25,596 research outputs found

    Mechanistic insights into the regulation of inflammatory pathology by A20

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    Immunomodulatory effects of resveratrol on human intestinal mast cell signaling in vitro and mast cell associated enteritis and colitis in mice

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    By releasing their pre-stored or de novo synthesized mediators, mast cells (MC) are important immunoregulatory cells responsible for a variety of inflammatory reactions. Although known to be major effector cells in immunoglobuline (Ig) E dependent allergic reactions, MC have been widely shown to play a role in various inflammations of the gut. Diseases of the gastrointestinal tract (GIT) are widespread and multicausal. Those affected suffer from the sometimes severe symptoms and may experience restrictions on their daily life. Even if conventional medication is applied routinely, aim of the past and current research is to establish supportive and/or alternative medication that is based on natural substances. These may be on the basis of small natural components like resveratrol, a stilbene mostly found in grapes. Numerous positive properties are attributed to resveratrol. These are anti-inflammatory, anti-cancerogenic, anti-oxidative, as well as neuroprotective effects. The use of substances of natural origin as so-called nutraceuticals can help to increase the acceptance of medication by those affected, but also to reduce and overcome the side effects associated with conventional treatment. Effects of resveratrol were examined on the reactivity of MC isolated from patients tissue undergoing bowel resection. The results of this work show that resveratrol exhibited potent inhibitory effects on high affinity IgE receptor mediated activation of MC, strongly inhibiting not only MC degranulation, but also gene expression of the pro-inflammatory cytokines C-X-C motif chemokine ligand (CXCL) 8, C-C motif chemokine ligand (CCL) 2, CCL3, CCL4 and tumor necrosis factor (TNF-) α. Ultimately, the intracellular signaling cascade triggered during MC activation via IgE receptor leads to mediator release. Following IgE receptor mediated activation, phosphorylation of signaling molecules like extracellular signal-regulated kinase (ERK) 1/2 and signal transducer and activator of transcription (STAT) 3, occurs. ERK1/2 was found to be responsible for phosphorylation of mitochondrial STAT3, which contributes significantly to MC degranulation. Treatment with resveratrol was able to inhibit the phosphorylation of STAT3 by more than 50 % and that of ERK1/2 by almost 100 %. Furthermore, the experiments performed succeeded in isolating the mitochondrial fraction from relatively low human intestinal MC (hiMC) numbers. Also, in this fraction we could detect phosphorylation of STAT3 and ERK1/2 after MC activation, which was reduced after treatment with resveratrol. Having shown the strong inhibitory effects in vitro, we set out to examine immunomodulatory effects of resveratrol in vivo. Presence and activity of MC are closely related to intestinal inflammations in consequence of food allergy (FA) and inflammatory bowel disease (IBD). In mice, FA can be studied using the ovalbumin (OVA)-induced allergic enteritis model and colitis can be studied using the IL-10 knockout (-/-) mice, which develop a spontaneous form of chronic colitis. We could show that the oral application of resveratrol inhibited the increase of MC numbers in the colon and duodenum of affected animals in both experimental settings. Less pronounced but still visible effects of resveratrol administration were observed in the colon with regard to epithelial damage, cell infiltration and reduction of goblet cell numbers. In all cases, based on a scoring system, the damage decreased to the level of the corresponding controls receiving no additive and in which no allergic enteritis was induced or nor colitis developed. Overall, allergic enteritis resulted in a weaker symptomatology, and IL-10-/- animals showed a delayed appearance of the typical symptoms. The results of this thesis show a strong inhibitory effect of resveratrol on hiMC. This could be detected for mediator release as well as on gene expression levels and in the phosphorylation of the signaling molecules ERK1/2 and STAT3, which we could also identify in the mitochondria of hiMC. We observed positive influences on MC-associated parameters in the OVA enteritis and IL-10-/- colitis mouse models. With regard to its use as nutraceutical, resveratrol could therefore come more of a focus in the future.Mastzellen sind wichtige immunregulatorische Zellen, die durch Freisetzung ihrer in den Granula gespeicherten oder der de novo synthetisierten Mediatoren fĂĽr eine Vielzahl von