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1.
Cell ; 181(7): 1502-1517.e23, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32559462

RESUMO

RNA viruses are a major human health threat. The life cycles of many highly pathogenic RNA viruses like influenza A virus (IAV) and Lassa virus depends on host mRNA, because viral polymerases cleave 5'-m7G-capped host transcripts to prime viral mRNA synthesis ("cap-snatching"). We hypothesized that start codons within cap-snatched host transcripts could generate chimeric human-viral mRNAs with coding potential. We report the existence of this mechanism of gene origination, which we named "start-snatching." Depending on the reading frame, start-snatching allows the translation of host and viral "untranslated regions" (UTRs) to create N-terminally extended viral proteins or entirely novel polypeptides by genetic overprinting. We show that both types of chimeric proteins are made in IAV-infected cells, generate T cell responses, and contribute to virulence. Our results indicate that during infection with IAV, and likely a multitude of other human, animal and plant viruses, a host-dependent mechanism allows the genesis of hybrid genes.


Assuntos
Capuzes de RNA/genética , Infecções por Vírus de RNA/genética , Proteínas Recombinantes de Fusão/genética , Regiões 5' não Traduzidas/genética , Animais , Bovinos , Linhagem Celular , Cricetinae , Cães , Humanos , Vírus da Influenza A/metabolismo , Camundongos , Proteínas Mutantes Quiméricas/genética , Proteínas Mutantes Quiméricas/metabolismo , Fases de Leitura Aberta/genética , Capuzes de RNA/metabolismo , Infecções por Vírus de RNA/metabolismo , Vírus de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Transcrição Gênica/genética , Proteínas Virais/metabolismo , Replicação Viral/genética
2.
J Am Chem Soc ; 146(23): 15833-15842, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38819396

RESUMO

Ruthenium(II) complexes are known to form η6-arene complexes with benzene-containing compounds through π-coordination, a property extensively utilized to initiate reactions not typically observed with free arenes. A prime example is nucleophilic aromatic substitution, where ruthenium-complexed aryl halides undergo nucleophilic attack, allowing the direct synthesis of diverse aromatic compounds by displacing halides with nucleophiles. However, this activation relies on the electron-withdrawing effect of the Ru(II) species, as well as is hindered by the resistance of η6-arenes to arene exchange. In the previous pursuit of catalysis, the emphasis of ligand design has centered on promoting arene exchange. In this study, we extended the ruthenium activation strategy to umpolung substitution reactions of phenols. The amination proceeds through a direct condensation between phenols and amines, with a key intermediate identified as [bis(η5-phenoxo)Ru], which is in situ generated from a commercially available ruthenium catalyst. In comparison with the well-studied cyclopentadienyl (Cp) type ligands, we demonstrated that an η5-phenoxo motif, as a superior alternative to Cp, contributes to the amination of phenols in two crucial ways: its less electron-donating nature enhances the withdrawing effect of the ruthenium unit, facilitating substitution on the phenol complex; its distinctive behavior in arene exchange allows for conducting the amination with a catalytic amount of metal. Additionally, hydrogen bonding, wherein the phenoxo serves as the acceptor, was found to be important for the substitution. The versatility of this ruthenium-catalyzed amination was validated by performing reactions with a diverse array of phenols exhibiting various electronic properties, in combination with a wide range of primary amines. This work exemplifies the expansion of the scope of π-coordination activation in catalysis through innovative ligand development.

3.
Bioorg Chem ; 143: 107031, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38086242

RESUMO

Hypobromous acid (HOBr), one of the significant reactive oxygen species (ROS) that acts as an important role in human immune system, however the increasing level of HOBr in human body can cause the disorder of eosinophils (EPO), leading to oxidative stress in organelles, and further causing a series of diseases. In this study, a ratiometric fluorescent probe DMBP based on Nile red skeleton was developed to detect HOBr specifically by the electrophilic substitution with HOBr. DMBP emits near-infrared (NIR) fluorescence at 653 nm, after reacting with HOBr, the emission wavelength of DMBP shifted blue and a new peak appeared at 520 nm, realizing a ratiometric examination of HOBr with a limit of detection of 89.00 nM. Based on its sensitive and specific response to HOBr, DMBP was applied in the visual imaging of HOBr in HepG2 cells and zebrafish. Foremost, probe DMBP has excellent lysosome targeting ability and NIR emission reduced the background interference of biological tissues, providing a potential analytical tool to further investigate the role of HOBr in lysosome.


