RESUMO
The monotonicity of color type in naturally colored cottons (NCCs) has become the main limiting factor to their widespread use, simultaneously coexisting with poor fiber quality. The synchronous improvement of fiber quality and color become more urgent and crucial as the demand for sustainable development increases. The homologous gene of wild cotton Gossypium stocksii LAC15 in G. hirsutum, GhLAC15, was also dominantly expressed in the developing fibers of brown cotton XC20 from 5 DPA (day post anthesis) to 25 DPA, especially at the secondary cell wall thickening stage (20 DPA and 25 DPA). In XC20 plants with downregulated GhLAC15 (GhLAC15i), a remarkable reduction in proanthocyanidins (PAs) and lignin contents was observed. Some of the key genes in the phenylpropane and flavonoid biosynthesis pathway were down-regulated in GhLAC15i plants. Notably, the fiber length of GhLAC15i plants showed an obvious increase and the fiber color was lightened. Moreover, we found that the thickness of cotton fiber cell wall was decreased in GhLAC15i plants and the fiber surface became smoother compared to that of WT. Taken together, this study revealed that GhLAC15 played an important role in PAs and lignin biosynthesis in naturally colored cotton fibers. It might mediate fiber color and fiber quality by catalyzing PAs oxidation and lignin polymerization, ultimately regulating fiber colouration and development.
Assuntos
Fibra de Algodão , Regulação da Expressão Gênica de Plantas , Gossypium , Lacase , Lignina , Proteínas de Plantas , Parede Celular/metabolismo , Cor , Gossypium/genética , Gossypium/metabolismo , Gossypium/enzimologia , Lacase/metabolismo , Lacase/genética , Lignina/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proantocianidinas/metabolismoRESUMO
PURPOSE: The essence of this scholarly work was to carefully outline the key factors intensifying the virulence and protracted contagion of COVID-19, particularly among individuals afflicted with hematologic malignancies (HM), in an epoch predominantly governed by the Omicron variant. METHODS: Adults with HM diagnosed with COVID-19 from November 2022 to February 2023 were monitored in this retrospective study. Patient blood samples yielded biochemical data, and COVID-19 was confirmed through RNA or antigen testing. The factors affecting severity and infection duration were examined using both univariate and multivariate logistic regression analyses. For calculating the overall survival probabilities, the Kaplan-Meier product limit approach was employed. RESULTS: In the examined cohort, 133 individuals diagnosed with HM and concomitantly infected with COVID-19 were scrutinized. Of the participants, 29.3% (39 patients) were classified as Severe/Critical, while the other 70.7% (94 patients) were categorized as Non-severe. A significant difference was observed in vaccination status: 61.7% of patients in the Non-severe group had received at least a two-dose vaccine regimen, whereas 61.5% of the Severe/Critical group had either minimal or only one dose of vaccination. The data analysis revealed that elevated C-reactive protein levels (≥ 100 mg/L) significantly raised the risk of severe/critical conditions in HM patients with COVID-19, as determined by advanced multivariate logistic regression. The odds ratio was 3.415 with a 95% confidence interval of 1.294-9.012 (p = 0.013). Patients who continued to have positive nucleic acid tests and ongoing symptoms beyond 30 days were categorized as having a persistent infection, whereas those who achieved infection control within this timeframe were categorized as having infection recovery. Of the HM cohort, 11 did not survive beyond 30 days after diagnosis. The results from a competing risk model revealed that increased interleukin-6 levels (HR: 2.626, 95% CI: 1.361-5.075; p = 0.004) was significantly associated with persistent infection. Conversely, receiving more than two vaccine doses (HR: 0.366, 95% CI: 0.158-0.846; p = 0.019), and having high IgG levels (≥ 1000 mg/dl) (HR: 0.364, 95% CI: 0.167-0.791; p = 0.011), were associated with infection recovery. There was a notable disparity in survival rates between patients with persistent infections and infection recovery, with those in the non-persistent group demonstrating superior survival outcomes (P < 0.001). CONCLUSIONS: In conclusion, the study determined that HM patients with COVID-19 and increased C-reactive protein levels had a higher likelihood of severe health outcomes. Persistent infection tended to be more prevalent in those with vaccine dosages (< 2 doses), lower IgG levels, and higher interleukin-6 levels.
