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In this study, we prepared a low-cost novel Cu/Cu2O/BC nanocomposite visible-light photocatalyst by the impregnation method using CuSO4·5H2O and rice husk biochar (BC) as raw materials and Na2S2O4 as a single reductant to improve the stability and dispersion of the Cu/Cu2O nanoparticles, in order to solve their aggregation tendency during photocatalysis. The morphology and structure of the Cu/Cu2O/BC were characterized using various analytical and spectroscopic techniques. The photocatalytic effect and cyclic stability of the synthesized photocatalyst on methyl orange (MO) removal were investigated under visible light radiation and various parameter conditions, including the mass ratio of BC to Cu/Cu2O, initial MO concentration, pH, temperature, and catalyst dosage. The results show that the synthesized Cu/Cu2O/BC nanocomposite composed of Cu/Cu2O spherical particles was loaded on the BC carrier, which has better stability and dispersion. The best adsorption-photocatalytic effect of the Cu/Cu2O/BC is exhibited when the mass ratio of BC to Cu/Cu2O is 0.2. A total of 100 mg of Cu/Cu2O/BC can remove 95% of the MO and 88.26% of the COD in the aqueous solution at pH = 6, T = 25 °C, and an initial MO concentration of 100 mg/L. After five cycles of degradation, the MO degradation rate in the sample can still remain at 78.41%. Both the quasi-secondary kinetic model and the Langmuir isothermal adsorption model describe the adsorption process. Additionally, the thermodynamic analysis demonstrates that the photocatalytic process follows the quasi-primary kinetic model and that the removal process is of spontaneous heat absorption. The photocatalyst described in this paper offers a cost-effective, easily prepared, and visible-light-responsive solution for water pollution treatment.
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Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD. In mouse tumor models, pulsed and low-level pyroptosis induced by DMB suppresses tumor growth without harming GSDMD-expressing immune cells. Protection is immune-mediated and abrogated in mice lacking lymphocytes. Vaccination with DMB-treated cancer cells protects mice from secondary tumor challenge, indicating that immunogenic cell death is induced. DMB treatment synergizes with anti-PD-1. DMB treatment does not alter circulating proinflammatory cytokine or leukocyte numbers or cause weight loss. Thus, our studies reveal a strategy that relies on a low level of tumor cell pyroptosis to induce antitumor immunity and raise the possibility of exploiting pyroptosis without causing overt toxicity.
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Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Ligação a Fosfato , Piroptose , Animais , Piroptose/efeitos dos fármacos , Camundongos , Proteínas de Ligação a Fosfato/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Feminino , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Quinoxalinas/farmacologia , Quinoxalinas/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , GasderminasRESUMO
The pollutants such as heavy metals, organic matter, and nitrates in soil and water pose challenges to environmental remediation technology. Nano zero valent iron has shown enormous potential in the field of environmental remediation due to its excellent adsorption performance. By using carbon based materials, rock minerals, biomolecules, etc., as supporting materials for nZVI, and through structural and performance modifications, its performance has been successfully optimized, reducing defects such as aggregation and easy oxidation of the material. This article compares and summarizes the modification effects of different loadings on nZVI, and comprehensively reviews the latest progress, preparation methods, and application of nZVI particles in soil and water remediation. Specifically, this article explores in detail the impact and mechanism of nZVI particles in commonly used antibiotics contaminated environments. Firstly, the combination methods of different types of materials with zero valent iron, as well as the synthesis methods and application scenarios of nZVI, were integrated. Secondly, the interaction mechanism between pollutants and nZVI was introduced in detail, including adsorption, redox reactions, and co-precipitation. Subsequently, environmental factors that affect repair efficiency were emphasized, such as pH value, coexisting components, oxygen, contact time, and temperature. Finally, the challenges faced by the application of nZVI in actual polluted soil and water bodies, as well as the prospects for its long-term efficacy and safety evaluation, are proposed to promote further development in the future.
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The empirical study aimed to explore the relationships among social media exposure, job stress, anxiety, and identity disturbance in a nonclinical setting in the COVID-19 pandemic context. An online questionnaire was administered to 282 participants in the United States of America (USA) during the COVID-19 pandemic. The study utilized a two-step Structural Equation Modeling (SEM) approach consisting of both measurement model and structural model testing. Relationships between the model variables of social media exposure, identity disturbance, anxiety, and job stress were analyzed using standardized beta coefficients, standard errors, t-values, and p-values. The results indicate that both social media exposure and job stress are associated with increased anxiety levels, which, in turn, influence identity disturbance. Moreover, there is a moderating effect of job stress on the relationship between social media exposure and anxiety, as well as the mediating effect of anxiety on the relationship between social media exposure and identity disturbance. The findings are valuable for organizations and can be used to develop programs aimed at mitigating the adverse effects of social media exposure on mental health. Prioritizing employee mental health through awareness and support initiatives is paramount, especially for those facing high stress and extensive social media use.