EntzĂĽndungsreaktionen verantwortlich sind. Mastzellen, die in erster Linie als Haupteffektorzellen bei von Immunoglobulin (Ig) E abhängigen allergischen Reaktionen bekannt sind, spielen auch bei diversen EntzĂĽndungen des Darmes eine Rolle. Erkrankungen des Gastrointestinaltraktes sind weit verbreitet und multikausal. Betroffene leiden aber immer mit unter der teils stark auftretenden Symptomatik und erfahren Einschränkungen im alltäglichen Leben. Auch wenn die herkömmliche Medikation zur Behandlung dieser Störungen routinemäßig Anwendung findet, ist es Ziel der Wissenschaft, eine unterstĂĽtzende sowie Alternativmedikation zu entwickeln, die auf natĂĽrlichen Ausgangssubstanzen, wie z.B. dem in Trauben vorkommenden Stilben Resveratrol, basiert. Resveratrol werden zahlreiche positive Eigenschaften zugeschrieben. Darunter fallen anti-inflammatorische, anti-kanzerogene, antioxidative, als auch neuroprotektive Eigenschaften. Ein Einsatz von Substanzen natĂĽrlichen Ursprungs als sogenanntes Nutraceutical kann einerseits dazu dienen, die Akzeptanz der Medikation bei Betroffenen zu erhöhen, aber auch, die mit der herkömmlichen Behandlungsmethode verbundenen, Nebenwirkungen zu mindern und zu ĂĽberwinden. Effekte von Resveratrol wurden auf die Reaktivität von Mastzellen, isoliert aus humanen intestinalen Resektionspräparaten (hiMC), geprĂĽft. Die Ergebnisse dieser Arbeit verdeutlichen, dass das Stilben starke inhibitorische Wirkung auf IgE-Rezeptor vermittelte Aktivierung von Mastzellen zeigt und dabei nicht nur die Mastzelldegranulation, sondern auch die Genexpression der pro-inflammatorischen Zytokine C-X-C motif chemokine ligand (CXCL) 8, C-C motif chemokine ligand (CCL) 2, CCL3, CCL4 und tumor necrosis factor (TNF-) α stark hemmt. Die, im Zuge der Mastzellaktivierung via IgE-Rezeptor, ausgelöste intrazelluläre Signalkaskade fĂĽhrt letztlich zur MediatorausschĂĽttung. Im Verlauf der Signalkaskade kommt es zur Phosphorylierung, d.h. der Aktivierung der SignalmolekĂĽle extracellular signal-regulated kinase (ERK) 1/2 und signal transducer and activator of transcription (STAT) 3. Dabei ist ERK1/2 fĂĽr die Phosphorylierung von mitochondrialem STAT3 verantwortlich, welches maĂźgeblich zur Mastzelldegranulation beiträgt. Die Behandlung mit Resveratrol fĂĽhrte dabei zur Hemmung der Phosphorylierung von STAT3 um mehr als 50 %, sowie die von ERK1/2 um fast 100 %. Des Weiteren gelang es uns, die mitochondriale Fraktion aus relativ geringen Mengen humaner intestinaler Mastzellen (hiMC) zu isolieren. Auch in dieser Fraktion konnten wir die Phosphorylierung von ERK1/2 und STAT3 nach Mastzellaktivierung detektieren, die nach einer Behandlung mit Resveratrol ebenfalls verringert war. Nachdem die stark hemmende Wirkung von Resveratrol in vitro gezeigt wurde, sollten die immunmodulatorischen Wirkungen auch in vivo ĂĽberprĂĽft werden. Das Vorhandensein und die Aktivität von MC stehen in engem Zusammenhang mit EntzĂĽndungen des Darms als Ursache von Nahrungsmittelallergien sowie chronisch-entzĂĽndlicher Darmerkrankungen (CED). Im Mausmodell kann man Nahrungsmittelallergie mit Hilfe einer Ovalbumin (OVA)-induzierten allergischen Enteritis und CED mit Hilfe der IL-10 knockout (-/-) Maus, bei der es zu einer spontan auftretenden chronischen Colitis kommt, experimentell untersuchen. Wir konnten zeigen, dass die orale Gabe von Resveratrol bei betroffenen Tieren im Allergiemodell (OVA) als auch im Modell der murinen Colitis (IL-10-/-) zu einer Hemmung des Anstiegs der Mastzellanzahl im Gewebe von Colon und Duodenum betroffener Tiere fĂĽhrte. Weniger stark ausgeprägte, aber dennoch sichtbare Effekte bei einer Resveratrol-Gabe konnten im Colon im Hinblick auf Epithelschädigung und bei der IL-10-/- Colitis auch im Hinblick auf Zellinfiltration sowie Reduktion der Anzahl an Gobletzellen beobachtet werden. In allen Fällen verringerten sich die Schädigungen auf das Level der jeweiligen Kontrolltiere ohne allergische Enteritis bzw. Colitis. Insgesamt kam es bei der allergischen Enteritis zu einer schwächer ausgeprägten Symptomatik, bei IL-10-/- Tieren kam es insgesamt zu einem verzögerten Auftreten der typischen Symptomatiken. Die Ergebnisse dieser Promotionsarbeit zeigen eine stark inhibitorische Wirkung von Resveratrol auf hiMC. Diese lieĂźen sich sowohl bei der Mediatorfreisetzung als auch auf Genexpressionslevel und in der Phosphorylierung der SignalmolekĂĽle ERK1/2 und STAT3 zeigen, bei denen es gelungen ist, sie auch in den Mitochondrien von hiMC nachzuweisen. Auch im Mausmodell bei der Untersuchung einer allergisch induzierten Enteritis sowie einer murinen Colitis aufgrund eines IL-10-/- konnten wir positive EinflĂĽsse auf Mastzell-assoziierte Parameter beobachten. Im Hinblick auf die Verwendung als Nutraceutical könnte Resveratrol deshalb zukĂĽnftig mehr in den Fokus rĂĽcken

