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Inflammation and elevated expression of high temperature requirement A serine peptidase 1 (HTRA1) are known high risk factors for age-related macular degeneration (AMD). However, the specific mechanism that HTRA1 causes AMD and the relationship between HTRA1 and inflammation remains unclear. We found that lipopolysaccharide (LPS) induced inflammation enhanced the expression of HTRA1, NF-κB, and p-p65 in ARPE-19 cells. Overexpression of HTRA1 up-regulated NF-κB expression, and on the other hand knockdown of HTRA1 down-regulated the expression of NF-κB. Moreover, NF-κB siRNA has no significant effect on the expression of HTRA1, suggesting HTRA1 works upstream of NF-κB. These results demonstrated that HTRA1 plays a pivotal role in inflammation, explaining possible mechanism of overexpressed HTRA1-induced AMD. Celastrol, a very common anti-inflammatory and antioxidant drug, was found to suppress inflammation by inhibiting phosphorylation of p65 protein efficaciously in RPE cells, which may be applied to the therapy of age-related macular degeneration.

The purpose of the present study was to investigate the effect of salidroside (Sal) on myocardial injury in lipopolysaccharide (LPS)‐induced endotoxemic in vitro and in vivo. SD rats were randomly divided into five groups: control group, LPS group (15 mg/kg), LPS plus dexamethasone (2 mg/kg), LPS plus Sal groups with different Sal doses (20, 40 mg/kg). Hemodynamic measurement and haematoxylin and eosin staining were performed. Serum levels of creatine kinase (CK), lactate dehydrogenase, the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH‐px), glutathione, tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and interleukin‐1β (IL‐1β) were measured after the rats were killed. iNOS, COX‐2, NF‐κB and PI3K/Akt/mTOR pathway proteins were detected by Western blot. In vitro, we evaluated the protective effect of Sal on rat embryonic heart‐derived myogenic cell line H9c2 induced by LPS. Reactive oxygen species (ROS) in H9c2 cells was measured by flow cytometry, and the activities of the antioxidant enzymes CAT, SOD, GSH‐px, glutathione‐S‐transferase, TNF‐α, IL‐6 and IL‐1β in cellular supernatant were measured. PI3K/Akt/mTOR signalling was examined by Western blot. As a result, Sal significantly attenuated the above indices. In addition, Sal exerts pronounced cardioprotective effect in rats subjected to LPS possibly through inhibiting the iNOS, COX‐2, NF‐κB and PI3K/Akt/mTOR pathway in vivo. Furthermore, the pharmacological effect of Sal associated with the ROS‐mediated PI3K/Akt/mTOR pathway was proved by the use of ROS scavenger, N‐acetyl‐l‐cysteine, in LPS‐stimulated H9C2 cells. Our results indicated that Sal could be a potential therapeutic agent for the treatment of cardiovascular disease.

IntroductionPeriodontal disease is a highly prevalent oral inflammatory disease that affects nearly half of adults 30 years or older in the United States. It is characterized byexcessive inflammation within the periodontal pockets typically in response to bacterial challenge and is characterized by inflamed gums, destruction of periodontal ligaments, alveolar bone loss, and tooth loss if left untreated. T cells are adaptive immune cells which play important roles in driving inflammation and alveolar bone loss during severe periodontitis. Additionally, several studies have reported associations between periodontal pathogens and chronic inflammation within the oral cavity to several systemic diseases, including inflammatory bowel disease, diabetes mellitus, cardiovascular diseases, cognitive decline and Alzheimer’s disease, chronic obstructive pulmonary disease, and certain cancers. CD5 is a glycoprotein receptor found on the surface of T cells that serves as a coinhibitory receptor that attenuates TCR signaling, and its immunoregulatory role has yet to be investigated in the context of periodontitis.MethodsHere, we characterize the functional differences between CD5 knockout T cells and wildtype T cells, including T cell activation, differentiation, and cytokine production, in an in vitro model used to investigate the effects of P. gingivalis LPS on oral epithelial and immune cells.Results and DiscussionIn this study we report that removal of CD5 increases T cell activation and effector/memory formation and increased CD4+ T cell Csf1 mRNA transcription while decreasing Rankl transcription. Together, these findings provide insights into the role of CD5 in modulating inflammation during periodontal disease.

Toll-like receptor (TLR) 4 belongs to the TLR family of receptors inducing pro-inflammatory responses to invading pathogens. TLR4 is activated by lipopolysaccharide (LPS, endotoxin) of Gram-negative bacteria and sequentially triggers two signaling cascades: the first one involving TIRAP and MyD88 adaptor proteins is induced in the plasma membrane, whereas the second engaging adaptor proteins TRAM and TRIF begins in early endosomes after endocytosis of the receptor. The LPS-induced internalization of TLR4 and hence also the activation of the TRIF-dependent pathway is governed by a GPI-anchored protein, CD14. The endocytosis of TLR4 terminates the MyD88-dependent signaling, while the following endosome maturation and lysosomal degradation of TLR4 determine the duration and magnitude of the TRIF-dependent one. Alternatively, TLR4 may return to the plasma membrane, which process is still poorly understood. Therefore, the course of the LPS-induced pro-inflammatory responses depends strictly on the rates of TLR4 endocytosis and trafficking through the endo-lysosomal compartment. Notably, prolonged activation of TLR4 is linked with several hereditary human diseases, neurodegeneration and also with autoimmune diseases and cancer. Recent studies have provided ample data on the role of diverse proteins regulating the functions of early, late, and recycling endosomes in the TLR4-induced inflammation caused by LPS or phagocytosis of E. coli. In this review, we focus on the mechanisms of the internalization and intracellular trafficking of TLR4 and CD14, and also of LPS, in immune cells and discuss how dysregulation of the endo-lysosomal compartment contributes to the development of diverse human diseases.

