SEARCH · Search PubMed

Results for “Inflammatory pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources

PubMed1998

Involvement of the spinoparabrachial pathway in inflammatory nociceptive processes: a c-Fos protein study in the awake rat.

The effect of graded inflammatory stimuli (intraplantar-carrageenan, 0.2, 1, and 6 mg/150 microl) on paw edema and c-Fos protein expression at two levels of the spinoparabrachial pathway, the spinal cord and parabrachial area (PB), were studied. The present study, in awake rats, is an extension of previous study (Bester et al. [1997] J. Comp. Neurol. 383:439-458) which evaluated, in anesthetized rats, the effect of graded cutaneous heat stimulation on c-Fos-expression at the same levels. At the spinal level, the c-Fos-protein-like-immunoreactive (c-Fos-LI) neurons were located primarily in superficial laminae ipsilateral to intraplantar carrageenan. The number of c-Fos-LI neurons increased dose dependently (r = 0.973, n = 24) for carrageenan, from a number close to zero for the saline injection. At the PB level, c-Fos was predominantly expressed contralateral to intraplantar carrageenan. c-Fos-LI neurons were located primarily around the pontomesencephalic junction in (i) a restricted pontine area, centered in the lateral crescent, and including an adjacent part of the outer portion of the external lateral subnucleus, and (ii) the mesencephalic superior lateral subnuclei. The number of c-Fos-LI neurons in the PB area was correlated with that in the superficial laminae (r = 0.935, n = 24) and with the paw edema (r = 0.931, n = 24). No significant changes in c-Fos expression were observed in the nucleus of the solitary tract and ventrolateral medulla. The close correlation between c-Fos expression at both the spinal and PB levels and inflammatory edema provides further evidence for the involvement of spinoparabrachial pathway in inflammatory nociceptive processes. The present results are congruent with the existence of electrophysiologically demonstrated spinoparabrachio-amygdaloid and -hypothalamic nociceptive pathways.

Animals↗

PubMed2006

[Effect of ubiquitin-proteasome pathway on inflammatory reaction in intestine and its barrier function in rats with postburn sepsis].

OBJECTIVE: To study the effect of ubiquitin-proteasome pathway inhibition on intestinal nuclear factor-KappaB (NF-KappaB) activity and tumor necrosis factor-alpha (TNF-alpha) release as well as plasma diamine oxidase (DAO) activity in rats with postburn sepsis. METHODS: Rats were subjected to 30% total body surface area (TBSA) full-thickness scald injury, followed by intraperitoneal injection of lipopolysaccharide (LPS) to mimic postburn sepsis. Sixty Wistar rats were randomly divided into normal control group, sepsis group, sepsis with proteasome inhibitor N-Acetyl leucinyl leucinyl norleucinal (ALLN) treatment group and sepsis with NF-KappaB inhibitor pyrrolidine dithiocarbamate (PDTC) treatment group. NF-KappaB activity, TNF-alpha protein content, and plasma DAO activity were determined by electrophoretic mobility shift assay (EMSA), enzyme-linked immunosorbent assay (ELISA), and spectrophotometric method, respectively. RESULTS: The results showed that NF-KappaB activity was markedly activated and reached its peak 1 hour after scalding and injection of LPS in each group (all P<0.01), then reduced gradually. Both ALLN and PDTC could decrease intestinal NF-KappaB activity at 1 hour and 2 hours after injury. TNF-alpha release was reduced by ALLN at 1 hour after injury (P<0.01). Plasma DAO activity was significantly elevated after scalding and injection of LPS (P<0.01). Pretreatment with PDTC or ALLN could not lower the activity of DAO. CONCLUSION: The results suggest that early treatment with inhibitor of ubiquitin-proteasome pathway might decrease the intestinal inflammatory reaction, but exert no effect on intestinal barrier function in rats with postburn sepsis.

