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1.
Cell Death Dis ; 15(2): 110, 2024 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-38310091

RESUMO

Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of AXL observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. AXL upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-α (TNF-α) and STING-type I interferon pathways. Pharmacological inhibition of AXL abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting AXL in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
2.
J Oleo Sci ; 73(2): 219-230, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38311411

RESUMO

Ginsenosides Rg3 and Rg5 obtained from Panax (ginseng) have shown significant anticancer activity via the PI3K-Akt signaling pathway. This study evaluated the anticancer and antimetastatic effects of a combination of Rg3 and Rg5 on lung cancer cells. A combination of Rg3 and Rg5 was treated for lung cancer cell line A549 and human lung tumor xenograft mouse model, and anti-metastatic effects on Matrigel plug implantation in mice. The combination of Rg3 and Rg5 showed potent antiproliferative effects on A549 cells with IC50 values of 44.6 and 36.0 µM for Rg3 and Rg5 respectively. The combination of Rg3 and Rg5 (30 µM each) showed 48% cell viability as compared to Rg3 (72% viability) and Rg5 (64% viability) at 30 µM concentrations. The combination of Rg3 and Rg5 induced apoptosis in A549 cells characterized by activation of caspase-9 and caspase-3 and cleavage of PARP, as well as suppression of the autophagic marker LC3A/B. The antitumoral potentials of the combination of Rg3 and Rg5 were ascertained in a lung tumor xenograft mouse model with high efficacy as compared to individual ginsenosides. The metastasislimiting properties of the combination of Rg3 and Rg5 were assessed in Matrigel plug implantation in mice which showed the potent efficacy of the combination as compared to individual ginsenoside. Mechanistically, the combination of Rg3 and Rg5 inhibited the expression of PI3K/Akt/mTOR and EGFR/VEGF signaling pathways in lung cancer cells. Results suggest that the combination of Rg3 and Rg5 suppressed the tumor cell proliferation in lung cancer cells and limited the rate of metastasis which further suggest that the combination has a significant effect as compared to the administration of single ginsenoside.


Assuntos
Ginsenosídeos , Neoplasias Pulmonares , Humanos , Camundongos , Animais , Neoplasias Pulmonares/tratamento farmacológico , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Apoptose , Proliferação de Células , Receptores ErbB/metabolismo , Receptores ErbB/farmacologia
3.
J Oleo Sci ; 73(2): 239-251, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38311413

RESUMO

Frog oil has been recognized for its nutritional and medicinal value. However, there is limited research on the role of frog oil in preventing obesity. In this study, we aimed to investigate the lipid composition of Quasipaa spinosa oil (QSO) and Rana catesbeiana oil (RCO) using lipidomics analysis. We compared the lipid accumulation effects of these two kinds of frog oils and soybean oil (SO) in Caenorhabditis elegans (C. elegans). Additionally, we determined the gene expression related to lipid metabolism and used the nhr-49 mutant (RB1716) and sir-2.1 mutant (VC199) for validation experiments. The results showed that the lipid composition of QSO and RCO was significantly different (p < 0.05), and QSO was rich in more polyunsaturated fatty acids (PUFAs). After feeding C. elegans, the lipid accumulation of the QSO group was the lowest among the three dietary oil groups. In addition, compared with RCO and SO, QSO significantly inhibited the production of malondialdehyde (MDA) and increased the activity of superoxide dismutase (SOD). The effects of three kinds of dietary oils on the fatty acid composition of C. elegans were significantly different. Compared with SO and RCO, QSO significantly up-regulated (p < 0.05) the expression of sir-2.1 and ech-1 genes. The results showed that QSO might reduce lipid accumulation through the SIRT1 and nuclear hormone signaling pathways. Such a situation was verified experimentally by the nhr-49 mutant (RB1716) and sir-2.1 mutant (VC199). This study proposed a new functional oil, laying the groundwork for developing functional foods from Quasipaa spinosa.


Assuntos
Caenorhabditis elegans , Gorduras Insaturadas na Dieta , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Rana catesbeiana/metabolismo , Ácidos Graxos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Gorduras Insaturadas na Dieta/farmacologia , Óleo de Soja/metabolismo , Metabolismo dos Lipídeos/genética
4.
NEJM Evid ; 3(1): EVIDoa2300171, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38320513

RESUMO

Targeted Inhibition of CYP11A1 in Prostate CancerIn this single-arm, multicenter, combined phase 1 and phase 2 study, patients with metastatic prostate adenocarcinoma with progression on prior androgen receptor pathway inhibitors and taxane-based chemotherapy were treated with ODM-208. A decrease in prostate-specific antigen levels of 50% or more occurred in 16/42 (38.1%) and 24/45 (53.3%) in phase 1 and 2 respectively. Responses mainly occurred in patients with androgen receptor mutations. Adrenal insufficiency was the dose-limiting toxicity.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Masculino , Humanos , Receptores Androgênicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Enzima de Clivagem da Cadeia Lateral do Colesterol , Antígeno Prostático Específico/uso terapêutico , Resultado do Tratamento , Antagonistas de Receptores de Andrógenos/farmacologia
5.
Hum Vaccin Immunother ; 20(1): 2304372, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38314761

RESUMO

The mechanisms of Pythium insidiosum-antigen (PIA) immunotherapy activating a patient's immune system are unknown. We evaluated the interleukin-8 (IL-8) serum levels during P. insidiosum infection and after vaccination with PIA in vascular pythiosis cases. Furthermore, we studied the anti-P. insidiosum activity of neutrophils stimulated with various concentrations of PIA ex vivo in 3 strains of P. insidiosum isolated from vascular pythiosis patients. IL-8 serum levels were evaluated using the ELISA technique. We assessed the effect of PIA-stimulated neutrophils on the viability of zoospores using MTT assay, visualized neutrophil extracellular trap (NET) formation via microscopy, and measured the levels of double-stranded DNA (dsDNA) using PicoGreen dsDNA quantitation assay in 3 strains of P. insidiosum isolated from vascular pythiosis patients. Serum levels of IL-8 gradually lowered from the early to the end phases of vaccination with PIA among the surviving group of vascular pythiosis cases. Neutrophils stimulated with 0.01 µg/ml PIA reduced zoospore viability significantly compared to PIA-unstimulated neutrophils for strain 1 and strain 3 (p < .05). Neutrophils stimulated with 0.01, 0.1, 1, and 10 µg/ml PIA exhibited significantly lower zoospore viability than PIA-unstimulated neutrophils for strain 2 (p < .05). IL-8 can be used as a biomarker for monitoring vascular pythiosis cases treated with the PIA vaccine. Also, anti-P. insidiosum activity of PIA-stimulated neutrophils was probably due to the disruption of cellular activity in zoospores rather than the mechanisms based on the formation of NETs.


Assuntos
Pitiose , Pythium , Animais , Humanos , Interleucina-8/farmacologia , Pythium/genética , Pitiose/terapia , Neutrófilos , Ensaio de Imunoadsorção Enzimática
6.
Redox Rep ; 29(1): 2313366, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38318818

RESUMO

Jaceosidin (JAC) is a natural flavonoid with anti-oxidant and other pharmacological activities; however, its anti-cancer mechanism remains unclear. We investigated the mechanism of action of JAC in gastric cancer cells. Cytotoxicity and apoptosis assays showed that JAC effectively killed multiple gastric cancer cells and induced apoptosis in human gastric adenocarcinoma AGS cells via the mitochondrial pathway. Network pharmacological analysis suggested that its activity was linked to reactive oxygen species (ROS), AKT, and MAPK signaling pathways. Furthermore, JAC accumulated ROS to up-regulate p-JNK, p-p38, and IκB-α protein expressions and down-regulate the p-ERK, p-STAT3, and NF-κB protein expressions. Cell cycle assay results showed that JAC accumulated ROS to up-regulate p21 and p27 protein expressions and down-regulate p-AKT, CDK2, CDK4, CDK6, Cyclin D1, and Cyclin E protein expressions to induce G0/G1 phase arrest. Cell migration assay results showed JAC accumulated ROS to down-regulate Wnt-3a, p-GSK-3ß, N-cadherin, and ß-catenin protein expressions and up-regulate E-cadherin protein expression to inhibit migration. Furthermore, N-acetyl cysteine pre-treatment prevented the change of these protein expressions. In summary, JAC induced apoptosis and G0/G1 phase arrest and inhibited migration through ROS-mediated signaling pathways in AGS cells.


Assuntos
Neoplasias Gástricas , Humanos , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Flavonoides/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
7.
J Cell Mol Med ; 28(3): e18114, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38323741

RESUMO

Patients with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL-3-independent cell proliferation through activation of the p-PDGFRB and p-STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell-derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs).