Lipopolysaccharides (LPSs) are bacterial surface glycolipids, produced by Gram-negative bacteria. LPS is known to determine acute inflammatory reactions, particularly in the context of sepsis. However, LPS can also trigger chronic inflammation. In this case, the source of LPS is not an external infection, but rather an increase in endogenous production, which is usually sustained by gut microbiota (GM), and LPS contained in food. The first site in which LPS can exert its inflammatory action is the gut: both GM and gut-associated lymphoid tissue (GALT) are influenced by LPS and shift towards an inflammatory pattern. The changes in GM and GALT induced by LPS are quite similar to the ones seen in IBD: GM loses diversity, while GALT T regulatory (Tregs) lymphocytes are reduced in number, with an increase in Th17 and Th1 lymphocytes. Additionally, the innate immune system is triggered, through the activation of toll-like receptor (TLR)-4, while the epithelium is directly damaged, further triggering inflammation. In this review, we will discuss the importance of the crosstalk between LPS, GM, and GALT, and discuss the possible implications.

Short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber contribute a significant proportion of daily energy requirement. Furthermore, these compounds are modulators of macrophage function and potential targets for the development of new drugs. The aims of this study were to evaluate the effects of three types of SCFAs (sodium acetate (NaAc), sodium propionate (NaP), and sodium butyrate (NaB)) on the production of NO and inducible nitric oxide synthase (iNOS) and proinflammatory and antiinflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin (IL-1, IL-6, and IL-10)) and to observe the effect of NaAc on inhibiting lipopolysaccharide (LPS)-induced NF-κB activation in LPS-stimulated RAW264.7 cells. The results show that three types of SCFAs (acetate, propionate, and butyrate) reduced the production of proinflammatory factors, including TNF-α, IL-1β, IL-6, and NO, and inhibited the vitality of iNOS. Meanwhile, SCFAs enhanced the production of antiinflammatory cytokine IL-10 in lower concentrations (1-1,200 μmol/L). Like NaB, NaAC inhibited LPS-induced NF-κB activation. These results may hold promise on the role that SCFAs have on the prevention and treatment of various inflammatory conditions.[PUBLICATION ABSTRACT]

BackgroundBacterial lipopolysaccharide (LPS) has been shown to accelerate atherosclerosis when administered parenterally to mice, and also to promote foam cell formation in macrophages cultured in vitro. However, it is not clear how LPS signaling promotes lipid accumulation in macrophages. We found that although LPS-induced foam cell formation was lower in Tlr4-/- macrophages than in wild-type control cells, it was not abolished, particularly at later timepoints. We therefore explored the hypothesis that the caspase-11 non-canonical inflammasome may contribute to LPS-induced foam cell formation.MethodsMurine J774 macrophages were cultured with LPS delivered extracellularly, or by transfection, in the presence or absence of caspase-11 inhibitors in vitro, and foam cell formation was quantified by microscopy and flow cytometry.ResultsLPS-induced lipid accumulation was independent of exogenous sources of lipid (e.g., serum or LDL), suggesting a prominent role for de novo lipogenesis. Foam cell formation was increased by transfection of LPS into the cytosol of macrophages, in comparison to extracellular delivery. However, both foam cell formation and LDH release (a marker of inflammasome activation) were elevated in response to non-transfected LPS, suggesting that extracellular LPS can both prime and activate caspase-11 at later timepoints (>48 h). Two specific inhibitors of caspase-11, wedelactone and scutellarin, significantly inhibited foam cell formation in response to LPS.ConclusionThe present findings suggest that caspase-11 signaling may contribute to LPS-induced foam cell formation in vitro. Further experiments using caspase-11 knockout macrophages and recombinant inflammasome models are planned to further investigate this hypothesis.Conflict of InterestNone Declared

The interaction between microglia and astrocytes significantly influences neuroinflammation. Microglia/astrocytes, part of the neurovascular unit (NVU), are activated by various brain insults. The local extracellular and intracellular signals determine their characteristics and switch of phenotypes. Microglia and astrocytes are activated into two polarization states: the pro-inflammatory phenotype (M1 and A1) and the anti-inflammatory phenotype (M2 and A2). During neuroinflammation, induced by stroke or lipopolysaccharides, microglia are more sensitive to pathogens, or damage; they are thus initially activated into the M1 phenotype and produce common inflammatory signals such as IL-1 and TNF-α to trigger reactive astrocytes into the A1 phenotype. These inflammatory signals can be amplified not only by the self-feedback loop of microglial activation but also by the unique anatomy structure of astrocytes. As the pathology further progresses, resulting in local environmental changes, M1-like microglia switch to the M2 phenotype, and M2 crosstalk with A2. While astrocytes communicate simultaneously with neurons and blood vessels to maintain the function of neurons and the blood-brain barrier (BBB), their subtle changes may be identified and responded by astrocytes, and possibly transferred to microglia. Although both microglia and astrocytes have different functional characteristics, they can achieve immune \"optimization\" through their mutual communication and cooperation in the NVU and build a cascaded immune network of amplification.