Amine Oxidase (Copper-Containing)↗

PubMed2026

Transcriptomic Insights into Acupuncture Mechanisms in Protecting Ovarian Function in Mice with Premature Ovarian Insufficiency.

OBJECTIVE: To explore the molecular mechanisms underlying the protective effect of acupuncture on ovarian function in mice with cyclophosphamide-induced premature ovarian insufficiency (POI) via transcriptomic analysis. METHODS: Twenty female C57BL/6 mice were divided into 4 groups: control, model, acupuncture, and non-meridian/non-acupoint (NOMA). POI was induced in the model, acupuncture, and non-meridian/non-acupoint groups via cyclophosphamide injection. The acupuncture group received acupuncture at Guanyuan (CV 4), bilateral Guilai (ST 29), and Sanyinjiao (SP 6) for 3 weeks. After the intervention, ovarian tissue weight and ovarian coefficient were calculated, serum levels of key reproductive hormones including follicle-stimulating hormone (FSH), luteinizing hormone (LH) and anti-Müllerian hormone (AMH) were detected, and ovarian histopathological changes were observed to evaluate ovarian function. Transcriptome sequencing was performed to identify differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to explore key functional terms and signaling pathways. Western blot was finally applied to validate the expression of core proteins related to mitochondrial function, endoplasmic reticulum stress and inflammatory pathways. RESULTS: The model group showed reduced ovarian weight and elevated FSH levels. The acupuncture group exhibited significantly higher ovarian weight and coefficient, lower FSH levels, and increased E2 and AMH levels compared to the model group (all P<0.01). Transcriptomic analysis revealed 4,021 DEGs between groups. GO and KEGG analyses revealed that these DEGs were mainly involved in oocyte development, steroid hormone synthesis, and pathways related to mitochondrial function, endoplasmic reticulum stress, and inflammatory signaling. Western blot analysis showed that acupuncture partially restored mitochondrial function markers cytochrome c oxidase subunit IV and NADH dehydrogenase 1 beta subcomplex subunit 8 and reduced endoplasmic reticulum stress markers (glucose-regulated protein 78 and Calnexin, P<0.01). It also downregulated pro-inflammatory proteins (IL-17R, IL-17A, NF-κB p65, p-NF-κB p65, ERK1/2, and p-ERK1/2) and upregulated proteins related to metabolic homeostasis (peroxisome proliferator-activated receptor γ, receptor-interacting protein 140, nicotinamide phosphoribosyltransferase, and sirtuin 1, P<0.01). CONCLUSION: Acupuncture effectively alleviates cyclophosphamide-induced POI in mice, improves ovarian function and follicular quality by regulating cellular functions and inflammatory pathways, suggesting a novel therapeutic approach for POI.

acupuncture↗

PubMed2002

Inflammation and the development of pancreatic cancer.

OBJECTIVE: Pancreatic cancer has an extremely poor prognosis and the cellular mechanisms contributing to pancreatic cancer are relatively unknown. The goals of this review are to present the epidemiological and experimental data that supports inflammation as a key mediator of pancreatic cancer development, to explain how inflammatory pathways may create an environment that supports tumor formation, and to discuss how the use of novel agents directed at these pathways may be used for the treatment of pancreatic malignancy. SUMMARY BACKGROUND DATA: Inflammation has been identified as a significant factor in the development of other solid tumor malignancies. Both hereditary and sporadic forms of chronic pancreatitis are associated with an increased risk of developing pancreatic cancer. The combined increase in genomic damage and cellular proliferation, both of which are seen with inflammation, strongly favors malignant transformation of pancreatic cells. Cytokines, reactive oxygen species, and mediators of the inflammatory pathway (e.g., NF-kappaB and COX-2) have been shown to increase cell cycling, cause loss of tumor suppressor function, and stimulate oncogene expression; all of which may lead to pancreatic malignancy. Anti-cytokine vaccines, inhibitors of pro-inflammatory NF-kappaB and COX-2 pathways, thiazolidinediones, and anti-oxidants are potentially useful for the prevention or treatment of pancreatic cancer. Redirection of experimental interests toward pancreatic inflammation and mechanisms of carcinogenesis may identify other novel anti-inflammatory agents or other ways to screen for or prevent pancreatic cancer. CONCLUSION: Pancreatic inflammation, mediated by cytokines, reactive oxygen species, and upregulated pro-inflammatory pathways, may play a key role in the early development of pancreatic malignancy.