Assuntos
Bromatos , Corantes Fluorescentes , Oxazinas , Árvores , Animais , Humanos , Peixe-Zebra , Lisossomos , Esqueleto
4.
J Formos Med Assoc ; 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38594163

RESUMO

OBJECTIVE: As the population ages, concerns about cognitive decline have become increasingly relevant in medical consultations. This study aims to analyze the interaction between muscle strength, lung function, and cognitive function in Chinese middle-aged and older adults, providing a theoretical basis for better prevention of cognitive decline. METHODS: This study used data from the China Health and Retirement Longitudinal Study (CHARLS) wave 3, including 13 716 participants aged 45 years or older. Cognitive function was assessed through two dimensions, resulting in a total score ranging from 0 to 31 points, with higher scores indicating better cognitive function. Muscle strength was measured using normalized grip strength and chair-standing time, while lung function was evaluated using peak expiratory flow (PEF). RESULTS: Total cognitive function scores exhibited significant correlations with grip strength, chair-standing time, and PEF. Muscle strength and lung function demonstrated significant associations with cognitive function, with lung function emerging as a notable mediating factor. This relationship persisted even after adjusting for potential confounding variables. Specifically, PEF played a substantial mediating role in linking grip strength to cognitive function scores (estimated indirect effect = 0.0132, boot-strapped standard error = 0.0015, boot-strapped standard 95% confidence interval = 0.0104, 0.0162). Additionally, PEF served as a significant mediator in the association between chair-standing time and cognitive function scores (estimated indirect effect = -0.0204, boot-strapped standard error = 0.0023, boot-strapped standard 95% confidence interval = -0.0251, -0.0159). CONCLUSION: The study highlights the importance of addressing declines in muscle strength and lung function to identify risk factors associated with cognitive function. Understanding these relationships can provide insights into potential pathways linking these variables and may aid in better prevention of cognitive decline. Further long-term longitudinal cohort studies are needed to explore the causality between these factors.

5.
Can J Infect Dis Med Microbiol ; 2024: 7502110, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38660494

RESUMO

Introduction: The development of combinatorial adjuvants is a promising strategy to boost vaccination efficiency. Accumulating evidence indicates that manganese exerts strong immunocompetence and will become an enormous potential adjuvant. Here, we described a novel combination of Mn2+ plus aluminum hydroxide (AH) adjuvant that significantly exhibited the synergistic immune effect. Methodology. Initially, IsdB3 proteins as the immune-dominant fragment of IsdB proteins derived from Staphylococcus aureus (S. aureus) were prepared. IsdB3 proteins were identified by western blotting. Furthermore, we immunized C57/B6 mice with IsdB3 proteins plus Mn2+ and AH adjuvant. After the second immunization, the proliferation of lymphocytes was measured by the cell counting kit-8 (CCK-8) and the level of IFN-γ, IL-4, IL-10, and IL-17 cytokine from spleen lymphocytes in mice and generation of the antibodies against IsdB3 in serum was detected with ELISA, and the protective immune response was assessed through S. aureus challenge. Results: IsdB3 proteins plus Mn2+ and AH obviously stimulated the proliferation of spleen lymphocytes and increased the secretion of IFN-γ, IL-4, IL-10, and IL-17 cytokine in mice, markedly enhanced the generation of the antibodies against IsdB3 in serum, observably decreased bacterial load in organs, and greatly improved the survival rate of mice. Conclusion: These data showed that the combination of Mn2+ and AH significantly acted a synergistic effect, reinforced the immunogenicity of IsdB3, and offered a new strategy to increase vaccine efficiency.

