Although genetic polymorphisms in the
gene are associated with a variety of diseases, the physiological function of LRRK2 remains poorly understood. In this study, we report a crucial role for LRRK2 ...in the activation of the NLRC4 inflammasome during host defense against
serovar Typhimurium infection.
deficiency reduced caspase-1 activation and IL-1β secretion in response to NLRC4 inflammasome activators in macrophages.
mice exhibited impaired clearance of pathogens after acute
Typhimurium infection. Mechanistically, LRRK2 formed a complex with NLRC4 in the macrophages, and the formation of the LRRK2-NLRC4 complex led to the phosphorylation of NLRC4 at Ser533. Importantly, the kinase activity of LRRK2 is required for optimal NLRC4 inflammasome activation. Collectively, our study reveals an important role for LRRK2 in the host defense by promoting NLRC4 inflammasome activation.
The mechanisms of hyperhomocysteinemia (HHcy) and hyperuricemia (HUA) that promote atherosclerosis were seldom explored and always indefinite. Therefore, we will discuss some new reviews about the ...role of HHcy and HUA in the pathogenesis of atherosclerosis.
This study was conducted by reading a lot of literature, including basic research and clinical application research.
HHcy is known as an independent risk factor for atherosclerosis. Possible mechanisms for the association between homocysteine and atherosclerosis include stimulating smooth muscle cell growth, reducing endothelial cell growth and endothelial cell relaxation, and decreasing synthesis of high-density lipoprotein. HUA causes endothelial dysfunction and thereby increases oxidative stress, inducing vascular smooth muscle cell proliferation and reducing endothelial nitric oxide bioavailability. HUA plays a role in the development and pathogenesis of metabolic syndrome, hypertension, stroke, and atherosclerosis.
Accelerated atherosclerosis may be a consequence of the combined effect of HHcy and HUA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Antibiotic residue has become an emerging environmental contaminant, while the toxicological effects and underlying mechanisms caused by the co-exposure to multiple veterinary antibiotics were rarely ...studied. In this study, male Sprague Dawley rats were exposed to monensin (M) (1, 2, 10 mg/(kg·body weight (BW)) combined with sulfamethazine (S) (60, 120, 600 mg/(kg·BW)) or single drugs for 28 consecutive days. The body weight, hematological and blood biochemical parameters, organ coefficients, and histopathology were analyzed to discover their combined toxicity effect. Transcriptomic analysis was used to reveal the possible mechanisms of their joint toxicity. Compared with the control group, the weight gain rate was significantly reduced in the H-M+S and H-S, and alkaline phosphatase in H-M+S was significantly increased. Furthermore, relative liver and kidneys weight was significantly increased, and the liver of H-M+S showed more severe lesions in histopathological analysis. For H-M+S, H-M and H-S, transcriptomic results showed that 344, 246, and 99 genes were differentially expressed, respectively. The Gene Ontology terms mainly differ in sterol biosynthetic process and steroid hydroxylase activity. The Kyoto Encyclopedia of Genes and Genome pathways showed abnormal retinol metabolism, metabolism of xenobiotics by cytochrome P450, and drug metabolism-cytochrome 450; the common 30 genes were screened from the network of protein-protein interaction. The results showed that mixed contamination of M and S produces hepatotoxicity by interfering with linoleic acid metabolism, retinol metabolism and CYP450 enzyme-dominated drug metabolism. Further analysis showed that Cyp1a2, Cyp2c61, Ugt1a3, and Ugt1a5 might be the key genes. These findings could provide more evidence for investigating the toxic effects and metabolism of mixed antibiotics contamination in mammals.
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•Co-exposure to hepatotoxicity caused by monensin and sulfamethazine in male SD rats.•Co-exposure to transcriptomic changes resulted from monensin and sulfamethazine in male SD rats.•Linoleic acid metabolism, retinol metabolism and drug metabolism were critical pathways for hepatotoxicity.•Cyp1a2, Cyp2c61, Ugt1a3 and Ugt1a5 might be the key genes for hepatotoxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Natural deep eutectic solvents (NADESs), as emerging green solvents, can efficiently extract natural products from natural resources. However, studies on the extraction of phenolic compounds from ...celtuce (
var.
) leaves (CLs) by NADESs are still lacking. This study screened the NADES L-proline-lactic acid (Pr-LA), combined it with ultrasound-assisted extraction (UAE) to extract phenolic compounds from CLs, and conducted a comparative study on the extraction effect with traditional extraction solvents. Both SEM and FT-IR confirmed that Pr-LA can enhance the degree of fragmentation of cell structures and improve the extraction rate of phenolic compounds. Molecular dynamics simulation results show that Pr-LA can improve the solubility of phenolic compounds and has stronger hydrogen bonds and van der Waals interactions with phenolic compounds. Single-factor and Box-Behnken experiments optimized the process parameters for the extraction of phenolic compounds from CLs. The second-order kinetic model describes the extraction process of phenolic compounds from CLs under optimal process parameters and provides theoretical guidance for actual industrial production. This study not only provides an efficient and green method for extracting phenolic compounds from CLs but also clarifies the mechanism of improved extraction efficiency, which provides a basis for research on the NADES extraction mechanism.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The cathode channel of an air-cooled proton exchange membrane fuel cell (PEMFC) adopts a straight flow channel for air supply and heat dissipation. Considering the present cathode flow channel, the ...type of the anode flow channel has an impact on the water and heat management of air-cooled PEMFCs. In this study, we established three-dimensional (3D) multi-physics field models to investigate the performance of three types of anode flow channels: straight flow channel, improved straight flow channel, and serpentine flow channel. Among the three flow channel types under the same voltage condition, the straight flow channel exhibited the best temperature control ability, smallest cathode stoichiometric ratio at the peak power density output, and highest power density. Moreover, the temperature distribution of membrane electrode assembly in the straight flow channel was the most uniform. The coupling of the high cathode air speed and electro-osmotic drag (EOD) easily caused the water loss of anode and cathode membrane electrodes and had an adverse effect on the performance of the fuel cell. The straight flow channel demonstrated the optimal performance with the highest water content.
