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Macrophages are instrumental in maintaining tissue homeostasis, modulating inflammation, and driving regeneration. The advent of omics techniques has led to the identification of numerous tissue-specific macrophage subtypes, thereby introducing the concept of the "macrophage niche". This paradigm underscores the ability of macrophages to adapt their functions based on environmental cues, such as tissue-specific signals. This adaptability is closely linked to their metabolic states, which are crucial for their function and role in health and disease. Macrophage metabolism is central to their ability to switch between proinflammatory and anti-inflammatory states. In this regard, environmental factors, including the extracellular matrix, cellular interactions, and microbial metabolites, profoundly influence macrophage behavior. Moreover, diet and gut microbiota significantly impact macrophage function, with nutrients and microbial metabolites influencing their activity and contributing to conditions like inflammatory bowel disease. Targeting specific macrophage functions and their metabolic processes is leading to the development of novel treatments for a range of chronic inflammatory conditions. The exploration of macrophage biology enriches our understanding of immune regulation and holds the promise of innovative approaches to managing diseases marked by inflammation and immune dysfunction, offering a frontier for scientific and clinical advancement., (© 2024 Wiley‐VCH GmbH.)

Immune-inflammatory, metabolic, oxidative, and nitrosative stress (IMO&NS) pathways and, consequently, neurotoxicity are involved in acute ischemic stroke (IS). The simultaneous assessment of multiple IMO&NS biomarkers may be useful to predict IS and its prognosis. The aim of this study was to identify the IMO&NS biomarkers, which predict short-term IS outcome. The study included 176 IS patients and 176 healthy controls. Modified Rankin scale (mRS) was applied within 8 h after IS (baseline) and 3 months later (endpoint). Blood samples were obtained within 24 h after hospital admission. IS was associated with increased white blood cell (WBC) counts, high sensitivity C-reactive protein (hsCRP), interleukin (IL-6), lipid hydroperoxides (LOOHs), nitric oxide metabolites (NOx), homocysteine, ferritin, erythrocyte sedimentation rate (ESR), glucose, insulin, and lowered iron, 25-hydroxyvitamin D [25(OH)D], total cholesterol, and high-density lipoprotein (HDL) cholesterol. We found that 89.4% of the IS patients may be correctly classified using the cumulative effects of male sex, systolic blood pressure (SBP), glucose, NOx, LOOH, 25(OH)D, IL-6, and WBC with sensitivity of 86.2% and specificity of 93.0%. Moreover, increased baseline disability (mRS ≥ 3) was associated with increased ferritin, IL-6, hsCRP, WBC, ESR, and glucose. We found that 25.0% of the variance in the 3-month endpoint (mRS) was explained by the regression on glucose, ESR, age (all positively), and HDL-cholesterol, and 25(OH)D (both negatively). These results show that the cumulative effects of IMO&NS biomarkers are associated with IS and predict a poor outcome at 3-month follow-up.

Chronic low-grade inflammation is a hallmark of aging, aka "inflammaging", which is linked to a wide range of age-associated diseases. Immune dysfunction increases disease susceptibility, and increases morbidity and mortality of aging. Innate immune cells, including monocytes, macrophages and neutrophils, are the first responders of host defense and the key mediators of various metabolic and inflammatory insults. Currently, the understanding of innate immune programming in aging is largely fragmented. Here we investigated the phenotypic and functional properties of innate immune cells in various peripheral tissues of young and aged mice under normal and endotoxic conditions. Under the steady state, aged mice showed elevated proinflammatory monocytes/macrophages in peripheral blood, adipose tissue, liver, and colon. Under lipopolysaccharide (LPS)-induced inflammatory state, the innate immune cells of aged mice showed a different response to LPS stimulus than that of young mice. LPS-induced immune responses displayed differential profiles in different tissues and cell types. In the peripheral blood, when responding to LPS, the aged mice showed higher neutrophils, but lower pro-inflammatory monocytes than that in young mice. In the peritoneal fluid, while young mice exhibited significantly elevated pro-inflammatory neutrophils and macrophages in response to LPS, aged mice exhibited decreased proinflammatory neutrophils and variable cytokine responses in macrophages. In the adipose tissue, LPS induced less infiltrated neutrophils but more infiltrated macrophages in old mice than young mice. In the liver, aged mice showed a more robust increase of pro-inflammatory macrophages compared to that in young mice under LPS stimulation. In colon, macrophages showed relatively mild response to LPS in both young and old mice. We have further tested bonemarrow derived macrophages (BMDM) from young and aged mice, we found that BMDM from aged mice have impaired polarization, displaying higher expression of pro-inflammatory markers than those from young mice. These data collectively suggest that innate immunity in peripheral tissues is impaired in aging, and the dysregulation of immunity is tissue- and cell-dependent. Our findings in the rodent model underscore the complexity of aging immunity. Further investigation is needed to determine whether the immune profile observed in aged mice is applicable in age-associated diseases in humans. [ABSTRACT FROM AUTHOR]

Introduction: Preclinical studies suggest that cannabinoid receptor type 2 (CB2R) activation has a therapeutic effect in animal models on chronic inflammation and vascular permeability, which are key pathological features of diabetic retinopathy (DR). A novel CB2R agonist, triazolopyrimidine RG7774, was generated through lead optimization of a high-throughput screening hit. The aim of this study was to characterize the pharmacology, absorption, distribution, metabolism, elimination, and toxicity (ADMET) profile of RG7774, and to explore its potential for managing the key pathological features associated with retinal disease in rodents. Methods: The in vitro pharmacology of RG7774 was investigated for CB2R binding and receptor activation using recombinant human and mouse CB2R expression in Chinese hamster ovary cells, and endogenous CB2R expression in human Jurkat cells, and rat and mouse spleen cells. The ADMET profile was evaluated and the effects of RG7774 on retinal permeability, leukocyte adhesion, and choroidal neovascularization (CNV) were investigated in rodent models of retinal disease. Pharmacokinetic (PK) parameters and the exposure-response relationship were characterized in healthy animals and in animals with laserinduced CNV. Results: RG7774was found to be a potent (EC50: 2.8 nMand Ki: 51.3 nM), selective, and full CB2R agonist with no signs of cannabinoid receptor type 1 (CB1R) binding or activation. The ligand showed a favorable ADMET profile and exhibited systemic and ocular exposure after oral delivery. Functional potency in vitro translated from recombinant to endogenous expression systems. In vivo, orally administered RG7774 reduced retinal permeability and leukocyte adhesion in rodents with lipopolysaccharide (LPS)-induced uveitis and streptozotocin (STZ)-induced DR, and reduced lesion areas in rats with laser-induced CNV with an ED50 of 0.32 mg/kg. Anatomically, RG7774 reduced the migration of retinal microglia to retinal lesions. Discussion: RG7774 is a novel, highly selective, and orally bioavailable CB2R agonist, with an acceptable systemic and ocular PK profile, and beneficial effects on retinal vascular permeability, leukocyte adhesion, and ocular inflammation in rodent animal models. Results support the development of RG7774 as a potential treatment for retinal diseases with similar pathophysiologies as addressed by the animal models. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBDs) are characterized by chronic gastrointestinal inflammation due to abnormal immune responses to gut microflora. The gut–brain axis is disrupted in IBDs, leading to neurobiological imbalances and affective symptoms. Systemic inflammation in IBDs affects the brain's inflammatory response system, hormonal axis, and blood–brain barrier integrity, influencing the gut microbiota. This review aims to explore the association between dysregulations in the gut–brain axis, serum biomarkers, and the development of cognitive disorders. Studies suggest a potential association between IBDs and the development of neurodegeneration. The mechanisms include systemic inflammation, nutritional deficiency, GBA dysfunction, and the effect of genetics and comorbidities. The objective is to identify potential correlations and propose future research directions to understand the impact of altered microbiomes and intestinal barrier functions on neurodegeneration. Serum levels of vitamins, inflammatory and neuronal damage biomarkers, and neuronal growth factors have been investigated for their potential to predict the development of neurodegenerative diseases, but current results are inconclusive and require more studies. [ABSTRACT FROM AUTHOR]