6.
Int J Mol Sci ; 24(4)2023 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-36835571

RESUMO

Myocardial infarction (MI) causes peripheral organ injury, in addition to cardiac dysfunction, including in the liver, which is known as cardiac hepatopathy. Aerobic exercise (AE) can effectively improve liver injury, although the mechanism and targets are currently not well established. Irisin, mainly produced by cleavage of the fibronectin type III domain-containing protein 5 (FNDC5), is a responsible for the beneficial effects of exercise training. In this study, we detected the effect of AE on MI-induced liver injury and explored the role of irisin alongside the benefits of AE. Wildtype and Fndc5 knockout mice were used to establish an MI model and subjected to AE intervention. Primary mouse hepatocytes were treated with lipopolysaccharide (LPS), rhirisin, and a phosphoinositide 3-kinase (PI3K) inhibitor. The results showed that AE significantly promoted M2 polarization of macrophages and improved MI-induced inflammation, upregulated endogenous irisin protein expression and activated the PI3K/ protein kinase B (Akt) signaling pathway in the liver of MI mice, while knockout of Fndc5 attenuated the beneficial effects of AE. Exogenous rhirisin significantly inhibited the LPS-induced inflammatory response, which was attenuated by the PI3K inhibitor. These results suggest that AE could effectively activate the FNDC5/irisin-PI3K/Akt signaling pathway, promote the polarization of M2 macrophages, and inhibit the inflammatory response of the liver after MI.


Assuntos
Fibronectinas , Fígado , Infarto do Miocárdio , Condicionamento Físico Animal , Animais , Camundongos , Fibronectinas/metabolismo , Lipopolissacarídeos , Fígado/metabolismo , Fígado/patologia , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Fatores de Transcrição
7.
Molecules ; 28(6)2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36985705

RESUMO

The COVID-19 pandemic caused by SARS-CoV-2 has majorly impacted public health and economies worldwide. Although several effective vaccines and drugs are now used to prevent and treat COVID-19, natural products, especially flavonoids, showed great therapeutic potential early in the pandemic and thus attracted particular attention. Quercetin, baicalein, baicalin, EGCG (epigallocatechin gallate), and luteolin are among the most studied flavonoids in this field. Flavonoids can directly or indirectly exert antiviral activities, such as the inhibition of virus invasion and the replication and inhibition of viral proteases. In addition, flavonoids can modulate the levels of interferon and proinflammatory factors. We have reviewed the previously reported relevant literature researching the pharmacological anti-SARS-CoV-2 activity of flavonoids where structures, classifications, synthetic pathways, and pharmacological effects are summarized. There is no doubt that flavonoids have great potential in the treatment of COVID-19. However, most of the current research is still in the theoretical stage. More studies are recommended to evaluate the efficacy and safety of flavonoids against SARS-CoV-2.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Pandemias , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Flavonoides/química , Quercetina/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/química
8.
Mod Rheumatol ; 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37861425

RESUMO

OBJECTIVES: This study investigates the relationship between locomotive syndrome (LS) and mental disorder (depression) in young Chinese college students. METHODS: Our study population (n = 165; mean age of 19.82 ±1.90 years) comprises college student residents at Tsinghua University in Beijing, China. Three screening methods were used to evaluate LS: 25-question Geriatric Locomotive Function Scale (GLFS-25), a two-step test, and a stand-up test. Depression was screened by the Chinese version of the Zung Self-Rating Depression Scale (ZSDS). RESULTS: The prevalence of LS and depression was 20.1% and 30.9%, respectively. The LS group had lower grip strength and higher ZSDS scores than the non-LS group. CONCLUSION: Young Chinese college students have a relatively high prevalence of LS, and LS and GLFS-25 scores were significantly related to depression. The present results suggest that management strategies for LS should consider depressive symptoms among young adults.