Assuntos
Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Neoplasias Hematológicas , Imunoglobulina G , SARS-CoV-2 , Humanos , COVID-19/sangue , COVID-19/imunologia , COVID-19/epidemiologia , COVID-19/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , China/epidemiologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/imunologia , Estudos Retrospectivos , SARS-CoV-2/imunologia , Imunoglobulina G/sangue , Adulto , Idoso , Anticorpos Antivirais/sangue , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , VacinaçãoRESUMO
BACKGROUND: Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients unsuitable for intensive chemotherapy. However, the clinical outcomes of patients treated with DAC as a monotherapy are far from satisfactory. Adding all-trans retinoic acid (ATRA) to DAC reportedly benefitted MDS and elderly AML patients. However, the underlying mechanisms remain unclear and need further explorations from laboratory experiments. METHODS: We used MDS and AML cell lines and primary cells to evaluate the combined effects of DAC and ATRA as well as the underlying mechanisms. We used the MOLM-13-luciferase murine xenograft model to verify the enhanced cytotoxic effect of the drug combination. RESULTS: The combination treatment reduced the viability of MDS/AML cells in vitro, delayed leukaemia progress, and extended survival in murine xenograft models compared to non- and mono-drug treated models. DAC application as a single agent induced Nrf2 activation and downstream antioxidative response, and restrained reactive oxygen species (ROS) generation, thus leading to DAC resistance. The addition of ATRA blocked Nrf2 activation by activating the RARα-Nrf2 complex, leading to ROS accumulation and ROS-dependent cytotoxicity. CONCLUSIONS: These results demonstrate that combining DAC and ATRA has potential for the clinical treatment of HR-MDS/AML and merits further exploration.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Animais , Camundongos , Idoso , Decitabina/farmacologia , Fator 2 Relacionado a NF-E2 , Espécies Reativas de Oxigênio , Antineoplásicos/uso terapêutico , Síndromes Mielodisplásicas/induzido quimicamente , Síndromes Mielodisplásicas/tratamento farmacológico , Tretinoína/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , AzacitidinaRESUMO
Single gene mutations in the RAS pathway are uncommon and of unknown significance in myelodysplastic syndrome (MDS) patients, RAS pathway-related gene mutations (RASwaymut ) as a whole may be significant and require further elucidation. The clinical and molecular data of 370 MDS patients who were newly diagnosed between 1 November 2016 and 31 August 2020 in our hospital were collected and retrospectively reviewed. RASwaymut were detected in 57 (15.41%) patients. Higher median percentage of marrow blasts (2% vs. 1%, P = 0.00), more co-mutated genes (4, interquartile range [IQR]: 2-5. vs. 2, IQR:1-4, P = 0.00), more higher risk patients according to international prognostic scoring system-revised (IPSS-R) (80.70% vs. 59.11%, P = 0.002) as well as higher acute myeloid leukemia transformation rate (35.09% vs. 14.38%, P = 0.02) were observed in patients with RASwaymut when compared to those with wild type RAS pathway-related genes (RASwaywt ). The most frequent co-mutated genes were ASXL1 (28.6%), TET2 (23.2%), U2AF1, RUNX1, TP53 (14.3%); DNMT3A (12.5%), among which ASXL1 mutation rate were significantly higher than those with RASwaywt (p < 0.05). RASwaymut had no significant effect on response to disease-modifying treatment in MDS patients. However, Overall survivals (OS) of RASwaymut patients were significantly shorter than those with RASwaywt (16.05 m. vs. 92.3 m, P = 0.00), especially in patients with marrow blasts less than 5% (P = 0.002), normal karyotype (P = 0.01) and lower risk (P = 0.00). While multivariate prognostic analysis showed that RASwaymut co-mutated with TET2 was an independent poor prognostic factor for all MDS patients (P = 0.00, hazrad ratio [HR] = 4.77 with 95% confidence interval [CI]: 2.4-9.51) and RASwaymut patients (P = 0.02, HR 2.76, 95% CI 1.21-6.29). In conclusion, RASwaymut was associated with higher IPSS-R risk, higher incidence of leukemic transformation thus shorter OS in MDS patients, it could be viewed as a whole to predict poor prognosis. Co-mutation with TET2 may promote disease progression and was an independent poor prognostic factor in MDS patients.
