RESUMO
Histone acetylation plays critical roles in chromatin remodeling, DNA repair, and epigenetic regulation of gene expression, but the underlying mechanisms are unclear. Proteasomes usually catalyze ATP- and polyubiquitin-dependent proteolysis. Here, we show that the proteasomes containing the activator PA200 catalyze the polyubiquitin-independent degradation of histones. Most proteasomes in mammalian testes ("spermatoproteasomes") contain a spermatid/sperm-specific α subunit α4 s/PSMA8 and/or the catalytic ß subunits of immunoproteasomes in addition to PA200. Deletion of PA200 in mice abolishes acetylation-dependent degradation of somatic core histones during DNA double-strand breaks and delays core histone disappearance in elongated spermatids. Purified PA200 greatly promotes ATP-independent proteasomal degradation of the acetylated core histones, but not polyubiquitinated proteins. Furthermore, acetylation on histones is required for their binding to the bromodomain-like regions in PA200 and its yeast ortholog, Blm10. Thus, PA200/Blm10 specifically targets the core histones for acetylation-mediated degradation by proteasomes, providing mechanisms by which acetylation regulates histone degradation, DNA repair, and spermatogenesis.
Assuntos
Reparo do DNA , Histonas/metabolismo , Proteínas Nucleares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Espermatogênese , Testículo/metabolismo , Acetilação , Sequência de Aminoácidos , Animais , Quebras de DNA de Cadeia Dupla , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas Nucleares/química , Estrutura Terciária de Proteína , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Alinhamento de SequênciaRESUMO
Cytoskeletal microtubules (MTs) are nucleated from γ-tubulin ring complexes (γTuRCs) located at MT organizing centers (MTOCs), such as the centrosome. However, the exact regulatory mechanism of γTuRC assembly is not fully understood. Here, we showed that the nonreceptor tyrosine kinase c-Abl was associated with and phosphorylated γ-tubulin, the essential component of the γTuRC, mainly on the Y443 residue by in vivo (immunofluorescence and immunoprecipitation) or in vitro (surface plasmon resonance) detection. We further demonstrated that phosphorylation deficiency significantly impaired γTuRC assembly, centrosome construction, and MT nucleation. c-Abl/Arg deletion and γ-tubulin Y443F mutation resulted in an abnormal morphology and compromised spindle function during mitosis, eventually causing uneven chromosome segregation. Our findings reveal that γTuRC assembly and nucleation function are regulated by Abl kinase-mediated γ-tubulin phosphorylation, revealing a fundamental mechanism that contributes to the maintenance of MT function.
Assuntos
Centro Organizador dos Microtúbulos , Microtúbulos , Proteínas Proto-Oncogênicas c-abl , Tubulina (Proteína) , Centrossomo/metabolismo , Centro Organizador dos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismoRESUMO
OBJECTIVE: To evaluate Chinese long-term economic impact of universal human leukocyte antigen B (HLA-B)*58:01 genotyping-guided urate-lowering therapy or febuxostat initiation therapy for gout patients with mild to moderate chronic kidney disease (CKD) from perspective of healthcare system. METHODS: A Markov model embedded in a decision tree was structured including four mutually exclusive health states (uncontrolled-on-therapy, controlled-on-therapy, uncontrolled-off-therapy, and death). Mainly based on Chinese real-world data, the incremental costs per quality-adjusted life years (QALYs) gained were evaluated from three groups (universal HLA-B*58:01 testing strategy, and no genotyping prior to allopurinol or febuxostat initiation therapy) at 25-year time horizon. All costs were adjusted to 2021 levels based on Chinese Consumer Price Index and were discounted by 5% annually. One-way and probability sensitivity analysis were performed. RESULTS: Among these three groups, universal HLA-B*58:01 genotyping was the most cost-effective strategy in base-case analysis according to Chinese average willingness-to-pay threshold of $37 654.50 per QALY. The based incremental cost-effectiveness ratio was $31784.55 per QALY, associated with 0.046 additional QALYs and $1463.81 increment costs per patient at a 25-year time horizon compared with no genotyping prior to allopurinol initiation strategy. Sensitivity analysis showed 64.3% robustness of these results. CONCLUSION: From Chinese perspective of healthcare system, HLA-B*58:01 genotyping strategy was cost-effective for gout patients with mild to moderate CKD in mainland China, especially in the most developed area, such as Beijing and Shanghai. Therefore, we suggest China's health authorities choose the genotyping strategy and make different recommendations according to the differences of local conditions.
