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The Tn antigen, an immature truncated O-glycosylation, is a promising biomarker for cancer detection and diagnosis. However, reliable methods for analyzing O-GalNAcylation and complex O-glycosylation are lacking. Here, we develop a novel method, MOTAI, for the sequential analysis of O-glycosylation using different O-glycoproteases. MOTAI conjugates glycopeptides on a solid support and releases different types of O-glycosylation through sequential enzymatic digestion by O-glycoproteases, including OpeRATOR and IMPa. Because OpeRATOR has less activity on O-GalNAcylation, MOTAI enriches O-GalNAcylation for subsequent analysis. We demonstrate the effectiveness of MOTAI by analyzing fetuin O-glycosylation and Jurkat cell lines. We then apply MOTAI to analyze colorectal cancer and benign colorectal polyps. We identify 32 Tn/sTn-glycoproteins and 43 T/sT-glycoproteins that are significantly increased in tumor tissues. Gene Ontology analysis reveals that most of these proteins are ECM proteins involved in the adhesion process of the intercellular matrix. Additionally, the protein disulfide isomerase CRELD2 has a significant difference in Tn expression, and the abnormally glycosylated T345 and S349 O-glycosylation sites in cancer group samples may promote the secretion of CRELD2 and ultimately tumorigenesis through ECM reshaping. In summary, MOTAI provides a powerful new tool for the in-depth analysis of O-GalNAcylation and complex O-glycosylation. It also reveals the upregulation of Tn/sTn-glycoproteins in colorectal cancer, which may provide new insights into cancer biology and biomarker discovery.
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Antígenos Glicosídicos Associados a Tumores , Humanos , Glicosilação , Antígenos Glicosídicos Associados a Tumores/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Células JurkatRESUMO
OBJECTIVE: Whether physical activity could reduce the risk of atrial fibrillation (AF) remains unclear. This study was to investigate the relationship of leisure-time physical activity (LTPA) with AF incidence among Chinese older adults. METHODS: A total of 3253 participants aged ≥60 years from the Guangzhou Heart Study were successfully followed between March 2018 and September 2019. LTPA was assessed using a modified Global Physical Activity Questionnaire. AF was ascertained by 12-lead electrocardiograms, 24-hour single-lead Holter and clinical examination. The Cox proportional hazards model was used to the estimate hazard ratio (HR) and 95% confidence interval (CI) after adjustment for confounders, and the population-attributable fraction (PAF) was estimated. RESULTS: A total of 76 (2.34%) new-onset cases of AF were identified during a median of 31.13 months of follow-up. After adjustment for confounders, subjects who had LTPA at least 10.0 metabolic equivalent (MET)-hours/week had a 55% lower risk of developing AF (HR: 0.45, 95%CI: 0.25-0.81), and at least 20 MET-hours/week reduced the risk by 45% (HR: 0.55, 95%CI: 0.34-0.92). At least 11% (PAF: 11%, 95%CI: 0%-20%) or 14% (PAF: 14%, 95%CI: 0%-26%) of AF cases could be avoided, respectively, if the subjects do LTPA at least 10 MET-hours/week or 20 MET-hours/week. A significant exposure-response trend was also observed between LTPA and AF risk (Plinear-trend = 0.002). For a specific LTPA, doing housework was associated with a 43% reduced risk, while engaging in ball games was associated with an increased risk. CONCLUSION: This prospective cohort study indicated that a higher LTPA volume was associated with a lower AF risk in Chinese older adults.
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Fibrilação Atrial , Exercício Físico , Atividades de Lazer , Humanos , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/prevenção & controle , Masculino , Feminino , Idoso , Estudos Prospectivos , Incidência , Pessoa de Meia-Idade , China/epidemiologia , Fatores de RiscoRESUMO
Constructing heterostructures of dual quantum-dots (QDs) is a promising way to achieve high performance in photocatalysis, but it still faces substantial synthetic challenges. Herein, we developed an in situ transformation strategy to coassemble ZnS QDs and C QDs into dual-quantum-dot heterostructural nanofibers (ZnS/C-DQDH). Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy results revealed the formation of strong Zn-O-C bonds at the interface between ZnS QDs and C QDs, improving the separation efficiency of photogenerated charge carriers. The ZnS/C-DQDH demonstrated remarkable photocatalytic activity in H2O2 production, with generation rates of 2896.4 µmol gcat-1 h-1 without sacrificial agents and 9879.3 µmol gcat-1 h-1 with ethanol as the sacrificial agent, significantly higher than the QD counterparts and surpassed state-of-the-art photocatalysts. Moreover, due to the nanofibrous feature, ZnS/C-DQDH demonstrated excellent stability and facile recyclability. This work provides a facile and large scalable method to gain dual-quantum-dot heterostructures and a promising alternative for photocatalytic H2O2 production.