Sepsis is a potentially fatal condition characterized by organ dysfunction caused by an imbalanced immune response to infection. Although an increased inflammatory response significantly contributes to the pathogenesis of sepsis, several molecular mechanisms underlying the progression of sepsis are associated with increased cellular reactive oxygen species (ROS) generation and exhausted antioxidant pathways. This review article provides a comprehensive overview of the involvement of ROS in the pathophysiology of sepsis and the potential application of antioxidants with antimicrobial properties as an adjunct to primary therapies (fluid and antibiotic therapies) against sepsis. This article delves into the advantages and disadvantages associated with the utilization of antioxidants in the therapeutic approach to sepsis, which has been explored in a variety of animal models and clinical trials. While the application of antioxidants has been suggested as a potential therapy to suppress the immune response in cases where an intensified inflammatory reaction occurs, the use of multiple antioxidant agents can be beneficial as they can act additively or synergistically on different pathways, thereby enhancing the antioxidant defense. Furthermore, the utilization of immunoadjuvant therapy, specifically in septic patients displaying immunosuppressive tendencies, represents a promising advancement in sepsis therapy. [ABSTRACT FROM AUTHOR]

B lymphocytes are immune cells studied predominantly in the context of peripheral humoral immune responses against pathogens. Evidence has been accumulating in recent years on the diversity of immunomodulatory functions that B cells undertake, with particular relevance for pathologies of the central nervous system (CNS). This review summarizes current knowledge on B cell populations, localization, infiltration mechanisms, and function in the CNS and associated tissues. Acute and chronic neurodegenerative pathologies are examined in order to explore the complex, and sometimes conflicting, effects that B cells can have in each context, with implications for disease progression and treatment outcomes. Additional factors such as aging modulate the proportions and function of B cell subpopulations over time and are also discussed in the context of neuroinflammatory response and disease susceptibility. A better understanding of the multifactorial role of B cell populations in the CNS may ultimately lead to innovative therapeutic strategies for a variety of neurological conditions. [ABSTRACT FROM AUTHOR]

Enterotoxigenic Bacteroides fragilis (ETBF) causes colitis and is implicated in inflammatory bowel diseases and colorectal cancer. The ETBF-secreted B. fragilis toxin (BFT) causes cleavage of the adherence junction, the E-cadherin, resulting in the large intestine showing IL-17A inflammation in wild-type (WT) mice. However, intestinal pathology by ETBF infection is not fully understood in B-cell-deficient mice. In this study, ETBF-mediated inflammation was characterized in B-cell-deficient mice (muMT). WT or muMT C57BL/6J mice were orally inoculated with ETBF and examined for intestinal inflammation. The indirect indicators for colitis (loss of body weight and cecum weight, as well as mortality) were increased in muMT mice compared to WT mice. Histopathology and inflammatory genes (Nos2, Il-1β, Tnf-α, and Cxcl1) were elevated and persisted in the large intestine of muMT mice compared with WT mice during chronic ETBF infection. However, intestinal IL-17A expression was comparable between WT and muMT mice during infection. Consistently, flow cytometry analysis applied to the mesenteric lymph nodes showed a similar Th17 immune response in both WT and muMT mice. Despite elevated ETBF colonization, the ETBF-infected muMT mice showed no histopathology or inflammation in the small intestine. In conclusion, B cells play a protective role in ETBF-induced colitis, and IL-17A inflammation is not attributed to prompted colitis in B-cell-deficient mice. Our data support the fact that B cells are required to ameliorate ETBF infection-induced colitis in the host. [ABSTRACT FROM AUTHOR]

Background: Eimeria genus belongs to the apicomplexan parasite phylum and is responsible for coccidiosis, an intestinal disease with a major economic impact on poultry production. Eimeria tenella is one of the most virulent species in chickens. In a previous study, we showed a negative impact of caecal microbiota on the physiopathology of this infection. However, the mechanism by which microbiota leads to the physiopathology remained undetermined. Macrophages play a key role in inflammatory processes and their interaction with the microbiota during E. tenella infection have never been investigated. We therefore examined the impact of microbiota on macrophages during E. tenella infection. Macrophages were monitored in caecal tissues by immunofluorescence staining with KUL01 antibody in non-infected and infected germ-free and conventional chickens. Caecal cells were isolated, stained, analyzed and sorted to examine their gene expression using high-throughput qPCR. Results: We demonstrated that microbiota was essential for caecal macrophage recruitment in E. tenella infection. Furthermore, microbiota promoted a pro-inflammatory transcriptomic profile of macrophages characterized by increased gene expression of NOS2, ACOD1, PTGS2, TNFα, IL1β, IL6, IL8L1, IL8L2 and CCL20 in infected chickens. Administration of caecal microbiota from conventional chickens to germ-free infected chickens partially restored macrophage recruitment and response. Conclusions: Taken together, these results suggest that the microbiota enhances the physiopathology of this infection through macrophage recruitment and activation. Consequently, strategies involving modulation of the gut microbiota may lead to attenuation of the macrophage-mediated inflammatory response, thereby limiting the negative clinical outcome of the disease. [ABSTRACT FROM AUTHOR]

Uncontrolled inflammation is a pathological state that underlies many diseases. Despite the development of numerous anti-inflammatory agents, the treatment of uncontrolled inflammation remains a challenging task. We developed a targeted delivery system for [5-(p-fluorophenyl)-2-ureido]thiophene-3-carboxamide (TPCA-1), a potent inhibitor of the NF-κB signaling pathway. The system comprises TPCA-1-loaded nanoparticles (NPs) functionalized with a monoclonal antibody (mAb) that specifically binds to the break point of the IgD6 region of the platelet/endothelial cell adhesion molecule-1 (PECAM-1) extracellular segment that is overexposed on the injured endothelium and activated macrophages during the pathogenesis of inflammation. In vitro binding and cellular uptake experiments revealed that the mAb modification on NPs could significantly enhance uptake by both Raw264.7 and HUVEC compared with unmodified NPs. In studies conducted at the cellular level focusing on anti-inflammatory and antioxidant effects, this formulation was found to effectively inhibit M1 polarization of macrophages, downregulate the secretion of pro-inflammatory cytokines, and reduce the production of reactive oxygen species (ROS) and nitric oxide (NO). In an animal model of vascular endothelial injury with acute inflammation, these NPs were capable of delivering TPCA-1 to inflammatory lesions in a targeted manner. Compared with the free agent-treated group, the NP-treated group exhibited reduced infiltration of inflammatory cells. In conclusion, our study demonstrates that this targeted delivery of TPCA-1-loaded NPs represents a promising strategy for improved mitigation of uncontrolled inflammation. [ABSTRACT FROM AUTHOR]

Neuroinflammation may be a pathogenic mediator and biomarker of neurodegeneration at the boundary between mild cognitive impairment (MCI) and early-stage Alzheimer's disease (AD). Whether neuroinflammatory processes are endogenous to the central nervous system (CNS) or originate from systemic (peripheral blood) sources could impact strategies for therapeutic intervention. To address this issue, we measured cytokine and chemokine immunoreactivities in simultaneously obtained lumbar puncture cerebrospinal fluid (CSF) and serum samples from 39 patients including 18 with MCI or early AD and 21 normal controls using a 27-plex XMAP bead-based enzyme-linked immunosorbent assay (ELISA). The MCI/AD combined group had significant (p < 0.05 or better) or statistically trend-wise (0.05 ≤ p ≤ 0.10) concordant increases in CSF and serum IL-4, IL-5, IL-9, IL-13, and TNF-α and reductions in GM-CSF, b-FGF, IL-6, IP-10, and MCP-1; CSF-only increases in IFN-y and IL-7 and reductions in VEGF and IL-12p70; serum-only increases in IL-1β, MIP-1α, and eotaxin and reductions in G-CSF, IL-2, IL-8 and IL-15; and discordant CSF–serum responses with reduced CSF and increased serum PDGF-bb, IL-17a, and RANTES. The results demonstrate simultaneously parallel mixed but modestly greater pro-inflammatory compared to anti-inflammatory or neuroprotective responses in CSF and serum. In addition, the findings show evidence that several cytokines and chemokines are selectively altered in MCI/AD CSF, likely corresponding to distinct neuroinflammatory responses unrelated to systemic pathologies. The aggregate results suggest that early management of MCI/AD neuroinflammation should include both anti-inflammatory and pro-neuroprotective strategies to help prevent disease progression. [ABSTRACT FROM AUTHOR]