Assuntos
Gota , Antígenos HLA-B , Insuficiência Renal Crônica , Humanos , Alopurinol/uso terapêutico , China , Análise Custo-Benefício , População do Leste Asiático , Febuxostat/uso terapêutico , Gota/tratamento farmacológico , Gota/genética , Supressores da Gota/uso terapêutico , Antígenos HLA-B/genética , Anos de Vida Ajustados por Qualidade de Vida , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/genéticaRESUMO
SARS-CoV-2 is the causative agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19) and poses a significant threat to global health. N protein (NP), which is a major pathogenic protein among betacoronaviruses, binds to the viral RNA genome to allow viral genome packaging and viral particle release. Recent studies showed that NP antagonizes interferon (IFN) induction and mediates phase separation. Using live SARS-CoV-2 viruses, this study provides solid evidence showing that SARS-CoV-2 NP associates with G3BP1 and G3BP2 in vitro and in vivo. NPSARS-CoV-2 could efficiently suppress G3BP-mediated SG formation and potentiate viral infection by overcoming G3BP1-mediated antiviral innate immunity. G3BP1 conditional knockout mice (g3bp1fl/fL, Sftpc-Cre) exhibit significantly higher lung viral loads after SARS-CoV-2 infection than wild-type mice. Our findings contribute to the growing body of knowledge regarding the pathogenicity of NPSARS-CoV-2 and provide insight into new therapeutics targeting NPSARS-CoV-2. IMPORTANCE In this study, by in vitro assay and live SARS-CoV-2 virus infection, we provide solid evidence that the SARS-CoV-2 NP associates with G3BP1 and G3BP2 in vitro and in vivo. NPSARS-CoV-2 could efficiently suppress G3BP-mediated SG formation and potentiate viral infection by overcoming antiviral innate immunity mediated by G3BP1 in A549 cell lines and G3BP1 conditional knockout mice (g3bp1-cKO) mice, which provide in-depth evidence showing the mechanism underlying NP-related SARS-CoV-2 pathogenesis through G3BPs.
Assuntos
COVID-19 , Proteínas do Nucleocapsídeo de Coronavírus , Proteínas de Ligação a Poli-ADP-Ribose , SARS-CoV-2 , Replicação Viral , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , COVID-19/imunologia , COVID-19/virologia , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , DNA Helicases/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Camundongos , Fosfoproteínas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo , Grânulos de Estresse , Replicação Viral/genéticaRESUMO
Three novel actinomycins, actimomycin S (1), neo-actinomycins C and D (2 and 3), and one new benzo[d]oxazole alkaloid (4) were isolated from the Streptomyces sp. strain S22, along with three known congeners F9 (5), X2 (6) and X0ß (7) and 2-acetylamino-3-hydroxyl-4-methyl-benzoic acid methyl ester (8). The structures of the new products were elucidated by spectroscopic methods, and the absolute configuration of amino acid residues was determined by Marfey's analysis. Actinomycin S contains an aspartic acid (Asp) residue in the ß-peptidolactone ring. This is the first report of an Asp residue within an actinomycin-type natural product. Notably, neo-actinomycins C and D feature a rare tetracyclic 5H-oxazolo[4,5-b]phenoxazine chromophore. Among these, neo-actinomycin D, with an unprecedented molecular formula, represents the highest molecular weight member in the actinomycin family. Actinomycins 1-3 exhibited antimicrobial activity against multiple resistant "ESKAPE" pathogens with MIC values ranging from 1.25 to 80.0 µg mL-1. In addition, 1-3 showed potent cytotoxic activities against the HepG2 liver carcinoma cell line with IC50 values of 0.10, 0.32, and 0.024 µM, respectively. Furthermore, 1 inhibited cell proliferation by inducing G0-G1 phase arrest in the cell cycle.
