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Extensive evidence supports the association between age‐related hearing loss (ARHL) and cognitive decline. It is, however, unknown whether a causal relationship exists between these two, or whether they both result from shared mechanisms. This paper intends to study this relationship through a comprehensive review of MRI findings as well as evidence of cellular alterations. Our review of structural MRI studies demonstrates that ARHL is independently linked to accelerated atrophy of total and regional brain volumes and reduced white matter integrity. Resting‐state and task‐based fMRI studies on ARHL also show changes in spontaneous neural activity and brain functional connectivity; and alterations in brain areas supporting auditory, language, cognitive, and affective processing independent of age, respectively. Although MRI findings support a causal relationship between ARHL and cognitive decline, the contribution of potential shared mechanisms should also be considered. In this regard, the review of cellular evidence indicates their role as possible common mechanisms underlying both age‐related changes in hearing and cognition. Considering existing evidence, no single hypothesis can explain the link between ARHL and cognitive decline, and the contribution of both causal (i.e., the sensory hypothesis) and shared (i.e., the common cause hypothesis) mechanisms is expected. [ABSTRACT FROM AUTHOR]

Studies with tissue plasminogen activator (t-PA) published in 1995 showed significant improvement in stroke outcome if the drug was administered within 3 hours from stroke onset. Several recent reports, however, show that less than 5% of stroke patients may be receiving t-PA in many parts of North America. This paper explores how this may be improved by examining some of the steps taken in Canada, where a recent audit showed that 8.2% of ischemic stroke patients received t-PA, and in those arriving within 2.5 hours to regional stroke centers in Ontario, 42.2% received t-PA. The paper also reviews the potential for t-PA to be given by more physicians, in remote regions using Telestroke, the possibility for using imaging characteristics rather than the onset of stroke as a determinant of eligibility for t-PA, the status of contraindications for thrombolysis, and the possibility of combining t-PA with immune modulation for improved stroke outcomes. [ABSTRACT FROM AUTHOR]

Biomarkers are biological characteristics that can be used to indicate health or disease. This paper reviews studies on biomarkers of low back pain (LBP) in human subjects. LBP is the leading cause of disability, caused by various spine-related disorders, including intervertebral disc degeneration, disc herniation, spinal stenosis, and facet arthritis. The focus of these studies is inflammatory mediators, because inflammation contributes to the pathogenesis of disc degeneration and associated pain mechanisms. Increasingly, studies suggest that the presence of inflammatory mediators can be measured systemically in the blood. These biomarkers may serve as novel tools for directing patient care. Currently, patient response to treatment is unpredictable with a significant rate of recurrence, and, while surgical treatments may provide anatomical correction and pain relief, they are invasive and costly. The review covers studies performed on populations with specific diagnoses and undefined origins of LBP. Since the natural history of LBP is progressive, the temporal nature of studies is categorized by duration of symptomology/disease. Related studies on changes in biomarkers with treatment are also reviewed. Ultimately, diagnostic biomarkers of LBP and spinal degeneration have the potential to shepherd an era of individualized spine medicine for personalized therapeutics in the treatment of LBP. [ABSTRACT FROM AUTHOR]

Mouse B-1 cells are not only major producers of steady-state natural antibodies but also rapid responders to infections and inflammation. These discrete functions may be the outcomes of distinct environmental or developmental triggers that drive B-1 cells toward IgM production or an effector cell fate. Alternatively, distinct B-1 cell subsets may exist, which differ in their functional plasticity. In this paper, we summarize existing data suggesting that B-1 cells form a heterogeneous group of cells with distinct developmental requirements and nonoverlapping functions. Most spleen B-1 cells differ in development from that of bone marrow and peritoneal cavity B-1 cells, in that they develop in the absence of natural IgM. Functional heterogeneity is revealed by findings that B-1 cells in the bone marrow and spleen, but not the peritoneal cavity, generate natural serum IgM, while the latter are rapid responders to inflammatory and infectious insults, resulting in their relocation to secondary lymphoid tissues. A clearer understanding of the developmental and functional differences within the B-1 cell pool may reveal how they might be harnessed for prophylaxis or therapy. [ABSTRACT FROM AUTHOR]

Glucocorticoids are widely used in rheumatoid arthritis (RA); however, their effectiveness and safety is still a subject of debate. In particular, when to introduce glucocorticoids, but also when and how to taper them, are important questions for clinicians. In this paper, we will discuss the place of glucocorticoids in the European League Against Rheumatism (EULAR) recommendations for the management of RA and review the literature that was the basis for these recommendations. The recommendations cover the introduction of glucocorticoids (and for whom they are recommended), doses and duration of treatment, and tapering strategies. Items still on the research agenda include more data on safety, particularly for long-term use, and small doses of glucocorticoids. [ABSTRACT FROM AUTHOR]

This paper presents commentaries on reflux-induced injury of human esophageal epithelium; inflammation in human reflux esophagitis; motor consequences of reflux-induced inflammation in esophageal epithelium; the microscopic morphology of esophageal squamous epithelium; intraluminal impedance in the evaluation of the esophageal mucosa; endoscopic tissue morphology of esophageal squamous epithelium; and the developmental biology of esophageal squamous epithelium. [ABSTRACT FROM AUTHOR]

This paper presents commentaries on whether eosinophilic esophagitis is a food allergy; inflammation in the context of eosinophilic esophagitis; whether eosinophilic esophagitis a cause of noncardiac chest pain; the role of endoscopy in the evaluation of eosinophilic esophagitis; and whether response to proton pump inhibitor therapy can distinguish eosinophilic esophagitis from gastroesophageal reflux disease. [ABSTRACT FROM AUTHOR]