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[This corrects the article DOI: 10.3389/fimmu.2024.1302903.].
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As an adsorbent, biochar has a highly porous structure and strong adsorption capacity, and can effectively purify the environment. In response to the increasingly serious problem of heavy metal pollution in water, this study used nano zero valent iron and rice husk biochar to prepare a new type of magnetic sheet-like biochar loaded nano zero valent iron (BC-nZVI) composite material through rheological phase reaction, showing remarkable advantages such as low cost, easy preparation, and superior environmental remediation effect. The physical and chemical properties and structure of the material were extensively characterized using various methods such as HRTEM, XPS, FESEM, EDS, XRD, FTIR, and RAMAN. Concurrently, batch experiments were undertaken to assess the removal efficiency of Pb(ii) by BC-nZVI, with investigations into the influence of pH value, temperature, soil water ratio, and initial concentration of heavy metal ion solution on its removal efficiency. The results indicate that the removal of Pb(ii) by BC-nZVI reaches an equilibrium state after around 120 minutes. Under the conditions of pH 6, temperature 20 °C, soil water ratio 1 : 5, and BC-nZVI dosage of 1 g L-1, BC-nZVI can reduce the Pb(ii) content in wastewater with an initial concentration of 30 mg L-1 to trace levels, and the treatment time is about 120 minutes. The analysis of adsorption kinetics and isotherms indicates that the adsorption process of Pb(ii) by BC-nZVI adheres to the quasi-second-order kinetic model and Langmuir model, suggesting a chemical adsorption process. Thermodynamic findings reveal that the adsorption of Pb(ii) by BC-nZVI is spontaneous. Furthermore, BC-nZVI primarily accumulates Pb(ii) through adsorption co-precipitation. BC-nZVI serves as an eco-friendly, cost-effective, and highly efficient adsorbent, showing promising capabilities in mitigating Pb(ii) heavy metal pollution. Its recoverability and reusability facilitated by an external magnetic field make it advantageous for remediating and treating lead-contaminated sites.
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Background & Aims: Previous studies demonstrated oxytocin treatment effectiveness in reducing mortality and reversing liver fibrosis in mice. However, the underlying mechanism remains obscure, given the absence of oxytocin receptor expression in hepatic stellate cells, the primary liver fibrosis effector cells. Methods: A comprehensive map of cell populations in fibrotic liver was generated using single-cell sequencing. The map enabled our study of the target cells of oxytocin action in the liver in more dimensions. Furthermore, we elucidated the mechanism of the oxytocin signaling system in hepatic macrophages using oxytocin receptor-specific knockout mice and liver fibrosis animal models. Results: The carbon tetrachloride-induced hepatic fibrosis and bile duct ligation hepatic fibrosis mouse models demonstrated that oxytocin reversed hepatic fibrosis in mice. The mapped liver cell populations demonstrated that oxytocin promoted the phenotypic switch from Ly6high to Ly6Clow in myeloid-derived macrophages. The phenotypic control of oxytocin signaling system activation on this phenotypic switch was validated using myeloid-specific oxytocin receptor knockout mice. Subsequent studies demonstrated that the calcium inward flow induced by oxytocin receptor activation activated the key orphan nuclear receptor NR4A1, which controls macrophage phenotypic switching. Specifically, calcium ions activated CREB, a key target regulator of NR4A1 expression. Conclusions: The findings established hepatic macrophages as a hub responsible for the oxytocin-mediated alleviation of liver fibrosis. This study revealed a novel pathway where oxytocin regulates macrophage phenotype. Impact and implications: Previous studies revealed for the first time the expression of oxytocin receptors in the liver. The present study shows that oxytocin reverses hepatic fibrosis and that hepatic macrophages are the central hub of oxytocin-mediated alleviation of hepatic fibrosis by promoting a phenotypic switch in hepatic macrophages, transitioning from Ly6high to Ly6Clow expression. The present study reveals a novel pathway by which oxytocin regulates macrophage phenotype. In addition, the potential applications of oxytocin and its analogues, as traditional drugs for clinical application, in the treatment of liver fibrosis deserve to be further explored.
