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Dengue virus (DENV) represents a significant global health burden, with 50% of the world's population at risk of infection, and there is an urgent need for next-generation vaccines. Virus-like particle (VLP)-based vaccines, which mimic the antigenic structure of the virus but lack the viral genome, are an attractive approach. Here, we describe a dengue VLP (DENVLP) vaccine which generates a neutralizing antibody response against all four DENV serotypes in 100% of immunized non-human primates for up to 1 year. Additionally, DENVLP vaccination produced no ADE response against any of four DENV serotypes in vitro. DENVLP vaccination reduces viral replication in a non-human primate challenge model. We also show that transfer of purified IgG from immunized monkeys into immunodeficient mice protects against subsequent lethal DENV challenge, indicating a humoral mechanism of protection. These results indicate that this DENVLP vaccine is immunogenic and can be considered for clinical evaluation. Immunization of non-human primates with a tetravalent DENVLP vaccine induces high levels of neutralizing antibodies and reduces the severity of infection for all four dengue serotypes.IMPORTANCEDengue is a viral disease that infects nearly 400 million people worldwide and causes dengue hemorrhagic fever, which is responsible for 10,000 deaths each year. Currently, there is no therapeutic drug licensed to treat dengue infection, which makes the development of an effective vaccine essential. Virus-like particles (VLPs) are a safe and highly immunogenic platform that can be used in young children, immunocompromised individuals, as well as healthy adults. In this study, we describe the development of a dengue VLP vaccine and demonstrate that it induces a robust immune response against the dengue virus for over 1 year in monkeys. The immunity induced by this vaccine reduced live dengue infection in both murine and non-human primate models. These results indicate that our dengue VLP vaccine is a promising vaccine candidate.
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Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra Dengue , Vírus da Dengue , Dengue , Vacinas de Partículas Semelhantes a Vírus , Animais , Feminino , Camundongos , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Dengue/prevenção & controle , Dengue/imunologia , Dengue/virologia , Vacinas contra Dengue/imunologia , Vacinas contra Dengue/administração & dosagem , Vírus da Dengue/imunologia , Modelos Animais de Doenças , Imunoglobulina G/imunologia , Macaca fascicularis , Macaca mulatta , Sorogrupo , Vacinação , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Replicação ViralRESUMO
BACKGROUND: The chromatin-remodeling enzymes BRG1 (brahma-related gene 1) and CHD4 (chromodomain helicase DNA-binding protein 4) independently regulate the transcription of genes critical for vascular development, but their coordinated impact on vessels in late-stage embryos has not been explored. METHODS: In this study, we genetically deleted endothelial Brg1 and Chd4 in mixed background mice (Brg1fl/fl;Chd4fl/fl;VE-Cadherin-Cre), and littermates that were negative for Cre recombinase were used as controls. Tissues were analyzed by immunostaining, immunoblot, and flow cytometry. Quantitative reverse transcription polymerase chain reaction was used to determine gene expression, and chromatin immunoprecipitation revealed gene targets of BRG1 and CHD4 in cultured endothelial cells. RESULTS: We found Brg1/Chd4 double mutants grew normally but died soon after birth with small and compact lungs. Despite having normal cellular composition, distal air sacs of the mutant lungs displayed diminished ECM (extracellular matrix) components and TGFß (transforming growth factor-ß) signaling, which typically promotes ECM synthesis. Transcripts for collagen- and elastin-related genes and the TGFß ligand Tgfb1 were decreased in mutant lung endothelial cells, but genetic deletion of endothelial Tgfb1 failed to recapitulate the small lungs and ECM defects seen in Brg1/Chd4 mutants. We instead found several ECM genes to be direct targets of BRG1 and CHD4 in cultured endothelial cells. CONCLUSIONS: Collectively, our data highlight essential roles for endothelial chromatin-remodeling enzymes in promoting ECM deposition in the distal lung tissue during the saccular stage of embryonic lung development.