Assuntos
Relevância Clínica , Síndromes Mielodisplásicas , Humanos , Estudos Retrospectivos , Mutação , Prognóstico , Síndromes Mielodisplásicas/genéticaRESUMO
The treatment of patients with refractory and/or relapsed (R/R) high-risk myelodysplastic syndrome (HR-MDS) remains a daunting clinical challenge. Venetoclax is a selective BCL-2 inhibitor, which combined with hypomethylating agents (HMAs), increased responses and prolonged survival in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of patients with R/R HR-MDS receiving combination azacytidine (AZA) plus 15-days duration of venetoclax (VEN-15d) in order to determine their efficacy and toxicity in this context. We showed that the overall response rate was 57.2% (20/35) and the median over survival was 14 months in R/R MDS. The most common treatment-emergent adverse events were peripheral blood cytopenias and infectious complications. Our retrospective study showed that the real-world experience of treating R/R MDS with AZA plus VEN-15d highlights an encouraging response rate with myelosuppression being the major toxicity. Of note, VEN-15d with AZA may salvage patients failing to respond optimally to HMAs and reduce the disease-burden for subsequent allogeneic stem cell transplantation in our analysis. These data of combination AZA plus VEN-15d in R/R MDS warrant further prospective evaluation in clinical trials.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Azacitidina/efeitos adversos , Estudos Retrospectivos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Mieloide Aguda/terapiaRESUMO
Near-field radiative heat transfer (NFRHT) governed by evanescent waves, provides a platform to thoroughly understand the transport behavior of nonradiative photons, and also has great potential in high-efficiency energy harvesting and thermal management at the nanoscale. It is more usual in nature that objects participate in heat transfer process in many-body form rather than the frequently-considered two-body scenarios, and the inborn mutual interactions among objects are important to be understood and utilized for practical applications. The last decade has witnessed considerable achievements on many-body NFRHT, ranging from the establishment of different calculation methods to various unprecedented heat transport phenomena that are distinct from two-body systems. In this invited review, we introduce concisely the basic physics of NFRHT, lay out various theoretical methods to deal with many-body NFRHT, and highlight unique functionalities realized in many-body systems and the resulting applications. At last, the key challenges and opportunities of many-body NFRHT in terms of fundamental physics, experimental validations, and potential applications are outlined and discussed.
RESUMO
BACKGROUND: Trisomy 8 positivity myelodysplastic syndrome with Behçet's disease is rare. Isolated trisomy 8 is a frequent cytogenetic abnormality in the MDS, but the characteristic of trisomy 8 and the association between trisomy 8 positivity myelodysplastic syndrome and Behçet's disease is unclear. CASE PRESENTATION: Here, we reported a 63-year-old man, who presented with fever, abdominal pain and hematochezia. Imaging studies revealed bowel wall thickening and mural hyperenhancement of terminal ileum and cecum. Colonoscopy found multiple round ulcers in terminal ileum, ileocecal valve and multiple yellow dotted pseudomembranous attachments throughout the colon. Capsule endoscopy also revealed multiple irregular ulcers in lower ileum. Serum C-reactive protein levels and fecal calprotectin were abnormally high. The clostridium difficile toxin A and B was positive. However, the patient's intestinal ulcers did not resolve after two weeks course of vancomycin. Considered that the patient was diagnosed as MDS-RAEB2 with a karyotype of 47 XX, + 8. And detailed inquiry of medical history revealed epifolliculitis and frequently recurrent oral ulcers 2 months before admission. A diagnosis of trisomy 8 positivity MDS with BD was made. Then he received glucocorticoid along with the 5th course of azacytidine. The follow-up endoscopy showed significantly improved intestinal ulcer 2 months after treatment. we report a rare disease and provide the diagnose and treatment ideas. CONCLUSIONS: We highlight the challenges and the process of thinking about of the diagnosis. This may provide a new idea for the diagnosis of intestinal ulcers.
