAT3 and Ser. In addition, CA was able to up‐regulate the expression levels of pathway‐related proteins of AhR, IL‐10, p‐Src, and p‐STAT3, and AhR knockdown was able to reduce LPS‐induced inflammatory responses and up‐regulate pathway‐related proteins, whereas CA treatment of AhR‐knockdown‐treated A549 cells did not show any statistically significant difference compared with the AhR knockdown group, demonstrating that CA exerts its pharmacological effects. These findings elucidated the mechanism of CA in the treatment of KP and demonstrated that CA is a potential therapeutic agent for KP. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) and intracranial aneurysm (IA) are serious arterial diseases in the aorta and brain, respectively. AAA and IA are associated with old age in males and females, respectively, and if rupture occurs, they carry high morbidity and mortality. Aneurysmal subarachnoid hemorrhage (SAH) due to IA rupture has a high rate of complication and fatality. Despite these severe clinical outcomes, preventing or treating these devastating diseases remains an unmet medical need. Inflammation and oxidative stress are shared pathologies of these vascular diseases. Therefore, therapeutic strategies have focused on reducing inflammation and reactive oxygen species levels. Interestingly, in response to cellular stress, the inducible heme oxygenase-1 (HO-1) is highly upregulated and protects against tissue injury. HO-1 degrades the prooxidant heme and generates molecules with antioxidative and anti-inflammatory properties, resulting in decreased oxidative stress and inflammation. Therefore, increasing HO-1 activity is an attractive option for therapy. Several HO-1 inducers have been identified and tested in animal models for preventing or alleviating AAA, IA, and SAH. However, clinical trials have shown conflicting results. Further research and the development of highly selective HO-1 regulators may be needed to prevent the initiation and progression of AAA, IA, or SAH.

Age-related macular degeneration (AMD) is a chronic disease, which progresses slowly from early to late stages over many years. Inflammation critically contributes to the pathogenesis of AMD. Here, we investigated the therapeutic potential of minocycline in a chronic model of AMD (i.e., the LysMCre-Socs3fl/flCx3cr1gfp/gfp double knockout [DKO] mice). Five-month-old DKO and wild type (WT) (Socs3fl/fl) mice were gavage fed with minocycline (25 mg/kg daily) or vehicle (distilled water) for 3 months. At the end of the treatment, visual function and retinal changes were examined clinically (using electroretinography, fundus photograph and optic coherence tomography) and immunohistologically. Three months of minocycline treatment did not affect the body weight, behaviour and general health of WT and DKO mice. Minocycline treatment enhanced the a-/b-wave aptitudes and increased retinal thickness in both WT and DKO. DKO mouse retina expressed higher levels of Il1b, CD68 and CD86 and had mild microglial activation, and decreased numbers of arrestin+ photoreceptors, PKCα+ and secretagogin+ bipolar cells compared to WT mouse retina. Minocycline treatment reduced microglial activation and rescued retinal neuronal loss in DKO mice. Our results suggest that long-term minocycline treatment is safe and effective in controlling microglial activation and preserving visual function in chronic models of AMD. [ABSTRACT FROM AUTHOR]

The subretinal space is devoid of any immune cells under normal conditions and is an immune privileged site. When photoreceptors and/or retinal pigment epithelial cells suffer from an injury, a wound healing process will be initiated. Retinal microglia and the complement system, as the first line of retinal defense, are activated to participate in the wound healing process. If the injury is severe or persists for a prolonged period, they may fail to heal the damage and circulating immune cells will be summoned leading to chronic inflammation and abnormal wound healing, i.e., subretinal or intraretinal fibrosis, a sight-threatening condition frequently observed in rhematogenous retinal detachment, age-related macular degeneration and recurrent uveoretinitis. Here, we discussed the principles of subretinal wound healing with a strong focus on the conditions whereby the damage is beyond the healing capacity of the retinal defense system and highlighted the roles of circulating immune cells in subretinal wound healing and fibrosis. [ABSTRACT FROM AUTHOR]