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Montagem e Desmontagem da Cromatina , DNA Helicases , Células Endoteliais , Regulação da Expressão Gênica no Desenvolvimento , Pulmão , Proteínas Nucleares , Fatores de Transcrição , Animais , DNA Helicases/metabolismo , DNA Helicases/genética , DNA Helicases/deficiência , Pulmão/embriologia , Pulmão/metabolismo , Pulmão/enzimologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Células Endoteliais/metabolismo , Células Endoteliais/enzimologia , Camundongos Knockout , Transdução de Sinais , Matriz Extracelular/metabolismo , Camundongos , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Camundongos Endogâmicos C57BL , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/genética , Fenótipo , Humanos , OrganogêneseRESUMO
Cell spreading is an initial and critical step in neutrophil adhesion and migration, leading to neutrophil recruitment to inflammatory tissues. Sideroflexin (Sfxn) family proteins are metabolite transporters located in the mitochondrial membrane. Recombinant SFXN5 protein is a citrate transporter in vitro; however, whether Sfxn5 regulates any cellular behavior or function remains unknown. In this study, we found that small interfering RNA transfection or morpholino injection achieving Sfxn5 deficiency in neutrophils significantly decreased neutrophil recruitment in mice and zebrafish, respectively. Sfxn5 deficiency impaired neutrophil spreading and spreading-associated cellular phenotypes, such as cell adhesion, chemotaxis, and ROS production. Actin polymerization is critical for neutrophil spreading, and we found that actin polymerization in spreading neutrophils was partially inhibited by Sfxn5 deficiency. Mechanistically, we observed that the levels of cytosolic citrate and its downstream metabolic products, acetyl-CoA and cholesterol, were decreased in Sfxn5-deficient neutrophils. The levels of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), a mediator for the regulation of actin polymerization by cholesterol, were reduced in the plasma membrane of Sfxn5-deficient neutrophils. Exogenous supplementation with citrate or cholesterol partially reversed the reduction in PI(4,5)P2 levels, defective neutrophil actin polymerization, and cell spreading. Altogether, we demonstrated that Sfxn5 maintains cytosolic citrate levels and ensures the synthesis of sufficient cholesterol to promote actin polymerization in a PI(4,5)P2-dependent manner during neutrophil spreading, which is essential for the eventual inflammatory recruitment of neutrophils. Our study revealed the importance of Sfxn5 in neutrophil spreading and migration, thus identifying, to our knowledge, for the first time, the physiological cellular functions of the Sfxn5 gene.
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Actinas , Neutrófilos , Animais , Camundongos , Actinas/metabolismo , Neutrófilos/metabolismo , Ácido Cítrico/metabolismo , Peixe-Zebra/metabolismo , Polimerização , Colesterol/metabolismoRESUMO
During viral infection, sensing of viral RNA by retinoic acid-inducible gene-I-like receptors (RLRs) initiates an antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA (virus-induced signal adaptor; also known as mitochondrial antiviral signaling protein [MAVS]). VISA is regulated by various posttranslational modifications (PTMs), such as polyubiquitination, phosphorylation, O-linked ß-d-N-acetylglucosaminylation (O-GlcNAcylation), and monomethylation. However, whether other forms of PTMs regulate VISA-mediated innate immune signaling remains elusive. Here, we report that Poly(ADP-ribosyl)ation (PARylation) is a PTM of VISA, which attenuates innate immune response to RNA viruses. Using a biochemical purification approach, we identified tankyrase 1 (TNKS1) as a VISA-associated protein. Viral infection led to the induction of TNKS1 and its homolog TNKS2, which translocated from cytosol to mitochondria and interacted with VISA. TNKS1 and TNKS2 catalyze the PARylation of VISA at Glu137 residue, thereby priming it for K48-linked polyubiquitination by the E3 ligase Ring figure protein 146 (RNF146) and subsequent degradation. Consistently, TNKS1, TNKS2, or RNF146 deficiency increased the RNA virus-triggered induction of downstream effector genes and impaired the replication of the virus. Moreover, TNKS1- or TNKS2-deficient mice produced higher levels of type I interferons (IFNs) and proinflammatory cytokines after virus infection and markedly reduced virus loads in the brains and lungs. Together, our findings uncover an essential role of PARylation of VISA in virus-triggered innate immune signaling, which represents a mechanism to avoid excessive harmful immune response.