This paper reviews the current understanding of the molecular basis of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-mediated pathway and discusses the role of PGC-1α in skeletal muscle atrophy caused by immobilization. PGC-1α is the master transcription regulator that stimulates mitochondrial biogenesis, by upregulating nuclear respiratory factors (NRF-1, 2) and mitochondrial transcription factor A (Tfam), which leads to increased mitochondrial DNA replication and gene transcription. PGC-1α also regulates cellular oxidant-antioxidant homeostasis by stimulating the gene expression of superoxide dismutase-2 (SOD2), catalase, glutathione peroxidase 1 (GPx1), and uncoupling protein (UCP). Recent reports from muscle-specific PGC-1α overexpression underline the importance of PGC-1α in atrophied skeletal muscle, demonstrate enhancement of the PGC-1α mitochondrial biogenic pathway, and reduced oxidative damage. Thus, PGC-1α appears to play a protective role against atrophy-linked skeletal muscle deterioration. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is associated with abnormal lipid metabolism, intense respiratory tract (RT) infection, and inflammation, eventually resulting in lung tissue destruction and respiratory failure. The CF RT inflammatory milieu, as reflected by airway secretions, includes a complex array of inflammatory mediators, bacterial products, and host secretions. It is dominated by neutrophils and their proteolytic and oxidative products and includes a wide spectrum of bioactive lipids produced by both host and presumably microbial metabolic pathways. The fairly recent advent of 'omics' technologies has greatly increased capabilities of further interrogating this easily obtainable RT compartment that represents the apical culture media of the underlying RT epithelial cells. This paper discusses issues related to the study of CF omics with a focus on the profiling of CF RT oxylipins. Challenges in their identification/quantitation in RT fluids, their pathways of origin, and their potential utility for understanding CF RT inflammatory and oxidative processes are highlighted. Finally, the utility of oxylipin metabolic profiling in directing optimal therapeutic approaches and determining the efficacy of various interventions is discussed. [ABSTRACT FROM AUTHOR]

The human endometrium is exposed to repeated inflammation every month, culminating in tissue breakdown and menstruation. Subsequently, the endometrium has a remarkable capacity for efficient repair and remodeling to enable implantation if fertilization takes place. Endometrial function is known to be governed by the ovarian hormones estradiol and progesterone. This review paper focuses on hormonal control of the cyclical tissue injury and repair that takes place in the local endometrial environment at the time of menstruation. Progesterone levels decline premenstrually as the corpus luteum regresses in the absence of pregnancy, and estradiol levels increase during the postmenstrual phase. The functional impact of these significant changes is discussed, including their immediate and downstream effects. Finally, we examine the contribution of aberrant endometrial function to the presentation of heavy menstrual bleeding and identify potential therapeutic targets for the treatment of this common gynecological problem. [ABSTRACT FROM AUTHOR]

Ambient air pollution has been linked to cardiovascular and respiratory morbidity and mortality in epidemiology studies. Frequently, oxidative and nitrosative stress are hypothesized to mediate these pollution effects, however precise mechanisms remain unclear. This paper describes the methodology for a major panel study to examine air pollution effects on these and other mechanistic pathways. The study took place during the drastic air pollution changes accompanying the 2008 Olympics in Beijing, China. After a general description of air pollution health effects, we provide a discussion of panel studies and describe the unique features of this study that make it likely to provide compelling results. This study should lead to a clearer and more precise definition of the role of oxidative and nitrosative stress, as well as other mechanisms, in determining acute morbidity and mortality from air pollution exposure. [ABSTRACT FROM AUTHOR]

Studies in various animal models of disease and repair with thymosin β4 (Tβ4), the major actin-sequestering molecule in mammalian cells, have provided the scientific foundation for the ongoing dermal, corneal, and cardiac wound repair multicenter clinical trials. Tβ4 has of multiple biological activities, which include down-regulation of inflammatory chemokines and cytokines, and promotion of cell migration, blood vessel formation, cell survival, and stem cell maturation. All of these activities contribute to the multiple wound healing properties that have been observed in animal studies. This paper reviews and discusses the topical and systemic uses of Tβ4 in various animal models that demonstrate its potential for clinical use. [ABSTRACT FROM AUTHOR]

The ability of B cells to negatively regulate cellular immune responses and inflammation has only recently been described. Hallmark papers from a number of distinguished laboratories have identified phenotypically diverse B-cell subsets with regulatory functions during distinct autoimmune diseases, including IL-10-producing B cells, CD5+ B-1a cells, CD1d+ marginal zone B cells, and transitional-2-marginal zone precursor B cells. Most recently, a numerically rare and phenotypically unique CD1dhiCD5+CD19hi subset of regulatory B cells has been identified in the spleens of both normal and autoimmune mice. CD1dhiCD5+ B cells with the capacity to produce IL-10 have been named B10 cells as they produce IL-10 exclusively and are the predominant B-cell source of IL-10. Remarkably, B10 cells are potent negative regulators of inflammation and autoimmunity in mouse models of disease in vivo. Herein, our current understanding of B10-cell development and function is reviewed in the context of previous studies that have identified and characterized regulatory B cells, emerging evidence for B10-cell regulation of tumor immunity, and the likelihood that B10 cells exist in humans. [ABSTRACT FROM AUTHOR]

Cytokine-based therapies have the potential to provide novel treatments for cancer, autoimmune diseases, and many types of infectious disease. However, to date, the full clinical potential of cytokines as drugs has been limited by a number of factors. To discuss these limitations and explore ways to overcome them, the FDA partnered with the New York Academy of Sciences in March 2009 to host a two-day forum to discuss more effective ways to harness the clinical potential of cytokines and cytokine antagonists as therapeutic agents. The first day was focused primarily on the use of recombinant cytokines as therapeutic agents for treatment of human diseases. The second day focused largely on the use of cytokine antagonists as therapeutic agents for treatment of human diseases. This issue of the Annals includes more than a dozen papers that summarize much of the information that was presented during this very informative two-day conference. [ABSTRACT FROM AUTHOR]