Carcinoma↗

PubMed2006

Role of the progesterone receptor (PR) in the regulation of inflammatory response pathways and aromatase in the breast.

There is convincing evidence to suggest that estrogen and inflammatory mediators play important roles in growth and progression of breast cancer. Moreover, local conversion of androgens to estrogens by aromatase (product of CYP19 gene) occurs in 70% of all breast cancers. The actions of aromatase in both the breast tumor and in surrounding adipose stromal and endothelial cells can result in high local levels of estrogen production that stimulate tumor growth. The efficacy of current endocrine therapies is predicted only if the tumor contains significant amounts of ER. Presence of PR in the tumor also is an important predictor of tumor aggressiveness and responsiveness to endocrine therapy. Immunoreactivity for aromatase in human breast tumors is highly correlated with that for cyclooxygenase 2 (COX-2), the rate-determining enzyme in prostanoid biosynthesis. COX-2 expression also is correlated with expression of HER-2/neu, an oncogene expressed in >30% of breast tumors. In this manuscript, we will review findings to suggest that induction of COX-2 by inflammatory cytokines acting through NF-kappaB contributes to the increase in CYP19 expression and breast cancer progression, and that PR plays a dominant protective role in breast cancer cells by antagonizing NF-kappaB activation of COX-2.

Animals↗

PubMed2004

Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors.

Almost all degenerative diseases of the CNS are associated with chronic inflammation. A central step in this process is the activation of brain mononuclear phagocyte cells, called microglia. While it is recognized that healthy neurons and astrocytes regulate the magnitude of microglia-mediated innate immune responses and limit excessive CNS inflammation, the endogenous signals governing this process are not fully understood. In the peripheral nervous system, recent studies suggest that an endogenous 'cholinergic anti-inflammatory pathway' regulates systemic inflammatory responses via alpha 7 nicotinic acetylcholinergic receptors (nAChR) found on blood-borne macrophages. These data led us to investigate whether a similar cholinergic pathway exists in the brain that could regulate microglial activation. Here we report for the first time that cultured microglial cells express alpha 7 nAChR subunit as determined by RT-PCR, western blot, immunofluorescent, and immunohistochemistry analyses. Acetylcholine and nicotine pre-treatment inhibit lipopolysaccharide (LPS)-induced TNF-alpha release in murine-derived microglial cells, an effect attenuated by alpha 7 selective nicotinic antagonist, alpha-bungarotoxin. Furthermore, this inhibition appears to be mediated by a reduction in phosphorylation of p44/42 and p38 mitogen-activated protein kinase (MAPK). Though preliminary, our findings suggest the existence of a brain cholinergic pathway that regulates microglial activation through alpha 7 nicotinic receptors. Negative regulation of microglia activation may also represent additional mechanism underlying nicotine's reported neuroprotective properties.

Acetylcholine↗

PubMed2005

The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy.