Microplastics (MPs) are recognized as environmental pollutants with potential implications for human health. Considering the rapid increase in obesity rates despite stable caloric intake, there is a growing concern about the link between obesity and exposure to environmental pollutants, including MPs. In this study, we conducted a comprehensive investigation utilizing in silico, in vitro, and in vivo approaches to explore the brain distribution and physiological effects of MPs. Molecular docking simulations were performed to assess the binding affinity of three plastic polymers (ethylene, propylene, and styrene) to immune cells (macrophages, CD4+, and CD8+ lymphocytes). The results revealed that styrene exhibited the highest binding affinity for macrophages. Furthermore, in vitro experiments employing fluorescence-labeled PS-MPs (fPS-MPs) of 1 μm at various concentrations demonstrated a dose-dependent binding of fPS-MPs to BV2 murine microglial cells. Subsequent oral administration of fPS-MPs to high-fat diet-induced obese mice led to the co-existence of fPS-MPs with immune cells in the blood, exacerbating impaired glucose metabolism and insulin resistance and promoting systemic inflammation. Additionally, fPS-MPs were detected throughout the brain, with increased activation of microglia in the hypothalamus. These findings suggest that PS-MPs significantly contribute to the exacerbation of systemic inflammation in high-fat diet-induced obesity by activating peripheral and central inflammatory immune cells. [ABSTRACT FROM AUTHOR]

Selenium is a main group element and an essential trace element in human health. It was discovered in selenocysteine (SeC) by Stadtman in 1974. SeC is an encoded natural amino acid hailed as the 21st naturally occurring amino acid (U) present in several enzymes and which exquisitely participates in redox biology. As it turns out, selenium bears a U-shaped toxicity curve wherein too little of the nutrient present in biology leads to disorders; concentrations that are too great, on the other hand, pose toxicity to biological systems. In light of many excellent previous reviews and the corpus of literature, we wanted to offer this current review, in which we present aspects of the clinical and biological literature and justify why we should further investigate Se-containing species in biological and medicinal contexts, especially small molecule-containing species in biomedical research and clinical medicine. Of central interest is how selenium participates in biological signaling pathways. Several clinical medical cases are recounted; these reports are mainly pertinent to human cancer and changes in pathology and cases in which the patients are often terminal. Selenium was an option chosen in light of earlier chemotherapeutic treatment courses which lost their effectiveness. We describe apoptosis, and also ferroptosis, and senescence clearly in the context of selenium. Other contemporary issues in research also compelled us to form this review: issues with CoV-2 SARS infection which abound in the literature, and we described findings with human patients in this context. Laboratory scientific studies and clinical studies dealing with two main divisions of selenium, organic (e.g., methyl selenol) or inorganic selenium (e.g., sodium selenite), are discussed. The future seems bright with the research and clinical possibilities of selenium as a trace element, whose recent experimental clinical treatments have so far involved dosing simply and inexpensively over a set of days, amounts, and time intervals. [ABSTRACT FROM AUTHOR]

Background: Thrombolytic agents such as tissue plasminogen activator (tPA) are the only drug class approved to treat ischemic stroke and are usually administered within 4.5 h. However, only ~20% of ischemic stroke patients are eligible to receive the therapy. We previously demonstrated that early intravenous administration of human amnion epithelial cells (hAECs) can limit brain inflammation and infarct growth in experimental stroke. Here, we have tested whether hAECs exert cerebroprotective effects in combination with tPA in mice. Methods: Male C57Bl/6 mice were subjected to middle cerebral artery occlusion for 60 min followed by reperfusion. Immediately following reperfusion, vehicle (saline, n = 31) or tPA (10 mg/kg; n = 73) was administered intravenously. After 30 min of reperfusion, tPA-treated mice were injected intravenously with either hAECs (1×106; n = 32) or vehicle (2% human serum albumin; n = 41). A further 15 sham-operated mice were treated with vehicle (n = 7) or tPA + vehicle (n = 8). Mice were designated to be euthanised at 3, 6 or 24 h post-stroke (n = 21, 31, and 52, respectively), and brains were collected to assess infarct volume, blood-brain barrier (BBB) disruption, intracerebral bleeding and inflammatory cell content. Results: There was no mortality within 6 h of stroke onset, but a high mortality occurred in tPA + saline-treated mice between 6 h and 24 h post-stroke in comparison to mice treated with tPA + hAECs (61% vs. 27%, p = 0.04). No mortality occurred within 24 h of sham surgery in mice treated with tPA + vehicle. We focused on early infarct expansion within 6 h of stroke and found that infarction was ~50% larger in tPA + saline-than in vehicle-treated mice (23 ± 3 mm³ vs. 15 ± 2 mm³, p = 0.02) but not in mice receiving tPA + hAECs (13 ± 2 mm3, p < 0.01 vs. tPA + saline) in which intracerebral hAECs were detected. Similar to the profiles of infarct expansion, BBB disruption and intracerebral bleeding in tPA + saline-treated mice at 6 h was 50-60% greater than in vehicle-treated controls (2.6 ± 0.5 vs. 1.6 ± 0.2, p = 0.05) but not after tPA + hAECs treatment (1.7 ± 0.2, p = 0.10 vs. tPA + saline). No differences in inflammatory cell content were detected between treatment groups. Conclusion: When administered following tPA in acute stroke, hAECs improve safety and attenuate infarct growth in association with less BBB disruption and lower 24 h mortality. [ABSTRACT FROM AUTHOR]

The most important predictors for outcomes after ischemic stroke, that is, for health deterioration and death, are chronological age and stroke severity; gender, genetics and lifestyle/environmental factors also play a role. Of all these, only the latter can be influenced after the event. Recurrent stroke may be prevented by antiaggregant/anticoagulant therapy, angioplasty of high-grade stenoses, and treatment of cardiovascular risk factors. Blood cell composition and protein biomarkers such as C-reactive protein or interleukins in serum are frequently considered as biomarkers of outcome. Here we aim to provide an up-to-date protein biomarker signature that allows a maximum of mechanistic understanding, to predict health deterioration following stroke. We thus surveyed protein biomarkers that were reported to be predictive for outcome after ischemic stroke, specifically considering biomarkers that predict long-term outcome (≥ 3 months) and that are measured over the first days following the event. We classified the protein biomarkers as immune‑inflammatory, coagulation-related, and adhesion-related biomarkers. Some of these biomarkers are closely related to cellular senescence and, in particular, to the inflammatory processes that can be triggered by senescent cells. Moreover, the processes that underlie inflammation, hypercoagulation and cellular senescence connect stroke to cancer, and biomarkers of cancer-associated thromboembolism, as well as of sarcopenia, overlap strongly with the biomarkers discussed here. Finally, we demonstrate that most of the outcome-predicting protein biomarkers form a close-meshed functional interaction network, suggesting that the outcome after stroke is partially determined by an interplay of molecular processes relating to inflammation, coagulation, cell adhesion and cellular senescence. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a typical joint disease associated with chronic inflammation. The nuclear factor-kappaB (NF-kB) pathway plays an important role in inflammatory activity and inhibiting NF-kB-mediated inflammation can be a potential strategy for treating OA. Flavonoids are a class of naturally occurring polyphenols with anti-inflammatory properties. Structurally, natural flavonoids can be divided into several sub-groups, including flavonols, flavones, flavanols/catechins, flavanones, anthocyanins, and isoflavones. Increasing evidence demonstrates that natural flavonoids exhibit protective activity against the pathological changes of OA by inhibiting the NF-kB signaling pathway. Potentially, natural flavonoids may suppress NF-kB signaling-mediated inflammatory responses, ECM degradation, and chondrocyte apoptosis. The different biological actions of natural flavonoids against the NF-kB signaling pathway in OA chondrocytes might be associated with the differentially substituted groups on the structures. In this review, the efficacy and action mechanism of natural flavonoids against the development of OA are discussed by targeting the NF-kB signaling pathway. Potentially, flavonoids could become useful inhibitors of the NF-kB signaling pathway for the therapeutic management of OA. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders. MCs located near the meninges communicate with microglia through the production of mediators such as histamine and tryptase, but also through the secretion of IL-1, IL-6 and TNF, which can create pathological effects in the brain. Preformed chemical mediators of inflammation and tumor necrosis factor (TNF) are rapidly released from the granules of MCs, the only immune cells capable of storing the cytokine TNF, although it can also be produced later through mRNA. The role of MCs in nervous system diseases has been extensively studied and reported in the scientific literature; it is of great clinical interest. However, many of the published articles concern studies on animals (mainly rats or mice) and not on humans. MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. This article explores the current understanding of MC activation by neuropeptide substance P (SP), corticotropin-releasing hormone (CRH), and neurotensin, and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38. [ABSTRACT FROM AUTHOR]