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Several interleukin-1 (IL-1) family members, including IL-1ß and IL-18, require processing by inflammasome-associated caspases to unleash their activities. Here, we unveil, by cryoelectron microscopy (cryo-EM), two major conformations of the complex between caspase-1 and pro-IL-18. One conformation is similar to the complex of caspase-4 and pro-IL-18, with interactions at both the active site and an exosite (closed conformation), and the other only contains interactions at the active site (open conformation). Thus, pro-IL-18 recruitment and processing by caspase-1 is less dependent on the exosite than the active site, unlike caspase-4. Structure determination by nuclear magnetic resonance uncovers a compact fold of apo pro-IL-18, which is similar to caspase-1-bound pro-IL-18 but distinct from cleaved IL-18. Binding sites for IL-18 receptor and IL-18 binding protein are only formed upon conformational changes after pro-IL-18 cleavage. These studies show how pro-IL-18 is selected as a caspase-1 substrate, and why cleavage is necessary for its inflammatory activity.
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Caspase 1 , Microscopia Crioeletrônica , Interleucina-18 , Transdução de Sinais , Interleucina-18/metabolismo , Caspase 1/metabolismo , Humanos , Inflamassomos/metabolismo , Animais , Conformação Proteica , Ligação Proteica , Sítios de Ligação , Camundongos , Receptores de Interleucina-18/metabolismo , Modelos Moleculares , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
Cancer as a devastating malignancy, seriously threatens human life and health, but most chemotherapeutics have long been criticized for unsatisfactory therapeutic efficacy due to drug resistance and severe off-target toxicity. Pyrimidines, including fused pyrimidines, are privileged scaffolds for various biological cancer targets and are the most important class of metalloenzyme carbonic anhydrase inhibitors. Pyrimidine-sulfonamide hybrids can act on different targets in cancer cells simultaneously and possess potent activity against various cancers, revealing that hybridization of pyrimidine with sulfonamide is a promising approach to generate novel effective anticancer candidates. This review aims to summarize the recent progress of pyrimidine-sulfonamide hybrids with anticancer potential, covering papers published from 2020 to present, to facilitate further rational design of more effective candidates.
[Box: see text].
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Antineoplásicos , Neoplasias , Pirimidinas , Sulfonamidas , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Estrutura Molecular , AnimaisRESUMO
Gasdermin D (GSDMD) is the common effector for cytokine secretion and pyroptosis downstream of inflammasome activation and was previously shown to form large transmembrane pores after cleavage by inflammatory caspases to generate the GSDMD N-terminal domain (GSDMD-NT)1-10. Here we report that GSDMD Cys191 is S-palmitoylated and that palmitoylation is required for pore formation. S-palmitoylation, which does not affect GSDMD cleavage, is augmented by mitochondria-generated reactive oxygen species (ROS). Cleavage-deficient GSDMD (D275A) is also palmitoylated after inflammasome stimulation or treatment with ROS activators and causes pyroptosis, although less efficiently than palmitoylated GSDMD-NT. Palmitoylated, but not unpalmitoylated, full-length GSDMD induces liposome leakage and forms a pore similar in structure to GSDMD-NT pores shown by cryogenic electron microscopy. ZDHHC5 and ZDHHC9 are the major palmitoyltransferases that mediate GSDMD palmitoylation, and their expression is upregulated by inflammasome activation and ROS. The other human gasdermins are also palmitoylated at their N termini. These data challenge the concept that cleavage is the only trigger for GSDMD activation. They suggest that reversible palmitoylation is a checkpoint for pore formation by both GSDMD-NT and intact GSDMD that functions as a general switch for the activation of this pore-forming family.