Oxidative stress and nuclear factor-kappaB (NF-kappaB) activation are linked to the pathogenesis of many metabolic, degenerative, and chronic inflammatory diseases. Activation of the receptor for advanced glycation end products (RAGE) by its specific ligand N(epsilon)-carboxymethyllysine (CML) results in the activation of NF-kappaB and the production of proinflammatory cytokines. To determine whether engagement of RAGE contributes to the pathogenesis of inflammatory myopathies, we performed immunohistochemical studies on the presence of CML-modified proteins, RAGE and activated NF-kappaB in muscle biopsies of patients with polymyositis (PM, n=10), dermatomyositis (DM, n=10), limb girdle muscular dystrophy (LGMD, n=10) and in 10 controls with normal muscle biopsy results. In inflammatory myopathies CML, RAGE and NF-kappaB were detected in mononuclear cells and in regenerating muscle fibers. CML, NF-kappaB and, to a lesser extent, RAGE were also found in degenerating muscle fibers, but colocalization of CML, RAGE and NF-kappaB was only seen in infiltrating mononuclear cells and regenerating muscle fibers. Immunofluorescence double labeling demonstrated an expression of CML, RAGE and NF-kappaB in CD4-, CD8-, CD22- and CD68-positive mononuclear cells. Western blot analysis showed an increased immunoreactivity for CML-modified proteins in PM and DM. In LGMD, CML, RAGE and NF-kappaB were found in regenerating muscle fibers and less frequently in degenerating muscle fibers, and with lower staining intensities than in inflammatory myopathies. Our data suggests that the CML-RAGE-NF-kappaB pathway is an evident proinflammatory pathomechanism in mononuclear effector cells in PM and DM. RAGE-mediated NF-kappaB activation may be involved in muscle fiber regeneration in inflammatory myopathies and LGMD.

Adult↗

PubMed2006

Phosphoregulation of signal transduction pathways in ischemia and reperfusion.

Ischemia/reperfusion (I/R) injury triggered by pathogenic processes, such as organ transplant dysfunction, stroke, myocardial infarction, and shock, stimulate both immune and inflammatory pathways. Inflammatory cell activation and cytotoxic cytokine expression are associated with reperfusion injury. The activation of these inflammatory mediators initiates several interconnected downstream cascades regulated by phosphorylation and dephosphorylation reactions. These complex phosphorylation-dependent signal transduction pathways ultimately initiate nuclear transcription of inflammatory as well as anti-inflammatory genes to repair and assist in the recovery of damaged cells. Radical oxygen species (ROS) production, under ischemic conditions, initiates a cascade of events regulated by phosphorylation/dephosphorylation reactions and inflammatory gene expression. This is a review of the current understanding of the phosphoregulatory mechanisms that mediate the complex processes of signal transduction secondary to I/R injury. The rationale for inhibiting or activating signaling pathways as a promising molecular target for ameliorating reperfusion injury in I/R-related diseases, such as stroke, myocardial infarction, and storage for transplantation, is discussed on the basis of a new understanding of the mechanisms modulating phosphoregulatory pathways. In addition, we present part of our ongoing research in this field with phosphoregulatory signal transduction and its potential application.

Animals↗

PubMed2006

Anti-inflammatory interventions in pregnancy: now and the future.

A growing body of evidence implicates inflammatory pathways in adverse reproductive outcomes. This expanding evidence suggests that anti-inflammatory interventions may hold promise in reducing the maternal and neonatal morbidities and mortalities associated with these obstetrical complications. Preterm birth, preeclampsia, pregnancy loss and adverse neonatal outcomes have all been associated with the activation of inflammatory pathways during pregnancy. Because of the number of observational human studies, as well as animal models of preterm birth, the mechanisms by which inflammation may promote preterm parturition and adverse effects on the fetus are beginning to be elucidated. Although the future use of anti-inflammatory interventions in this context holds significant promise, much research is still warranted. Only when the pathogenesis of obstetrical complications is more fully understood can meaningful therapeutic interventions become a realistic goal.

Anti-Inflammatory Agents↗

PubMed2002

Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor.

