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1.
Food Res Int ; 187: 114310, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38763627

RESUMO

Rice bran was modified by steam explosion (SE) treatment to investigate the impact of different steam pressure (0.4, 0.8, 1.2, 1.6, and 2.0 MPa) with rice bran through 60 mesh and rice bran pulverization (60, 80, and 100 mesh) with the steam pressure of 1.2 MPa on the structure, thermal stability, physicochemical and functional characteristics of insoluble dietary fiber (IDF) extracted from rice bran. IDF with SE treatment from scanning electron microscopy images showed a porous honeycomb structure, and lamellar shape in IDF became obvious with the increase of steam pressure. The relative crystallinity and polymerization degree of crystalline regions in IDF from rice bran with SE treatment from X-ray diffraction analysis were decreased. Differential scanning calorimetry results showed that thermal stability of IDF with SE treatment increased with the increase of crushing degree. The results of FT-IR also suggested that some glycosidic and hydrogen bonds in IDF could be broken, and some cellulose and hemicellulose were degraded during SE process. The physicochemical and functional characteristics of IDF, including water-holding capacity, oil-holding, glucose adsorption capacity, α-amylase and pancreatic lipase inhibition capacity were decreased with the increase of steam pressure and crushing degree. The swelling and nitrite adsorption capacities of IDF were increased first and then decreased with the increase of steam pressure. The physicochemical and functional characteristics of IDF from rice bran were improved after SE treatment, which might provide references for the utilization of IDF from rice bran with SE treatment.


Assuntos
Fibras na Dieta , Oryza , Tamanho da Partícula , Pressão , Vapor , Oryza/química , Fibras na Dieta/análise , Manipulação de Alimentos/métodos , Solubilidade , Difração de Raios X , Temperatura Alta , Espectroscopia de Infravermelho com Transformada de Fourier , Microscopia Eletrônica de Varredura , Varredura Diferencial de Calorimetria
2.
ACS Appl Mater Interfaces ; 16(23): 29917-29929, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38813785

RESUMO

Radiotherapy commonly causes damage to healthy tissues, particularly radiation-induced skin injury (RISI) that affects a significant majority of patients undergoing radiotherapy. Effective treatments for RISI are lacking. This study focuses on the pathogenesis of RISI, which primarily involves oxidative stress. Excessive reactive oxygen species (ROS) generation during radiation induces damage to biological macromolecules, triggering oxidative stress and inflammation. To address this, ergothioneine (EGT), a natural and biocompatibile thiol compound with excellent antioxidant activity, is explored as a potential radiation-protective agent. By utilizing its specific transport and absorption in the skin tissue, as well as its efficient and stable clearance of radiation-induced "ROS storm", EGT is combined with sodium hyaluronate (NaHA) to develop a novel radiation protective dressing suitable for the skin. This EGT-NaHA dressing demonstrates an effective ability to scavenge free radicals and reduce oxidative stress in vitro and in vivo, reducing cellular apoptosis and inflammation. These results demonstrate the protective properties of EGT against RISI, with far-reaching implications for research and development in the field of radioprotection.


Assuntos
Bandagens , Ergotioneína , Ácido Hialurônico , Estresse Oxidativo , Protetores contra Radiação , Pele , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Ergotioneína/farmacologia , Ergotioneína/química , Animais , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Pele/patologia , Camundongos , Humanos , Protetores contra Radiação/farmacologia , Protetores contra Radiação/química , Protetores contra Radiação/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/farmacologia , Antioxidantes/química , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/prevenção & controle
3.
Int Immunopharmacol ; 135: 112326, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38796967