Assuntos
Antineoplásicos , Streptomyces , Dactinomicina , Streptomyces/metabolismo , Antineoplásicos/farmacologia , Análise Espectral , Aminoácidos/metabolismoRESUMO
Inflammatory bowel disease (IBD) is a global health burden whose existing treatment is largely dependent on anti-inflammatory agents. Despite showing some therapeutic actions, their clinical efficacy and adverse events are unacceptable. Resolution as an active and orchestrated phase of inflammation involves improper inflammatory response with three key triggers, specialized pro-resolving mediators (SPMs), neutrophils and phagocyte efferocytosis. The formyl peptide receptor 2 (FPR2/ALX) is a human G protein-coupled receptor capable of binding SPMs and participates in the resolution process. This receptor has been implicated in several inflammatory diseases and its association with mouse model of IBD was established in some resolution-related studies. Here, we give an overview of three reported FPR2/ALX agonists highlighting their respective roles in pro-resolving strategies.
Assuntos
Doenças Inflamatórias Intestinais , Receptores de Formil Peptídeo , Animais , Camundongos , Humanos , Receptores de Formil Peptídeo/metabolismo , Inflamação/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/metabolismo , Neutrófilos/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológicoRESUMO
A unique ring C-expanded angucyclinone, oxemycin A (1), and seven new ring-cleavage derivatives (2-5 and 9-11) were isolated from the marine actinomycete Streptomyces pratensis KCB-132, together with eight known analogues (6-8 and 12-16). Their structures were elucidated by spectroscopic analyses, single-crystal X-ray diffractions, and NMR and ECD calculations. Among these atypical angucyclinones, compound 1 represented the first seven-membered ketoester in the angucyclinone family, which sheds light on the origin of fragmented angucyclinones with C-ring cleavage at C-12/C-12a in the Baeyer-Villiger hypothesis, such as 2-4, while the related "nonoxidized" analogues 5-8 seem to originate from a diverse pathway within the Grob fragmentation hypothesis. Additionally, we have succeeded in the challenging separation of elmenols E and F (12) into their four stereoisomers, which remained stable in aprotic solvents but rapidly racemized under protic conditions. Furthermore, the absolute configurations of LS1924 and its isomers (14 and 15) were assigned by ECD calculations for the first time. Surprisingly, these two bicyclic acetals are susceptible to hydrolysis in solution, resulting in fragmented derivatives 17 and 18 with C-ring cleavage between C-6a and C-7. Compared with ring C-modified angucyclinones, ring A-cleaved 11 was more active to multiple resistant "ESKAPE" pathogens with MIC values ranging from 4.7 to 37.5 µg/mL.
Assuntos
Actinobacteria , Streptomyces , Antraquinonas , AcetaisRESUMO
BRUCE/Apollon is a membrane-associated inhibitor of apoptosis protein that is essential for viability and has ubiquitin-conjugating activity. On initiation of apoptosis, the ubiquitin ligase Nrdp1/RNF41 promotes proteasomal degradation of BRUCE. Here we demonstrate that BRUCE together with the proteasome activator PA28γ causes proteasomal degradation of LC3-I and thus inhibits autophagy. LC3-I on the phagophore membrane is conjugated to phosphatidylethanolamine to form LC3-II, which is required for the formation of autophagosomes and selective recruitment of substrates. SIP/CacyBP is a ubiquitination-related protein that is highly expressed in neurons and various tumors. Under normal conditions, SIP inhibits the ubiquitination and degradation of BRUCE, probably by blocking the binding of Nrdp1 to BRUCE. On DNA damage by topoisomerase inhibitors, Nrdp1 causes monoubiquitination of SIP and thus promotes apoptosis. However, on starvation, SIP together with Rab8 enhances the translocation of BRUCE into the recycling endosome, formation of autophagosomes, and degradation of BRUCE by optineurin-mediated autophagy. Accordingly, deletion of SIP in cultured cells reduces the autophagic degradation of damaged mitochondria and cytosolic protein aggregates. Thus, by stimulating proteasomal degradation of LC3-I, BRUCE also inhibits autophagy. Conversely, SIP promotes autophagy by blocking BRUCE-dependent degradation of LC3-I and by enhancing autophagosome formation and autophagic destruction of BRUCE. These actions of BRUCE and SIP represent mechanisms that link the regulation of autophagy and apoptosis under different conditions.