9.
J Chem Phys ; 156(21): 214104, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35676128

RESUMO

Quantitively comparing the features between different electronic excited states (ESs) is a crucial task in both potential energy surface (PES) studies and excited-state fragmentation approaches. However, it is still a challenging problem in regard to the comparison of complex and highly degenerate systems. Herein, we present a transition orbital projection (TOP) method to calculate the similarity of different ESs based on the configuration vectors of two types of transition densities. It fully considers four significant problems, including phase, hole-particle bijectivity, orbital permutation, and sign of configuration coefficients. TOP state-tracking-based excited-state optimization shows high robustness in several high-symmetric systems, which are difficult to describe with traditional state-tracking approaches. The TOP state-tracking method is expected to be widely applied to the PES of photochemical reactions, ES molecular dynamics to track the diabatic states, and fragmentation approaches for local excitation of large systems.

10.
Childs Nerv Syst ; 38(5): 939-945, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35284945

RESUMO

OBJECTIVE: Hydrocephalus is one of the most significant comorbidities of pediatric suprasellar tumors. Up to 37.5-68.0% of patients were diagnosed with hydrocephalus at admission. However, after surgical resection of the tumor, 9.3-51.4% of the hydrocephalus will persist and require a ventriculoperitoneal shunt (VPS) surgery. The purpose of this study was to identify the risk factors associated with postresection shunting in children with suprasellar tumors. METHODS: We conducted a retrospective analysis of children who underwent surgery for suprasellar tumors at our department from February 2011 to December 2020. We used univariate and multivariate analysis to screen the factors that might be correlated with postoperative shunt placement, taking into account patients' characteristics, tumor histology/size/calcification, the severity of preoperative hydrocephalus, the involvement of ventricles, external ventricular drainage (EVD) placement, postoperative intraventricular hematoma, the extent of resection, and other surgical details. RESULTS: A total of 124 children who underwent surgery for suprasellar tumors were included in our study. Hydrocephalus was present in 55 patients (44.3%) at admission; 23 patients (18.5%) received VPS implantation after tumor removal. Univariate analysis showed that the involvement of ventricles (p = 0.002), moderate/severe preoperative hydrocephalus (p = 0.001), postoperative intraventricular hematoma (p = 0.005), and EVD implantation (p = 0.001) were significantly associated with postoperative VPS. Multivariate analysis confirmed that only ventricle involvement (p = 0.002; OR = 5.6; 95%CI 1.8-17.2) and intraventricular hematoma (p = 0.01; OR = 10.7; 95%CI 1.8-64.2) were independent risk factors for postresection shunting. CONCLUSION: Ventricle involvement and intraventricular hematoma can be identified as independent predictors for postoperative shunting in pediatric suprasellar tumors.


Assuntos
Doença pelo Vírus Ebola , Hidrocefalia , Neoplasias , Criança , Hematoma/complicações , Doença pelo Vírus Ebola/complicações , Humanos , Hidrocefalia/etiologia , Hidrocefalia/patologia , Hidrocefalia/cirurgia , Neoplasias/complicações , Estudos Retrospectivos , Fatores de Risco
11.
Int J Mol Sci ; 23(8)2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35457111

