Toll-like receptors (TLRs) induce inflammation and tissue repair through multiple signaling pathways. The Nrf2 pathway plays a key role in defending against the tissue damage incurred by microbial ...infection or inflammation-associated diseases. The critical event that mediates TLR-induced Nrf2 activation is still poorly understood. In this study, we found that lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists activate Nrf2 signaling and the activation is due to the reduction of Keap1, the key Nrf2 inhibitor. TLR signaling-induced Keap1 reduction promoted Nrf2 translocation from the cytoplasm to the nucleus, where it activated transcription of its target genes. TLR agonists modulated Keap1 at the protein posttranslation level through autophagy. TLR signaling increased the expression of autophagy protein p62 and LC3-II and induced their association with Keap1 in the autophagosome-like structures. We also characterized the interaction between p62 and Keap1 and found that p62 is indispensable for TLR-mediated Keap1 reduction: TLR signaling had no effect on Keap1 if cells lacked p62 or if cells expressed a mutant Keap1 that could not interact with p62. Our study indicates that p62-mediated Keap1 degradation through autophagy represents a critical linkage for TLR signaling regulation of the major defense network, the Nrf2 signaling pathway.
Osteoarthritis (OA) is a common joint disease that can cause gradual disability among the aging population. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key transcription factor that ...regulates the expression of phase II antioxidant enzymes that provide protection against oxidative stress and tissue damage. The use of histone deacetylase inhibitors (HDACi) has emerged as a potential therapeutic strategy for various diseases. They have displayed chondroprotective effects in various animal models of arthritis. Previous studies have established that Nrf2 acetylation enhances Nrf2 functions. Here we explore the role of Nrf2 in the development of OA and the involvement of Nrf2 acetylation in HDACi protection of OA.
Two OA models-monosodium iodoacetate (MIA) articular injection and destabilization of the medial meniscus (DMM)-were used with wild-type (WT) and Nrf2-knockout (Nrf2-KO) mice to demonstrate the role of Nrf2 in OA progression. A pan-HDACi, trichostatin A (TSA), was administered to examine the effectiveness of HDACi on protection from cartilage damage. The histological sections were scored. The expression of OA-associated matrix metalloproteinases (MMPs) 1, 3, and 13 and proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were assayed. The effectiveness of HDACi on OA protection was compared between WT and Nrf2-KO mice.
Nrf2-KO mice displayed more severe cartilage damage in both the MIA and DMM models. TSA promoted the induction of Nrf2 downstream proteins in SW1353 chondrosarcoma cells and in mouse joint tissues. TSA also reduced the expression of OA-associated proteins MMP1, MMP3, and MMP13 and proinflammatory cytokines TNF-α, IL-1β, and IL-6. TSA markedly reduced the cartilage damage in both OA models but offered no significant protection in Nrf2-KO mice.
Nrf2 has a major chondroprotective role in progression of OA and is a critical molecule in HDACi-mediated OA protection.
AKT is involved in a number of key cellular processes including cell proliferation, apoptosis and metabolism. Hyperactivation of AKT is associated with many pathological conditions, particularly ...cancers. Emerging evidence indicates that arginine methylation is involved in modulating AKT signaling pathway. However, whether and how arginine methylation directly regulates AKT kinase activity remain unknown. Here we report that protein arginine methyltransferase 5 (PRMT5), but not other PRMTs, promotes AKT activation by catalyzing symmetric dimethylation of AKT1 at arginine 391 (R391). Mechanistically, AKT1-R391 methylation cooperates with phosphatidylinositol 3,4,5 trisphosphate (PIP3) to relieve the pleckstrin homology (PH)-in conformation, leading to AKT1 membrane translocation and subsequent activation by phosphoinositide-dependent kinase-1 (PDK1) and the mechanistic target of rapamycin complex 2 (mTORC2). As a result, deficiency in AKT1-R391 methylation significantly suppresses AKT1 kinase activity and tumorigenesis. Lastly, we show that PRMT5 inhibitor synergizes with AKT inhibitor or chemotherapeutic drugs to enhance cell death. Altogether, our study suggests that R391 methylation is an important step for AKT activation and its oncogenic function.
The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth, proliferation, and metabolism by integrating various environmental inputs including growth factors, nutrients, and ...energy, among others. mTOR signaling has been demonstrated to control almost all fundamental cellular processes, such as nucleotide, protein and lipid synthesis, autophagy, and apoptosis. Over the past fifteen years, mapping the network of the mTOR pathway has dramatically advanced our understanding of its upstream and downstream signaling. Dysregulation of the mTOR pathway is frequently associated with a variety of human diseases, such as cancers, metabolic diseases, and cardiovascular and neurodegenerative disorders. Besides genetic alterations, aberrancies in post-translational modifications (PTMs) of the mTOR components are the major causes of the aberrant mTOR signaling in a number of pathologies. In this review, we summarize current understanding of PTMs-mediated regulation of mTOR signaling, and also update the progress on targeting the mTOR pathway and PTM-related enzymes for treatment of human diseases.