Inflammation, particularly low-grade chronic inflammation, appears to affect several brain functions, from early brain development to the development of neurodegenerative disorders and perhaps some psychiatric diseases. On the other hand, nutrition and dietary components and patterns have a plethora of anti- and pro-inflammatory effects that could be linked to cognitive function. Even a modest effect of nutrition on cognitive decline could have significant implications for public health. This paper summarizes the available evidence regarding inflammation as a key mechanism in cognitive function and nutritional pro- or anti-inflammatory effects with the purpose of linking the apparent disparate disciplines of nutrition, immunity, and neurology. [ABSTRACT FROM AUTHOR]

Dysregulated systemic inflammation with excess activation of proinflammatory transcription factor nuclear factor-κB (NF-κB)—activated by inflammatory signals—compared to the anti-inflammatory transcription factor glucocorticoid receptor-α (GRα)—activated by endogenous or exogenous glucocorticoids (GCs)—is an important pathogenetic mechanism for pulmonary and extrapulmonary organ dysfunction in patients with acute respiratory distress syndrome (ARDS). Activation of one transcription factor in excess of the binding (inhibitory) capacity of the other shifts cellular responses toward increased (dysregulated) or decreased (regulated) transcription of inflammatory mediators over time. Recent data indicate that failure to improve in ARDS (unresolving ARDS) is frequently associated with failure of the activated GRs to downregulate the transcription of inflammatory cytokines despite elevated levels of circulating cortisol, a condition defined as systemic inflammationassociated acquired GC resistance; it is potentially reversible with prolonged GC supplementation. In the first part of this paper, after a brief description of inflammation in ARDS and our model of translational research, we review the two cellular signaling pathways that are central to the regulation of inflammation—the stimulatory NF-κB and the inhibitory GR. In the second part, we review findings of recent studies indicating that excessive inflammatory activity in patients with unresolving ARDS may induce noncompensated GC resistance in target organs. In the third part, we review factors affecting cellular response to GC and potential mechanisms involved in inflammation-associated GC resistance. [ABSTRACT FROM AUTHOR]

Cardiac arrest has many implications for morbidity and mortality. Few interventions have been shown to improve return of spontaneous circulation (ROSC) and long‐term outcomes after cardiac arrest. Ischemic‐reperfusion injury upon achieving ROSC creates an imbalance between oxygen supply and demand. Multiple events occur in the postcardiac arrest period, including excitotoxicity, mitochondrial dysfunction, and oxidative stress and inflammation, all of which contribute to ongoing brain injury and cellular death. Given that complex pathophysiology underlies global brain hypoxic ischemia, neuroprotective strategies targeting multiple stages of the neuropathologic cascade should be considered as a means of mitigating secondary neuronal injury and improving neurologic outcomes and survival in cardiac arrest victims. In this review article, we discuss a number of different pharmacologic agents that may have a potential role in targeting these injurious pathways following cardiac arrest. Pharmacologic therapies most relevant for discussion currently include memantine, perampanel, magnesium, propofol, thiamine, methylene blue, vitamin C, vitamin E, coenzyme Q10, minocycline, steroids, and aspirin. [ABSTRACT FROM AUTHOR]

Thymosin β4 (Tβ4) has been found to have several biological activities related to antiscarring and reduced fibrosis. For example, the anti-inflammatory properties of Tβ4 and its splice variant have been shown in the eye and skin. Moreover, Tβ4 treatment prevents profibrotic gene expression in cardiac and in hepatic cells in vitro and in vivo. In a recent study on scleroderma patients it was hypothesized that Tβ4 may exert a protective effect during human lung injury. In an ongoing study, we have explored the putative Tβ4 protective role in the lung context by utilizing a well-known in vivo model. We have observed significant protective effects of Tβ4 on bleomycin-induced lung damage, the main outcomes being the halting of the inflammatory process and a substantial reduction of histological evidence of lung injury. [ABSTRACT FROM AUTHOR]

Macrophage‐mediated regulation of chondrocytes plays an important role in promoting temporomandibular joint (TMJ) inflammation. We investigated whether extracellular vesicles (EVs) derived from M1 macrophages (M1‐EVs) have a proinflammatory effect on TMJ inflammation and what the associated mechanisms are. In vitro, purified THP‐1 cell–derived M1‐EVs were applied to human TMJ condylar chondrocytes, and in vivo M1‐EVs derived from bone marrow–derived macrophages (BMDMs) were injected into rat TMJs. The levels of IL‐6, IL‐8, IL‐1β, and matrix metalloproteinase were then evaluated and found to be upregulated in the chondrocytes and rat TMJs. MicroRNA sequencing analysis was performed to identify differential expression of miRNAs, including miR‐1246. High expression of miR‐1246 in M1‐EVs from synovial fluid of patients with TMJ osteoarthritis and synovitis was verified by RT‐PCR. We then identified miR‐1246 targets GSK3β and Axin2 and found that miR‐1246 inhibits GSK3β and Axin2 expression, causing activation of the Wnt/β‐catenin pathway and inflammation in condylar chondrocytes. Our study found that M1‐EVs promote inflammation by transfer of miR‐1246 to condylar chondrocytes, thus providing new insight into one mechanism that can promote TMJ inflammation. [ABSTRACT FROM AUTHOR]

Many studies have shown that vitamin D (VD) deficiency may be a risk factor for neurodevelopmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, although causative mechanisms remain unknown. In this study, we investigated the potential role and effect of VD on maternal diabetes induced autism‐related phenotypes. The in vitro study found that enhancing genomic VD signaling by overexpressing the VD receptor (VDR) in human neural progenitor cells ACS‐5003 protects against hyperglycemia‐induced oxidative stress and inflammation by activating Nrf2 and its target genes, including SOD2 and HMOX1, and accordingly, VDR gene knockdown worsens the problem. In the two in vivo models we explored, maternal diabetes was used to establish an animal model of relevance to ASD, and mice lacking 25‐hydroxyvitamin D 1‐alpha‐hydroxylase (the rate‐limiting enzyme in the synthesis of 1,25(OH)2D3) were used to develop a model of VD deficiency (VDD). We show that although prenatal VDD itself does not produce ASD‐relevant phenotypes, it significantly potentiates maternal diabetes induced epigenetic modifications and autism‐related phenotypes. Postnatal manipulation of VD has no effect on maternal diabetes induced autism‐related phenotypes. We conclude that VDD potentiates maternal diabetes induced autism‐related phenotypes in offspring by epigenetic mechanisms. This study adds to other preclinical studies linking prenatal VDD with a neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