Aims and Objectives: To explore whether dual‐lumen power injectable peripherally inserted central catheters (PICCs) could be effectively and safely applied in allogeneic hematopoietic stem cell transplantation (allo‐HSCT) and for serum cyclosporine level monitoring. Background: Compared to conventional central venous access devices, PICC provides a feasible route not only for fluid infusion, but also for blood sample collection in patients undergoing oncological treatments. Design: A prospective observational study was conducted according to the STROBE guidelines. Methods: We prospectively evaluated the applications and complications of power injectable PICCs in 52 consecutive allo‐HSCT recipients. We also compared the cyclosporine levels in 188 paired blood samples, simultaneously obtained via power injectable PICCs and percutaneous venous puncture, to investigate whether power injectable PICC is a feasible route for cyclosporine concentration monitoring in allo‐HSCT. Results: The median PICC placement duration was 29 days. The insertion‐site blood oozing and central line‐associated bloodstream infection rates were 36.5% (19/52) and 26.9% (14/52), respectively, indicating the feasibility of these PICCs for various applications in allo‐HSCT. No power injectable PICC‐related thrombotic adverse events were identified; 90.4% (47/52) of cases with power injectable PICC removal occurred because of lack of medical utility, suggesting that power injectable PICC‐related complications were manageable. However, cyclosporine levels in samples obtained via these PICCs were significantly higher than those in samples obtained via percutaneous venous puncture (261.5 ± 139.2 vs. 232.4 ± 253.6 ng/ml; p = 0.019 [set 1]; 254.8 ± 89.3 vs. 225.1 ± 233.3 ng/ml; p<0.001 [set 2]; 283.6 ± 103.9 vs. 238.0 ± 254.7 ng/ml; p = 0.006 [set 3]; 291.0 ± 94.9 vs. 266.0 ± 274.7 ng/ml; p = 0.016 [set 4]). Conclusion: The power injectable PICC is a feasible venous access device for allo‐HSCT. Relevance to clinical practice: The dual‐lumen power injectable PICCs provided a reliable access for blood sample collection, decreasing the number of blind percutaneous venous punctures in allo‐HSCT. However, its application in cyclosporine level monitoring needs further investigation. [ABSTRACT FROM AUTHOR]

Purpose: To validate the protective effect of a mammalian target of rapamycin (mTOR) inhibitor on human retinal pigment epithelium (RPE) cells challenged with 7-ketocholesterol (7-KC) and explored the underlying mechanisms. Methods: Human primary RPE (hRPE) cells and ARPE-19 cells were cultured with or without 10 nM of rapamycin for 6 h before being exposed to 10 μM of 7-KC for 24 h. The transcriptome of 7-KC challenged ARPE-19 cells was investigated by RNA sequencing (RNA-seq). The effects of 7-KC and rapamycin on the viability of ARPE-19 cells were measured with CCK-8. Gene expression was verified by real-time PCR, and protein levels were determined by ELISA or Western blotting. Results: The expression of IL-6, IL-8, and vascular endothelial growth factor (VEGF) in RPE cells was markedly increased after stimulation with 7-KC for 12/24 h compared with the controls. RNA-seq showed that a total of 10,243 genes were differentially expressed, with 5,518 genes upregulated and 4,725 genes downregulated between the 7-KC treated and the control group. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that 7-KC stimulation activated mTOR signaling and other pathways, including adherent junction, MAPK, and Wnt signalings. mTOR inhibitor rapamycin significantly suppressed the elevation of IL-6, IL-8, and VEGF stimulated by 7-KC. Rapamycin not only decreased the level of phosphorylated mTOR, P70S6K, 4EBP1 but also inhibited the activation of MAPK pathway. Conclusions: Inhibition of mTOR signaling pathway suppressed the elevation of inflammatory cytokines IL-6, IL-8, and the angiogenic agent VEGF induced by 7-KC. The protective effect of rapamycin was associated with its downregulation on MAPK pathway. [ABSTRACT FROM AUTHOR]