Background and objectiveThe correlation (Rs > 0.7) of neutrophils expressing the dual endothelin1/signal peptide receptor (DEspR+CD11b+/CD66b+) with severity of hypoxemia (SF-ratio) and multi-organ failure (SOFA-score) in patients with acute respiratory distress syndrome (ARDS) suggest the hypothesis that the DEspR+ neutrophil-subset is an actionable therapeutic target in ARDS. To test this hypothesis, we conducted in vivo studies to validate DEspR+ neutrophil-subset as therapeutic target and test efficacy of DEspR-inhibition in acute neutrophilic hyperinflammation models.MethodsWe performed tests in lipopolysaccharide (LPS)-induced acute neutrophilic inflammation in three species – human, rhesus macaque, rat – with increasing dose-dependent severity. We measured DEspR+CD66b+ neutrophils in bronchoalveolar lavage fluid (BALF) in healthy volunteers (HVs) 24-hours after segmental LPS-challenge by ChipCytometry, and DEspR+CD11b+ neutrophils in whole blood and BALF in an LPS-induced transient acute lung injury (ALI) model in macaques. We determined anti-DEspR antibody efficacy in vivo in LPS-ALI macaque model and in high-mortality LPS-induced encephalopathy in hypertensive rats.ResultsChipCytometry detected increased BALF total neutrophil and DEspR+CD66b+ neutrophil counts after segmental LPS-challenge compared to baseline ( P =0.034), as well as increased peripheral neutrophil counts and neutrophil-lymphocyte ratio (NLR) compared to pre-LPS level ( P < 0.05). In the LPS-ALI macaque model, flow cytometry detected increased DEspR+ and DEspR[-] neutrophils in BALF, which was associated with moderate-severe hypoxemia. After determining pharmacokinetics of single-dose anti-DEspR[hu6g8] antibody, one-time pre-LPS anti-DEspR treatment reduced hypoxemia ( P =0.03) and neutrophil influx into BALF (P =0.0001) in LPS-ALI vs vehicle mock-treated LPS-ALI macaques. Ex vivo live cell imaging of macaque neutrophils detected greater “intrinsic adhesion to hard-surface” in DEspR+ vs DEspR[-] neutrophils ( P < 0.001). Anti-DEspR[hu6g8] antibody abrogated intrinsic high adhesion in DEspR+ neutrophils, but not in DEspR[-] neutrophils ( P < 0.001). In the LPS-encephalopathy rat model, anti-DEspR[10a3] antibody treatment increased median survival ( P =0.0007) and exhibited brain target engagement and bioeffects.ConclusionDetection of increased DEspR+ neutrophil-subset in human BALF after segmental LPS-challenge supports the correlation of circulating DEspR+ neutrophil counts with severity measure (SOFA-score) in ARDS. Efficacy and safety of targeted inhibition of DEspR+CD11b+ neutrophil-subset in LPS-induced transient-ALI and high-mortality encephalopathy models identify a potential therapeutic target for neutrophil-mediated secondary tissue injury.

The analysis and the assessment of interconnected photovoltaic (PV) modules under different shading conditions and various shading patterns are presented in this paper. The partial shading conditions (PSCs) due to the various factors reduce the power output of PV arrays, and its characteristics have multiple peaks due to the mismatching losses between PV panels. The principal objective of this paper is to model, analyze, simulate and evaluate the performance of PV array topologies such as series-parallel (SP), honey-comb (HC), total-cross-tied (TCT), ladder (LD) and bridge-linked (BL) under different shading patterns to produce the maximum power by reducing the mismatching losses (MLs). Along with the conventional PV array topologies, this paper also discusses the hybrid PV array topologies such as bridge-linked honey-comb (BLHC), bridge-linked total-cross-tied (BLTCT) and series-parallel total-cross-tied (SPTCT). The performance analysis of the traditional PV array topologies along with the hybrid topologies is carried out during static and dynamic shading patterns by comparing the various parameters such as the global peak (GP), local peaks (LPs), corresponding voltage and current at GP and LPs, fill factor (FF) and ML. In addition, the voltage and current equations of the HC configuration under two shading conditions are derived, which represents one of the novelties of this paper. The various parameters of the SPR-200-BLK-U PV module are used for PV modeling and simulation in MATLAB/Simulink software. Thus, the obtained results provide useful information to the researchers for healthy operation and power maximization of PV systems.