Biochemistry, Genetics and Molecular Biology › Molecular Biology

S100 Proteins and Annexins

Works Count: 39930

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Description

This cluster of papers focuses on the structure, function, and pathology of S100 proteins, a multigenic family of calcium-modulated proteins with roles in inflammation, neurodegeneration, cancer biomarkers, traumatic brain injury, innate immunity, glial fibrillary acidic protein, metastasis, and phagocytes.

Keywords

S100 Proteins; Inflammation; Calcium Modulated Proteins; Neurodegeneration; Cancer Biomarkers; Traumatic Brain Injury; Innate Immunity; Glial Fibrillary Acidic Protein; Metastasis; Phagocytes

Galactocerebroside is a specific cell-surface antigenic marker for oligodendrocytes in culture

1978-08-01

Martin Raff , Rhona Mirsky , Kay L. Fields +6 more

IL-22 Inhibits Epidermal Differentiation and Induces Proinflammatory Gene Expression and Migration of Human Keratinocytes

2005-03-15

Katia Boniface , François‐Xavier Bernard , Martine Garcia +3 more

IL-22 belongs to a family of cytokines structurally related to IL-10, including IL-19, IL-20, IL-24, and IL-26. In contrast to IL-10, IL-22 has proinflammatory activities. IL-22 signals through a class … IL-22 belongs to a family of cytokines structurally related to IL-10, including IL-19, IL-20, IL-24, and IL-26. In contrast to IL-10, IL-22 has proinflammatory activities. IL-22 signals through a class II cytokine receptor composed of an IL-22-binding chain, IL-22RA1, and the IL-10RB subunit, which is shared with the IL-10R. In the present study, we show that short-term cultured human epidermal keratinocytes express a functional IL-22R but no IL-10R. Accordingly, IL-22 but not IL-10 induces STAT3 activation in keratinocytes. Using a cDNA array screening approach, real-time RT-PCR, and Western blot analysis, we demonstrate that IL-22 up-regulates, in a dose-dependent manner, the expression of S100A7, S100A8, S100A9, a group of proinflammatory molecules belonging to the S100 family of calcium-binding proteins, as well as the matrix metalloproteinase 3, the platelet-derived growth factor A, and the CXCL5 chemokine. In addition, IL-22 induces keratinocyte migration in an in vitro injury model and down-regulates the expression of at least seven genes associated with keratinocyte differentiation. Finally, we show that IL-22 strongly induces hyperplasia of reconstituted human epidermis. Taken together, these results suggest that IL-22 plays an important role in skin inflammatory processes and wound healing.

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Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase

1993-05-01

Lars Kjeldsen , Anni Johnsen , Henrik Sengeløv +1 more

A 25-kDa protein was found to be associated with purified human neutrophil gelatinase. Polyclonal antibodies raised against gelatinase not only recognized gelatinase but also this 25-kDa protein. Specific antibodies against … A 25-kDa protein was found to be associated with purified human neutrophil gelatinase. Polyclonal antibodies raised against gelatinase not only recognized gelatinase but also this 25-kDa protein. Specific antibodies against the 25-kDa protein were obtained by affinity purification of the gelatinase antibodies. Immunoblotting and immunoprecipitation studies demonstrated the 135-kDa form of gelatinase to be a complex of 92-kDa gelatinase and the 25-kDa protein, and the 220-kDa form was demonstrated to be a homodimer of the 92-kDa protein, thus explaining the 220-, 135-, and 92-kDa forms characteristic of neutrophil gelatinase. The 25-kDa protein was purified to apparent homogeneity from exocytosed material from phorbol myristate acetate-stimulated neutrophils. The primary structure of the 25-kDa protein was determined as a 178-residue protein. It was susceptible to treatment with N-glycanase, and one N-glycosylation site was identified. The sequence did not match any known human protein, but showed a high degree of similarity with the deduced sequences of rat alpha 2-microglobulin-related protein and the mouse protein 24p3. It is thus a new member of the lipocalin family. The function of the 25-kDa protein, named neutrophil gelatinase-associated lipocalin (NGAL), remains to be determined.

S100 proteins structure functions and pathology

2002-01-01

Claus W. Heizmann

S100 proteins regulate intracellular processes such as cell growth and motility, cell cycle regulation, transcription and differentiation. Twenty members have been identified so far, and altogether, S100 proteins represent the … S100 proteins regulate intracellular processes such as cell growth and motility, cell cycle regulation, transcription and differentiation. Twenty members have been identified so far, and altogether, S100 proteins represent the largest subgroup in the EF-hand Ca2+ -binding protein family. A unique feature of these proteins is that individual members are localized in specific cellular compartments from which some are able to relocate upon Ca2+ activation, transducing the Ca2+ signal in a temporal and spacial manner by interacting with different targets specific for each S100 protein. Some members are even secreted from cells exerting extracellular, cytokine-like activities partially via the surface receptor RAGE (receptor for advanced glycation endproducts) with paracrine effects e.g. on neurons, promoting their survival during development or after injury. Another important aspect is that 14 bona fide S100 genes are found in a gene cluster on human chromosome 1q21 where a number of chromosomal abnormalities occur. This results in a deregulated expression of some S100 genes associated with neoplasias. Recently, S100 proteins have received increasing attention due to their close association with several human diseases including cardiomyopathy, neurodegenerative disorders and cancer. They have also been proven to be valuable in the diagnostic of these diseases, as predictive markers of improving clinical management, outcome and survival of patients and are considered having a potential as drug targets to improve therapies.

Annexins: From Structure to Function

2002-04-01

Volker Gerke , Stephen E. Moss

Annexins are Ca 2+ and phospholipid binding proteins forming an evolutionary conserved multigene family with members of the family being expressed throughout animal and plant kingdoms. Structurally, annexins are characterized … Annexins are Ca 2+ and phospholipid binding proteins forming an evolutionary conserved multigene family with members of the family being expressed throughout animal and plant kingdoms. Structurally, annexins are characterized by a highly α-helical and tightly packed protein core domain considered to represent a Ca 2+ -regulated membrane binding module. Many of the annexin cores have been crystallized, and their molecular structures reveal interesting features that include the architecture of the annexin-type Ca 2+ binding sites and a central hydrophilic pore proposed to function as a Ca 2+ channel. In addition to the conserved core, all annexins contain a second principal domain. This domain, which NH 2 -terminally precedes the core, is unique for a given member of the family and most likely specifies individual annexin properties in vivo. Cellular and animal knock-out models as well as dominant-negative mutants have recently been established for a number of annexins, and the effects of such manipulations are strikingly different for different members of the family. At least for some annexins, it appears that they participate in the regulation of membrane organization and membrane traffic and the regulation of ion (Ca 2+ ) currents across membranes or Ca 2+ concentrations within cells. Although annexins lack signal sequences for secretion, some members of the family have also been identified extracellularly where they can act as receptors for serum proteases on the endothelium as well as inhibitors of neutrophil migration and blood coagulation. Finally, deregulations in annexin expression and activity have been correlated with human diseases, e.g., in acute promyelocytic leukemia and the antiphospholipid antibody syndrome, and the term annexinopathies has been coined.

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Proinflammatory Activities of S100: Proteins S100A8, S100A9, and S100A8/A9 Induce Neutrophil Chemotaxis and Adhesion

2003-03-15

Carle Ryckman , Karen Vandal , Pascal Rouleau +2 more

Abstract S100A8 and S100A9 are small calcium-binding proteins that are highly expressed in neutrophil and monocyte cytosol and are found at high levels in the extracellular milieu during inflammatory conditions. … Abstract S100A8 and S100A9 are small calcium-binding proteins that are highly expressed in neutrophil and monocyte cytosol and are found at high levels in the extracellular milieu during inflammatory conditions. Although reports have proposed a proinflammatory role for these proteins, their extracellular activity remains controversial. In this study, we report that S100A8, S100A9, and S100A8/A9 caused neutrophil chemotaxis at concentrations of 10−12–10−9 M. S100A8, S100A9, and S100A8/A9 stimulated shedding of L-selectin, up-regulated and activated Mac-1, and induced neutrophil adhesion to fibrinogen in vitro. Neutralization with Ab showed that this adhesion was mediated by Mac-1. Neutrophil adhesion was also associated with an increase in intracellular calcium levels. However, neutrophil activation by S100A8, S100A9, and S100A8/A9 did not induce actin polymerization. Finally, injection of S100A8, S100A9, or S100A8/A9 into a murine air pouch model led to rapid, transient accumulation of neutrophils confirming their activities in vivo. These studies 1) show that S100A8, S100A9, and S100A8/A9 are potent stimulators of neutrophils and 2) strongly suggest that these proteins are involved in neutrophil migration to inflammatory sites.

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S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature)

2004-08-27

Ingo Marenholz , Claus W. Heizmann , G. Fritz

A Novel Geneiba1in the Major Histocompatibility Complex Class III Region Encoding an EF Hand Protein Expressed in a Monocytic Lineage

1996-07-01

Yoshinori Imai , Iwao Ibata , Daisuke Ito +2 more

Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines.

1987-12-01

Teizo Yoshimura , Koji Matsushima , Shuji Tanaka +4 more

Stimulated human monocytes release several proteins thought to play a role in inflammation, including interleukin 1, tumor necrosis factor, and plasminogen activator. We have purified another proinflammatory protein that is … Stimulated human monocytes release several proteins thought to play a role in inflammation, including interleukin 1, tumor necrosis factor, and plasminogen activator. We have purified another proinflammatory protein that is chemotactic for human neutrophils from conditioned medium of lipopolysaccharide-stimulated monocytes. After a series of steps that included anion-exchange chromatography, gel filtration, and HPLC on cation-exchange and reverse-phase columns, an apparently pure protein was obtained that migrated as a single 7-kDa band on NaDodSO4/polyacrylamide gels under reducing or nonreducing conditions. The amino acid composition of this monocyte-derived neutrophil chemotactic factor was different from that of interleukin 1 and tumor necrosis factor. N-terminal amino acid sequence of the first 42 residues was determined. This portion of the molecule has up to 56% sequence similarity with several proteins that may be involved in host responses to infection or tissue injury. It is identical to a portion of a sequence deduced from an mRNA induced by staphylococcal enterotoxin treatment of human leukocytes. At the optimal concentration of 10 nM, 50% of neutrophils added to chemotaxis assay wells migrated toward the pure attractant. Potency and efficacy are comparable to that of fMet-Leu-Phe, which is often used as a reference. In contrast to many attractants, the protein was not chemotactic for human monocytes.