Bupleurum polysaccharides (BPs) is isolated from Bupleurum smithii var. parvifolium , a key traditional Chinese medicine. The study was to investigate the effects of BPs on diabetic kidney injury. After two intraperitoneal injections of streptozotozin (STZ) 100 mg·kg−1, renal injury in diabetic mice was induced and BPs was orally administrated at dosages of 30 and 60 mg·kg−1·d−1. The STZ injected mice developed renal function damage, renal inflammation and fibrosis known as diabetic kidney disease (DKD). BPs significantly reduced serum creatinine level and urinary albumin excretion rate, with the attenuated swelling of kidneys. BPs treatment obviously alleviated the pathological damage of renal tissue. The progression of renal injury in BPs treated mice was inhibited with less expression of type IV collagen (Col IV), fibronectin (FN) and α -smooth muscle actin (α -SMA). The inhibition of inflammation in kidney was associated with the reduced level of tumor necrosis factor- α (TNF- α) and interleukin-6 (IL-6). BPs administration suppressed the over-expression of toll like receptor 4 (TLR4) and high-mobility group box 1 (HMGB1) with lowered activity of nuclear factor kappa B (NF- κ B) in renal tissue of diabetic mice. Oral administration of BPs effectively prevented the development ofrenal injury in diabetic mice. This study suggested that the protection provided by BPs might affect through the interruption of HMGB1-TLR4 pathway, leading to the inhibition of renal inflammation and fibrotic process. [ABSTRACT FROM AUTHOR]

Spermine oxidase (Smox) is a member of the polyamine oxidases and has been demonstrated to be involved in ischemic brain damage. In this study, we found that Smox expression was increased in a rat middle cerebral artery occlusion (MCAO) model and in cultured primary neurons after oxygen-glucose deprivation and reoxygenation (OGD/R). Smox downregulation by the adeno-associated virus RNA interference system significantly reduced the MCAO-induced brain infarct volume and neurological deficits and decreased neuronal apoptosis and inflammatory reactions. In addition, significant microglial activation and increased IL-6 and TNF-α expression were observed in microglia treated with supernatant from neurons after OGD/R. However, a significant reduction in microglial activation as well as IL-6 and TNF-α expression was observed in microglia treated with supernatant from Smox downregulated neurons after OGD/R. Therefore, the results indicated that Smox is an important mediator of cerebral ischemia injury and may be a therapeutic target for cerebral ischemia patients. [ABSTRACT FROM AUTHOR]

The retina is an immune privileged tissue, which is protected from external and internal insults by its blood-retina barriers and immune suppressive microenvironment. Apart from the avoidance and tolerance strategies, the retina is also protected by its own defense system, i.e., microglia and the complement system. The immune privilege and defense mechanisms work together to maintain retinal homeostasis. During aging, the retina is at an increased risk of developing various degenerative diseases such as age-related macular degeneration, diabetic retinopathy, and glaucomatous retinopathy. Previously, we have shown that aging induces a para-inflammatory response in the retina. In this review, we explore the impact of aging on retinal immune regulation and the connection between homeostatic control of retinal immune privilege and para-inflammation under aging conditions and present a view that may explain why aging puts the retina at risk of developing degenerative diseases. [ABSTRACT FROM AUTHOR]

Abstract Houttuynia cordata polysaccharide (HCP) is extracted from Houttuynia cordata , a key traditional Chinese medicine. The study was to investigate the effects of HCP on intestinal barrier and microbiota in H1N1 virus infected mice. Mice were infected with H1N1 virus and orally administrated HCP at a dosage of 40 mg(kg−1(d−1. H1N1 infection caused pulmonary and intestinal injury and gut microbiota imbalance. HCP significantly suppressed the expression of hypoxia inducible factor-1 α and decreased mucosubstances in goblet cells, but restored the level of zonula occludens-1 in intestine. HCP also reversed the composition change of intestinal microbiota caused by H1N1 infection, with significantly reduced relative abundances of Vibrio and Bacillus , the pathogenic bacterial genera. Furthermore, HCP rebalanced the gut microbiota and restored the intestinal homeostasis to some degree. The inhibition of inflammation was associated with the reduced level of Toll-like receptors and interleukin-1 β in intestine, as well as the increased production of interleukin-10. Oral administration of HCP alleviated lung injury and intestinal dysfunction caused by H1N1 infection. HCP may gain systemic treatment by local acting on intestine and microbiota. This study proved the high-value application of HCP. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is the progressive degeneration of retinal blood vessels and neurons. Inflammation is known to play an important role in the pathogenesis of DR. During diabetes, metabolic disorder leads to the release of damage-associated molecular patterns (DAMPs) both in the retina and elsewhere in the body. The innate immune system provides the first line of defense against the DAMPs. In the early stages of DR when the blood retinal barrier (BRB) is intact, retinal microglia and the complement system are activated at low levels. This low-level of inflammation (para-inflammation) is believed to be essential to maintain homeostasis and restore functionality. However, prolonged stimulation by DAMPs in the diabetic eye leads to maladaptation of the innate immune system and dysregulated para-inflammation may contribute to DR development. In the advanced stages of DR where immune privilege is comprised, circulating immune cells and serum proteins may infiltrate the retina and participate in retinal chronic inflammation and retinal vascular and neuronal damage. This review discusses how the innate immune system is activated in diabetes and DR. The view also discusses why the protective immune response becomes detrimental in DR. [ABSTRACT FROM AUTHOR]