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Gasderminas , Lipoilação , Proteínas de Ligação a Fosfato , Espécies Reativas de Oxigênio , Animais , Feminino , Humanos , Masculino , Camundongos , Aciltransferases/metabolismo , Microscopia Crioeletrônica , Cisteína/metabolismo , Gasderminas/química , Gasderminas/metabolismo , Inflamassomos/metabolismo , Lipossomos/metabolismo , Lipossomos/química , Mitocôndrias/metabolismo , Proteínas de Ligação a Fosfato/química , Proteínas de Ligação a Fosfato/metabolismo , Piroptose , Espécies Reativas de Oxigênio/metabolismo , Células THP-1RESUMO
OBJECTIVE: The study aims to examine the involvement of lincRNA00907 in the advancement of non-alcoholic steatohepatitis (NASH). METHODS: The examination was conducted to assess the expression of linc00907 in liver tissues from NASH patients and healthy individuals. High-fat diets induced NASH in mouse models, while palmitic acid/oleic acid treatment was used to create in vitro cell models. Various techniques, such as qRT-PCR, Oil Red O staining and gene knockdown/overexpression, were used to assess the impact of linc00907 on genes related to lipid metabolism and immunity, as well as intracellular lipid accumulation. Furthermore, dual-luciferase reporter assays were carried out to confirm the connection between miRNA-942-5p and linc00907 or TAOK1 mRNA. RESULTS: Linc00907 was found to be significantly upregulated in both NASH patients and NASH mouse models. Overexpression of linc00907 led to an increase in intracellular lipid accumulation, while knockdown of linc00907 resulted in decreased lipid content. It was found that miRNA-942-5p binds with linc00907, and their interaction was confirmed in dual-luciferase reporter assays. Additionally, TAOK1 was predicted to be a downstream target of miRNA-942-5p, and the upregulation of TAOK1 due to linc00907 was reversed by miRNA-942-5p overexpression. linc00907 overexpression reduces apoptosis but can be reversed by TAOK1 knockdown. The reduction of TAOK1 counteracted the impact of linc00907 on gene expression associated with lipid metabolism and immunity, as well as on the accumulation of intracellular lipids. CONCLUSIONS: Our research suggests that linc00907 functions as a competitive endogenous RNA (ceRNA) by sequestering miRNA-942-5p, thus increasing the expression of TAOK1 and encouraging lipid accumulation in hepatocytes, leading to the aggravation of NASH development. Targeting the linc00907/miRNA-942-5p/TAOK1 axis may hold therapeutic potential for the treatment of NASH.
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MicroRNAs , Hepatopatia Gordurosa não Alcoólica , RNA Longo não Codificante , Animais , Humanos , Masculino , Camundongos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
BACKGROUND: Necroptosis-related long noncoding RNAs (lncRNAs) play crucial roles in cancer initiation and progression. Nevertheless, the role and mechanism of necroptosis-related lncRNAs in soft tissue sarcomas (STS) is so far unknown and needs to be explored further. METHODS: Clinical and genomic data were obtained from the UCSC Xena database. All STS patients' subclusters were performed by unsupervised consensus clustering method based on the prognosis-specific lncRNAs, and then assessed their survival advantage and immune infiltrates. In addition, we explored the pathways and biological processes in subclusters through gene set enrichment analysis. At last, we established the necroptosis-related lncRNA-based risk signature (NRLncSig) using the least absolute shrinkage and selection operator (LASSO) method, and explored the prediction performance and immune microenvironment of this signature in STS. RESULTS: A total of 911 normal soft tissue samples and 259 STS patients were included in current study. 39 prognosis-specific necroptosis-related lncRNAs were selected. Cluster 2 had a worse survival than the cluster 1 and characterized by different immune landscape in STS. A worse outcome in the high-risk group was observed by survival analysis and indicated an immunosuppressive microenvironment. The ROC curve analyses illustrated that the NRLncSig performing competitively in prediction of prognosis for STS patients. In addition, the nomogram presents excellent performance in predicting prognosis, which may be more beneficial towards STS patients' treatment. CONCLUSIONS: Our result indicated that the NRLncSig could be a good independent predictor of prognosis, and significantly connected with immune microenvironment, thereby providing new insights into the roles of necroptosis-related lncRNAs in STS.
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RNA Longo não Codificante , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Necroptose , Prognóstico , Microambiente TumoralRESUMO
BACKGROUND: The association between obstructive sleep apnea syndrome (OSAS) and mortality has not been extensively researched among individuals with varying diabetic status. This study aimed to compare the relationship of OSAS with all-cause and cause-specific mortality in US individuals with or without diabetes based on data from the National Health and Nutrition Examination Survey (NHANES). METHODS: The study included participants from the NHANES 2005-2008 and 2015-2018 cycles with follow-up information. OSAS data (OSAS.MAP10) was estimated from the questionnaire. Hazard ratios (HRs) and the 95% confidence interval (CI) of OSAS for mortality were calculated by Cox regression analysis in populations with different diabetes status. The relationships between OSAS and mortality risk were examined using survival curves and restricted cubic spline curves. RESULTS: A total of 13 761 participants with 7.68 ± 0.042 follow-up years were included. In the nondiabetic group, OSAS.MAP10 was positively associated with all-cause, cardiovascular, and cancer mortality. In individuals with prediabetes, OSAS.MAP10 was positively related to all-cause mortality (HR 1.11 [95% CI: 1.03-1.20]) and cardiovascular mortality (HR 1.17 [95% CI: 1.03-1.33]). The relationship between OSAS.MAP10 and the risk of all-cause mortality and cancer mortality exhibited L-shaped curves in diabetes patients (both with nonlinear p values <.01). Further threshold effect analysis revealed that OSAS was positively related to death risk when OSAS.MAP10 exceeded the threshold scores. CONCLUSION: The relationship between OSAS and mortality differed among participants with or without diabetes. Individualized clinical treatment plans should be developed in clinical practice to reduce the risk of death for patients with different metabolic conditions.