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BACKGROUND: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Children with TOF would be confronted with neurological impairment across their lifetime. Our study aimed to identify the risk factors for cerebral morphology changes and cognition in postoperative preschool-aged children with TOF. METHODS: We used mass spectrometry (MS) technology to assess the levels of serum metabolites, Wechsler preschool and primary scale of intelligence-Fourth edition (WPPSI-IV) index scores to evaluate neurodevelopmental levels and multimodal magnetic resonance imaging (MRI) to detect cortical morphological changes. RESULTS: Multiple linear regression showed that preoperative levels of serum cortisone were positively correlated with the gyrification index of the left inferior parietal gyrus in children with TOF and negatively related to their lower visual spaces index and nonverbal index. Meanwhile, preoperative SpO2 was negatively correlated with levels of serum cortisone after adjusting for all covariates. Furthermore, after intervening levels of cortisone in chronic hypoxic model mice, total brain volumes were reduced at both postnatal (P) 11.5 and P30 days. CONCLUSIONS: Our results suggest that preoperative serum cortisone levels could be used as a biomarker of neurodevelopmental impairment in children with TOF. Our study findings emphasized that preoperative levels of cortisone could influence cerebral development and cognition abilities in children with TOF.
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Cortisona , Cardiopatias Congênitas , Tetralogia de Fallot , Criança , Humanos , Pré-Escolar , Animais , Camundongos , Tetralogia de Fallot/cirurgia , Cardiopatias Congênitas/cirurgia , Fatores de Risco , CogniçãoRESUMO
Objectives: This study aimed to investigate the individual and joint associations of sedentary behaviour, physical activity (PA), sleep and breakfast eating on health-related quality of life (HRQoL) amongst Chinese junior high school students. Methods: Data were from 783 junior high school students who participated in a health behaviour and health survey in Jining city of Shandong province of China. HRQoL was measured by the EuroQol five-dimensional questionnaire, youth version (EQ-5D-Y). Multivariable logistic and linear regressions were applied to examine the associations between health behaviours and HRQoL. Results: Multivariable regression analyses showed that using a computer ≥ 2 h a day (vs. < 2 h/day) is associated with increased likelihood of having health problems in the three EQ-D-Y dimensions, including walking, looking after self and doing usual activities. Lower PA is associated with more problems in feeling worried, sad or unhappy, and with a lower visual analogue scale (VAS) score. Students who had insufficient sleep time (e.g., <7 h/day), and skipped eating breakfast were more likely to experience lower HRQoL in the dimensions of having pain or discomfort, and feeling worried, sad or unhappy, and a lower VAS score than those students who had longer sleep time and no breakfast skipping. Students who reported having the combined ≥ 2 unhealthy behaviours relative to the peers with 0-1 unhealthy behaviours were more likely to have lower HRQoL. Conclusion: The findings in the present study underline the importance of promoting healthy behaviours in order to improve HRQoL amongst Chinese junior high school students.
