Proteolethargy is a pathogenic mechanism in chronic disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE273733 | GEO | 2025/01/15
REPOSITORIES: GEO
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Project description:Metabolic syndrome is associated with chronic low-grade inflammation which plays an important role in the pathogenesis of insulin resistance. Salsalate is a non-steroidal anti-inflammatory drug that reduces levels of inflammatory mediators. In the current study, we tested the effects of salsalate on inflammation, oxidative stress and metabolic disturbances in an animal model of inflammation and metabolic syndrome, using spontaneously hypertensive rats that transgenically express human C-reactive protein (SHR-CRP). We treated 15-month-old male transgenic SHR-CRP rats with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP rats were fed a standard diet without salsalate. In a similar fashion, we studied a group of nontransgenic SHR treated with salsalate and an untreated group of nontransgenic SHR controls. Parameters of inflammation and glucose and lipid metabolism were measured using standard methods. Statistical significance was evaluated by two-way ANOVA. In the SHR-CRP transgenic strain, we found that salsalate treatment decreased circulating levels of inflammatory markers TNFï¡ and MCP-1 and levels of human CRP as well as reduced levels of lipopreroxidation products in the liver and kidney cortex. Lipidomics analysis of eicosanoids confirmed anti-inflammatory effects of salsalate. Reduced inflammation and oxidative stress were associated with increased sensitivity of skeletal muscles to insulin action and greater tolerance to glucose and with reduced glucose oxidation and incorporation in brown adipose tissue (BAT). In SHR controls with no CRP-induced inflammation, salsalate treatment was associated with reduced body weight, lower levels of serum free fatty acids, total and HDL cholesterol and increased palmitate oxidation and incorporation in BAT. Salsalate regulated lipid metabolism by affecting expression of genes from PPAR signaling pathways and inflammation by affecting expression from MAPK signaling and NOD-like receptor signaling pathways. In summary, in the presence of high levels of human CRP, salsalate reduced inflammation which was associated with reduced oxidative stress and amelioration of insulin resistance in skeletal muscle and glucose intolerance while in non-transgenic SHR rats, salsalate ameliorated dyslipidemia and activated BAT. Thus it is possible that amelioration of insulin resistance and glucose intolerance in SHR-CRP rats treated with salsalate is due to reduced inflammation while amelioration of dyslipidemia in SHR rats treated with salsalate is due to activation of BAT. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.
2017-01-15 | E-MTAB-5079 | biostudies-arrayexpress
Project description:BACKGROUND Familial diarrheas are mostly severe recessive diseases. Here we describe the clinical picture and dominant genetic cause of a novel disease in 32 members of a Norwegian family. The chronic diarrhea is of early onset, relatively mild, and is combined with increased susceptibility to intestinal inflammation, ileus and oesophagitis. METHODS Whole genome SNP-analysis was used to identify a single candidate locus for dominant diarrhea on chromosome 12, followed by sequencing of the GU2CY gene. This encodes guanylyl cyclase 2C, an intestinal receptor for bacterial heat-stable enterotoxins and the peptides uroguanylin and guanylin. Functional studies of a missense mutation were performed after heterologous expression of the mutant receptor in HEK293T cells. The therapeutic response to metformin, an inhibitor of the cystic fibrosis transmembrane regulator (CFTR), was investigated in 5 patients. RESULTS We identified heterozygosity for the first described pathogenic human mutation (c.2519G>T ) in the GUCY2C gene. The mutant receptor showed increased cGMP production in response to its ligands. This may cause hyperactivation of the CFTR and consequent increased chloride and water secretion from the enterocytes, resulting in chronic diarrhea. Treatment with the CFTR-inhibitor metformin significantly reduced the frequency of stools in affected individuals by 34-45%. CONCLUSIONS Increased GC-C signaling disturbs normal bowel function, as shown by the diverse symptoms in our patients, and seems to have a pro-inflammatory effect, either through increased Cl- secretion or additional effects of elevated cellular cGMP. The importance of genetic variants in the GC-C-CFTR-pathway for conditions like Crohn’s disease and IBS should be further explored. Linkage analysis was performed (Allegro v 2.0) using Affymetrix 250K SNP arrays according to the manufacturer's directions on DNA extracted from peripheral blood samples. This accession number contains the data for 25 individuals of family branch A in the article.