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Proteínas Adaptadoras de Transdução de Sinal , Imunidade Inata , Infecções por Vírus de RNA , Vírus de RNA , Tanquirases , Ubiquitina-Proteína Ligases , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células HEK293 , Humanos , Imunidade Inata/genética , Camundongos , Infecções por Vírus de RNA/imunologia , Vírus de RNA/imunologia , Tanquirases/genética , Tanquirases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
Patchoulol, a valuable compound belonging to the sesquiterpenoid family, is the primary component of patchouli oil produced by Pogostemon cablin (P. cablin). It has a variety of pharmacological and biological activities and is widely used in the medical and cosmetic industries. However, despite its significance, there is a lack of research on the transcriptional modulation of patchoulol biosynthesis.Salicylic acid (SA), is a vital plant hormone that serves as a critical signal molecule and plays an essential role in plant growth and defense. However, to date, no studies have explored the modulation of patchoulol biosynthesis by SA. In our study, we discovered that the application of SA can enhance the production of patchoulol. Utilizing transcriptome analysis of SA-treated P. cablin, we identified a crucial downstream transcription factor, PatWRKY71. The transcription level of PatWRKY71 was significantly increased with the use of SA. Furthermore, our research has revealed that PatWRKY71 was capable of binding to the promoter of PatPTS, ultimately leading to an increase in its expression. When PatWRKY71 was silenced by a virus, the expression of both PatWRKY71 and PatPTS was reduced, resulting in the down-regulation of patchoulol production. Through our studies, we discovered that heterologous expression of PatWRKY71 leads to an increase in the sensitivity of Arabidopsis to salt and Cd, as well as an outbreak of reactive oxygen species (ROS). Additionally, we uncovered the regulatory role of PatWRKY71 in both patchoulol biosynthesis and plant defense response. This discovery provided a theoretical basis for the improvement of the content of patchoulol and the resistance of P. cablin through genetic engineering.
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Arabidopsis , Pogostemon , Sesquiterpenos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Plantas/metabolismo , Pogostemon/genética , Sesquiterpenos/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismoRESUMO
The rise of MXene-based materials with fascinating physical and chemical properties has attracted wide attention in the field of biomedicine, because it can be exploited to regulate a variety of biological processes. The biomedical applications of MXene are still in its infancy, nevertheless, the comprehensive evaluation of MXene's biosafety is desperately needed. In this review, the composition and the synthetic methods of MXene materials are first introduced from the view of biosafety. The evaluation of the interaction between MXene and cells, as well as the safety of different forms of MXene applied in vivo are then discussed. This review provides a basic understanding of MXene biosafety and may bring new inspirations to the future applications of MXene-based materials in biomedicine.
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Contenção de Riscos Biológicos , Nitritos , Elementos de TransiçãoRESUMO
Persistent psychological stress can affect immune homeostasis and is a key factor in the development of depression. Many efforts are focused on the identifcation of pathways that link the immune system and mood disorders. Here, we found that psychological stress caused an increase in the frequency of brain-associated neutrophils and the level of neutrophil-specific antigen CD177 on peripheral neutrophils in male mice. Upregulated levels of blood CD177 are associated with depression in humans. Neutrophil depletion or Cd177 deficiency protected mice from stress-induced behavioral deficits. Importantly, adoptive transfer of CD177+ neutrophils from stressed mice increased the frequency of brain-associated leukocytes, including neutrophils, and caused behavioral defects in naive mice. These effects may be related to the endothelial adhesion advantage of CD177+ neutrophils and the interference of serine protease on endothelial junction. Our findings suggest a critical link between circulating CD177+ neutrophils and psychological stress-driven behavioral disorder.
Assuntos
Comportamento Animal , Camundongos Endogâmicos C57BL , Neutrófilos , Estresse Psicológico , Animais , Neutrófilos/metabolismo , Masculino , Estresse Psicológico/metabolismo , Estresse Psicológico/imunologia , Camundongos , Comportamento Animal/fisiologia , Proteínas Ligadas por GPI/metabolismo , Receptores de Superfície Celular/metabolismo , Depressão/metabolismo , Depressão/imunologia , Encéfalo/metabolismo , HumanosRESUMO
BACKGROUND: The chromatin-remodeling enzyme BRG1 (brahma-related gene 1) regulates gene expression in a variety of rapidly differentiating cells during embryonic development. However, the critical genes that BRG1 regulates during lymphatic vascular development are unknown. METHODS: We used genetic and imaging techniques to define the role of BRG1 in murine embryonic lymphatic development, although this approach inadvertently expanded our study to multiple interacting cell types. RESULTS: We found that omental macrophages fine-tune an unexpected developmental process by which erythrocytes escaping from naturally discontinuous omental blood vessels are collected by nearby lymphatic vessels. Our data indicate that circulating fibrin(ogen) leaking from gaps in omental blood vessels can trigger inflammasome-mediated IL-1ß (interleukin-1ß) production and secretion from nearby macrophages. IL-1ß destabilizes adherens junctions in omental blood and lymphatic vessels, contributing to both extravasation of erythrocytes and their uptake by lymphatics. BRG1 regulates IL-1ß production in omental macrophages by transcriptionally suppressing the inflammasome trigger RIPK3 (receptor interacting protein kinase 3). CONCLUSIONS: Genetic deletion of Brg1 in embryonic macrophages leads to excessive IL-1ß production, erythrocyte leakage from blood vessels, and blood-filled lymphatics in the developing omentum. Altogether, these results highlight a novel context for epigenetically regulated crosstalk between macrophages, blood vessels, and lymphatics.