Assuntos
Enteropatias , Síndromes Mielodisplásicas , Colonoscopia , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Trissomia , Úlcera/tratamento farmacológicoRESUMO
Patients with lower-risk myelodysplastic syndromes (LR-MDS) as defined by the International Prognostic Scoring System (IPSS) have more favorable prognosis in general, but significant inter-individual heterogeneity exists. In this study, we examined the molecular profile of 15 MDS-relevant genes in 159 patients with LR-MDS using next-generation sequencing. In univariate COX regression, shorter overall survival (OS) was associated with mutation status of ASXL1 (P = .001), RUNX1 (P = .031), EZH2 (P = .049), TP53 (P = .016), SRSF2 (P = .046), JAK2 (P = .040), and IDH2 (P = .035). We also found significantly shorter OS in patients with an adjusted TET2 variant allele frequency (VAF) ≥18% versus those with either an adjusted TET2 VAF <18% or without TET2 mutations (median: 20.4 vs 47.8 months; P = .020; HR = 2.183, 95%CI: 1.129-4.224). After adjustment for IPSS, shorter OS was associated with mutation status of ASXL1 (P < .001; HR = 4.306, 95% CI: 2.144-8.650), TP53 (P = .004; HR = 4.863, 95% CI: 1.662-14.230) and JAK2 (P = .002; HR = 5.466, 95%CI: 1.848-16.169), as well as adjusted TET2 VAF ≥18% (P = .008; HR = 2.492, 95% CI: 1.273-4.876). Also, OS was increasingly shorter as the number of mutational factors increased (P < .001). A novel prognostic scoring system incorporating the presence/absence of the four independent mutational factors into the IPSS further stratified LR-MDS patients into three prognostically different groups (P < .001). The newly developed scoring system redefined 10.1% (16/159) of patients as a higher-risk group, who could not be predicted by the currently prognostic models. In conclusion, integration of the IPSS with mutation status/burden of certain MDS-relevant genes may improve the prognostication of patients with LR-MDS and could help identify those with worse-than-expected prognosis for more aggressive treatment.
Assuntos
Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Síndromes Mielodisplásicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sequência de DNA/métodos , Análise de Sobrevida , Adulto JovemRESUMO
Patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS) or higher-risk MDS have limited treatment options and poor prognosis. Our previous single-center study of decitabine followed by low dose idarubicin and cytarabine (D-IA) in patients with myeloid neoplasms showed promising primary results. We therefore conducted a multicenter study of D-IA regimen in AML evolving from MDS and higher-risk MDS. Patients with AML evolving from MDS or refractory anemia with excess blasts type 2 (RAEB-2) (based on the 2008 WHO classification) were included. The D-IA regimen (decitabine, 20 mg/m2 daily, days 1 to 3; idarubicin, 6 mg/m2 daily, days 4 to 6; cytarabine 25 mg/m2 every 12 hours, days 4 to 8; granulocyte colony stimulating factor [G-CSF], 5 µg/kg, from day 4 until neutrophil count increased to 1.0 × 109 /L) was administered as induction chemotherapy. Seventy-one patients were enrolled and treated, among whom 44 (62.0%) had AML evolving from MDS and 27 (38.0%) had RAEB-2. Twenty-eight (63.6%) AML patients achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi): 14 (31.8%) patients had CR and 14 (31.8%) had CRi. Six (22.2%) MDS patients had CR and 15 (55.6%) had marrow complete remission. The median overall survival (OS) was 22.4 months for the entire group, with a median OS of 24.2 months for AML and 20.0 months for MDS subgroup. No early death occurred. In conclusion, the D-IA regimen was effective and well tolerated, representing an alternative option for patients with AML evolving from MDS or MDS subtype RAEB-2.