Since its discovery, Helicobacter pylori (H. pylori) has attracted attention in the biomedical world with its numerous pathophysiologic implications, both gastrointestinal and systemic. Beyond its well‐established carcinogenic properties, emerging evidence also supports "harmful" proinflammatory and neurodegenerative roles of H. pylori. On the other hand, H. pylori infection has been proposed to be "protective" against several diseases, such as asthma and gastroesophageal reflux disease. Eosinophilic esophagitis (EoE) is a relatively new, allergen/immune–mediated disease, which has also been linked to these considerations. Main arguments are a postulated shift of immune responses by H. pylori from T helper 2 (TH2) to TH1 polarization, as well as a potential decline of the H. pylori burden with the dramatic parallel rise of ΕοΕ: a series of observational studies reported an inverse association. In this review, we counter these arguments by providing further epidemiological data, which point out that this generalization might be rather incomplete. We also discuss the limitations of the existing studies evaluating a possible association. Furthermore, we provide current evidence on common pathogenetic components, which share both entities. In summary, the claim that H. pylori is protective against EoE is rather incomplete, and further mechanistic studies are necessary to elucidate a possible association. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide gas (H2S) is a chemical weapon and a common environmental pollutant. H2S intoxication is lethal to humans and animals. H2S contact to the eye can cause vision loss. However, the molecular mechanisms associated with H2S toxicity to the cornea remain unclear, and no specific therapy exists to mitigate ocular damage from H2S. Here, we report H2S‐induced cytotoxicity and the parameters contributing to the molecular mechanisms associated with corneal toxicity using primary human corneal stromal fibroblasts (hCSFs) in vitro. Sodium hydrosulfide (NaSH) was used as a source of H2S, and the cytotoxicity of H2S was determined by treating hCSF cells with varying concentrations of NaSH (0–10 mM) for 0–72 hours. Changes in cell proliferation, oxidative stress factors, and the expression of inflammatory and fibrotic genes were studied using standard commercial kits and qRT‐PCR. NaSH exposure to hCSFs showed dose‐ and time‐dependent cytotoxicity. The IC50 of NaSH was determined to be 5.35 mM. NaSH 5.35 mM exposure led to significantly decreased cytochrome c oxidase activity, increased ROS production, and increased expression of inflammatory and fibrotic genes in hCSF cells. H2S/NaSH exposure alters normal mitochondrial function, oxidative stress, and inflammatory and fibrotic gene responses in corneal stromal fibroblasts in vitro. [ABSTRACT FROM AUTHOR]

Organophosphate (OP) nerve agents are a threat to both the military and civilians. OP exposure causes cholinergic crisis and status epilepticus (SE) because of irreversible inhibition of acetylcholinesterase that can be life‐threatening if left untreated. OP survivors develop long‐term morbidity, such as cognitive impairment and motor dysfunction, because of oxidative stress and progressive neuroinflammation and neurodegeneration, which act as disease promoters. Current medical countermeasures (MCMs) do not mitigate these pathologies. Therefore, our goal was to target these disease promoters using diapocynin (DPO), an NADPH oxidase inhibitor, in addition to MCMs, in a rat diisopropylfluorophosphate (DFP) model. The DFP‐intoxicated rats were treated with DPO (300 mg/kg, oral, six doses, 12‐h intervals) or vehicle 2 h following behavioral SE termination with diazepam. The DPO treatment significantly rescued DFP‐induced motor impairment and attenuated epileptiform spiking during the first 72 h after DFP exposure in severely seizing rats despite no difference in epileptiform spike rate between the vehicle and DPO groups in mild SE rats. DPO significantly reduced DFP‐induced reactive astrogliosis, neurodegeneration, GP91phox, glutathiolated protein, serum nitrite, and proinflammatory cytokines and chemokines, such as interleukins (ILs) IL‐1α, IL‐6, IL‐2, IL‐17A, leptin, and IP‐10, in the hippocampus. Collectively, these data support a neuroprotective role of DPO in an OP‐induced neurotoxicity model. [ABSTRACT FROM AUTHOR]

Coordination between the nervous and innate immune systems to maintain bone homeostasis is largely uncharacterized. The present study investigated the sensory–immune interaction in resting alveolar bone and healing socket by surgical sensory denervation. Bone histomorphometry and immunohistochemistry showed that sensory denervation resulted in moderate suppression of bone remodeling, with a proinflammatory milieu manifested by increased neutrophil recruitment and possible alternations in macrophage phenotypes along the resting bone surface. This denervation effect intensified when bone remodeling was triggered by tooth extraction, as revealed by disrupted temporospatial variations in macrophage subpopulations and neutrophil infiltration, which were closely associated with a dramatic decline in socket bone filling and residual ridge height. Antagonism of calcitonin gene‐related peptide (CGRP) brought about similar antianabolic and proinflammatory effects as sensory denervation, suggesting that sensory nerves may monitor the bony milieu by CGRP. Depletion of macrophages, rather than neutrophils, ruled out CGRP effects, illustrating that macrophages were the primary immune mechanism that linked sensory innervation, innate immunity, and bone. The data support that sensory innervation is required for control of innate immune responses and maintenance of bone homeostasis. Sensory neuropeptides, such as CGRP, are a possible target for the development of proanabolic treatments in bone disease by modulating innate immune responses. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) pathogenesis is mediated largely through the actions of proteolytic enzymes such as matrix metalloproteinase (MMP) 13. The transcriptional regulator CITED2, which suppresses the expression of MMP13 in chondrocytes, is induced by interleukin (IL)‐4 in T cells and macrophages, and by moderate mechanical loading in chondrocytes. We tested the hypothesis that CITED2 mediates cross‐talk between IL‐4 signaling and mechanical loading‐induced pathways that result in chondroprotection, at least in part, by downregulating MMP13. IL‐4 induced CITED2 gene expression in human chondrocytes in a dose‐ and time‐dependent manner through JAK/STAT signaling. Mechanical loading combined with IL‐4 resulted in additive effects on inducing CITED2 expression and downregulating of MMP13 in human chondrocytes in vitro. In vivo, IL‐4 gene knockout (KO) mice exhibited reduced basal levels of CITED2 expression in chondrocytes. While moderate treadmill running induced CITED2 expression and reduced MMP13 expression in wild‐type mice, these effects were blunted (for CITED2) or abolished (for MMP13) in chondrocytes of IL‐4 gene KO mice. Moreover, intra‐articular injections of mouse recombinant IL‐4 combined with regular cage activity mitigated post‐traumatic OA to a greater degree compared to immobilized mice treated with IL‐4 alone. These data suggest that using moderate loading to enhance IL‐4 may be a potential therapeutic strategy for chondroprotection in OA. [ABSTRACT FROM AUTHOR]