Assuntos
Autofagia , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Animais , Apoptose , Autofagossomos/metabolismo , Dano ao DNA , Fibroblastos , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Camundongos , UbiquitinaçãoRESUMO
INTRODUCTION: Little is known about the relationship between exposure levels of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and comorbidities of systemic lupus erythematosus (SLE) in children. This study aims to explore this association. METHODS: Longitudinal data from SLE children, who were taking MMF for immunosuppression and under therapeutic drug monitoring (TDM), were retrospectively collected. Area under the concentration-time curve of mycophenolic acid (MPA) over 24 hours (AUC0-24h) was estimated with Bayesian methods. Logistic regression and random forest models were used to explore the association between comorbidities and MPA exposure levels. RESULTS: This study included 107 children with 358 times of follow-up (median age 169.02 months). The incidence of diabetes, acute kidney injury (AKI), or pneumonia was significantly associated with AUC0-24h (odds ratio [OR] 0.991, 95% confidence interval [CI] 0.982-0.999), SLE duration (OR 1.012, 95% CI 1.002-1.022), lymphocyte percentage (OR 0.959, 95% CI 0.925-0.991), plasma albumin levels (OR 0.891, 95% CI 0.843-0.940), use of aspirin (OR 0.292, 95% CI 0.126-0.633) and hydroxychloroquine (OR 0.407, 95% CI 0.184-0.906). The random forest model showed that albumin and AUC0-24h were two important predictors. The case group (with the three comorbidities) had a mean AUC0-24h of 73.63 mg · h/L, while the control group had a mean AUC0-24h of 100.39 mg · h/L. CONCLUSIONS: Increased levels of MPA exposure are associated with decreased incidence odds of diabetes, AKI or pneumonia in SLE children. An AUC0-24h of 100.39 mg · h/L or an AUC0-12h of 50.20 mg · h/L could be used as the targeted exposure level for clinical practice.
Assuntos
Monitoramento de Medicamentos , Imunossupressores , Lúpus Eritematoso Sistêmico , Ácido Micofenólico , Adolescente , Área Sob a Curva , Teorema de Bayes , Criança , Pré-Escolar , Comorbidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/sangue , Ácido Micofenólico/uso terapêutico , Estudos RetrospectivosRESUMO
Juvenile dermatomyositis (JDM) is a rare systemic autoimmune disease specifically affecting children. Mycophenolate mofetil (MMF) is an immunosuppressant used to treat JDM. Mycophenolic acid (MPA) is an active metabolite of MMF. This study aimed to develop a population pharmacokinetic (PPK) model of MPA in children with JDM and optimize the limited sampling strategy (LSS). Fifteen JDM patients treated with MMF, at a median age of 7.35 (range, 3.09-16.1) years, were included. Blood samples were collected at 30 minutes pre-dose, 20 minutes, 60 minutes and 180 minutes post-dose to measure the MPA concentrations. Data were retrospectively collected from the electronic medical records. A two-compartment model with first-order absorption, lag time in absorption, and first-order elimination was developed. Height and co-administered cotrimoxazole were added as the covariates to the model. Concentrations at different time points were simulated and area under the concentration-time curve (AUC0-12 h) was calculated. By removing one sampling point at a time, AUC0-12 h from three-point sampling strategy was re-calculated via Bayesian approach. AUC0-12 h from the three-point sampling strategy (by removing the point at 20 minutes post-dose) had the strongest correlation with AUC0-12 h from the four-point sampling strategy (Pearson's r = 0.971).