In acute ischemic stroke (AIS), there are no data on whether oxidative stress biomarkers have effects above and beyond known risk factors and measurements of stroke volume. This study was conducted in 122 mild-moderate AIS patients and 40 controls and assessed the modified ranking scale (mRS) at baseline, and 3 and 6 months later. We measured lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products, paraoxonase 1 (PON1) activities and PON1 Q192R genotypes, high density lipoprotein cholesterol (HDL), sulfhydryl (-SH) groups), and diffusion-weighted imaging (DWI) stroke volume and fluid-attenuated inversion recovery (FLAIR) signal intensity. We found that (a) AIS is characterized by lower chloromethyl acetate CMPAase PON1 activity, HDL and -SH groups and increased LOOH and neurotoxicity (a composite of LOOH, inflammatory markers and glycated hemoglobin); (b) oxidative and antioxidant biomarkers strongly and independently predict mRS scores 3 and 6 months later, DWI stroke volume and FLAIR signal intensity; and (c) the PON1 Q192R variant has multiple effects on stroke outcomes that are mediated by its effects on antioxidant defenses and lipid peroxidation. Lipid peroxidation and lowered -SH and PON1-HDL activity are drug targets to prevent AIS and consequent neurodegenerative processes and increased oxidative reperfusion mediators due to ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Animal models of multiple sclerosis (MS), specifically experimental autoimmune encephalomyelitis (EAE), have been used extensively to develop anti-inflammatory treatments. However, the similarity between MS and one particular EAE model does not end at inflammation. MS and chronic EAE induced in C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 share many neuropathologies. Beyond both having white matter lesions in spinal cord, both also have widespread neuropathology in the cerebral cortex, hippocampus, thalamus, striatum, cerebellum, and retina/optic nerve. In this review, we compare neuropathologies in each of these structures in MS with chronic EAE in C57BL/6 mice, and find evidence that this EAE model is well suited to study neuroaxonal degeneration in MS. [ABSTRACT FROM AUTHOR]

The gut epithelium not only provides a physical barrier to separate a noxious outside from a sterile inside but also allows for highly regulated interactions between bacteria and their products, and components of the immune system. Homeostatic maintenance of an intact epithelial barrier is paramount to health, requiring an intricately regulated and highly adaptive response of various cells of the immune system. Prolonged homeostatic imbalance can result in chronic inflammation, tumorigenesis and inefficient antitumor immune control. Here we provide an update on the role of innate lymphoid cells, macrophages and dendritic cells, which collectively play a critical role in epithelial barrier maintenance and provide an important linkage between the classical innate and adaptive arm of the immune system. These interactions modify the capacity of the gut epithelium to undergo continuous renewal, safeguard against tumor formation and provide feedback to the gut microbiome, which acts as a seminal contributor to cellular homeostasis of the gut. [ABSTRACT FROM AUTHOR]

Increase of deposits of amyloid β peptides in the extracellular matrix is landmark during Alzheimer's Disease (AD) due to the imbalance in the production vs. clearance. This accumulation of amyloid β deposits triggers microglial activation. Microglia plays a dual role in AD, a protective role by clearing the deposits of amyloid β peptides increasing the phagocytic response (CD163, IGF-1 or BDNF) and a cytotoxic role, releasing free radicals (ROS or NO) and proinflammatory cytokines (TNF- α, IL-1 β) in response to reactive gliosis activated by the amyloid β aggregates. Microglia activation correlated with an increase KV1.3 channels expression, protein levels and current density. Several studies highlight the importance of KV1.3 in the activation of inflammatory response and inhibition of neural progenitor cell proliferation and neuronal differentiation. However, little is known about the pathways of this activation in neural stem cells differentiation and proliferation and the role in amyloid β accumulation. In recent studies using in vitro cells derived from mice models, it has been demonstrated that KV1.3 blockers inhibit microglia-mediated neurotoxicity in culture reducing the expression and production of the pro-inflammatory cytokines IL-1 β and TNF- α through the NF-kB and p38MAPK pathway. Overall, we conclude that KV1.3 blockers change the course of AD development, reducing microglial cytotoxic activation and increasing neural stem cell differentiation. However, further investigations are needed to establish the specific pathway and to validate the use of this blocker as therapeutic treatment in Alzheimer patients. [ABSTRACT FROM AUTHOR]

Osteoarthritis is a common crippling and degenerative disease resulting in irreversible functional changes due to damage of the cartilage and other tissues of the joint. With limited safe and effective pharmaceutical treatments, the demand and use for alternative therapeutic approaches with symptomatic relief for OA patients have increased. Clinical, pre-clinical, and in vitro studies have demonstrated that polyphenols can exert pain-relieving symptoms coupled with increased functional capacity in OA models. This review will highlight studies carried out in the last five years to define the efficacies and underlying mechanisms in polyphenols such as quercetin, resveratrol, curcumin, epigallocatechin-3-gallate, rosmarinic acid, genistein, ginger, berries, silver fir, pine bark, and Boswellia. Most of these studies indicate that polyphenols exhibit their beneficial roles through regulating changes at the biochemical and molecular levels, inducing or inhibiting various signaling pathways related to inflammation and oxidative stress. Polyphenols have also been implicated in modulating microRNA at the posttranscriptional level to counteract OA pathogenesis. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) leads to significant morbidity and mortality worldwide. Glomerulonephritis (GN) is the second leading cause of CKD resulting in end stage renal failure. The most severe and rapidly progressive type of GN is characterized by glomerular crescent formation. The current therapies for crescentic GN, which consist of broad immunosuppressive drugs, are partially effective, non-specific, toxic and cause many serious side effects including infections, cancer, and cardiovascular problems. Therefore, new and safer therapies are needed. Human amniotic epithelial cells (hAECs) are a type of stem cell which are isolated from the placenta after birth. They represent an attractive and novel therapeutic option for the treatment of various inflammatory conditions owing to their unique and selective immunosuppressive ability, as well as their excellent safety profile and clinical applicability. In this review, we will discuss the immunopathogenesis of crescentic GN, issues with currently available treatments and how hAECs offer potential to become a new and harmless treatment option for this condition. [ABSTRACT FROM AUTHOR]

