scholarly journals 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Shan-Ting Liao ◽  
Chao Han ◽  
Ding-Qiao Xu ◽  
Xiao-Wei Fu ◽  
Jun-Song Wang ◽  
...  
Keyword(s):  
Aerobic Glycolysis ◽  
Glycolytic Enzyme ◽  
Cysteine Residue ◽  
Glycolytic Flux ◽  
Flux Analysis ◽  
Activated Macrophages ◽  
A Cell ◽  
Anti Inflammatory ◽  
Heptelidic Acid

Abstract Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by U13C glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.

scholarly journals Sizes and Sufficient Quantities of MSC Microspheres for Intrathecal Injection to Modulate Inflammation in Spinal Cord Injury

Nano LIFE ◽  
2015 ◽  
Vol 05 (04) ◽  
pp. 1550004 ◽  
Author(s):  
Suneel Kumar ◽  
Joanne Babiarz ◽  
Sayantani Basak ◽  
Jae Hwan Kim ◽  
Jeffrey Barminko ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Lumbar Spine ◽  
White Matter ◽  
Intrathecal Injection ◽  
Critical Parameters ◽  
Activated Macrophages ◽  
Cord Injury ◽  
Anti Inflammatory

Microencapsulation of mesenchymal stem cells (MSC) in alginate facilitates cell delivery, localization and survival, and modulates inflammation in vivo. However, we found that delivery of the widely used ∼ 0.5mm diameter encapsulated MSC (eMSC) by intrathecal injection into spinal cord injury (SCI) rats was highly variable. Injections of smaller (∼ 0.2 mm) diameter eMSC into the lumbar spine were much more reproducible and they increased the anti-inflammatory macrophage response around the SCI site. We now report that injection of small eMSC [Formula: see text][Formula: see text]cm caudal from the rat SCI improved locomotion and myelin preservation 8 weeks after rat SCI versus control injections. Because preparation of sufficient quantities of small eMSC for larger studies was not feasible and injection of the large eMSC is problematic, we have developed a procedure to prepare medium-sized eMSC ([Formula: see text][Formula: see text]mm diameter) that can be delivered more reproducibly into the lumbar rat spine. The number of MSC incorporated/capsule in the medium sized capsules was [Formula: see text]5-fold greater than that in small capsules and the total yield of eMSC was ∼ 20-fold higher than that for the small capsules. Assays with all three sizes of eMSC capsules showed that they inhibited TNF-[Formula: see text] secretion from activated macrophages in co-cultures, suggesting no major difference in their anti-inflammatory activity in vitro. The in vivo activity of the medium-sized eMSC was tested after injecting them into the lumbar spine 1 day after SCI. Histological analyses 1 week later showed that eMSC reduced levels of activated macrophages measured by IB4 staining and increased white matter sparing in similar regions adjacent to the SCI site. The combined results indicate that ∼ 0.35 mm diameter eMSC reduced macrophage inflammation in regions where white matter was preserved during critical early phases after SCI. These techniques enable preparation of eMSC in sufficient quantities to perform pre-clinical SCI studies with much larger numbers of subjects that will provide functional analyses of several critical parameters in rodent models for CNS inflammatory injury.

scholarly journals In Vivo Metabolism of [1,6-13C2]Glucose Reveals Distinct Neuroenergetic Functionality between Mouse Hippocampus and Hypothalamus

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 50
Author(s):  
Antoine Cherix ◽  
Rajesh Sonti ◽  
Bernard Lanz ◽  
Hongxia Lei
Keyword(s):  
Metabolic Flux ◽  
Aerobic Glycolysis ◽  
Resonance Spectroscopy ◽  
Flux Analysis ◽  
Gamma Aminobutyric Acid ◽  
Atp Production ◽  
Functional Features ◽  
Metabolic Dependence ◽  
The Brain

Glucose is a major energy fuel for the brain, however, less is known about specificities of its metabolism in distinct cerebral areas. Here we examined the regional differences in glucose utilization between the hypothalamus and hippocampus using in vivo indirect 13C magnetic resonance spectroscopy (1H-[13C]-MRS) upon infusion of [1,6-13C2]glucose. Using a metabolic flux analysis with a 1-compartment mathematical model of brain metabolism, we report that compared to hippocampus, hypothalamus shows higher levels of aerobic glycolysis associated with a marked gamma-aminobutyric acid-ergic (GABAergic) and astrocytic metabolic dependence. In addition, our analysis suggests a higher rate of ATP production in hypothalamus that is accompanied by an excess of cytosolic nicotinamide adenine dinucleotide (NADH) production that does not fuel mitochondria via the malate-aspartate shuttle (MAS). In conclusion, our results reveal significant metabolic differences, which might be attributable to respective cell populations or functional features of both structures.