2012-04-09 | E-GEOD-31260 | biostudies-arrayexpress
Project description:Inflammation, oxidative and dicarbonyl stress play important roles in the pathophysiology of type 2 diabetes. Metformin is the first-line drug of choice for the treatment of type 2 diabetes because it effectively suppresses gluconeogenesis in the liver, however, its “pleiotropic“ effects remain controversial. In the current study, we tested the effects of metformin on inflammation, oxidative and dicarbonyl stress in an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP). In the SHR-CRP transgenic strain, we found that metformin treatment decreased circulating levels of inflammatory response marker IL6 while levels of human CRP remained unchanged and metformin also significantly reduced oxidative stress (levels of conjugated dienes and TBARS) in the liver while no significant effects were observed in SHR control rats. In addition, in the presence of high human CRP, metformin reduced methylglyoxal levels in left ventricles but not in kidneys. Finally, metformin treatment reduced adipose tissue lipolysis. Possible molecular mechanisms of metformin action studied by gene expression profiling in the liver revealed deregulated genes from inflammatory, insulin signaling, AMP-activated protein kinase (AMPK) signaling and gluconeogenesis pathways. It can be concluded that in the presence of high levels of human CRP metformin protects against inflammation, oxidative and dicarbonyl stress in the heart and ameliorates insulin resistance and dyslipidemia.
2016-07-03 | E-MTAB-3791 | biostudies-arrayexpress
Project description:The aim of the present project is to assess the effects of the chronic diseases and their associated treatments chronic paediatric diseases (CPD), to further understand their impact on physical fitness for public health perspectives. This is an innovative approach in the treatment of chronic paediatric diseases . This project should yield results that help improving treatments for children and adolescents with chronic paediatric diseases throughout physical activity as therapy, reduced pain, fatigue and inflammation, and improvement in physical fitness and life quality. The originality and novelty of this project is to combine architectural, functional and metabolic components of skeletal muscle to further understand the impact of chronic paediatric diseases as a function of treatment, disease activity and maturation status (prepubertal, pubertal or post pubertal).
This study will aim at assessing muscular function (force production capacity and fatigability) in specific or ecologic situations so as to get information about muscle functioning on isolated muscle group (here knee extensors) or during whole body exercise. Moreover, results arising from muscle architecture or quality will allow understanding the decrease in strength or endurance reported in the literature. The data collected will allow us to further understand the impact of the disease on structural, functional and metabolic parameters. Finally, the understanding of these alterations will provide information enabling to establish recommendations in physical activity (PA) to reduce or even counter the effect of the chronic inflammation and prevent at long-term overweight and cardiovascular risks.
The long-term objective is to contribute establishing recommendations or guidelines for prescribing physical activity during medical therapy. Values obtained in pathological children will be compared to those of control children matched for gender and maturation.
| 2302790 | ecrin-mdr-crc
Project description:The pathogenic determinants of chronic periodontitis leading to extra-oral comorbidity are unclear. This study was conducted to investigate the main determinants that correlate chronic periodontitis and systemic diseases via periodontitis-evoked molecular changes in immune cells resolved by therapy. Single-cell RNA sequencing using peripheral blood mononuclear cells was performed to compare the molecular and biological differences in immune cells of 4 pre- and 4 post-treatment patients and 4 healthy donors. Periodontal treatment was one-day full-arch scaling and root planning for full mouth disinfection. Altered expression of genes involved in the inflammatory response in the patients was compared with that in healthy donors following therapeutic intervention. The common representative genes across diverse cell types were investigated; those genes were associated with periodontitis-pathogenic bacterial systemic diseases. These important factors correlating chronic periodontitis and systemic inflammatory diseases at the single-cell level may serve as therapeutic targets.
2022-11-09 | GSE174609 | GEO
Project description:Exercise has been shown to improve health status and prevent the progression and development of numerous chronic diseases associated with chronic inflammation
2018-11-12 | MSV000083129 | MassIVE
Project description:Macrophages are main drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis. The rate-limiting step for transcription of >70% of inducible genes in macrophages is RNA Polymerase II (Pol II) promoter-proximal pause release, yet, the specific role of Pol II pausing in inflammation or whether it can be modulated therapeutically is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages enhanced the transcriptional response of paused anti-inflammatory genes to LPS, followed by secondary attenuation of inflammatory signaling, and reduced severity of K/BxN-serum transfer (ST) arthritis in mice. To disrupt Pol II pause establishment pharmacologically, we employed covalent inhibitors of the TFIIH-associated cyclin-dependent kinase (CDK) 7, THZ1 and YKL-5-124. Both dramatically reduced Pol II pausing in murine and human macrophages, broadly suppressed induction of pro- but not anti-inflammatory genes, and rapidly reversed pre-established inflammatory macrophage polarization by TNF+IFNγ. In vivo, CDK7i ameliorated the acute K/BxN-ST and chronic progressive hTNF-transgenic arthritis in mice. Finally, CDK7i downregulated a pathogenic gene expression signature in synovial explants from arthritis patients. We propose that interfering with Pol II pausing by targeting CDK7 represents a novel therapeutic opportunity for inflammatory diseases.