RESUMO

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Recent research has revealed that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), containing specific miRNAs, possess immunomodulatory properties and have demonstrated therapeutic potential in the treatment of MS. This study aimed to investigate the role MSC-EVs, containing microRNA-181a-5p (miR-181a-5p) in both experimental autoimmune encephalomyelitis (EAE), an established animal model of MS, and lipopolysaccharide-stimulated BV2 microglia. We evaluated clinical symptoms and inflammatory responses in EAE mice following intrathecal injections of MSC-EVs. MSC-EVs containing miR-181a-5p were co-cultured with microglia to explore their impact on inflammation and cell pyroptosis. We validated the interaction between miR-181a-5p and its downstream regulators and conducted in vivo verification by injecting manipulated EVs containing miR-181a-5p into EAE mice. Our results demonstrated that MSC-EVs, containing miR-181a-5p reduced the clinical symptoms of EAE mice. Furthermore, we observed downregulation of miR-181a-5p in EAE model mice, and its expression was restored after treatment with MSC-EVs, which corresponded to suppressed microglial inflammation and pyroptosis. Additionally, EVs containing miR-181a-5p mitigated spinal cord injury and demyelination in EAE mice. Mechanistically, ubiquitin-specific protease 15 (USP15) exhibited high expression in EAE mice, and miR-181a-5p was specifically targeted and bound to USP15, thereby regulating the RelA/NEK7 axis. In conclusion, MSC-EVs containing miR-181a-5p inhibit microglial inflammation and pyroptosis through the USP15-mediated RelA/NEK7 axis, thus alleviating the clinical symptoms of EAE. These findings present a potential therapeutic approach for the treatment of MS.


Assuntos
Encefalomielite Autoimune Experimental , Vesículas Extracelulares , Camundongos Endogâmicos C57BL , MicroRNAs , Microglia , Animais , Encefalomielite Autoimune Experimental/terapia , Encefalomielite Autoimune Experimental/imunologia , MicroRNAs/genética , MicroRNAs/metabolismo , Vesículas Extracelulares/metabolismo , Camundongos , Microglia/metabolismo , Feminino , Células-Tronco Mesenquimais/metabolismo , Piroptose , Linhagem Celular , Esclerose Múltipla/terapia , Humanos , Modelos Animais de Doenças , Lipopolissacarídeos , Doenças Desmielinizantes/terapia
4.
Biomed Pharmacother ; 174: 116447, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38518606

RESUMO

Sepsis-induced acute respiratory distress syndrome (ARDS) causes significant fatalities worldwide and lacks pharmacological intervention. Alveolar fluid clearance (AFC) plays a pivotal role in the remission of ARDS and is markedly impaired in the pathogenesis of ARDS. Here, we demonstrated that erythropoietin could effectively ameliorate lung injury manifestations and lethality, restore lung function and promote AFC in a rat model of lipopolysaccharide (LPS)-induced ARDS. Moreover, it was proven that EPO-induced restoration of AFC occurs through triggering the total protein expression of ENaC and Na,K-ATPase channels, enhancing their protein abundance in the membrane, and suppressing their ubiquitination for degeneration. Mechanistically, the data indicated the possible involvement of EPOR/JAK2/STAT3/SGK1/Nedd4-2 signaling in this process, and the pharmacological inhibition of the pathway markedly eliminated the stimulating effects of EPO on ENaC and Na,K-ATPase, and subsequently reversed the augmentation of AFC by EPO. Consistently, in vitro studies of alveolar epithelial cells paralleled with that EPO upregulated the expression of ENaC and Na,K-ATPase, and patch-clamp studies further demonstrated that EPO substantially strengthened sodium ion currents. Collectively, EPO could effectively promote AFC by improving ENaC and Na,K-ATPase protein expression and abundance in the membrane, dependent on inhibition of ENaC and Na,K-ATPase ubiquitination, and resulting in diminishing LPS-associated lung injuries.