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The success of ocrelizumab in reducing confirmed disability accumulation in primary progressive multiple sclerosis (PPMS) via CD20-targeted depletion implicates B cells as causal agents in the pathogenesis of PPMS. This review explores the possible mechanisms by which B cells contribute to disease progression in PPMS, specifically exploring cytokine production, antigen presentation, and antibody synthesis. B cells may contribute to disease progression in PPMS through cytokine production, specifically GM-CSF and IL-6, which can drive naïve T-cell differentiation into pro-inflammatory Th1/Th17 cells. B cell production of the cytokine LT-α may induce follicular dendritic cell production of CXCL13 and lead indirectly to T and B cell infiltration into the CNS. In contrast, production of IL-10 by B cells likely induces an anti-inflammatory effect that may play a role in reducing neuroinflammation in PPMS. Therefore, reduced production of IL-10 may contribute to disease worsening. B cells are also capable of potent antigen presentation and may induce pro-inflammatory T-cell differentiation via cognate interactions. B cells may also contribute to disease activity via antibody synthesis, although it's unlikely the benefit of ocrelizumab in PPMS occurs via antibody decrement. Finally, various B cell subsets likely promulgate pro- or anti-inflammatory effects in MS. [ABSTRACT FROM AUTHOR]

Background: Interleukin 23 is a critical cytokine in the pathogenesis of multiple sclerosis. But the local impact of interleukin 23 on the course of neuroinflammation is still not well defined. To further characterize the effect of interleukin 23 on CNS inflammation, we recently described a transgenic mouse model with astrocyte-specific expression of interleukin 23 (GF-IL23 mice). The GF-IL23 mice spontaneously develop a progressive ataxic phenotype with cerebellar tissue destruction and inflammatory infiltrates with high amounts of B cells most prominent in the subarachnoid and perivascular space.Methods: To further elucidate the local impact of the CNS-specific interleukin 23 synthesis in autoimmune neuroinflammation, we induced a MOG35-55 experimental autoimmune encephalomyelitis (EAE) in GF-IL23 mice and WT mice and analyzed the mice by histology, flow cytometry, and transcriptome analysis.Results: We were able to demonstrate that local interleukin 23 production in the CNS leads to aggravation and chronification of the EAE course with a severe paraparesis and an ataxic phenotype. Moreover, enhanced multilocular neuroinflammation was present not only in the spinal cord, but also in the forebrain, brainstem, and predominantly in the cerebellum accompanied by persisting demyelination. Thereby, interleukin 23 creates a pronounced proinflammatory response with accumulation of leukocytes, in particular B cells, CD4+ cells, but also γδ T cells and activated microglia/macrophages. Furthermore, transcriptome analysis revealed an enhanced proinflammatory cytokine milieu with upregulation of lymphocyte activation markers, co-stimulatory markers, chemokines, and components of the complement system.Conclusion: Taken together, the GF-IL23 model allowed a further breakdown of the different mechanisms how IL-23 drives neuroinflammation in the EAE model and proved to be a useful tool to further dissect the impact of interleukin 23 on neuroinflammatory models. [ABSTRACT FROM AUTHOR]

Hepatic ischemia and reperfusion injury (IRI) is an acute inflammatory process that results from surgical interventions, such as liver resection surgery or transplantation, or hemorrhagic shock. This pathology has become a severe clinical issue, due to the increasing incidence of hepatic cancer and the high number of liver transplants. So far, an effective treatment has not been implemented in the clinic. Despite its importance, hepatic IRI has not attracted much interest as an inflammatory disease, and only a few reviews addressed it from a therapeutic perspective with drug delivery nanosystems. In the last decades, drug delivery nanosystems have proved to be a major asset in therapy because of their ability to optimize drug delivery, either by passive or active targeting. Passive targeting is achieved through the enhanced permeability and retention (EPR) effect, a main feature in inflammation that allows the accumulation of the nanocarriers in inflammation sites, enabling a higher efficacy of treatment than conventional therapies. These systems also can be actively targeted to specific compounds, such as inflammatory markers and overexpressed receptors in immune system intermediaries, allowing an even more specialized therapy that have already showed encouraging results. In this manuscript, we review drug delivery nanosystems designed for hepatic IRI treatment, addressing their current state in clinical trials, discussing the main hurdles that hinder their successful translation to the market and providing some suggestions that could potentially advance their clinical translation. [ABSTRACT FROM AUTHOR]

Over the past years, Human Amnion Epithelial Cells (hAECs), a placental stem cell, are gaining higher attention from the scientific community as they showed several advantages over other types of stem cells, including availability, easy accessibility, reduced rejection rate, non-tumorigenicity, and minimal legal constraint. Recently, natural compounds are used to stimulate stem cell differentiation and proliferation and to enhance their disease-treating potential. A polyphenolic compound 3,4,5-Tri-O-Caffeoylquinic Acid (TCQA) has been previously reported to induce human neural stem cell differentiation and may affect melanocyte stem cell differentiation as well. In this study, TCQA was tested on 3D cultured hAECs after seven days of treatment, and then, microarray gene expression profiling was conducted of TCQA-treated and untreated control cells on day 0 and day 7. Analyses revealed that TCQA treatment significantly enriched pigment and neural cells sets; besides, genes linked with neurogenesis, oxidation–reduction process, epidermal development, and metabolism were positively regulated. Interestingly, TCQA stimulated cell cycle arrest-related pathways and differentiation signaling. On the other hand, TCQA decreased interleukins and cytokines expression and this due to its anti-inflammatory properties as a polyphenolic compound. Results were validated to highlight the main activities of TCQA on hAECs, including differentiation, cell cycle arrest, and anti-inflammatory. This study highlights the important role of hAECs in regenerative medicine and the use of natural compounds to regulate their fate. 4ntr2z8GsC-Lz3nsa9SfYx Video abstract [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with a prevalence of 20%–30% in the general population. NAFLD is associated with increased risk of cardiovascular disease and may progress to cirrhosis with time. The purpose of this study was to predict the risks associated with NAFLD and advanced fibrosis on the Fatty Liver Index (FLI) and the 'NAFLD fibrosis 4' calculator (FIB-4), to enable physicians to make more optimal preventive medical decisions. A prospective cohort of apparently healthy volunteers from the Tel Aviv Medical Center Inflammation Survey (TAMCIS), admitted for their routine annual health check-up. Data from the TAMCIS database were subjected to machine learning classification models to predict individual risk after extensive data preparation that included the computation of independent variables over several time points. After incorporating the time covariates and other key variables, this technique outperformed the predictive power of current popular methods (an improvement in AUC above 0.82). New powerful factors were identified during the predictive process. The findings can be used for risk stratification and in planning future preventive strategies based on lifestyle modifications and medical treatment to reduce the disease burden. Interventions to prevent chronic disease can substantially reduce medical complications and the costs of the disease. The findings highlight the value of predictive analytic tools in health care environments. NAFLD constitutes a growing burden on the health system; thus, identification of the factors related to its incidence can make a strong contribution to preventive medicine. [ABSTRACT FROM AUTHOR]

Toll-Like Receptor 9 (TLR9) is an ancient receptor integral to the primordial functions of inflammation and metabolism. TLR9 functions to regulate homeostasis in a healthy system under acute stress. The literature supports that overactivation of TLR9 under the chronic stress of obesity is a critical driver of the pathogenesis of NASH and NASH-associated fibrosis. Research has focused on the core contributions of the parenchymal and non-parenchymal cells in the liver, adipose, and gut compartments. TLR9 is activated by endogenous circulating mitochondrial DNA (mtDNA). Chronically elevated circulating levels of mtDNA, caused by the stress of overnutrition, are observed in obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and NASH. Clinical evidence is supportive of TLR9 overactivation as a driver of disease. The role of TLR9 in metabolism and energy regulation may have an underappreciated contribution in the pathogenesis of NASH. Antagonism of TLR9 in NASH and NASH-associated fibrosis could be an effective therapeutic strategy to target both the inflammatory and metabolic components of such a complex disease. [ABSTRACT FROM AUTHOR]