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Inhibition of interleukin 1β converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage

1997-03-04

Hideaki Hara , Robert M. Friedlander , Valeria Gagliardini +6 more

The interleukin 1β converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases. During reperfusion after filamentous middle cerebral … The interleukin 1β converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases. During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immunoreactive interleukin 1β (IL-1β) levels increased in ischemic mouse brain. Ischemic injury decreased after intracerebroventricular injections of ICE-like protease inhibitors, N -benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chloromethylketone, or a relatively selective inhibitor of CPP32-like caspases, N -benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N -benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FMK decreased ICE-like cleavage products and tissue immunoreactive IL-1β levels in ischemic mouse brain and reduced tissue damage when administered to rats as well. Only z-VAD.FMK and acetyl-Tyr-Val-Ala-Asp-chloromethylketone reduced brain swelling, and N -benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced increase in tissue IL-1β levels. The three cysteine protease inhibitors significantly improved behavioral deficits, thereby showing that functional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death. Finally, we examined the effect of z-VAD.FMK on excitotoxicity and found that it protected against α-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N -methyl- d -aspartate-induced excitotoxic brain damage. Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage.

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The glucose oxidase-DAB-nickel method in peroxidase histochemistry of the nervous system

1988-02-01

Siyun Shu , Gong Ju , Lingzhi Fan

The Neutrophil-Activating Protein (NAP-1) Is Also Chemotactic for T Lymphocytes

1989-03-17

Christian Grønhøj , Arthur O. Anderson , Ettore Appella +2 more

T lymphocyte chemotactic factor (TCF) was purified to homogeneity from the conditioned media of phytohemagglutinin-stimulated human blood mononuclear leukocytes by a sequence of chromatography procedures. The amino-terminal amino acid sequence … T lymphocyte chemotactic factor (TCF) was purified to homogeneity from the conditioned media of phytohemagglutinin-stimulated human blood mononuclear leukocytes by a sequence of chromatography procedures. The amino-terminal amino acid sequence of the purified TCF showed identity with neutrophil-activating protein (NAP-1). Both TCF and recombinant NAP-1 (rNAP-1) were chemotactic for neutrophils and T lymphocytes in vitro supporting the identity of TCF with NAP-1. Injection of rNAP-1 into lymphatic drainage areas of lymph nodes in Fisher rats caused accelerated emigration of only lymphocytes in high endothelial venules. Intradermal injection of rNAP-1 caused dose-dependent accumulation of neutrophils and lymphocytes.

Differentiated Rat Glial Cell Strain in Tissue Culture

1968-07-26

Philippe Benda , J. Lightbody , Gordon Sato +2 more

Rat glial tumors, induced by injections of N -nitrosomethylurea, were plated and propagated in culture. Among a few cell strains obtained, one clone contains S-100 protein, which is unique to … Rat glial tumors, induced by injections of N -nitrosomethylurea, were plated and propagated in culture. Among a few cell strains obtained, one clone contains S-100 protein, which is unique to brain in vertebrates. Stationary-phase cultures contain approximately ten times more S-100 protein per cell than exponentially growing cells. When injected into newborn rats, cells producing S-100 grew as a glial tumor, which contained S-100 protein.

S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles

2001-07-01

Rosario Donato

Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts.

1985-12-01

Jean‐Michel Dayer , Bruce Beutler , Anthony Cerami

Cachectin/TNF (tumor necrosis factor), an endotoxin-induced murine macrophage hormone implicated in the pathogenesis of cachexia and shock, has been found capable of stimulating collagenase and prostaglandin E2 (PGE2) production by … Cachectin/TNF (tumor necrosis factor), an endotoxin-induced murine macrophage hormone implicated in the pathogenesis of cachexia and shock, has been found capable of stimulating collagenase and prostaglandin E2 (PGE2) production by isolated human synovial cells and dermal fibroblasts. This bioactivity associated with cachectin is comparable to that observed with the monokine interleukin 1 (IL-1), previously suggested as the major mediator of proteolysis. The ability of cachectin/TNF to stimulate collagenase and PGE2 production suggests that it may play a role in tissue destruction and remodelling, as these processes occur in inflammatory diseases.

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S100 proteins in cancer

2015-01-23

Anne R. Bresnick , David J. Weber , Danna B. Zimmer

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Calmodulin Plays a Pivotal Role in Cellular Regulation

1980-01-04

Wai Yiu Cheung

The role of calcium ions (Ca2+) in cell function is beginning to be unraveled at the molecular level as a result of recent research on calcium-binding proteins and particularly on … The role of calcium ions (Ca2+) in cell function is beginning to be unraveled at the molecular level as a result of recent research on calcium-binding proteins and particularly on calmodulin. These proteins interact reversibly with Ca2+ to form a protein . Ca2+ complex, whose activity is regulated by the cellular flux of Ca2+. Many of the effects of Ca2+ appear to be exerted through calmodulin-regulated enzymes.

Expression cloning of the TGF-β type II receptor, a functional transmembrane serine/threonine kinase

1992-02-01

Herbert Y. Lin , Xiao‐Fan Wang , Elinor Ng-Eaton +2 more

Multifunctional α-enolase: its role in diseases

2001-06-01

Vijay Pancholi

S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules

2006-08-30

Dirk Foell , Helmut Wittkowski , Thomas Vogl +1 more

Abstract Damage-associated molecular pattern (DAMP) molecules have been introduced as important proinflammatory factors of innate immunity. One example known for many years to be expressed in cells of myeloid origin … Abstract Damage-associated molecular pattern (DAMP) molecules have been introduced as important proinflammatory factors of innate immunity. One example known for many years to be expressed in cells of myeloid origin are phagocytic S100 proteins, which mediate inflammatory responses and recruit inflammatory cells to sites of tissue damage. An emerging concept of pattern recognition involves the multiligand receptor foradvanced glycation end products (RAGE) and Toll-like receptors (TLRs) in sensing not only pathogen-associated molecular patterns (PAMPs) but also endogenous DAMPs, including S100 proteins. S100A8, S100A9, and S100A12 are found at high concentrations in inflamed tissue, where neutrophils and monocytes belong to the most abundant cell types. They exhibit proinflammatory effects in vitro at concentrations found at sites of inflammation in vivo. Although S100A12 binds to RAGE, at least part of the proinflammatory effects of the S100A8/S100A9 complex depend upon interaction with other receptors. Because of the divergent expression patterns, the absence of S100A12 in rodents, the different interaction partners described, and the specific intracellular and extracellular effects reported for these proteins, it is important to differentiate between distinct S100 proteins rather than subsuming them with the term “S100/calgranulins.” Analyzing the molecular basis of the specific effects exhibited by these proteins in greater detail bears the potential to elucidate important mechanisms of innate immunity, to establish valid biomarkers of phagocytic inflammation, and eventually to reveal novel targets for innovative anti-inflammatory therapies.

Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis

2006-11-26

Sachie Hiratsuka , Akira Watanabe , Hiroyuki Aburatani +1 more

Metal Chelation and Inhibition of Bacterial Growth in Tissue Abscesses

2008-02-14

Brian D. Corbin , Erin H. Seeley , Andrea Raab +7 more

Bacterial infection often results in the formation of tissue abscesses, which represent the primary site of interaction between invading bacteria and the innate immune system. We identify the host protein … Bacterial infection often results in the formation of tissue abscesses, which represent the primary site of interaction between invading bacteria and the innate immune system. We identify the host protein calprotectin as a neutrophil-dependent factor expressed inside Staphylococcus aureus abscesses. Neutrophil-derived calprotectin inhibited S. aureus growth through chelation of nutrient Mn2+ and Zn2+: an activity that results in reprogramming of the bacterial transcriptome. The abscesses of mice lacking calprotectin were enriched in metal, and staphylococcal proliferation was enhanced in these metal-rich abscesses. These results demonstrate that calprotectin is a critical factor in the innate immune response to infection and define metal chelation as a strategy for inhibiting microbial growth inside abscessed tissue.

Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000).

2000-01-01

Lawrence F. Eng , Roopa S. Ghirnikar , Yuen L. Lee

PGP 9.5—a new marker for vertebrate neurons and neuroendocrine cells

1983-11-01

Richard J. Thompson , John F Doran , Peter Jackson +2 more

Annexins: linking Ca2+ signalling to membrane dynamics

2005-06-01

Volker Gerke , Carl E. Creutz , Stephen E. Moss

Reactive Gliosis and the Multicellular Response to CNS Damage and Disease

2014-01-01

Joshua E. Burda , Michael V. Sofroniew

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Immunoperoxidase localization of glial fibrillary acidic protein in radial glial cells and astrocytes of the developing rhesus monkey brain

1980-10-01

Pat Levitt , Pasko Rakić

Abstract Peroxidase‐antiperoxidase (PAP) immunohistochemical staining, utilizing a specific antibody to the glial fibrillary acidic protein (GFA), was employed to analyze gliogenesis in the central nervous system of rhesus monkeys ranging … Abstract Peroxidase‐antiperoxidase (PAP) immunohistochemical staining, utilizing a specific antibody to the glial fibrillary acidic protein (GFA), was employed to analyze gliogenesis in the central nervous system of rhesus monkeys ranging in age from embryonic day 38(E38) to birth (E165) and through the second postnatal month. All major subdivisions of the brain contain glial cells, recognized by the presence of dark brown horseradish peroxidase (HRP) reaction product. Neuronal elements are not stained with this immunocytochemical technique. The first class of glial cell to appear during development are the radial glial cells; the radial glial fibers fan out from the ventricular and subventricular zones, where their cell bodies reside, to the pial surface where they terminate with conical endfeet. These glial cells appear within the first third of gestation, being present in the spinal cord and brainstem by E41; in the diencephalon by E45; and in the telencephalon and cerebellum by E47. The next class of glia to appear is the Bergmann glial cell of the cerebellar cortex, which can be stained by E54. Bergmann glial cells located below the Purkinje cell layer issue parallel processes which extend up to the pial surface. Within each major subdivision of the brain, massive numbers of elongated glial fibers continually alter their distinctive patterns to maintain constant ventricular‐pial surface relationships during the major tectogenetic changes which occur throughout embryonic development. In Nissl‐counterstained sections columns of migrating neurons are observed juxtaposed to GFA‐positive radial and Bergmann glial fibers. Radial glial cells assume a variety of transitional forms during the process of their transformation into mature astrocytes. This transformation occurs in each structure at specific embryonic ages and is initiated after neuronal migration has begun to subside. The number of astroglial cells increases at an accelerated pace after neurogenesis is complete. The immunohistochemical localization of radial glial fibers at relatively early stages of embryonic development indicates that glial cells are present concomitantly with neurons, raising the possibility that at least two distinct populations of cell precursors compose the proliferative zones. Furthermore, the demonstration of large numbers of radial glial cells in all brain regions during the peak of neuronal migration and a close structural relationship between elongated glial fibers and migrating neurons support the concept that glia play a significant role in the guidance and compartmentalization of neuronal elements during development.

