Seasonal variations in the oxidative stress and inflammatory potential of PM in Tehran using an alveolar macrophage model; The role of chemical composition and sources
The current study was designed to assess the association between temporal variations in urban PM chemical composition, sources, and the oxidative stress and inflammatory response in an alveolar macrophage (AM) model. A year-long sampling campaign collected PM samples at the Sharif University in Tehran, Iran. PM-induced reactive oxygen species (ROS) production was measured both with an acellular dithiothreitol consumption assay (DTT-ROS; ranged from 2.1 to 9.3 nmoles min m) and an in vitro macrophage-mediated ROS production assay (AM-ROS; ranged from 125 to 1213 μg Zymosan equivalents m). The production of tumor necrosis factor alpha (TNF-α; ranged from ~60 to 518 pg TNF-α m) was quantified as a marker of the inflammatory potential of the PM. PM-induced DTT-ROS and AM-ROS were substantially higher for the colder months' PM (1.5-fold & 3-fold, respectively) compared with warm season. Vehicular emission tracers, aliphatic diacids, and hopanes exhibited moderate correlation with ROS measures. TNF-α secretion exhibited a markedly different pattern than ROS activity with a 2-fold increase in the warm months compared to the rest of the year. Gasoline vehicles and residual oil combustion were moderately associated with both ROS measures (R ≥ 0.67, p < 0.05), while diesel vehicles exhibited a strong correlation with secreted TNF-α in the cold season (R = 0.89, p < 0.05). mRNA expression of fourteen genes including antioxidant response and pro-inflammatory markers were found to be differentially modulated in our AM model. HMOX1, an antioxidant response gene, was up-regulated throughout the year. Pro-inflammatory genes (e.g. TNF-α and IL1β) were down-regulated in the cold season and displayed moderate to weak correlation with crustal elements (R > 0.5, p < 0.05). AM-ROS activity showed an inverse relationship with genes including SOD2, TNF, IL1β and IL6 (R ≥ -0.66, p < 0.01). Our findings indicate that Tehran's PM has the potential to induce oxidative stress and inflammation responses in vitro. In the current study, these responses included NRF2, NF-κB and MAPK pathways.
Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway
The importance of gut microbiota in human health and pathophysiology is undisputable. Despite the abundance of metagenomics data, the functional dynamics of gut microbiota in human health and disease remain elusive. Urolithin A (UroA), a major microbial metabolite derived from polyphenolics of berries and pomegranate fruits displays anti-inflammatory, anti-oxidative, and anti-ageing activities. Here, we show that UroA and its potent synthetic analogue (UAS03) significantly enhance gut barrier function and inhibit unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. Importantly, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction in addition to anti-inflammatory activities. Cumulatively, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing inflammation to protect from colonic diseases.
Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice
The transcription factor Nrf2 (NF-E2-related factor 2) plays a critical role in oxidative stress responses. While activation of Nrf2 signaling is known to exert anti-inflammatory effects, Nrf2 function in inflammation-mediated autoimmune disorders, such as type 1 diabetes, is not well established. To address the roles of Nrf2 in protection against autoreactive T-cell-induced type 1 diabetes, we used non-obese diabetic (NOD) mice, a polygenic model of human type 1 diabetes, to generate a genetic model that allowed us to assess the contribution of Nrf2 activation to preventing and/or treating type 1 diabetes. As Keap1 negatively regulates Nrf2, we used Keap1 gene knockdown driven by either hypomorphic or knockout alleles of Keap1,which enhances Nrf2 signaling to moderate and excess levels, respectively. We found that Nrf2 activation in NOD::Keap1FA/- mice inhibited T-cell infiltration within or near the islets, ameliorated impairment of insulin secretion, and prevented development of diabetes mellitus in the NOD mice. Notably, Nrf2 activation decreased both plasma interferon-γ (IFN-γ) levels and IFN-γ-positive cell numbers in the pancreatic islets. These findings were also observed in mice with two hypomorphic Keap1 alleles (Keap1FA/FA). Both NOD::Keap1FA/- and NOD::Keap1FA/FA mice had decreased incidence of diabetes mellitus, demonstrating that the activation of Nrf2 signaling prevents the onset of type 1 diabetes mellitus in NOD mice. Thus, Nrf2 appears to be a potential target for preventing and treating type 1 diabetes.