Background The receptor for advanced glycation end products (RAGE), a multiligand receptor, has been proved to be implicated in inflammatory responses in chronic obstructive pulmonary disease (COPD). In this study, we investigated the role of RAGE in cigarette smoke (CS)-induced airway inflammation in COPD. Methods Wild-type (WT) and RAGE gene knockout (KO) mice were exposed to mainstream CS or room air for 2 h twice daily, 6 days per week for consecutive 4 weeks. Cell counts and proinflammatory cytokines were measured in bronchoalveolar lavage fluid (BALF). Lung tissues were collected for histological examination and gene expression profiling by cDNA microarray. Results CS exposure induced significant airway inflammation in WT mice evidenced by histological inflammatory changes in HE stain with increased neutrophils and proinflammatory cytokines in the BALF, which were all attenuated by RAGE KO. cDNA microarray indicated a total of 179 upregulated genes and 351 downregulated genes in mouse lungs. Among these genes, S100 proteins (S100A8 and S100A9), the RAGE common ligands, were significantly downregulated, which were validated by real-time qPCR. Further analyses by Gene Ontology, KEGG and Disease Ontology suggested these differentiated expressed genes significantly related to the immune-inflammatory responses in lungs via crosstalking with a complicated network of signaling pathways. Conclusions Knockout of RAGE significantly ameliorates mainstream CS-induced airway inflammation in mice possibly via downregulating S100A8/A9 expression and its related immune-inflammatory responses. [ABSTRACT FROM AUTHOR]

Rationale: How host genetic factors affect Mycobacterium tuberculosis (Mtb) infection outcomes remains largely unknown. SP110b, an IFN-induced nuclear protein, is the nearest human homologue to the mouse Ipr1 protein that has been shown to control host innate immunity to Mtb infection. However, the function(s) of SP110b remains unclear.Objectives: To elucidate the role of SP110b in controlling host immunity and susceptibility to tuberculosis (TB), as well as to identify the fundamental immunological and molecular mechanisms affected by SP110b.Methods: Using cell-based approaches and mouse models of Mtb infection, we characterized the function(s) of SP110b/Ipr1. We also performed genetic characterization of patients with TB to investigate the role of SP110 in controlling host susceptibility to TB.Measurements and Main Results: SP110b modulates nuclear factor-κB (NF-κB) activity, resulting in downregulation of tumor necrosis factor-α (TNF-α) production and concomitant upregulation of NF-κB-induced antiapoptotic gene expression, thereby suppressing IFN-γ-mediated monocyte and/or macrophage cell death. After Mtb infection, TNF-α is also downregulated in Ipr1-expressing mice that have alleviated cell death, less severe necrotic lung lesions, more efficient Mtb growth control in the lungs, and longer survival. Moreover, genetic studies in patients suggest that SP110 plays a key role in modulating TB susceptibility in concert with NFκB1 and TNFα genes.Conclusions: These results indicate that SP110b plays a crucial role in shaping the inflammatory milieu that supports host protection during infection by fine-tuning NF-κB activity, suggesting that SP110b may serve as a potential target for host-directed therapy aimed at manipulating host immunity against TB. [ABSTRACT FROM AUTHOR]

