RESUMO
BACKGROUND: Acute Myeloid Leukemia (AML) is a fast-developing invading cancer that impacts the blood and bone marrow, marked by the rapid proliferation of abnormal white blood cells. Chemotherapeutic agents, a primary treatment for AML, encounter clinical limitations such as poor solubility and low bioavailability. Previous studies have highlighted antibiotics as effective in inducing cancer cell death and potentially preventing metastasis. Besides, insulin is known to activate the PI3K/Akt pathway, often disrupted in cancers, leading to enhanced cell survival and resistance to apoptosis. In light of the above-mentioned points, we examined the anti-cancer impact of antibiotics Ciprofloxacin (CP) and Salinomycin (SAL) and their combination on KG1-a cells in the presence and absence of insulin. METHODS: This was accomplished by exposing KG1-a cells to different doses of CP and SAL alone, in combination, and with or without insulin for 24-72 h. Cell viability was evaluated using the MTT assay. Besides, apoptotic effects were examined using Hoechst staining and Annexin-V/PI flow cytometry. The expression levels of Bax, p53, BIRC5, Akt, PTEN, and FOXO1 were analyzed through Real-Time PCR. RESULTS: CP and SAL demonstrated cytotoxic and notable pro-apoptotic impact on KG1-a cells by upregulating Bax and p53 and downregulating BIRC5, leading to G0/G1 cell cycle arrest and prevention of the PI3K-Akt signaling pathway. Our findings demonstrated that combination of CP and SAL promote apoptosis in the KG1-a cell line by down-regulating BIRC5 and Akt, as well as up-regulating Bax, p53, PTEN, and FOXO1. Additionally, the findings strongly indicated that insulin effectively mitigates apoptosis by enhancing Akt expression and reducing FOXO1 and PTEN gene expression in the cells treated with CP and SAL. CONCLUSION: Our findings showed that the combined treatment of CP and SAL exhibit a strong anti-cancer effect on leukemia KG1-a cells. Moreover, it was discovered that the PI3K-Akt signaling can be a promising target in leukemia treatment particularly in hyperinsulinemia condition.
Assuntos
Apoptose , Sobrevivência Celular , Ciprofloxacina , Insulina , Piranos , Humanos , Ciprofloxacina/farmacologia , Apoptose/efeitos dos fármacos , Piranos/farmacologia , Linhagem Celular Tumoral , Insulina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Forkhead Box O1/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proliferação de Células/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Policetídeos de PoliéterRESUMO
Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.
Assuntos
Antineoplásicos , Apoptose , Ferroptose , Doadores de Óxido Nítrico , Neoplasias de Mama Triplo Negativas , Animais , Feminino , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Ferroptose/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/uso terapêutico , Doadores de Óxido Nítrico/síntese química , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Oxidiazóis/química , Oxidiazóis/farmacologia , Piranos/química , Piranos/farmacologiaRESUMO
To address lymphatic metastasis in lung cancer, we developed the Au@Gd-SiO2-HA-LyP-1 nanoprobe, assessing its diagnostic and therapeutic capabilities. This nanoprobe integrates a Au core with a Gd-SiO2 shell and dual-targeting HA-LyP-1 molecules. We evaluated its size, shape, and functional properties using various characterization techniques, alongside in vivo and in vitro toxicity tests. The spherical nanoprobes have a 50 nm diameter and contain 1.37% Gd. They specifically target lymphatic metastasis sites and tumor cells, showing enhanced MRI contrast and effective, targeted DOX delivery with reduced normal tissue toxicity. The Au@Gd-SiO2-HA-LyP-1 nanoprobe is a promising tool for diagnosing and treating lung cancer lymphatic metastasis, featuring dual-targeting and superior imaging capabilities.