Assuntos
Vasos Sanguíneos/metabolismo , DNA Helicases/metabolismo , Interleucina-1beta/metabolismo , Vasos Linfáticos/metabolismo , Proteínas Nucleares/metabolismo , Omento/metabolismo , Fatores de Transcrição/metabolismo , Junções Aderentes/metabolismo , Animais , Vasos Sanguíneos/embriologia , DNA Helicases/genética , Eritrócitos/metabolismo , Inflamassomos/metabolismo , Vasos Linfáticos/embriologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Omento/irrigação sanguínea , Omento/embriologia , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: During infectious diseases, proinflammatory cytokines transiently destabilize interactions between adjacent vascular endothelial cells (ECs) to facilitate the passage of immune molecules and cells into tissues. However, in the lung, the resulting vascular hyperpermeability can lead to organ dysfunction. Previous work identified the transcription factor ERG (erythroblast transformation-specific-related gene) as a master regulator of endothelial homeostasis. Here we investigate whether the sensitivity of pulmonary blood vessels to cytokine-induced destabilization is due to organotypic mechanisms affecting the ability of endothelial ERG to protect lung ECs from inflammatory injury. METHODS: Cytokine-dependent ubiquitination and proteasomal degradation of ERG were analyzed in cultured HUVECs (human umbilical vein ECs). Systemic administration of TNFα (tumor necrosis factor alpha) or the bacterial cell wall component lipopolysaccharide was used to cause a widespread inflammatory challenge in mice; ERG protein levels were assessed by immunoprecipitation, immunoblot, and immunofluorescence. Murine Erg deletion was genetically induced in ECs (Ergfl/fl;Cdh5[PAC]-CreERT2), and multiple organs were analyzed by histology, immunostaining, and electron microscopy. RESULTS: In vitro, TNFα promoted the ubiquitination and degradation of ERG in HUVECs, which was blocked by the proteasomal inhibitor MG132. In vivo, systemic administration of TNFα or lipopolysaccharide resulted in a rapid and substantial degradation of ERG within lung ECs but not ECs of the retina, heart, liver, or kidney. Pulmonary ERG was also downregulated in a murine model of influenza infection. Ergfl/fl;Cdh5(PAC)-CreERT2 mice spontaneously recapitulated aspects of inflammatory challenges, including lung-predominant vascular hyperpermeability, immune cell recruitment, and fibrosis. These phenotypes were associated with a lung-specific decrease in the expression of Tek-a gene target of ERG previously implicated in maintaining pulmonary vascular stability during inflammation. CONCLUSIONS: Collectively, our data highlight a unique role for ERG in pulmonary vascular function. We propose that cytokine-induced ERG degradation and subsequent transcriptional changes in lung ECs play critical roles in the destabilization of pulmonary blood vessels during infectious diseases.
Assuntos
Doenças Transmissíveis , Fatores de Transcrição , Humanos , Camundongos , Animais , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Lipopolissacarídeos/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Citocinas/metabolismo , Doenças Transmissíveis/metabolismo , Células Cultivadas , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismoRESUMO
The importance of sulfonyl-group-containing compounds, such as sulfonamides, sulfones, sulfinate esters, and sulfonyl fluorides, in pharmaceuticals, bioactive molecules, and natural products cannot be overstated. The new development of palladium-catalyzed sulfonylation via SO2 insertion represents a crucial advancement in organic synthesis, enabling the direct α,α-difunctionalization of SO2 and providing efficient access to an array of structure-diverse sulfonyl-containing compounds. Although there have been numerous reviews about SO2 insertion, many of them only cover specific aspects of palladium-catalyzed reactions, leading to an oversight of some important works. Besides, these reviews often lack detailed discussions and systematic conclusion on reaction mechanisms, and fail to comprehensively summarize the significant research achievements in palladium-catalyzed reactions over the past few years. Herein, we aim to systematically consolidate the recent advances in palladium-catalyzed sulfonylation via SO2 insertion, elucidate the underlying reaction mechanism, and highlight some unsolved challenges in this segment. This review seeks to serve as a valuable resource for researchers, assisting in the continued development of palladium-catalyzed sulfonylation methodologies.
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PURPOSE: To evaluate the impact of two different parameters (body position and distension medium) on the rectal sensory test in patients with functional constipation and provide data support for the development of standardized operating procedures in clinical practice. METHODS: Based on a single-center process of the rectal sensory test, 39 patients with functional constipation were recruited for rectal sensory test under different body positions and distension mediums. RESULTS: Among the items of the Constipation Scoring System, the score of frequency of bowel movements showed a negative correlation with the first constant sensation volume (r = -0.323, P = 0.045). Conversely, the score of painful evacuation effort showed a positive correlation with the desire to defecate volume (r = 0.343, P = 0.033). There was a statistically significant difference in the first constant sensation volume (when the distension medium was gas) measured in different body positions (left lateral position, sitting position, squatting position), and the data measured in the squatting position were significantly higher than those in left lateral position (P < 0.05). In terms of research on distension medium, it was found that the first constant sensation volume measured in the squatting position (when the distension medium was water) was significantly lower than that of gas (P < 0.05). CONCLUSION: For patients with functional constipation, there are differences in the results of rectal sensory tests between body positions and distension mediums. When conducting multicenter studies, it is necessary to unify the standard operating procedure (SOP) for operational details to ensure consistency and reliability of the test results.
Assuntos
Constipação Intestinal , Posicionamento do Paciente , Reto , Humanos , Constipação Intestinal/fisiopatologia , Constipação Intestinal/diagnóstico , Feminino , Reto/fisiopatologia , Masculino , Adulto , Pessoa de Meia-Idade , Posicionamento do Paciente/métodos , Defecação/fisiologia , Sensação/fisiologia , Idoso , Adulto JovemRESUMO
A chemical investigation of a cold-seep-sediment-derived fungus, Pseudallescheria boydii CS-793, resulted in characterization of 10 novel bergamotene-derived sesquiterpenoids, pseuboyenes A-J (1-10). Their structures were elucidated by spectroscopic and X-ray crystallographic analyses as well as using the modified Mosher's method. Compound 1 represents the first example of a ß-bergamotene containing a 6-oxobicyclo[3.2.1]octane nucleus adducted with a methyl lactate unit, while 8-10 involve a skeletal rearrangement from bergamotene. Compounds 2-5 showed significant antifungal activities against Colletotrichum gloeosporioides Penz. and Fusarium oxysporum with MICs ranging from 0.5 to 8 µg/mL. Compound 4 exhibited an in vitro anti-F. proliferatum effect with an EC50 value of 1.0 µg/mL.
Assuntos
Antifúngicos , Testes de Sensibilidade Microbiana , Pseudallescheria , Sesquiterpenos , Antifúngicos/farmacologia , Antifúngicos/química , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Estrutura Molecular , Colletotrichum/efeitos dos fármacos , Fusarium/efeitos dos fármacos , Cristalografia por Raios XRESUMO
Marine natural products play an important role in biopesticides. Seven new secondary metabolites with different structural classes, including two cycloheptapeptides, scortide A (1) and scortide B (2), two 19-nor-diterpenoids, talascortene H (3) and talascortene I (4), two diterpenoid acids, talascortene J (5) and talascortene K (6), and one triterpenoid, talascortene L (7) were isolated and identified from the sea-anemone-derived endozoic fungus Talaromyces scorteus AS-242. Their structures were comprehensively assigned by spectroscopic data analysis, single-crystal X-ray diffraction, tandem mass spectrometry, and electronic circular dichroism (ECD) calculations. The result of the antimicrobial assay demonstrated that compounds 1 - 6 have inhibitory activity against several human, aquatic, and plant pathogens with minimum inhibitory concentration (MIC) values ranging from 1 to 64 µg/mL. Specially, compounds 2 and 4 showed significant activities against the pathogenic fungus Curvularia spicifera with the MIC value of 1 µg/mL, providing an experimental basis of 2 and 4 with the potential as lead compounds to be developed into biopesticides.
