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PubMed2026

Reframing the asthma microbiome: Multikingdom, multisite, and multiomic perspectives.

The field of asthma microbiome research has shifted rapidly in recent years. Advances in sequencing technology have led to an increased ability to characterize multikingdom microbial species and integration with host -omics profiling to enhance future translational applications. Traditional bacteria-centric, cross-sectional studies are giving way to mechanistic frameworks that incorporate fungi, viruses, and host-immune interactions. In this state-of-the-art review of emerging concepts in microbiome asthma research, we first propose a structured framework to consider microbiome studies across 5 major domains-microbial kingdom, site of sampling, integration with host -omics, clinical outcome domain, and translational relevance-in order to synthesize recent high-impact human microbiome studies in asthma. We highlight emerging evidence that fungal and viral communities contribute independently to asthma risk and that human microbial communities are linked to distinct inflammatory and immune pathways shaped by host genetic susceptibility.

Asthma↗
PubMed2026

Microglial modulation in general anesthesia: molecular.

General anesthetics profoundly alter brain function and consciousness, yet the mechanisms underlying these effects remain incompletely understood. Although traditional studies have primarily focused on neuronal targets, accumulating evidence suggests that microglia dynamically respond to anesthetic exposure and may participate in anesthesia-associated neurophysiological changes. Beyond their established immune functions, microglia are increasingly implicated in synaptic remodeling, metabolic regulation, neuronal activity surveillance, and neuron-glia communication. Recent studies indicate that different classes of anesthetic agents modulate microglial activity through diverse and context-dependent mechanisms involving inflammatory signaling, purinergic pathways, calcium dynamics, mitochondrial metabolism, and neural circuit interactions. These responses are associated with postoperative neurocognitive disorders, altered synaptic plasticity, and anesthesia-related changes in brain states. In this review, we summarize current evidence regarding the effects of volatile anesthetics, intravenous anesthetics, and analgesics on microglial function and discuss the molecular, functional, and circuit-level mechanisms underlying anesthesia-associated neuron-microglia interactions. We further highlight the dynamic and heterogeneous nature of microglial responses during anesthesia and discuss current limitations in the field, including the lack of temporally resolved and cell-specific approaches. Understanding these processes may provide insights into anesthesia-associated neurocognitive dysfunction and support the development of neuroimmune-targeted strategies in anesthesiology.

General anesthesia↗
PubMed2005

Fourth International Workshop on immunology of pre-eclampsia, December 2004, Reunion, France.

The Fourth International Workshop on 'Reproductive Immunology, Immunological Tolerance and Immunology of Pre-eclampsia' was held in the Island of La Reunion in December 2004. Besides intense sharing of immunological data, it included also epidemiological studies from South Africa, USA and Australia, as well as genetic studies from South Africa and Mauritius, discussions on the future of graft transplant tolerance, implications of inositol-phosphoglycans in the pathogenesis of pre-eclampsia (PE), pathways to the inflammatory syndrome and other topics. Participants shared the belief that we may be witnessing significant steps forward in our comprehension of PE as an immunological event, with a prominent role for deregulation of the innate immune system, probably controlled by T cells and cytokine networks at the feto-placental interface. There was a growing consensus for an NK cell (KIR)-dependent event, with regulation exerted by T cells, as well as an important role for HLA-C presentation/recognition and HLA-G in mediating inflammatory cytokine imbalance, with an emphasis on IL-12 and IL-16 It is hoped that the next Workshop in 2006 will prove the immune involvement by dissecting the NK/Treg/Ts cell and HLA-CI HLA-G circuits leading to cytokine and vascular dysfunction.

Female↗
PubMed2026

Human brown fat metabolism associates with systemic branched-chain amino acids homeostasis.