Assuntos
Doxorrubicina , Ouro , Metástase Linfática , Dióxido de Silício , Humanos , Ouro/química , Animais , Camundongos , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/administração & dosagem , Dióxido de Silício/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Imageamento por Ressonância Magnética/métodos , Gadolínio/química , Piranos/química , Piranos/farmacologia , Linhagem Celular Tumoral , Peptídeos CíclicosRESUMO
Lipophilic shellfish toxins (LSTs) are widely distributed in marine environments worldwide, potentially threatening marine ecosystem health and aquaculture safety. In this study, two large-scale cruises were conducted in the Bohai Sea and the Yellow Sea, China, in spring and summer 2023 to clarify the composition, concentration, and spatial distribution of LSTs in the water columns and sediments. Results showed that okadaic acid (OA), dinophysistoxin-1 (DTX1) and/or pectenotoxin-2 (PTX2) were detected in 249 seawater samples collected in spring and summer. The concentrations of ∑LSTs in seawater were ranging of ND (not detected) -13.86, 1.60-17.03, 2.73-17.39, and 1.26-30.21 pmol L-1 in the spring surface, intermediate, bottom water columns and summer surface water layers, respectively. The detection rates of LSTs in spring and summer seawater samples were 97% and 100%, respectively. The high concentrations of ∑LSTs were mainly distributed in the north Yellow Sea and the northeast Bohai Sea in spring, and in the northeast Yellow Sea, the waters around Laizhou Bay and Rongcheng Bay in summer. Similarly, only OA, DTX1 and PTX2 were detected in the surface sediments. Overall, the concentration of ∑LSTs in the surface sediments of the northern Yellow Sea was higher than that in other regions. In sediment cores, PTX2 was mainly detected in the upper sediment samples, whereas OA and DTX1 were detected in deeper sediments, and LSTs can persist in the sediments for a long time. Overall, OA, DTX1 and PTX2 were widely distributed in the water column and surface sediments in the Bohai Sea and the Yellow Sea, China. The results of this study contribute to the understanding of spatial distribution of LSTs in seawater and sediment environmental media and provide basic information for health risk assessment of phycotoxins.
Assuntos
Monitoramento Ambiental , Sedimentos Geológicos , Toxinas Marinhas , Ácido Okadáico , Piranos , Água do Mar , China , Água do Mar/química , Sedimentos Geológicos/química , Toxinas Marinhas/análise , Ácido Okadáico/análise , Ácido Okadáico/análogos & derivados , Piranos/análise , Frutos do Mar/análise , Poluentes Químicos da Água/análise , Estações do Ano , Animais , Oceanos e Mares , Macrolídeos/análise , Toxinas de Poliéter , FuranosRESUMO
Salinomycin (Sal) has attracted considerable attention in the field of tumor treatment, especially for its inhibitory effect on cancer stem cells (CSCs) and drug-resistant tumor cells. However, its solubility and targeting specificity pose significant challenges to its pharmaceutical development. Sal-A6, a novel peptide-drug conjugate (PDC), was formed by linking the peptide A6 targeting the CSC marker CD44 with Sal using a specific linker. This conjugation markedly enhances the physicochemical properties of Sal and compared to Sal, Sal-A6 demonstrated a significantly increased activity against ovarian cancer. Furthermore, Sal-A6, employing a disulfide bond as a linker, exhibited bystander killing effect. Moreover, it induces substantial cytotoxic effect on both cancer stem cells and drug-resistant cells in addition to enhance chemosensitivity of resistant ovarian cancer cells. In summary, the results indicated that Sal-A6, a novel PDC derived from Sal, has potential therapeutic applications in the treatment of ovarian cancer and drug-resistant patients. Additionally, this discovery offers insights for developing PDC-type drugs using Sal as a foundation.
Assuntos
Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Células-Tronco Neoplásicas , Neoplasias Ovarianas , Peptídeos , Piranos , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Piranos/farmacologia , Piranos/química , Piranos/síntese química , Células-Tronco Neoplásicas/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Peptídeos/farmacologia , Peptídeos/química , Peptídeos/síntese química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Efeito Espectador/efeitos dos fármacos , Estrutura Molecular , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Policetídeos de PoliéterRESUMO
Lipophilic shellfish toxins (LSTs) threaten the ecosystem health and seafood safety. To comprehensively investigate the spatiotemporal distribution of common LSTs in phytoplankton, zooplankton and economic shellfish, three cruises were conducted in five typical offshore aquaculture regions of Shandong province, China, including Haizhou Bay, Jiaozhou Bay, Sanggou Bay, Sishili Bay and Laizhou Bay, in spring (March-April), summer (July-August) and autumn (November-December). This study revealed significant variability in the composition and content of LSTs in phytoplankton samples collected from different regions. Pectenotoxin-2 (PTX2), dinophysistoxin-1 (DTX1) and okadaic acid (OA) were mainly detected in the ranges of not detected (nd)-5045 pmol g-1 dry weight (dw), nd-159 pmol g-1 dw, and nd-154 pmol g-1 dw, respectively. In zooplankton, DTX1 and OA were the predominant components of LSTs, with the highest levels of ∑LSTs in spring ranging from nd to 406 pmol g-1 dw. Spearman's correlation analysis between LSTs and environmental factors indicated significant correlations for the contents of homo-yessotoxin (hYTX), gymnodimine-A (GYM-A), and spirolide-1 (SPX1) with these factors. Totally relatively low levels of LSTs with dominative DTX1 were detected in economic shellfish, which showed a low risk to seafood safety for human health.