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Diabetes Mellitus , Neoplasias , Apneia Obstrutiva do Sono , Adulto , Humanos , Estudos de Coortes , Inquéritos Nutricionais , Causas de Morte , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/diagnósticoRESUMO
Background: Immune checkpoint therapy, involving the programmed cell death 1 (PD-1) monoclonal antibody, has revolutionized the treatment of cancer. Tertiary lymphatic structure (TLS) serves as an immune indicator to predict the efficacy of PD-1 antibody therapy. However, there is no clear result whether the distribution, quantity, and maturity of TLS can be effective indicators for predicting the clinical efficacy of anti-PD1 immunotherapy in patients with colorectal cancer (CRC). Methods: Fifty-seven patients who underwent surgical resection and thirty-nine patients who received anti-PD-1 immunotherapy were enrolled in this retrospective study. Immunohistochemical staining and multiple fluorescence immunohistochemistry were used to evaluate the mismatch repair (MMR) subtypes and TLS distribution, quantity, and maturity, respectively. Results: A comprehensive patient score system was built based on TLS quantity and maturity. We found that the proportion of patients with score >1 was much higher in the deficient mismatch repair(dMMR) group than in the proficient mismatch repair(pMMR) group, and this difference was mainly due to intratumoral TLS. Patient score, based on the TLS evaluation of whole tumor, peritumor, or intratumor, was used to evaluate the efficacy of anti-PD1 immunotherapy. Based only on the intratumor TLS evaluation, the proportion of patients with a score >1 was higher in the response (PR + CR) group than in the non-response (PD) group. Multivariate analysis revealed that patient scores were positively correlated with the clinical efficacy of immunotherapy. Further analysis of immune-related progression-free survival was performed in patients with CRC who received anti-PD-1 immunotherapy. Patients with score >1 based on the intratumor TLS evaluation had significantly better survival. Conclusions: These results suggest that the patient score based on intratumor TLS evaluation may be a good immune predictive indicator for PD-1 antibody therapy in patients with CRC.
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Neoplasias Colorretais , Receptor de Morte Celular Programada 1 , Humanos , Estudos Retrospectivos , Neoplasias Colorretais/patologia , Prognóstico , Imunoterapia/métodosRESUMO
Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD membrane translocation and pore formation are not fully understood. Here, using a proteomic approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner. S-palmitoylation of GSDMD at Cys191/Cys192 (human/mouse), catalyzed by palmitoyl acyltransferases ZDHHC5 and ZDHHC9 and facilitated by reactive oxygen species (ROS), directly mediated membrane translocation of GSDMD-NT but not full-length GSDMD (GSDMD-FL). Palmitoylation of GSDMD-FL could be induced before inflammasome activation by stimuli such as lipopolysaccharide (LPS), consequently serving as an essential molecular event in macrophage priming. Inhibition of GSDMD palmitoylation suppressed macrophage pyroptosis and IL-1ß release, mitigated organ damage, and enhanced the survival of septic mice. Thus, GSDMD-NT palmitoylation is a key regulatory mechanism controlling GSDMD membrane localization and activation, which may offer an additional target for modulating immune activity in infectious and inflammatory diseases.