Circulating branched-chain amino acids (BCAAs) are linked with insulin resistance, but the human tissues contributing to systemic BCAA homeostasis remain incompletely defined. Brown adipose tissue (BAT) is a metabolically active adipose depot associated with favourable insulin sensitivity, yet its role in BCAA metabolism in humans remains unclear. We tested whether human BAT metabolism is associated with circulating BCAA levels, BAT-resident BCAA-catabolic signatures, and longitudinal changes in systemic BCAA homeostasis. We studied 83 adults who underwent metabolic phenotyping, PET-CT assessment of cold-stimulated BAT metabolism, and serum metabolomic profiling at room temperature and during acute mild cold exposure. Supraclavicular BAT biopsies from 25 participants were analysed by transcriptomics and metabolomics, and 40 participants were re-examined for circulating BCAA profiles after approximately five years. Participants with high BAT metabolism had lower circulating BCAA levels than those with low BAT metabolism. Within BAT, metabolically active individuals exhibited lower relative BCAA abundance together with higher expression of genes involved in BCAA catabolism. These BAT BCAA-catabolic signatures aligned with thermogenic capacity and indices of systemic insulin sensitivity. In contrast, individuals with low BAT metabolism showed increases in circulating BCAAs over five years. Integrative analyses further linked circulating lipopolysaccharide, a marker of metabolic endotoxemia, with higher BAT BCAA and aminomalonate abundance, together with transcriptional patterns involving inflammatory and mitochondrial pathways. Together, these findings identify human BAT metabolism as a tissue phenotype linked to systemic BCAA homeostasis and extend the role of human BAT beyond thermogenesis, suggesting that BAT-associated BCAA handling may contribute to systemic metabolic health.

Humans↗
PubMed2006

Differential gene expression in the rat cochlea after exposure to impulse noise.

Understanding the molecular biology of noise trauma is vital to developing effective and timely interventions. In a model of explosion-mediated impulse noise injury, differential gene expression was studied in whole rat cochlea preparations at 3 and 24 h following the exposure. We developed a technique using mRNA from a single cochlea on each oligonucleotide microarray to avoid pooling of mRNA samples. Application of a conservative statistical analysis approach resulted in the identification of 61 differentially expressed genes. Within 3 h after the exposure, there was an up-regulation of immediate early genes, mainly transcription factors and genes involved in the tissue's response to oxidative stress. No genes were found to be significantly down-regulated. At 24 h following the exposure, up-regulated genes included members of inflammatory and antioxidant pathways and one gene involved in glutathione metabolism was down-regulated. A subset of genes was confirmed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The present study demonstrates the power of the microarray technique in providing a global view of the gene regulation following noise exposure, and in identifying genes that may be mechanistically important in hearing loss, and thereby serve as a basis for the development of therapeutic interventions.

Acoustic Stimulation↗
PubMed2005

Roles of poly(ADP-ribose) polymerase activation in the pathogenesis of diabetes mellitus and its complications.

Activation of poly(ADP-ribose) polymerase (PARP) plays a role in the pathogenesis of beta-cell necrosis that occurs in response to autoimmune disease associated with Type I diabetes. In addition, PARP activation also plays a role in the pathogenesis of endothelial injury that underlies the ethiology of various diabetic complications (vasculopathy, cardiomyopathy, retinopathy, neuropathy), which develop on the basis of chronically elevated circulating glucose levels in diabetes. Both during the pathogenesis of diabetes and during the pathogenesis of diabetic complications, free radical and oxidant production leads to DNA strand-breakage which activates the nuclear enzyme PARP and initiates an energy consuming, inefficient cellular metabolic cycle with transfer of the ADP-ribosyl moiety of NAD+ to protein acceptors. These processes lead to the functional impairment of the affected cells (beta-cells or vascular endothelial cells, respectively). PARP also promotes the activation of various pro-inflammatory signal transduction pathways. During the last two decades, a growing number of experimental studies demonstrated the beneficial effects PARP inhibition in various models of diabetes and diabetic complications. The current review provides an overview of the experimental evidence implicating PARP as a causative factor in the pathogenesis of diabetes and diabetic complications in vitro and in vivo.

Animals↗
PubMed2004

MD-2: the Toll 'gatekeeper' in endotoxin signalling.

