Dataset Information

The Abilities of Salidroside on Ameliorating Inflammation, Skewing the Imbalanced Nucleotide Oligomerization Domain-Like Receptor Family Pyrin Domain Containing 3/Autophagy, and Maintaining Intestinal Barrier Are Profitable in Colitis.

ABSTRACT: Salidroside (Sal), as a major glycoside extracted from Rhodiola rosea L., has exhibited its mighty anti-aging, anti-oxidant, anti-cancer, anti-inflammation, and neuroprotective effects in many diseases. Recently, it has showed its protective effect in colitis mice by activating the SIRT1/FoxOs pathway. Whereas, it is not known whether Sal has other protective mechanisms on dextran sulfate sodium (DSS)-induced colitis in mice. In this study, we investigated the protective effects and mechanisms of Sal on DSS-induced colitis in mice. The results demonstrated Sal was a competent candidate in the treatment of ulcerative colitis (UC). Sal remitted DSS-induced disease activity index (DAI), colon length shortening, and colonic pathological damage. Simultaneously, Sal alleviated excessive inflammation by reversing the IL-1?, TNF-?, and IL-10 protein levels in DSS-treated mice. Western blot analysis revealed that Sal inhibited p65 and p38 activation together with peroxisome proliferator-activated receptor (PPAR?) up-regulation. In addition, Sal skewed the imbalanced activation of nucleotide oligomerization domain-like receptor family pyrin domain containing 3 inflammasome and autophagy contributing to colitis recovery. The damaged intestinal barrier induced by DSS was also alleviated along with plasma lipopolysaccharides (LPS) reduction after Sal treatment. In vitro, Sal showed PPAR?-dependent anti-inflammatory effect in LPS-stimulated RAW264.7 cells. In summary, our results demonstrated that Sal might be an effective factor for UC treatment and its pharmacological value deserved further development.

SUBMITTER: Liu J

PROVIDER: S-EPMC6901016 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Abilities of Salidroside on Ameliorating Inflammation, Skewing the Imbalanced Nucleotide Oligomerization Domain-Like Receptor Family Pyrin Domain Containing 3/Autophagy, and Maintaining Intestinal Barrier Are Profitable in Colitis.

Liu Jiuxi J Cai Jiapei J Fan Peng P Zhang Naisheng N Cao Yongguo Y

Frontiers in pharmacology 20191202

Salidroside (Sal), as a major glycoside extracted from <i>Rhodiola rosea</i> L., has exhibited its mighty anti-aging, anti-oxidant, anti-cancer, anti-inflammation, and neuroprotective effects in many diseases. Recently, it has showed its protective effect in colitis mice by activating the SIRT1/FoxOs pathway. Whereas, it is not known whether Sal has other protective mechanisms on dextran sulfate sodium (DSS)-induced colitis in mice. In this study, we investigated the protective effects and mecha ...[more]

PMID: 31849652

Similar Datasets

Project description:AimsThis study hypothesized that activation of endothelial nucleotide oligomerization domain-like receptor protein with pyrin domain containing 3 (Nlrp3) inflammasomes directly produces endothelial dysfunction during hypercholesterolemia, which is distinct from its canonical roles in inflammation.ResultsAcute hypercholesterolemia in mice was induced by intraperitoneal administration of poloxamer 407 (0.5?g/kg) for 24?h. Endothelial dysfunction was assessed by evaluating endothelium-dependent vasodilation in isolated, perfused, and pressurized coronary arteries in response to bradykinin (10(-10)-10(-6) M) and acetylcholine (10(-9)-10(-5) M). Impaired endothelium-dependent vasodilation was observed in Nlrp3(+/+) mice with acute hypercholesterolemia, which was markedly ameliorated in Nlrp3(-/-) mice. Treatment of mice with inhibitors for caspase-1 or high mobility group box 1 (HMGB1) significantly restored endothelium-dependent vasodilation in Nlrp3(+/+) mice with acute hypercholesterolemia. Confocal microscopic analysis demonstrated that hypercholesterolemia markedly increased caspase-1 activity and HMGB1 expression in coronary arterial endothelium of Nlrp3(+/+) mice, which was absent in Nlrp3-deficient mice. Further, recombinant HMGB1 directly induced endothelial dysfunction in normal Nlrp3(+/+) coronary arteries. In vitro, Nlrp3 inflammasome formation and its activity were instigated in cultured endothelial cells by cholesterol crystal, a danger factor associated with hypercholesterolemia. Moreover, cholesterol crystals directly induced endothelial dysfunction in coronary arteries from Nlrp3(+/+) mice, which was attenuated in Nlrp3(-/-) arteries. Such cholesterol crystal-induced impairment was associated with enhanced superoxide production, downregulation of endothelial nitric oxide synthase activity, and pyroptosis.Innovation and conclusionOur data provide the first evidence that activation of endothelial Nlrp3 inflammasome directly impairs endothelial function beyond its canonical inflammatory actions. This novel non-canonical action of Nlrp3 inflammasomes may initiate or exacerbate vascular injury during hypercholesterolemia.