An acidic protein isolated from fibrous astrocytes

1971-05-01

Lawrence F. Eng , Jean‐Jacques Vanderhaeghen , A. Bignami +1 more

Interleukin‐8, a chemotactic and inflammatory cytokine

1992-07-27

Marco Baggiolini , Ian Clark‐Lewis

Interleukin‐8 (IL‐8) belongs to a family of small, structurally related cytokines similar to platelet factor 4. It is produced by phagocytes and mesenchymal cells exposed to inflammatory stimuli (e.g., interleukin‐1 … Interleukin‐8 (IL‐8) belongs to a family of small, structurally related cytokines similar to platelet factor 4. It is produced by phagocytes and mesenchymal cells exposed to inflammatory stimuli (e.g., interleukin‐1 or tumor necrosis factor) and activates neutrophils inducing, chemotaxis, exocytosis and the respiratory burst. In vivo, IL‐8 elicits a massive neutrophil accumulation at the site of injection. Five neutrophil‐activating cytokines similar to IL‐8 in structure and function have been identified recently. IL‐8 and the related cytokines are produced in several tissues upon infection, inflammation, ischemia, trauma etc., and are thought to be the main cause of local noutrophil accumulation.

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The S100 protein family: History, function, and expression

1995-01-01

Danna B. Zimmer , Emily H. Cornwall , Aimee Landar +1 more

Intracellular and extracellular roles of S100 proteins

2003-03-12

Rosario Donato

Abstract S100, a multigenic family of non‐ubiquitous Ca 2+ ‐modulated proteins of the EF‐hand type expressed in vertebrates exclusively, has been implicated in intracellular and extracellular regulatory activities. Members of … Abstract S100, a multigenic family of non‐ubiquitous Ca 2+ ‐modulated proteins of the EF‐hand type expressed in vertebrates exclusively, has been implicated in intracellular and extracellular regulatory activities. Members of this protein family have been shown to interact with several effector proteins within cells thereby regulating enzyme activities, the dynamics of cytoskeleton constituents, cell growth and differentiation, and Ca 2+ homeostasis. Structural information indicates that most of S100 proteins exist in the form of antiparallelly packed homodimers (in some cases heterodimers), capable of functionally crossbridging two homologous or heterologous target proteins in a Ca 2+ ‐dependent (and, in some instances, Ca 2+ ‐independent) manner. In addition, extracellular roles have been described for several S100 members, although secretion (via an unknown mechanism) has been documented for a few of them. Extracellular S100 proteins have been shown to exert regulatory effects on inflammatory cells, neurons, astrocytes, microglia, and endothelial and epithelial cells, and a cell surface receptor, RAGE, has been identified as a potential S100A12 and S100B receptor transducing the effects of these two proteins on inflammatory cells and neurons. Other cell surface molecules with ability to interact with S100 members have been identified, suggesting that RAGE might not be a universal S100 protein receptor and/or that a single S100 protein might interact with more than one receptor. Collectively, these data indicate that members of the S100 protein family are multifunctional proteins implicated in the regulation of a variety of cellular activities. Microsc. Res. Tech. 60:540–551, 2003. © 2003 Wiley‐Liss, Inc.

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Annexins: the problem of assessing the biological role for a gene family of multifunctional calcium- and phospholipid-binding proteins

1994-04-01

Patrick Raynal , Harvey B. Pollard

Neurone-specific enolase is a molecular marker for peripheral and central neuroendocrine cells

1978-12-01

Donald E. Schmechel , Paul J. Marangos , Milton Brightman

The structure-activity relations of synthetic peptides as chemotactic factors and inducers of lysosomal secretion for neutrophils.

1976-05-01

H J Showell , Richard J. Freer , S H Zigmond +4 more

24 di-, tri-, and tetrapeptides have been synthesized as a start of a systematic study of the structural requirements for chemotactic activity and lysosomal enzyme-releasing ability in rabbit neutrophils. All … 24 di-, tri-, and tetrapeptides have been synthesized as a start of a systematic study of the structural requirements for chemotactic activity and lysosomal enzyme-releasing ability in rabbit neutrophils. All but two of them are N-formyl methionyl peptides. Using the method of Zigmond and Hirsch (10), two representative peptides, F-Met-Leu-Phe and F-Met-Met-Met, were shown to stimulate directed, as well as, random locomotion; thus, they were truly chemotactic. The various peptides showed a wide spread in activity. F-Met-Leu-Phe, the most active peptide studied, had an ED50 for induced migration of 7 X 10(-11) M and for lysozyme and beta-glucuronidase release of 2.4 X 10(-10) M and 2.6 X 10(-10) M, respectively; the least active, Met-Leu-Glu was 26 million times less active in these respects. The relation of activity to structure is exceedingly specific, very small changes in structure making large changes in activity. Moreover, this specificity exhibits a definite regularity and pattern; the activity of a given peptide depends not only on its constituent amino acids but on the position of the amino acid in the peptide chain. Most striking in this last regards is the high activity conferred by phenylalanine when it is in the carboxyl terminal position of a tripeptide, whereas, as the second amino acid from the NH2 terminal end whether in a tripeptide or a dipeptide, it contributes no more to the activity than other amino acids with hydrophobic side chains such as leucine or methionine. The high activity and the specificity and nature of the structural requirements strongly suggest that the primary interaction of peptide and neutrophil leading to either chemotaxis or lysosomal enzyme release is a binding of the peptide with a stereospecific receptor on the neutrophil surface. Whether all chemotactic factors act through the same receptor is not known. An essentially exact correlation exists between the concentrations of the various synthetic peptides required to induce migration and their ability to induce release of lysozyme or beta-glucuronidase. This implies that these two neutrophil functions are triggered by teh same primary interaction; possibly, the binding of the peptides to the same putative receptor. A higher concentration of a given peptide is required to stimulate lysosomal enzyme release than a corresponding migratory response. A slightly but significantly higher concentration of peptide is required to induce beta-glucuronidase secretion than lysozyme release.

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Sequence motifs for calmodulin recognition

1997-04-01

Allen R. Rhoads , Felix Friedberg

Calmodulin (CaM) is recognized as a major calcium sensor and orchestrator of regulatory events through its interaction with a diverse group of cellular proteins. Many investigations have focused on defining … Calmodulin (CaM) is recognized as a major calcium sensor and orchestrator of regulatory events through its interaction with a diverse group of cellular proteins. Many investigations have focused on defining the region of interaction between CaM and its cellular targets and the action of CaM on target protein function. Because CaM can bind with high affinity to a relatively small α-helical region of many proteins, success in clearly defining the essential elements of CaM binding motifs seems feasible and should provide a means of identifying CaM binding proteins. Three recognition motifs for CaM interaction are discussed in the context of experimental investigations of a variety of CaM target proteins. A modified version of the IQ motif as a consensus for Ca2+-independent binding and two related motifs for Ca2+-dependent binding, termed 18-14 and 1-5-10 based on the position of conserved hydrophobic residues, are proposed. Although considerable sequence diversity is observed among the different binding regions, these three classes of recognition motifs exist for many of the known CaM binding proteins.—Rhoads, A. R., Friedberg, F. Sequence motifs for calmodulin recognition. FASEB J. 11, 331-340 (1997)

Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils.

1989-10-01

Marco Baggiolini , Andrew J. Walz , Steven L. Kunkel

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Annexin A1 and glucocorticoids as effectors of the resolution of inflammation

2008-12-23

Mauro Perretti , Fulvio D’Acquisto

International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the Formyl Peptide Receptor (FPR) Family

2009-06-01

Richard D. Ye , François Boulay , Ji Ming Wang +5 more

Formyl peptide receptors (FPRs) are a small group of seven-transmembrane domain, G protein-coupled receptors that are expressed mainly by mammalian phagocytic leukocytes and are known to be important in host … Formyl peptide receptors (FPRs) are a small group of seven-transmembrane domain, G protein-coupled receptors that are expressed mainly by mammalian phagocytic leukocytes and are known to be important in host defense and inflammation. The three human FPRs (FPR1, FPR2/ALX, and FPR3) share significant sequence homology and are encoded by clustered genes. Collectively, these receptors bind an extraordinarily numerous and structurally diverse group of agonistic ligands, including N-formyl and nonformyl peptides of different composition, that chemoattract and activate phagocytes. N-formyl peptides, which are encoded in nature only by bacterial and mitochondrial genes and result from obligatory initiation of bacterial and mitochondrial protein synthesis with N-formylmethionine, is the only ligand class common to all three human receptors. Surprisingly, the endogenous anti-inflammatory peptide annexin 1 and its N-terminal fragments also bind human FPR1 and FPR2/ALX, and the anti-inflammatory eicosanoid lipoxin A4 is an agonist at FPR2/ALX. In comparison, fewer agonists have been identified for FPR3, the third member in this receptor family. Structural and functional studies of the FPRs have produced important information for understanding the general pharmacological principles governing all leukocyte chemoattractant receptors. This article aims to provide an overview of the discovery and pharmacological characterization of FPRs, to introduce an International Union of Basic and Clinical Pharmacology (IUPHAR)-recommended nomenclature, and to discuss unmet challenges, including the mechanisms used by these receptors to bind diverse ligands and mediate different biological functions.