Sepsis occurs when a systemic infection induces an uncontrolled inflammatory response that results in generalized organ dysfunction. The exacerbated peripheral inflammation can induce, in turn, neuroinflammation which may result in severe impairment of the central nervous system (CNS). Indeed, the ensuing blood–brain barrier disruption associated with sepsis promotes glial activation and starts a storm of proinflammatory cytokines in the CNS that leads to brain dysfunction in sepsis survivors. Endotoxic shock induced in mice by peripheral injection of lipopolysaccharides closely resembles the peripheral and central inflammation observed in sepsis. In this review, we provide an overview of the neuroinflammatory features in sepsis and of recent progress toward the development of new anti‐neuroinflammatory therapies seeking to reduce mortality and morbidity in sepsis survivors. Sepsis occurs when a systemic infection induces an uncontrolled inflammatory response that results in generalized organ dysfunction. The exacerbated peripheral inflammation can induce, in turn, neuroinflammation, which may result in severe impairment of the central nervous system. In this review, we provide an overview of the neuroinflammatory features in sepsis and of recent progress toward the developing of new anti‐neuroinflammatory therapies seeking to reduce mortality and morbidity in sepsis survivors. [ABSTRACT FROM AUTHOR]

Cancer is the second leading cause of death worldwide and has become a global burden. It has long been known that inflammation is related to cancer, as inflammatory components have been identified in the tumor microenvironment and support tumor progression. Among the key inflammatory mediators, leukotrienes were found to be involved in cancer development. In particular, leukotriene B4, which is converted from leukotriene A4 by leukotriene A4 hydrolase (LTA4H), has been implicated in several types of cancer. In addition, LTA4H has attracted attention because of purported roles in inflammation and cancer development. Herein, we review the history of LTA4H, its emerging roles in cancer development, and the development of LTA4H inhibitors in cancer prevention and therapy. It has long been known that inflammation is related to cancer. Among the key inflammatory mediators, leukotrienes were found to be involved in cancer development. In particular, leukotriene B4, which is converted from leukotriene A4 by leukotriene A4 hydrolase (LTA4H), has been implicated in several types of cancer. We review some of the history of LTA4H, its emerging roles in cancer development, development of LTA4H inhibitors in cancer prevention, and therapy. [ABSTRACT FROM AUTHOR]

Abstract: Although at first glance inflammation and social behavior may appear unrelated, research points to an important role for inflammation in shaping social processes. This review summarizes findings in this field, specifically highlighting work that provides support for the idea that inflammation can lead to (1) increases in sensitivity to negative, threatening social experiences and (2) increases in sensitivity to positive, socially rewarding experiences. These diverging sensitivities in response to inflammation may depend on context and be adaptive for recuperation and recovery from illness. This review also discusses the implications of these findings for health and future research, including implications for depression, loneliness, and inflammatory disorders. [ABSTRACT FROM AUTHOR]

Social welfare, better health care, and urbanization have greatly improved human health and well-being. On the other hand, Western societies suffer from the downsides of the elevated standard of living. Among other factors, the Western diet (poor in dietary fiber), lack of contact with natural biodiversity, and excessive antibiotic use are known to be associated with the increase in chronic inflammatory disorders. Limited exposure to microbial biodiversity, in combination with severe lifestyle-related disturbances to commensal microbial communities, especially during early life, is changing the diversity and composition of human microbiota. In this review, we try to promote and apply ecological theory to understand the dynamics and diversity of human commensal microbiota. In this context, we explore the changes in the microbiota that are relevant to human health, especially in light of the rise of chronic inflammatory disorders. We try to elucidate the underlying ecological mechanisms behind these disorders and provide potential solutions for their avoidance. [ABSTRACT FROM AUTHOR]

The molecular pathology of sulfur mustard injury is complex, with at least nine inflammation-related enzymes and receptors upregulated in the zone of the insult. A new approach wherein inhibitors of these targets have been linked by hydrolyzable bonds, either one to one or via separate preattachment to a carrier molecule, has been shown to significantly enhance the therapeutic response compared with the individual agents. This article reviews the published work of the authors in this drug development domain over the last 8 years. [ABSTRACT FROM AUTHOR]

Mindfulness meditation represents a mental training framework for cultivating the state of mindful awareness in daily life. Recently, there has been a surge of interest in how mindfulness meditation improves human health and well-being. Although studies have shown that mindfulness meditation can improve self-reported measures of disease symptomatology, the effect that mindfulness meditation has on biological mechanisms underlying human aging and disease is less clear. To address this issue, we conducted the first comprehensive review of randomized controlled trials examining the effects of mindfulness meditation on immune system parameters, with a specific focus on five outcomes: (1) circulating and stimulated inflammatory proteins, (2) cellular transcription factors and gene expression, (3) immune cell count, (4) immune cell aging, and (5) antibody response. This analysis revealed substantial heterogeneity across studies with respect to patient population, study design, and assay procedures. The findings suggest possible effects of mindfulness meditation on specific markers of inflammation, cell-mediated immunity, and biological aging, but these results are tentative and require further replication. On the basis of this analysis, we describe the limitations of existing work and suggest possible avenues for future research. Mindfulness meditation may be salutogenic for immune system dynamics, but additional work is needed to examine these effects. [ABSTRACT FROM AUTHOR]