Assuntos
Anemia Refratária com Excesso de Blastos/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Evolução Clonal , Epigênese Genética , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Anemia Refratária com Excesso de Blastos/genética , Anemia Refratária com Excesso de Blastos/patologia , Citarabina/administração & dosagem , Decitabina/administração & dosagem , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Decitabine and low-dose chemotherapy are common treatments for intermediate and high risk myelodysplastic syndromes (MDS). In this study, we retrospectively assessed the efficacy and toxicity of the two regimens for MDS-refractory anemia with excess blasts (MDS-RAEB) patients. A total of 112 patients with a diagnosis of MDS-RAEB are included. The overall response (OR) and complete remission (CR) rate was comparable between the two groups (OR: 64.1% vs. 66.7%, pâ¯=â¯0.60; CR: 23.4% vs. 31.3%, pâ¯=â¯0.64). The OR rates of 20â¯mg/m2/day and 15â¯mg/m2/day decitabine regimen were comparable (69.0% vs. 60.0%, pâ¯=â¯0.46). Overall survival (OS) did not differ significantly between the groups (20.7 vs. 13.5â¯months, pâ¯=â¯0.17). In a subgroup analysis that included only patients at ≥60â¯years of age, survival benefit of decitabine was apparent (20.6 vs. 10.0â¯months, pâ¯=â¯0.03). In hematological toxicities, the lowest count of platelet in the decitabine group was higher significantly. And, the incidence of Grade 3-4 infection in the decitabine group was lower significantly. Our results demonstrate that both decitabine and low-dose chemotherapy are effective for MDS-RAEB, but decitabine was safer. Decitabine might be a better choice for patients at ≥60â¯years of age.
Assuntos
Anemia Refratária com Excesso de Blastos/tratamento farmacológico , Anemia Refratária com Excesso de Blastos/mortalidade , Antimetabólitos Antineoplásicos/uso terapêutico , Decitabina/uso terapêutico , Adulto , Idoso , Anemia Refratária com Excesso de Blastos/diagnóstico , Anemia Refratária com Excesso de Blastos/etiologia , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Biomarcadores , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Feminino , Testes Genéticos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/mortalidade , Razão de Chances , Prognóstico , Resultado do TratamentoRESUMO
We retrospectively analyzed 101 primary MDS patients with complex karyotype during January 2010 and April 2017.The median overall survival (OS) time was 13 (95% CI 9.98-16.02) months, and there was no significant difference in OS for different treatment. Chromosome 5/7 involvement was common (78.22%, 79/101) and associated with shorter OS (12â¯months vs. 28â¯months, Pâ¯<â¯0.01) Monosomal karyotype (MK) is overlapped with CK in 79 patients, but was not statistically associated with shorter OS. While in 59 cases with genes sequenced, 57 (96.61%) patients were found to have at least one mutation of known significance, and TP53 was the most frequent (74.58%, 44/59), the median OS of patients with TP53 mutation was shorter than those without (10 vs. 27â¯months, Pâ¯<â¯0.01). Multivariate analysis demonstrated that only TP53 mutation was the strongest independent prognostic factor for OS. Moreover, high variant allele frequency (VAF) of TP53 mutation (median VAF was 70.00%) was seen and associated with adverse survival (9â¯months vs. 13â¯months, pâ¯=â¯0.04). In conclusion, MDS patients with CK implied an unfavorable outcome regardless of any treatment, TP53 mutation occurs at a high frequency and has a higher VAF, both were associated with worse survival.