Lipopolysaccharide (LPS) from the outer cell wall of Gram-negative bacteria is a potent stimulator of the mammalian innate immune system. The Toll-like receptor 4 (TLR4) pathway triggers the inflammatory responses induced by LPS in a process that requires the interaction of LPS-bound myeloid differentiation-2 (MD-2) with TLR4. Here we propose two possible mechanisms for LPS recognition and signalling that take into account both the structural information available for TLR4 and MD-2, and the determinants of endotoxicity, namely, the acylation and phosphorylation patterns of LPS. In our first model, LPS induces the association of two TLR4-MD-2 heterodimers by binding to two different molecules of MD-2 through the acyl chains of lipid A. In our second model, the binding of LPS to a single TLR4-MD-2 complex facilitates the recruitment of a second TLR4-MD-2 heterodimer. These models contrast with the activation of Drosophila Toll, where the receptor is crosslinked by a dimeric protein ligand.

Animals↗
PubMed2005

Oedematogenic activity induced by Kunitz-type inhibitors from Dimorphandra mollis seeds.

Proteinase inhibitors from plants represent a form of storage protein or may be involved in plant defense mechanisms against pests and diseases. In this study, we have investigated the oedematogenic activity of DMTI (20 kDa) and DMTI-II (23 kDa), two serine proteinases inhibitors isolated from Dimorphandra mollis (Leguminosae-Mimosoideae) seeds, belonging to the Kunitz family. Paw oedema was induced in male Wistar rats, and measured before and selected times after injection of the proteinase inhibitors. Injection of DMTI-II (3-100 microg/paw) induced a dose-dependent rat paw oedema of rapid onset and short duration, whereas DMTI (3-100 microg/paw) caused a discrete response. The histamine/5-HT receptor antagonist cyproheptadine (2 mg/kg) markedly reduced the DMTI-II-induced oedema. The bradykinin B2 receptor antagonist JE 049 (0.6 mg/kg), the tachykinin NK1 receptor antagonist SR140333 (100 microg/kg) or the NK2 receptor antagonist SR48968 (1 mg/kg) all significantly reduced the DMTI-II-induced oedema. Depletion of sensory neuropeptides by capsaicin also resulted in a significant reduction of oedema formation. In rat isolated peritoneal mast cells, DMTI-II failed to directly release histamine. In conclusion, the proteinase inhibitor DMTI-II induces rat paw oedema by triggering the formation of different inflammatory mediators and pathways, where mast cells and sensory fibers seem to play a pivotal role.

Animals↗
PubMed2003

RAGE-mediated MAPK activation by food-derived AGE and non-AGE products.

Investigating the cellular effects of food compounds formed by heat treatment during processing, we recently demonstrated the expression of the receptor for advanced glycation endproducts (RAGE) and the p44/42 MAP kinase activation by casein-N(epsilon )-(carboxymethyl)lysine (casein-CML), a food-derived AGE, in the intestinal cell line Caco-2. In this work, we report a Caco-2 p44/42 MAP kinase activation by bread crust and coffee extract. After identification, quantification, and synthesis of two key compounds formed in association with the process-induced heat impact applied to bread dough and coffee beans, those compounds, namely the AGE pronyl-glycine and the non-AGE N-methylpyridinium, were also demonstrated for the first time to activate the p44/42 MAP kinase through binding to RAGE in Caco-2 cells. Blocking of RAGE by an antagonistic antibody and expression of C-terminally truncated RAGE resulted in a reduced Caco-2- and HEK-293-MAP kinase activation. These findings unequivocally point to a RAGE-mediated activating effect of chemically defined food-derived, thermally generated products, both, AGEs and non-AGEs, on cellular signal transduction pathways involved in inflammatory response and cellular proliferation.

Antibodies↗
PubMed2003

Histamine: A mediator of inflammation.