•Three type of 3D five-layer PEMFC models have been established.•Thermal, water and mass transport of air-cooled fuel cell were studied.•Straight flow channel is the most appropriate anode type for the air-cooled fuel cell.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•The prevalence of muscle fatigue and insomnia up to 1 year after COVID-19 was high•The prevalence of anxiety or depression up to 1 year after COVID-19 was high•Survivors with radiological anomalies ...were older•Survivors with impairment of DLCO had higher urea nitrogen levels•The levels of SARS-CoV-2 NAb and IgG at 1 year after discharge were decreased
To evaluate the long-term consequences of COVID-19 survivors one year after recovery, and to identify the risk factors associated with abnormal patterns in chest imaging manifestations or impaired lung function.
COVID-19 patients were recruited and prospectively followed up with symptoms, health-related quality of life, psychological questionnaires, 6-minute walking test, chest computed tomography (CT), pulmonary function tests, and blood tests. Multivariable logistic regression models were used to evaluate the association between the clinical characteristics and chest CT abnormalities or pulmonary function.
Ninety-four patients with COVID-19 were recruited between January 16 and February 6, 2021. Muscle fatigue and insomnia were the most common symptoms. Chest CT scans were abnormal in 71.28% of participants. The results of multivariable regression showed an increased odds in age. Ten patients had diffusing capacity of the lung for carbon monoxide (DLCO) impairment. Urea nitrogen concentration on admission was significantly associated with impaired DLCO. IgG levels and neutralizing activity were significantly lower compared with those in the early phase.
One year after hospitalization for COVID-19, a cohort of survivors were mainly troubled with muscle fatigue and insomnia. Pulmonary structural abnormalities and pulmonary diffusion capacities were highly prevalent in surviving COVID-19 patients. It is necessary to intervene in the main target population for long-term recovery.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This work investigates wireless covert communication in a multi-sensor asymmetric noise scenario. We adopt KL (Kullback-Leibler) divergence as the covertness constraint metric and mutual information ...as the transmission rate metric. To accurately approximate KL divergence and mutual information in covert communication, we employ the Taylor series expansion technique. Analytical expressions for KL divergence and mutual information in covert communication are derived, and we optimize the amplitude gain and phase angles based on these analytical expressions. Our findings underscore the importance of phase angle selection in covert communication within asymmetric noise systems. We propose an effective method for optimizing the transmission amplitude gain and phase angles in scenarios with asymmetric noise. Numerical results validate the effectiveness and superiority of our proposed method.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Interleukin 17 (IL-17) is a signature cytokine of Th17 cells. We previously reported that deletion of NF-κB activator 1 (Act1), the key transducer of IL-17 receptor signaling, from the ...neuroectodermal lineage in mice (neurons, oligodendrocytes and astrocytes) results in attenuated severity of experimental autoimmune encephalomyelitis (EAE). Here we examined the cellular basis of this observation. EAE disease course was unaffected by deletion of Act1 in neurons or mature oligodendrocytes, and Act1 deletion in astrocytes only modestly affected disease course. Deletion of Act1 in NG2(+) glia resulted in markedly reduced EAE severity. Furthermore, IL-17 induced characteristic inflammatory mediator expression in NG2(+) glial cells. IL-17 also exhibited strong inhibitory effects on the maturation of oligodendrocyte lineage cells in vitro and reduced their survival. These data identify NG2(+) glia as the major CNS cellular target of IL-17 in EAE. The sensitivity of oligodendrocyte lineage cells to IL-17-mediated toxicity further suggests a direct link between inflammation and neurodegeneration in multiple sclerosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Dysregulation of inflammatory cell death is a key driver of many inflammatory diseases. Pyroptosis, a highly inflammatory form of cell death, uses intracellularly generated pores to disrupt ...electrolyte homeostasis and execute cell death. Gasdermin D, the pore-forming effector protein of pyroptosis, coordinates membrane lysis and the release of highly inflammatory molecules, such as interleukin-1β, which potentiate the overactivation of the innate immune response. However, to date, there is no pharmacologic mechanism to disrupt pyroptosis. Here, we identify necrosulfonamide as a direct chemical inhibitor of gasdermin D, the pyroptotic pore-forming protein, which binds directly to gasdermin D to inhibit pyroptosis. Pharmacologic inhibition of pyroptotic cell death by necrosulfonamide is efficacious in sepsis models and suggests that gasdermin D inhibitors may be efficacious clinically in inflammatory diseases.
Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a ...chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17-mediated cascade via the IL-17R-Act1-TRAF4-MEKK3-ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17-induced sustained expansion of p63(+) basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17-induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17-dependent sustained activation of the TRAF4-ERK5 axis for keratinocyte proliferation and tumor formation.
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