Assuntos
Cariótipo , Síndromes Mielodisplásicas/genética , China , Cromossomos Humanos Par 5 , Cromossomos Humanos Par 7 , Frequência do Gene , Humanos , Mutação , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Proteína Supressora de Tumor p53/genéticaRESUMO
Although cytarabine has been widely considered as one of the chemotherapy drugs for high-risk myelodysplastic syndromes (MDS), the overall response rate is only approximately 20-30%. Nuclear factor erythroid 2-related factor 2 (NRF2, also called NFE2L2) has been shown to play a pivotal role in preventing cancer cells from being affected by chemotherapy. However, it is not yet known whether NRF2 can be used as a prognostic biomarker in MDS, or whether elevated NRF2 levels are associated with cytarabine resistance. Here, we found that NRF2 expression levels in bone marrow from high-risk patients exceeded that of low-risk MDS patients. Importantly, high NRF2 levels are correlated with inferior outcomes in MDS patients (n=137). Downregulation of NRF2 by the inhibitor Luteolin, or lentiviral shRNA knockdown, enhanced the chemotherapeutic efficacy of cytarabine, while MDS cells treated by NRF2 agonist Sulforaphane showed increased resistance to cytarabine. More importantly, pharmacological inhibition of NRF2 could sensitize primary high-risk MDS cells to cytarabine treatment. Mechanistically, downregulation of dual specificity protein phosphatase 1, an NRF2 direct target gene, could abrogate cytarabine resistance in NRF2 elevated MDS cells. Silencing NRF2 or dual specificity protein phosphatase 1 also significantly sensitized cytarabine treatment and inhibited tumors in MDS cells transplanted mouse models in vivo Our study suggests that targeting NRF2 in combination with conventional chemotherapy could pave the way for future therapy for high-risk MDS.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Citarabina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Fosfatase 1 de Especificidade Dupla/genética , Regulação da Expressão Gênica , Síndromes Mielodisplásicas/genética , Fator 2 Relacionado a NF-E2/genética , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Sequência de Bases , Sítios de Ligação , Células Cultivadas , Citarabina/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fosfatase 1 de Especificidade Dupla/metabolismo , Técnicas de Inativação de Genes , Loci Gênicos , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Modelos Biológicos , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ligação ProteicaAssuntos
Síndromes Mielodisplásicas , Humanos , Prognóstico , Síndromes Mielodisplásicas/genética , Mutação , CariótipoRESUMO
Starting from 9-methyl-1,2,3,4,9,9a-hexahydro-4aH-pyrido[2,3-b]indol-4a-ol, or indole-3-acetonitrile, 40 new calycanthaceous alkaloid analogs were synthesized in excellent yields. The prepared compounds were evaluated for biological activity against acetylcholinesterase and a broad range of plant pathogen fungi. The results of bioassays indicated that the majority of tested compounds displayed comparable or better in vitro bioactivity than the positive control. Notably, compounds b8 and b9 showed higher activity against Verticillium dahlia than chlorothalonil, with MIC values of 62.5 and 7.81⯵gâ¯mL-1, respectively. Compound b3 had a higher activity against Bacillus cereus, with a MIC value of 15.63⯵gâ¯mL-1. Compounds c2 and c11 revealed potent activity against acetylcholinesterase, with MIC values of 0.01 and 0.1â¯ngâ¯mL-1, respectively. Analysis of the molecular docking modes of c2 and c11 with Torpedo californica acetylcholinesterase indicated a medium strong hydrogen bond interaction between the hydroxyl groups of both the ligands and the phenolic hydroxyl of Try121 at a distance of approximately 2.4â¯Å. The results obtained in this study will be useful for the further design and structural optimization of calycanthaceous alkaloids as potential agrochemical lead compounds for plant disease control.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Inibidores da Colinesterase/farmacologia , Alcaloides Indólicos/farmacologia , Pirróis/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antifúngicos/síntese química , Antifúngicos/metabolismo , Bactérias/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Fungos/efeitos dos fármacos , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Pirróis/síntese química , Pirróis/metabolismo , Relação Estrutura-Atividade , TorpedoRESUMO
Neurons are highly polarized cells with an axon and dendritic arbors. It is still not well studied that how formation and elaboration of axon and dendrites is controlled by diffusible signaling factors such as glutamate via specific receptors. We found that N-methyl-D-aspartate (NMDA) receptors were enriched (stage 2-3) but decreased expression (stage 4-5) at tip of axon of cultured hippocampal neurons during distinct development stages. Inhibition of NMDA receptor activity by competitive antagonist DL-2-amino-5-phosphonovalerate (APV) or channel blocker MK801 promoted axonal outgrowth at the early stages, whereas inhibited dendritic development in later stages. Meanwhile, knockdown of NMDA receptors also promoted axonal outgrowth and branch in immature neurons. Furthermore, GluN2B but not GluN2A subunit inhibited axonal outgrowth in immature hippocampal neurons. Finally, we found that NMDA receptors inhibited axonal outgrowth by inactivating Akt and activating GSK-3ß signaling in a calcineurin-dependent manner. Taken together, our results demonstrate that stabilization GSK-3ß activation in the axon growth cone by Ca2+ influx through NMDA receptors may be involved in regulation of axon formation in immature neurons at early stages.