Histamine and its receptors, including the recently discovered receptors (H(3) and H(4)), novel sources of histamine, and the place of histamine in mediator networks continue to be areas of great interest. The 4 major subtypes of histamine receptors, H(1) to H(4), differ in their location, second messengers, and histamine-binding characteristics. In addition, it would appear that different histamine receptor agonists and antagonists bind to different portions of the receptor complex. A fifth receptor subtype, the intracellular H(IC), has only been defined by its location within cell types that are not traditionally associated with histamine. In airway tissue, most cells express at least 1 subtype of histamine receptor; however, blockade of these receptors does not completely abolish the inflammatory response. In addition, some H(1)-antihistamines might also exert anti-inflammatory effects by pathways independent of H(1)-receptor binding. Studies of selected second-generation H(1)-antihistamines have shown that these agents inhibit the release of certain cytokines from basophils, acting at a point downstream from the calcium signaling pathway. It has not yet been determined whether this action represents a class effect.

Anaphylaxis↗
PubMed1995

Bronchoprotective role for endogenous prostaglandin E2.

The possibility that impaired production of bronchoprotective factors contributes to the pathogenesis of asthma cannot be excluded. Prostaglandin E2 (PGE2) could be such a factor. It is a dominant cyclo-oxygenase product of airway epithelium and smooth muscle; it has inhibitory effects on inflammatory cells and pathways involved in bronchoconstriction at concentrations known to occur in the airway; inhalation of PGE2 has considerable bronchoprotective effects in patients with asthma; and manoeuvres that increase or decrease endogenous production of PGE2 have beneficial and deleterious effects on airway function.

Asthma↗
PubMedDate not supplied

Evolution of heat shock protein and immunity.

Heat shock proteins (hsps) are among the most abundant intracellular proteins. Their synthesis is rapidly up-regulated by various 'stressors' including temperature, glucose deprivation, infection and cancer. Certain hsps are able to: (i). associate and chaperone a large variety of cellular peptides; (ii). be efficiently internalized by antigen presenting cells (APC) through receptor-mediated endocytosis; (iii). channel antigenic peptides they chaperone in the APC's MHC class I presentation pathway; (iv). and stimulate inflammatory cytokines, chemokines and co-stimulatory molecules through the NFkappab signaling pathway. Extracellular release of hsps upon necrotic cell death and their modulated access at the surface of some cells, can be considered as a putative 'danger' signal. Based on the ancient origins and structural conservation of hsps, it has been proposed that, the role of hsps in immunity emerged early in evolution and to be widespread in extant organisms. Data from studies with the frog Xenopus support this proposition.

Animals↗
PubMed2001

Tyrosine phosphorylation of the linker for activator of T cells in mast cells by stimulation with the high affinity IgE receptor.

Aggregation of the high affinity IgE receptors (FcepsilonRI) on basophils and mast cells, members of the immune receptor family, initiates a cascade of events that results in the release of inflammatory mediators. This pathway involves the activation of several protein-tyrosine kinases, including Lyn, Syk, Btk, and Fak that induce the tyrosine phosphorylation of various proteins. The linker for activation of T cells (LAT), was originally found as a ZAP-70 tyrosine kinase substrate that linked T cell receptors to cellular activation, and was expressed in T cells, NK cells and mast cells. Here we show that LAT expressed in the RBL-2H3 rat mast cell line is tyrosine-phosphorylated after aggregation of FcepsilonRI. The tyrosine phosphorylation of the LAT was dramatically enhanced after receptor aggregation. Furthermore, a tyrosine-phosphorylated 80-kDa protein associated with LAT transiently after receptor aggregation. GST fusion proteins containing parts of PLCgamma or PI3 kinase can bind LAT. These results suggest that LAT plays an important role not only in T cell, but also in mast cell activation, and that the association among these signaling molecules is critical for FcepsilonRI-mediated intracellular signal transduction in mast cells.

Animals↗
PubMed2002

[Physiopathology and curative treatment of meningococcal diseases: current aspects].

Early administration of antibiotics as soon as the diagnosis of meningococcemia has been evoked is a significant therapeutic advance. However, the poor outcome of these diseases whose mortality remains high despite the current techniques of reanimation shows that improving the vaccination against meningococci is still of actuality. Diagnosing rapidly severe meningococcal disease is also a means for acting against the pathological activation of the inflammatory and coagulation pathways. Significant advances have been made in understanding the physiopathology of the meningococcal purpura fulminans especially about the deleterious role of the deficiency of the protein C and the antithrombin III. It is too soon to advance that the prognosis of these diseases has been improved by these new therapeutic approaches but the results of preliminary clinical studies are encouraging. However, informing parents about the first skin abnormalities seen in infants with purpura fulminans is essential in attempt to improve the efficiency of these new therapeutic strategies.