Assuntos
Receptor beta de Fator de Crescimento Derivado de Plaquetas , Fator de Transcrição STAT5 , Humanos , Animais , Camundongos , Mesilato de Imatinib , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Transcrição STAT5/genética , Transdução de Sinais , Carcinogênese , Transformação Celular Neoplásica , Inibidores de Proteínas Quinases/farmacologia , Proteína 2 de Ligação a Repetições Teloméricas
8.
Sci Rep ; 14(1): 3146, 2024 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-38326464

RESUMO

Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells.


Assuntos
Neuromielite Óptica , Humanos , Citocinas/metabolismo , Complexo Antígeno-Anticorpo/metabolismo , Leucócitos Mononucleares/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Rituximab/farmacologia , Rituximab/uso terapêutico , Rituximab/metabolismo , Autoanticorpos , Aquaporina 4 , Proteínas do Sistema Complemento/metabolismo , Imunoglobulina G/metabolismo
9.
Sci Rep ; 14(1): 3099, 2024 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-38326539

RESUMO

Sparganii Rhizoma-Curcumae Rhizoma (SR-CR) is a classic drug pair for the treatment of castration-resistant prostate cancer (CRPC), but its mechanism has not been clarified. The study aims to elucidate the potential mechanism of SR-CR in the management of CRPC. The present study employed the TCMSP as well as the SwissTargetPrediction platform to retrieve the chemical composition and targets of SR-CR. The therapeutic targets of CRPC were identified through screening the GeneCards, Disgenet, and OMIM databases. Subsequently, the Venny online platform was utilized to identify the shared targets between the SR-CR and CRPC. The shared targets were enrichment analysis using the Bioconductor and Kyoto encyclopedia of genes and genomes (KEGG) databases. The active ingredients and core targets were verified through molecular docking and were validated using PC3 cells in the experimental validation phase. A total of 7 active ingredients and 1126 disease targets were screened from SR-CR, leading to a total of 59 shared targets. Gene Ontology (GO) analysis resulted in 1309 GO entries. KEGG pathways analysis yielded 121 pathways, primarily involving cancer-related signaling pathways. The results from molecular docking revealed stable binding interactions between the core ingredients and the core targets. In vitro cellular assays further demonstrated that SR-CR effectively suppressed the activation of the Prostate cancer signaling pathway in PC3 cells, leading to the inhibition of cell proliferation and promotion of apoptosis. The SR-CR exert therapeutic effects on CRPC by inhibiting cell proliferation and promoting apoptosis through the Prostate cancer signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Simulação de Acoplamento Molecular , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Apoptose , Proliferação de Células , Bases de Dados Factuais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico
10.
J Enzyme Inhib Med Chem ; 39(1): 2305856, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38326989

RESUMO

A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (7a-o) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds 7a-o were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI50 values ranging from 28 to 104 nM, compared to Erlotinib (GI50 = 33 nM), and compounds 7i-m were the most potent. Compounds 7h, 7i, 7j, 7k, and 7l were evaluated as dual EGFR/VEGFR-2 inhibitors. These in vitro experiments demonstrated that compounds 7j, 7k, and 7l are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds 7j, 7k, and 7l were evaluated for their apoptotic potential activity, where findings indicated that compounds 7j, 7k, and 7l promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.


Assuntos
Antineoplásicos , Triazóis , Estrutura Molecular , Relação Estrutura-Atividade , Cloridrato de Erlotinib/farmacologia , Simulação de Acoplamento Molecular , Triazóis/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Antineoplásicos/química , Receptores ErbB/metabolismo , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral
11.
Pharm Biol ; 62(1): 162-169, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38327157