Assuntos
Monitoramento Ambiental , Toxinas Marinhas , Ácido Okadáico , Fitoplâncton , Piranos , Frutos do Mar , Zooplâncton , Toxinas Marinhas/análise , China , Animais , Frutos do Mar/análise , Ácido Okadáico/análise , Ácido Okadáico/análogos & derivados , Piranos/análise , Análise Espaço-Temporal , Estações do Ano , Contaminação de Alimentos/análise , Toxinas de Poliéter , Furanos , MacrolídeosRESUMO
Cyclophosphamide is an anti-neoplastic drug that has shown competence in the management of a broad range of malignant tumors. In addition, it represents a keystone agent for management of immunological conditions. Despite these unique properties, induction of lung toxicity may limit its clinical use. Omarigliptin is one of the dipeptidyl peptidase-4 inhibitors that has proven efficacy in management of diabetes mellitus. Rosinidin is an anthocyanidin flavonoid that exhibited promising results in management of diseases characterized by oxidative stress, inflammation, and apoptosis. The present work investigated the possible effects of omarigliptin with or without rosinidin on cyclophosphamide-induced lung toxicity with an exploration of the molecular mechanisms that contribute to these effects. In a rodent model of cyclophosphamide elicited lung toxicity, the potential efficacy of omarigliptin with or without rosinidin was investigated at both the biochemical and the histopathological levels. Both omarigliptin and rosinidin exhibited a synergistic ability to augment the tissue antioxidant defenses, mitigate the inflammatory pathways, restore glucagon-like peptide-1 levels, modulate high mobility group box 1 (HMGB1)/receptors of advanced glycation end products (RAGE)/nuclear factor kappa B (NF-κB) axis, downregulate the fibrogenic mediators, and create a balance between the pathways involved in apoptosis and the autophagy signals in the pulmonary tissues. In conclusion, omarigliptin/rosinidin combination may be introduced as a novel therapeutic modality that attenuates the different forms of lung toxicities induced by cyclophosphamide.
Assuntos
Ciclofosfamida , Peptídeo 1 Semelhante ao Glucagon , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Piranos , Transdução de Sinais , Animais , Ciclofosfamida/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Masculino , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ratos , Fosfatidilinositol 3-Quinases/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Piranos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Antocianinas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Ratos Wistar , Pirimidinas/farmacologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Proteína Forkhead Box O1 , Compostos Heterocíclicos com 2 AnéisRESUMO
We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, or laninamivir). This observational study was conducted at 10 outpatient clinics across 9 prefectures in Japan during the 2012-2013 and 2019-2020 influenza seasons. Patients with influenza rapid antigen test positive were treated with one of four anti-influenza drugs. The type/subtype of influenza viruses were identified from MDCK or MDCK SIAT1 cell-grown samples using two-step real-time PCR. Daily self-reported body temperature after treatment were used to evaluate the duration of fever by treatment group and various underlying factors. Among 1742 patients <19 years old analyzed, 452 (26.0%) were A(H1N1)pdm09, 827 (48.0%) A(H3N2), and 463 (26.0%) influenza B virus infections. Among fours treatment groups, baloxavir showed a shorter median duration of fever compared to oseltamivir in univariate analysis for A(H1N1)pdm09 virus infections (baloxavir, 22.0 h versus oseltamivir, 26.7 h, P < 0.05; laninamivir, 25.5 h, and zanamivir, 25.0 h). However, this difference was not significant in multivariable analyses. For A(H3N2) virus infections, there were no statistically significant differences observed (20.3, 21.0, 22.0, and 19.0 h) uni- and multivariable analyses. For influenza B, baloxavir shortened the fever duration by approximately 15 h than NAIs (20.3, 35.0, 34.3, and 34.1 h), as supported by uni- and multivariable analyses. Baloxavir seems to have comparable clinical effectiveness with NAIs on influenza A but can be more effective for treating pediatric influenza B virus infections than NAIs.