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Nível de Saúde , Qualidade de Vida , Adolescente , Humanos , Estudantes , China/epidemiologia , Comportamentos Relacionados com a SaúdeRESUMO
Ribonuclease (RNA) modifications can alter cellular function and lead to differential immune responses by acting as discriminators between RNAs from different phyla. RNA glycosylation has recently been observed at the cell surface, and its dysregulation in disease may change RNA functions. However, determining which RNA substrates can be glycosylated remains to be explored. Here, we develop a solid-phase chemoenzymatic method (SPCgRNA) for targeting glycosylated RNAs, by which glycosylated RNA substrates can be specifically recognized. We found the differential N-glycosylation of small RNAs in hTERT-HPNE and MIA PaCa-2 cancer cells using SPCgRNA. RNA-Seq showed that the changes in glyco-miRNAs prepared from SPCgRNA were consistent with those of traditional methods. The KEGG signaling pathway analysis revealed that differential miRNA glycosylation can affect tumor cell proliferation and survival. Further studies found that NGI-1 significantly inhibited the proliferation, migration, and circulation of MIA PaCa-2 and promoted cell apoptosis. In addition, ß-1,4-galactosyltransferase 1 (B4GALT1) not only affected the expression level of glycosylated miRNAs hsa-miR-21-5p but also promoted cell apoptosis and inhibited the cell cycle possibly through the p53 signaling pathway, while B4GALT1 and p53 were also affected following the hsa-miR-21-5p increase. These results suggest that B4GALT1 may catalyze miRNAs glycosylation, which further promotes cancer cell progression.
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RNA , Glicosilação , RNA/química , RNA/metabolismo , Oxirredução , Perfilação da Expressão Gênica , Humanos , Linhagem Celular Tumoral , Transdução de SinaisRESUMO
Mucin-type O-glycosylation is an important protein post-translational modification that is abundantly expressed on cell surface proteins. Protein O-glycosylation plays a variety of roles in cellular biological functions including protein structure and signal transduction to the immune response. Cell surface mucins are highly O-glycosylated and are the main substance of the mucosal barrier that protects the gastrointestinal or respiratory tract from infection by pathogens or microorganisms. Dysregulation of mucin O-glycosylation may impair mucosal protection against pathogens that can invade cells to trigger infection or immune evasion. Truncated O-glycosylation, also known as Tn antigen or O-GalNAcylation, is highly upregulated in diseases such cancer, autoimmune disorders, neurodegenerative diseases, and IgA nephropathy. Characterization of O-GalNAcylation helps decipher the role of Tn antigen in physiopathology and therapy. However, the analysis of O-glycosylation, specifically the Tn antigen, remains challenging due to the lack of reliable enrichment and identification assays compared to N-glycosylation. Here, we summarize recent advances in analytical methods for O-GalNAcylation enrichment and identification and highlight the biological role of the Tn antigen in various diseases and the clinical implications of identifying aberrant O-GalNAcylation.
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Carbonaceous surface, as one of the major carriers in coal combustion, was found to exert great influence on the nitric oxide with carbon monoxide (NO-CO) reaction. Although there have been some studies addressing the NO-CO reaction, the inherent mechanism remains obscure. In this work, some updated mechanisms with details were proposed at the electronic level. Using density functional theory calculations, the preferred pathways were identified with three channels consisting of homogeneous, Eley-Rideal (E-R), and Langmuir-Hinshelwood (L-H) heterogeneous reactions. The reasons for the difference in energy barrier among the three mechanisms were revealed by analyzing the chemical bond and electronic transfer. Results show that among these channels, the NO-CO reaction is more likely to occur along the E-R mechanism, due to its lower energy barrier of the rate-determining step. Compared to the L-H mechanism, there is a higher degree of electronic localization between NO molecules at the initial stage of the E-R mechanism. As a result, the NO dimer formation of the E-R mechanism has a lower energy barrier than that of the L-H mechanism. Meanwhile, a large number of electrons floods into the N-N, N-O, and O-O bonds of NO dimer in the homogeneous reaction, which certainly gets more difficult for the dissociation of O atoms in the gas phase. Accordingly, the following stage of N2 formation in the homogeneous reaction has a higher energy barrier than that in both the E-R and L-H reactions. Compared to the L-H mechanism, the E-R mechanism exhibits a lower degree of electronic localization between N2O and carbonaceous surface, suggesting that the interfacial interaction in the E-R mechanism is weaker. As a result, N2 is easier to remove from the carbonaceous surface in the E-R mechanism than in the L-H mechanism. To sum up, the results deepen the knowledge about the NO-CO reaction, which will help to further develop the oxy-fuel combustion technology.