Project description:The formation of multimerized protein assemblies has emerged as a core component of immune signal amplification, yet the biochemical basis of this phenomenon remains unclear for many mammalian proteins within host defense pathways. The interferon-inducible protein 16 (IFI16) is a viral DNA sensor that oligomerizes upon binding to nuclear viral DNA and induces downstream antiviral responses. Here, we identify the pyrin domain (PYD) residues that mediate IFI16 oligomerization in a charge-dependent manner. Based on structure modeling, these residues are predicted to be surface exposed within distinct α-helices. By generating oligomerization-deficient mutants, we demonstrate that IFI16 homotypic clustering is necessary for its assembly onto parental viral genomes at the nuclear periphery upon herpes simplex virus 1 (HSV-1) infection. Preventing oligomerization severely hampered the capacity of IFI16 to induce antiviral cytokine expression, suppress viral protein levels, and restrict viral progeny production. Restoring oligomerization via residue-specific charge mimics partially rescued IFI16 antiviral roles. We show that pyrin domains from PYHIN proteins are functionally interchangeable, facilitating cooperative assembly with the IFI16 HINs, highlighting an inherent role for pyrin domains in antiviral response. Using immunoaffinity purification and targeted mass spectrometry, we establish that oligomerization promotes IFI16 interactions with proteins involved in transcriptional regulation, including PAF1C, UBTF, and ND10 bodies. We further discover PAF1C as an HSV-1 restriction factor. Altogether, our study uncovers intrinsic properties that govern IFI16 oligomerization, which serves as a signal amplification platform to activate innate immune responses and to recruit transcriptional regulatory proteins that suppress HSV-1 replication.IMPORTANCE The ability of mammalian cells to detect the genomes of nuclear-replicating viruses via cellular DNA sensors is fundamental to innate immunity. Recently, mounting evidence is supporting the universal role of polymerization in these host defense factors as a signal amplification strategy. Yet, what has remained unclear are the intrinsic properties that govern their immune signal transmission. Here, we uncover the biochemical basis for oligomerization of the nuclear DNA sensor, IFI16. Upon infection with herpes simplex virus 1 (HSV-1) in human fibroblasts, we characterize the contribution of IFI16 oligomerization to downstream protein interactions and antiviral functions, including cytokine induction and suppression of HSV-1 replication. Until now, the global characterization of oligomerization-dependent protein interactions for an immune receptor has never been explored. Our integrative quantitative proteomics, molecular CRISPR/Cas9-based assays, mutational analyses, and confocal microscopy shed light on the dynamics of immune signaling cascades activated against pathogens.

Project description:Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin (IL)-1?-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease. CAPS is associated with gain-of-function missense mutations in NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), the gene encoding NLRP3. Moreover, most mutations leading to MWS occurred in exon 3 of NLRP3 gene. Here, we reported a novel mutation occurred in exon 1 of NLRP3 gene in an MWS patient and attempted to explore the pathogenic mechanism.Genetic sequence analysis of NLRP3 was performed in an MWS patient who presented with periodic fever, arthralgia, and multiform skin lesions. NLRP3 was also analyzed in this patient's parents and 50 healthy individuals. Clinical examinations including X-ray examination, skin biopsy, bone marrow aspiration smear, and blood test of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum levels of IL-1?, immunoglobulin E (IgE), antineutrophil cytoplasmic antibodies, antinuclear antibodies, and extractable nuclear antigen were also analyzed. The protein structure of mutant NLRP3 inflammasome was calculated by SWISS-MODEL software. Proteins of wild type and mutant components of NLRP3 inflammasome were expressed and purified, and the interaction abilities between these proteins were tested by surface plasmon resonance (SPR) assay.X-ray examination showed no abnormality in the patient's knees. Laboratory tests indicated an elevation of CRP (233.24 mg/L) and ESR (67 mm/h) when the patient had fever. Serum IL-1? increased to 24.37 pg/ml, and serum IgE was higher than 2500.00 IU/ml. Other blood tests were normal. Bone marrow aspiration smear was normal. A novel point mutation c.92A>T in exon 1 of NLRP3 gene was identified, which caused a p.D31V mutation in pyrin domain (PYD) of NLRP3. SPR assay showed that this point mutation may strengthen the interaction between the PYD of NLRP3 and the PYD of the apoptosis-associated speck-like protein. The mutation c.92A>T in exon 1 of the NLRP3 gene was not found in the patient's parents and 50 healthy individuals.The mutation c.92A>T in exon 1 of the NLRP3 gene is a novel mutation associated with MWS. The p.D31V mutation might promote the activation of NLRP3 inflammasome and induce MWS in this patient.

Dataset Information

The Abilities of Salidroside on Ameliorating Inflammation, Skewing the Imbalanced Nucleotide Oligomerization Domain-Like Receptor Family Pyrin Domain Containing 3/Autophagy, and Maintaining Intestinal Barrier Are Profitable in Colitis.

Publications

The Abilities of Salidroside on Ameliorating Inflammation, Skewing the Imbalanced Nucleotide Oligomerization Domain-Like Receptor Family Pyrin Domain Containing 3/Autophagy, and Maintaining Intestinal Barrier Are Profitable in Colitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure