RESUMEN
Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.
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Ansiedad/metabolismo , Conducta Animal/fisiología , Encefalopatías Metabólicas/metabolismo , Estrés Psicológico/metabolismo , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/patología , Animales , Ansiedad/genética , Ansiedad/inmunología , Ansiedad/fisiopatología , Encefalopatías Metabólicas/genética , Encefalopatías Metabólicas/fisiopatología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Modelos Animales de Enfermedad , Humanos , Ratones , Dinámicas Mitocondriales/genética , Oligodendroglía/metabolismo , Oligodendroglía/patología , Análisis de la Célula Individual , Estrés Psicológico/genética , Estrés Psicológico/fisiopatología , Transcriptoma/genética , Xantina/metabolismoRESUMEN
Fever is an evolutionarily conserved response that confers survival benefits during infection. However, the underlying mechanism remains obscure. Here, we report that fever promoted T lymphocyte trafficking through heat shock protein 90 (Hsp90)-induced α4 integrin activation and signaling in T cells. By inducing selective binding of Hsp90 to α4 integrins, but not ß2 integrins, fever increased α4-integrin-mediated T cell adhesion and transmigration. Mechanistically, Hsp90 bound to the α4 tail and activated α4 integrins via inside-out signaling. Moreover, the N and C termini of one Hsp90 molecule simultaneously bound to two α4 tails, leading to dimerization and clustering of α4 integrins on the cell membrane and subsequent activation of the FAK-RhoA pathway. Abolishment of Hsp90-α4 interaction inhibited fever-induced T cell trafficking to draining lymph nodes and impaired the clearance of bacterial infection. Our findings identify the Hsp90-α4-integrin axis as a thermal sensory pathway that promotes T lymphocyte trafficking and enhances immune surveillance during infection.
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Fiebre/inmunología , Proteínas HSP90 de Choque Térmico/metabolismo , Integrina alfa4/metabolismo , Infecciones por Salmonella/inmunología , Salmonella typhimurium/inmunología , Linfocitos T/inmunología , Animales , Carga Bacteriana , Adhesión Celular , Movimiento Celular , Dimerización , Quinasa 1 de Adhesión Focal/metabolismo , Vigilancia Inmunológica , Integrina alfa4/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , Transducción de Señal , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
Although targeting the tumor metabolism is performed in cooperation with immunotherapy in the era of precision oncology, ignorance of immune cells' metabolism has resulted in unstable antitumor responses. Tumor-infiltrating regulatory T cells (TI-Tregs) are unique, overcoming the hypoxic, acidic, and nutrient-deficient tumor microenvironments (TMEs) and maintaining immunosuppressive functions. However, secondary autoimmunity caused by systemic Treg depletion remains the 'Sword of Damocles' for current Treg-targeted therapies. In this opinion piece, we propose that metabolically reprogrammed TI-Tregs might represent an obstacle to cancer therapies. Indeed, metabolism-based Treg-targeted therapy might provide higher selectivity for clearing TI-Tregs than traditional kinase/checkpoint inhibitors and chemokine/chemokine receptor blockade; it might also restore the efficacy of targeting the tumor metabolism and eliminate certain metabolic barriers to immunotherapy.
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Neoplasias , Humanos , Linfocitos T Reguladores , Medicina de Precisión , Inmunoterapia/métodos , Inmunidad , Microambiente TumoralRESUMEN
Hypoxia-inducible factor-1 (HIF-1) is a critical transcription factor that regulates the expression of genes involved in cellular adaptation to low oxygen levels. Aberrant regulation of the HIF-1 signaling pathway is linked to various human diseases. Previous studies have established that HIF-1α is rapidly degraded in a von Hippel-Lindau protein (pVHL)-dependent manner under normoxic conditions. In this study, we find that pVHL binding protein 1 (VBP1) is a negative regulator of HIF-1α but not HIF-2α using zebrafish as an in vivo model and in vitro cell culture models. Deletion of vbp1 in zebrafish caused Hif-1α accumulation and upregulation of Hif target genes. Moreover, vbp1 was involved in the induction of hematopoietic stem cells (HSCs) under hypoxic conditions. However, VBP1 interacted with and promoted the degradation of HIF-1α in a pVHL-independent manner. Mechanistically, we identify the ubiquitin ligase CHIP and HSP70 as new VBP1 binding partners and demonstrate that VBP1 negatively regulated CHIP and facilitated CHIP-mediated degradation of HIF-1α. In patients with clear cell renal cell carcinoma (ccRCC), lower VBP1 expression was associated with worse survival outcomes. In conclusion, our results link VBP1 with CHIP stability and provide insights into underlying molecular mechanisms of HIF-1α-driven pathological processes.
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Carcinoma de Células Renales , Neoplasias Renales , Animales , Humanos , Pez Cebra/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Factores de Transcripción/metabolismo , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Proteínas del Citoesqueleto , Chaperonas MolecularesRESUMEN
A key step in the activation of canonical Wnt signaling is the interaction between ß-catenin and Tcf/Lefs that forms the transcription activation complex and facilitates the expression of target genes. Eukaryotic initiation factor 4A3 (EIF4A3) is an ATP-dependent DEAD box-family RNA helicase and acts as a core subunit of the exon junction complex (EJC) to control a series of RNA post-transcriptional processes. In this study, we uncover that EIF4A3 functions as a Wnt inhibitor by interfering with the formation of ß-catenin/Tcf transcription activation complex. As Wnt stimulation increases, accumulated ß-catenin displaces EIF4A3 from a transcriptional complex with Tcf/Lef, allowing the active complex to facilitate the expression of target genes. In zebrafish embryos, eif4a3 depletion inhibited the development of the dorsal organizer and pattern formation of the anterior neuroectoderm by increasing Wnt/ß-catenin signaling. Conversely, overexpression of eif4a3 decreased Wnt/ß-catenin signaling and inhibited the formation of the dorsal organizer before gastrulation. Our results reveal previously unreported roles of EIF4A3 in the inhibition of Wnt signaling and the regulation of embryonic development in zebrafish.
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Factor 4A Eucariótico de Iniciación/metabolismo , Vía de Señalización Wnt/fisiología , Pez Cebra/embriología , Animales , Embrión no Mamífero/metabolismo , Factor 4A Eucariótico de Iniciación/genética , Regulación del Desarrollo de la Expresión Génica , Activación Transcripcional , Proteínas Wnt/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
The eukaryotic multisubunit Elongator complex has been shown to perform multiple functions in transcriptional elongation, histone acetylation and tRNA modification. However, the Elongator complex plays different roles in different organisms, and the underlying mechanisms remain unexplored. Moreover, the biological functions of the Elongator complex in human fungal pathogens remain unknown. In this study, we verified that the Elongator complex of the opportunistic fungal pathogen Aspergillus fumigatus consists of six subunits (Elp1-6), and the loss of any subunit results in similarly defective colony phenotypes with impaired hyphal growth and reduced conidiation. The catalytic subunit-Elp3 of the Elongator complex includes a S-adenosyl methionine binding (rSAM) domain and a lysine acetyltransferase (KAT) domain, and it plays key roles in the hyphal growth, biofilm-associated exopolysaccharide galactosaminogalactan (GAG) production, adhesion and virulence of A. fumigatus; however, Elp3 does not affect H3K14 acetylation levels in vivo. LC-MS/MS chromatograms revealed that loss of Elp3 abolished the 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) modification of tRNA wobble uridine (U34), and the overexpression of tRNAGlnUUG and tRNAGluUUC, which normally harbor mcm5s2U modifications, mainly rescues the defects of the Δelp3 mutant, suggesting that tRNA modification rather than lysine acetyltransferase is responsible for the primary function of Elp3 in A. fumigatus. Strikingly, global proteomic comparison analyses showed significantly upregulated expression of genes related to amino acid metabolism in the Δelp3 mutant strain compared to the wild-type strain. Western blotting showed that deletion of elp3 resulted in overexpression of the amino acid starvation-responsive transcription factor CpcA, and deletion of CpcA markedly reversed the defective phenotypes of the Δelp3 mutant, including attenuated virulence. Therefore, the findings of this study demonstrate that A. fumigatus Elp3 functions as a tRNA-modifying enzyme in the regulation of growth, GAG production, adhesion and virulence by maintaining intracellular amino acid homeostasis. More broadly, our study highlights the importance of U34 tRNA modification in regulating cellular metabolic states and virulence traits of fungal pathogens.
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Aspergillus fumigatus , Histona Acetiltransferasas , Humanos , Uridina/genética , Aspergillus fumigatus/genética , Aspergillus fumigatus/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Virulencia , Proteómica , Cromatografía Liquida , Espectrometría de Masas en Tándem , ARN de Transferencia/genética , ARN de Transferencia/química , ARN de Transferencia/metabolismo , AminoácidosRESUMEN
Currently, the L-malic acid titer achieved through Aspergillus niger fermentation reaches 201 g/L, meeting industrial demands satisfactorily. However, the co-presence of structurally similar fumaric acid and succinic acid in fermentation products suggests a theoretical potential for further improvement in L-malic acid production. In the tricarboxylic acid cycle, fumarate reductase mediates the conversion of succinic acid to fumaric acid. Subsequently, fumarase catalyzes the conversion of fumaric acid to L-malic acid. Notably, both enzymatic reactions are reversible. Our investigation revealed that A. niger contains only one mitochondria-located fumarase FumA. Employing CRISPR-Cas9 technology, we performed a replacement of the fumA promoter with a doxycycline-induced promoter Tet. Under non-inducing condition, the conditional strain exhibited increased levels of fumaric acid and succinic acid. It strongly suggests that FumA mainly promotes the flow of fumaric acid to L-malic acid. Furthermore, a promoter PmfsA that is exclusively activated in a fermentation medium by calcium carbonate was identified through RNA-sequencing screening. Utilizing PmfsA to regulate fumA expression led to a 9.0% increase in L-malic acid titer, an 8.75% increase in yield (glucose to L-malic acid), and an 8.86% enhancement in productivity. This research serves as a significant step toward expediting the industrialization of L-malic acid synthesis via biological fermentation. Additionally, it offers valuable insights for the biosynthesis of other organic acids.IMPORTANCEThis study focuses on enhancing L-malic acid synthesis by modifying the tricarboxylic acid cycle within the mitochondria of Aspergillus niger. We emphasize the significant role of fumarase in converting fumaric acid into L-malic acid, enhancing our understanding of metabolic pathways in A. niger. The precise regulation of fumA is highlighted as a key factor in enhancing L-malic acid production. Furthermore, this research introduces a stringent conditional promoter (PmfsA), exclusively activated by CaCO3. The utilization of PmfsA for fumA expression resulted in heightened L-malic acid titers. The progress in metabolic engineering and bioprocess optimization holds promise for expediting industrial L-malic acid synthesis via biological fermentation. Moreover, it carries implications for the biosynthesis of various other organic acids.
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Aspergillus niger , Fumarato Hidratasa , Fumaratos , Aspergillus niger/genética , Aspergillus niger/metabolismo , Fumarato Hidratasa/genética , Fumarato Hidratasa/metabolismo , Malatos/metabolismo , Ácido SuccínicoRESUMEN
Histone acetyltransferase (HAT)-mediated epigenetic modification is essential for diverse cellular processes in eukaryotes. However, the functions of HATs in the human pathogen Aspergillus fumigatus remain poorly understood. In this study, we characterized the functions of MOZ, Ybf2/Sas3, Sas2, and Tip60 (MYST)-family histone acetyltransferase something about silencing (Sas3) in A. fumigatus. Phenotypic analysis revealed that loss of Sas3 results in significant impairments in colony growth, conidiation, and virulence in the Galleria mellonella model. Subcellular localization and Western blot analysis demonstrated that Sas3 localizes to nuclei and is capable of acetylating lysine 9 and 14 of histone H3 in vivo. Importantly, we found that Sas3 is critical for the cell wall integrity (CWI) pathway in A. fumigatus as evidenced by hypersensitivity to cell wall-perturbing agents, altered cell wall thickness, and abnormal phosphorylation levels of CWI protein kinase MpkA. Furthermore, site-directed mutagenesis studies revealed that the conserved glycine residues G641 and G643 and glutamate residue E664 are crucial for the acetylation activity of Sas3. Unexpectedly, only triple mutations of Sas3 (G641A/G643A/E664A) displayed defective phenotypes similar to the Δsas3 mutant, while double or single mutations did not. This result implies that the role of Sas3 may extend beyond histone acetylation. Collectively, our findings demonstrate that MYST-family HAT Sas3 plays an important role in the fungal development, virulence, and cell wall integrity in A. fumigatus. IMPORTANCE: Epigenetic modification governed by HATs is indispensable for various cellular processes in eukaryotes. Nonetheless, the precise functions of HATs in the human pathogen Aspergillus fumigatus remain elusive. In this study, we unveil the roles of MYST-family HAT Sas3 in colony growth, conidiation, virulence, and cell wall stress response in A. fumigatus. Particularly, our findings demonstrate that Sas3 can function through mechanisms unrelated to histone acetylation, as evidenced by site-directed mutagenesis experiments. Overall, this study broadens our understanding of the regulatory mechanism of HATs in fungal pathogens.
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Aspergillus fumigatus , Histona Acetiltransferasas , Humanos , Aspergillus fumigatus/genética , Aspergillus fumigatus/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/química , Histona Acetiltransferasas/metabolismo , Histonas/genética , Histonas/metabolismo , Virulencia , Pared Celular/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismoRESUMEN
Mitogen-activated protein kinase (MAPK) signalling cascades are functionally important signalling modules in eukaryotes. Transcriptome reprogramming of immune-related genes is a key process in plant immunity. Emerging evidence shows that plant MAPK cascade is associated with processing (P)-body components and contributes to transcriptome reprogramming of immune-related genes. However, it remains largely unknown how this process is regulated. Here, we show that OsMPK12, which is induced by Magnaporthe oryzae infection, positively regulates rice blast resistance. Further analysis revealed that OsMPK12 directly interacts with enhancer of mRNA decapping protein 4 (OsEDC4), a P-body-located protein, and recruits OsEDC4 to where OsMPK12 is enriched. Importantly, OsEDC4 directly interacts with two decapping complex members OsDCP1 and OsDCP2, indicating that OsEDC4 is a subunit of the mRNA decapping complex. Additionally, we found that OsEDC4 positively regulates rice blast resistance by regulating expression of immune-related genes and maintaining proper mRNA levels of some negatively-regulated genes. And OsMPK12 and OsEDC4 are also involved in rice growth and development regulation. Taken together, our data demonstrate that OsMPK12 positively regulates rice blast resistance via OsEDC4-mediated mRNA decay of immune-related genes, providing new insight into not only the new role of the MAPK signalling cascade, but also posttranscriptional regulation of immune-related genes.
RESUMEN
Receptor-like kinases (RLKs) are major regulators of the plant immune response and play important roles in the perception and transmission of immune signals. RECEPTOR LIKE KINASE 902 (RLK902) is at the key node in leucine-rich repeat receptor-like kinase interaction networks and positively regulates resistance to the bacterial pathogen Pseudomonas syringae in Arabidopsis. However, the function of RLK902 in fungal disease resistance remains obscure. In this study, we found that the expression levels of OsRLK902-1 and OsRLK902-2, encoding two orthologues of RLK902 in rice, were induced by Magnaporthe oryzae, chitin, and flg22 treatment. osrlk902-1 and osrlk902-2 knockout mutants displayed enhanced susceptibility to M. oryzae. Interestingly, the osrlk902-1 rlk902-2 double mutant exhibited similar disease susceptibility, hydrogen peroxide production, and callose deposition to the two single mutants. Further investigation showed that OsRLK902-1 interacts with and stabilizes OsRLK902-2. The two OsRLKs form a complex with OsRLCK185, a key regulator in chitin-triggered immunity, and stabilize it. Taken together, our data demonstrate that OsRLK902-1 and OsRLK902-2, as well as OsRLCK185 function together in regulating disease resistance to M. oryzae in rice.