RESUMO

CONTEXT: Jian Gan powder (JGP) is a Chinese medicine compound comprised ginseng, Radix Paeoniae Alba, Radix Astragali, Salvia miltiorrhiza, Yujin, Rhizoma Cyperi, Fructus aurantii, Sophora flavescens, Yinchen, Bupleurum and licorice. OBJECTIVE: This study explored the inhibitory effects, polarization and potential mechanisms associated with JGP in macrophages. MATERIALS AND METHODS: RAW264.7 cells were randomly divided into six groups for 24 h: control, lipopolysaccharide (LPS), overexpression, 1% JGP, 2% JGP, 4% JGP, 8% JGP and 16% JGP. The effects of JGP on RAW264.7 cell proliferation were assessed using colony formation assays and cell counting kit-8 (CCK-8) assays. The Transwell assay was used to evaluate its impact on RAW264.7 cell migration. Moreover, we analysed the interleukin-6 (IL-6)/signal transducer and activator of the transcription 3 (IL-6/STAT3) signaling pathway using quantitative real-time PCR and Western blotting. Furthermore, we examined the M1/M2 polarization levels. RESULTS: Unlike LPS stimulation, JGP serum treatment markedly suppressed macrophage proliferation and migration capacity, while STAT3 overexpression enhanced RAW264.7 cell proliferation and migration. JGP inhibited the proliferation and migration of RAW264.7 cells by attenuating the IL-6/STAT3 signaling pathway. Furthermore, it inhibited macrophage M1 polarization, promoting M2 polarization. DISCUSSION AND CONCLUSIONS: JGP effectively suppressed the cellular function of RAW264.7 cells by down-regulating the IL-6/STAT3 signaling pathway and modulating macrophage M1/M2 polarization. These findings provide valuable theoretical and experimental basis for considering the potential clinical application of JGP in the treatment of immune-mediated liver injury in clinical practice.


Assuntos
Interleucina-6 , Lipopolissacarídeos , Pós/metabolismo , Pós/farmacologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos , Proliferação de Células
12.
Redox Rep ; 29(1): 2312320, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38329114

RESUMO

Burns and burn sepsis, characterized by persistent and profound hypercatabolism, cause energy metabolism dysfunction that worsens organ injury and systemic disorders. Glutamine (Gln) is a key nutrient that remarkably replenishes energy metabolism in burn and sepsis patients, but its exact roles beyond substrate supply is unclear. In this study, we demonstrated that Gln alleviated liver injury by sustaining energy supply and restoring redox balance. Meanwhile, Gln also rescued the dysfunctional mitochondrial electron transport chain (ETC) complexes, improved ATP production, reduced oxidative stress, and protected hepatocytes from burn sepsis injury. Mechanistically, we revealed that Gln could activate SIRT4 by upregulating its protein synthesis and increasing the level of Nicotinamide adenine dinucleotide (NAD+), a co-enzyme that sustains the activity of SIRT4. This, in turn, reduced the acetylation of shock protein (HSP) 60 to facilitate the assembly of the HSP60-HSP10 complex, which maintains the activity of ETC complex II and III and thus sustain ATP generation and reduce reactive oxygen species release. Overall, our study uncovers a previously unknown pharmacological mechanism involving the regulation of HSP60-HSP10 assembly by which Gln recovers mitochondrial complex activity, sustains cellular energy metabolism and exerts a hepato-protective role in burn sepsis.


Assuntos
Queimaduras , Sepse , Sirtuínas , Humanos , Glutamina/metabolismo , Glutamina/farmacologia , Metabolismo Energético , Trifosfato de Adenosina/metabolismo , Queimaduras/metabolismo , Sepse/tratamento farmacológico , Sepse/metabolismo , Fígado/metabolismo , Proteínas Mitocondriais/metabolismo , Sirtuínas/metabolismo
13.
PLoS Biol ; 22(2): e3002205, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38300958

RESUMO

Cells must access resources to survive, and the anatomy of multicellular structures influences this access. In diverse multicellular eukaryotes, resources are provided by internal conduits that allow substances to travel more readily through tissue than they would via diffusion. Microbes growing in multicellular structures, called biofilms, are also affected by differential access to resources and we hypothesized that this is influenced by the physical arrangement of the cells. In this study, we examined the microanatomy of biofilms formed by the pathogenic bacterium Pseudomonas aeruginosa and discovered that clonal cells form striations that are packed lengthwise across most of a mature biofilm's depth. We identified mutants, including those defective in pilus function and in O-antigen attachment, that show alterations to this lengthwise packing phenotype. Consistent with the notion that cellular arrangement affects access to resources within the biofilm, we found that while the wild type shows even distribution of tested substrates across depth, the mutants show accumulation of substrates at the biofilm boundaries. Furthermore, we found that altered cellular arrangement within biofilms affects the localization of metabolic activity, the survival of resident cells, and the susceptibility of subpopulations to antibiotic treatment. Our observations provide insight into cellular features that determine biofilm microanatomy, with consequences for physiological differentiation and drug sensitivity.