Assuntos
Antivirais , Dibenzotiepinas , Febre , Guanidinas , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Vírus da Influenza B , Influenza Humana , Morfolinas , Oseltamivir , Piranos , Piridonas , Ácidos Siálicos , Triazinas , Zanamivir , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Antivirais/uso terapêutico , Antivirais/farmacologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/genética , Criança , Zanamivir/uso terapêutico , Zanamivir/análogos & derivados , Zanamivir/farmacologia , Triazinas/uso terapêutico , Triazinas/farmacologia , Guanidinas/uso terapêutico , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Piridonas/uso terapêutico , Dibenzotiepinas/uso terapêutico , Japão , Feminino , Masculino , Pré-Escolar , Oseltamivir/uso terapêutico , Febre/tratamento farmacológico , Febre/virologia , Adolescente , Morfolinas/uso terapêutico , Lactente , Estações do Ano , Tiepinas/uso terapêutico , Tiepinas/farmacologia , Oxazinas/uso terapêutico , Fatores de Tempo , Benzoxazinas/uso terapêuticoRESUMO
Salinomycin (Sal) has been recently discovered as a novel chemotherapeutic agent against various cancers including prostate cancer which is one of the most commonly diagnosed cancers affecting male populations worldwide. Herein we designed salinomycin nanocarrier (Sal-NPs) to extend its systemic circulation and to increase its anticancer potential. Prepared nanoform showed high encapsulation and sustained release profile for salinomycin. The present study elucidated the cytotoxicity and mechanism of apoptotic cell death of Sal-NPs against prostate cancer both in vitro and in vivo. At all measured concentrations, Sal-NPs showed more significant cytotoxicity to DU145 and PC3 cells than Sal alone. This effect was mediated by apoptosis, as confirmed by ROS generation, loss of MMP and cell cycle arrest at the G1 phase in both cells. Sal-NPs efficiently inhibited migration of PC3 and DU145 cells via effectively downregulating the epithelial mesenchymal transition. Also, the results confirmed that Sal-NPs can effectively inhibit the induction of Prostate adenocarcinoma in male Wistar rats. Sal-NPs treatment exhibited a decrease in tumour sizes, a reduction in prostate weight, and an increase in body weight, which suggests that Sal-NPs is more effective than salinomycin alone. Our results suggest that the molecular mechanism underlying the Sal-NPs anticancer effect may lead to the development of a potential therapeutic strategy for treating prostate adenocarcinoma.
Assuntos
Adenocarcinoma , Antineoplásicos , Apoptose , Portadores de Fármacos , Transição Epitelial-Mesenquimal , Nanopartículas , Neoplasias da Próstata , Piranos , Ratos Wistar , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Animais , Piranos/farmacologia , Piranos/administração & dosagem , Apoptose/efeitos dos fármacos , Humanos , Ratos , Linhagem Celular Tumoral , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Portadores de Fármacos/química , Nanopartículas/química , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Movimento Celular/efeitos dos fármacos , Células PC-3 , Sistemas de Liberação de Medicamentos/métodos , Policetídeos de PoliéterRESUMO
Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1ß in the kidney. Harp was a promising anti-HUA agent.
Assuntos
Glicosídeos , Hiperuricemia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piranos , Ácido Úrico , Animais , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Ácido Úrico/sangue , Masculino , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , Piranos/farmacologia , Piranos/uso terapêutico , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , NF-kappa B/metabolismo , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: An analysis was conducted in Japan to determine the most cost-effective neuraminidase inhibitor for the treatment of influenza virus infections from the healthcare payer's standpoint. OBJECTIVE: This study reanalysed the findings of a previous study that had some limitations (no probabilistic sensitivity analysis and quality of life scores measured by the EQ-5D-3L instead of the EQ-5D-5L) and used a decision tree model with only three health conditions. METHODS: This study incorporated new data from a network meta-analysis study into the first examination. The second examination involved constructing a new decision tree model encompassing seven health conditions and identifying costs, which consisted of medical costs and drug prices based on the 2020 version of the Japanese medical fee index. Effectiveness outcomes were measured using EQ-5D-5L questionnaires for adult patients with a history of influenza virus infections within a 14-day time horizon. Deterministic and probabilistic sensitivity analyses were performed to examine the uncertainty. RESULTS: In the first examination, the base-case cost-effectiveness analysis confirmed that oseltamivir outperformed laninamivir, zanamivir and peramivir, making it the most cost-effective neuraminidase inhibitor. The second examination revealed that oseltamivir dominated the other agents. Both deterministic and probabilistic sensitivity analyses showed robust results that validated oseltamivir as the most cost effective among the four neuraminidase inhibitors. CONCLUSIONS: This study thus reaffirms oseltamivir's position as the most cost-effective neuraminidase inhibitor for the treatment of influenza virus infections in Japan from the perspective of healthcare payment. These findings can help decision makers and healthcare providers in Japan.