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O-Glycosylation is one of the most common protein post-translational modifications (PTM) and plays an essential role in the pathophysiology of diseases. However, the complexity of O-glycosylation and the lack of specific enzymes for the processing of O-glycans and their O-glycopeptides make O-glycosylation analysis challenging. Recently, research on O-glycosylation has received attention owing to technological innovation and emerging O-glycoproteases. Several serine/threonine endoproteases have been found to specifically cleave O-glycosylated serine or threonine, allowing for the systematic analysis of O-glycoproteins. In this review, we first assessed the field of protein O-glycosylation over the past decade and used bibliometric analysis to identify keywords and emerging trends. We then summarized recent advances in O-glycosylation, covering several aspects: O-glycan release, site-specific elucidation of intact O-glycopeptides, identification of O-glycosites, characterization of different O-glycoproteases, mass spectrometry (MS) fragmentation methods for site-specific O-glycosylation assignment, and O-glycosylation data analysis. Finally, the role of O-glycosylation in health and disease was discussed.
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Glicopeptídeos , Glicoproteínas , Glicosilação , Glicopeptídeos/química , Glicoproteínas/química , Polissacarídeos/química , Treonina , SerinaRESUMO
Background: Limited evidence was available on the association of the integrated effect of multidimensional lifestyle factors with mortality among Chinese populations. This cohort study was to examine the effect of combined lifestyle factors on the risk of mortality by highlighting the number of healthy lifestyles and their overall effects. Methods: A total of 11,395 participants from the Guangzhou Heart Study (GZHS) were followed up until 1 January 2020. Individual causes of death were obtained from the platform of the National Death Registry of China. The healthy lifestyle index (HLI) was established from seven dimensions of lifestyle, and lifestyle patterns were extracted from eight dimensions of lifestyle using principal component analysis (PCA). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazard regression model. Results: During 35,837 person-years of follow-up, 184 deaths (1.61%) were observed, including 64 from cardiovascular disease. After adjustment for confounders, HLI was associated with a 50% (HR: 0.50, 95% CI: 0.25-0.99) reduced risk of all-cause mortality when comparing the high (6-7 lifestyle factors) with low (0-2 lifestyle factors) categories. Three lifestyle patterns were defined and labeled as pattern I, II, and III. Lifestyle pattern II with higher factor loadings of non-smoking and low-level alcohol drinking was associated with a decreased risk of all-cause mortality (HR: 0.63, 95% CI: 0.43-0.92, P -trend = 0.023) when comparing the high with low tertiles of pattern score, after adjustment for confounders. Every 1-unit increment of pattern II score was associated with a decreased risk (HR: 0.97, 95% CI: 0.95-0.99) of all-cause mortality. The other two patterns were not associated with all-cause mortality, and the association of cardiovascular mortality risk was observed with neither HLI nor any lifestyle pattern. Conclusion: The results suggest that the more dimensions of the healthy lifestyle the lower the risk of death, and adherence to the lifestyle pattern characterized with heavier loading of non-smoking and low-level alcohol drinking reduces the risk of all-cause mortality. The findings highlight the need to consider multi-dimensional lifestyles rather than one when developing health promotion strategies.
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Advances in bioanalytical technology have accelerated the analysis of complex protein glycosylation, which is beneficial to understand glycosylation in drug discovery and disease diagnosis. Due to its biological uniqueness in the course of disease occurrence and development, disease-specific glycosylation requires quantitative characterization of protein glycosylation. We provide a comprehensive review of recent advances in glycosylation analysis, including workflows for glycoprotein digestion, glycopeptide separation and enrichment, and mass spectrometry sequencing. We specifically focus on different strategies for glycopeptide enrichment through physical interaction, chemical oxidation, or metabolic labeling of intact glycopeptides. Recent advances and challenges of O-glycosylation analysis are presented, and the development of improved enrichment methods combining different proteases to analyze O-glycosylation is also proposed.