A high–resolution emission inventory of primary air pollutants of 18 cities in Henan region, as the representative of central plains of China, was developed based on the combination of bottom–up and ...top-down methods. It was found that the emissions of sulfur dioxide (SO2), nitrogen oxides (NOx), carbon monoxide (CO), particulate matter with an aerodynamic diameter of 10 mm or less (PM10), particulate matter with an aerodynamic diameter of 2.5 mm or less (PM2.5), Volatile Organic Compounds (VOCs) and ammonia (NH3) in 2016 were 780.4, 1682.9, 7152.8, 1440.3, 757.2, 1110.7, and 982.0 Gg, respectively. The emissions of the three major PM2.5 species, namely, Organic carbon (OC), Elemental carbon (EC), and sulfate (SO42−), were 161.2, 83.1, and 64.6 Gg, respectively. Stationary combustion was the largest contributor to SO2, NOx, CO, and PM2.5 emissions with 71.6%, 49.0%, 34.1%, and 24.7% contributions, respectively. Dust was the dominant source of PM10 emissions (42.4%), whereas industrial process was the largest contributor to VOCs emission (34.8%). Agricultural source contributed 87.7% of NH3 emission. The emissions were mainly distributed over the northwest and central part of Henan, and cities of Anyang, Zhengzhou, Luoyang, Pingdingshan, and Jiaozuo were the major contributors. Large NH3 emissions occurred during May to September, and high emissions of other pollutants were found from October to January. According to the Gini coefficients of per capital Gross Domestic Product (GDP) distribution among multiple air pollutants, the SO2 and NH3 emissions had high regional disparity, and the cities of Anyang and Zhengzhou had a high economic–environment inequity. Furthermore, this results were evaluated by comparing with other studies and the trend of spatiotemporal observed ambient concentration, which proves that the results are reliable. This work may benefit the government to further understand current local emission characteristics and formulation of targeted air pollution control measures.
Display omitted
•The emission inventory shows that the main contribution of different pollutants and different region differed significantly.•Spatiotemporal variations and comparison of monitoring data were investigated.•The major speciation of PM2.5 emissions were organic carbon (OC), elemental carbon (EC), and sulfate (SO42−).•Regional disparity and inequity of emission at city level were discussed by using Lorenz curve and Gini coefficient.
Sinomenine is originally derived from medicinal herb and used preferentially in treatment of rheumatoid diseases in Far East regions. SIN has strong anti-inflammatory and immune-regulatory ...properties, acting mainly through inhibiting NF-kB signaling. Although the upstream target through which SIN affects NF-kB activity is unknown, evidence suggests that SIN might regulate inflammation through Nrf2 signaling. In this study we explored the role of Nrf2 in mediating SIN’s anti-inflammation and kidney protection in a mouse model of obstructive nephropathy. We found that SIN is an activator of Nrf2 signaling. It markedly increased Nrf2 protein level, Nrf2 nuclear translocation, Nef2 transcription capacity, and the downstream protein expression. We further demonstrated that SIN activation of Nrf2 is likely due to its repression of the Nrf2 inhibitor Keap1 since it drastically reduced Keap1 protein through the PKC-sensitive ubiquitination-proteasomal degradation. SIN treatment of nephropathy mice effectively reduced the kidney damage and inflammatory responses, balanced renal oxidative stress, and improved the pathological protein expression in an Nrf2 dependent manner. In addition, SIN also Nrf2-dependently modulated macrophage M1/M2 polarization and inhibited the IkBα phosphorylation and NF-kB nuclear translocation, hence revealing an important upstream event that contributed to its anti-inflammation and tissue protection. Taken together our study has identified a novel pathway through which SIN exerts its anti-inflammation and renal protective functions, and provided a molecular basis for SIN potential applications in the treatment of kidney and other inflammatory disorders.
Display omitted
•SIN reduces inflammation, oxidative stress, and renal damage in UUO mice.•SIN is an Nrf2 activator and it activates Nrf2 signaling through Keap1 degradation.•SIN inhibits the M1 and promotes the M2 polarization in macrophages.•SIN Nrf2-dependently relieves renal inflammation and NF-kB signaling.•Nrf2 is essential for SIN functions in inflammation inhibition and renoprotection.
Size-resolved samples were collected using a 14-stage impactor during four seasons in Zhengzhou and analyzed for 26 elements to calculate the health risks from atmospheric particle-bound metals. High ...concentrations of heavy metals were observed in ultrafine (10.2 (Ni)–66.9 (Cd) ng m−3) or submicrometer (11.4 (Ni)–134 (Pb) ng m−3) mode in winter. Two size-dependent models were used to estimate the deposition of inhaled toxic metals in various regions of the human respiratory system. Results show that heavy metals deposited in the alveolar region ranged from 7.6 (As)–375 (Al) ng m−3 and were almost concentrated in ultrafine and fine modes. Cd (2.2–8.6) may cause accumulative non-carcinogenic health effects on children, and Cr (1.0 × 10−4–2.2 × 10−4) may lead to carcinogenic health risks for nearby residents around the sampling site. The major sources by principal component analysis that contributed to Cr and Cd in ultrafine and fine particles were coal combustion, vehicular and industrial emissions. The atmospheric dry deposition fluxes of Cr and Cd were between 0.7 and 1.9 μg m−2 day−1 calculated by a multi-step method. From the environmental and public health perspective, environmental agencies must control the emission of heavy metals in the atmosphere.
