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Activation of AMPK suppresses NF-B signaling in macrophages . A and B, activation of AMPK by AICAR or CA-1AMPK inhibits NF-B luciferase reporter activity. RAW264.7 macrophages expressing pcDNA3.1, CA-1AMPK, or DN-1AMPK were co-transfected with pNFB-Luc vectors. After 5 h, cells were then treated overnight with vehicle (BSA for stearate and H 2 O for LPS), LPS (100 ng/ml), and stearate (250 M) with or without AICAR (2 mM). n 6. C, activation of AMPK blocks NF-B (p65) binding to the IL-6 promoter in ChIP assay. D, SYBR Green quantitative PCR was used to measure the promoter DNA immunoprecipitated by the anti-p65 antibody; n 3. All data are expressed as mean S.E. *, p 0.05. A.U., arbitrary units.
Source publication
In this study, we aim to determine cellular mechanisms linking nutrient metabolism to the regulation of inflammation and insulin resistance. The nutrient sensors AMP-activated protein kinase (AMPK) and SIRT1 show striking similarities in nutrient sensing and regulation of metabolic pathways. We find that the expression, activity, and signaling of t...
Contexts in source publication
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... of 1AMPK Antago- nizes NF-B in Macrophages-We further explored whether AMPK acts on the NF-B pathway to antagonize cytokine expression. Activation of the AMPK signaling pathway by AICAR or CA- 1AMPK significantly suppressed NF-B luciferase reporter activity induced by stearate (Fig. 5A) or LPS ( Fig. 5B) in macrophages. To further confirm the inhibitory effect of AMPK on NF-B signaling, we combined ChIP assays with SYBR Green quantitative PCR to examine the NF-B subunit p65 binding to the consensus sequence of the IL-6 promoter in vivo. Activating AMPK by AICAR prevented stearate-in- duced p65 DNA binding to the IL-6 ...
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... of 1AMPK Antago- nizes NF-B in Macrophages-We further explored whether AMPK acts on the NF-B pathway to antagonize cytokine expression. Activation of the AMPK signaling pathway by AICAR or CA- 1AMPK significantly suppressed NF-B luciferase reporter activity induced by stearate (Fig. 5A) or LPS ( Fig. 5B) in macrophages. To further confirm the inhibitory effect of AMPK on NF-B signaling, we combined ChIP assays with SYBR Green quantitative PCR to examine the NF-B subunit p65 binding to the consensus sequence of the IL-6 promoter in vivo. Activating AMPK by AICAR prevented stearate-in- duced p65 DNA binding to the IL-6 promoter, which ...
Context 3
... of AMPK on NF-B signaling, we combined ChIP assays with SYBR Green quantitative PCR to examine the NF-B subunit p65 binding to the consensus sequence of the IL-6 promoter in vivo. Activating AMPK by AICAR prevented stearate-in- duced p65 DNA binding to the IL-6 promoter, which can be mimicked by overexpression of CA-1AMPK and blocked by DN-1AMPK (Fig. 5C). Quantitation of immu- noprecipitated DNA by the SYBR Green PCR further con- firmed these findings (Fig. 5D). These data suggest that the anti-inflammatory effect of the AMPK signaling pathway is mainly mediated via inactivation of NF-B ...
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... p65 binding to the consensus sequence of the IL-6 promoter in vivo. Activating AMPK by AICAR prevented stearate-in- duced p65 DNA binding to the IL-6 promoter, which can be mimicked by overexpression of CA-1AMPK and blocked by DN-1AMPK (Fig. 5C). Quantitation of immu- noprecipitated DNA by the SYBR Green PCR further con- firmed these findings (Fig. 5D). These data suggest that the anti-inflammatory effect of the AMPK signaling pathway is mainly mediated via inactivation of NF-B ...
Citations
... Chromium could also reduce reactive oxygen species (ROS) and TNF-α, inhibit the expression of NF-kB, and decrease the expression of vascular cell adhesion molecule 1 (VCAM-1), thereby improving endothelial dysfunction [36]. Chromium also activates the cellular energy sensor 5' AMP-activated protein kinase (AMPK), which inhibits the activation of the NF-kB signaling pathway and the expression of inflammatory cytokines [37]. These anti-inflammatory and antioxidant properties may contribute to the regulation of blood pressure. ...
Background and Aim
The impact of trace elements and heavy metals on human health has attracted widespread attention. However, the correlation between urinary chromium concentrations and blood pressure remains unclear and inadequately reported, and the aim of this study was to investigate the relationship between urinary chromium concentrations and blood pressure in adults in the United States (US).
Methods
We utilized data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018 for this study. Multivariate logistic regression and multivariate linear regression were used to explore the association of urinary chromium concentrations with hypertension and blood pressure. Additionally, we also performed subgroup analysis and restricted cubic splines (RCS).