Assuntos
Antivirais , Análise Custo-Benefício , Farmacoeconomia , Influenza Humana , Metanálise em Rede , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/economia , Antivirais/economia , Antivirais/uso terapêutico , Japão , Neuraminidase/antagonistas & inibidores , Oseltamivir/economia , Oseltamivir/uso terapêutico , Adulto , Árvores de Decisões , Zanamivir/uso terapêutico , Zanamivir/economia , Piranos/economiaRESUMO
In counter-current chromatography (CCC), linear scale-up is an ideal amplification strategy. However, when transferring from analytical to predictable preparative processes with high throughput, linear scale-up would be challenging due to limitations imposed by differences in instrument parameters, such as gravitational forces, tubing cross-section area, tubing length, column volume and flow rate. Some effective scale-up strategies have been studied for different instrument parameters, but so far, these scale-up works have only been tested on standard circular (SC) tubing. The previous research of our group found that rectangular horizontal (RH) tubing can double the separation efficiency compared with conventional SC tubing, and has industrial production potential. This paper used the separation of tilianin from Dracocephalum moldavica L. as an example to demonstrate how to scale up the optimized process from analytical SC tubing to preparative RH tubing. After systematic optimization of solvent systems, sample concentration and flow rate on the analytical CCC, the optimized parameters obtained were successfully transferred to the preparative CCC. The results showed that a crude sample of 2.07 g was successfully separated using a solvent system of n-hexane - ethyl acetate - ethanol - water (1:4:1:5, v/v/v/v) in reversed phase mode, and the three consecutive separations produced a total of 380 mg tilianin in 75 min with high purities of 98.3%, as analyzed by HPLC. The total throughput achieved from the analytical to semi-preparative scale was improved by 138 times (from 12 mg/h to 1.66 g/h), while the column volume was increased by only 46.5 times (from 15.5 mL to 720 mL). This is the successful application of CCC for the separation and purification of tilianin. Given that SC tubing is the traditional configuration for CCC columns, this study is a necessary step to prove the applicability of RH tubing columns for routine use and potential large-scale industrial applications.
Assuntos
Distribuição Contracorrente , Distribuição Contracorrente/métodos , Distribuição Contracorrente/instrumentação , Glicosídeos/isolamento & purificação , Glicosídeos/análise , Glicosídeos/química , Piranos/isolamento & purificação , Piranos/análise , Solventes/química , Hexanos/química , Lamiaceae/química , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Etanol/química , Acetatos/química , FlavonoidesRESUMO
Alzheimer's disease (AD) and other taupathies are neurodegenerative disorders associated with the amyloid deposition of the Tau protein in the brain. This amyloid formation may be inhibited by small molecules, which is recognized as one of the best therapeutic strategies to stop the progression of the disease. This work focuses on the small nucleating segment, hexapeptide-paired helical filament 6 (PHF6), responsible for Tau aggregation. Using computational modeling and classical molecular dynamics simulations, we show that PHF6 monomers collapse in water to form ß-sheet rich structures, and the main olive oil polyphenol oleuropein aglycone (OleA) prevents peptide aggregation significantly. We gradually increase the ratio of the PHF6-OleA from 1:1 to 1:3 and find that for the 1:1 ratio, the peptide monomers are prone to form aggregated structures, while for the 1:2 ratio, the formation of the extended ß-sheet structure is significantly less. For a 1:3 ratio of protein/OleA, the peptide residues are sufficiently crowded by OleA molecules through hydrogen bonding, hydrophobic interactions, and π-π stacking; hence, the peptide chains prefer to exist in a monomeric random coil conformation.