Anti-Bacterial Agents↗
PubMed2001

Serine proteinase inhibitors from nematodes and the arms race between host and pathogen.

Serine proteinase inhibitors are encoded by a large gene family of long evolutionary standing. Recent discoveries of parasite proteins that inhibit human serine proteinases, together with the complete genomic sequence from Caenorhabditis elegans, have provided a set of new serine proteinase inhibitors from more primitive metazoan animals such as nematodes. The structural features (e.g. reactive centre residues), gene organization (including intron arrangements) and inhibitory function and targets (e.g. inflammatory and coagulation pathway proteinase) all contribute important new insights into proteinase inhibitor evolution. Some parasite products have evolved that block enzymes in the mammalian host, but the human host responds with a significant immune response to the parasite inhibitors. Thus, infection produces a finely balanced conflict between host and pathogen at the molecular level, and this might have accelerated the evolution of these proteins in parasitic species as well as their hosts.

Amino Acid Sequence↗
PubMedDate not supplied

Proteolytically activated receptor-3. A member of an emerging gene family of protease receptors expressed on vascular endothelial cells and platelets.

Macromolecular assembly and generation of serine proteases on cellular surfaces is critically involved in regulation of hemostatic, inflammatory, or fibrinolytic pathways. The concept that a number of these serine proteases may effect cellular activation and proliferative responses has engendered an emerging paradigm focusing on the molecular mechanisms regulating cellular/protease interactions. Previous data suggest that some of these cellular responses are mediated by a novel class of G protein-coupled proteolytically activated receptors. Proteolytically activated receptor-3 (PAR-3) is the third member of this rapidly emerging gene family, all three of which (PAR-1, PAR-2, PAR-3) are known to co-cluster in the human genome, and are expressed on vascular endothelial cells, cells which critically regulate the hemostatic repertoire. This review will focus on the genetics of these receptors (emphasizing recent advances in the identification and characterization of PAR-3), review known structure/function similarities, and outline potential links in regulation of the hemostatic response by protease generation on the endothelial cell surface.

Animals↗
PubMed2006

Human glial cell culture models of inflammation in the central nervous system.

Research into human central nervous system (CNS) disorders has traditionally focused on interconnecting neurons, thought to be the most important functional elements in the CNS. Consequently, animal models have developed as the central paradigm in CNS drug development. However, evidence is accumulating that suggests glial cells play a much more important role in health and disease in the CNS than has been previously acknowledged. Brain development, neurotransmission, inflammatory and neuroprotective pathways and blood-brain barrier functions rely on glial cells. It is also the case that human glial cell cultures adequately mimic in vivo glial cell behaviour, providing a novel and valuable tool for CNS drug discovery and development.

Animals↗
PubMed2006

Effect of cyanidin-3-O-glucoside on UVB-induced response in human keratinocytes.

One of the most significant risk factors associated with the development of skin disease is exposure to UVB radiation from the sun. In particular, UVB light can activate inflammatory and apoptotic pathways, leading to skin damage. Anthocyanins, a group of flavonoids present in many common vegetable foods, are known for their chemopreventive activity. The aim of this study was to evaluate the efficacy of cyanidin-3-O-glucoside (C3G) on modulation of cellular responses following exposure to UVB doses in human keratinocytes (HaCaT). In our study, UVB-exposed cells showed significant increase of the translocation of transcription factors NF-kB and AP-1, overexpression of the proinflammatory cytokine IL-8, cleavage of procaspase-3 (a key step in apoptotic pathway), and DNA fragmentation. All these effects elicited by UVB exposure were clearly inhibited by pretreating HaCaT cells with C3G. In conclusion, our data demonstrate that C3G can protect skin cells against the adverse effects of UVB radiation and suggest that it might successfully be employed as a skin photoprotective agent.

Anthocyanins↗