Thrombospondin-1 promotes fibro-adipogenic stromal expansion and contractile dysfunction of the diaphragm in obesity.

Pulmonary disorders affect 40%-80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop diaphragm muscle weakness.

Thrombospondin-1 promotes fibro-adipogenic stromal expansion and contractile dysfunction of the diaphragm in obesity.

Pulmonary disorders impact 40-80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop diaphragmatic weakness.

Sustained Increases in Immune Transcripts and Immune Cell Trafficking During the Recovery of Experimental Brain Ischemia.

Background And Purpose: Stroke is a major cause of chronic neurological disability. There is considerable interest in understanding how acute transcriptome changes evolve into subacute and chronic patterns that facilitate or limit spontaneous recovery. Here we mapped longitudinal changes in gene expression at multiple time points after stroke in mice out to 6 months.

An Increase of Excitatory-to-Inhibitory Synaptic Balance in the Contralateral Cortico-Striatal Pathway Underlies Improved Stroke Recovery in BDNF Val66Met SNP Mice.

Despite negative association in cognition and memory, mice harboring BDNF SNP (BDNF) exhibit enhanced motor recovery accompanied by elevated excitatory synaptic markers VGLUT1 and VGLUT2 in striatum contralateral to unilateral ischemic stroke. The cortico-striatal pathway is a critical gateway for plasticity of motor/gait function. We hypothesized that enhanced excitability of the cortico-striatal pathway, especially of the contralateral hemisphere, underlies improved motor recovery.

Membrane-Tethered Metalloproteinase Expressed by Vascular Smooth Muscle Cells Limits the Progression of Proliferative Atherosclerotic Lesions.

Background: The MMP (matrix metalloproteinase) family plays diverse and critical roles in directing vascular wall remodeling in atherosclerosis. Unlike secreted-type MMPs, a member of the membrane-type MMP family, MT1-MMP (membrane-type 1 MMP; MMP14), mediates pericellular extracellular matrix degradation that is indispensable for maintaining physiological extracellular matrix homeostasis. However, given the premature mortality exhibited by MT1-MMP-null mice, the potential role of the proteinase in atherogenesis remains elusive.

Deletion of Calponin 2 in Mouse Fibroblasts Increases Myosin II-Dependent Cell Traction Force.

Cell traction force (CTF) plays a critical role in controlling cell shape, permitting cell motility, and maintaining cellular homeostasis in many biological processes such as angiogenesis, development, wound healing, and cancer metastasis. Calponin is an actin filament-associated cytoskeletal protein in smooth muscles and multiple types of non-muscle cells. An established biochemical function of calponin is the inhibition of myosin ATPase in smooth muscle cells.

Cell Surface CD36 Protein in Monocyte/Macrophage Contributes to Phagocytosis during the Resolution Phase of Ischemic Stroke in Mice.

Infiltrating monocyte-derived macrophages (M-M) influence stroke-induced brain injury. Although the inflammatory nature of M-M in acute stroke has been well documented, their role during the resolution phase of stroke is less clear. With emerging evidence for the involvement of scavenger receptors in innate immunity, this study addresses an M-M CD36 role in mediating phagocytosis during the recovery phase of stroke.

Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke.

Unlabelled: Stroke is the world's leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance recovery. Daidzein, a soy isoflavone, is a clinically approved agent that has a neuroprotective effect in vitro, and it promotes axon growth in an animal model of optic nerve crush. The current study investigates the efficacy of daidzein on neuroprotection and functional recovery in a clinically relevant mouse model of stroke recovery.

Lack of the scavenger receptor CD36 alters microglial phenotypes after neonatal stroke.

The stage of brain development at the time of stroke has a major impact on the pathophysiological mechanisms of ischemic damage, including the neuroinflammatory response. Microglial cells have been shown to contribute to acute and subchronic injury in adult stroke models, whereas in neonatal rodents we showed that microglial cells serve as endogenous neuroprotectants early following transient middle cerebral artery occlusion, limiting neuroinflammation and injury. In the neonate, microglial depletion or lack of the scavenger receptor CD36 exacerbates injury.

Matrix metalloproteinase-8 plays a pivotal role in neuroinflammation by modulating TNF-α activation.