Assuntos
Dermatomiosite/metabolismo , Imunossupressores/farmacocinética , Ácido Micofenólico/farmacocinética , Adolescente , Teorema de Bayes , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Meropenem, a broad-spectrum carbapenem, is frequently used to treat severe bacterial infections in critically ill children. Recommendations for meropenem doses in adult infections are available; however, few studies have been published regarding the use of meropenem in children with sepsis, especially in those receiving continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO). We aimed to investigate the pharmacokinetic (PK) parameters of meropenem in children with sepsis receiving extracorporeal life support (ECLS). METHODS: This was a prospective observational clinical study of children with sepsis receiving ECMO or CRRT in the paediatric intensive care unit (PICU) of a children's hospital. The enrolled children received 20 mg/kg meropenem infusion over 1 hour, every 8 hours, and were grouped into children receiving ECMO, children receiving CRRT and children receiving neither ECMO nor CRRT. Plasma meropenem concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The key PK parameters were determined using the non-compartmental approach. RESULTS AND DISCUSSION: Twenty-seven patients were finally enrolled. The eCLCR of the CRRT group was lower than that of the ECMO group. The values of elimination half-life (t1/2 ), area under the plasma concentration-time curve (AUCtau ), area under the plasma concentration-time curve from time zero to infinity (AUC0-∞ ), and total clearance (CL) in the ECMO group were not different from those of the other groups (all p > 0.05). However, the AUCtau (p = 0.0137) and AUC0-∞ (p = 0.0234) significantly decreased after filtration through a hemofiltration membrane in patients receiving CRRT. WHAT IS NEW AND CONCLUSION: No significant alterations in the PK parameters of meropenem occurred in children with sepsis administered ECMO and/or CRRT. Further investigations including PK modelling could provide evidence for appropriate meropenem dosing regimens during ECLS administration.
Assuntos
Antibacterianos/farmacocinética , Oxigenação por Membrana Extracorpórea , Meropeném/farmacocinética , Sepse/tratamento farmacológico , Antibacterianos/uso terapêutico , Área Sob a Curva , Criança , Pré-Escolar , Creatinina/sangue , Estado Terminal , Feminino , Meia-Vida , Humanos , Lactente , Masculino , Meropeném/uso terapêutico , Taxa de Depuração Metabólica , Estudos ProspectivosRESUMO
Strepyrazinone (1), a tricyclic diketopiperazine derivative with a carbon skeleton unprecedented in natural products, was isolated from the marine-derived Streptomyces sp. B223. Its structure was elucidated by spectroscopic analyses and electronic circular dichroism calculation. Compound 1 showed cytotoxic activity against HCT-116 cancer cell lines with an IC50 value of 0.34 µM.
Assuntos
Antineoplásicos , Streptomyces , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Dicetopiperazinas/farmacologia , Células HCT116 , Humanos , Estrutura MolecularRESUMO
The use of a silicone rubber composite insulator has become an important aspect to ensure the safe operation of an electrical power grid. This study introduces a preparation method of a superhydrophobic silicone rubber surface using a simple preparation process at low cost and with excellent performance, which can be used in the mass production of silicone rubber composite insulators. In this study, the combination of a compression molding process and a template method was used to prepare the product. A microstructure composed of numerous boat-shaped grooves was constructed on the surface of silicone rubber. The modification of a low surface energy material is not required. The static contact angle with water after the high-temperature treatment exceeds 150°, and the rolling angle is under 10°. Excellent performance has been observed in terms of self-cleaning effect, aging resistance, and mechanical and droplet bounce properties. It has been shown that the loss of superhydrophobic properties, due to the prolonged immersion in water, can be restored by a high temperature heating process.