Assuntos
Canais Epiteliais de Sódio , Eritropoetina , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório , Sepse , ATPase Trocadora de Sódio-Potássio , Ubiquitinação , Animais , Canais Epiteliais de Sódio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Eritropoetina/farmacologia , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Ubiquitinação/efeitos dos fármacos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/metabolismo , Masculino , Ratos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Lipopolissacarídeos , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças
5.
Biochem Biophys Res Commun ; 705: 149742, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38460438

RESUMO

l-norleucine, an isomer of leucine, stimulates the anabolic process of insulin. However, it is not known if and how it improves insulin sensitivity and insulin resistance. This experiment describes the generation of an insulin resistance model using high glucose-induced cells and the administration of 1.0 mmol/L l-norleucine for 48 h, to observe the effects on metabolism and gene expression in skeletal muscle cells. The results showed that l-norleucine significantly increased mitochondrial ATP content, decreased the amount of reactive oxygen species (ROS) and promoted the expression of mitochondrial generation-related genes TFAM, AMPK, PGC-1α in cells under high glucose treatment; at the same time, l-norleucine also increased glucose uptake, suggesting that l-norleucine increased insulin sensitivity and improved insulin resistance. This study suggesting that l-norleucine improves insulin resistance by ameliorating oxidative stress damage of mitochondria, improving mitochondrial function, and improving insulin sensitivity in skeletal muscle cell caused by high glucose, rather than by altering mitochondrial efficiency.


Assuntos
Resistência à Insulina , Humanos , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Mitocôndrias/metabolismo , Insulina/metabolismo , Norleucina/metabolismo , Norleucina/farmacologia , Glucose/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Mitocôndrias Musculares/metabolismo
6.
J Glob Antimicrob Resist ; 36: 223-229, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38185239

RESUMO

OBJECTIVES: The dissemination of antibiotic resistance genes (ARGs) from the environment, including agricultural sources, is of increasing concern. In this study, we examined the antibiotic resistance profile and genomic sequence of a strain of Chryseobacterium indoltheticum obtained from an agricultural location. METHODS: The multidrug-resistant bacterial strain POL15 was isolated from the wastewater of a livestock farm in China. Whole-genome sequencing was performed followed by bioinformatics analyses to identify integrative and conjugative elements (ICEs) and ARGs. Mating assays were performed to analyse ICE transferability. RESULTS: Whole-genome sequencing and annotation showed that the genome of POL15 encodes ARGs. Additionally, an ICE named ICECiPOL15, which carries a class C ß-lactamase-encoding gene blaAQU, was identified in the POL15 genome. Genes encoding an integrase, an excisionase, a relaxase, a type IV coupling protein and conjugative transposon proteins involved in a type IV secretion system were also identified in ICECiPOL15. Sequence alignment revealed that ICECiPOL15 might have evolved from other Chryseobacterium species. The horizontal transferability of ICECiPOL15 was demonstrated by mating experiments between C. indoltheticum POL15 and Escherichia coli DL21. CONCLUSIONS: This study represents the first characterization of a mobilizable antibiotic resistance ICE in a species of C. indoltheticum and provides evidence that C. indoltheticum strains could be important reservoirs and vehicles for ARGs on livestock farms.


Assuntos
Chryseobacterium , Resistência beta-Lactâmica , Genômica , Farmacorresistência Bacteriana Múltipla/genética
7.
Int J Biol Macromol ; 258(Pt 2): 129036, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38151081

RESUMO

High-fat and high-fructose diet (HFFD) consumption can induce cognitive dysfunction and gut microbiota disorder. In the present study, the effects of the polysaccharides from the fruits of Lycium barbarum L. (LBPs) on HFFD-induced cognitive deficits and gut microbiota dysbiosis were investigated. The results showed that intervention of LBPs (200 mg/kg/day) for 14 weeks could significantly prevent learning and memory deficits in HFFD-fed mice, evidenced by a reduction of latency and increment of crossing parameters of platform quadrant in Morris water maze test. Moreover, oral administration of LBPs enhanced the expression of postsynaptic density protein 95 and brain-derived neurotrophic factor and reduced the activation of glial cells in hippocampus. Besides, LBPs treatment enriched the relative abundances of Allobaculum and Lactococcus and reduced the relative abundance of Proteobacteria in gut bacterial community of HFFD-fed mice, accompanied by increased levels of short-chain fatty acids (SCFAs) as well as expression of associated G protein-coupled receptors. Furthermore, LBPs intervention prevented insulin resistance, obesity and colonic inflammation. Finally, a significant correlation was observed among neuroinflammation associated parameters, gut microbiota and SCFAs through Pearson correlation analysis. Collectively, these findings suggested that the regulation of gut microbiota might be the potential mechanism of LBPs on preventing cognitive dysfunction induced by HFFD.