Adipose tissue inflammation and macrophage polarization are tightly associated with the development of obesity-associated insulin resistance. Our previous studies have demonstrated the triterpenoids-enriched extract from the aerial parts of Salvia miltiorrhiza (TTE) could significantly improve atherosclerosis in LDLR-/- mice. However, its molecular mechanisms of TTE ameliorating insulin resistance remain unclear. In the present study, obesity model with insulin resistance induced by feeding high-fat diet (HFD) was established. Dietary TTE attenuated hyperlipidemia, improved glucose intolerance in mice and mediated the activation of IRS-1/PI3K/Akt insulin signaling pathway. Meanwhile, dietary TTE also attenuated macrophage infiltrations into adipose tissue and modified the phenotype ratio of M1/M2 macrophages. Furthermore, our results showed that TTE regulated the polarization of macrophages partly via adenosine monophosphate-activated kinase (AMPK). Taken together, these findings suggested that TTE has a potential clinical utility in improving insulin resistance. Its mechanisms might be contributed to its beneficial effects on macrophage polarization via AMPK. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Mechanical ventilation is a life-saving procedure for patients with acute respiratory failure, although it may cause pulmonary vascular inflammation and leakage, leading to ventilator-induced lung injury (VILI). Ly6C+high monocytes are involved in the pathogenesis of VILI. In this study, we investigated whether pulmonary infiltrated Ly6C+high monocytes produce vascular endothelial growth factor (VEGF) and contribute to VILI. Methods: A clinically relevant two-hit mouse model of VILI, with intravenous lipopolysaccharide (LPS, 20 ng/mouse) immediately before high tidal volume (HTV, 20 mL/kg) ventilation (LPS+HTV), was established. Blood gas and respiratory mechanics were measured to ensure the development of VILI. Flow cytometry and histopathological analyses revealed pulmonary infiltration of leukocytes subsets. Clodronate liposomes were intravenously injected to deplete pulmonary monocytes. In vitro endothelial cell permeability assay with sorted Ly6C+high monocytes condition media assessed the role of Ly6C+high monocytes in vascular permeability. Results: LPS+HTV significantly increased total proteins, TNF-α, IL-6, vascular endothelial growth factor (VEGF) and mononuclear cells in the bronchoalveolar lavage fluid (BALF). Pulmonary Ly6C+high monocytes (SSClowCD11b+F4/80+Ly6C+high), but not Ly6C+low monocytes (SSClowCD11b+F4/80+Ly6C+low), were significantly elevated starting at 4 hr. Clodronate liposomes were able to significantly reduce pulmonary Ly6C+high monocytes, and VEGF and total protein in BALF, and restore PaO2/FiO2. There was a strong correlation between pulmonary Ly6C+high monocytes and BALF VEGF (R2 = 0.8791, p<0.001). Moreover, sorted Ly6C+high monocytes were able to produce VEGF, resulting in an increased permeability of endothelial cell monolayer in an in vitro endothelial cell permeability assay. Conclusion: VEGF produced by pulmonary infiltrated Ly6C+high monocytes regulates vasculature permeability in a two-hit model of HTV-induced lung injury. Ly6C+high monocytes play an important role in the pathogenesis of VILI. [ABSTRACT FROM AUTHOR]

The retina, an immune privileged tissue, has specialized immune defense mechanisms against noxious insults that may exist in diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), uveoretinitis and glaucoma. The defense system consists of retinal innate immune cells (including microglia, perivascular macrophages, and a small population of dendritic cells) and the complement system. Under normal aging conditions, retinal innate immune cells and the complement system undergo a low-grade activation (parainflammation) which is important for retinal homeostasis. In disease states such as AMD and DR, the parainflammatory response is dysregulated and develops into detrimental chronic inflammation. Complement activation in the retina is an important part of chronic inflammation and may contribute to retinal pathology in these disease states. Here, we review the evidence that supports the role of uncontrolled or dysregulated complement activation in various retinal degenerative and angiogenic conditions. We also discuss current strategies that are used to develop complement-based therapies for retinal diseases such as AMD. The potential benefits of complement inhibition in DR, uveoretinitis and glaucoma are also discussed, as well as the need for further research to better understand the mechanisms of complement-mediated retinal damage in these disease states. [ABSTRACT FROM AUTHOR]