RESUMO
20(s)-ginsenoside Rg3 is a red ginseng-derived compound with the formula C42H72O13 that has been increasingly used by humans, leading to safety concerns regarding this use. In the current study, we conducted a 26-week study during which 20(S)-ginsenoside Rg3 (0, 7, 20, or 60â¯mg/kg) was continuously administered orally to Beagle dogs in order to explore its toxicity in these animals, with control dogs receiving a vehicle capsule. In total, 10 dogs received each dose of this compound (nâ¯=â¯5 male, nâ¯=â¯5 female per dose). Animals were continuously monitored for a 26-week administration period and a subsequent 4-week follow-up recovery period. At the end of study, we observed no evidence of 20(S)-ginsenoside Rg3 toxicity in clinical indications, body weight, food intake, ophthalmoscopy, electrocardiogram, urinalysis, hematology, serum biochemistry, gross and histopathology findings. However, the kidney relative weight of animals receiving 60â¯mg/kg of compound was significantly elevated relative to control animals (5.15⯱â¯0.88 vs. 4.11⯱â¯0.59. Pâ¯<â¯0.05), and this effect was reversed after 4-week recovery period. Based on these results, the NOAEL value for orally administered 20(S)-ginsenoside Rg3 in dogs is 20â¯mg/kg.
Assuntos
Antineoplásicos Fitogênicos/toxicidade , Ginsenosídeos/toxicidade , Administração Oral , Animais , Cães , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Testes de Toxicidade SubcrônicaRESUMO
The transcription factor Runx1 is an essential regulator of definitive hematopoiesis, megakaryocyte (MK) maturation, and lymphocyte differentiation. Runx1 mutations that interfere with its transcriptional activity are often present in leukemia patients. Recent work demonstrated that the transcriptional activity of Runx1 is regulated by kinase-mediated phosphorylation. In this study, we showed that c-Abl, but not Arg tyrosine kinase, associated with Runx1 both in cultured cells and in vitro. c-Abl-mediated tyrosine phosphorylation in the Runx1 transcription inhibition domain negatively regulated the transcriptional activity of Runx1 and inhibited Runx1-mediated MK maturation. Consistent with these findings, increased numbers of MKs were detected in the spleens and bone marrow of abl gene conditional knockout mice. Our findings demonstrate an important role of c-Abl kinase in Runx1-mediated MK maturation and platelet formation and provide a potential mechanism of Abl kinase-regulated hematopoiesis.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Megacariócitos/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Animais , Sítios de Ligação , Plaquetas/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/química , Regulação da Expressão Gênica , Células HEK293 , Humanos , Células K562 , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-abl/genética , Transcrição GênicaRESUMO
The different impacts, especially on soil physicochemical and microbial characteristics, among disinfestation methods based on different principles (including physical, chemical, and biological) have not been illustrated well. Here, we used steam sterilization, dazomet fumigation, and reductive soil disinfestation (RSD) methods representative of physical, chemical, and biological soil disinfestation, respectively, to disinfest seriously degraded greenhouse soils before watermelon cultivation in one season. Compared with the control, RSD significantly decreased the soil nitrate content by 85.9% and the electrical conductivity by 52.0% and increased the soil pH to 7.44. Although all three soil disinfestations significantly decreased the abundance of the pathogen Fusarium oxysporum by 83.0-99.2%, their impacts on soil microbial characteristics were variable. Briefly, steam sterilization significantly changed multiple bacterial and fungal properties. Dazomet fumigation impacted mainly fungal properties, such as abundance, diversity, and community structure, but RSD significantly decreased bacterial diversity and altered the bacterial community structure. Although the differences mentioned above got smaller after watermelon cultivation, the plant performances differed dramatically in different soils. The largest plant biomass, fruit ratio, and yield were found in the RSD-treated soil, whereas the lowest fruit ratio and yield were found in the steam-sterilized soil. The soil nitrate content, electrical conductivity, bacterial diversity and community structure, and some specific microbial agents, such as Aspergillus, Cladosporium, and Pseudomonas, were correlated with plant performance. RSD is a promising soil disinfestation strategy to support plant growth in intensively cultivated greenhouse soils with serious problems, such as acidification, salinization, and pathogen accumulation.