RESUMO

The aberrant activation of the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) pathway is common in pancreatic ductal adenocarcinomas (PDAC). The application of inhibitors against PI3K and AKT has been considered as a therapeutic option. We investigated PDAC cell lines exposed to increasing concentrations of MK-2206 (an AKT1/2/3 inhibitor) and Buparlisib (a pan-PI3K inhibitor). Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated. Further, whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were performed to analyze the recurrent aberrations and expression profiles of the inhibitor target genes and the genes frequently mutated in PDAC (Kirsten rat sarcoma virus (KRAS), Tumor protein p53 (TP53)). MK-2206 and Buparlisib demonstrated pronounced cytotoxic effects and limited cell-line-specific effects in cell death induction. WES revealed two sequence variants within the direct target genes (PIK3CA c.1143C > G in Colo357 and PIK3CD c.2480C > G in Capan-1), but a direct link to the Buparlisib response was not observed. RNA-seq demonstrated that the expression level of the inhibitor target genes did not affect the efficacy of the corresponding inhibitors. Moreover, increased resistance to MK-2206 was observed in the analyzed cell lines carrying a KRAS variant. Further, increased resistance to both inhibitors was observed in SU.86.86 carrying two TP53 missense variants. Additionally, the presence of the PIK3CA c.1143C > G in KRAS-variant-carrying cell lines was observed to correlate with increased sensitivity to Buparlisib. In conclusion, the present study reveals the distinct antitumor effects of PI3K/AKT pathway inhibitors against PDAC cell lines. Aberrations in specific target genes, as well as KRAS and TP53, individually or together, affect the efficacy of the two PI3K/AKT pathway inhibitors.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Aminopiridinas , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Compostos Heterocíclicos com 3 Anéis , Humanos , Morfolinas , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais , Neoplasias Pancreáticas
12.
Int J Mol Sci ; 23(8)2022 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-35457227

RESUMO

Casein kinase II (CK2) and cyclin-dependent kinases (CDKs) frequently interact within multiple pathways in pancreatic ductal adenocarcinoma (PDAC). Application of CK2- and CDK-inhibitors have been considered as a therapeutic option, but are currently not part of routine chemotherapy regimens. We investigated ten PDAC cell lines exposed to increasing concentrations of silmitasertib and dinaciclib. Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated, and bioinformatic clustering was used to classify cell lines into sensitive groups based on their response to inhibitors. Furthermore, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) was conducted to assess recurrent mutations and the expression profile of inhibitor targets and genes frequently mutated in PDAC, respectively. Dinaciclib and silmitasertib demonstrated pronounced and limited cell line specific effects in cell death induction, respectively. WES revealed no genomic variants causing changes in the primary structure of the corresponding inhibitor target proteins. RNA-Seq demonstrated that the expression of all inhibitor target genes was higher in the PDAC cell lines compared to non-neoplastic pancreatic tissue. The observed differences in PDAC cell line sensitivity to silmitasertib or dinaciclib did not depend on target gene expression or the identified gene variants. For the PDAC hotspot genes kirsten rat sarcoma virus (KRAS) and tumor protein p53 (TP53), three and eight variants were identified, respectively. In conclusion, both inhibitors demonstrated in vitro efficacy on the PDAC cell lines. However, aberrations and expression of inhibitor target genes did not appear to affect the efficacy of the corresponding inhibitors. In addition, specific aberrations in TP53 and KRAS affected the efficacy of both inhibitors.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Caseína Quinase II/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Óxidos N-Cíclicos , Humanos , Indolizinas , Naftiridinas , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fenazinas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Compostos de Piridínio , Neoplasias Pancreáticas
13.
Int J Mol Sci ; 22(22)2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34830222

RESUMO

Exercise training has been reported to alleviate cardiac fibrosis and ameliorate heart dysfunction after myocardial infarction (MI), but the molecular mechanism is still not fully clarified. Fibroblast growth factor 21 (FGF21) exerts a protective effect on the infarcted heart. This study investigates whether exercise training could increase FGF21 protein expression and regulate the transforming growth factor-ß1 (TGF-ß1)-Smad2/3-MMP2/9 signaling pathway to alleviate cardiac fibrosis following MI. Male wild type (WT) C57BL/6J mice and Fgf21 knockout (Fgf21 KO) mice were used to establish the MI model and subjected to five weeks of different types of exercise training. Both aerobic exercise training (AET) and resistance exercise training (RET) significantly alleviated cardiac dysfunction and fibrosis, up-regulated FGF21 protein expression, inhibited the activation of TGF-ß1-Smad2/3-MMP2/9 signaling pathway and collagen production, and meanwhile, enhanced antioxidant capacity and reduced cell apoptosis in the infarcted heart. In contrast, knockout of Fgf21 weakened the cardioprotective effects of AET after MI. In vitro, cardiac fibroblasts (CFs) were isolated from neonatal mice hearts and treated with H2O2 (100 µM, 6 h). Recombinant human FGF21 (rhFGF21, 100 ng/mL, 15 h) and/or 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR, 1 mM, 15 h) inhibited H2O2-induced activation of the TGF-ß1-Smad2/3-MMP2/9 signaling pathway, promoted CFs apoptosis and reduced collagen production. In conclusion, exercise training increases FGF21 protein expression, inactivates the TGF-ß1-Smad2/3-MMP2/9 signaling pathway, alleviates cardiac fibrosis, oxidative stress, and cell apoptosis, and finally improves cardiac function in mice with MI. FGF21 plays an important role in the anti-fibrosis effect of exercise training.