scholarly journals MicroRNA-16-1-3p Represses Breast Tumor Growth and Metastasis by Inhibiting PGK1-Mediated Warburg Effect

2020 ◽  
Vol 8 ◽  
Author(s):  
Tianxin Ye ◽  
Yingchun Liang ◽  
Deyu Zhang ◽  
Xuewu Zhang
Keyword(s):  
Breast Cancer ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Phosphoglycerate Kinase ◽  
Glycolytic Enzyme ◽  
Breast Cancer Patients ◽  
Atp Production ◽  
Glycolysis Pathway

The Warburg effect (aerobic glycolysis) is a hallmark of cancer and is becoming a promising target for diagnosis and therapy. Phosphoglycerate kinase 1 (PGK1) is the first adenosine triphosphate (ATP)-generating glycolytic enzyme in the aerobic glycolysis pathway and plays an important role in cancer development and progression. However, how microRNAs (miRNAs) regulate PGK1-mediated aerobic glycolysis remains unknown. Here, we show that miR-16-1-3p inhibits PGK1 expression by directly targeting its 3′-untranslated region. Through inhibition of PGK1, miR-16-1-3p suppressed aerobic glycolysis by decreasing glucose uptake, lactate and ATP production, and extracellular acidification rate, and increasing oxygen consumption rate in breast cancer cells. Aerobic glycolysis regulated by the miR-16-1-3p/PGK1 axis is critical for modulating breast cancer cell proliferation, migration, invasion and metastasis in vitro and in vivo. In breast cancer patients, miR-16-1-3p expression is negatively correlated with PGK1 expression and breast cancer lung metastasis. Our findings provide clues regarding the role of miR-16-1-3p as a tumor suppressor in breast cancer through PGK1 suppression. Targeting PGK1 through miR-16-1-3p could be a promising strategy for breast cancer therapy.

Inhibition of LPS-Induced iNOS, COX-2 and Inflammatory Mediator Expression by Paeonol through the MAPKs Inactivation in RAW 264.7 Cells

2009 ◽  
Vol 37 (01) ◽  
pp. 181-194 ◽  
Author(s):  
Hee-Sung Chae ◽  
Ok-Hwa Kang ◽  
Young-Seob Lee ◽  
Jang-Gi Choi ◽  
You-Chang Oh ◽  
...  
Keyword(s):  
Inflammatory Mediator ◽  
Raw 264.7 Cells ◽  
Erk Activation ◽  
Analgesic Effects ◽  
A Cell ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Analgesic Activities ◽  
Biting Time

We evaluated the in vivo anti-inflammatory and analgesic activities of orally administered paeonol in mice, and also investigated the anti-inflammatory activity of paeonol in a cell line. Paeonol significantly reduced the edema induced by arachidonic acid in rats. The analgesic effects were assayed using 2 different models, i.e., by acetic acid-induced writhing response and by formalin induced licking and biting time. Moreover, we examined the effects of paeonol on the release of inflammatory mediators such as NO , PGE2 and IL-6. Our results demonstrated that paeonol inhibited LPS induced expression of NO , PGE2 and IL-6. Paeonol prevented LPS induced iNOS, COX-2 and ERK activation. Therefore, paeonol appears to have potential as a treatment for inflammatory disease and analgesic.

scholarly journals Tiliroside Ameliorates Ulcerative Colitis by Restoring the M1/M2 Macrophage Balance via the HIF-1α/glycolysis Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Hongda Zhuang ◽  
Qi Lv ◽  
Chao Zhong ◽  
Yaru Cui ◽  
Luling He ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Therapeutic Approach ◽  
Activity Index ◽  
Aerobic Glycolysis ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Inflammatory Status ◽  
Promising Therapeutic Approach ◽  
Anti Inflammatory