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Glicopeptídeos , Proteômica , Glicoproteínas , Glicosilação , Espectrometria de MassasRESUMO
This study explored the phytoestrogen-like effect of Siwu Decoction(SWD) and the estrogen receptor(ER)-mediated molecular mechanism based on network pharmacology and in vivo experiment. The active components and targets of SWD were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), and related targets of "estrogen" from GeneCards and Online Mendelian Inheritance in Man(OMIM). Cytoscape and STRING were employed to construct the protein-protein interaction(PPI) network and "chemical component-target-disease" network and core targets were identified, followed by Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment of the core targets by R software. For the in vivo experiment, the 22-day-old SD female rats were treated(ig) with SWD for 4 days. Via hematoxylin-eosin(HE) staining, the morphological changes of rat uterus were observed. Reverse transcriptase-polymerase chain reaction(RT-PCR) was performed to detect mRNA expression of ER subtypes, estrogen-related targets, and the main regulatory factors in the estrogen signaling pathway. The results indicated 74 targets of SWD exerted phytoestrogen-like effect. KEGG pathway enrichment result suggested that estrogen signaling pathway was closely related to the phytoestrogen-like effect of SWD. Rats in SWD group demonstrated significantly thickened endometrium and significantly decreased expression of ERα, ERß, and G protein-coupled estrogen receptor(GPER) mRNA in ovarian tissue. In addition, significant lowering of ERα and ERß mRNA expression and significant rise of GPER mRNA expression in uterine tissue were observed in the SWD group. The expression of mitogen-activated protein kinase(MAPK) p38, MEK1/2 and extracellular signal-regulated kinase(ERK)1/2 mRNA was significantly low while that of epidermal growth factor receptor(EGFR) mRNA was significantly high in both ovarian and uterine tissues of SWD group compared with those in the control group. In conclusion, the phytoestrogen-like effect of SWD is closely related to the estrogen signaling pathway. The result lays a basis for revealing molecular mechanism of SWD in the treatment of gynecological diseases.
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Medicamentos de Ervas Chinesas , Animais , Medicamentos de Ervas Chinesas/farmacologia , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Estrogênios/farmacologia , Feminino , Humanos , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fitoestrógenos , RNA Mensageiro , Ratos , Receptores de Estrogênio/genéticaRESUMO
In this paper, the novel 3D N-doped magnetic porous carbon spheres (3D N-MPCSs) was constructed via a simple template-free and self-doping method, followed by a direct carbonization of polymer with Fe3+ for simultaneous activation and magnetization. For the first time, the designed 3D N-MPCSs was used as multifunctional (for extraction and magnetic separation) adsorbents for microwave-assisted derivatization and magnetic solid phase extraction, which exhibited excellent extraction ability for its large surface area, mesoporous structure, spherical morphology, and incorporation of N/O heteroatoms. Moreover, when the microwave-assisted derivatization was combined with the magnetic solid phase extraction, the extraction, derivatization and concentration was completed simultaneously within 135 s. Furthermore, this method has a low detection limit (0.059-0.073 ng mL-1) and high enhancement factors (333 < EFs < 382) for trace biogenic amine (BAs). The recoveries were between 92.3 and 108.8% with relative standard deviations less than 5.9%. Overall, a simple, rapid, efficient and sensitive method for the analysis of BAs in food samples was developed, which provided the basis for routine detection of food safety.
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Carbono , Micro-Ondas , Aminas Biogênicas/análise , Cromatografia Líquida de Alta Pressão , Limite de Detecção , Porosidade , Extração em Fase Sólida/métodosRESUMO
Dysregulated surface glycoproteins play an important role in tumor cell proliferation and progression. Abnormal glycosylation of these glycoproteins may activate tumor signal transduction and lead to tumor development. The tumor microenvironment alters its molecular composition, some of which regulate protein glycosylation biosynthesis. The glycosylation of saliva proteins in lung cancer patients is different from healthy controls, in which the glycans of cancer patients are highly sialylated and hyperfucosylated. Most studies have shown that O-glycans from cancer are truncated O-glycans, while N-glycans contain fucoses and sialic acids. Because glycosylation analysis is challenging, there are few reports on how glycosylation of saliva proteins is related to the occurrence or progression of lung cancer. In this review, we discussed glycoenzymes involved in protein glycosylation, their changes in tumor microenvironment, potential tumor biomarkers present in body fluids, and abnormal glycosylation of saliva or lung glycoproteins. We further explored the effect of glycosylation changes on tumor signal transduction, and emphasized the role of receptor tyrosine kinases in tumorigenesis and metastasis.