2025-01-29 | GSE255372 | GEO
Project description:Macrophages are main drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis1-4. The rate-limiting step for transcription of >70% of inducible genes in macrophages is RNA Polymerase II (Pol II) promoter-proximal pause release5-7, yet, the specific role of Pol II pausing in inflammation or whether it can be modulated therapeutically is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages enhanced the transcriptional response of paused anti-inflammatory genes to LPS, followed by secondary attenuation of inflammatory signaling, and reduced severity of K/BxN-serum transfer (ST) arthritis in mice. To disrupt Pol II pause establishment pharmacologically, we employed covalent inhibitors of the TFIIH-associated cyclin-dependent kinase (CDK) 7, THZ1 and YKL-5-124. Both dramatically reduced Pol II pausing in murine and human macrophages, broadly suppressed induction of pro- but not anti-inflammatory genes, and rapidly reversed pre-established inflammatory macrophage polarization by TNF+IFNγ. In vivo, CDK7i ameliorated the acute K/BxN-ST and chronic progressive hTNF-transgenic arthritis in mice. Finally, CDK7i downregulated a pathogenic gene expression signature in synovial explants from arthritis patients. We propose that interfering with Pol II pausing by targeting CDK7 represents a novel therapeutic opportunity for inflammatory diseases.
2025-01-29 | GSE255108 | GEO
Project description:Glucocorticoids play a key role in metabolic adaptation during stress, such as fasting and starvation. Excess and/or chronic glucocorticoid exposure, however, cause metabolic disorders that include insulin resistance dyslipidemia and hepatic steatosis. We previously showed that chronic glucocorticoid treatment elevates hepatic production of ceramides and sphingosine-1-phosphate (S1P). Ceramides are converted to sphingosine that is further converted to S1P. We showed that ceramide-initiated signaling in turn inhibits insulin signaling and increases lipogenic program in hepatocytes. However, the role of S1P, a signaling molecule that modulates physiological responses through membrane S1P receptors (S1PRs), in glucocorticoid actions is unclear. Here we found that inhibiting S1PR2 activity, but not S1PR1 and S1PR3, resulted in improved glucocorticoid-induced insulin resistance. Similarly, reducing hepatic S1PR2 expression showed similar results. Interestingly, reducing S1PR2 expression did not affect the ability of glucocorticoids to modify insulin signaling. Instead, glucocorticoids enhanced gluconeogenesis was reduced. Moreover, glucocorticoid-induced dyslipidemia and fatty liver was also compromised in mice with reduced hepatic S1PR2 expression. Indeed, RNA sequencing analysis showed that lipogenic, gluconeogenic and glycolytic genes are significantly lower in glucocorticoid-treated hepatic S1PR2 knockdown mice than those of glucocorticoid-treated hepatic scramble small hairpin RNA (shRNA) expressing mice (Control). Overall, our studies highlight the importance role of S1PR2 signaling in the mediating glucocorticoid regulation on gluconeogenesis and hepatic lipid homeostasis.
2023-05-13 | GSE150626 | GEO
Project description:Persistent mucosal inflammation and microbial infection are characteristic of Chronic Rhinosinusitis (CRS). Though mucosal microbiota dysbiosis is a characteristic feature of other chronic inflammatory diseases, the relationship between sinus microbiota composition and CRS is unknown. Here we demonstrate, using comparative microbiome profiling of a cohort of CRS patients and healthy subjects, that the sinus microbiota of CRS patients exhibit significantly reduced bacterial diversity. Characteristic of this community collapse is the depletion of multiple, phylogenetically distinct, Lactic Acid Bacteria and the concomitant increase in relative abundance of a single species, Corynebacterium tuberculostearicum. Recapitulating the conditions observed in our human cohort in a murine model confirmed the pathogenic potential of C. tuberculostearicum and the critical necessity for a replete mucosal microbiota to protect against this species. Moreover, we provide evidence that Lactobacillus sakei, identified from our comparative microbiome analyses as a potentially protective species, affords defense against C. tuberculostearicum sinus infection, even in the context of a depleted sinus bacterial community. These studies demonstrate that sinus mucosal health is highly dependent on the composition of the resident microbiota, and identifies a new sino-pathogen and a strong bacterial candidate for therapeutic intervention. A total of 14 samples were profiled for microbiome composition: 7 from non-sinusitis patients, and 7 from patients with clinically diagnosed chronic sinusitis.
2012-07-31 | E-GEOD-37850 | biostudies-arrayexpress