Assuntos
Terapia por Exercício/métodos , Fatores de Crescimento de Fibroblastos/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/terapia , Miocárdio/patologia , Transdução de Sinais/genética , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Apoptose/genética , Células Cultivadas , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/genética , Fibroblastos/metabolismo , Fibrose , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Recombinantes/metabolismo
14.
Int J Mol Sci ; 22(23)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34884478

RESUMO

Bruton's tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) in the B-cell receptor (BCR) signaling pathway are considered potential therapeutic targets for the treatment of B-cell lymphomas, among which, diffuse large B-cell lymphoma (DLBCL) is the most common type. Herein, we comparatively evaluated the single and combined application of the BTK inhibitor ibrutinib and the selective PI3Kγ inhibitor AS-605240 in the canine DLBCL cell line CLBL-1. For further comparison, key findings were additionally analyzed in canine B-cell leukemia GL-1 and human DLBCL cell line SU-DHL-4. While ibrutinib alone induced significant anti-proliferative effects on all cell lines in a dose-dependent manner, AS-605240 only induced anti-proliferative effects at high concentrations. Interestingly, ibrutinib and AS-605240 acted synergistically, reducing cell proliferation and increasing apoptosis/necrosis in all cell lines and inducing morphological changes in CLBL-1. Moreover, the combined application of ibrutinib and AS-605240 reduced relative phosphorylation and, in some instances, the levels of the BTK, AKT, GSK3ß, and ERK proteins. Comparative variant analysis of RNA-seq data among canine B- and T-lymphoid cell lines and primary B-cell lymphoma samples revealed potentially high-impact somatic variants in the genes that encode PI3K, which may explain why AS-605240 does not singly inhibit the proliferation of cell lines. The combination of ibrutinib and AS-605240 represents a promising approach that warrants further in vivo evaluation in dogs, potentially bearing significant value for the treatment of human DLBCL.


Assuntos
Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Sinergismo Farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Fosfatidilinositol 3-Quinases/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Piperidinas/farmacologia , Adenina/farmacologia , Animais , Apoptose , Proliferação de Células , Cães , Quimioterapia Combinada , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Transdução de Sinais , Células Tumorais Cultivadas
15.
J Environ Manage ; 278(Pt 2): 111573, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33137687

RESUMO

This study investigated impacts of silver nanoparticles (AgNPs) on nitrogen removal within constructed wetlands (CWs) with different flow directions. The obtained results showed that addition of AgNPs at 0.5 and 2 mg/L significantly inhibited NH4+-N removal, resulting from lower abundances of functional genes (amoA and nxrA) within CWs. And higher abundances of amoA and nxrA genes at 0.5 mg/L were observed in downward flow CW, leading to better NH4+-N removal, compared to upward flow CW. Besides, nitrifying genes amoA and nxrA in upward flow CW at 2.0 mg/L exhibited higher than downward flow CW, explaining better NH4+-N removal in upward flow CW. 0.5 mg/L AgNPs significantly declined NO3--N and TN removal, resulted from decreasing abundances of nirK, nirS and nosZ. In contrast, abundances of nirK, nirS and nosZ genes had slightly lower or higher than before adding AgNPs in upward flow CW, leading to lower NO3--N and TN effluent concentrations. High throughput sequencing also indicated the changes of functional bacterial community after exposing to AgNPs.