Fatty acid binding proteins (FABPs) are small intracellular proteins that reversibly bind fatty acids and other hydrophobic ligands. In cestodes, due to their inability to synthesise fatty acids and cholesterol de novo, FABPs, together with other lipid binding proteins, have been proposed as essential, involved in the trafficking and delivery of such lipophilic metabolites. Pharmacological agents that modify specific parasite FABP function may provide control of lipid signalling pathways, inflammatory responses and metabolic regulation that could be of crucial importance for the parasite development and survival. Echinococcus multilocularis and Echinococcus granulosus are, respectively, the causative agents of alveolar and cystic echinococcosis (or hydatidosis). These diseases are included in the World Health Organization's list of priority neglected tropical diseases. Here, we explore the potential of FABPs from cestodes as drug targets. To this end, we have applied a target repurposing approach to identify novel inhibitors of Echinococcus spp. FABPs. An ensemble of computational models was developed and applied in a virtual screening campaign of DrugBank library. 21 hits belonging to the applicability domain of the ensemble models were identified, and 3 of the hits were assayed against purified E. multilocularis FABP, experimentally confirming the model's predictions. Noteworthy, this is to our best knowledge the first report on isolation and purification of such four FABP, for which initial structural and functional characterization is reported here. [ABSTRACT FROM AUTHOR]

Neuroinflammation can be defined as an inflammatory response within the central nervous system (CNS) mediated by a complex crosstalk between CNS-resident and infiltrating immune cells from the periphery. Triggers for neuroinflammation not only include pathogens, trauma and toxic metabolites, but also autoimmune diseases such as neuromyelitis optica spectrum disorders and multiple sclerosis (MS) where the inflammatory response is recognized as a disease-escalating factor. B cells are not considered as the first responders of neuroinflammation, yet they have recently gained focus as a key component involved in the disease pathogenesis of several neuroinflammatory disorders like MS. Traditionally, the prime focus of the role of B cells in any disease, including neuroinflammatory diseases, was their ability to produce antibodies. While that may indeed be an important contribution of B cells in mediating disease pathogenesis, several lines of recent evidence indicate that B cells are multifunctional players during an inflammatory response, including their ability to present antigens and produce an array of cytokines. Moreover, interaction between B cells and other cellular components of the immune system or nervous system can either promote or dampen neuroinflammation depending on the disease. Given that the interest in B cells in neuroinflammation is relatively new, the precise roles that they play in the pathophysiology and progression of different neuroinflammatory disorders have not yet been well-elucidated. Furthermore, the possibility that they might change their function during the course of neuroinflammation adds another level of complexity and the puzzle remains incomplete. Indeed, advancing our knowledge on the role of B cells in neuroinflammation would also allow us to tackle these disorders better. Here, we review the available literature to explore the relationship between autoimmune and infectious neuroinflammation with a focus on the involvement of B cells in MS and viral infections of the CNS. [ABSTRACT FROM AUTHOR]

Local injection of tumor necrosis factor-alpha (TNF-α) at bone fracture sites during the early stage of the inflammatory response is reported to improve fracture repair in a murine model. However, the underlying mechanism is unclear. Endochondral bone formation, a process that is highly related to fracture repair, requires a certain amount of chondrocyte hypertrophy. This study aimed to investigate the effect of TNF-α on the differentiation of murine chondrogenic ATDC5 cells and the underlying mechanism. In this study, improved chondrogenic differentiation of ATDC5 cells was achieved by brief TNF-α stimulation. Moreover, the expression of Yes-associated protein 1 (YAP1) was suppressed after brief TNF-α stimulation. The expressions of inflammatory mediators and chondrogenic and hypertrophic-associated genes in ATDC5 cells triggered by TNF-α were suppressed in the YAP1 overexpression group but enhanced in the YAP1 knockdown group. Mechanistically, TNF-α-induced activation of the 5ʹ AMP-activated protein kinase (AMPK) signaling pathway was regulated by YAP1, as revealed by the phosphorylated-AMPK/AMPK change ratios in the YAP1 overexpression and knockdown groups, respectively. Moreover, the potential for TNF-α to enhance chondrogenic differentiation could be partially reversed with an AMPK inhibitor. Taken together, we demonstrate, for the first time, that YAP1 modulates the ability of TNF-α to enhance chondrocyte differentiation partly through AMPK signaling. [ABSTRACT FROM AUTHOR]

Microglia play an essential role in maintaining central nervous system (CNS) homeostasis, as well as responding to injury and disease. Most neurological disorders feature microglial activation, a process whereby microglia undergo profound morphological and transcriptional changes aimed at containing CNS damage and promoting repair, but often resulting in overt inflammation that sustains and propagates the neurodegenerative process. This is especially evident in multiple sclerosis (MS), were microglial activation and microglia-driven neuroinflammation are considered key events in the onset, progression, and resolution of the disease. Our understanding of microglial functions in MS has widened exponentially in the last decade by way of new tools and markers to discriminate microglia from other myeloid populations. Consequently, the complex functional and phenotypical diversity of microglia can now be appreciated. This, in combination with a variety of animal models that mimic specific features and processes of MS, has contributed to filling the gap of knowledge in the cascade of events underlying MS pathophysiology. The purpose of this review is to present the most up to date knowledge of the dynamic responses of microglia in the commonly used animal models of MS, specifically the immune-mediated experimental autoimmune encephalomyelitis (EAE) model, and the chemically-induced cuprizone and lysolecithin models. Elucidating the spectrum of microglial functions in these models, from detrimental to protective, is essential to identify emerging targets for therapy and guide drug discovery efforts. [ABSTRACT FROM AUTHOR]

Background and Aim: Non‐alcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma. Currently, lifestyle modification is the only effective treatment. We have shown that human amnion epithelial cells (hAECs) reduce inflammation and fibrosis in toxin‐induced liver injury models. We examined the effect of these cells and the soluble factors released by the cells into culture medium (hAEC conditioned medium [hAEC‐CM]) in a diet‐induced murine NASH model. Methods: C57BL/6J male mice received a Western "fast food diet" for 42 weeks. Group 1 received an intraperitoneal injection of 2 × 106 hAECs at week 34, group 2 received an additional hAEC dose at week 38, and group 3 received thrice weekly hAEC‐CM injections intraperitoneal for 8 weeks from week 34. Liver fibrosis area, inflammation, and fibrosis regulators were measured by immunohistochemistry, qPCR, and gelatin zymography. Metabolic parameters were also assessed. Results: Fast food diet‐fed mice demonstrated peri‐cellular hepatic fibrosis, inflammation, and steatosis typical of NASH. Liver fibrosis area was reduced by 40% in hAEC‐treated and hAEC‐CM‐treated mice. hAEC treatment significantly reduced pSMAD 2/3 signaling and the number of activated hepatic stellate cells and liver macrophages. Matrix metalloproteinase 2 and 9 gene and protein expression were variably affected. hAEC treatment did not alter the NASH activity score or metabolic parameters such as bodyweight, total cholesterol, or glucose tolerance. Conclusion: Human amnion epithelial cell and hAEC‐CM significantly reduced hepatic inflammation and fibrosis in a diet‐induced non‐alcoholic fatty liver disease model. Although hAEC and hAEC‐CM did not affect the metabolic components of NASH, their therapeutic potential is promising and warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: The cholinergic anti-inflammatory pathway, positioned at the interface of the nervous and immune systems, is the efferent limb of the "inflammatory reflex" which mainly signals through the vagus nerve. As such, the brain can modulate peripheral inflammatory responses by the activation of vagal efferent fibers. Importantly, immune cells in the spleen express most cholinergic system components such as acetylcholine (ACh), choline acetyltransferase, acetylcholinesterase, and both muscarinic and nicotinic ACh receptors, making communication between both systems possible. In general, this communication down-regulates the inflammation, achieved through different mechanisms and depending on the cells involved. Summary: With the awareness that the cholinergic anti-inflammatory pathway serves to prevent or limit inflammation in peripheral organs, vagus nerve stimulation has become a promising strategy in the treatment of several inflammatory conditions. Both pharmacological and non-pharmacological methods have been used in many studies to limit organ injury as a consequence of inflammation. Key Messages: In this review, we will highlight our current knowledge of the cholinergic anti-inflammatory pathway, with emphasis on its potential clinical use in the treatment of inflammation-triggered kidney injury. [ABSTRACT FROM AUTHOR]