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Piroptose , Animais , Humanos , Camundongos , Gasderminas , Lipoilação , ProteômicaRESUMO
AIMS: Huntington's disease (HD) is a progressive neurodegenerative disorder with heterogeneous clinical manifestations. Identifying distinct clinical clusters and their relevant biomarkers could elucidate the underlying disease pathophysiology. METHODS: Following the Enroll-HD program initiated in 2018.09, we have recruited 104 HD patients (including 21 premanifest) and 31 health controls at Beijing Tiantan Hospital. Principal components analysis and k-means cluster analysis were performed to determine HD clusters. Chi-square test, one-way ANOVA, and covariance were used to identify features among these clusters. Furthermore, plasma cytokines levels and brain structural imaging were used as biomarkers to delineate the clinical features of each cluster. RESULTS: Three clusters were identified. Cluster 1 demonstrated the most severe motor and nonmotor symptoms except for chorea, the lowest whole brain volume, the plasma levels of IL-2 were higher and significantly associated with cluster 1. Cluster 2 was characterized with the most severe chorea and the largest pallidum volume. Cluster 3 had the most benign motor symptoms but moderate psychiatric problems. CONCLUSION: We have identified three HD clusters via clinical manifestations with distinct biomarkers. Our data shed light on better understanding about the pathophysiology of HD.
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Coreia , Doença de Huntington , Humanos , Doença de Huntington/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neuroimagem , BiomarcadoresRESUMO
BACKGROUND: Finding a drug for early intervention in the hepatic fibrosis process has important clinical significance. Previous studies have suggested SUMOylation as a potential target for intervention in hepatic fibrosis. However, the role of SAE1, a marker of SUMOylation, in hepatic fibrosis is unknown. Additionally, whether ginkgolic acid (GA), a SUMOylation inhibitor, inhibits hepatic fibrosis by inhibiting SUMO1-activating enzyme subunit 1 (SAE1) should be further investigated. METHODS: Liver tissues of patients with hepatic cirrhosis and a rat model of hepatic fibrosis constructed with CCl4 (400 mg/kg, twice weekly) or TAA (200 mg/kg, twice weekly) were selected, and the degree of hepatic fibrosis was then evaluated using H&E, Sirius red, and Masson's trichrome staining. After knockdown or overexpression of SAE1 in hepatic stellate cells, the expression levels of ferroptosis and hepatic fibrosis markers were measured in vitro. After intervention with a ferroptosis inhibitor, the expression levels were again measured in vivo and in vitro. RESULTS: We first demonstrated that SAE1 increased in patients with hepatic cirrhosis. Subsequently, testing of the rat hepatic fibrosis model confirmed that GA reduced the expression of SAE1 and improved hepatic fibrosis in rats. Then, we used hepatic stellate cell lines to confirm in vitro that GA inhibited SAE1 expression and induced ferroptosis, and that overexpression of SAE1 or inhibition of ferroptosis reversed this process. Finally, we confirmed in vivo that GA induced ferroptosis and alleviated the progression of hepatic fibrosis, while inhibiting ferroptosis also reversed the progression of hepatic fibrosis in rats. CONCLUSION: SAE1 is a potential anti-fibrotic target protein, and GA induces ferroptosis of hepatic stellate cells by targeting SAE1 to exert an anti-hepatic fibrosis effect, which lays an experimental foundation for the future clinical application of its anti-hepatic fibrosis effect.
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Ferroptose , Salicilatos , Humanos , Ratos , Animais , Transdução de Sinais , Cirrose Hepática/metabolismo , Fígado , Células Estreladas do Fígado , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/farmacologiaRESUMO
A Gram-stain-negative, motile (by single polar flagellum) and rod-shaped bacterium, designated W1-6T, was isolated from a sediment of drainage ditch in winery in Guiyang, south-western China. Strain W1-6T showed the highest 16S rRNA gene sequence similarities with the type strain of Acidovorax wautersii (98.1%) and Simplicispira lacusdiani (97.9%). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain W1-6T was placed adjacent to the members of the genus Simplicispira and formed a separat subclade. Cells showed oxidase and catalase negative reactions. The only respiratory quinone detected was ubiquinone-8 (Q-8). Summed feature 3 (C16:1 ω7c and/or C16:1 ω6c), C16:0 and summed feature 8 (C18:1 ω7c and/or C18:1 ω6c) were predominant cellular fatty acids (> 10%) of strain W1-6T. Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and five unidentified phospholipids were found in the polar lipid extraction. The genomic DNA G + C content was 65.6%. Strain W1-6T shared the highest digital DNA-DNA hybridization [dDDH, (27.6%)] and average nucleotide identity [ANI (84.3%)] values with the type strain of S. lacusdiani. The dDDH and ANI values were below the cutoff level (dDDH 70%; ANI 95-96%) for species delineation. The polyphasic characteristics indicated that the strain W1-6T represents a novel species of the genus Simplicispira, for which the name Simplicispira sedimenti sp. nov. is proposed. The type strain is W1-6T (= CGMCC 1.16274T = NBRC 115624T).