Assuntos
Nanopartículas Metálicas , Áreas Alagadas , Desnitrificação , Nitrogênio/análise , Prata , Eliminação de Resíduos Líquidos , Águas Residuárias
16.
Am J Physiol Renal Physiol ; 318(3): F826-F834, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32036700

RESUMO

Excessive fructose intake causes metabolic syndrome and lipid accumulation in the kidney and leads to renal dysfunction and damage. Exercise (Ex) improves lipids regulation, but the mechanisms are unclarified in the kidney. In the present study, male Sprague-Dawley rats were allocated to groups fed with control or high-fructose (HFr) diet. Part of rats in each group underwent aerobic treadmill Ex for 12 wk. Drug treatment was performed as the fenofibrate gavage during the last 4 wk on HFr diet-fed rats. Renal function, histological changes, and expression of regulators involved in fatty acid (FA) metabolism were assessed. In CON diet-fed groups, Ex did not affect renal function or histology and significantly increased renal expression of FA ß-oxidation regulators including acyl-CoA dehydrogenases (CADs), acyl-CoA oxidase, peroxisome proliferator-activated receptor (PPAR)-α, and PPAR-γ coactivator (PGC)-1α and lipogenic factors including acetyl-CoA carboxylase (ACCα), FA synthase (FAS), and sterol regulatory element-binding protein 1c. HFr caused albuminuria, lipid accumulation, and renal pathohistological changes, which were attenuated by Ex but not by fenofibrate. HFr decreased renal expression of medium- and short-chain CADs and PPAR-α and increased renal expression of ACCα, FAS, and sterol regulatory element-binding protein 1c. Ex increased expression of CADs, carnitine palmitoyltransferase type I, acyl-CoA oxidase, PPAR-α, and PGC-1α and decreased renal expression of ACCα and FAS in HFr diet-fed rats. The Ex-induced FA metabolism alteration was similar to that in the fenofibrate-treated group. In conclusion, the present study indicates that Ex enhanced renal FA metabolism, which might protect the kidney in lipid dysregulation diseases.


Assuntos
Ácidos Graxos/metabolismo , Fenofibrato/farmacologia , Frutose/administração & dosagem , Rim/fisiologia , Atividade Motora , Ração Animal , Animais , Dieta , Carboidratos da Dieta , Fenofibrato/administração & dosagem , Hipolipemiantes/administração & dosagem , Hipolipemiantes/farmacologia , Masculino , Oxirredução , Ratos , Ratos Sprague-Dawley , Regulação para Cima
17.
Zhonghua Nan Ke Xue ; 26(7): 639-644, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-33377721

RESUMO

OBJECTIVE: To investigate the effect of Cuscuta chinensis flavonoids (CCF) on the expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) in the testis of the rat with oligozoospermia (OZ). METHODS: Thirty SD male rats were randomly divided into three groups of equal number, blank control, OZ model control and CCF intervention. The OZ model was established in the latter two groups by intraperitoneal injection of cyclophosphamide at 30 mg/kg qd for 5 successive days. From the 6th day, the rats in the CCF intervention group were treated intragastrically with mixed suspension of CCF at 5 mL/kg and those in the other two groups with normal saline, all for 4 weeks. The epididymal sperm concentration and motility and the testicular morphology were examined and the expression of GM-CSF in the testis tissue detected with the SELDI Protein Chip. RESULTS: Compared with the rats in the blank control and CCF intervention groups, the OZ model controls showed dramatically decreased epididymal sperm concentration and motility (both P < 0.01) and significant morphological changes in the testis with deformed seminiferous tubules and reduced number and disordered arrangement of spermatogenic cells. Normal testicular morphology was observed in the CCF intervention group and there were no statistically significant differences in sperm concentration and motility between the CCF intervention and blank control groups (P > 0.05). The expression of GM-CSF was significantly up-regulated in the testis tissue of the OZ model controls but lower than the minimum value obtained with the SELDI Protein Chip in the blank control and CCF intervention groups. CONCLUSIONS: Cuscuta chinensis flavonoids can significantly down-regulate the expression of GM-CSF in the testis of the rats with cyclophosphamide-induced oligozoospermia.