The appearance of mammalian-specific skin features was a key evolutionary event contributing for the elaboration of physiological processes such as thermoregulation, adequate hydration, locomotion, and inflammation. Skin inflammatory and autoimmune processes engage a population of skin-infiltrating T cells expressing a specific C-C chemokine receptor (CCR10) which interacts with an epidermal CC chemokine, the skin-specific C-C motif chemokine ligand 27 (CCL27). CCL27 is selectively produced in the skin by keratinocytes, particularly upon inflammation, mediating the adhesion and homing of skin-infiltrating T cells. Here, we examined the evolution and coding condition of Ccl27 in 112 placental mammalian species. Our findings reveal that a number of open reading frame inactivation events such as insertions, deletions, and start and stop codon mutations independently occurred in Cetacea, Pholidota, Sirenia, Chiroptera, and Rodentia, totalizing 18 species. The diverse habitat settings and lifestyles of Ccl27-eroded lineages probably implied distinct evolutionary triggers rendering this gene unessential. For example, in Cetacea, the rapid renewal of skin layers minimizes the need for an elaborate inflammatory mechanism, mirrored by the absence of epidermal scabs. Our findings suggest that the convergent and independent loss of Ccl27 in mammalian evolution concurred with unique adaptive roads for skin physiology. [ABSTRACT FROM AUTHOR]

Introduction: Uveitis is an eye disease characterized by inflammation of the uvea and an early and exhaustive diagnosis is essential for its treatment. The aim of our study is to assess the potential toxicity and anti-inflammatory efficacy of Bevacizumab in an experimental uveitis model by subcutaneously injecting lipopolysaccharide into Lewis rats and to clarify its mechanism. Material and Methods: Blood–aqueous barrier integrity was assessed 24 h after endotoxin-induced uveitis (EIU) by analyzing two parameters: cell count and protein concentration in aqueous humors. Histopathology of all eye structures was also studied. Enzyme-linked immunosorbent analyses of the aqueous humor samples were performed in order to calculate the diverse chemokine and cytokine protein levels and oxidative stress-related markers were also evaluated. Results: The aqueous humor’s cellular content significantly increased in the group treated with only Bevacizumab, but it had no effect on retina histopathological grading. Nevertheless, the inflammation noted in ocular structures when administering Bevacizumab with endotoxin was mostly prevented since aqueous humor cell content considerably lowered, and concomitantly with a sharp drop in uveal, vitreous, and retina histopathological grading. The values of the multi-faceted cytokine IL-2 also significantly decreased (p < 0.05 vs. endotoxin group), and the protective IL-6 and IL-10 cytokines values rose with related anti-oxidant system recovery (p < 0.05 vs. endotoxin group). Concurrently, some related M1 macrophage chemokines substantially increased, e.g., GRO/KC, a chemokine that also displays any kind of protective role. Conclusion: All these results revealed that 24 h after being administered, Bevacizumab treatment in EIU significantly prevented inflammation in various eye structures and correct results in efficacy vs. toxicity balance were obtained. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small noncoding RNAs that broadly affect cellular and physiological function in all multicellular organisms. Here, the role of miRNAs in neuroinflammation is considered. miRNAs are 21- to 23-oligonucleotide RNAs that regulate translation of specific RNAs by binding to complementary regulatory RNA sequences, thereby causing mRNA degradation or sequestration. More than 5000 miRNAs likely exist in humans, and each miRNA binds an average of 200 RNAs. Specific immunomodulatory miRNAs can regulate a set of RNAs in a coordinated manner, suggesting that effective miRNA-based therapeutic manipulations for neuroinflammatory conditions may be revealed. For instance, miRNAs that preferentially inhibit translation of many cellular anti-inflammatory proteins could drive a pro-inflammatory response. Key pro-inflammatory (miR-155, miR-27b, miR-326), anti-inflammatory (miR-124, miR-146a, miR-21, miR-223), and mixed immunomodulatory (let-7 family) miRNAs regulate neuroinflammation in various pathologies, including spinal cord injury, multiple sclerosis, ischemic stroke, and Alzheimer’s disease. miRNAs represent a newly revealed layer of physiological complexity, the therapeutic benefits of which remain to be fully explored and exploited. In this review, we discuss the role of miRNAs in neuroinflammatory regulation and discuss how controlling miRNAs could alter cellular machinery to improve neuroinflammatory dynamics. [ABSTRACT FROM AUTHOR]

Peripheral inflammatory processes are involved in Alzheimer's disease (AD). We aimed to determine whether plasma inflammatory mediator levels at diagnosis are associated with cognitive decline through a 2-year follow-up in AD patients. Patients (n = 109, mean age 79.44 (6.82) years) were included at diagnosis with MMSE scores between 16 and 25, with C-reactive protein <10 mg/L, and without any acute or chronic inflammation status. Plasma IL-1β, IL-6, TNF-α, and CCL5 were measured using Luminex X-MAP technology at baseline, and after one year and two years of follow-up. The mean values of IL-1β, IL-6, TNF-α, and CCL5 at diagnosis were 0.3, 1.94, 6.57, and 69,615.81 pg/mL, respectively. Mean cognitive decline in MMSE was 3.35 points. No correlation between plasmatic value of IL-1β, IL-6, TNF-α, or CCL5 at diagnosis and cognitive decline during the two years of follow-up was found. Cognitive decline in AD does not appear to be predictable by the tested inflammatory mediators. [ABSTRACT FROM AUTHOR]

Adenomyosis is a pathological gynaecological condition characterized by benign invasion of the endometrium into the myometrium. High intensity focused ultrasound (HIFU) is one of the most common therapeutic strategies for the treatment of adenomyosis. However, the efficacy of single HIFU therapy is insufficient for the treatment of patients with adenomyosis. In the present study, the efficacy of HIFU and metformin for the treatment of adenomyosis was analyzed in 274 patients with adenomyosis who were admitted to Jinan Maternity and Child Care Hospital. The results demonstrated that there was a significant reduction in menstrual flow and pain between patients who received HIFU and metformin, and those who received single HIFU treatment (P<0.01). Furthermore, the outcomes demonstrated that inflammatory cytokines levels were significantly lower compared with the baseline values (P<0.01). In conclusion, the outcomes of the current study indicate that combined HIFU and metformin treatment is more efficacious in patients with enlarged adenomyosis compared with single HIFU treatment. [ABSTRACT FROM AUTHOR]

Aims Spironolactone (SPL) improves endothelial dysfunction and survival in heart failure. Immune modulation, including poorly understood mineralocorticoid receptor (MR)-independent effects of SPL might contribute to these benefits and possibly be useful in other inflammatory cardiovascular diseases such as pulmonary arterial hypertension. Methods and results Using human embryonic kidney cells (HEK 293) expressing specific nuclear receptors, SPL suppressed NF-jB and AP-1 reporter activity independent of MR and other recognized nuclear receptor partners. NF-κB and AP-1 DNA binding were not affected by SPL and protein synthesis blockade did not interfere with SPL-induced suppression of inflammatory signalling. In contrast, proteasome blockade to inhibit degradation of xeroderma pigmentosum group B complementing protein (XPB), a subunit of the general transcription factor TFIIH, or XPB overexpression both prevented SPL-mediated suppression of inflammation. Similar to HEK 293 cells, a proteasome inhibitor blocked XPB loss and SPL suppression of AP-1 induced target genes in human pulmonary artery endothelial cells (PAECs). Unlike SPL, eplerenone (EPL) did not cause XPB degradation and failed to similarly suppress inflammatory signalling. SPL combined with siRNA XPB knockdown further reduced XPB protein levels and had the greatest effect on PAEC inflammatory gene transcription. Using chromatin-immunoprecipitation, PAEC target gene susceptibility to SPL was associated with low basal RNA polymerase II (RNAPII) occupancy and TNFa-induced RNAPII and XPB recruitment. XP patient-derived fibroblasts carrying an N-terminal but not C-terminal XPB mutations were insensitive to both SPL-mediated XPB degradation and TNFα-induced target gene suppression. Importantly, SPL treatment decreased whole lung XPB protein levels in a monocrotaline rat model of pulmonary hypertension and reduced inflammatory markers in an observational cohort of PAH patients. Conclusion SPL has important anti-inflammatory effects independent of aldosterone and MR, not shared with EPL. Druginduced, proteasome-dependent XPB degradation may be a useful therapeutic approach in cardiovascular diseases driven by inflammation. [ABSTRACT FROM AUTHOR]