Assuntos
Simulação de Dinâmica Molecular , Azeite de Oliva , Proteínas tau , Azeite de Oliva/química , Proteínas tau/química , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inibidores , Oligopeptídeos/química , Humanos , Glucosídeos Iridoides/química , Glucosídeos Iridoides/farmacologia , Monoterpenos Ciclopentânicos , Acetatos , PiranosRESUMO
Omarigliptin (OMG) is an antidiabetic drug indicated for the treatment of type 2 diabetes mellitus. Forced degradation studies are practical experiments to evaluate the stability of drugs and to establish degradation profiles. Herein, we present the investigation of the degradation products (DPs) of OMG formed under various stress conditions. OMG was subjected to hydrolytic (alkaline and acidic), oxidative, thermal, and photolytic forced degradation. A stability-indicating ultra-fast liquid chromatography method was applied to separate and quantify OMG and its DPs. Five DPs were adequately separated and detected in less than 6 min, while other published methods detected four DPs. MS was applied to identify and obtain information on the structural elucidation of the DPs. Three m/z DPs confirmed previously published research, and two novel DPs were described in this paper. The toxicity of OMG and its DPs were investigated for the first time using in vitro cytotoxicity assays, and the sample under oxidative conditions presented significant cytotoxicity. Based on the results from forced degradation studies, OMG was found to be labile to hydrolysis, oxidation, photolytic, and thermal stress conditions. The results of this study contribute to the quality control and stability profile of OMG.
Assuntos
Estabilidade de Medicamentos , Compostos Heterocíclicos com 2 Anéis , Piranos , Cromatografia Líquida de Alta Pressão/métodos , Piranos/química , Piranos/análise , Piranos/toxicidade , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/análise , Compostos Heterocíclicos com 2 Anéis/toxicidade , Espectrometria de Massas/métodos , Humanos , Sobrevivência Celular/efeitos dos fármacos , Reprodutibilidade dos Testes , Hipoglicemiantes/química , Hipoglicemiantes/análise , Oxirredução , Modelos LinearesRESUMO
Karrikins and strigolactones govern plant development and environmental responses through closely related signaling pathways. The transcriptional repressor proteins SUPPRESSOR OF MAX2 1 (SMAX1), SMAX1-like2 (SMXL2), and D53-like SMXLs mediate karrikin and strigolactone signaling by directly binding downstream genes or by inhibiting the activities of transcription factors. In this study, we characterized the non-transcriptional regulatory activities of SMXL proteins in Arabidopsis. We discovered that SMAX1 and SMXL2 with mutations in their ethylene-response factor-associated amphiphilic repression (EAR) motif had undetectable or weak transcriptional repression activities but still partially rescued the hypocotyl elongation defects and fully reversed the cotyledon epinasty defects of the smax1 smxl2 mutant. SMAX1 and SMXL2 directly interact with PHYTOCHROME INTERACTION FACTOR 4 (PIF4) and PIF5 to enhance their protein stability by interacting with phytochrome B (phyB) and suppressing the association of phyB with PIF4 and PIF5. The karrikin-responsive genes were then identified by treatment with GR24ent-5DS, a GR24 analog showing karrikin activity. Interestingly, INDOLE-3-ACETIC ACID INDUCIBLE 29 (IAA29) expression was repressed by GR24ent-5DS treatment in a PIF4- and PIF5-dependent and EAR-independent manner, whereas KARRIKIN UPREGULATED F-BOX 1 (KUF1) expression was induced in a PIF4- and PIF5-independent and EAR-dependent manner. Furthermore, the non-transcriptional regulatory activity of SMAX1, which is independent of the EAR motif, had a global effect on gene expression. Taken together, these results indicate that non-transcriptional regulatory activities of SMAX1 and SMXL2 mediate karrikin-regulated seedling response to red light.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Furanos , Regulação da Expressão Gênica de Plantas , Luz , Plântula , Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/efeitos da radiação , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Plântula/genética , Plântula/efeitos da radiação , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Furanos/farmacologia , Furanos/metabolismo , Piranos/farmacologia , Piranos/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Hipocótilo/genética , Hipocótilo/crescimento & desenvolvimento , Hipocótilo/metabolismo , Mutação , Luz Vermelha , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
Parkinson's disease (PD) is a neurodegenerative condition characterized by both motor and non-motor symptoms. Although PD is commonly associated with a decline of dopaminergic neurons in the substantia nigra, other diagnostic criteria and biomarkers also exist. In the search for novel therapeutic agents, chromene and pyran derivatives have shown potential due to their diverse pharmacological activities. This study utilizes a comprehensive computational approach to investigate the viability of chromene/pyran compounds as potential treatments for PD. The drug-likeness characteristics of these molecules were analyzed using ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) studies. Molecular docking was performed against PDB ID: 2V5Z. The best three molecules chosen were compound 7, compound 24, and compound 67 have a binding energy of -6.7, -8.6, and -10.9 kcal/mol. Molecules demonstrating positive blood-brain barrier permeability, good solubility, and favorable binding affinity were further evaluated using Density Functional Theory (DFT) calculations and Molecular Dynamics (MD) simulations to assess their electronic structure and stability. DFT calculations indicated that molecule 82 has a dipole moment of 15.70 D. RMSD and RMSF results confirmed the stability of the complexes over a 100â ns simulation, with a maximum of 3 hydrogen bonds formed.