Assuntos
Testes de Sensibilidade Microbiana , Talaromyces , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Relação Dose-Resposta a Droga , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Fungicidas Industriais/isolamento & purificação , Estrutura Molecular , Relação Estrutura-Atividade , Talaromyces/química , Talaromyces/metabolismo , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologiaRESUMO
Cytosolic double-stranded DNA (dsDNA) is frequently accumulated in cancer cells due to chromosomal instability or exogenous stimulation. Cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, which is activated upon binding to dsDNA to synthesize the crucial second messenger 2'3'-cyclic GMP-AMP (2'3'-cGAMP) that in turn triggers stimulator of interferon genes (STING) signaling. The canonical role of cGAS-cGAMP-STING pathway is essential for innate immunity and viral defense. Recent emerging evidence indicates that 2'3'-cGAMP plays an important role in cancer progression via cell autonomous and non-autonomous mechanisms. Beyond its role as an intracellular messenger to activate STING signaling in tumor cells, 2'3'-cGAMP also serves as an immunotransmitter produced by cancer cells to modulate the functions of non-tumor cells especially immune cells in the tumor microenvironment by activating STING signaling. In this review, we summarize the synthesis, transmission, and degradation of 2'3'-cGAMP as well as the dual functions of 2'3'-cGAMP in a STING-dependent manner. Additionally, we discuss the potential therapeutic strategies that harness the cGAMP-mediated antitumor response for cancer therapy.
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Neoplasias , Nucleotídeos Cíclicos , Humanos , Neoplasias/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Nucleotídeos Cíclicos/metabolismo , Animais , Sistemas do Segundo Mensageiro , Proteínas de Membrana/metabolismo , Transdução de Sinais , Progressão da Doença , Microambiente Tumoral/imunologia , Nucleotidiltransferases/metabolismoRESUMO
This study aimed to investigate the effects and safety of 308 nm excimer laser (308 nm EL) and tacrolimus ointment (TO) in the treatment of facial vitiligo (FV). We searched Cochrane Library, PUBMED, EMBASE, CNKI, and WANGFANG from inception to June 1, 2023. Outcomes included overall response rate (ORR), total adverse reaction rate (TARR), recurrence rate at 3-month (RR-3) and recurrence rate at 6-month (RR-6). The outcome data were presented as odds ratios (OR) with 95% confidence intervals (CI). The risk of bias was assessed by Cochrane risk-of-bias tool and data analysis was performed by RevMan 5.4 software. This study included a total of 19 trials involving 2085 patients. When comparing 308 nm EL monotherapy with 308 nm EL plus TO, significant differences in the ORR (OR = 4.29, 95% CI [2.97, 6.19], I2 = 0%, P < 0.001), RR-3 (OR = 0.18, 95% CI [0.05, 0.69], I2 = 0%, P = 0.01), and RR-6 (OR = 0.38, 95% CI [0.14, 1.03], I2 = 39%, P = 0.06) were found between the two managements. When comparing TO monotherapy with TO plus 308 nm EL, its results showed significant differences in the ORR (OR = 4.21, 95% CI [2.90, 6.11], I2 = 0%, P < 0.001), TARR (OR = 0.42, 95% CI [0.22, 0.81], I2 = 4%, P = 0.009), and RR-3 (OR = 0.32, 95% CI [0.01, 8.03], P = 0.49) between the two modalities. The results of this study suggest that the combination of 308 nm EL and TO is more effective than either treatment alone for the treatment of FV.