Assuntos
Biota/efeitos dos fármacos , Biota/efeitos da radiação , Desinfecção/métodos , Controle de Pragas/métodos , Microbiologia do Solo , Anti-Infecciosos/farmacologia , Fenômenos Químicos/efeitos dos fármacos , Fenômenos Químicos/efeitos da radiação , Frutas/crescimento & desenvolvimento , Fumigação , Temperatura Alta , Solo/química , Vapor , Tiadiazinas/farmacologiaRESUMO
Four new norterpene cyclic peroxides (1-4), together with three known norterpene cyclic peroxides were isolated from the Xisha Islands Sponge Diacarnus megaspinorhabdosa. Their structures were elucidated on the basis of spectroscopic analyses and comparison with the related model compounds. The compounds (1-7) were evaluated for the inhibitory activity against the malaria parasite Plasmodium falciparum, all of them showed significant antimalarial activity with IC50 values in the range of 1.6-8.6 µM.
Assuntos
Antimaláricos/farmacologia , Peróxidos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Poríferos/química , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/isolamento & purificação , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Peróxidos/síntese química , Peróxidos/química , Peróxidos/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Chemical investigation on CH2Cl2 extract of the marine sponge Diacarnus megaspinorhabdosa resulted in the isolation of two new farnesylacetone derivatives 1-2, a new γ-lactone 3, a known dinorditerpenone 4 and four known norsesterterpene peroxides 5-8. Their structures were elucidated by using one and two dimensional (1D and 2D)-NMR, high resolution-electrospray ionization (HR-ESI)-MS, and comparison with the literature. Compounds 1 and 2 were cis/trans-olefinic isomers and determined through nuclear Overhauser effect spectroscopy (NOESY) experiment. The absolute configuration of 3 was established by comparison of circular dichroism (CD) data with known lactones. The cytotoxic activities of the compounds were evaluated against five cancer cell lines, and compound 3 showed moderate cytotoxicity activities against cancer cell lines HeLa, H446, NCI-H460, SGC-7901 and MCF-7, with IC50 values in the range of 18.5 to 47.1 µM.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Lactonas/farmacologia , Peróxidos/farmacologia , Poríferos/química , Sesterterpenos/farmacologia , Terpenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Linhagem Celular Tumoral , Células HeLa , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Neoplasias/tratamento farmacológico , Peróxidos/química , Peróxidos/isolamento & purificação , Sesterterpenos/química , Sesterterpenos/isolamento & purificação , Terpenos/química , Terpenos/isolamento & purificaçãoRESUMO
OBJECTIVE: The environmental fitness of metalaxyl-resistant isolate of Phytophthora capsici was studied for assessing the risk of metalaxyl-resistant P. capsici. METHODS: We studied the main biological characteristics, competitive ability on plate, pathogenicity on pepper plant and adaptability in soil of the laboratory-induced metalaxyl-resistant isolate of P. capsici (Pc2-3 strain), with the metalaxyl-sensitive isolate (Pc2 strain, the wild-type) as the control. RESULTS: The zoosporangia production, releasing rate of zoosporangia and germination rate of zoospores of Pc2-3 were less than that of Pc2. The temperature range, optimum temperature range and initial pH range for mycelia growth of Pc2-3 were consistent with that of Pc2, but mycelia growth rate of Pc2-3 was lower than that of Pc2. Pc2-3 exhibited significantly weak competitive ability compared with Pc2 on carrots plate. Disease incidence of pepper inoculated with Pc2-3 (14.3%) was significantly lower than that of Pc2 (88. 6% ). When pepper plant was inoculated by mixtures of zoospore suspension of Pc2-3 and Pc2 at same ratio, the disease incidence, closing to that by Pc2 strain, was 75.7% . And all the strains isolated from diseased plants in the treatment were metalaxyl-sensitive. The density of P. capsis Pc2-3 was 0.28 times of Pc2 after the soil inoculated with Pc2-3 and Pc2 respectively at same zoospores density was incubated for 20 days. Otherwise, the ratio of Pc2-3 to Pc2 was 0.42 if the metalaxyl concentration in the soil was 300 mg/kg dry soil. No matter the soil temperature and humidity were beneficial to survival of P. capsici or not, Pc2-3 showed lower soil adaptability than Pc2. CONCLUSION: The environmental fitness of metalaxyl-resistant P. capsis Pc2-3 was weaker than the metalaxyl- sensitive strain Pc2 (the wild-type).