    Role of macrophages in pulmonary arterial hypertension

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    Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary vascular disease characterized by progressive pulmonary artery pressure elevation, increased pulmonary vascular resistance and ultimately right heart failure. Studies have demonstrated the involvement of multiple immune cells in the development of PAH in patients with PAH and in experimental PAH. Among them, macrophages, as the predominant inflammatory cells infiltrating around PAH lesions, play a crucial role in exacerbating pulmonary vascular remodeling in PAH. Macrophages are generally polarized into (classic) M1 and (alternative) M2 phenotypes, they accelerate the process of PAH by secreting various chemokines and growth factors (CX3CR1, PDGF). In this review we summarize the mechanisms of immune cell action in PAH, as well as the key factors that regulate the polarization of macrophages in different directions and their functional changes after polarization. We also summarize the effects of different microenvironments on macrophages in PAH. The insight into the interactions between macrophages and other cells, chemokines and growth factors may provide important clues for the development of new, safe and effective immune-targeted therapies for PAH

    Classification related to immunogenic cell death predicts prognosis, immune microenvironment characteristics, and response to immunotherapy in lower-grade gliomas

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    BackgroundImmunogenic cell death (ICD) is a form of cell death that elicits immune responses against the antigens found in dead or dying tumor cells. Growing evidence implies that ICD plays a significant role in triggering antitumor immunity. The prognosis for glioma remains poor despite many biomarkers being reported, and identifying ICD-related biomarkers is imminent for better-personalized management in patients with lower-grade glioma (LGG).Materials and methodsWe identified ICD-related differentially expressed genes (DEGs) by comparing gene expression profiles obtained across Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) cohorts. On the foundation of ICD-related DEGs, two ICD-related clusters were identified through consensus clustering. Then, survival analysis, functional enrichment analysis, somatic mutation analysis, and immune characteristics analysis were performed in the two ICD-related subtypes. Additionally, we developed and validated a risk assessment signature for LGG patients. Finally, we selected one gene (EIF2AK3) from the above risk model for experimental validation.Results32 ICD-related DEGs were screened, dividing the LGG samples from the TCGA database into two distinct subtypes. The ICD-high subgroup showed worse overall survival (OS), greater immune infiltration, more active immune response process, and higher expression levels of HLA genes than the ICD-low subgroup. Additionally, nine ICD-related DEGs were identified to build the prognostic signature, which was highly correlated with the tumor-immune microenvironment and could unambiguously be taken as an independent prognostic factor and further verified in an external dataset. The experimental results indicated that EIF2AK3 expression was higher in tumors than paracancerous tissues, and high-expression EIF2AK3 was enriched in WHO III and IV gliomas by qPCR and IHC, and Knockdown of EIF2AK3 suppressed cell viability and mobility in glioma cells.ConclusionWe established novel ICD-related subtypes and risk signature for LGG, which may be beneficial to improving clinical outcome prediction and guiding individualized immunotherapy