Assuntos
Disfunção Cognitiva , Microbioma Gastrointestinal , Lycium , Camundongos , Animais , Glicemia , Frutas , Frutose , Polissacarídeos/farmacologia , Dieta , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL
8.
Eur J Med Chem ; 265: 116079, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38150962

RESUMO

In this work, a series of novel coumarin-based derivatives were designed and synthesized as tubulin polymerization inhibitors targeting the colchicine binding site, and their antiproliferative activities against MGC-803, HCT-116 and KYSE30 cells were evaluated. Among them, the compound I-3 (MY-1442) bearing a 6-methoxy-1,2,3,4-tetrahydroquinoline group exhibited most potent inhibitory activities on MGC-803 (IC50 = 0.034 µM), HCT-116 (IC50 = 0.081 µM) and KYSE30 cells (IC50 = 0.19 µM). Further mechanism studies demonstrated that compound I-3 (MY-1442) could directly bind to the colchicine binding site of ß-tubulin to inhibit tubulin polymerization and microtubules at the cellular level. The results of molecular docking indicated there were well binding interactions between compound I-3 (MY-1442) and the colchicine binding site of ß-tubulin. Compound I-3 (MY-1442) also exhibited effective anti-proliferation, pro-apoptosis, and anti-migration abilities against gastric cancer cells MGC-803. Additionally, compound I-3 (MY-1442) could regulate the expression of cell cycle- and apoptosis-related proteins. Importantly, compound I-3 (MY-1442) could significantly inhibit tumor growth in the MGC-803 xenograft tumor model with a TGI rate of 65.5 % at 30 mg/kg/day. Taken together, this work suggested that the coumarin skeleton exhibited great potential to be a key pharmacophore of tubulin polymerization inhibitors for the discovery of anticancer agents.


Assuntos
Antineoplásicos , Neoplasias Gástricas , Humanos , Colchicina/farmacologia , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Simulação de Acoplamento Molecular , Neoplasias Gástricas/tratamento farmacológico , Polimerização , Proliferação de Células , Sítios de Ligação , Cumarínicos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais
9.
Food Funct ; 14(18): 8631-8645, 2023 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-37670564

RESUMO

The high-fat and high-fructose diet (HFFD) is a common diet in westernized societies, which worsens disturbances in gut microbiota and bile acid (BA) metabolism. Herein, the present study aimed to investigate the effects of the water extract of Lycium barbarum fruits (LBE) on gut microbiota and BA metabolism in mice with HFFD-induced neuroinflammation. The results showed that supplementation of LBE for 14 weeks remarkably ameliorated weight gain and insulin resistance and suppressed microglial activation and neural neuroinflammation induced by HFFD. The results of Morris water maze and Y-maze tests demonstrated that LBE attenuated HFFD-induced cognitive impairment. Moreover, LBE elevated hepatic BA biosynthesis and excretion of BAs and increased elimination of BAs via the feces. Notably, LBE supplementation resulted in the enrichment of tauroursodeoxycholic acid in the cortex and hippocampus. Furthermore, the 16S rDNA sequencing results showed that LBE could modulate the structure of gut microbiota, and in the meantime decrease the relative abundance of Clostridium_XlVa, which is associated with BA homeostasis. Additionally, LBE exerted neuroprotective effects involving the increment of Lactococcus, known as a potentially beneficial bacterium. These results demonstrated that LBE could ameliorate neuroinflammation and cognitive impairment in HFFD-induced mice through the gut-liver-brain axis, which might be due to the regulation of BA homeostasis and gut microbiota in mice.