Suppression of lung inflammation by the ethanol extract of Chung-Sang and the possible role of Nrf2
Asian traditional herbal remedies are typically a concoction of a major and several complementary herbs. While balancing out any adverse effect of the major herb, the complementary herbs could dilute the efficacy of the major herb, resulting in a suboptimal therapeutic effect of an herbal remedy. Here, we formulated Chung-Sang (CS) by collating five major herbs, which are used against inflammatory diseases, and tested whether an experimental formula composed of only major herbs is effective in suppressing inflammation without significant side effects.
Hepatoprotective effects and structure-activity relationship of five flavonoids against lipopolysaccharide/d-galactosamine induced acute liver failure in mice
Acute liver failure (ALF) is a distinct clinical syndrome with high mortality and characterized by metabolic derangements, neurological complication, and multiple failures. Flavonoids exert great biological properties on anti-oxidation, anti-inflammation, and anti-apoptosis. After lipopolysaccharide (LPS)/d-galactosamine (d-GalN) administration, five flavonoids inhibited oxidative activities with reducing nitric oxide synthase (iNOS), malondialdehyde (MDA), and improving catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). They reduced the serum levels of alanine and aspartate aminotransferase (ALT, AST) and pro-inflammatory cytokines, prevented the phosphorylation of IKK, IκBα, and NF-κB/p65 in the NF-κB signaling pathway. Additionally five flavonoids inhibited hepatocyte apoptosis through increasing Bcl-2/Bax ratio and suppressing the Caspase family proteins. Chrysin, luteolin, apigenin, hesperetin and 3', 4'-dimethoxy hesperetin have apparently hepato-protective effects against ALF induced by LPS/d-GalN. The study found, the C2C3 double bond at A ring, and the hydroxyl group of C3' or C4' at B ring increased the protective activities, however, the effect of hydroxymethylation at C3' and C4' was reversed. In addition, apigenin has good hepatoprotective effects and potential as a promising therapeutic agent for ALF in clinical application.
Oxidative and Inflammatory Events in Prion Diseases: Can They Be Therapeutic Targets?
Prion diseases are a group of incurable infectious terminal neurodegenerative diseases caused by the aggregated misfolded PrPsc in selected mammals including humans. The complex physical interaction between normal prion protein PrPc and infectious PrPsc causes conformational change from the α- helix structure of PrPc to the β-sheet structure of PrPsc, and this process is repeated. Increased oxidative stress is one of the factors that facilitate conversion of PrPc to PrPsc. This overview presents evidence to show that increased oxidative stress and inflammation are involved in the progression of this disease. Evidence is given for the participation of redox-sensitive metals Cu and Fe with PrPsc in inducing oxidative stress by disturbing the homeostasis of these metals. The fact that some antioxidants block the toxicity of misfolded PrPc peptide supports the role of oxidative stress in prion disease. After exogenous infection in mice, PrPsc enters the follicular dendritic cells where PrPsc replicates before neuroinvasion where they continue to replicate and cause inflammation leading to neurodegeneration. Therefore, reducing levels of oxidative stress and inflammation may decrease the rate of the progression of this disease. It may be important order to reduce oxidative stress and inflammation at the same time. This may be achieved by increasing the levels of antioxidant enzymes by activating the Nrf2 pathway together with simultaneous administration of dietary and endogenous antioxidants. It is proposed that a mixture of micronutrients could enable these concurrent events thereby reducing the progression of human prion disease.
Proteomic profiling of RAW264.7 macrophage cells exposed to graphene oxide: insights into acute cellular responses
Although the toxicity and molecular mechanisms of graphene oxide (GO) have been reported for several cell types, no proteomic study of GO has yet been conducted on macrophage cells. In this study, we used proteomics based on stable isotope labeling with amino acids in cell culture (SILAC) to quantify the proteomic changes in macrophage RAW 264.7 cells following GO treatment. We found 73 proteins that were significantly dysregulated after GO treatment. The down-regulated proteins included many ribosomal subunit proteins, indicating that GO affected cell growth. The most elevated proteins were lipoprotein lipase (LPL) and lysozyme 1 (LYZ1) which have not been reported before, and both can be used as candidate markers for GO exposure. Further enrichment analysis of the up-regulated proteins indicated these proteins are associated with the integrin complex and membrane rafts, as well as with two signal pathways: the phagosome and steroid biosynthesis pathways. We confirmed a GO concentration-dependent increase in membrane rafts and the production of phagosomes. GO exposure also induced necrotic cell death and an inflammation response in RAW 264.7 cells. We also observed an increase in the oxidative stress response (ROS) and autophagy, and the results suggest that ROS induced autophagy by the ROS-NRF2-P62 pathway.