Assuntos
Calcineurina/genética , Glicogênio Sintase Quinase 3 beta/genética , Plasticidade Neuronal/genética , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de N-Metil-D-Aspartato/genética , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Calcineurina/metabolismo , Cálcio/metabolismo , Cátions Bivalentes , Maleato de Dizocilpina/farmacologia , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/embriologia , Hipocampo/metabolismo , Transporte de Íons , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de SinaisRESUMO
A total of 29 novel tetrahydropyrroloindol-based calycanthaceous alkaloid derivatives were synthesized from indole-3-acetonitrile in good yields. The synthesized compounds were evaluated against nine strains of bacteria and a wide range of plant pathogen fungi. Bioassay results revealed that majority of the compounds displayed similar or higher in vitro antimicrobial activities than the positive control. The biological activities also indicated that substituents at R4 and R5 significantly affect the activities. Notably, compound c4 was found to be most active among the tested calycanthaceous analogues and might be a novel potential leading compound for further development as an antifungal agent. The results could pave the way for further design and structural modification of calycanthaceous alkaloids as antimicrobial agents.
Assuntos
Alcaloides , Anti-Infecciosos , Bactérias/crescimento & desenvolvimento , Fusarium/crescimento & desenvolvimento , Alcaloides/síntese química , Alcaloides/química , Alcaloides/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologiaRESUMO
Sepsis is one of the most common causes of mortality in intensive care units. Although sepsis-associated encephalopathy (SAE) is reported to be a leading manifestation of sepsis, its pathogenesis remains to be elucidated. In this study, we investigated whether exogenous recombinant human erythropoietin (rhEPO) could protect brain from neuronal apoptosis in the model of SAE. We showed that application of rhEPO enhanced Bcl-2, decreased Bad in lipopolysaccharide treated neuronal cultures, and improved neuronal apoptosis in hippocampus of cecal ligation and peroration rats. We also found that rhEPO increased the expression of phosphorylated AKT, and the antiapoptotic role of rhEPO could be abolished by phosphoinositide 3-kinase (PI3K)/AKT inhibitor LY294002 or SH-5. In addition, systemic sepsis inhibited the hippocampal-phosphorylated mammalian target of rapamycin (mTOR) and p70S6K (downstream substrates of PKB/AKT signaling), which were restored by administration of exogenous rhEPO. Moreover, treatment with mTOR-signaling inhibitor rapamycin or transfection of mTOR siRNA reversed the neuronal protective effects of rhEPO. Finally, exogenous rhEPO rescued the emotional and spatial cognitive defects without any influence on locomotive activity. These results illustrated that exogenous rhEPO improves brain dysfunction by reducing neuronal apoptosis, and AKT/mTOR signaling is likely to be involved in this process. Application of rhEPO may serve as a potential therapy for the treatment of SAE.