Assuntos
Benzopiranos , Teoria da Densidade Funcional , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Doença de Parkinson , Piranos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Piranos/química , Piranos/farmacologia , Piranos/metabolismo , Humanos , Benzopiranos/química , Benzopiranos/metabolismo , Benzopiranos/farmacologia , Estrutura Molecular , Barreira Hematoencefálica/metabolismo , Antiparkinsonianos/química , Antiparkinsonianos/farmacologia , Antiparkinsonianos/metabolismoRESUMO
The process of creating a series of 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a-q) involved reacting 6-methoxynaphthalen-2-ol (1), the appropriate aromatic aldehydes (2a-q), and malononitrile (3) in an absolute ethanol/piperidine solution under Ultrasonic irradiation. However, the attempt to create 3-amino-1-aryl-1H-benzo[f]chromene-2,8-dicarbonitrile (6a, d, e) was unsuccessful when 6-cyanonaphthalen-2-ol (5) was stirred at room temperature, reflux, Microwave irradiation, or Ultrasonic irradiation. In addition, the target molecules were screened against Staphylococcus aureus (MRSA), Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, Escherichia coli and Klebsiella pneumonia, as well as a panel of three human cancer cells lines such as MCF-7, HCT-116, HepG-2 and two normal cell lines HFL-1 and WI-38. The obtained results confirmed that the pyran derivatives (4 m, i, k) which have a double chlorine at 3,4/2,3/2,5-positions, a single halogen atom 3-Cl/4-Br (4c, e) and a double bromine at 3,5-positions with a single methoxy group at 2-position (4n), of phenyl ring, and, to a lesser extent, other pyran derivatives with monoihalogenated (4a, b, d, f), dihalogenated (4 g, h, j, l) or trisubstituent phenyl ring (4o, p, q). Furthermore, compounds 4b-e, g, i, j, m, and n showed negligible activity against the two normal cell lines, HFL-1 and WI-38. Moreover, compound 4 g exhibited the strongest antimicrobial activity among the other pyran derivatives (4a-f, g-q) when compared to Ciprofloxacin. The MIC was assessed and screened for compound 4 g, revealing bactericidal effects. Lastly, SAR and molecular docking were studied.
Assuntos
Antineoplásicos , Testes de Sensibilidade Microbiana , Piranos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Piranos/farmacologia , Piranos/química , Piranos/síntese química , Linhagem Celular Tumoral , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Simulação de Acoplamento Molecular , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/síntese química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Relação Estrutura-Atividade , Escherichia coli/efeitos dos fármacosRESUMO
The effect of salinomycin sodium alone and in combination with functional oils on performance and microbiota of broiler infected Eimeria were evaluated. 512 broilers were randomly assigned to 4 treatments (8 replicates, 16 birds/pen): a Control group (any additives); Ionophore group: salinomycin supplementation at 66 ppm (SS66); Ionophore +0.075% Functional oil (FO) group (SS66 + FO supplementation at 750 ppm); and Ionophore +0.10% FO group (SS66 + FO supplementation at 1000 ppm). At 14 days of age, birds were gavaged with 1 mL of a saline solution containing sporulated oocysts of E. tenella, E. acervulina and E. maxima. Performance indices were measured weekly. At 28 days, intestinal content was collected for microbiota analysis. Broilers of Control group presented the worst performance indices. Broilers of Ionophore + FO (0.075% and 0.10%) groups exhibited a higher BW at 28 days of age. The supplementation of Ionophore +0.075% FO resulted in a higher relative proportion of Firmicutes and a lower proportion of Actinobacteria in the ileum-jejunum. Lactobacillaceae was the dominant family in the jejunal, and ileal microbiotas of broilers fed diets supplemented with Ionophore, Ionophore +0.075% FO and Ionophore +0.10% FO. The supplementation of ionophore yielded higher numbers of Lactobacillaceae, Enterobactereaceae and Cloritridiaceae in the cecal. Ionophore associated with FO controlled the Lactobacillaceae, Enterobactereaceae and Cloritridiaceae families present in the cecum. Therefore, the combination of salinomycin with functional oil showed synergistic effect on performance and modulation of intestinal microbiota of broilers challenged with Eimeria.