Assuntos
Antibacterianos , Infecções por Pseudomonas , Humanos , Antibacterianos/farmacologia , Pseudomonas aeruginosa/metabolismo , Biofilmes , Infecções por Pseudomonas/microbiologia , Fímbrias Bacterianas
14.
PLoS One ; 19(2): e0297708, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38306352

RESUMO

Our objective is to propose a method capable of disentangling the magnitude, the speed, and the duration or decay rate of the time course of response to rapid antidepressant therapies. To this end, we introduce a computational model of the time course of response to a single treatment with a rapid antidepressant. Numerical simulation is used to evaluate whether model parameters can be accurately estimated from observed data. Finally, we compare our computational modelling-based approach with linear mixed effects modelling in terms of their ability to detect changes in the magnitude and time-course of response to rapid antidepressant therapies in simulated randomized trials. Simulation experiments show that the parameters of our computational model can be accurately recovered using nonlinear least squares. Parameter estimation accuracy is stable over noise levels reaching as high as 25% of the true antidepressant effect magnitude. Comparison of our approach to mixed effects modelling using simulated randomized controlled trial data demonstrates an inability of linear mixed models to disentangle effect magnitude and time course, while our computational model accurately separates these response components. Our modelling approach may accurately identify the (A) magnitude, (B) speed, and (C) durability or decay rate of response to rapid antidepressant therapies. Future studies should fit this model to data from real clinical trials, and use resulting parameter estimates to uncover predictors and causes of different elements of the temporal course of antidepressant response.


Assuntos
Antidepressivos , Psicoterapia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Causalidade , Simulação por Computador , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
BMC Oral Health ; 24(1): 175, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38308290

RESUMO

This study evaluated the efficacy of a formulated remineralizing gallic acid (GA) varnish in treating artificial enamel caries lesions. Fifty-five intact bovine incisors were collected. Enamel blocks (5 × 9 mm) were prepared. A third of each block's surface remained intact. Primary carious lesions were induced on the middle and bottom thirds of the blocks by immersing the samples in a demineralization solution for 6 h. The bottom third of the blocks were further remineralized by randomly applying 0.5%, 2%, or 8% GA varnishes and 2.26% fluoride varnish (V varnish, Vericom, Seoul, Korea), or the varnish base without active ingredients (n = 11 each). The specimens were immersed in a remineralizing solution for 4 h and then subjected to a 2-hour immersion in the demineralizing solution. After six days of pH cycling, the surface microhardness was measured at depths of 30, 75, and 120 µm. The percentage of surface microhardness recovery (SMHR%) was compared among the groups using the Shapiro-Wilk, ANOVA, and Tukey HSD post-hoc tests (α = 0.05). The SMHR% of all experimental groups was higher than the control group at 30 µm (p < 0.05). The 0.5% GA varnish showed the highest SMHR% at all depths; however, the difference with the other experimental groups was significant at a depth of 30 µm (p < 0.05). The SMHR% of the fluoride and the 2% and 8% GA varnishes was comparable at all depths. All treatments potentially remineralize enamel lesions, with 0.5% GA varnish having the greatest effect, particularly on the top surface layer. As such, this newly developed varnish may emerge as a promising alternative to fluoride varnish.


Assuntos
Cárie Dentária , Fluoretos Tópicos , Animais , Bovinos , Cárie Dentária/prevenção & controle , Esmalte Dentário , Fluoretos Tópicos/farmacologia , Fluoretos Tópicos/uso terapêutico , Remineralização Dentária
16.
Sci Rep ; 14(1): 2881, 2024 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-38311678

RESUMO

Radiation-attenuated sporozoite (RAS) vaccines can completely prevent blood stage Plasmodium infection by inducing liver-resident memory CD8+ T cells to target parasites in the liver. Such T cells can be induced by 'Prime-and-trap' vaccination, which here combines DNA priming against the P. yoelii circumsporozoite protein (CSP) with a subsequent intravenous (IV) dose of liver-homing RAS to "trap" the activated and expanding T cells in the liver. Prime-and-trap confers durable protection in mice, and efforts are underway to translate this vaccine strategy to the clinic. However, it is unclear whether the RAS trapping dose must be strictly administered by the IV route. Here we show that intradermal (ID) RAS administration can be as effective as IV administration if RAS are co-administrated with the glycolipid adjuvant 7DW8-5 in an ultra-low inoculation volume. In mice, the co-administration of RAS and 7DW8-5 in ultra-low ID volumes (2.5 µL) was completely protective and dose sparing compared to standard volumes (10-50 µL) and induced protective levels of CSP-specific CD8+ T cells in the liver. Our finding that adjuvants and ultra-low volumes are required for ID RAS efficacy may explain why prior reports about higher volumes of unadjuvanted ID RAS proved less effective than IV RAS. The ID route may offer significant translational advantages over the IV route and could improve sporozoite vaccine development.