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PURPOSE: Chronic intermittent hypoxia (CIH) plays a key role in the complications of obstructive sleep apnea (OSA), which is strongly associated with retinal and optic nerve diseases. Additionally, the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathway plays an important protective role in neuronal injury. In the present study, we investigated the role of 7,8-dihydroxyflavone (7,8-DHF) in regulating CIH-induced injury in mice retinas and rat primary retinal ganglion cells (RGCs). METHODS: C57BL/6 mice and in vitro primary RGCs were exposed to CIH or normoxia and treated with or without 7,8-DHF. The mice eyeballs or cultured cells were then taken for histochemistry, immunofluorescence or biochemistry, and the protein expression of the BDNF/TrkB signaling pathway analysis. RESULTS: Our results showed that CIH induced oxidative stress (OS) in in vivo and in vitro models and inhibited the conversion of BDNF precursor (pro-BDNF) to a mature form of BDNF, which increased neuronal cell apoptosis. 7,8-DHF reduced the production of reactive oxygen species (ROS) caused by CIH and effectively activated TrkB signals and downstream protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) survival signaling pathways, which upregulated the expression of mature BDNF. ANA-12 (a TrkB specific inhibitor) blocked the protective effect of 7,8-DHF. CONCLUSION: In short, the activation of the BDNF/TrkB signaling pathway alleviated CIH-induced oxidative stress damage of the optic nerve and retinal ganglion cells. 7,8-DHF may serve as a promising agent for OSA related neuropathy.
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Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Hipóxia Celular/efeitos dos fármacos , Flavonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Receptor trkB/efeitos dos fármacos , Receptor trkB/fisiologia , Células Ganglionares da Retina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Inulin as a commercial prebiotic could selectively promote the growth of beneficial gut microbes such as lactic acid bacteria (LAB). Whether LAB in rabbit gut possesses the capability to metabolize and utilize inulin is little known. Therefore, this study recovered 94 LAB strains from neonate rabbits and found that only 29% (28/94) could metabolize inulin with both species- and strain-specificity. The most vigorous inulin-degrading strain, Lacticaseibacillus paracasei YT170, could efficiently utilize both short-chain and long-chain components through thin-layer chromatography analysis. From genomic analysis, a predicted fosRABCDXE operon encoding putative cell wall-anchored fructan ß-fructosidase, five fructose-transporting proteins and a pts1BCA operon encoding putative ß-fructofuranosidase and sucrose-specific IIBCA components were linked to long-chain and short-chain inulin utilization respectively. This study provides a mechanistic rationale for effect of inulin administration on rabbits and lays a foundation for synbiotic applications aimed at modulating the intestinal microbiota of young rabbits.
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AIMS: Hepatocyte necroptosis is a critical event in the progression of non-alcoholic fatty liver disease (NAFLD). Obstructive sleep apnea hypopnea syndrome (OSAHS) and chronic intermittent hypoxia (CIH) may be linked with the pathogenesis and the severity of NAFLD. However, the potential role of necroptosis in OSAHS-associated NAFLD has not been evaluated. The present study investigated whether IH could affect NAFLD progression through promoting receptor-interacting protein kinase-3 (RIPK3)-dependent necroptosis, oxidative stress, and inflammatory response, and further elucidated the underlying molecular mechanisms. MAIN METHODS: LO2 cells were treated with palmitic acid (PA) and subjected to IH, and necroptosis, oxidative stress, and inflammation were assessed. The high-fat choline-deficient (HFCD)-fed mouse model was also used to assess the effects of CIH in experimental NAFLD in vivo. KEY FINDINGS: In this study, we found that RIPK3-mediated necroptosis was activated both in the PA plus IH-treated LO2 cells and liver of HFCD/CIH mice, and which could trigger oxidative stress and inflammatory response by decreasing Nrf2 and increasing p-P65. RIPK3 downregulation significantly reduced hepatocyte necroptosis, and ameliorated oxidative stress and inflammation through modulating Nrf2/NFκB pathway in vitro and vivo. Similarly, pretreatment with TBHQ, an activator of Nrf2, effectively blocked the generation of oxidative productions and inflammatory cytokines. In addition, RIPK3 inhibitor GSK-872 or TBHQ administration obviously alleviated hepatic injury, including histology, transaminase activities, and triglyceride contents in vivo. SIGNIFICANCE: IH aggravates NAFLD via RIPK3-dependent necroptosis-modulated Nrf2/NFκB signaling pathway, and which should be considered as a potential therapeutic strategy for the treatment of NAFLD with OSASH.