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Structure And Evolution Of Calcium-Modulated Protein

1980-01-01

Robert H. Kretsinger

This review suggests that the intracellular functions of calcium are best understood in terms of calcium's functioning as a second messenger. Further, when functioning as a second messenger, calcium completes … This review suggests that the intracellular functions of calcium are best understood in terms of calcium's functioning as a second messenger. Further, when functioning as a second messenger, calcium completes its mission not by transferring charge nor by binding to lipid but by binding to specific targets, calcium-modulated proteins. This concept is broadly interpreted to include proteins involved in calcium transport. There is strong evidence that many, if not all, of these calcium-modulated proteins are homologs. Their structures and properties are contrasted to those of extracellular calcium-binding proteins which are not homologous to one another or to the intracellular calcium-modulated proteins. Finally, this line of thought leads to a suggestion of the evolutionary reason for the choice of calcium as the sole inorganic second messenger.

A soluble protein characteristic of the nervous system

1965-06-01

Blake W. Moore

The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome.

1989-01-01

Anders Waage , P Brandtzæg , Alfred Halstensen +2 more

Serum samples from patients with meningococcal disease were examined for the presence of IL-6, TNF-alpha, and LPS. Median serum concentration of IL-6 was 1,000 times higher in patients with septic … Serum samples from patients with meningococcal disease were examined for the presence of IL-6, TNF-alpha, and LPS. Median serum concentration of IL-6 was 1,000 times higher in patients with septic shock (189 ng/ml) than in patients with bacteriaemia, meningitis, or combined septic shock and meningitis. 11 of 21 patients with serum levels greater than 3.0 ng/ml died, whereas all 58 patients with serum levels at less than or equal to 3.0 ng/ml, survived. All four patients with serum IL-6 levels greater than 750 ng/ml, died. IL-1 was detected in serum from three patients who also had high serum levels of IL-6, TNF-alpha, and LPS, and rapidly fatal courses. IL-6 appeared to be released into serum later than TNF-alpha, and was detected in serum for up to 36 h. The half-life of IL-6 and TNF-alpha was calculated to be 103 +/- 27 min and 70 +/- 11 min, respectively. These data indicate that a complex pattern of cytokines exists in serum from patients with meningococcal septic shock, and that the release of IL-6 and IL-1, in addition to TNF-alpha, is associated with fatal outcome.

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The endogenous Toll–like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer

2009-05-18

Jan Ehrchen , Cord Sunderkötter , Dirk Foell +2 more

The innate immune system is crucial for initiation and amplification of inflammatory responses. During this process, phagocytes are activated by PAMPs that are recognized by PRRs. Phagocytes are also activated … The innate immune system is crucial for initiation and amplification of inflammatory responses. During this process, phagocytes are activated by PAMPs that are recognized by PRRs. Phagocytes are also activated by endogenous danger signals called alarmins or DAMPs via partly specific, partly common PRRs. Two members of the S100 protein family, S100A8 and S100A9, have been identified recently as important endogenous DAMPs. The complex of S100A8 and S100A9 (also called calprotectin) is actively secreted during the stress response of phagocytes. The association of inflammation and S100A8/S100A9 was discovered more than 20 years ago, but only now are the molecular mechanisms involved in danger signaling by extracellular S100A8/S100A9 beginning to emerge. Taking advantage of mice lacking the functional S100A8/S100A9 complex, these molecules have been identified as endogenous activators of TLR4 and have been shown to promote lethal, endotoxin-induced shock. Importantly, S100A8/S100A9 is not only involved in promoting the inflammatory response in infections but was also identified as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. This proinflammatory action of S100A8/S100A9 involves autocrine and paracrine mechanisms in phagocytes, endothelium, and other cells. As a net result, extravasation of leukocytes into inflamed tissues and their subsequent activation are increased. Thus, S100A8/S100A9 plays a pivotal role during amplification of inflammation and represents a promising new therapeutic target.

Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system.

1985-10-01

J K Boyles , Robert E. Pitas , Elaine V. Wilson +2 more

The plasma protein apolipoprotein (apo) E is an important determinant of lipid transport and metabolism in mammals. In the present study, immunocytochemistry has been used to identify apo E in … The plasma protein apolipoprotein (apo) E is an important determinant of lipid transport and metabolism in mammals. In the present study, immunocytochemistry has been used to identify apo E in specific cells of the central and peripheral nervous systems of the rat. Light microscopic examination revealed that all astrocytes, including specialized astrocytic cells (Bergmann glia of the cerebellum, tanycytes of the third ventricle, pituicytes of the neurohypophysis, and Müller cells of the retina), possessed significant concentrations of apo E. In all of the major subdivisions of the central nervous system, the perinuclear region of astrocytic cells, as well as their cell processes that end on basement membranes at either the pial surface or along blood vessels, were found to be rich in apo E. Extracellular apo E was present along many of these same surfaces. The impression that apo E is secreted by astrocytic cells was confirmed by electron microscopic immunocytochemical studies, which demonstrated the presence of apo E in the Golgi apparatus. Apo E was not present in neurons, oligodendroglia, microglia, ependymal cells, and choroidal cells. In the peripheral nervous system, apo E was present within the glia surrounding sensory and motor neurons; satellite cells of the dorsal root ganglia and superior cervical sympathetic ganglion as well as the enteric glia of the intestinal ganglia were reactive. Apo E was also present within the non-myelinating Schwann cells but not within the myelinating Schwann cells of peripheral nerves. These results suggest that apo E has an important, previously unsuspected role in the physiology of nervous tissue.

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Calbindin D-28k and parvalbumin in the rat nervous system

1990-01-01

Marco R. Celio

Functions of S100 Proteins

2012-12-10

Rosario Donato , Brian R. Cannon , Guglielmo Sorci +4 more

The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which … The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion.

2016 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With EACTS

2016-12-28

Paulus Kirchhof , Stefano Benussi , Dipak Kotecha +7 more

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S100A8/A9 in Inflammation

2018-06-11

Siwen Wang , Rui Song , Ziyi Wang +3 more

S100A8 and S100A9 (also known as MRP8 ang MRP14, respectively) are Ca2+ binding proteins belonging to the S100 family. They often exist in the form of heterodimer, while homodimer exists … S100A8 and S100A9 (also known as MRP8 ang MRP14, respectively) are Ca2+ binding proteins belonging to the S100 family. They often exist in the form of heterodimer, while homodimer exists very little because of the stability. S100A8/A9 is constitutively expressed in neutrophils and monocytes as a Ca2+ sensor, participating in cytoskeleton rearrangement and arachidonic acid metabolism. During inflammation, S100A8/A9 is released actively and exerts a critical role in modulating the inflammatory response by stimulating leukocyte recruitment and inducing cytokine secretion. S100A8/A9 serves as a candidate biomarker for diagnosis and follow-up as well as a predictive indicator of therapeutic responses to inflammation-associated diseases. As blockade of S100A8/A9 activity using small-molecule inhibitors or antibodies improves pathological conditions in murine models, the heterodimer has potential as a therapeutic target. In this review, we provide a comprehensive and detailed overview of the distribution and biological functions of S100A8/A9 and highlight its application as a diagnostic and therapeutic target in inflammation-associated diseases.

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Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19

2020-08-05

Aymeric Silvin , Nicolas Chapuis , Garett Dunsmore +7 more

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LRP: a multifunctional scavenger and signaling receptor

2001-09-15

Joachim Herz , Dudley K. Strickland

Multiligand receptorsLigand families and subgroups and their binding sites on LRP LRP recognizes at least 30 different ligands (Table 1) that represent several families of proteins.These include lipoproteins, proteinases, proteinaseinhibitor … Multiligand receptorsLigand families and subgroups and their binding sites on LRP LRP recognizes at least 30 different ligands (Table 1) that represent several families of proteins.These include lipoproteins, proteinases, proteinaseinhibitor complexes, ECM proteins, bacterial toxins, viruses, and various intracellular proteins.

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The S100 family of EF-hand calcium-binding proteins: functions and pathology

1996-04-01

Beat W. Schäfer

Effects of histone acetyltransferase and deacetylase inhibitors on the expression of S100A genes after TLR4 and TLR2 stimulation in human dental pulp cells

2025-06-24

Holger Jungbluth , Dominik Kraus , Diana Lalaouni +3 more | Heliyon

Edaravone-Dexborneol slows down pathological progression and cognitive decline via inhibiting S100A9 in APPswe/PS1dE9 mice

2025-06-21

Rui Mao , Shu Shu , Min Sun +7 more | Alzheimer s Research & Therapy

Edaravone-Dexborneol (EDB) presents therapeutic effects due to its anti-inflammatory, antioxidant and anti-apoptotic properties, and has been widely used in ischemic stroke. However, the detailed efficacy and potential target of EDB … Edaravone-Dexborneol (EDB) presents therapeutic effects due to its anti-inflammatory, antioxidant and anti-apoptotic properties, and has been widely used in ischemic stroke. However, the detailed efficacy and potential target of EDB in Alzheimer's disease (AD) are still elusive. Male APPswe/PS1dE9 mice were administered with EDB intraperitoneally from 3.5 to 8 months of age. The cognition of mice was assessed by behavioral tests. Synaptic alternations in the hippocampus were detected by electrophysiology and Golgi staining. β-amyloid (Aβ) pathology was mainly observed by immunofluorescence. Oxidative stress-related indicators were evaluated by dedicated kits, while quantitative PCR and ELISA were used to detect pro-inflammatory factors. Proteomics analysis further identified the potential target of EDB. EDB was capable of delaying the cognitive decline and ameliorating the synaptic loss in APPswe/PS1dE9 mice. In addition to the anti-inflammation and anti-oxidation effects, EDB treatment mightily ablated the Aβ plaque by promoting microglial phagocytosis. Particularly, we first discovered that EDB could directly bind to S100A9, a pathological molecule that aggravates Aβ pathology and induces oxidative stress and neuroinflammation. EDB inhibited the expression, functional threonine phosphorylation and self-assembly of S100A9. Our results indicate that EDB can improve cognitive function and slow down AD progression, and it may serve as a potential agent for AD and other S100A9-related diseases.