Matrix metalloproteinases (MMPs) play important roles in normal brain development and synaptic plasticity, although aberrant expression of MMPs leads to brain damage, including blood-brain barrier disruption, inflammation, demyelination, and neuronal cell death. In this article, we report that MMP-8 is upregulated in LPS-stimulated BV2 microglial cells and primary cultured microglia, and treatment of MMP-8 inhibitor (M8I) or MMP-8 short hairpin RNA suppresses proinflammatory molecules, particularly TNF-α secretion. Subsequent experiments showed that MMP-8 exhibits TNF-α-converting enzyme (TACE) activity by cleaving the prodomain of TNF-α (A(74)/Q(75), A(76)/V(77) residues) and, furthermore, that M8I inhibits TACE activity more efficiently than TAPI-0, a general TACE inhibitor.

Genetic deletion of CD36 enhances injury after acute neonatal stroke.

Objective: The scavenger receptor CD36 is injurious in acute experimental focal stroke and neurodegenerative diseases in the adult. We investigated the effects of genetic deletion of CD36 (CD36ko) on acute injury, and oxidative and inflammatory signaling after neonatal stroke.

Methods: Postnatal day 9 CD36ko and wild-type (WT) mice were subjected to a transient middle cerebral artery occlusion (MCAO).

Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1.

The mutation or overexpression of alpha-synuclein protein plays a pivotal role in the pathogenesis of Parkinson's disease. In our preliminary experiments, we found that alpha-synuclein induced the expression of matrix metalloproteinases (MMPs) (MMP-1, -3, -8, and -9) in rat primary cultured microglia. Thus, the current study was undertaken to determine the roles of MMPs in alpha-synuclein-induced microglial activation.

Regulation of matrix metalloproteinase-9 gene expression in MPP+- or 6-OHDA-treated human neuroblastoma SK-N-BE(2)C cells.

The aberrant expression of matrix metalloproteinases (MMPs) is known to play an important role in various neurodegenerative diseases, such as Parkinson's disease. In the present study, we found that two well-known dopaminergic neurotoxins, 6-OHDA and MPP(+), induced the expression of MMP-9 in SK-N-BE(2)C human neuroblastoma and Cath.a mouse dopaminergic cell lines.

The neuroprotective role of tissue inhibitor of metalloproteinase-2 in MPP+- or 6-OHDA-treated SK-N-BE(2)C and SH-SY5Y human neuroblastoma cells.

Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs), and the aberrant expressions of MMPs are strongly associated with neuroinflammation and neuronal cell death. In the present study, we found that two well-known dopaminergic neurotoxins, MPP(+) and 6-OHDA, reduced TIMP-2 expression at the mRNA and protein levels in two human neuroblastoma cell lines (SK-N-BE(2)C and SH-SY5Y). To investigate the role of TIMP-2, these cells were transfected with TIMP-2 expression plasmid and viabilities were compared after treating cells with MPP(+) or 6-OHDA.

Inhibition of MMP-3 or -9 suppresses lipopolysaccharide-induced expression of proinflammatory cytokines and iNOS in microglia.

Recently, matrix metalloproteinases (MMPs) are emerging as important molecules in neuroinflammation as well as neuronal cell death. However, the role of MMPs in activated microglia remains unclear. In the present study, we found that expressions of MMP-1, -3, -8 and -9 were significantly induced by single or combined treatment of immunostimulants lipopolysaccharide (LPS) or phorbol myristate acetate (PMA) in primary cultured microglia and BV2 microglial cells.

Inhibition of matrix metalloproteinase-9 gene expression by an isoflavone metabolite, irisolidone in U87MG human astroglioma cells.

Matrix metalloproteinase-9 (MMP-9) plays an important role in mediating the invasion and angiogenic process of malignant gliomas. This study was undertaken to determine if an isoflavone metabolite, irisolidone, inhibits MMP-9 expression in human astroglioma cells. Irisolidone was found to inhibit the secretion and protein expression of MMP-9 induced by PMA in U87 MG glioma cells, accompanied by the inhibition of MMP-9 mRNA expression and promoter activity.

Anti-inflammatory mechanisms of isoflavone metabolites in lipopolysaccharide-stimulated microglial cells.

The microglial activation plays an important role in neurodegenerative diseases by producing several proinflammatory cytokines and nitric oxide (NO). We found that three types of isoflavones and their metabolites that are transformed by the human intestinal microflora suppress lipopolysaccharide (LPS)-induced release of NO and tumor necrosis factor (TNF)-alpha in primary cultured microglia and BV2 microglial cell lines. The inhibitory effect of the isoflavone metabolites (aglycon form) was more potent than that of isoflavones (glycoside form).

Curcumin suppresses phorbol ester-induced matrix metalloproteinase-9 expression by inhibiting the PKC to MAPK signaling pathways in human astroglioma cells.