Assuntos
Vacinas Antimaláricas , Malária , Camundongos , Animais , Esporozoítos , Linfócitos T CD8-Positivos , Glicolipídeos , Malária/parasitologia , Adjuvantes Imunológicos/farmacologia , Adjuvantes Farmacêuticos , Camundongos Endogâmicos BALB C
17.
Anim Sci J ; 95(1): e13917, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38323750

RESUMO

Allicin is a sulfur-containing compound extracted from raw garlic (Allium sativum L.). We compared the effect of allicin addition on growth performance, serum biochemical parameters, and rumen microbiota of goats compared to monensin. Twenty-four Anhui white goats were assigned randomly to one of three dietary treatments: 1) a basal diet (CON); 2) the basal diet with allicin addition at 750 mg per head per day (AC); 3) the basal diet with monensin addition at 30 mg per kg of diet (MS). Animals were fed for 8 weeks. Results showed the average daily gain, and feed efficiency was increased with allicin and monensin addition. Serum levels of IgG, total superoxide dismutase, and glutathione peroxidase were higher in the AC group than those in the CON and MS groups. The microbiota analysis revealed that monensin addition mainly affected genera related to carbohydrate and protein metabolism, and allicin mainly affected genera related to energy metabolism and intestinal health. In conclusion, allicin could improve growth performance and have advantages over monensin in improving the antioxidant capacity and immune function of goats. Allicin may be a potential alternative to monensin.


Assuntos
Dissulfetos , Alho , Microbiota , Ácidos Sulfínicos , Animais , Ração Animal/análise , Antioxidantes/metabolismo , Dieta/veterinária , Suplementos Nutricionais/análise , Cabras/metabolismo , Monensin/farmacologia , Rúmen/metabolismo
18.
Sci Rep ; 14(1): 2953, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316867

RESUMO

Hypertension is a public health problem. Failure to control blood pressure figures is responsible for morbidity and premature mortality. This study aims to describe the characteristics of hypertensive patients followed at primary health care centers in Marrakech. Between May 2021 and December 2022, a cross-sectional study of 922 hypertension patients attending primary health care centers in Marrakech was done. To gather socio-demographic, behavioral, and clinical data, as well as hypertension treatment features and the care-patient-physician triad, a face-to-face questionnaire was employed. To identify risk factors associated with uncontrolled blood pressure, multivariate logistic regression was used. Uncontrolled blood pressure was found in 73.5% of people. The patients' average age was 63.4 ± 9.4 years (mean ± standard deviation), and 524 (77.3%) were women. Tobacco consumption (Adjusted Odd Ratio of 4.34; 95% CI [1.58-11.9]); lack of self-monitoring of hypertension (AOR of 1.69; 95% CI [1.14-2.52]); a family history of hypertension (AOR of 1.58; 95% CI [1.12-2.22]); overweight or obesity (AOR of 1.73; 95% CI [1.15-2.58]); and nonadherence to antihypertensive medication (AOR of 1.58; 95% CI [1.05-2.38]) were identified as risk factors for uncontrolled blood pressure. In hypertensive individuals, the percentage of uncontrolled blood pressure is considerable. It is essential to provide therapeutic education classes for hypertension patients in order to strengthen their power and autonomy in managing their hypertension.