The adipose tissue is a source of inflammatory proteins, such as TNF, IL-6, and CXCL8. Most of their production occurs in macrophages that act as scavengers of dying adipocytes. The application of an orbital mechanical force for 6-10 min at 97 g to the adipose tissue, lipoaspirated and treated according to Coleman procedures, abolishes the expression of TNF-α and stimulates the expression of the anti-inflammatory protein TNF-stimulated gene-6 (TSG-6). This protein had protective and anti-inflammatory effects when applied to animal models of rheumatic diseases. We examined biopsy, lipoaspirate, and mechanically activated fat and observed that in addition to the increased TSG-6, Sox2, Nanog, and Oct4 were also strongly augmented by mechanical activation, suggesting an effect on stromal cell stemness. Human adipose tissue-derived mesenchymal stem cells (hADSCs), produced from activated fat, grow and differentiate normally with proper cell surface markers and chromosomal integrity, but their anti-inflammatory action is far superior compared to those mesenchymal stem cells (MSCs) obtained from lipoaspirate. The expression and release of inflammatory cytokines from THP-1 cells was totally abolished in mechanically activated adipose tissue-derived hADSCs. In conclusion, we report that the orbital shaking of adipose tissue enhances its anti-inflammatory properties, and derived MSCs maintain such enhanced activity. [ABSTRACT FROM AUTHOR]

Inflammation is associated with every health condition, and is an important component of many pathologies such as cardiovascular diseases. Circulating levels of soluble endoglin have been shown to be higher in the serum of patients with cardiovascular diseases with a significant inflammatory component. The aim of this study was to evaluate the implication of circulating soluble endoglin in the inflammatory response. For this purpose, a transgenic mouse expressing human soluble endoglin (sEng+) was employed, and three different inflammatory approaches were used to mimic inflammatory conditions in different tissues. This study shows that control sEng+ mice have a normal inflammatory state. The lung and kidney injury induced by the inflammatory agents was reduced in sEng+ mice, especially the intra-alveolar and kidney infiltrates, suggesting a possible reduction in inflammation induced by soluble endoglin. To deepen into this possible effect, the leukocyte number in the bronchoalveolar lavage and air pouch lavage was evaluated and a significant reduction of neutrophil infiltration in LPS-treated lungs and ischemic kidneys from sEng+ with respect to WT mice was observed. Additionally, the mechanisms through which soluble endoglin prevents inflammation were studied. We found that in sEng+ animals the increment of proinflammatory cytokines, TNFα, IL1β and IL6, induced by the inflammatory stimulus was reduced. Soluble endoglin also prevents the augmented adhesion molecules, ICAM, VCAM and E-selectin induced by the inflammatory stimulus. In addition, vascular permeability increased by inflammatory agents was also reduced by soluble endoglin. These results suggest that soluble endoglin modulates inflammatory-related diseases and open new perspectives leading to the development of novel and targeted approaches for the prevention and treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is associated with local and systemic inflammation that induces many changes in the skeletal health. Locally, periarticular bone loss and juxta-articular bone erosions may occur while joint ankylosis, generalized bone loss, osteoporosis, and fractures may develop secondary to inflammation. The aim of this narrative review is to summarize the clinical evidence for abnormal skeletal health in RA, the effects of disease modifying anti-rheumatic drugs (DMARDS) on bone health, and the effects of drugs for the prevention or treatment of osteoporosis in the RA population. [ABSTRACT FROM AUTHOR]

Excessive neutrophil activation accompanied by delayed apoptotic cell death in inflammatory conditions causes progressive damage of cells and tissues, leading to life-threatening multiple organ dysfunction syndrome. Previous work suggested that circulating serum factors during inflammation are critically involved in the suppression of neutrophil cell death although the identity of these antiapoptotic mediators remained elusive. In this study, we identified the acute phase protein α-1 Antitrypsin (AAT) as a potent suppressor of staurosporine (STS)-induced apoptosis in human neutrophils through a mechanism implicating caspases-independent pathways. We show here that serum levels of AAT, potentially in part released by stimulated neutrophils, are markedly elevated in major trauma patients suffering from systemic inflammatory response syndrome (SIRS). Notably, AAT depletion from serum increased sensitivity of human neutrophils for STS-induced cell death. In fact, AAT was demonstrated to confer intrinsic apoptosis resistance by preventing PKC/Akt inactivation and subsequent proteasomal degradation of antiapoptotic Mcl-1 protein in response to STS treatment. Neither MAP kinase ERK1/2 nor caspases were found to be involved in AAT-triggered antiapoptotic pathways in neutrophils. In summary, these results establish a novel pivotal role of circulating AAT in mediating survival by antagonizing the proapoptotic action of the PKC inhibitor STS and should be considered for AAT augmentation therapies in future. [ABSTRACT FROM AUTHOR]

Ventilation of preterm neonates causes pulmonary inflammation that can contribute to lung injury, propagate systemically and result in long-term disease. Modulation of this initial response may reduce lung injury and its sequelae. We aimed to determine the effect of human amnion epithelial cells (hAECs) on immune activation and lung injury in preterm neonatal lambs. Preterm lambs received intratracheal hAECs (90x106) or vehicle, prior to 2 h of mechanical ventilation. Within 5 min of ventilation onset, lambs also received intravenous hAECs (90x106) or vehicle. Lung histology, bronchoalveolar lavage (BAL) cell phenotypes, and cytokine profiles were examined after 2 h of ventilation, and in unventilated controls. Histological indices of lung injury were higher than control, in vehicle-treated ventilated lambs but not in hAEC-treated ventilated lambs. Ventilation-induced pulmonary leukocyte recruitment was greater in hAEC-treated lambs than in vehicle-treated lambs. Lung IL-1β and IL-6 mRNA expression was higher in vehicle- and hAEC-treated ventilated lambs than in controls but IL-8 mRNA levels were greater than control only in vehicle-treated ventilated lambs. Numbers of CD44+ and CD21+ lymphocytes and macrophages from the lungs were altered in vehicle- and hAEC-treated ventilated lambs. Numbers of CD8+ macrophages were lower in hAEC-treated ventilated lambs than in vehicle-treated ventilated lambs. Indices of systemic inflammation were not different between vehicle- and hAEC-treated lambs. Human amnion epithelial cells modulate the pulmonary inflammatory response to ventilation in preterm lambs, and reduce acute lung injury. Immunomodulatory effects of hAECs reduce lung injury in preterm neonates and may protect against longer-term respiratory disease. [ABSTRACT FROM AUTHOR]

In the past two decades it has become clear that in addition to antigen presentation and antibody production B cells play prominent roles in immune regulation. While B cell-derived IL-10 has garnered much attention, B cells also effectively regulate inflammation by a variety of IL-10-independent mechanisms. B cell regulation has been studied in both autoimmune and inflammatory diseases. While collectively called regulatory B cells (Breg), no definitive phenotype has emerged for B cells with regulatory potential. This has made their study challenging and thus unique B cell regulatory mechanisms have emerged in a disease-dependent manner. Thus to harness the therapeutic potential of Breg, further studies are needed to understand how they emerge and are induced to evoke their regulatory activities. [ABSTRACT FROM AUTHOR]