Retinal degeneration comprises a group of diseases whereby either the retinal neurons or the neurovascular unit degenerates leading to the loss of visual function. Although the initial cause varies in different conditions, inflammation is known to play an important role in disease pathogenesis. Recent advances in molecular and cell biology and systems biology have yielded unexpected findings, including the heterogeneity of immune cells in the degenerative retina, bidirectional neuron-microglia cross talk, and links to the gut microbiome. Here we discuss the immune response in retinal degenerative conditions, taking into account both regional (retinal) and systemic factors. We propose to classify retinal degeneration into dry and wet forms based on whether the blood-retinal barrier (BRB) is breached and fluid is accumulated in retinal parenchyma. The dry form has a relatively intact BRB and is characterised by progressive retinal thinning. Immune response to degenerative insults is dominated by the retinal defence system, which remains to be regulated by neurons. In contrast, the wet form has retinal oedema due to BRB damaged. Inflammation is executed by infiltrating immune cells as well as the retinal defence system. The gut microbiome will have easy access to the retina in wet retinal degeneration and may affect significantly retinal immune response. [Display omitted] • The retina is an immune privilege tissue and has a high level of control over its immune response. • Genetic, environmental risk factors and senescence can influence retinal immune response. • Based on the structural integrity of BRB, retinal degeneration can be classified into dry and wet forms. • Microglia is a key player of immune response to both dry and wet forms of retinal degeneration. • Retina has more control over the immune response to dry retinal degeneration than that to wet retinal degeneration. [ABSTRACT FROM AUTHOR]

Background: Reactive microglia are commonly seen in retinal degenerative diseases, and neurotoxic microglia responses can contribute to photoreceptor cell death. We and others have previously shown that translocator protein (18 kDa) (TSPO) is highly induced in retinal degenerations and that the selective TSPO ligand XBD173 (AC-5216, emapunil) exerts strong anti-inflammatory effects on microglia in vitro and ex vivo. Here, we investigated whether targeting TSPO with XBD173 has immuno-modulatory and neuroprotective functions in two mouse models of acute retinal degeneration using bright white light exposure.Methods: BALB/cJ and Cx3cr1(GFP/+) mice received intraperitoneal injections of 10 mg/kg XBD173 or vehicle for five consecutive days, starting 1 day prior to exposure to either 15,000 lux white light for 1 h or 50,000 lux focal light for 10 min, respectively. The effects of XBD173 treatment on microglia and Müller cell reactivity were analyzed by immuno-stainings of retinal sections and flat mounts, fluorescence-activated cell sorting (FACS) analysis, and mRNA expression of microglia markers using quantitative real-time PCR (qRT-PCR). Optical coherence tomography (OCT), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stainings, and morphometric analyses were used to quantify the extent of retinal degeneration and photoreceptor apoptosis.Results: Four days after the mice were challenged with bright white light, a large number of amoeboid-shaped alerted microglia appeared in the degenerating outer retina, which was nearly completely prevented by treatment with XBD173. This treatment also down-regulated the expression of TSPO protein in microglia but did not change the TSPO levels in the retinal pigment epithelium (RPE). RT-PCR analysis showed that the microglia/macrophage markers Cd68 and activated microglia/macrophage whey acidic protein (Amwap) as well as the pro-inflammatory genes Ccl2 and Il6 were reduced after XBD173 treatment. Light-induced degeneration of the outer retina was nearly fully blocked by XBD173 treatment. We further confirmed these findings in an independent mouse model of focal light damage. Retinas of animals receiving XBD173 therapy displayed significantly more ramified non-reactive microglia and more viable arrestin-positive cone photoreceptors than vehicle controls.Conclusions: Targeting TSPO with XBD173 effectively counter-regulates microgliosis and ameliorates light-induced retinal damage, highlighting a new pharmacological concept for the treatment of retinal degenerations. [ABSTRACT FROM AUTHOR]

Interleukin-33 (IL-33) is associated with several important immune-mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here, we investigated the function of IL-33 in the development of experimental autoimmune uveitis (EAU). IL-33 and IL-33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL-33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL-33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2-deficient mice developed exacerbated EAU compared with WT mice, and administration of IL-33 toWTmice significantly reduced EAU severity. The attenuated EAU in IL-33-treated mice was accompanied by decreased frequency of IFN-γ + and IL-17+ CD4+ T cells and reduced IFN-γ and IL-17 production but with increased frequency of IL-5+ and IL-4+ CD4 T cells and IL-5 production in the draining lymph node and spleen. Macrophages from the IL-33-treated mice show a significantly higher polarization toward an alternatively activated macrophage phenotype. Our results therefore demonstrate that the endogenous IL-33/ST2 pathway plays an important role in EAU, and suggest that IL-33 represents a potential option for treatment of uveitis. [ABSTRACT FROM AUTHOR]