Assuntos
Hipertensão , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Pressão Sanguínea , Estudos Transversais , Marrocos/epidemiologia , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Fatores de Risco
19.
Sci Rep ; 14(1): 2908, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316885

RESUMO

Breast cancer is the most common diagnosed cancer, the HER2-positive subtype account for 15% of all breast cancer. HER2-targeted therapy is the mainstay treatment for HER2-positive breast cancer. Cuproptosis is a novel form of programmed cell death, and is caused by mitochondrial lipoylation and destabilization of iron-sulfur proteins triggered by copper, which was considered as a key player in various biological processes. However, the roles of cuproptosis-related genes in HER2-positive breast cancer remain largely unknown. In the present study, we constructed a prognostic prediction model of HER2-positive breast cancer patients using TCGA database. Dysregulated genes for cells resistant to HER2-targeted therapy were analyzed in the GEO dataset. KEGG pathway, GO enrichment and GSEA was performed respectively. The immune landscape of DLAT was analyzed by CIBERSORT algorithm and TIDE algorithm. HER2-positive breast cancer patients with high CRGs risk score showed shorter OS. DLAT was downregulated and correlated with better survival of HER2-positive breast cancer patients (HR = 3.30, p = 0.022). High expressed DLAT was associated with resistant to HER2-targeted therapy. Knocking down DLAT with siRNA increased sensitivity of breast cancer to trastuzumab. KEGG pathway and GO enrichment of DEGs indicated that DLAT participates in various pathways correlated with organelle fission, chromosome segregation, nuclear division, hormone-mediated signaling pathway, regulation of intracellular estrogen receptor signaling pathway, condensed chromosome and PPAR signaling pathway. There was a negative correlation between TIDE and DLAT expression (r = - 0.292, p < 0.001), which means high DLAT expression is an indicator of sensitivity to immunotherapy. In conclusion, our study constructed a four CRGs signature prognostic prediction model and identified DLAT as an independent prognostic factor and associated with resistant to HER2-targeted therapy for HER2-positive breast cancer patients.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Prognóstico , Algoritmos , Apoptose , Cobre
20.
BMC Ophthalmol ; 24(1): 56, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317063

RESUMO

BACKGROUND: To report the microbiological isolates, aetiology, complications, antibiotic susceptibilities, and clinical remission of dacryocystitis and canaliculitis in a prominent tertiary ophthalmic teaching and referral hospital located in northern China and to offer appropriate recommendations for preventing and formulating drug treatment strategies. METHODS: This prospective study recruited a total of 477 participants who had been diagnosed with either dacryocystitis or canaliculitis. The cohort comprised 307 patients with chronic dacryocystitis, 111 patients with acute dacryocystitis, and 59 patients with canaliculitis. Purulent discharge from the lacrimal duct was collected using a sterile swab and immediately subjected to microbial culture. Antimicrobial susceptibility testing was conducted following established protocols. All participants were scheduled for follow-up visits within 14 days after receiving antibiotic therapy. RESULTS: The present findings indicated that women exhibited a higher susceptibility to the condition, as evidenced by the occurrence of 367 cases in comparison to 110 cases among men. Among the 477 patients, definitive causes were established in 59 individuals, accounting for 12.4% of the patients. Additionally, ocular complications were reported by 132 patients, representing 27.7% of the total. Monocular involvement was observed in the majority of cases, with 402 out of 477 patients (84.3%) affected, while binocular involvement was present in 75 patients (15.7%). In total, 506 microbiological strains were recovered from 552 eyes, with Staphylococcus epidermidis (16.4%) being the most prevalent microorganism. Other predominant isolates included Corynebacterium macginleyi (9.1%), Staphylococcus aureus (5.1%), Streptococcus pneumoniae (4.9%), Haemophilus (4.4%), Propionibacterium acnes (3.5%), and Eikenella corrodens (3.1%). Among the 12 isolated fungi, Candida parapsilosis accounted for 66.7%. The susceptibility to antimicrobial agents tested in gram-negative bacilli (79.5%) was observed to be higher than that of anaerobic bacteria (76.7%) and gram-positive cocci (55.4%). With pharmacological therapy, the remission rate of acute dacryocystitis (72.7%) was found to be higher than that of canaliculitis (53.3%) and chronic dacryocystitis (42.3%). CONCLUSIONS: This study highlights the microbial spectrum of dacryocystitis and canaliculitis, particularly C.macginleyi, E.corrodens and C.parapsilosis, which are also more frequently isolated. Vancomycin and imipenem may be more effective treatment options. Most cases have an unknown aetiology, and essential preventive measures involve postoperative cleansing of the lacrimal passage following eye and nasal surgeries, as well as the proactive management of rhinitis.


Assuntos
Canaliculite , Dacriocistite , Aparelho Lacrimal , Masculino , Humanos , Feminino , Estudos Prospectivos , Dacriocistite/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Hospitais de Ensino
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