Uncovering common disease mechanisms and critical biomarkers in Crohn’s disease with concurrent psoriasis and exploring potential therapeutic agents

2025-06-20

Tianqi Liu , Xiaoqing Zhang , Ruiqi Chen +5 more | PLoS ONE

Research findings show a substantial correlation between Crohn's disease and psoriasis. However, the exact cause or pathogenesis of the concurrent manifestations of these two conditions in the same individuals remains … Research findings show a substantial correlation between Crohn's disease and psoriasis. However, the exact cause or pathogenesis of the concurrent manifestations of these two conditions in the same individuals remains uncertain. This research aimed to scrutinize the important molecules and mechanisms responsible for the concomitance of Crohn's disease and Psoriasis by using quantitative bioinformatics utilizing a publicly available RNA sequencing repository. The database Gene Expression Omnibus were assessed, specifically for Crohn's disease (GSE95095) and psoriasis (GSE13355). The 'limma' library of the R programming syntax is employed to identify differentially expressed genes. The Search Tool for Interacting Genes dataset was utilized to study the interaction between proteins networks. The Cytoscape software was utilized to efficiently view and analyse these Protein-Protein Interaction networks. The ctoHubba Cytoscape plugin helps in the selection of hub genes. These hub genes have been confirmed using data from GSE102133 for Crohn's disease and GSE14905 for psoriasis. The ROC curves were utilized in this study to assess the diagnostic value of the hub genes. Moreover, new research involving gene-set enriched studies and the study of immunological surveillance associated with these specific genes is attainable. Among the identified common DEGs, 40 genes were downregulated and 37 were upregulated, totaling 77 genes. Crohn's disease and Psoriasis had a higher concentration of pathways associated with inflammation. After validation, functionality of hub genes was confirmed for S100A12, CXCL8, IL1RN, S100A9, CXCL10, MMP1, CXCL1, FPR1, CXCR2, and S100A8. The hub genes showed an increase in expression in response to neutrophil infiltration. The expression of S100A12, CXCL8, IL1RN, S100A9, CXCL10, MMP1, CXCL1, FPR1, CXCR2, and S100A8 was found to be significantly linked to immune processes such as neutrophil activation, neutrophil chemotaxis, and neutrophil migration associated with Crohn's and Psoriasis disease. This bioinformatics study has elucidated S100A12, CXCL8, IL1RN, S100A9, CXCL10, MMP1, CXCL1, FPR1, CXCR2, and S100A8 as the central genes in the pathogenesis of CD and Psoriasis comorbidity. The significance of neutrophil infiltration in promoting inflammatory and immune-mediated dysfunction seems to be crucial in the etiology of concurrent Crohn's and Psoriasis, offering an avenue for diagnostic and therapeutic methods.

Correction: Emerging roles of cohesin-STAG2 in cancer

2025-06-20

Julia S. Scott , Lobna Ayadi , Emmanouela Epeslidou +5 more | Oncogene

Effect on Different Glial Cell Types of S100B Modulation in Multiple Sclerosis Experimental Models

2025-06-20

Maria De Carluccio , Gabriele Di Sante , Maria Elisabetta Clementi +7 more | International Journal of Molecular Sciences

It has been demonstrated that S100B actively participates in neuroinflammatory processes of different diseases of the central nervous system (CNS), such as experimental autoimmune encephalomyelitis (EAE), a recognized animal model … It has been demonstrated that S100B actively participates in neuroinflammatory processes of different diseases of the central nervous system (CNS), such as experimental autoimmune encephalomyelitis (EAE), a recognized animal model for multiple sclerosis (MS). The inhibition of S100B activity using pentamidine and of S100B synthesis using arundic acid are able to determine an amelioration of the clinical and pathologic parameters of MS with milder and delayed symptoms. This study further goes in detail on the role of S100B, and in particular of astrocytic S100B, in these neuroinflammatory processes. To this aim, we used a model of S100B knockout (KO) mice. As expected, S100B protein levels were significantly reduced in the S100B KO mouse strain resulting in an amelioration of clinical and pathological parameters (clinical and morphological analyses). To dissect the potential mechanisms that could explain the role of S100B in the development of EAE, we sorted, cultured, and compared glial subpopulations (astrocytes, oligodendrocytes, and microglia) derived from S100B KO and wild type mice, through flow cytometric panels and ELISA. Glial cells were analyzed for proinflammatory molecules showing a significant reduction of TNFα protein in mice where S100B was silenced. To dissect the role of S100B in MS, we cultured astrocytes and microglial cells magnetically sorted and enriched from the brains of EAE-affected animals, both from KO and wild type animals. Both genetic silencing of S100B and pharmacological inhibition with S100B-targeting compounds demonstrated a direct impact on specific subpopulations of astrocytes (mainly), oligodendrocytes, and microglia. The present results further individuate astrocytic S100B as a key factor and as a potential therapeutic target for EAE neuroinflammatory processes.

Glial Fibrillary Acidic Protein vs. S100B to Identify Astrocytes Impacted by Sex and High Fat Diet

2025-06-18

Beenhwa Grace Lee , Charlotte Schultz , Arnalda Zhao +3 more | Physiology & Behavior

The brain modulates energy balance by coordinating energy intake and energy expenditure to prevent metabolic diseases. Most research has focused on the role of neurons in this process, but recent … The brain modulates energy balance by coordinating energy intake and energy expenditure to prevent metabolic diseases. Most research has focused on the role of neurons in this process, but recent work also implicates roles for astrocytes in energy balance. For example, astrocytes in the arcuate nucleus of the hypothalamus become reactive after mice are fed high fat diet (HFD) and their altered function is thought to contribute to obesity. However, limitations in labeling astrocytes in other brain areas has hindered determination of their roles in normal and altered energy balance. Reactive astrocytes increase expression of glial fibrillary acidic protein (GFAP), hence, GFAP has been commonly used as an astrocyte marker. Yet, there is scant immunolabeling of GFAP in brains of chow-fed mice, despite the presence of abundant astrocytes. These findings underscore the need for a marker to visualize astrocytes throughout the brain during normal physiology and exposure to diet-induced obesity, to permit study of how and where they contribute to energy balance. Here we compared immunofluorescence labeling of GFAP and another protein expressed in astrocytes, the S100 calcium binding protein beta (S100B), in brain sections from chow- and HFD-fed female and male mice. We compared the number of labeled cells in areas pertinent to control of ingestive behavior including the arcuate nucleus, lateral hypothalamic area, paraventricular nucleus, lateral preoptic area, and the periaqueductal gray. There was low GFAP expression throughout these brain regions that increased in some brain areas from HFD-fed mice, but intriguingly this only occurred in males. In contrast, S100B labeled more cells than GFAP in each of these areas but its expression was not altered by HFD or sex in most cases. Overall, these data suggest that S100B is superior to GFAP for visualizing astrocytes throughout the brain in both sexes regardless of diet exposure. This study will be a useful resource for researchers who want to identify and study astrocytes in response to diet and in other physiological contexts.

Human annexin A5 promotes glioma progression by targeting the MAPK/CD44 pathway

2025-06-18

Wen-Ting Liu , Tao Xiong , Hu Sun +3 more | Frontiers in Oncology

Background Gliomas are the most common intracranial malignant tumors. In this study, we aimed to identify the hub genes and investigate the pathophysiological significance of ANXA5 in glioma. Methods The … Background Gliomas are the most common intracranial malignant tumors. In this study, we aimed to identify the hub genes and investigate the pathophysiological significance of ANXA5 in glioma. Methods The differentially expressed genes (DEGs) between tumor and adjacent tissues from glioma patients were acquired from the Gene Expression Omnibus (GEO) database. Functional enrichment analysis and protein-protein interaction (PPI) network construction of overlapping DEGs were performed. The GEPIA and CGGA databases were used to explore hub gene expression. The effect of hub genes on prognosis and tumor-infiltrating immune cells was analyzed via GEPIA, CGGA, and TIMER2 databases. Additionally, ANXA5 expression was measured by qRT-PCR and Western blotting. The effects of ANXA5 were assessed by CCK-8, colony formation, Transwell, and flow cytometry assays. Moreover, the roles of ANXA5 were identified in vivo . Results The DEGs were enriched in cell surface receptor signaling pathway, immune response, and MAPK signaling pathway. The selected hub genes were included ANXA5 , STAT1 , CD44 , CAV1 , ANXA2 , and MAPT . Among them, expression of ANXA5 , STAT1 , CD44 , CAV1 , and ANXA2 was strongly correlated with patient prognosis and was also involved in the tumor microenvironment. Furthermore, ANXA5 knockdown significantly inhibited the migration and proliferation of glioma cells in vitro and in vivo . Meanwhile, we found that the expression of CD44 was monitored by ANXA5 , and ANXA5 promoted the migration and proliferation of glioma cells via the MAPK/CD44 pathway. Conclusion Taken together, our data showed that ANXA5 could contribute to cell proliferation and metastasis of glioma by targeting the MAPK/CD44 axis.