Purpose: RAGE regulates pro-inflammatory responses in diverse cells and tissues. This study has investigated if RAGE plays a role in immune cell mobilization and choroidal neovascular pathology that is associated with the neovascular form of age-related macular degeneration (nvAMD). Methods: RAGE null (RAGE−/−) mice and age-matched wild type (WT) control mice underwent laser photocoagulation to generate choroidal neovascularization (CNV) lesions which were then analyzed for morphology, S100B immunoreactivity and inflammatory cell infiltration. The chemotactic ability of bone marrow derived macrophages (BMDMs) towards S100B was investigated. Results: RAGE expression was significantly increased in the retina during CNV of WT mice (p<0.001). RAGE−/− mice exhibited significantly reduced CNV lesion size when compared to WT controls (p<0.05). S100B mRNA was upregulated in the lasered WT retina but not RAGE−/− retina and S100B immunoreactivity was present within CNV lesions although levels were less when RAGE−/− mice were compared to WT controls. Activated microglia in lesions were considerably less abundant in RAGE−/− mice when compared to WT counterparts (p<0.001). A dose dependent chemotactic migration was observed in BMDMs from WT mice (p<0.05–0.01) but this was not apparent in cells isolated from RAGE−/− mice. Conclusions: RAGE-S100B interactions appear to play an important role in CNV lesion formation by regulating pro-inflammatory and angiogenic responses. This study highlights the role of RAGE in inflammation-mediated outer retinal pathology. [ABSTRACT FROM AUTHOR]

Previous studies from our laboratory demonstrated that zileuton, a selective 5-lipoxygenase (5-LOX) inhibitor, attenuates ischemic brain damage in rats of focal cerebral ischemia. Enormous evidences showed that inflammatory reaction and neuronal apoptosis are the two important pathophysiological events in ischemia-induced brain damage. Our previous studies demonstrate that zileuton attenuates ischemic brain damage via inhibiting inflammatory reaction. The present study was performed to explore whether 5-LOX inhibitor zileuton attenuates neuronal apoptosis following focal cerebral ischemia and further investigate the potent mechanisms underlying its neuroprotection. Adult male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO) for 72 h, then received intragastric gavage with zileuton or vehicle as a bolus after the onset of MCAO. Neurological deficit scores, cerebral infarct volume, and neuronal damage were measured 72 h after MCAO. TUNEL staining was performed to measure the extent of neuronal apoptosis. Reverse transcription-polymerase chain reaction was performed to determine the expression of caspase-1 mRNA. Western blot was performed to determine the expression of procaspase-3 and cleaved caspase-3 in rat brain. Neurological deficit scores, infarct volume, and neuronal damage were significantly attenuated by administration of zileuton. MCAO caused the elevation of neuronal apoptosis, which was significantly inhibited by the administration of zileuton. MCAO caused the over-expression of caspase-1 and cleaved caspase-3, both of which were significantly inhibited by the administration of zileuton. Expression of procaspase-3 was reduced after MCAO, which was significantly up-regulated by administration of zileuton. Our studies suggested that 5-LOX inhibitor zileuton reduces MCAO-induced brain damage and neuronal apoptosis, which might be associated with the inhibition of caspase-1 and the regulation of caspase-3. [ABSTRACT FROM AUTHOR]