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Proteínas de Arabidopsis , Arabidopsis , Magnaporthe , Oryza , Resistencia a la Enfermedad/genética , Complejo Antígeno-Anticuerpo/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Arabidopsis/metabolismo , Quitina/metabolismo , Oryza/metabolismo , Enfermedades de las Plantas/microbiología , Magnaporthe/fisiología , Proteínas Quinasas/metabolismo , Proteínas de Arabidopsis/metabolismoRESUMEN
INTRODUCTION: Asthma has been attributed to Th1/Th2 imbalance and inappropriate Th2 responses to environmental allergens. MicroRNAs (miRNAs), 21 to 23 RNA molecules, are first found in mammals and have been implicated in various biological activities. Our previous study found that miR-410 effectively ameliorates airway inflammation in the ovalbumin (OVA)-induced asthma murine model. However, the role of miR-410 in regulating helper T (Th) cell differentiation is not clear. In the present study, we aimed to explore the regulatory effects of miR-410 on the differentiation of Th cells through both in vivo and in vitro studies. METHODS: Dual-luciferase reporter assay was used to find if miR-410 has any direct binding position with VEGF mRNAs. PBMC and CD4+ T cells were isolated and stimulated with OVA. The miR-410 mimics and inhibitors were transfected into CD4+ T cells. The differentiation of Th cells was evaluated by enzyme-linked immunosorbent assay (ELISA) for the concentration of IL-4, IFN-γ, and TGF-ß levels in supernatants. Western Blot was used to detect protein expression and phosphorylation of PI3K and AKT. BALB/c mice were kept in a specific pathogen-free condition and received sterile OVA-free food and water. OVA-induced asthmatic mice model was established. ELISA was used to measure the bronchoalveolar lavage fluid (BALF) concentrations of IL-4, IFN-γ, TGF-ß, and VEGF. Hematoxylin and eosin staining and immunohistochemical staining were conducted to analyze inflammatory cell infiltration, pathological changes, and the expression of VEGF. RESULTS: Dual-luciferase reporter assay showed that miR-410 has no direct binding position with VEGF mRNAs. In the OVA-primed mononuclear cells compared to normal cells, IFN-γ and TGF-ß were decreased while IL-4 and VEGF were increased. This change was reversed while miRNA-410 mimics were transfected into CD4+ T cells. Besides, the OVA-primed CD4+ T cells treated with miR-410 decrease the proliferation of cytokine of Th2 cells as well as phosphorylation of PI3K, and AKT. In OVA-induced asthma mice, IFN-γ and TGF-ß were decreased in BALF while the IL-4 and VEGF were increased. OVA-induced mice with asthma treated with miR-410 mimics showed marked reductions in the infiltration of inflammatory cells as well as IL-4 and VEGF in BALF. The immunohistochemical staining of the expression of VEGF also decreased in OVA-induced asthma mice with the instillation of miR-410. CONCLUSIONS: In this study, we revealed that miR-410 could regulate the differentiation of Th cells via the PI3K-AKT-VEGF signaling pathway in asthma.
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Asma , MicroARNs , Animales , Ratones , Asma/metabolismo , Líquido del Lavado Bronquioalveolar , Diferenciación Celular , Modelos Animales de Enfermedad , Interleucina-4 , Leucocitos Mononucleares , Luciferasas/metabolismo , Pulmón/patología , Mamíferos/genética , Mamíferos/metabolismo , Ratones Endogámicos BALB C , MicroARNs/genética , Ovalbúmina/efectos adversos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta , Factor A de Crecimiento Endotelial Vascular/efectos adversosRESUMEN
Autoimmune regulator (Aire) and TGF-ß signaling play important roles in central tolerance and peripheral tolerance, respectively, by eliminating or suppressing the activity of autoreactive T cells. We previously demonstrated that dnTGFßRII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC)-like disease. We hypothesized that by introducing the Aire gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that, while dnTGFßRII Aire-/- mice do manifest key histological and serological features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA sequencing (RNA-seq) and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFßRII Aire-/- mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8+ T cell infiltrates. Depleting CD8+ T cells using an anti-CD8α antibody significantly alleviated hepatic inflammation and prolonged the life span of these mice. Finally, RNA-seq data indicated the clonal expansion of hepatic CD8+ T cells. In conclusion, these mice developed an autoreactive CD8+ T-cell-mediated autoimmune cholangitis with concurrent hepatitis that exhibited key histological and serological features of the AIH-PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease. © 2023 The Pathological Society of Great Britain and Ireland.