Results
A total of 2958 participants were enrolled in this study. The overall mean systolic blood pressure and diastolic blood pressure were 123.98 ± 0.60, 72.66 ± 0.57 mmHg, respectively. The prevalence of hypertension was found in 41.31% of the whole participants. In the fully adjusted model, we did not observe a correlation between urinary chromium concentrations and the risk of hypertension and systolic blood pressure. However, we found a negative association between urinary chromium concentrations and diastolic blood pressure. In subgroup analysis, we observed a positive association between urinary chromium and the risk of hypertension among participants older than 60 years of age and those who were Non-Hispanic Black. The interaction term highlighted the influence of age and race on this positive association. We also found a negative association of urinary chromium with diastolic blood pressure in male, participants who were current smokers, overweight, and other races, as well as those without alcohol use and anti-hypertensive drug use. However, the interaction term only revealed the influence of alcohol consumption on the negative association.
Conclusion
Our study suggested that urinary chromium concentrations may show a negative association with diastolic blood pressure and this association was significantly dependent on alcohol consumption. Besides, a positive association between urinary chromium and the risk of hypertension was also found among participants older than 60 years of age and those who were Non-Hispanic Black.
... We next investigated if the anti-inflammatory effect of I3A in RAW macrophages that we previously reported (Krishnan et al., 2018) depends on AMPK activation. We used siRNA to knock down prkaa1, the gene encoding AMPKα1, the main form of AMPKα in murine macrophages (Yang et al., 2010), and measured its effect on pro-inflammatory cytokine expression. The knockdown efficiency was ~50% for mRNA ( Figure 6-figure supplement 2A), ~40-50% for AMPK protein, and ~50-60% for p-AMPK ( Figure 6-figure supplement 2B, C), and the knockdown was stable for up to 96 hr at both mRNA and protein levels. ...
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota-derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and Tnfa and fatty acid-induced inflammatory responses in an aryl-hydrocarbon receptor (AhR)-dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet-induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic triglycerides (TG), liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A’s beneficial effects likely reflect the metabolite’s direct actions on the liver. Administration of I3A partially reversed WD-induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β-oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to non-alcoholic steatohepatitis (NASH).
... Macrophage polarisation involves the regulation of multiple signalling pathways and transcriptional networks, including NF-κB, peroxisome proliferatoractivated receptor-gamma (PPAR-γ), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), MAPK, Janus kinase/signal transducer and activator of transcription (JAK/STAT), Wnt/β-catenin and AMPK signalling pathways [56]. Given that AMPK is the important trigger for macrophage polarisation, we have discussed the role of only the AMPK signalling pathway in this review [47,51,55,[57][58][59][60][61][62][63] (Fig. 2). ...
... In addition, AMPK inhibits inflammatory signalling in macrophages and drives the transformation of proinflammatory M1 macrophages to anti-inflammatory M2 macrophages, which are crucial for chronic inflammation-induced insulin resistance [111]. In macrophageadipocyte co-culture systems, inactivation of AMPKα1 has been shown to inhibit insulin signalling and glucose uptake and upregulate JNK phosphorylation in adipocytes, indicating the activation of the JNK pathway, which is a key inflammatory pathway leading to insulin resistance [57,70]. Consistently, in vivo studies have demonstrated that mice lacking AMPKβ1 in haematopoietic cells exhibit the loss of AMPK activity in macrophages, accompanied by the increased accumulation of M1 macrophages in the liver and accelerated development of insulin resistance in response to diets that promote obesity [70,112]. ...
AMP-activated protein kinase (AMPK) is a ubiquitous sensor of energy and nutritional status in eukaryotic cells. It plays a key role in regulating cellular energy homeostasis and multiple aspects of cell metabolism. During macrophage polarisation, AMPK not only guides the metabolic programming of macrophages, but also counter-regulates the inflammatory function of macrophages and promotes their polarisation toward the anti-inflammatory phenotype. AMPK is located at the intersection of macrophage metabolism and inflammation. The metabolic characteristics of macrophages are closely related to immune-related diseases, infectious diseases, cancer progression and immunotherapy. This review discusses the structure of AMPK and its role in the metabolism, function and polarisation of macrophages. In addition, it summarises the important role of the AMPK pathway and AMPK activators in the development of macrophage-related diseases.
... AMPK is often activated by phosphorylation of Thr172 of the α subunit and regulates synthesis or catabolism [25,26]. There is a negative association between AMPK activities and obesity/inflammation [27,28]. Consistently, there are very high energy need in PACs in pancreatitis [22]. ...