    Slowest first passage times, redundancy, and menopause timing

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    Biological events are often initiated when a random "searcher" finds a "target," which is called a first passage time (FPT). In some biological systems involving multiple searchers, an important timescale is the time it takes the slowest searcher(s) to find a target. For example, of the hundreds of thousands of primordial follicles in a woman's ovarian reserve, it is the slowest to leave that trigger the onset of menopause. Such slowest FPTs may also contribute to the reliability of cell signaling pathways and influence the ability of a cell to locate an external stimulus. In this paper, we use extreme value theory and asymptotic analysis to obtain rigorous approximations to the full probability distribution and moments of slowest FPTs. Though the results are proven in the limit of many searchers, numerical simulations reveal that the approximations are accurate for any number of searchers in typical scenarios of interest. We apply these general mathematical results to models of ovarian aging and menopause timing, which reveals the role of slowest FPTs for understanding redundancy in biological systems. We also apply the theory to several popular models of stochastic search, including search by diffusive, subdiffusive, and mortal searchers.Comment: 55 pages, 7 figure

    Consumption of sugar sweetened beverages, artificially sweetened beverages and fruit juices and risk of type 2 diabetes, hypertension, cardiovascular disease, and mortality: A meta-analysis

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    Introduction: Sugar-sweetened beverage (SSB) intake is associated with an increased risk of cardiometabolic diseases. However, evidence regarding associations of artificially sweetened beverages (ASBs) and fruit juices with cardiometabolic diseases is mixed. In this study, we aimed to investigate the association between the SSB, ASB and fruit juice consumption with the incidence of cardiometabolic conditions and mortality. Methods: Relevant prospective studies were identified by searching PubMed, Web of Science, Embase, and Cochrane Library until December 2022 without language restrictions. The pooled relative risk (RR) and 95% confidence intervals (CIs) were estimated for the association of SSBs, ASBs, and fruit juices with the risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and mortality by using random-effect models. Results: A total of 72 articles were included in this meta-analysis study. Significantly positive associations were observed between the consumption of individual beverages and T2D risk (RR: 1.27; 95% CI: 1.17, 1.38 for SSBs; RR: 1.32; 95% CI: 1.11, 1.56 for ASBs; and RR:0.98; 95% CI: 0.93, 1.03 for fruit juices). Moreover, our findings showed that intakes of SSBs and ASBs were significantly associated with risk of hypertension, stroke, and all-cause mortality (RR ranging from 1.08 to 1.54; all p < 0.05). A dose-response meta-analysis showed monotonic associations between SSB intake and hypertension, T2D, coronary heart disease (CHD), stroke and mortality, and the linear association was only significant between ASB consumption and hypertension risk. Higher SSB and ASB consumptions were associated with a greater risk of developing cardiometabolic diseases and mortality. Fruit juice intake was associated with a higher risk of T2D. Conclusion: Therefore, our findings suggest that neither ASBs nor fruit juices could be considered as healthier beverages alternative to SSBs for achieving improved health. Systematic Review Registration: [PROSPERO], identifier [No. CRD42022307003]

    Ultra-small bacteria and archaea exhibit genetic flexibility towards groundwater oxygen content, and adaptations for attached or planktonic lifestyles