Pro-inflammatory pathways participate in the pathogenesis of atherosclerosis. However, the role of endogenous anti-inflammatory pathways in atheroma has received much less attention. Therefore, using cDNA microarrays, we screened for genes regulated by prostaglandin E(2) (PGE(2)), a potential endogenous anti-inflammatory mediator, in lipopolysaccharide (LPS)-treated human macrophages (MPhi). PGE(2) (50 nm) attenuated LPS-induced mRNA and protein expression of chemokines including monocyte chemoattractant protein-1, interleukin-8, macrophage inflammatory protein-1alpha and -1beta, and interferon-inducible protein-10. PGE(2) also inhibited the tumor necrosis factor-alpha-, interferon-gamma-, and interleukin-1beta-mediated expression of these chemokines. In contrast to the case of MPhi, PGE(2) did not suppress chemokine expression in human endothelial and smooth muscle cells (SMC) treated with LPS and pro-inflammatory cytokines. To assess the potential paracrine effect of endogenous PGE(2) on macrophage-derived chemokine production, we co-cultured MPhi with SMC in the presence of LPS. In these co-cultures, cyclooxygenase-2-dependent PGE(2) production exceeded that in the mono-cultures, and MIP-1beta declined significantly compared with MPhi cultured without SMC. We further documented prominent expression of the PGE(2) receptor EP4 in MPhi in both culture and human atheroma. Moreover, a selective EP4 antagonist completely reversed PGE(2)-mediated suppression of chemokine production. Thus, endogenous PGE(2) may modulate inflammation during atherogenesis and other inflammatory diseases by suppressing macrophage-derived chemokine production via the EP4 receptor.

Anti-Inflammatory Agents↗

PubMed2006

Distinct requirements for Hfe in basal and induced hepcidin levels in iron overload and inflammation.

Hepcidin is a negative regulator of iron absorption produced mainly by the liver in response to changes in iron stores and inflammation, and its levels have been shown to regulate the intestinal basolateral iron transporter ferroportin1 (Fp1). Hereditary hemochromatosis patients and Hfe-deficient mice show inappropriate expression of hepcidin but, in apparent contradiction, still retain the ability to regulate iron absorption in response to alterations of iron metabolism. To further understand the molecular relationships among Hfe, hepcidin, and Fp1, we investigated hepcidin and Fp1 regulation in Hfe-deficient mice (Hfe-/- and beta2m-/-) in response to iron deprivation, iron loading, and acute inflammation. We found that whereas basal hepcidin levels were manifestly dependent on the presence of Hfe and on the mouse background, all Hfe-deficient mice were still able to regulate hepcidin in situations of altered iron homeostasis. In the liver, Fp1 was modulated in opposite directions by iron and LPS, and its regulation in Hfe-deficient mice was similar to that observed in wild-type mice. In addition, we found that iron-deprived mice were able to mount a robust response after LPS challenge and that Toll-like receptor 4 (TLR-4)-deficient mice fail to regulate hepcidin expression in response to LPS. In conclusion, these results suggest that although Hfe is necessary for the establishment of hepcidin basal levels, it is dispensable for hepcidin regulation through both the iron-sensing and inflammatory pathways, and hepatic Fp1 regulation is largely independent of hepcidin and Hfe. The inflammatory pathway overrides the iron-sensing pathway and is TLR-4 dependent.

Animals↗

PubMed2000

Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.

Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

Acetylcholine↗

PubMed1976

The alternate complement pathway in inflammatory bowel disease. Quantitation of the C3 proactivator (factor B) protein.

A component of the complement system's alternate pathway was investigated in ulcerative colitis and Crohn's disease. The mean C3PA (Factor B) titer in normals was 74 +/- 15%; in ulcerative colitis, 92 +/- 18%; and in Crohn's disease, 119+/- 24%. Significance was at the P less than 0.001 level when the mean values for the ulcerative colitis and the Crohn's disease groups were compared to normal subjects. Titers did not change significantly with exacerbation or amelioration of the diseases or when patient groups were analyzed according to the mode of treatment received.

Blood Proteins↗

PubMed2005

[Influence on the cytokines expression on hepatic tissue by inhibition the signal pathway of inflammatory mediators following extensive hepatectomy in rats].