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Hipóxia/complicações , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Necroptose , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Apneia Obstrutiva do Sono/complicações , Animais , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Hidroquinonas/farmacologia , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Estresse Oxidativo , Ácido Palmítico/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais , Apneia Obstrutiva do Sono/metabolismoRESUMO
Immunoglobulin A vasculitis (IgAV), also known as Henoch-Schönlein Purpura, is one of the most common kind of systemic vasculitis in children, and due to the involvement of small blood vessels throughout the body, this disease can cause a variety of symptoms in different organs. Our aim was to review the data on various systemic manifestations of IgAV. A research of the literature was performed in PubMed database, utilizing the MeSH terms "IgA vasculitis" and "Henoch Schönlein Purpura". According to the predetermined structure of the manuscript, we extracted and sorted out the relevant data. Clinically, almost all the patients will present with palpable skin purpura, together with arthritis, gastrointestinal tract involvement, or kidney damage. Other rare systemic manifestations include neurological symptoms, scrotal involvement, and cardiopulmonary disease. When uncommon complications occur, patients may be misdiagnosed as other diseases, thus delaying treatment. Although the course of IgAV is mostly self-limited, misdiagnosis can also lead to a poor prognosis. A comprehensive awareness to the clinical manifestations of IgAV is the necessary prerequisite for its timely diagnosis. Prompt diagnosis and adequate treatment are essential for optimal results.
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Vasculite por IgA , Vasculite , Criança , Humanos , Vasculite por IgA/diagnóstico , Imunoglobulina A , Pele , Vasculite/diagnósticoRESUMO
In recent years, gold compounds have gained more and more attentions in the design of new metal anticancer drugs. Numerous researches have reported that gold compounds, in addition to their widely studied cytotoxic antitumor effects, also reverse tumor immune escape and directly facilitate the functions of immune cells, leading to enhanced anticancer effects. This review mainly summarizes our current understandings of antitumor effects of gold drugs and their relationships with various aspects of antitumor immunity, including innate immunity, adaptive immunity, immunogenic cell death, and immune checkpoints, as well as their roles in adverse effects. Some recent examples of anticancer gold compounds are highlighted. The property of gold compounds is expected to combine with anticancer immunotherapy, such as immune checkpoint inhibitors, to develop new anticancer therapeutic strategies.
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BACKGROUNDFatal cases of COVID-19 are increasing globally. We retrospectively investigated the potential of immunologic parameters as early predictors of COVID-19.METHODSA total of 1018 patients with confirmed COVID-19 were enrolled in our 2-center retrospective study. Clinical feature, laboratory test, immunological test, radiological findings, and outcomes data were collected. Univariate and multivariable logistic regression analyses were performed to evaluate factors associated with in-hospital mortality. Receiver operator characteristic (ROC) curves and survival curves were plotted to evaluate their clinical utility.RESULTSThe counts of all T lymphocyte subsets were markedly lower in nonsurvivors than in survivors, especially CD8+ T cells. Among all tested cytokines, IL-6 was elevated most significantly, with an upward trend of more than 10-fold. Using multivariate logistic regression analysis, IL-6 levels of more than 20 pg/mL and CD8+ T cell counts of less than 165 cells/µL were found to be associated with in-hospital mortality after adjusting for confounding factors. Groups with IL-6 levels of more than 20 pg/mL and CD8+ T cell counts of less than 165 cells/µL had a higher percentage of older and male patients as well as a higher proportion of patients with comorbidities, ventilation, intensive care unit admission, shock, and death. Furthermore, the receiver operating curve of the model combining IL-6 (>20 pg/mL) and CD8+ T cell counts (<165 cells/µL) displayed a more favorable discrimination than that of the CURB-65 score. The Hosmer-Lemeshow test showed a good fit of the model, with no statistical significance.CONCLUSIONIL-6 (>20 pg/mL) and CD8+ T cell counts (<165 cells/µL) are 2 reliable prognostic indicators that accurately stratify patients into risk categories and predict COVID-19 mortality.FundingThis work was supported by funding from the National Natural Science Foundation of China (no. 81772477 and 81201848).