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    Aquifers are populated by highly diverse microbial communities, including unusually small bacteria and archaea. The recently described Patescibacteria (or Candidate Phyla Radiation) and DPANN radiation are characterized by ultra-small cell and genomes sizes, resulting in limited metabolic capacities and probable dependency on other organisms to survive. We applied a multi-omics approach to characterize the ultra-small microbial communities over a wide range of aquifer groundwater chemistries. Results expand the known global range of these unusual organisms, demonstrate the wide geographical range of over 11,000 subsurfaceadapted Patescibacteria, Dependentiae and DPANN archaea, and indicate that prokaryotes with ultra-small genomes and minimalistic metabolism are a characteristic feature of the terrestrial subsurface. Community composition and metabolic activities were largely shaped by water oxygen content, while highly site-specific relative abundance profiles were driven by a combination of groundwater physicochemistries (pH, nitrate-N, dissolved organic carbon). We provide insights into the activity of ultra-small prokaryotes with evidence that they are major contributors to groundwater community transcriptional activity. Ultra-small prokaryotes exhibited genetic flexibility with respect to groundwater oxygen content, and transcriptionally distinct responses, including proportionally greater transcription invested into amino acid and lipid metabolism and signal transduction in oxic groundwater, along with differences in taxa transcriptionally active. Those associated with sediments differed from planktonic counterparts in species composition and transcriptional activity, and exhibited metabolic adaptations reflecting a surfaceassociated lifestyle. Finally, results showed that groups of phylogenetically diverse ultra-small organisms co-occurred strongly across sites, indicating shared preferences for groundwater conditions.publishedVersio

    The anti-inflammatory effects of photobiomodulation are mediated by cytokines: Evidence from a mouse model of inflammation

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    There is an urgent need for therapeutic approaches that can prevent or limit neuroinflammatory processes and prevent neuronal degeneration. Photobiomodulation (PBM), the therapeutic use of specific wavelengths of light, is a safe approach shown to have anti-inflammatory effects. The current study was aimed at evaluating the effects of PBM on LPS-induced peripheral and central inflammation in mice to assess its potential as an anti-inflammatory treatment. Daily, 30-min treatment of mice with red/NIR light (RL) or RL with a 40 Hz gamma frequency flicker for 10 days prior to LPS challenge showed anti-inflammatory effects in the brain and systemically. PBM downregulated LPS induction of key proinflammatory cytokines associated with inflammasome activation, IL-1β and IL-18, and upregulated the anti-inflammatory cytokine, IL-10. RL provided robust anti-inflammatory effects, and the addition of gamma flicker potentiated these effects. Overall, these results demonstrate the potential of PBM as an anti-inflammatory treatment that acts through cytokine expression modulation

    Pharmacological effects of baicalin in lung diseases

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    The flavonoids baicalin and baicalein were discovered in the root of Scutellaria baicalensis Georgi and are primarily used in traditional Chinese medicine, herbal supplements and healthcare. Recently, accumulated investigations have demonstrated the therapeutic benefits of baicalin in treating various lung diseases due to its antioxidant, anti-inflammatory, immunomodulatory, antiapoptotic, anticancer, and antiviral effects. In this review, the PubMed database and ClinicalTrials website were searched with the search string “baicalin” and “lung” for articles published between September 1970 and March 2023. We summarized the therapeutic role that baicalin plays in a variety of lung diseases, such as chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, pulmonary hypertension, pulmonary infections, acute lung injury/acute respiratory distress syndrome, and lung cancer. We also discussed the underlying mechanisms of baicalin targeting in these lung diseases

    Macrophage polarization states in atherosclerosis

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    Atherosclerosis, a chronic inflammatory condition primarily affecting large and medium arteries, is the main cause of cardiovascular diseases. Macrophages are key mediators of inflammatory responses. They are involved in all stages of atherosclerosis development and progression, from plaque formation to transition into vulnerable plaques, and are considered important therapeutic targets. Increasing evidence suggests that the modulation of macrophage polarization can effectively control the progression of atherosclerosis. Herein, we explore the role of macrophage polarization in the progression of atherosclerosis and summarize emerging therapies for the regulation of macrophage polarization. Thus, the aim is to inspire new avenues of research in disease mechanisms and clinical prevention and treatment of atherosclerosis
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