Assuntos
Eritropoetina/uso terapêutico , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sepse/tratamento farmacológico , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Ceco/patologia , Cognição/efeitos dos fármacos , Emoções/efeitos dos fármacos , Epoetina alfa , Eritropoetina/administração & dosagem , Eritropoetina/farmacologia , Humanos , Ligadura , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Punções , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Sepse/patologia , Sepse/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
Enhancing the aerodynamic performance of bristled wings is an important topic for small flying robotics. This paper numerically investigates this situation at very low Reynolds numbers by using elliptic cylinders as the bristles instead of circular cylinders. Optimal configuration of the bristled wing with five elliptic cylinders is obtained, which corresponds to the maximum lift. The results show that, compared with the case of circular cylindrical bristles, the aerodynamic performance of the elliptical bristles can be enhanced effectively. The enhancement can be more significant as the aspect ratio of the ellipses increases and the gap width decreases. The bristled wing generates more lift compared to a flat-plate wing with a length five times that of the major axis of an ellipse. For the cases that the attack angleαfor the whole wing is equal to those for the elliptical bristlesθ, the optimal attack angle for ellipses maximizing the total lift force of the five-bristle model is between 40° and 45°. Forα ≠θwith the Reynold numberRe⪠0.1, the optimal ellipse attack angle is between 40° and 45°. Forα ≠θwithReâ¼ 1, the optimal ellipse attack angle deviates heavier from the range between 40° and 45° at someαvalues and reaches approximately 32° atα= 20°. This paper can lay a foundation for optimal design of small flying robotics and enhancement of flow through porous structures in future.
Assuntos
Voo Animal , Robótica , Animais , Fenômenos Biomecânicos , Modelos Biológicos , Asas de AnimaisRESUMO
BACKGROUND: The incidence of gastric cancer remains high, and it is the sixth most common cancer and the fourth leading cause of cancer deaths worldwide. Oral contrast-enhanced ultrasonography is a simple, non-invasive, and painless method for the diagnosis of gastric tumors. AIM: To explore the diagnostic value of oral contrast-enhanced ultrasonography for the detection of gastric tumors. METHODS: The screening results based on oral contrast-enhanced ultrasonography and electronic gastroscopy were compared with those of the postoperative pathological examination. RESULTS: Among 42 patients with gastric tumors enrolled in the study, the diagnostic accordance rate was 95.2% for oral contrast-enhanced ultrasonography (n = 40) and 90.5% for electronic gastroscopy (n = 38) compared with postoperative pathological examination. The Kappa value of consistency test with pathological findings was 0.812 for oral contrast-enhanced ultrasonography and 0.718 for electronic gastroscopy, and there was no significant difference between them (P = 0.397). For the TNM staging of gastric tumors, the accuracy rate of oral contrast-enhanced ultrasonography was 81.9% for the overall T staging and 50%, 77.8%, 100%, and 100% for T1, T2, T3, and T4 staging, respectively. The sensitivity and specificity were both 100% for stages T3 and T4. The diagnostic accuracy rate of oral contrast-enhanced ultrasonography was 93.8%, 80%, 100%, and 100% for stages N0, N1-N3, M0, and M1, respectively. CONCLUSION: The accordance rate of qualitative diagnosis by oral contrast-enhanced ultrasonography is comparable to that of gastroscopy, and it could be used as the preferred method for the early screening of gastric tumors.
RESUMO
Electromagnetic wave lensing, a common physical phenomenon recognized in visible light for centuries, finds extensive applications in manipulating light in optical systems such as telescopes and cameras. Magnetohydrodynamic wave is a common perturbation phenomenon in the corona. By using high spatio-temporal resolution observations from the Solar Dynamics Observatory, here, we report the observation of a magnetohydrodynamic wave lensing in the highly ionized and magnetized coronal plasma, where quasi-periodic wavefronts emanated from a flare converged at a specific point after traversing a coronal hole. The entire process resembles an electromagnetic wave lensing from the source to the focus. Meanwhile, the magnetohydrodynamic wave lensing is well reproduced through a magnetohydrodynamic numerical simulation with full spatio-temporal resolution. We further investigate potential applications for coronal seismology, as the lensing process encodes information on the Alfvén speed, in conjunction with favorable geometric and density variations.