Previous studies have shown that CCL2/CX3CR1 deficient mice on C57BL/6N background (with rd8 mutation) have an early onset (6 weeks) of spontaneous retinal degeneration. In this study, we generated CCL2−/−CX3CR1GFP/GFP mice on the C57BL/6J background. Retinal degeneration was not detected in CCL2−/−CX3CR1GFP/GFP mice younger than 6 months. Patches of whitish/yellowish fundus lesions were observed in 17∼60% of 12-month, and 30∼100% of 18-month CCL2−/−CX3CR1GFP/GFP mice. Fluorescein angiography revealed no choroidal neovascularisation in these mice. Patches of retinal pigment epithelium (RPE) and photoreceptor damage were detected in 30% and 50% of 12- and 18-month CCL2−/−CX3CR1GFP/GFP mice respectively, but not in wild-type mice. All CCL2−/−CX3CR1GFP/GFP mice exposed to extra-light (∼800lux, 6 h/day, 6 months) developed patches of retinal atrophy, and only 20–25% of WT mice which underwent the same light treatment developed atrophic lesions. In addition, synaptophysin expression was detected in the outer nucler layer (ONL) of area related to photoreceptor loss in CCL2−/−CX3CR1GFP/GFP mice. Markedly increased rhodopsin but reduced cone arrestin expression was observed in retinal outer layers in aged CCL2−/−CX3CR1GFP/GFP mice. GABA expression was reduced in the inner retina of aged CCL2−/−CX3CR1GFP/GFP mice. Significantly increased Müller glial and microglial activation was observed in CCL2−/−CX3CR1GFP/GFP mice compared to age-matched WT mice. Macrophages from CCL2−/−CX3CR1GFP/GFP mice were less phagocytic, but expressed higher levels of iNOS, IL-1β, IL-12 and TNF-α under hypoxia conditions. Our results suggest that the deletions of CCL2 and CX3CR1 predispose mice to age- and light-mediated retinal damage. The CCL2/CX3CR1 deficient mouse may thus serve as a model for age-related atrophic degeneration of the RPE, including the dry type of macular degeneration, geographic atrophy. [ABSTRACT FROM AUTHOR]

The circulating follistatin and high-sensitivity C-reactive protein (hsCRP) concentrations were significantly higher in 155 Taiwanese women with polycystic ovary syndrome (PCOS) than in 37 healthy controls. Follistatin and hsCRP levels in both the PCOS and control groups were significantly correlated with each other independent of obesity and insulin resistance. [Copyright &y& Elsevier]

Abstract: Para-inflammation is a tissue adaptive response to noxious stress or malfunction and has characteristics that are intermediate between basal and inflammatory states (Medzhitov, 2008). The physiological purpose of para-inflammation is to restore tissue functionality and homeostasis. Para-inflammation may become chronic or turn into inflammation if tissue stress or malfunction persists for a sustained period. Chronic para-inflammation contributes to the initiation and progression of many human diseases including obesity, type 2 diabetes, atherosclerosis, and age-related neurodegenerative diseases. Evidence from our studies and the studies of some others suggests that para-inflammation also exists in the aging retina in physiological conditions and might contribute to age-related retinal pathologies. The purpose of this review is to introduce the notion of “para-inflammation” as a state between frank, overt destructive inflammation and the non-inflammatory removal of dead or dying cells by apoptosis, to the retinal community. In diabetes and atherosclerosis, leukocytes particularly monocytes and vascular endothelial cells are constantly under noxious stress due to glycaemic and/or lipidaemic dysregulation. These blood-borne stresses trigger para-inflammatory responses in leukocytes and endothelial cells by up-regulating the expression of adhesion molecules or releasing cytokines/chemokines, which in turn cause abnormal leukocyte–endothelial interactions and ultimately vascular damage. In the aging retina, on the other hand, oxidized lipoproteins and free radicals are considered to be major causes of tissue stress and serve as local triggers for retinal para-inflammation. Microarray analysis has revealed the up-regulation of a large number of inflammatory genes, including genes involved in complement activation and inflammatory cytokine/chemokine production, in the aging retina. Para-inflammatory responses in the neuroretina of aged mice are characterized by microglial activation and subretinal migration, and breakdown of blood–retinal barrier. At the retinal/choroidal interface para-inflammation is manifested by complement activation in Bruch''s membrane and RPE cells, and microglia accumulation in subretinal space. With age, para-inflammatory changes have also been observed in the choroidal tissue, evidenced by 1) increased thickness of choroid; 2) increased number of CD45+CRIg+ macrophages; 3) morphological abnormalities in choroidal melanocytes; and 4) fibrosis in choroidal tissue. An increased knowledge of contribution of retinal para-inflammation to various pathological conditions is essential for the better understanding of the pathogenesis of various age-related retinal diseases including diabetic retinopathy, glaucoma and age-related macular degeneration. [Copyright &y& Elsevier]