This review presents recent evidence implicating microRNAs (miRNAs) in the beneficial effects of resveratrol (trihydroxystilbene), a nonflavonoid plant polyphenol, with emphasis on its anti-inflammatory effects. Many diseases and pathologies have been linked, directly or indirectly, to inflammation. These include infections, injuries, atherosclerosis, diabetes mellitus, obesity, cancer, osteoarthritis, age-related macular degeneration, demyelination, and neurodegenerative diseases. Resveratrol can both decrease the secretion of proinflammatory cytokines (e.g., IL-6, IL-8, and TNF-α) and increase the production of anti-inflammatory cytokines; it also decreases the expression of adhesion proteins (e.g., ICAM-1) and leukocyte chemoattractants (e.g., MCP-1). Resveratrol's primary targets appear to be the transcription factors AP-1 and NF-κB, as well as the gene COX2. Although no mechanistic link between any particular miRNA and resveratrol has been identified, resveratrol effects depend at least in part upon the modification of the expression of a variety of miRNAs that can be anti-inflammatory (e.g., miR-663), proinflammatory (e.g., miR-155), tumor suppressing (e.g., miR-663), or oncogenic (e.g., miR-21). [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase, which plays pivotal roles in integrating growth signals on a cellular level. To support proliferation and survival under stress, two interacting complexes that harbor mTOR, mTORC1 and mTORC2, promote the transcription of genes involved in carbohydrate metabolism and lipogenesis, enhance protein translation, and inhibit autophagy. Although rapamycin was originally developed as an inhibitor of T cell proliferation for preventing organ transplant rejection, its molecular target, mTOR, has been subsequently identified as a central regulator of metabolic cues that drive lineage specification in the immune system. Owing to oxidative stress, the activation of mTORC1 has emerged as a central pathway for the pathogenesis of systemic lupus erythematosus and other autoimmune diseases. Paradoxically, mTORC1 has also been identified as a mediator of the Warburg effect that allows cell survival under hypoxia. Rapamycin and new classes of mTOR inhibitors are being developed to block not only transplant rejection and autoimmunity but also to treat obesity and various forms of cancer. Through preventing these diseases, personalized mTOR blockade holds promise to extend life span. [ABSTRACT FROM AUTHOR]

Exposure to combustion-related particulate matter (PM), at concentrations experienced by populations throughout the world, contributes to pulmonary and cardiac disease through multiple mechanistic pathways that are complex and interdependent. Current evidence supports an interactive chain of events linking pollution-induced pulmonary and systemic oxidative stress, inflammatory events, and translocation of particle constituents with an associated risk of vascular dysfunction, atherosclerosis, altered cardiac autonomic function, and ischemic cardiovascular and obstructive pulmonary diseases. Because oxidative stress is believed to play such an instrumental role in these pathways, the capacity of particulate pollution to cause damaging oxidative reactions (the oxidative potential) has been used as an effective exposure metric, identifying toxic components and sources within diverse ambient PM mixes that vast populations are subjected to-from traffic emissions on busy roads in urban areas to biomass smoke that fills homes in rural areas of the developing world. [ABSTRACT FROM AUTHOR]

Inflammation is a central feature of stable chronic obstructive pulmonary disease (COPD) and involves both activation of structural cells of the airways and the lungs and the activation and/or recruitment of infiltrating inflammatory cells. This results in enhanced expression of many pro-inflammatory proteins and reduced expression of some anti-inflammatory mediators. An altered protein expression is generally associated with concomitant changes in gene expression profiles in a cell-specific manner. Increased understanding of the role of transcription factors and of the signaling pathways leading to their activation in stable COPD will provide new targets to enable the development of potential anti-inflammatory drugs. Several new compounds targeting these pathways and/or transcription factors are now in development for the treatment of stable COPD. Furthermore, glucocorticoids drugs already in clinical use act through their own transcription factor, the glucocorticoid receptor, to control the expression of inflammatory and anti-inflammatory genes. [ABSTRACT FROM AUTHOR]

Neutrophils, the most abundant circulating cells in humans, are major pathogen-killing immune cells. For many years, these cells were considered to be simple killers at the 'bottom' of immune responses. However, recent studies have revealed more sophisticated mechanisms associated with neutrophilic cytotoxic functions, and neutrophils have been shown to contribute to various infectious and inflammatory diseases. In this review, we discuss the key features of neutrophils during inflammatory responses, from their release from the bone marrow to their death in inflammatory loci. We also discuss the expanding roles of neutrophils that have been identified in the context of several inflammatory diseases. We further focus on the mechanisms that regulate neutrophil recruitment to inflamed tissues and neutrophil cytotoxic activities against both pathogens and host tissues. [ABSTRACT FROM AUTHOR]

Endogenous glucocorticoids are implicated in the development and resolution of inflammation. Until recently it was thought that these glucocorticoids arose primarily from the adrenal gland. However, it is now known that several cell types can generate active glucocorticoids within their cytoplasm through expression of the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. In a more limited range of cell types, glucocorticoids can be inactivated by the related 11β-HSD2 enzyme. Both enzymes are regulated by inflammation in various settings. In rheumatoid arthritis, 11β-HSD activity is present in the inflamed synovium and appears to influence articular and extraarticular disease processes. The generation of active glucocorticoids in the synovium is strongly linked to the level of inflammation. This local production of glucocorticoids is likely to have paracrine consequences and could underpin inflammation-associated bone loss. The role of 11β-HSD enzymes in the severity and persistence of inflammatory arthritis in a clinical setting is currently being explored. [ABSTRACT FROM AUTHOR]