Assuntos
Cuscuta/química , Flavonoides/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Oligospermia , Testículo/efeitos dos fármacos , Animais , Masculino , Oligospermia/induzido quimicamente , Oligospermia/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Ratos , Ratos Sprague-Dawley , Espermatozoides , Testículo/metabolismo
18.
J Formos Med Assoc ; 118(6): 1062-1072, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30522855

RESUMO

BACKGROUND: Reduced muscle strength, as measured by handgrip strength (HS), has been associated with an increased risk of cardiovascular disease (CVD). The aim of this study was to examine the association between different HS indexes and CVD risk factors in elderly Chinese individuals. We also determine optimal cutoffs of HS indexes for predicting CVD risk factors. METHODS: Data were obtained from 603 men and 789 women aged ≥60 years (average age 66.8 ± 6.4 y). These study participants were recruited in the suburb area of Tianjin, China. An individual was considered a patient when they exhibited any one of three CVD risk factors: diabetes mellitus, hypertension and dyslipidemia. All participants were interviewed face-to-face. In addition, serum samples were collected from all participants, and all participants underwent measures of anthropometry and HS. RESULTS: The optimal cutoffs were 0.376 of HS/weight in men and 0.726 of HS/body fat mass in women for predicting diabetes mellitus. The adjusted odds ratios (ORs) of at least one CVD risk factor for those with low muscle strength identified by HS/body fat mass were 2.14 (95% confidence interval [CI]: 1.53, 3.44; p < 0.001) in men and 2.32 (95% CI: 1.60, 3.29; p < 0.001) in women. CONCLUSION: HS/body fat mass appear to be the index best associated with CVD risk factors except diabetes mellitus in men. The optimal cutoffs of HS indexes have the potential to identify elderly adults at risk of CVD.


Assuntos
Adiposidade , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Dislipidemias/epidemiologia , Força da Mão , Hipertensão/epidemiologia , Idoso , Índice de Massa Corporal , Peso Corporal , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Vida Independente , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores de Risco , População Suburbana
20.
J Formos Med Assoc ; 117(2): 101-108, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28416075

RESUMO

BACKGROUND: Assessment of the association of muscle strength and muscle mass with osteoporosis (OP) is of special interest as muscles are a potential target for interventions (i.e., strength training). METHODS: A cross-sectional descriptive study encompassing people aged ≥ 60 years (average age: 66.9 ± 6.2 years; men, n = 516; women, n = 652) in the Hangu area of Tianjin, China. The study populations were invited to participate in a comprehensive geriatric assessment. OS was identified by measuring the calcaneal using a quantitative ultrasound and a T score of less than -2.5. Muscle characteristics included grip strength and appendicular skeletal muscle mass (ASM). RESULTS: The prevalence of OS in this study was 61.6% (male 52.1%, female 69.1%). Grip strength was negatively related to OS and after adjusting for all other variables, higher grip strength was found to be associated with a lower OS risk (p = 0.023). ASM/height2 was not associated with OS (p = 0.205). CONCLUSION: Based on our study, muscle strength rather than muscle mass is negatively associated with OS in older people; thus, we should pay more attention to muscle strength training in the early stage of the OS.


Assuntos
Força da Mão , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/fisiopatologia , Osteoporose/fisiopatologia , Idoso , China , Estudos Transversais , Feminino , Avaliação Geriátrica , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Prevalência
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