Assuntos
Ração Animal , Galinhas , Coccidiose , Dieta , Suplementos Nutricionais , Eimeria , Microbioma Gastrointestinal , Policetídeos de Poliéter , Doenças das Aves Domésticas , Piranos , Animais , Galinhas/crescimento & desenvolvimento , Piranos/farmacologia , Piranos/administração & dosagem , Coccidiose/veterinária , Coccidiose/tratamento farmacológico , Coccidiose/parasitologia , Microbioma Gastrointestinal/efeitos dos fármacos , Eimeria/efeitos dos fármacos , Doenças das Aves Domésticas/parasitologia , Doenças das Aves Domésticas/microbiologia , Doenças das Aves Domésticas/tratamento farmacológico , Ração Animal/análise , Dieta/veterinária , Distribuição Aleatória , Ionóforos/farmacologia , Ionóforos/administração & dosagem , Coccidiostáticos/farmacologia , Coccidiostáticos/administração & dosagem , MasculinoRESUMO
The development of near-infrared organic fluorescent dyes with tunable emission profiles is highly required in the field of biological sensing and imaging. In this paper, we designed and synthesized two organic fluorescent dyes, DCM-1 and DCM-2, through the hybridization of indolizine and dicyanomethylene-4H-pyran skeleton. These two compounds show near-infrared fluorescence with emission maximum approximately at 640 and 680 nm, respectively. Notably, both DCM-1 and DCM-2 have specific responses to viscosity without being interfered by biological relevant species. Cell experiments demonstrate that DCM-1 and DCM-2 can detect dynamic changes in viscosity within living cells, suggesting their potential applications in chemical biology research.
Assuntos
Corantes Fluorescentes , Indolizinas , Piranos , Indolizinas/química , Indolizinas/síntese química , Viscosidade , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Humanos , Piranos/química , Espectrometria de Fluorescência , Células HeLa , Espectroscopia de Luz Próxima ao Infravermelho/métodosRESUMO
2,6-Diaryl-4H-tetrahydro-thiopyran-4-ones and corresponding sulfoxide and sulfone derivatives were designed to lower the major toxicity of their parent anti-kinetoplatidal diarylideneacetones through a prodrug effect. Novel diastereoselective methodologies were developed and generalized from diarylideneacetones and 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones to allow the introduction of a wide substitution profile and to prepare the related S-oxides. The in vitro biological activity and selectivity of diarylideneacetones, 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones, and their S-sulfoxide and sulfone metabolites were evaluated against Trypanosoma brucei brucei, Trypanosoma cruzi, and various Leishmania species in comparison with their cytotoxicity against human fibroblasts hMRC-5. The data revealed that the sulfides, sulfoxides, and sulfones, in which the Michael acceptor sites are temporarily masked, are less toxic against mammal cells while the anti-trypanosomal potency was maintained against T. b. brucei, T. cruzi, L. infantum, and L. donovani, thus confirming the validity of the prodrug strategy. The mechanism of action is proposed to be due to the involvement of diarylideneacetones in cascades of redox reactions involving the trypanothione system. After Michael addition of the dithiol to the double bonds, resulting in an elongated polymer, the latter-upon S-oxidation, followed by syn-eliminations-fragments, under continuous release of reactive oxygen species and sulfenic/sulfonic species, causing the death of the trypanosomal parasites in the micromolar or submicromolar range with high selectivity indexes.