The SH-2 containing inositol 5′-polyphosphatase 1 (SHIP1) is a multifunctional protein expressed predominantly, but not exclusively, by hematopoietic cells. SHIP1 removes the 5′-phosphate from the product of PI3K, PI(3,4,5)P3, to generate PI(3,4)P2. Both PIP species influence the activity level of Akt and ultimately regulate cell survival and differentiation. SHIP1 also harbors several protein interaction domains that endow it with many nonenzymatic cell signaling or receptor masking functions. In this review, we discuss the opposing roles of SHIP1 in cancer and in mucosal inflammation. On one hand, germline loss of SHIP1 causes myeloid lung consolidation and severe inflammation in the ileum, a phenotype that closely mimics human Crohn's disease and can be rescued by reconstitution with SHIP1-competent T cells. On the other, transient inhibition of the enzymatic activity of SHIP1 in cancer cells leads to apoptosis and enhances survival in lethal murine xenograft models. Overall, careful dissection of the different pathological mechanisms involved in several diseases provides novel opportunities for therapeutic intervention targeting SHIP1. [ABSTRACT FROM AUTHOR]

Immunological hypotheses have become increasingly prominent when studying the etiology of schizophrenia. Autoimmune diseases, and especially the number of infections requiring hospitalization, have been identified as significant risk factors for schizophrenia in a dose-response relationship, which seem compatible with an immunological hypothesis for subgroups of patients with schizophrenia. Inflammation and infections may affect the brain through many different pathways that are not necessarily mutually exclusive and can possibly increase the risk of schizophrenia in vulnerable individuals. However, the findings could also be an epiphenomenon and not causal, due to, for instance, common genetic vulnerability, which could be supported by the observations of an increased prevalence of autoimmune diseases and infections in parents of patients with schizophrenia. Nevertheless, autoimmune diseases and infections should be considered in the treatment of individuals with schizophrenia symptoms, and further research is needed of the immune system's possible contributing pathogenic factors in the etiology of schizophrenia. [ABSTRACT FROM AUTHOR]

Chronic low-grade inflammation, in particular increased concentrations of proinflammatory cytokines such as interleukin (IL)-6 in the circulation, is observed with increasing age, but it is also as a consequence of various medical and psychological conditions, as well as life-style choices. Since molecules such as IL-6 have pleiotropic effects, consequences are wide ranging. This short review summarizes the evidence showing how IL-6 elevations in the context of inflammatory disease affect the organism, with a focus on sleep-related symptoms and fatigue; and conversely, how alterations in sleep duration and quality stimulate increased concentrations of IL-6 in the circulation. Research showing that acute as well as chronic psychological stress also increase concentrations of IL-6 supports the notion of a close link between an organism's response to physiological and psychological perturbations. The findings summarized here further underscore the particular importance of IL-6 as a messenger molecule that connects peripheral regulatory processes with the CNS. [ABSTRACT FROM AUTHOR]

Acrolein (2-propenal) is a highly reactive α,β-unsaturated aldehyde and a respiratory irritant that is ubiquitously present in the environment but that can also be generated endogenously at sites of inflammation. Acrolein is abundant in tobacco smoke, which is the major environmental risk factor for chronic obstructive pulmonary disease (COPD), and elevated levels of acrolein are found in the lung fluids of COPD patients. Its high electrophilicity makes acrolein notorious for its facile reaction with biological nucleophiles, leading to the modification of proteins and DNA and depletion of antioxidant defenses. As a consequence, acrolein results in oxidative stress as well as altered intracellular signaling and gene transcription/translation. In pulmonary cells, acrolein, at subtoxic concentrations, can activate intracellular stress kinases, alter the production of inflammatory mediators and proteases, modify innate immune response, induce mucus hypersecretion, and damage airway epithelium. A better comprehension of the mechanisms underlying acrolein effects in the airways may suggest novel treatment strategies in COPD. [ABSTRACT FROM AUTHOR]

Glycobiology has contributed tremendously to the discovery and characterization of cancer-related biomarkers containing glycans (i.e., glyco-biomarkers) and a more detailed understanding of cancer biology. It is now recognized that most chronic diseases involve some elements of chronic inflammation; these include cancer, Alzheimer's disease, and metabolic syndrome (including consequential diabetes mellitus and cardiovascular diseases). By extending the knowledge and experience of the glycobiology community regarding cancer biomarker discovery, we should be able to contribute to the discovery of diagnostic/prognostic glyco-biomarkers of other chronic diseases that involve chronic inflammation. Future integration of large-scale 'omics'-type data (e.g., genomics, epigenomics, transcriptomics, proteomics, and glycomics) with computational model building, or a systems glycobiology approach, will facilitate such efforts. [ABSTRACT FROM AUTHOR]

The receptor for advanced glycation endproducts (RAGE) was first described as a signal transduction receptor for advanced glycation endproducts (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids that accumulate in diabetes and in inflammatory foci. The discovery that RAGE was a receptor for inflammatory S100/calgranulins and high mobility group box 1 (HMGB1) set the stage for linking RAGE to both the consequences and causes of types 1 and 2 diabetes. Recent discoveries regarding the structure of RAGE as well as novel intracellular binding partner interactions advance our understanding of the mechanisms by which RAGE evokes pathological consequences and underscore strategies by which antagonism of RAGE in the clinic may be realized. Finally, recent data tracking RAGE in the clinic suggest that levels of soluble RAGEs and polymorphisms in the gene encoding RAGE may hold promise for the identification of patients who are vulnerable to the complications of diabetes and/or are receptive to therapeutic interventions designed to prevent and reverse the damage inflicted by chronic hyperglycemia, irrespective of its etiology. [ABSTRACT FROM AUTHOR]