Advances in Circulating Biomarkers for Neurodegenerative Diseases, Traumatic Brain Injuries, and Central Nervous System Tumors

2025-06-18

Ming Yang , A.M. Zhang , Chen Meng +1 more | Annals of Laboratory Medicine

Neurological disorders, including neurodegenerative diseases, traumatic brain injuries (TBI), and central nervous system (CNS) tumors, are complex conditions that significantly impact patients globally. Timely diagnosis and monitoring are critical for … Neurological disorders, including neurodegenerative diseases, traumatic brain injuries (TBI), and central nervous system (CNS) tumors, are complex conditions that significantly impact patients globally. Timely diagnosis and monitoring are critical for improving outcomes, driving the need for reliable biomarkers. Specifically, biomarkers detectable in cerebrospinal fluid (CSF) and blood offer important insights into disease presence and progression. This review explores the evolution of circulating blood biomarkers for neurodegenerative diseases, TBI, and CNS tumors, highlighting advanced detection technologies from enzyme-linked immunosorbent assays (ELISAs) to electrochemiluminescence (ECL) assays, single-molecule arrays (Simoa), and mass spectrometry. Advanced technologies with enhanced sensitivity and specificity, particularly in detecting low-abundance analytes, facilitate the investigation of CSF biomarkers for various neurological disorders. We also describe the progress in blood-based biomarkers for , emerging as less invasive alternatives to CSF sampling. Clinically, the implementation of Alzheimer's disease (AD) blood biomarkers Aβ42/Aβ40 ratio and Apolipoprotein E isoform-specific peptide can aid the diagnosis, while p-tau181 and p-tau217 differentiates AD dementia from non-AD neurodegenerative diseases. Blood glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 are used in ruling out mild TBI. Despite these innovations, challenges remain, including assay standardization, sensitivity/specificity trade-offs, and the requirement for longitudinal studies to understand biomarker utility over time. Future research should focus on addressing these challenges to fully realize the potential of blood-based biomarkers in neurological disorder diagnostics and patient care.

Interrogating the plasma proteome of repetitive head impact exposure and chronic traumatic encephalopathy

2025-06-16

Rowan Saloner , Kaitlin B. Casaletto , Sruti Rayaprolu +7 more | Molecular Neurodegeneration

Abstract Background Exposure to repetitive head impacts (RHI) is associated with increased risk for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, and other neuropathological changes. Biological drivers of RHI-related neurodegeneration … Abstract Background Exposure to repetitive head impacts (RHI) is associated with increased risk for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, and other neuropathological changes. Biological drivers of RHI-related neurodegeneration are not well understood. We interrogated the plasma proteome in aging adults with prior RHI compared to healthy controls (CTL) and individuals with Alzheimer’s disease (AD), including a subset characterized neuropathologically at autopsy. Methods Proximity extension assay (Olink Explore®) quantified 2,779 plasma proteins in 22 RHI patients (all AD-biomarker negative), 39 biomarker-confirmed AD, and 44 CTL. A subset of participants went to autopsy ( N = 16) allowing for comparisons of the antemortem plasma proteome between autopsy-confirmed CTE + ( N = 7) and CTE- ( N = 9). Differential abundance and co-expression network analyses identified plasma proteomic signatures of RHI, which were functionally annotated using gene ontology and cell type enrichment analysis. Nonparametric correlations examined plasma proteomic associations with orthogonally-measured plasma biomarkers, global cognitive function, and semi-quantitative ratings of neuropathology burden at autopsy. Results Differential abundance analysis revealed 434 increased (vs. 6 decreased) proteins in RHI vs. CTL and 193 increased (vs. 14 decreased) in RHI vs. AD. Network analysis identified 9 protein co-expression modules (M1-M9), of which 7 were elevated in RHI compared to AD or CTL. Modules with increased abundance in RHI were enriched for mitochondrial/metabolic, cell division, and immunovascular (e.g., cell adhesion, TNF-signaling) processes. RHI-related modules exhibited strong and selective correlations with immunoassay-based plasma IL-6 in RHI cases, including the M2 TNF-signaling/cell adhesion module which harbored proteins that strongly tracked with cognitive function. RHI-related plasma protein signatures were similar in the subset of participants with autopsy-confirmed CTE, including immune and metabolic modules that positively correlated with medial temporal lobe tau and TDP-43 burden. Conclusions Molecular pathways in plasma most consistently implicated in RHI were tied to immune response, mitochondrial function, and cell metabolism. RHI-related proteomic signatures tracked with antemortem cognitive severity and postmortem neuropathological burden, providing converging evidence for their role in disease progression. Differentially abundant proteins and co-expression modules in RHI may inform mechanisms linking RHI to increased dementia risk, thus guiding diagnostic biomarker and therapeutic development for at-risk populations.

Proximity labelling-based identification of vascular homing peptide receptors

2025-06-15

Rasmus Enno , Maarja Haugas , Kārlis Pleiko +2 more | bioRxiv (Cold Spring Harbor Laboratory)

Identifying the receptors of vascular homing peptides (VHPs) is critical for mechanistic understanding and development of peptide-guided precision therapeutics. Conventional receptor discovery methods, such as affinity chromatography, require cell disruption … Identifying the receptors of vascular homing peptides (VHPs) is critical for mechanistic understanding and development of peptide-guided precision therapeutics. Conventional receptor discovery methods, such as affinity chromatography, require cell disruption and often expose intracellular proteins, resulting in high background and low specificity. To overcome these limitations, we developed a proximity labelling approach that tags proteins near VHP receptors on intact live cells. Cells were incubated with VHP-horseradish peroxidase (HRP) complexes, which, upon hydrogen peroxide treatment, activate biotin-tyramide to produce short-lived radicals that covalently label nearby membrane proteins. Using the prototypic C-end Rule peptide RPARPAR and its known receptor neuropilin-1 (NRP-1), we validated this method by successful receptor tagging and mass spectrometric identification. Using RPARPAR-HRP conjugates, we achieved selective proximity labeling of membrane proteins in NRP-1-positive PPC1 cells, with a 3- to 5-fold increase in fluorescence intensity over controls by flow cytometry. Affinity purification and Western blotting identified a strong ~130 kDa band corresponding to NRP-1 exclusively in labeled PPC1 cells. Mass spectrometry analysis revealed a ~20-fold enrichment of NRP-1 and significant enrichment of integrins (ITGAV, ITGB1, ITGA3), ALCAM, EPHA2, CD109, and PLXNB2 in RPARPAR-labeled samples compared to controls. This approach could be broadly used for molecular mapping of the homing peptide interactome and its spatial proximity in live cells, streamlining the discovery of homing peptide receptors and their associated partners.

888-P: Targeting Toxic Human IAPP Aggregation in Type 2 Diabetes Development with Antimicrobial Peptides

2025-06-13

Jyh‐Ping Chen , Adrian Kee Keong Teo , Surajit Bhattacharjya | Diabetes

Introduction and Objective: Human islet amyloid polypeptide (hIAPP) is a pancreatic β-cell neuropeptide hormone co-secreted with insulin. However, it is also amyloidogenic. The hypersecretion of hIAPP in pre-diabetes is hypothesised … Introduction and Objective: Human islet amyloid polypeptide (hIAPP) is a pancreatic β-cell neuropeptide hormone co-secreted with insulin. However, it is also amyloidogenic. The hypersecretion of hIAPP in pre-diabetes is hypothesised to induce its aggregation, which may contribute to β-cell failure during T2D progression. Currently, no hIAPP aggregation inhibitors have advanced to clinical trials. Our study aims to identify anti-microbial peptides (AMPs) that can inhibit hIAPP aggregation and rescue the pancreatic β-cells from hIAPP-induced toxicity. Methods: Thioflavin T (ThT) binding assay was used to assess AMP inhibition of hIAPP monomer aggregation and secondary nucleated aggregation over 20-40h. The half-maximal inhibitory concentration (IC50) of the selected peptide was then determined via titration with hIAPP. Changes in fibril morphology following AMP addition to hIAPP were visualised through transmission electron microscopy (TEM) after 48h. Selected AMP was then tested in mouse insulinoma cells (MIN6) that were incubated with hIAPP to evaluate their protective effect through a cell viability assay. Results: Six AMPs were tested based on their possible structural affinity with hIAPP aggregates. A helical AMP significantly inhibited the fibrillization of hIAPP monomers for over 40h and reduced secondary nucleated aggregation kinetics. The AMP was found to be a high-affinity inhibitor of hIAPP aggregation with an IC50 of 12.66μM. TEM also showed that hIAPP amyloids formed in the presence of the AMP had shorter and fewer fibrils. Subsequent incubation of 10μM of hIAPP with 20μM of AMP improved MIN6 cell viability and ameliorated hIAPP-induced cytotoxicity. Conclusion: We have validated our ThT kinetic assay with the results of cellular viability experiments to ascertain the effectiveness of AMP in protecting pancreatic β-cells from hIAPP-associated toxicity. Our study underpins the potential of AMPs as a promising tool for therapeutic application in T2D. Disclosure J. Chen: None. A. Teo: Stock/Shareholder; BetaLife Pte Ltd. S. Bhattacharjya: None. Funding Ministry of Education, Singapore

Abstract P1-07-26: Annexin A6 modulates the secretion of pro-inflammatory cytokines and exosomes via membrane fusion with SNAP 23 in triple negative breast cancer

2025-06-13

Nobelle Sakwe , Portia L. Thomas , Josiah Ochieng +1 more | Clinical Cancer Research

Abstract The role of Annexin A6 (AnxA6) in the secretion of pro-inflammatory cytokines (PICs) and exosomes in triple negative breast cancer cells remains to be fully elucidated. However, understanding how … Abstract The role of Annexin A6 (AnxA6) in the secretion of pro-inflammatory cytokines (PICs) and exosomes in triple negative breast cancer cells remains to be fully elucidated. However, understanding how AnxA6 influences or whether it is involved in the secretion of PICs and exosomes is still debatable. PICs are largely known to be secreted into the cancer microenvironment through exocytosis. Moreover, previous studies have reported the involvement of PICs in drug resistance and metastasis during exocytosis. We had previously shown that AnxA6 is secreted as a component of extracellular vesicles and that breast cancer cells secrete annexins via the exosomal pathway. Here, we examined the secretory function of AnxA6 in monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8) cytokines that contribute to triple negative breast cancer (TNBC) progression and we show that the secretion of cytokines and exosomes is AnxA6-dependent. AnxA6 upregulation in TNBC cells promotes increased extracellular vesicles (EVs) secretion. We equally show that cholesterol loading into EVs may also be AnxA6-dependent and that lapatinib-induced upregulation of AnxA6 leads to increased cytokine secretion in MDA-MB-468 lapatinib-resistant (LAP-R) cells. Furthermore, we demonstrate that lapatinib-induced upregulation of AnxA6 expression in EVs in MDA-468 LAP-R cells also leads to increased cholesterol accumulation. SNAP 23 interacts with AnxA6 for increased secretion through fusion of vesicles with plasma membrane. Together, these data not only suggest that PIC, exosome secretion, and cholesterol enrichment is AnxA6-dependent, but also provide evidence that induced AnxA6 upregulation triggered by chronic lapatinib treatment will lead to increased PIC secretion in the cells, which is bad for TNBC progression and poor patient outcome. Citation Format: Nobelle Sakwe, Portia Thomas, Josiah Ochieng, Amos M. Sakwe. Annexin A6 modulates the secretion of pro-inflammatory cytokines and exosomes via membrane fusion with SNAP 23 in triple negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-07-26.