Corrigendum to "Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway" [Redox Biol. 18 (2018) 124-137]
Omega 3 rich diet modulates energy metabolism via GPR120-Nrf2 crosstalk in a novel antioxidant mouse model
With obesity rates reaching epidemic proportions, more studies concentrated on reducing the risk and treating this epidemic are vital. Redox stress is an important metabolic regulator involved in the pathophysiology of cardiovascular disease, Type 2 diabetes, and obesity. Oxygen and nitrogen-derived free radicals alter glucose and lipid homeostasis in key metabolic tissues, leading to increases in risk of developing metabolic syndrome. Oxidants derived from dietary fat differ in their metabolic regulation, with numerous studies showing benefits from a high omega 3 rich diet compared to the frequently consumed "western diet" rich in saturated fat. Omega 3 (OM3) fatty acids improve lipid profile, lower inflammation, and ameliorate insulin resistance, possibly through maintaining redox homeostasis. This study is based on the hypothesis that altering endogenous antioxidant production and/or increasing OM3 rich diet consumption will improve energy metabolism and maintain insulin sensitivity. We tested the comparative metabolic effects of a diet rich in saturated fat (HFD) and an omega 3-enriched diet (OM3) in the newly developed 'stress-less' mice model that overexpresses the endogenous antioxidant catalase. Eight weeks of dietary intervention showed that mice overexpressing endogenous catalase compared to their wild-type controls when fed an OM3 enriched diet, in contrast to HFD, activated GPR120-Nrf2 cross-talk to maintain balanced energy metabolism, normal circadian rhythm, and insulin sensitivity. These findings suggest that redox regulation of GPR120/FFAR4 might be an important target in reducing risk of metabolic syndrome and associated diseases.
N-Palmitoylethanolamine-oxazoline (PEA-OXA): A new therapeutic strategy to reduce neuroinflammation, oxidative stress associated to vascular dementia in an experimental model of repeated bilateral common carotid arteries occlusion
Recent studies revealed that pharmacological modulation of NAE-hydrolyzing acid amidase (NAAA) can be achieved with PEA oxazoline (PEA-OXA). Hence, the aim of the present work was to thoroughly evaluate the anti-inflammatory and neuroprotective effects of PEA-OXA in an experimental model of vascular dementia (VaD) induced by bilateral carotid arteries occlusion. At 24 h after VaD induction, animals were orally administered with 10 mg/kg of PEA-OXA daily for 15 days.
Hydrogen gas reduces HMGB1 release in lung tissues of septic mice in an Nrf2/HO-1-dependent pathway
Lung injury is a vital contributor of mortality in septic patients. Our previous studies have found that molecular hydrogen (H), which has anti-oxidant, anti-inflammatory, and anti-apoptosis effects, had a therapeutic effect on a septic animal model through increasing expression of nuclear factor-erythroid 2-related factor 2 (Nrf2). The aim of this research was to investigate the effects of 2% H gas inhalation on sepsis-induced lung injury and its underlying mechanisms.
Tempol relieves lung injury in a rat model of chronic intermittent hypoxia via suppression of inflammation and oxidative stress
Obstructive sleep apnea (OSA) is confirmed to cause lesions in multiple organs, especially in the lung tissue. Tempol is an antioxidant that has been reported to restrain inflammation and oxidative stress, with its role in OSA-induced lung injury being unclear. This study aimed to investigate the beneficial effect of tempol on chronic intermittent hypoxia (IH)-induced lung injury.