The history of the tetracyclines involves the collective contributions of thousands of dedicated researchers, scientists, clinicians, and business executives over the course of more than 60 years. Discovered as natural products from actinomycetes soil bacteria, the tetracyclines were first reported in the scientific literature in 1948. They were noted for their broad spectrum antibacterial activity and were commercialized with clinical success beginning in the late 1940s to the early 1950s. The second-generation semisynthetic analogs and more recent third-generation compounds show the continued evolution of the tetracycline scaffold toward derivatives with increased potency as well as efficacy against tetracycline-resistant bacteria, with improved pharmacokinetic and chemical properties. Their biologic activity against a wide spectrum of microbial pathogens and their uses in mammalian models of inflammation, neurodegeneration, and other biological systems indicate that the tetracyclines will continue to be successful therapeutics in infectious diseases and as potential therapeutics against inflammation-based mammalian cell diseases. [ABSTRACT FROM AUTHOR]

The following includes commentaries on clinical features and imaging of Barrett's esophagus (BE); the clinical factors that influence the development of BE; the influence of body fat distribution and central obesity; the role of adipocytokines and proinflammatory markers in carcinogenesis; the role of body mass index (BMI) in healing of Barrett's epithelium; the role of surgery in prevention of carcinogenesis in BE; the importance of double-contrast esophagography and cross-sectional images of the esophagus; and the value of positron emission tomography/computed tomography. [ABSTRACT FROM AUTHOR]

[18F]Fluorodeoxyglucose positron emission tomography (FDG PET) can be used to visualize large-vessel inflammation in giant-cell arteritis, Takayasu arteritis, and other types of aortitis. In patients with symptoms compatible with polymyalgia rheumatica, findings of increased FDG-uptake in the shoulders, hips, as well as the spinous processes of the cervical and lumbar spine, may suggest this diagnosis. In patients with giant-cell arteritis, there is increased metabolic activity within the aortic wall on FDG PET scintigraphy, indicating inflammation of the aorta, whichmay be a predictor of a higher potential for aortic dilatation. [ABSTRACT FROM AUTHOR]

Blood concentrations of hydrogen sulfide (H2S) are markedly elevated in several animal models of inflammation. Pharmacological inhibition of H2S synthesis reduces inflammation and swelling, suggesting that H2S is a potential inflammatory mediator. However, it is currently unknown whether H2S synthesis is perturbed in human inflammatory conditions or whether H2S is present in synovial fluid. We analyzed paired plasma and synovial fluid (SF) aspirates from rheumatoid arthritis (RA; n= 20) and osteoarthritis (OA; n= 4) patients and plasma from age matched healthy volunteers ( n= 20). Median plasma H2S concentrations from healthy volunteers and RA and OA patients were 37.6, 36.6, and 37.6 μM, respectively. In RA patients, median synovial fluid H2S levels (62.4 μM) were significantly higher than paired plasma ( P= 0.002) and significantly higher than in synovial fluid from OA patients (25.1 μM; P= 0.009). SF H2S levels correlated with clinical indices of disease activity (tender joint count, r= 0.651; P < 0.05) and markers of chronic inflammation; Europhile count ( r=−0.566; P < 0.01) and total white cell count ( r=−0.703; P < 0.01). Our study shows for the first time that H2S is present in synovial fluid and levels correlated with inflammatory and clinical indices in RA patients. [ABSTRACT FROM AUTHOR]

The neuroendocrine theory of aging identified a cluster of conditions (hypertension, obesity, dyslipidemia, diabetes type 2, menopause, late onset depression, vascular cognitive impairment, impairment of immune defense, and some forms of cancer, e.g., breast and prostate) as age-associated neuroendocrine disorders (AAND). Obesity, dyslipidemia, hypertension, and type 2 diabetes were later described as metabolic syndromes (MetS). Chronic inflammation is currently considered as a common feature of MetS/AAND. One of the mechanisms by which chronic inflammation might trigger and/or maintain the development of MetS/AAND is transcriptional induction of indoleamine 2,3-dioxygenase (IDO), rate-limiting enzyme of tryptophan (TRY)–kynurenine (KYN) pathway, by pro-inflammatory cytokines (PIC). Activation of IDO shifts TRY metabolism from serotonin synthesis to formation of “kynurenines.” Diminished serotonin production is associated with mental depression while increased formation of kynurenines might contribute to development of MetS/AAND via their apoptotic, neurotoxic, and pro-oxidative effects, and upregulation of inducible nitric oxide synthase, phospholipase A2, arachidonic acid, prostaglandin, 5-lipoxygenase, and leukotriene cascade. The combined presence of high producers of alleles of polymorphic PIC genes (e.g., interferon-gamma and tumor necrosis factor alpha) might account for the genetic predisposition to high levels of PIC production, leading to “superinduction” of IDO. The other rate-limiting enzyme of the TRY–KYN pathway, TRY 2,3-dioxygenase, is activated by substrate (TRY) and cortisol. Therefore, KYN–TRY metabolism might be the meeting point for gene-environment interaction and a new target for prevention and treatment of MetS/AAND. [ABSTRACT FROM AUTHOR]

Galectins, β-galactoside-binding animal lectins, are differentially expressed by various immune cells as well as a wide range of other cell types. Extracellularly, galectins are able to exhibit bivalent or multivalent interactions with cell-surface glycans on various immune cells and exert various effects. These include cytokine and mediator production, cell adhesion, apoptosis, and chemoattraction. In addition, they can form lattices with cell-surface glycoprotein receptors, resulting in modulation of receptor functions, including clustering and endocytosis. Intracellularly, galectins can participate in signaling pathways and modulate biologic responses. These include apoptosis, cell differentiation, and cell migration. Thus, a large body of literature indicates that galectins play important roles in the immune and inflammatory responses through regulating the homeostasis and functions of immune cells. The use of mice deficient in individual galectins has provided additional evidence for the contributions of these proteins to these responses. Current research indicates that galectins play important roles in the development of acute inflammation as well as chronic inflammation associated with allergies, autoimmune diseases, atherosclerosis, infectious processes, and cancer. Thus, recombinant proteins or specific galectin inhibitors may be used as therapeutic agents for inflammatory diseases. [ABSTRACT FROM AUTHOR]