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Colangitis , Hepatitis Autoinmune , Cirrosis Hepática Biliar , Ratones , Animales , Hepatitis Autoinmune/genética , Hepatitis Autoinmune/metabolismo , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/metabolismo , Linfocitos T CD8-positivos , Colangitis/genética , Colangitis/metabolismoRESUMEN
In this work, a quantitative structure-antioxidant activity relationship of flavonoids was performed using a machine learning (ML) method. To achieve lipid-soluble, highly antioxidant flavonoids, 398 molecular structures with various substitute groups were designed based on the flavonoid skeleton. The hydrogen dissociation energies (ΔG1, ΔG2, and ΔG3) related to multiple hydrogen atom transfer processes and the solubility parameter (δ) of flavonoids were calculated using molecular simulation. The group decomposition results and the calculated antioxidant parameters constituted the ML data set. The artificial neural network and random forest models were constructed to predict and analyze the contribution of the substitute groups and positions to the antioxidant activity. The results showed the hydroxyl group at positions B4', B5', and B6' and the branched alkyl group at position C3 in the flavonoid skeleton were the optimal choice for improving antioxidant activity and compatibility with apolar organic materials. Compared to the pyrogallol group-grafted flavonoid, the designed potent flavonoid decreased ΔG1 and δ by 2.2 and 15.1%, respectively, while ΔG2 and ΔG3 kept the favorable lower values. These findings suggest that an efficient flavonoid prefers multiple ortho-phenolic hydroxyl groups and suitable sites with hydrophobic groups. The combination of molecular simulation and the ML method may offer a new research approach for the molecular design of novel antioxidants.
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Antioxidantes , Flavonoides , Aprendizaje Automático , Relación Estructura-Actividad Cuantitativa , Flavonoides/química , Antioxidantes/química , Antioxidantes/farmacología , Estructura Molecular , Simulación de Dinámica Molecular , Diseño de Fármacos , TermodinámicaRESUMEN
Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg-1·d-1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.
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Lesión Renal Aguda , Cisplatino , Indicán , Factor de Necrosis Tumoral alfa , Animales , Lesión Renal Aguda/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Humanos , Ratones , Masculino , Células RAW 264.7 , Ratas , Ratones Endogámicos C57BL , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Ratas Sprague-Dawley , Sinaptofisina/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Uremia/metabolismo , Uremia/complicaciones , Línea Celular TumoralRESUMEN
BACKGROUND Previous studies have suggested that autophagy, a cellular process regulated by ATG7, plays a critical role in ovarian physiology and pathology. In this study, our objective was to examine ATG7 levels in women with and without polycystic ovary syndrome (PCOS) and to explore potential associations between serum ATG7 levels and PCOS. MATERIAL AND METHODS The study included 188 women diagnosed with PCOS, matched with an equal number of healthy women for comparison. Serum levels of ATG7 were determined using the ELISA technique, and the difference was assessed using an independent samples t test. The association between ATG7 serum levels and the risk of developing PCOS was evaluated by using a multivariable logistic regression model. Additionally, the potential of ATG7 to predict PCOS was investigated through logistic regression and receiver operating characteristic (ROC) analysis. RESULTS Our study found that women with PCOS had significantly lower serum ATG7 levels than their healthy counterparts. Lower ATG7 levels were associated with a higher risk of developing PCOS after adjusting for various confounding variables. The combination of ATG7 with HOMA-IR performed well in predicting PCOS, with an AUC of 92.3%, a sensitivity of 88.3%, and a specificity of 85.3%. CONCLUSIONS Our study found that serum ATG7 levels were significantly lower in women with PCOS and were associated with an increased risk of developing PCOS. This suggests that ATG7 could potentially serve as a biomarker for diagnosing and managing PCOS.