The aberrant expression of matrix metalloproteinase-9 (MMP-9) is implicated in the invasion and angiogenesis process of brain tumor. This study has investigated the effects of curcumin on MMP-9 expression in human astroglioma cell lines. Curcumin significantly inhibited the MMP-9 enzymatic activity and protein expression that was induced by PMA.

Repression of interferon-gamma-induced inducible nitric oxide synthase (iNOS) gene expression in microglia by sodium butyrate is mediated through specific inhibition of ERK signaling pathways.

We have reported recently that sodium butyrate suppressed IFN-gamma, but not the LPS-mediated induction of nitric oxide and TNF-alpha in microglia via the specific inhibition of NF-kappaB. In order to further determine the upstream signaling mechanism involved in the IFN-gamma-specific down-regulation of iNOS by sodium butyrate in microglia, this study investigated the effect of sodium butyrate on the MAP kinase activities. Sodium butyrate significantly repressed the phosphorylation of ERK induced by IFN-gamma, but had little effect on that induced by LPS.

Ginseng saponin metabolite suppresses phorbol ester-induced matrix metalloproteinase-9 expression through inhibition of activator protein-1 and mitogen-activated protein kinase signaling pathways in human astroglioma cells.

Aberrant expression of matrix metalloproteinase-9 (MMP-9) is implicated in the process of invasion and angiogenesis of malignant tumors as well as in inflammatory diseases of the CNS. Therefore, the development of compounds that can inhibit or suppress MMP-9 is required to treat brain tumors. We investigated the effects of a ginseng saponin metabolite, compound K (20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol), on MMP-9 expression in human astroglioma cells.

A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia.

Excessive proinflammatory cytokine and NO production by activated microglia play a role in neurodegenerative disorders. In this study, we found that a new compound KL-1037 suppressed LPS-induced NO release/inducible nitric oxide synthase expression in BV2 mouse microglial cells. In addition, KL-1037 prominently diminished LPS-induced production of pro-inflammatory cytokines such as TNF-alpha, IL-1 beta and IL-6, while it increased anti-inflammatory IL-10 and TGF-beta 1 production.

Sodium butyrate suppresses interferon-gamma-, but not lipopolysaccharide-mediated induction of nitric oxide and tumor necrosis factor-alpha in microglia.

In the present study, we demonstrate that sodium butyrate repressed IFN-gamma-induced expression of iNOS and TNF-alpha, but had little effect on LPS-induced expression in BV2 murine microglial cells. Sodium butyrate significantly inhibited NF-kappa B binding and NF-kappa B-mediated transcription induced by IFN-gamma, suggesting that the anti-inflammatory effect of sodium butyrate is mediated via specific inhibition of the NF-kappa B pathway. IFN-gamma is a major stimulator of innate and adaptive immune response.

Differential regulation of inducible nitric oxide synthase and cytokine gene expression by forskolin and dibutyryl-cAMP in lipopolysaccharide-stimulated murine BV2 microglial cells.

This study shows that two cAMP elevating agents, dibutyryl-cAMP (dbcAMP) and forskolin, regulate the expression of several cytokines and inducible nitric oxide synthase (iNOS) in a different manner. Both dbcAMP and forskolin repressed lipopolysaccharide (LPS)-induced TNF-alpha expression and enhanced anti-inflammatory cytokine IL-10 level in the BV2 microglia. In contrast, they differentially regulated the iNOS, IL-6 and IL-1beta expression levels.

Regulation of the tyrosine hydroxylase gene promoter by histone deacetylase inhibitors.

Tyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine to 3,4-dihydroxy-L-phenylalanine, which is the first and rate-limiting step in catecholamine biosynthesis. In the present study, we report that treatment with the histone deacetylase (HDAC) inhibitors, trichostatin A (TSA) or sodium butyrate, prominently induces the TH promoter activity in both non-neuronal and neuronal cell lines. By analyzing a series of deletional reporter constructs, we also determined that the proximal 151bp region of the TH promoter is largely responsible for TSA-mediated activation.

Selective modulation of lipopolysaccharide-stimulated cytokine expression and mitogen-activated protein kinase pathways by dibutyryl-cAMP in BV2 microglial cells.

Cyclic AMP is a very important regulator in a wide range of biological processes, including inflammatory reactions. To investigate the role of cAMP in microglia, we examined the effect of dibutyryl-cAMP (dbcAMP) on lipopolysaccharide (LPS)-stimulated cytokine expression and signaling pathways in murine BV2 microglial cells. DbcAMP strongly suppressed LPS-induced TNF-alpha expression, without affecting NO, IL-6 or TGF-beta1 expression.