Analysis of serum S100A12, soluble advanced glycation end products receptor, and gut microbiome in elderly patients with colorectal cancer

2025-06-13

Shi-Xing Qiao , Ming-Liao Niu , Weitao Liang +3 more | World Journal of Gastrointestinal Oncology

BACKGROUND Colorectal cancer (CRC) ranks among the most prevalent malignancies in elderly populations, and chemotherapy resistance remains a critical clinical challenge. Emerging evidence highlights the interplay between chronic inflammation, gut … BACKGROUND Colorectal cancer (CRC) ranks among the most prevalent malignancies in elderly populations, and chemotherapy resistance remains a critical clinical challenge. Emerging evidence highlights the interplay between chronic inflammation, gut microbiome dysbiosis, and CRC progression. Proinflammatory cytokines [e.g. , interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α)] and mediators like S100 calcium-binding protein A12 (S100A12)/soluble receptor for advanced glycation end products (sRAGE) are implicated in tumorigenesis, while gut microbial imbalances may exacerbate inflammatory microenvironments conducive to chemotherapy resistance. However, the triad relationship between S100A12/sRAGE, gut microbiota profiles, and chemotherapy efficacy in elderly patients with CRC remains unexplored, limiting biomarker-driven therapeutic strategies. AIM To analyze the correlation between serum levels of S100A12, sRAGE, gut microbiome dysbiosis, and systemic inflammation in elderly patients with CRC and to assess their predictive value for chemotherapy efficacy. METHODS A retrospective analysis was conducted on the clinical data of 120 elderly patients with advanced-stage CRC who visited our hospital from August 2023 to May 2024. These patients were enrolled in the study group. Additionally, 120 healthy individuals undergoing routine health check-ups during the same period were selected as the control group. Serum S100A12, sRAGE, IL-6, and TNF-α levels were measured by ELISA, and fresh stool samples were collected before chemotherapy to analyze gut microbiome composition in the study group. Follow-up observations were conducted after chemotherapy. Pearson correlation analysis was used to explore the relationship between serum S100A12, sRAGE levels, and gut microbiome dysbiosis in patients with CRC. The predictive diagnostic value of pre-chemotherapy serum S100A12 and sRAGE levels for chemotherapy efficacy was assessed using receiver operating characteristic curves. RESULTS Pre-chemotherapy serum S100A12, sRAGE, IL-6, and TNF-α levels were significantly elevated in patients with CRC vs controls (all P < 0.05). These biomarkers progressively increased with microbiota dysbiosis severity (severe vs mild dysbiosis: S100A12: 340.26 ± 52.39 μg/L vs 302.53 ± 56.97 μg/L; sRAGE: 525.64 ± 37.32 ng/L vs 441.38 ± 48.73 ng/L, P < 0.05) and correlated strongly with IL-6 (r = 0.712) and TNF-α (r = 0.698). Post-chemotherapy, biomarker levels decreased (P < 0.05), coinciding with beneficial microbiota recovery (Bifidobacterium 176%, Lactobacillus 153%) and pathogenic taxa reduction (Escherichia coli 62%). The combined S100A12/sRAGE model predicted chemotherapy resistance with an area under the curve of 0.914 (sensitivity = 86.07%, specificity = 88.89%), outperforming individual biomarkers. CONCLUSION Elevated serum S100A12 and sRAGE in elderly patients with CRC reflected gut microbiome dysbiosis and systemic inflammation, driven by IL-6/TNF-α signaling. Their post-chemotherapy decline parallels microbiota restoration, supporting a microbiome-inflammation-biomarker axis. The combined biomarker model offers robust clinical utility for chemotherapy efficacy prediction and personalized therapeutic strategies.

Revisiting the role of Annexins in membrane trafficking

2025-06-13

Thomas Grewal , Volker Gerke , Jesper Nylandsted +2 more | Cellular and Molecular Life Sciences

Exploring the Clinical Implication of S100A9 in Ulcerative Colitis and Its Progression to Cancer: A Journey from Inflammation to Cancer

2025-06-13

Jaehwan Cheon , Soo‐Jin Kim , Jae‐Hyung Park +1 more | International Journal of Molecular Sciences

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation and debilitating symptoms that considerably impair life quality. UC is particularly prevalent in younger populations, where early … Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation and debilitating symptoms that considerably impair life quality. UC is particularly prevalent in younger populations, where early diagnosis remains challenging owing to nonspecific symptoms and the potential progression to colitis-associated cancer (CAC). The GSE177044 dataset, consisting of whole blood samples, was analyzed to identify differentially expressed genes, perform gene annotation, analyze key signaling pathways, and detect key hub genes in UC using protein–protein interaction networks. Multiple UC datasets composed of colonic samples were used for validation and examination of methylation and age-related gene expression patterns. Further analyses were performed to explore the association between these key hub genes and colon adenocarcinoma (COAD). We identified four key hub genes—lipocalin-2 (LCN2), matrix metalloproteinase-9 (MMP9), S100 calcium-binding protein A9 (S100A9), and olfactomedin-4 (OLFM4)—significantly up-regulated in UC, with S100A9 showing epigenetic regulation and age-dependent expression patterns. Additionally, S100A9 was strongly associated with poor prognosis in COAD, displaying hypo-methylation and elevated expression, especially in myeloid cell types, and links to altered immune and molecular subtypes. Our findings confirmed the hypo-methylation-driven up-regulation of LCN2, S100A9, and OLFM4 in UC, suggesting their potential as blood-based diagnostic biomarkers. Notably, S100A9 has emerged as a promising biomarker for the early diagnosis of ulcerative colitis, particularly in pediatric and adolescent patients with UC. Moreover, S100A9 holds potential as a precision target to prevent progression from UC to CAC.

Dissecting liver inflammation ecosystem identifies annexin A1 as a pro-resolving target for liver failure

2025-06-12

Yu Xia , Weihong Tian , Xuanwen Bao +7 more | Hepatology

Background and Aims: Acute-on-chronic liver failure (ACLF) is driven by systemic inflammation and immune dysregulation. This study aims to characterize the immune landscape in ACLF and identify potential therapeutic targets. … Background and Aims: Acute-on-chronic liver failure (ACLF) is driven by systemic inflammation and immune dysregulation. This study aims to characterize the immune landscape in ACLF and identify potential therapeutic targets. Approach and Results: We employed single-cell RNA sequencing, visium spatial sequencing, bulk RNA sequencing, and bioinformatics analysis to profile immune cells in ACLF livers compared to acute liver failure (ALF), decompensated cirrhosis (DC), and controls. ACLF livers exhibited a distinct immune signature with increased neutrophils, particularly CCL4 + subsets, which drive unresolved inflammation by recruiting additional neutrophils and inflammatory CD14 + S100A9 + monocytes. Resident Kupffer cells were reduced, and monocytes differentiated into TREM2 + macrophages with an M1-like pro-inflammatory phenotype, exacerbating inflammation. Additionally, lymphoid cells showed significant dysfunction, with reduced NK cells and relatively expanded T cells exhibiting diminished cytotoxicity or pro-inflammatory cytokine production. Cell-cell communication analysis identified the ANXA1-FPR1 axis as a key interaction between T cells and myeloid cells, serving as a negative feedback mechanism to dampen inflammation. Plasma and hepatic ANXA1 levels were elevated in ACLF patients, correlating with disease severity. In preclinical model, the ANXA1 peptide Ac2-26 improved liver function, reduced inflammation, and promoted macrophage polarization from M1 to M2. In vitro, Ac2-26 inhibited CCL4-mediated monocyte chemotaxis and M1 polarization, effects partially blocked by the FPR1 inhibitor Randialic acid B. Mechanically, Ac2-26 activated AMPK and inhibited mTOR signaling. Conclusions: Our findings provide a comprehensive immune profile in ACLF and highlight ANXA1 as a potential therapeutic target for resolving immune dysregulation and improving outcomes in ACLF.

S100 A16 promotes the progression of osteosarcoma by activating the PI3 K/AKT signaling pathway through ANXA2

2025-06-06

Ying-Ying Xiang , Jiang‐Hua Liu , Xin Yi +3 more | Scientific Reports

Abstract Osteosarcoma is a common primary malignant bone tumor. S100A16 gene was reported to highly expressed in several tumor tissues while the relationship between S100A16 and osteosarcoma remains less well-understood. … Abstract Osteosarcoma is a common primary malignant bone tumor. S100A16 gene was reported to highly expressed in several tumor tissues while the relationship between S100A16 and osteosarcoma remains less well-understood. This study aimed to investigate the expression characteristics of S100A16 in osteosarcoma and the mechanism by which it promotes osteosarcoma progression. Firstly, by analyzing databases and assessing mRNA and protein level, we found that the expression of S100A16 was significantly promoted in osteosarcoma, as compared with normal tissue. Then transfection techniques were employed to upregulate and downregulate S100A16 in osteosarcoma cells, the results demonstrated that S100A16 can increase osteosarcoma cell viability, migration and invasion capacities, while decline osteosarcoma cell apoptosis. GSEA (gene set enrichment analysis) revealed that increased expression of S100A16 was enriched in the PI3K/AKT pathway. Cellular experiments showed that the S100A16 promoted osteosarcoma progression by activating the PI3K/AKT signaling pathway, and upregulated expression of ANXA2, a crucial protein in occurrence and development of tumors. We also found that overexpression of ANXA2 can restore the decreased levels of p-PI3K and p-AKT induced by S100A16 inhibition, which indicated that S100A16 stimulates PI3K/AKT pathway activation via ANXA2. To sum up, S100A16 can promotes osteosarcoma progression by activating the PI3K/AKT signaling pathway through ANXA2, suggesting that the S100A16/ANXA2 axis may represent a novel therapeutic target for osteosarcoma.