Obese people with acute pancreatitis (AP) have an increased risk of developing severe acute pancreatitis (SAP), which prolongs the length of hospital stay and increases mortality. Thus, elucidation of the mechanisms through which SAP occurs in obese individuals will provide clues for possible treatment targets. Differences in early events in obese or lean patients with AP have not been conclusively reported. We selected C57BL/6 mice as lean mice models, ob/ob mice or diet induced obese (DIO) mice as obese mice models and then induced experimental AP in mice via injections of caerulein. There were suppressed p-AMPK expressions in the pancreas of obese mice, compared with same-age lean C57BL/6 mice, which were further reduced in AP mice models. Obese AP mice were treated using AICAR, a direct AMPK agonist, which prevented pancreatic damage and cell death, suppressed pancreatic enzyme levels in serum, reduced the areas of fat saponification in the peritoneal cavity, prevented injury in other organs and decreased mice mortality rate. Further assays showed that AICAR activates p-AMPK to stabilize pro-caspase-8. Pro-caspase-8 enhances RIPK3 degradation, inhibits pancreatic acinar cell necroptosis, and downregulates the release of pancreatic enzymes. Thus, activation of AMPK by AICAR alleviates pancreatic acinar cell necroptosis and converts SAP to mild acute pancreatitis in obese mice.
... Besides effects on metabolites and nutrient supply, exercise directly impacts intracellular signaling cascades and transcription factors playing an important role in metabolic regulation, such as adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and hypoxia-inducible factor 1-alpha (HIF1α) [97][98][99][100][101][102][103][104]. Furthermore, contraction-associated secretion of myokines is known to reprogram immune cell metabolism, e.g., of macrophages: Exercise-derived IL-6 and IL-10 have been shown to increase oxidative metabolism in macrophages [105][106][107][108]. ...
Simple Summary
Tumors escape from the host immune control by upregulation of inhibitory immune checkpoints. Immune checkpoint inhibition (ICI) has become the standard of care for many cancer entities. However, several patients do not respond to ICI because of primary or secondary resistance. Patients not benefitting from checkpoint inhibitors frequently display an immunosuppressive tumor phenotype. Combination therapy with drugs enhancing immunosurveillance improves ICI efficacy. Since physical activity can boost immune response, exercise might be a promising combinatorial therapeutic approach for ICI. Here, we review preclinical and clinical data about the impact of exercise on anti-tumor immunity and checkpoint inhibitor therapy.
Abstract
Immune checkpoint inhibition (ICI) has revolutionized cancer therapy. However, response to ICI is often limited to selected subsets of patients or not durable. Tumors that are non-responsive to checkpoint inhibition are characterized by low anti-tumoral immune cell infiltration and a highly immunosuppressive tumor microenvironment. Exercise is known to promote immune cell circulation and improve immunosurveillance. Results of recent studies indicate that physical activity can induce mobilization and redistribution of immune cells towards the tumor microenvironment (TME) and therefore enhance anti-tumor immunity. This suggests a favorable impact of exercise on the efficacy of ICI. Our review delivers insight into possible molecular mechanisms of the crosstalk between muscle, tumor, and immune cells. It summarizes current data on exercise-induced effects on anti-tumor immunity and ICI in mice and men. We consider preclinical and clinical study design challenges and discuss the role of cancer type, exercise frequency, intensity, time, and type (FITT) and immune sensitivity as critical factors for exercise-induced impact on cancer immunosurveillance.
... Functional damage to sebaceous glands plays a role in the pathogenesis of many inflammatory skin diseases, including psoriasis [88]. It is noteworthy that a reduced amount of SIRT1 is also found in the sebaceous glands of patients with psoriasis [89]. RSV is an activator of the AMPK-SIRT1 pathway, improving lipid accumulation and reducing inflammation in human keratinocytes, highlighting the importance of SIRT1 s anti-inflammatory properties in sebaceous glands [85]. ...
Psoriasis is the most common chronic inflammatory skin disease with a genetic basis. It is characterised by keratinocyte hyperproliferation, parakeratosis and inflammatory cell infiltration. Psoriasis negatively affects a patient's physical and emotional quality of life. Sirtuins (SIRTs; silent information regulators) are an evolutionarily conserved group of enzymes involved in the post-translational modification of proteins, including deacetylation, polyADP-ribosylation, demalonylation and lipoamidation. SIRTs are involved in a number of cellular pathways related to ageing, inflammation, oxidative stress, epigenetics, tumorigenesis, the cell cycle, DNA repair and cell proliferation, positioning them as an essential component in the pathogenesis of many diseases, including psoriasis. Activation of SIRT1 counteracts oxidative-stress-induced damage by inhibiting the mitogen-activated protein kinases (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways and may mitigate pathological events in psoriasis. There is a significant reduction in the expression of SIRT1, SIRT2, SIRT3, SIRT4 and SIRT5 and an increase in the expression of SIRT6 and SIRT7 in psoriasis. The aim of the review is to draw the attention of physicians and scientists to the importance of SIRTs in dermatology and to provide a basis and impetus for future discussions, research and pharmacological discoveries to modulate SIRT activity. In light of the analysis of the mode of action of SIRTs in psoriasis, SIRT1-SIRT5 agonists and SIRT6 and SIRT7 inhibitors may represent new therapeutic options for the treatment of psoriasis.