OBJECTIVE: To investigate the impact of AG490, a cytokine signaling inhibitor, on cytokine signaling pathway with phosphorylation levels of Janus kinase 2 (Jak2) and singal transducers and activators of transcription 3 (Stat3), and liver pro-/anti-inflammatory cytokine expressions. METHODS: Rats were divided into two groups after surgery: control group, without treatment; AG490 group, with AG490 (1 mg.kg(-1).12 h(-1)) administration intraperitoneally, immediately and through 36 hs after the operation. Western blotting was used to detect the levels of phosphorylated Jak2 and Stat3. Semi-quantitative RT-PCR was employed to examine Interleukin-6 (IL-6) and Interleukin-10 (IL-10) expression. RESULTS: At 8 h and 12 h post-operatively, the phosphorylation levels of Jak2 and Stat3 were significantly inhibited in the AG490 group when compared with the control group. The DNA levels of IL-6 in the liver of the AG490 group rat at the same time points were also decreased, whereas IL-10 levels markedly increased. These changes made the ratio of IL-6/IL-10 dropped significantly. CONCLUSIONS: AG490 ameliorates the overwhelming inflammatory response via a mechanism of blocking cytokine signaling transduction and consequently suppresses the ratio of pro-/anti-inflammatory cytokine expression, which exerts potential clinical implications of use of anti-inflammatory agents in hepatic surgery.

Animals↗

PubMed2004

Inflammatory signaling pathway containing TRAF6 contributes to neointimal formation via diverse mechanisms.

OBJECTIVE: The purpose of this study was to investigate the contribution of inflammatory signaling containing tumor necrosis factor receptor-associated factor 6 (TRAF6) to neointimal formation in a balloon injury model of rabbit carotid artery. METHODS: Male Japanese white rabbits fed a normal diet were used. We transferred the dominant negative (DN) form of TRAF6 to a rabbit carotid artery that was subjected to balloon injury by in vivo electroporation method, and then evaluated its effect on intimal lesion formation after balloon injury. RESULTS: An expression plasmid vector containing the TRAF6 DN sequence was successfully transferred to arterial wall cells, and its inhibitory effect on inflammatory signaling was confirmed by the marked suppression of nuclear factor-kappaB (NFkappaB) activity after injury. Morphometric analyses revealed significant inhibition of intimal lesion formation at 7 days after injury. Cell replication and accumulation of macrophages in the media were significantly decreased, and apoptosis was enhanced on day 2. Cell migration to the intima was suppressed on day 4. Extracellular signal-regulated kinase1/2 (ERK1/2) activity at 2 h after injury was also down-regulated. Interestingly, intimal cell replication was significantly blocked when TRAF6 DN was transfected at 7 days after injury. CONCLUSION: TRAF6 plays important roles in cell replication and migration, besides promotion of inflammatory cell infiltration and suppression of apoptosis.

Animals↗

PubMed2005

Acetylsalicylic acid improves lipid-induced insulin resistance in healthy men.

CONTEXT AND OBJECTIVE: Insulin resistance is a central feature of type 2 diabetes. Salicylates prevent lipid-induced insulin resistance in rodents by interrupting inflammatory pathways. We therefore investigated whether salicylates reduce lipid-induced insulin resistance in humans by affecting inflammatory pathways as reflected by serum adipocytokines. PARTICIPANTS AND INTERVENTION: Ten healthy men were included in a crossover intervention study. Four euglycemic-hyperinsulinemic clamps were performed, one without pretreatment, one with prior 2-h lipid infusion, one after pretreatment with 4 g acetylsalicylic acid (ASA), and one with ASA pretreatment and prior lipid infusion. MAIN OUTCOME MEASURE: Lipid-induced insulin resistance was quantified by the euglycemic-hyperinsulinemic clamp technique running at least 2 h. Repeated-measures ANOVA on two factors was used for comparison, and results were Bonferroni adjusted for multiple measurements. ASA effects on serum adipocytokines were addressed by comparing the areas under the curves. RESULTS: Glucose infusion rate (M value) of the control clamp without pretreatment was 6.3 (+/- 0.6) mg/kg.min. ASA pretreatment did not change glucose infusion rates (P = 0.6). Lipid infusion significantly decreased the M value to 4.1 (+/- 0.6) mg/kg.min (P = 0.008). After ASA pretreatment and lipid infusion, the M value was 4.8 (+/- 0.7) mg/kg.min and was significantly improved, compared with the lipid-only clamp (P = 0.036 after Bonferroni's adjustment). General biomarkers of inflammatory processes (IL-6, C-reactive protein), the insulin-sensitizing mediator adiponectin, and circulating adiponectin oligomers were unchanged by ASA pretreatment. CONCLUSIONS: ASA pretreatment attenuated lipid-induced insulin resistance in healthy humans. This acute insulin-sensitizing effect of ASA was unrelated to changes of circulating inflammatory markers.