Assuntos
Alanina/análogos & derivados , Capsicum/microbiologia , Fungicidas Industriais/farmacologia , Phytophthora/efeitos dos fármacos , Phytophthora/fisiologia , Alanina/farmacologia , Farmacorresistência Fúngica , Ecossistema , Doenças das Plantas/microbiologia , Solo/químicaRESUMO
BACKGROUND: Anti-disialoganglioside (anti-GD2) monoclonal antibodies are effective immunotherapeutic drugs for treating neuroblastoma, yet their toxicity spectrum is unclear. OBJECTIVE: This study aimed to assess the toxicity profiles of three anti-GD2 monoclonal antibodies (dinutuximab, dinutuximab ß, and naxitamab) in clinical applications by mining and evaluating the adverse drug reaction (ADR) signals from the US Food and Drug Administration Adverse Event Reporting System. METHODS: Data in the US Food and Drug Administration Adverse Event Reporting System from the time anti-GD2 monoclonal antibodies became available in the market to the first quarter of 2023 were searched. The signals of anti-GD2 monoclonal antibody-associated ADRs were quantified using four types of algorithms, including the reporting odds ratio, the proportional reporting ratio, the combination of the proportional reporting ratio and χ2 statistic method used by the UK Medicines and Healthcare Products Regulatory Agency, and the Bayesian confidence propagation neural network. The ADRs were categorized by System Organ Class based on the Medical Dictionary for Regulatory Activities, and were sorted according to the frequency and signal strength of ADRs. RESULTS: A total of 370 adverse drug event reports with anti-GD2 monoclonal antibodies listed as the 'primary suspected drugs' were identified, with 116 ADR signals detected, of which 22 were not in the drug labels. Among the adverse drug event reports, 276 reports concerned dinutuximab/dinutuximab ß as primary suspected drugs with 90 ADR signals, involving 19 System Organ Classes, of which 21 signals were not in the label; 94 adverse drug event reports concerned naxitamab as the primary suspected drug with 26 ADR signals, involving 11 System Organ Classes, of which one was not in the label. For dinutuximab/dinutuximab ß-related ADRs, the top five most frequent were "fever", "abdominal pain", "elevated aspartate aminotransferase (AST)", "elevated alanine aminotransferase (ALT)" and "hypotension"; the top five most intensive signals were "hypoalbuminemia", "elevated AST", "capillary leakage syndrome", "hypoxia" and "elevated ALT". For naxitamab-related ADRs, the top five most frequent were "hypotension", "pain", "urticarial", "hypertension" and "rash"; the top five most intensive signals were "hypotension", "urticaria", "hypoxemia", "bronchospasm" and "hypertension". Involved System Organ Classes included "investigations" and "respiratory, thoracic and mediastinal disorders" containing the most types of ADR signals in dinutuximab/dintuximab ß-related ADRs and naxitamab-related ADRs, respectively. CONCLUSIONS: Our study comprehensively analyzed the toxicity profiles of anti-GD2 monoclonal antibodies and provides an important reference for clinical monitoring and ADR identification of these drugs.