... Cellular inflammatory responses require bioenergetic adaptations to mediate effector functions. Knockdown of the energy sensor adenosine monophosphate-activated protein kinase (AMPK) increases pro-inflammatory cytokines; conversely, activation of AMPK increases anti-inflammatory expression (66,67), in part through activation of the NAD-dependent SIRT1 deacetylation of the p65 subunit of NF-kB (68,69). The interplay between the AMPK->NAD->SIRT pathway and NF-kB-driven inflammation with aging requires further study. ...
Age-related changes in immune competency and inflammation play a role in the decline of physical function. In this review of the conference on Function-Promoting Therapies held in March 2022, we discuss the biology of aging and geroscience with an emphasis on decline in physical function and the role of age-related changes in immune competence and inflammation. More recent studies in skeletal muscle and aging highlighting a crosstalk between skeletal muscle, neuromuscular feedback, and immune cell subsets are also discussed. The value of strategies targeting specific pathways that affect skeletal muscle and more systems-wide approaches that provide benefits in muscle homeostasis with aging are underscored. Goals in clinical trial design and the need for incorporating differences in life history when interpreting results from these intervention strategies are important. Where applicable, references are made to papers presented at the conference. We conclude by underscoring the need to incorporate age-related immune competency and inflammation when interpreting results from interventions that target specific pathways predicted to promote skeletal muscle function and tissue homeostasis.
... We next investigated if the anti-inflammatory effect of I3A in RAW macrophages that we previously reported (Krishnan et al., 2018) depends on AMPK activation. We used siRNA to knock down prkaa1, the gene encoding AMPKα1, the main form of AMPKα in murine macrophages (Yang et al., 2010), and measured its effect on pro-inflammatory cytokine expression. The knockdown efficiency was ~50% for mRNA ( Figure 6-figure supplement 2A), ~40-50% for AMPK protein, and ~50-60% for p-AMPK ( Figure 6-figure supplement 2B, C), and the knockdown was stable for up to 96 hr at both mRNA and protein levels. ...
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and TNF-a and fatty acid induced inflammatory responses in an aryl-hydrocarbon receptor (AhR) dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic TG, liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A’s beneficial effects likely reflect the metabolite’s direct actions on the liver. Administration of I3A partially reversed WD induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β-oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to NASH.
... We next investigated if the anti-inflammatory effect of I3A in RAW macrophages that we previously reported (14) depends on AMPK activation. We used siRNA to knock down prkaa1, the gene encoding AMPKα1, the main form of AMPKα in murine macrophages (25) , and measured its effect on pro-inflammatory cytokine expression. The knockdown efficiency was ∼50% for mRNA ( Fig. S8A), ∼ 40-50% for AMPK protein, and ∼50 -60% for p-AMPK (Figs. ...
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and TNF-a and fatty acid induced inflammatory responses in an aryl-hydrocarbon receptor (AhR) dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic TG, liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A’s beneficial effects likely reflect the metabolite’s direct actions on the liver. Administration of I3A partially reversed WD induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β-oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to NASH.
... The protective mechanism of ASA includes the activation of the 5 adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, which attenuates oxidative stress. AMPK mediates energy metabolism at the intracellular level and can suppress various pathological oxidative stressors or inflammatory responses in IVD [15]. The activity of the AMPK signaling pathway leads to a significant decrease in the production of oxidative stressors, including reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) [16,17]. ...
Intervertebral disc degeneration (IDD) and associated conditions are an important problem in modern medicine. The onset of IDD may be in childhood and adolescence in patients with a genetic predisposition. With age, IDD progresses, leading to spondylosis, spondylarthrosis, herniated disc, spinal canal stenosis. One of the leading mechanisms in the development of IDD and chronic back pain is an imbalance between pro-inflammatory and anti-inflammatory cytokines. However, classical therapeutic strategies for correcting cytokine imbalance in IDD do not give the expected response in more than half of the cases. The purpose of this review is to update knowledge about new and promising therapeutic strategies based on the correction of the molecular mechanisms of cytokine imbalance in patients with IDD. This review demonstrates that knowledge of the molecular mechanisms of the imbalance between pro-inflammatory and anti-inflammatory cytokines may be a new key to finding more effective drugs for the treatment of IDD in the setting of acute and chronic inflammation.