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Tacrolimo , Vitiligo , Humanos , Tacrolimo/uso terapêutico , Vitiligo/radioterapia , Lasers de Excimer/uso terapêutico , Pomadas , Terapia CombinadaRESUMO
BACKGROUND: The harlequin ladybird Harmonia axyridis (Coleoptera: Coccinellidae), native to Asia, has been introduced to other major continents where it has caused serious negative impacts on local biodiversity. Though notable advances to understand its invasion success have been made during the past decade, especially with then newer molecular tools, the conclusions reached remain to be confirmed with more advanced genomic analyses and especially using more samples from larger geographical regions across the native range. Furthermore, although H. axyridis is one of the best studied invasive insect species with respect to life history traits (often comparing invasive and native populations), the traits responsible for its colonization success in non-native areas warrant more research. RESULTS: Our analyses of genome-wide nuclear population structure indicated that an eastern Chinese population could be the source of all non-native populations and revealed several putatively adaptive candidate genomic loci involved in body color variation, visual perception, and hemolymph synthesis. Our estimates of evolutionary history indicate (1) asymmetric migration with varying population sizes across its native and non-native range, (2) a recent admixture between eastern Chinese and American populations in Europe, (3) signatures of a large progressive, historical bottleneck in the common ancestors of both populations and smaller effective sizes of the non-native population, and (4) the southwest origin and subsequent dispersal routes within its native range in China. In addition, we found that while two mitochondrial haplotypes-Hap1 and Hap2 were dominant in the native range, Hap1 was the only dominant haplotype in the non-native range. Our laboratory observations in both China and USA found statistical yet slight differences between Hap1 and Hap2 in some of life history traits. CONCLUSIONS: Our study on H. axyridis provides new insights into its invasion processes into other major continents from its native Asian range, reconstructs a geographic range evolution across its native region China, and tentatively suggests that its invasiveness may differ between mitochondrial haplotypes.
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Besouros , Animais , Besouros/genética , Haplótipos , Fenótipo , Genômica , Variação Biológica da PopulaçãoRESUMO
BACKGROUND: The continuously developing pesticide resistance is a great threat to agriculture and human health. Understanding the mechanisms of insecticide resistance is a key step in dealing with the phenomenon. Insect cuticle is recently documented to delay xenobiotic penetration which breaks the previous stereotype that cuticle is useless in insecticide resistance, while the underlying mechanism remains scarce. RESULTS: Here, we find the integument contributes over 40.0% to insecticide resistance via different insecticide delivery strategies in oriental fruit fly. A negative relationship exists between cuticle thickening and insecticide penetration in resistant/susceptible, also in field strains of oriental fruit fly which is a reason for integument-mediated resistance. Our investigations uncover a regulator of insecticide penetration that miR-994 mimic treatment causes cuticle thinning and increases susceptibility to malathion, whereas miR-994 inhibitor results in opposite phenotypes. The target of miR-994 is a most abundant cuticle protein (CPCFC) in resistant/susceptible integument expression profile, which possesses capability of chitin-binding and influences the cuticle thickness-mediated insecticide penetration. Our analyses find an upstream transcriptional regulatory signal of miR-994 cascade, long noncoding RNA (lnc19419), that indirectly upregulates CPCFC in cuticle of the resistant strain by sponging miR-994. Thus, we elucidate the mechanism of cuticular competing endogenous RNAs for regulating insecticide penetration and demonstrate it also exists in field strain of oriental fruit fly. CONCLUSIONS: We unveil a regulatory axis of lnc19419 ~ miR-994 ~ CPCFC on the cuticle thickness that leads to insecticide penetration resistance. These findings indicate that competing endogenous RNAs regulate insecticide resistance by modulating the cuticle thickness and provide insight into the resistance mechanism in insects.