Macrophages polarized to different phenotypes critically contribute to colitis development by coordinating inflammatory and anti-inflammatory processes. Herein, targeting the balance between the pro-inflammatory M1 and the anti-inflammatory M2 macrophage phenotypes can be a novel therapeutic approach for colitis. In the present study, we firstly demonstrated that tiliroside possessed the ability to alleviate the clinical symptoms of colitis as evidenced by decreased disease activity index (DAI) scores, longer colon length, reduced myeloperoxidase (MPO) activity, and improvement of colonic pathological damage in vivo. Furthermore, we showed that tiliroside modulated the balance between M1 and M2 macrophages toward a more anti-inflammatory status in colonic lamina propria but has little effect on the T cell population and epithelial barrier function in colitis mice. The macrophage depletion study further showed the protective effect of tiliroside was macrophage dependent in vivo. Mechanistically, our study demonstrated that tiliroside regulated cellular metabolism by inhibiting aerobic glycolysis in LPS and IFNγ stimulated macrophages. At the molecular level, tiliroside facilitated the proteasomal degradation of HIF-1α and downregulated mRNA expressions of HIF-1α dependent glycolytic enzymes in macrophages. Collectively, our data highlight the aberrant M1/M2 macrophage polarization in the initiation and development of ulcerative colitis and put forth the stage for considering tiliroside as a metabolic regulator in reprogramming macrophage polarization, which may serve as a promising therapeutic approach for treatment of inflammation-associated and metabolic disorders.

scholarly journals Itaconate Inhibits TET DNA Dioxygenases to Dampen Inflammatory Responses

2021 ◽  
Author(s):  
Dan Ye ◽  
Leilei Chen ◽  
Carmen Morcelle ◽  
Zhouli Cheng ◽  
Xiufei Chen ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Inflammatory Responses ◽  
Aerobic Glycolysis ◽  
Dna Demethylation ◽  
Metabolic Reprogramming ◽  
Immune Response Gene ◽  
Metabolic Enzyme ◽  
Active Dna Demethylation ◽  
Anti Inflammatory

Abstract The immune-response gene 1 (IRG1) plays a key role in anti-pathogen defense, as deletion of Irg1 in mice causes severe defects in response to bacterial and viral infection, and decreased survival1, 2. IRG1 transcription is rapidly induced by pathogen infection and inflammatory conditions primarily in cells of myeloid lineage3. IRG1 encodes a mitochondrial metabolic enzyme, aconitate decarboxylase 1 (ACOD1), that catalyzes the decarboxylation of cis-aconitate to produce the anti-inflammatory metabolite itaconic acid (ITA)4. Several molecular processes are affected by ITA, including succinate dehydrogenase (SDH) inhibition5, resulting in succinate accumulation and metabolic reprogramming6, 7, and alkylation of protein cysteine residues, inducing the electrophilic stress response mediated by NRF2 and IκBζ8, 9 and impairing aerobic glycolysis10. However, the mechanisms by which ITA exerts its profound anti-inflammatory effect still remains to be fully elucidated. Here, we show that ITA is a potent inhibitor of the TET family DNA dioxygenases, which catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) during the process of active DNA demethylation. ITA binds to the same site of α-ketoglutarate (α-KG) in TET2, inhibiting its catalytic activity. Lipopolysaccharides (LPS) treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals TET2 is a major target of ITA in suppressing LPS-induced genes, including those regulated by NF-κB and STAT signaling pathways. In vivo, ITA decreases 5hmC, reduces LPS-induced acute pulmonary edema and lung and liver injury, and protects mice against lethal endotoxaemia in a manner that is dependent on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory response.

scholarly journals Protective Effect of Piplartine against LPS-Induced Sepsis through Attenuating the MAPKs/NF-κB Signaling Pathway and NLRP3 Inflammasome Activation

2021 ◽  
Vol 14 (6) ◽  
pp. 588
Author(s):  
Chi-Han Huang ◽  
Shu-Chi Wang ◽  
I-Chen Chen ◽  
Yi-Ting Chen ◽  
Po-Len Liu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ex Vivo ◽  
Biological Properties ◽  
Inflammasome Activation ◽  
Activated Macrophages ◽  
Nlrp3 Inflammasome Activation ◽  
Tnf Α ◽  
Anti Inflammatory