Generation of decellularized human brain tissue for investigating cell-matrix interactions: a proof-of-concept study

2025-06-05

Roemel Jeusep Bueno , Camila Fernández‐Zapata , Maren Salla +7 more | Frontiers in Bioengineering and Biotechnology

The brain extracellular matrix (ECM) regulates myelin repair and regeneration following a demyelinating event by interacting with neuronal progenitors and immune cells. Therefore, generation and characterization of decellularized human brain … The brain extracellular matrix (ECM) regulates myelin repair and regeneration following a demyelinating event by interacting with neuronal progenitors and immune cells. Therefore, generation and characterization of decellularized human brain tissue (DHBT) in regions with distinct neuroregenerative capacities are essential to determine factors modulating the cellular regenerative behavior. We have established an effective decellularization protocol for the human neural stem cell (NSC)-rich subventricular zone (SVZ) as well as, frontal cortex (FC) and white matter (WM), and defined region-specific matrisomes with comparative proteomics. Subsequently, as proof-of-concept, survival and differentiation of NSCs and monocytes within the DHBT were investigated. The proteomic analysis of the DHBT confirmed the retention of matrisome proteins such as COL4A1, FBB, NCAN, ANXA2. Unique to the SVZ were LGI3 and C1QB, while annexins, S100A and TGM2 were found in FC; S100B was exclusive to the WM. NSCs cultured within WM and FC acquired an astrocytic phenotype, but both astrocytic and oligodendrocytic phenotypes were promoted by the SVZ DHBT. Moreover, imaging mass cytometry analysis indicated an anti-inflammatory phenotype differentiation of monocytes seeded on SVZ and WM. Thus, the established model is suitable for investigation of ECM properties and assessment of cell-matrix interactions.

[Clinical phenotype and genotype analysis of neuroinflammation, autoinflammation, splenomegaly and anemia syndrome caused by IRAK4 gene variantion].

2025-06-02

Shie‐Ming Peng , Shiru Yuan , Z. X. Sun +3 more

Objective: To summarize the clinical and genetic features of neuroinflammation, autoinflammation, splenomegaly and anemia (NASA) syndrome and investigate the pathogenic mechanism. Methods: The clinical data of 2 patients diagnosed with … Objective: To summarize the clinical and genetic features of neuroinflammation, autoinflammation, splenomegaly and anemia (NASA) syndrome and investigate the pathogenic mechanism. Methods: The clinical data of 2 patients diagnosed with NASA syndrome at Department of Pediatrics, Peking Union Medical College Hospital were retrospectively analyzed. Variants were identified by gene panel sequencing and confirmed by Sanger sequencing. The function of IRAK4 gene variants was studied in vitro. Results: Among the 2 patients, case 1 was an 8-year-old girl and case 2 was a 10-year-old boy. Both patients presented in early childhood with anemia and hepatosplenomegaly. Case 1 was also experienced recurrent seizures. Laboratory examinations showed elevated inflammatory markers and neuroimaging revealed bilateral basal ganglia calcification. In case 2, anemia and inflammation markers were well controlled after treatment with tocilizumab, while case 1 succumbed to recurrent seizures. Genetic tests verified compound heterozygous variants in IRAK4 gene: case 1 carries a nonsense variant c.592G>T (p.G198X) and a missense variant c.248A>C (p.D83A), which were respectively from the parents; case 2 carries a c.831+3A>G variant and a frameshift variant c.540delT (p.F180Lfs*26), and the former was inherited from the father and the latter from the mother. The reverse transcription and Sanger sequencing results confirmed that c.831+3A>G variant led to exon 7 skipping. In vitro studies indicated that c.592G>T, c.540delT and c.831+3A>G variants resulted in truncated interleukin-1 receptor-associated kinase-4 (IRAK4) protein while c.248A>C do not cause changes in IRAK4 protein expression level and protein length. Conclusions: NASA syndrome should be considered in children with early-onset anemia, hepatosplenomegaly, recurrent seizures, elevated inflammatory markers and intracranial calcification. IRAK4 gene variants may lead to impaired anti-inflammatory function of IRAK4 protein, contributing to the autoinflammatory phenotype.

Diagnostic value of the combined detection of serum tumor necrosis factor-α and fecal calprotectin in early sepsis-related encephalopathy

2025-06-02

Chenghong OuYang , Chang‐Hun Yang , Qi Wu +2 more | Frontiers in Medicine

To investigate the value of tumor necrosis factor-α (TNF-α) and fecal calprotectin in the early diagnosis and prognosis of sepsis-associated encephalopathy (SAE). We recruited 150 patients with sepsis, admitted from … To investigate the value of tumor necrosis factor-α (TNF-α) and fecal calprotectin in the early diagnosis and prognosis of sepsis-associated encephalopathy (SAE). We recruited 150 patients with sepsis, admitted from January 2020 to January 2022. Of these, 80 patients had SAE and 70 patients did not. The levels of serum TNF-α and fecal calprotectin of patients while in the intensive care unit were measured and correlated with the acute physiology and chronic health evaluation scoring system II (APACHE II) score, the sequential organ failure assessment (SOFA) score and 28-day mortality. We examined the value of TNF-α and fecal calprotectin in the diagnosis and prognosis of SAE. The APACHE II and SOFA scores and 28-day mortality of the SAE group were significantly higher than those of the sepsis group, which indicated that the condition of the SAE group was more critical. In the SAE group, TNF-α and fecal calprotectin levels were positively correlated with the APACHE II and SOFA scores (P < 0.05), which may be related to disease severity. Assessing TNF-α level alongside fecal calprotectin level is highly valuable for the diagnosis of SAE and determining poor prognoses in SAE patients. TNF-α and fecal calprotectin may be involved in the pathogenesis of SAE. Both have high specificity and sensitivity for early SAE diagnosis. Moreover, they have good predictive value and can serve as prognostic indicators.

Comparison of total calprotectin levels with S100A8 and S100A9 subunit levels in critically ill patients

2025-06-02

Kristina Sejersen , Aleksandra Mandic Havelka , Miklós Lipcsey +1 more | Scandinavian Journal of Clinical and Laboratory Investigation

Calprotectin is a 24 kD heterodimer of calcium-binding proteins S100A8 and S100A9. At present, there is a lack of knowledge about the specificity of various methods for calprotectin detection, whether … Calprotectin is a 24 kD heterodimer of calcium-binding proteins S100A8 and S100A9. At present, there is a lack of knowledge about the specificity of various methods for calprotectin detection, whether they measure only dimers between S100A8 and S100A9, S100A8-S100A8 dimers, S100A9/S100A9 dimers, or free subunits. This study aimed to compare total calprotectin levels with those of its subunits, S100A8 and S100A9, in ICU patients. This prospective observational study includes 271 sepsis and non-sepsis patients. Inclusion criteria were admission to intensive care and the presence or need for an arterial catheter. Plasma total calprotectin was measured at ICU admission and the following two days by particle-enhanced turbidimetric (PETIA) calprotectin reagents from Gentian AS and a Mindray BS380 chemistry analyzer. S100A8 and S100A9 were analyzed by commercial sandwich ELISA DY4570-05, and DY5578, R&D Systems, respectively. Sepsis was defined according to Sepsis-3 as suspected infection and a Sequential organ failure assessment (SOFA) >2 on admission. Receiver operating characteristic (ROC) analysis showed that total calprotectin had a larger area under the curve (AUC) for distinguishing sepsis from non-sepsis patients (0.67) compared to S100A8 (0.59) and S100A9 (0.52). For predicting 30-day mortality, S100A9 had a higher AUC value (0.64) than S100A8 (0.59). However, weak correlations between total calprotectin and its subunits suggest no significant predictive relationship for 30-day mortality, while also highlighting potential assay harmonization challenges across manufacturers.

Different regulation of alpha-1 antitrypsin production in neutrophils of ZZ-AATD patients under hypoxic conditions

2025-06-01

M Magallón , Lucía Bañuls , Silvia Castillo +6 more | Archivos de Bronconeumología

Therapeutic potential of the annexin A family in atherosclerosis

2025-06-01

Suha Jarad , Dawei Zhang | Clinical and Translational Discovery

Abstract Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality and morbidity worldwide despite advancements in therapeutic options for the management of atherosclerosis (AS). Treatments that lower low‐density lipoprotein … Abstract Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality and morbidity worldwide despite advancements in therapeutic options for the management of atherosclerosis (AS). Treatments that lower low‐density lipoprotein (LDL) cholesterol levels, such as statins or proprotein convertase subtilisin/kexin type 9 inhibitors, have effectively reduced ASCVD risk. However, residual CVD risk remains high, highlighting the need for additional effective therapies. Recently, colchicine has been approved for managing AS, introducing new avenues for targeting inflammation, a key process in AS. Various factors contribute to AS progression, such as endothelial dysfunction, leukocyte transmigration, vascular smooth muscle cell migration and phenotype‐switching, increased lipid retention, production of pro‐inflammatory cytokines and regulated cell death processes such as apoptosis. The annexin A (AnxA) family of proteins is well‐known for their ability to bind Ca 2+ and phospholipids, and they play diverse roles in inflammation, cell proliferation, migration, differentiation and signalling. Several AnxA proteins have been implicated in essential processes involved in AS development, including endothelial dysfunction, leukocyte transmigration and apoptosis. In this mini‐review, we highlight the roles of AnxA1, AnxA2, AnxA5, AnxA6, AnxA7 and AnxA8 in AS development and progression and their therapeutic potential in AS management.

Oleic acid inhibits the proliferation, invasion and migration of tongue squamous cell carcinoma cells under high glucose conditions through S100A9-HK2/PKM2-SOD2 signaling pathway

2025-06-01

Yujie Ma , Rong Liu , Juan Zhan +5 more | Tissue and Cell

SAS-Therapie ohne Effekt auf die Kognition

2025-06-01

Ilias Masouris | InFo Neurologie + Psychiatrie