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Proteína 7 Relacionada con la Autofagia , Resistencia a la Insulina , Síndrome del Ovario Poliquístico , Curva ROC , Humanos , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/metabolismo , Femenino , Adulto , Proteína 7 Relacionada con la Autofagia/metabolismo , Estudios de Casos y Controles , Modelos Logísticos , Biomarcadores/sangre , Autofagia , Adulto JovenRESUMEN
OBJECTIVE: Hydroxychloroquine (HCQ) is a US Food and Drug Administration (FDA)-approved treatment for systemic lupus erythematosus (SLE) through inhibition of antigen presentation and subsequent reduction in T cell activation. Psoriasis relapse after antimalarial therapy have been reported in up to 18% of patients with psoriasis. Here, we explored the role of HCQ on exacerbating dermatitis utilizing an imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model. METHODS: Thirty-six C57BL/6 female mice were divided into six groups: wild-type control, IMQ-Only, pre-treat HCQ (30 mg/kg and 60 mg/kg HCQ), and co-treat HCQ with IMQ (30 mg/kg and 60 mg/kg HCQ). Besides control, all were topically treated with IMQ for 5 days. Pharmacological effects and mechanisms of HCQ were assessed by clinical severity of dermatitis, histopathology, and flow cytometry. HaCaT cells were co-treated with both HCQ and recombinant IL-17A, followed by the detection of proinflammatory cytokine expression and gene profiles through enzyme-linked immunosorbent assay and next-generation sequencing. RESULTS: In the pre-treated and co-treated HCQ groups, skin redness and scaling were significantly increased compared to the IMQ-Only group, and Th17 cell expression was also upregulated. Acanthosis and CD11b+IL23+ dendritic cell (DC) infiltration were observed in the HCQ treatment group. IL-6 overexpression was detected in both the HaCaT cells and skin from the experimental mice. Psoriasis-related genes were regulated after being co-treated with HCQ and recombinant IL-17A in HaCaT cells. CONCLUSIONS: HCQ exacerbates psoriasis-like skin inflammation by increasing the expression of IL-6, stimulating DC infiltration, and promoting Th17 expression in the microenvironment of the skin. KEY MESSAGES: This study provided possible mechanisms for inducing psoriasis during HCQ treatment through an animal model.
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Dermatitis , Psoriasis , Humanos , Femenino , Animales , Ratones , Imiquimod/efectos adversos , Interleucina-17 , Hidroxicloroquina/efectos adversos , Interleucina-6/metabolismo , Ratones Endogámicos C57BL , Psoriasis/inducido químicamente , Queratinocitos , Piel , Dermatitis/metabolismo , Dermatitis/patología , Modelos Animales de Enfermedad , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Postoperative pain control is pivotal for surgical care; it facilitates patient recovery. Although patient-controlled analgesia (PCA) has been available for decades, inadequate pain control remains. Nurses' knowledge of and attitude toward PCA may influence the efficacy on clinic application. PURPOSE: The purpose of this study is to evaluate nurses' knowledge of and attitude toward postoperative PCA and investigate the associated factors. METHODS: This is a cross-sectional study. We enrolled registered nurses from a 2200-bed medical center in northern Taiwan within one year. The participants completed an anonymous self-reported PCA knowledge inventory and PCA attitude inventory. Data were analyzed descriptively and associated were tested using logistic regression. RESULTS: With 303 participants enrolled, we discovered that nurses had limited knowledge of and a negative attitude toward PCA. Under half of the participants know how to set up a bolus dose and lockout intervals. The majority held misconceptions regarding side effect management for opioids. The minority agree to increase the dose when a patient experienced persistent pain or suggested the use of PCA. Surprisingly, participants with a bachelor's or master's degree had lower knowledge scores than those with a junior college degree. Those with 6-10 years of work experience also are lower than those with under 5 years of experience. However, the participants with experience of using PCA for patient care had higher knowledge scores and a more positive attitude. CONCLUSIONS: Although postoperative PCA has been available for decades and education programs are routinely provided, nurses had limited knowledge of and a negative attitude toward PCA. A higher education level and longer work experience were not associated with more knowledge. The current education programs on PCA should be revised to enhance their efficacy in delivering up-to-date knowledge and situation training which may convey supportive attitude toward clinical application of PCA.