Piplartine (or Piperlongumine) is a natural alkaloid isolated from Piper longum L., which has been proposed to exhibit various biological properties such as anti-inflammatory effects; however, the effect of piplartine on sepsis has not been examined. This study was performed to examine the anti-inflammatory activities of piplartine in vitro, ex vivo and in vivo using murine J774A.1 macrophage cell line, peritoneal macrophages, bone marrow-derived macrophages and an animal sepsis model. The results demonstrated that piplartine suppresses iNOS and COX-2 expression, reduces PGE2, TNF-α and IL-6 production, decreases the phosphorylation of MAPKs and NF-κB and attenuates NF-κB activity by LPS-activated macrophages. Piplartine also inhibits IL-1β production and suppresses NLRP3 inflammasome activation by LPS/ATP- and LPS/nigericin-activated macrophages. Moreover, piplartine reduces the production of nitric oxide (NO) and TNF-α, IL-6 and IL-1β, decreases LPS-induced tissue damage, attenuates infiltration of inflammatory cells and enhances the survival rate. Collectively, these results demonstrate piplartine exhibits anti-inflammatory activities in LPS-induced inflammation and sepsis and suggest that piplartine might have benefits for sepsis treatment.

scholarly journals The Anti-Inflammatory Activity of a Novel Fused-Cyclopentenone Phosphonate and Its Potential in the Local Treatment of Experimental Colitis

2015 ◽  
Vol 2015 ◽  
pp. 1-10
Author(s):  
Dorit Moradov ◽  
Helena Shifrin ◽  
Efrat Harel ◽  
Mirela Nadler-Milbauer ◽  
Marta Weinstock ◽  
...  
Keyword(s):  
Rat Model ◽  
Local Treatment ◽  
Experimental Colitis ◽  
Inflammatory Activity ◽  
Mucosal Inflammation ◽  
Activated Macrophages ◽  
Aminosalicylic Acid ◽  
Anti Inflammatory

A novel fused-cyclopentenone phosphonate compound, namely, diethyl 3-nonyl-5-oxo-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-ylphosphonate (P-5), was prepared and testedin vitro(LPS-activated macrophages) for its cytotoxicity and anti-inflammatory activity andin vivo(DNBS induced rat model) for its potential to ameliorate induced colitis. Specifically, the competence of P-5 to reduce TNFα, IL-6, INFγ, MCP-1, IL-1α, MIP-1α, and RANTES in LPS-activated macrophages was measured. Experimental colitis was quantified in the rat model, macroscopically and by measuring the activity of tissue MPO and iNOS and levels of TNFαand IL-1β. It was found that P-5 decreased the levels of TNFαand the tested proinflammatory cytokines and chemokines in LPS-activated macrophages. In the colitis-induced rat model, P-5 was effective locally in reducing mucosal inflammation. This activity was equal to the activity of local treatment with 5-aminosalicylic acid. It is speculated that P-5 may be used for the local treatment of IBD (e.g., with the aid of colon-specific drug platforms). Its mode of action involves inhibition of the phosphorylation of MAPK ERK but not of p38 and had no effect on IκBα.

scholarly journals Production and Characterization of Chitooligosaccharides: Evaluation of Acute Toxicity, Healing, and Anti-Inflammatory Actions

2021 ◽  
Vol 22 (19) ◽  
pp. 10631
Author(s):  
Rafael Caetano Lisbôa Castro de Andrade ◽  
Nathália Kelly de Araújo ◽  
Manoela Torres-Rêgo ◽  
Allanny Alves Furtado ◽  
Alessandra Daniele-Silva ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Wound Repair ◽  
Biological Properties ◽  
In Vivo Models ◽  
Fibroblast Migration ◽  
A Cell ◽  
Anti Inflammatory ◽  
Two Stages

The search for promising biomolecules such as chitooligosaccharides (COS) has increased due to the need for healing products that act efficiently, avoiding complications resulting from exacerbated inflammation. Therefore, this study aimed to produce COS in two stages of hydrolysis using chitosanases derived from Bacillus toyonensis. Additionally, this study aimed to structurally characterize the COS via mass spectrometry, to analyze their biocompatibility in acute toxicity models in vivo, to evaluate their healing action in a cell migration model in vitro, to analyze the anti-inflammatory activity in in vivo models of xylol-induced ear edema and zymosan-induced air pouch, and to assess the wound repair action in vivo. The structural characterization process pointed out the presence of hexamers. The in vitro and in vivo biocompatibility of COS was reaffirmed. The COS stimulated the fibroblast migration. In the in vivo inflammatory assays, COS showed an antiedematogenic response and significant reductions in leukocyte migration, cytokine release, and protein exudate. The COS healing effect in vivo was confirmed by the significant wound reduction after seven days of the experiment. These results indicated that the presence of hexamers influences the COS biological properties, which have potential uses in the pharmaceutical field due to their healing and anti-inflammatory action.

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