Mechanisms and Therapeutic Targets of Depression After Intracerebral Hemorrhage
The relationship between depression and intracerebral hemorrhage (ICH) is complicated. One of the most common neuropsychiatric comorbidities of hemorrhagic stroke is Post-ICH depression. Depression, as a neuropsychiatric symptom, also negatively impacts the outcome of ICH by enhancing morbidity, disability, and mortality. However, the ICH outcome can be improved by antidepressants such as the frequently-used selective serotonin reuptake inhibitors. This review therefore presents the mechanisms of post-ICH depression, we grouped the mechanisms according to inflammation, oxidative stress (OS), apoptosis and autophagy, and explained them through their several associated signaling pathways. Inflammation is mainly related to Toll-like receptors (TLRs), the NF-kB mediated signal pathway, the PPAR-γ-dependent pathway, as well as other signaling pathways. OS is associated to nuclear factor erythroid-2 related factor 2 (Nrf2), the PI3K/Akt pathway and the MAPK/P38 pathway. Moreover, autophagy is associated with the mTOR signaling cascade and the NF-kB mediated signal pathway, while apoptosis is correlated with the death receptor-mediated apoptosis pathway, mitochondrial apoptosis pathway, caspase-independent pathways and others. Furthermore, we found that neuroinflammation, oxidative stress, autophagy, and apoptosis experience interactions with one another. Additionally, it may provide several potential therapeutic targets for patients that might suffer from depression after ICH.
Phloretin Prevents Diabetic Cardiomyopathy by Dissociating Keap1/Nrf2 Complex and Inhibiting Oxidative Stress
Hyperglycemia induces chronic inflammation and oxidative stress in cardiomyocyte, which are the main pathological changes of diabetic cardiomyopathy (DCM). Treatment aimed at these processes may be beneficial in DCM. Phloretin (PHL), a promising natural product, has many pharmacological activities, such as anti-inflammatory, anticancer, and anti-oxidative function. The aim of this study was to investigate whether PHL could ameliorate the high glucose-mediated oxidation, hypertrophy, and fibrosis in H9c2 cells and attenuate the inflammation- and oxidation-mediated cardiac injury. In this study, PHL induced significantly inhibitory effect on the expression of pro-inflammatory, hypertrophy, pro-oxidant, and fibrosis cytokines in high glucose-stimulated cardiac H9c2 cells. Furthermore, PHL decreased the levels of serum lactate dehydrogenase, aspartate aminotransferase, and creatine kinase-MB, and attenuated the progress in the fibrosis, oxidative stress, and pathological parameters via Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2-related factor 2 (Nrf2) pathway in diabetic mice. In additional, molecular modeling and immunoblotting results confirmed that PHL might obstruct the interaction between Nrf2 and Keap1 through direct binding Keap1, and promoting Nrf2 expression. These results provided evidence that PHL could suppress high glucose-induced cardiomyocyte oxidation and fibrosis injury, and that targeting Keap1/Nrf2 may provide a novel therapeutic strategy for human DCM in the future.
Novel Curcumin C66 That Protects Diabetes-Induced Aortic Damage Was Associated with Suppressing JNK2 and Upregulating Nrf2 Expression and Function
Diabetes-related cardiovascular diseases are leading causes of the mortality worldwide. Our previous study has explored the protective effect of curcumin analogue C66 on diabetes-induced pathogenic changes of the aorta. In the present study, we sought to reveal the underlying protective mechanisms of C66. Diabetes was induced in male WT and JNK2 mice with a single intraperitoneal injection of streptozotocin. Diabetic mice and age-matched nondiabetic mice were randomly treated with either vehicle (WT, WT DM, JNK2, and JNK2DM) or C66 (WT + C66, WT DM + C66, JNK2 + C66, and JNK2DM + C66) for three months. Aortic oxidative stress, cell apoptosis, inflammatory changes, fibrosis, and Nrf2 expression and function were assessed by immunohistochemical staining for the protein level and real-time PCR method for mRNA level. The results suggested that either C66 treatment or JNK2 deletion can reverse diabetes-induced aortic oxidative stress, cell apoptosis, inflammation, and fibrosis. Nrf2 was also found to be activated either by C66 or JNK2 deletion. However, C66 had no extra effect on diabetic aortic damage or Nrf2 activation without JNK2. These results suggest that diabetes-induced pathological changes in the aorta can be protected by C66 mainly via inhibition of JNK2 and accompanied by the upregulation of Nrf2 expression and function.