RESUMEN
BACKGROUND: Air volatile organic compounds (VOCs) cause allergic reaction mainly via the respiratory tract or skin. OBJECTIVE: This study aimed to investigate the association between daily visits by patients with urticaria and short-term changes in exposure to ambient air VOCs. METHODS: The dependent variable was information from patients with urticaria at a medical center in Kaohsiung, Taiwan, from 2014/01/01 to 2018/07/31. The multivariable model included one-day average 75th percentile values of air VOCs and meteorologic data retrieved from Taiwan Air Quality Monitoring Network database, and was analyzed using a case-crossover study design and conditional logistic regression. RESULTS: Total daily clinic visits for urticaria were significantly positively associated with higher levels of 4 VOCs (ethylbenzene, toluene, m-/p-xylene, and o-xylene (adjusted odds ratio (AOR: 1.03-1.28)) on the visit days, and 10 VOC levels on the fourth lag day (benzene, ethylbenzene, toluene, m-/p-xylene, o-xylene, 1,3,5-trimethylbenzene, n-hexane, methylcyclohexane, cyclohexane, and ethylene (AOR: 1.02-3.02)). Analyses of age and gender subgroups revealed that men showed resistance on the visit day, and women, older, and younger patients were more vulnerable. Men were influenced by higher benzene levels (AOR = 1.24) on the fourth lag day. Higher values of more than 6 VOCs on the fourth lag day significantly affected women, younger and older patients (AOR: 1.04-6.5). The most notable VOCs were methylcyclohexane (women AOR = 3.28, younger AOR = 3.82) and 1,3,5-trimethylbenzene (women AOR = 2.77, older AOR = 6.5) on the fourth lag day, which had the lowest concentrations but highest influence. CONCLUSION: The concentration of certain air VOCs significantly affected daily visits for urticaria.
RESUMEN
OBJECTIVES: To assess the link between the administration of biologic disease-modifying antirheumatic drugs (bDMARDs) and the risk of malignancy in human leukocyte antigen B27 (HLA-B27)-positive patients with ankylosing spondylitis (AS) experiencing sustained inflammation. METHODS: Between 2006 and 2021, 1445 HLA-B27-positive patients with AS were retrospectively evaluated. Among them, 112 patients required bDMARD therapy. The study compared conventional therapy with bDMARDs and investigated the risk factors for developing malignancies. RESULTS: During 8253 patient-years of follow-up, 38 (2.6%) patients developed various malignancies, including lung, liver, breast, and colon cancer. The risk of malignancy was significantly higher in the bDMARD-treated group compared to PS-matched groups receiving conventional synthetic DMARDs (csDMARD) and non-steroidal anti-inflammatory drugs. The cumulative risk of malignancies increased significantly after 6 years of follow-up. All patients who developed malignancy after bDMARD therapy received tumor necrosis factor-α inhibitors. Requiring bDMARD therapy, requiring bDMARDs in combination with csDMARD therapy, and being diagnosed with AS after 30 years of age were independent risk factors for developing malignancy. CONCLUSIONS: HLA-B27-positive AS patients with sustained inflammation requiring biologic therapy, particularly if diagnosed after age 30, may have an increased risk of malignancy. Regular cancer screenings are advisable for these patients while undergoing biologic treatment.
Asunto(s)
Antirreumáticos , Productos Biológicos , Antígeno HLA-B27 , Neoplasias , Espondilitis Anquilosante , Humanos , Espondilitis Anquilosante/tratamiento farmacológico , Antígeno HLA-B27/inmunología , Femenino , Masculino , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Productos Biológicos/uso terapéutico , Productos Biológicos/efectos adversos , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Factores de Riesgo , Inflamación/inmunología , Inflamación/tratamiento farmacológicoRESUMEN
Polycystic ovary syndrome(PCOS) is a highly prevalent endocrine and reproductive disorder characterized by ovulatory dysfunction, hyperandrogenism(HA), and polycystic ovarian morphology(PCOM). It is often accompanied by insulin resistance(IR), obesity, and metabolic disorders and can lead to cardiovascular diseases, endometrial carcinoma and many other late complications, seriously affecting the physical and mental health and quality of life in premenopausal women. The etiology of PCOS is still unknown and many scholars assume that mitochondrial dysfunction may represent a major pathogenic factor in PCOS in recent years. With a holistic view, treatment based on syndrome differentiation, and multi-system and multi-target treatment manner, traditional Chinese medicine(TCM) can mitigate the symptoms and signs of PCOS from multiple aspects. Although there have been reviews on the mechanism of mitochondrial dysfunction in PCOS, there is still a lack of reviews on the intervention of mitochondrial function by TCM to treat PCOS. Therefore, this paper focuses on the role of mitochondrial dysfunction in PCOS and summarizes the studies about the TCM intervention of PCOS by regulating the mitochondrial function, inflammation, oxidative stress(OS), autophagy, and apoptosis in the last five years, aiming to shed new light on the prevention and treatment of PCOS with TCM.