Display omitted
•High concentrations of heavy metals were observed in ultrafine or submicrometer mode in winter.•Heavy metals deposited in alveolar region were concentrated in ultrafine and fine modes.•Health risks from Cr and Cd deposited in alveolar region were high.
Cr and Cd in ultrafine and fine particles emitted from coal combustion, vehicle and industry were easily deposited in the alveolar region and led to high health risks for residents.
Direct contact condensation (DCC) is a phenomenon observed when steam interacts with subcooled water, exhibiting higher heat and mass transfer rates compared to wall condensation. It has garnered ...significant interest across industries such as nuclear, chemical, and power due to its advantageous characteristics. In the context of pressure-relief tanks, understanding and optimizing the DCC process are critical for safety and efficiency. The efficiency of pressure-relief tanks depends on the amount of steam condensed per unit of time, which directly affects their operational parameters and design. This study focuses on investigating the direct gas–liquid contact condensation process in pressure-relief tanks using computational fluid dynamics (CFD). Through experimental validation and a sensitivity analysis, the study provides insights into the influence of inlet steam parameters and basin temperature on the steam plume characteristics. Furthermore, steady-state and transient calculation models are developed to simulate the behaviour of the pressure-relief tank, providing valuable data for safety analysis and design optimization. There is a relatively high-pressure area in the upper part of the bubble hole of the pressure-relief tube, and the value increases as it is closer to the holes. The steam velocity in the bubbling hole near the 90° elbow position is higher. This study contributes to the understanding of steam condensation dynamics in pressure-relief tanks. When the steam emission and pressure are fixed, the equilibrium temperature increases linearly as the initial temperature increases (where a = 1, b = 20 in y = a x+ b correlation), the equilibrium pressure increases nearly exponentially, and the equilibrium gas volume decreases. When the steam emission and initial temperature are fixed, the equilibrium temperature does not change as the steam discharge pressure increases. The correlations between the predicted equilibrium parameters and the inlet steam parameters and tank temperature provide valuable insights for optimizing a pressure-relief tank design and improving the operational safety in diverse industrial contexts.
A highly resolved temporal and spatial Pearl River Delta (PRD) regional emission inventory for the year 2006 was developed with the use of best available domestic emission factors and activity data. ...The inventory covers major emission sources in the region and a bottom–up approach was adopted to compile the inventory for those sources where possible. The results show that the estimates for SO
2, NO
x, CO, PM
10, PM
2.5 and VOC emissions in the PRD region for the year 2006 are 711.4 kt, 891.9 kt, 3840.6 kt, 418.4 kt, 204.6 kt, and 1180.1 kt, respectively. About 91.4% of SO
2 emissions were from power plant and industrial sources, and 87.2% of NO
x emissions were from power plant and mobile sources. The industrial, mobile and power plant sources are major contributors to PM
10 and PM
2.5 emissions, accounting for 97.7% of the total PM
10 and 97.2% of PM
2.5 emissions, respectively. Mobile, biogenic and VOC product-related sources are responsible for 90.5% of the total VOC emissions. The emissions are spatially allocated onto grid cells with a resolution of 3 km × 3 km, showing that anthropogenic air pollutant emissions are mainly distributed over PRD central-southern city cluster areas. The preliminary temporal profiles were established for the power plant, industrial and on-road mobile sources. There is relatively low uncertainty in SO
2 emission estimates with a range of −16% to +21% from power plant sources, medium to high uncertainty for the NO
x emissions, and high uncertainties in the VOC, PM
2.5, PM
10 and CO emissions.
Industrial sector-based VOC source profiles are reported for the Pearl River Delta (PRD) region, China, based source samples (stack emissions and fugitive emissions) analyzed from sources operating ...under normal conditions. The industrial sectors considered are printing (letterpress, offset and gravure printing processes), wood furniture coating, shoemaking, paint manufacturing and metal surface coating. More than 250 VOC species were detected following US EPA methods TO-14 and TO-15. The results indicated that benzene and toluene were the major species associated with letterpress printing, while ethyl acetate and isopropyl alcohol were the most abundant compounds of other two printing processes. Acetone and 2-butanone were the major species observed in the shoemaking sector. The source profile patterns were found to be similar for the paint manufacturing, wood furniture coating, and metal surface coating sectors, with aromatics being the most abundant group and oxygenated VOCs (OVOCs) as the second largest contributor in the profiles. While OVOCs were one of the most significant VOC groups detected in these five industrial sectors in the PRD region, they have not been reported in most other source profile studies. Such comparisons with other studies show that there are differences in source profiles for different regions or countries, indicating the importance of developing local source profiles.
•VOC source samples were directly collected from normally operating plants.•Source characteristics exhibited differences among different sectors or processes.•Oxygenated VOCs were one of most VOC groups in the source profiles.•Obvious differences in source profiles among different regions were found.
PDF