Assuntos
Inseticidas , MicroRNAs , Humanos , Animais , Inseticidas/farmacologia , Malation/farmacologia , Pele , Agricultura , Drosophila , MicroRNAs/genéticaRESUMO
Brown root rot disease (BRRD) is a highly destructive tree disease. Early diagnosis of BRRD has been challenging because the first symptoms and signs are often observed after extensive tissue colonization. Existing molecular detection methods, all based on the internal transcribed spacer (ITS) region, were developed without testing against global Phellinus noxius isolates, other wood decay fungi, or host plant tissues. This study developed SYBR Green real-time quantitative PCR (qPCR) assays for P. noxius. The primer pair Pn_ITS_F/Pn_ITS_R targets the ITS, and the primer pair Pn_NLR_F/Pn_NLR_R targets a P. noxius-unique group of homologous genes identified through a comparative genomics analysis. The homologous genes belong to the nucleotide-binding-oligomerization-domain-like receptor (NLR) superfamily. The new primer pairs and a previous primer pair G1F/G1R were optimized for qPCR conditions and tested for specificity using 61 global P. noxius isolates, five other Phellinus species, and 22 non-Phellinus wood decay fungal species. While all three primer pairs could detect as little as 100 fg (about 2.99 copies) of P. noxius genomic DNA, G1F/G1R had the highest specificity and Pn_NLR_F/Pn_NLR_R had the highest efficiency. To avoid false positives, the cutoff Cq values were determined as 34 for G1F/G1R, 29 for Pn_ITS_F/Pn_ITS_R, and 32 for Pn_NLR_F/Pn_NLR_R. We further validated these qPCR assays using Ficus benjamina seedlings artificially inoculated with P. noxius, six tree species naturally infected by P. noxius, rhizosphere soil, and bulk soil. The newly developed qPCR assays provide sensitive detection and quantification of P. noxius, which is useful for long-term monitoring of BRRD status.
RESUMO
The objective was to determine the prevalence of foodborne pathogens in food in Longnan City, Gansu Province, China. In this research, we conducted tests on baked foods, catering foods, meat, and fruits and vegetables sold in supermarkets, farmers' markets, restaurants, retail stores, street stalls, and school canteens from 2013 to 2022. We analyzed the variety of foodborne pathogens (Salmonella, Staphylococcus aureus, Listeria monocytogenes, Bacillus cereus, and diarrheagenic Escherichia coli) in different sites and food types. Once foodborne pathogens were detected in the sample, it was deemed unqualified. The total detection rates of foodborne pathogens were 1.559%, 3.349%, 1.980%, 1.040%, 3.383%, and 1.303% in food from supermarkets, farmers' markets, restaurants, retail stores, street stalls, and school canteens, respectively. No pathogenic bacteria were detected in baked foods. Salmonella, S. aureus, L. monocytogenes, B. cereus, and diarrheagenic E. coli were detected in catering foods, among which B. cereus had the highest detection rate. Salmonella was the most common pathogenic bacteria detected in meat, while the detection rate of pathogenic bacteria in fruits and vegetables was low, with only one positive sample for diarrheagenic E. coli. Among the six sites, street stalls (3.382%) and farmers' markets (3.349%) had higher detection rates of pathogens. In general, the detection rate of pathogens from 2013 to 2022 was not high, but there were also some hidden dangers. Catering food is vulnerable to pathogen contamination, and street stalls and farmers' markets are the main sites of pollution. According to the above findings, the regulatory authorities should continue to strengthen supervision, guarantee food safety through early warning, and reduce the risk of food contamination.
Assuntos
Escherichia coli , Listeria monocytogenes , Staphylococcus aureus , Microbiologia de Alimentos , Contaminação de Alimentos/análise , Salmonella , Verduras/microbiologiaRESUMO
BACKGROUND: Both vestibular schwannoma (VS) and Meniere's disease (MD) patients underwent hydrops MRI to clarify the relationship between VS and endolymphatic hydrops (EH). METHODS: Eighty patients with VS or MD underwent an inner ear test battery followed by hydrops MRI, and were then divided into 3 groups. Group A comprised 58 MD patients (62 ears) with positive EH but negative VS. Group B included 18 VS patients (18 ears) with negative EH, while Group C consisted of 4 patients (4 ears) who had VS concomitant with EH. Another 14 MD patients who tested negative for EH on hydrops MRI were initially excluded from this cohort, but were later included for comparison. RESULTS: The decreasing prevalence of EH at the cochlea, saccule and utricle in Group A was identified in 59 (95%), 42 (68%) and 40 (65%) ears, respectively, mimicking a declining sequence of abnormality rates running from audiometry (86%), cervical vestibular-evoked myogenic potential (cVEMP) test (55%) to the ocular (oVEMP) test (53%). However, such decreasing trend was not identified in Groups B and C. In Groups C and A combined, 4 (6%) of 62 EH patients had concomitant VS. Conversely, 4 (18%) of 22 VS patients in Groups C and B combined had concurrent EH. CONCLUSION: A very low (6%) rate of VS in EH patients indicates that VS in EH patients may be coincidental. In contrast, EH was identified in 18% prevalence of VS patients, mirroring the 22% prevalence of cochlear EH demonstrated in VS donors through histopathological studies.