Adiponectin↗

PubMed2002

High circulating levels of the IL-1 type II decoy receptor in critically ill patients with sepsis: association of high decoy receptor levels with glucocorticoid administration.

The objective of this study was to evaluate whether the interleukin (IL)-1 decoy receptor (R), a negative pathway of regulation of IL-1, is correlated with severity of infection in critically ill patients and reflects the activation of anti-inflammatory pathways by glucocorticoid hormones. Plasma samples were obtained from 101 consecutive, critically ill patients admitted to the intensive care unit with different severities of microbial infection, as defined by standardized criteria. Here, we report that the IL-1 type II decoy R(II) is elevated in critically ill patients, especially in severe, systemic infection and culture-positive infections. In patients with a marked systemic inflammatory response syndrome 4, a pronounced, sepsis-induced further increase of circulating IL-1 decoy RII levels was evident. Thirty-six patients treated with glucocorticoid hormones had significantly higher levels of IL-1 decoy RII, but lower IL-6 and C-reactive protein, than 67 untreated subjects. The usefulness of IL-1RII, in particular as a potential marker for the activation of anti-inflammatory pathways or for responsiveness to anti-inflammatory agents such as glucocorticoid hormones, deserves further analysis.

Anti-Inflammatory Agents↗

PubMed2026

Multiomic Integration Reveals Novel miRNA-mRNA-Protein Expression Profile in the Aged Female Retina.

PURPOSE: Aging is a leading risk factor for retinal degeneration. MicroRNAs (miRNAs) regulate posttranscriptional gene suppressors and influence inflammation and oxidative stress, two processes disrupted during retinal aging. This study aimed to identify age-related miRNA-mRNA-protein associations between young and older retinas and uncover dysregulated pathways that may contribute to retinal degeneration. METHODS: Retinal function was assessed using electroretinography (ERG), and microgliosis was quantified by microglial immunohistochemistry (IHC). A multiomics approach was used to examine molecular changes in older (30-month-old) female C57BL/6J mouse retinas and compared with young female (3-month-old) controls. Illumina sequencing profiled short miRNAs (20 bp) and bulk mRNAs (150 bp), while total proteomics via mass spectrometry assessed protein expression. Bioinformatic analyses included targetome analysis (miRNet), pathway enrichment (Gene Ontology), and clustering to identify age-associated molecular targets and pathways. RESULTS: Retinas from older mice displayed neuronal dysfunction and increased microgliosis. Sequencing revealed significant dysregulation of miRNAs linked to immune and inflammatory pathways, supported by enrichment of their predicted mRNA targets. In the older mice, mRNA expression showed broad inflammatory activation, though only 14% of dysregulated mRNAs overlapped with predicted miRNA targets. Proteomic profiling revealed a disconnect between RNA and protein expression, yet all omics layers showed enrichment in inflammatory pathways. Integrated analysis identified associations involving several gene regulatory networks in the older retina. CONCLUSIONS: This study demonstrates that at an advanced age, miRNA expression and their predicted downstream regulatory networks are dysregulated, highlighting potential molecular mechanisms underlying age-related retinal degeneration.

Animals↗