Assuntos
Eixo Encéfalo-Intestino , Lycium , Animais , Camundongos , Doenças Neuroinflamatórias , Dieta , Ácidos e Sais Biliares , Frutose/efeitos adversos
10.
Turk J Gastroenterol ; 34(10): 1078-1087, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37737216

RESUMO

BACKGROUND/AIMS: This study aimed to assess obesity-related indices in predicting nonalcoholic fatty liver disease (NAFLD) in the United States. These indices were analyzed separately in previous studies, but evidence comparing them together was still lacking. MATERIALS AND METHODS: We analyzed data from 8126 individuals in the National Health and Nutrition Examination Survey (NHANES) database and measured their body mass index (BMI), body roundness index (BRI), a body shape index, conicity index, body adiposity index, abdominal volume index (AVI), and waist-hip ratio. We used logistic analyses with odds ratios to evaluate the association between obesity-related indices and NAFLD and compared their diagnostic ability by receiver operating characteristic (ROC) curves, areas under the curve (AUCs), and net reclassification improvement (NRI). RESULTS: The AVI had the highest AUC (0.835 at controlled attenuation parameter [CAP] scores 263 dB/m and 0.831 at CAP scores 285 dB/m) in the ROC curve analysis. The AVI also showed better discriminatory ability than BMI (NRI = 0.0331 at CAP scores 263 dB/m and 0.0328 at CAP scores 285 dB/m), the same as BRI (NRI = 0.0283 at CAP scores 263 dB/m and 0.0272 at CAP scores 285 dB/m). In males, AVI (AUC = 0.8501 at CAP scores 263 dB/m and 0.8466 at CAP scores 285 dB/m) and BRI (AUC = 0.8517 at CAP scores 263 dB/m and 0.8497 at CAP scores 285 dB/m) had better predictive ability than BMI and similar to females. This was consistent across different age and race groups. CONCLUSION: AVI and BRI were better predictors of NAFLD than BMI.


Assuntos
Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Masculino , Feminino , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Inquéritos Nutricionais , Obesidade/complicações , Índice de Massa Corporal , Curva ROC
11.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 35(7): 752-756, 2023 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-37545455

RESUMO

OBJECTIVE: To investigate the efficacy of arterial partial pressure of oxygen (PaO2), procalcitonin (PCT) combined with ROX index in predicting the timing of tracheal intubation in patients with acute severe pancreatitis (SAP). METHODS: A case-control study was conducted. A total of 148 patients with SAP admitted to Hunan Provincial People's Hospital from January 2019 to December 2022 were selected as the research objects. According to whether endotracheal intubation was used after admission during hospitalization, the patients were divided into the intubation group (102 cases) and non-intubation group (46 cases). Gender, age, white blood cell count (WBC), lymphocyte count (LYM), platelet count (PLT), C-reactive protein (CRP), hemoglobin (Hb), PCT, PaO2, arterial partial pressure of carbon dioxide (PaCO2), arterial bicarbonate ion (HCO3-) 1 day after admission, arterial lactic acid (Lac), lactate dehydrogenase (LDH), heart rate (HR), respiratory rate (RR), pulse oxygen saturation (SpO2), oxygenation index (PaO2/FiO2), blood pressure, worst ROX index (ROX index = SpO2/FiO2/RR) within 30 minutes of admission and 30 minutes before intubation of the two groups were measured. Multivariate Logistic regression was used to analyze the independent risk factors for the timing of endotracheal intubation in patients with SAP. The receiver operator characteristic curve (ROC curve) was used to determine the optimal predictive cut-off value for endotracheal intubation. RESULTS: There were no significant differences in age, gender, WBC, LYM, CRP, Hb, LDH, HR and blood pressure at admission between the two groups. The PLT, Lac, PCT and RR in the intubation group were significantly higher than those in the un-intubation group, and HCO3-, PaO2, SpO2, PaO2/FiO2, the worst ROX index within 30 minutes after admission and 30 minutes before intubation were significantly lower than those in the non-intubation group (all P < 0.05). Logistic regression analysis showed that the worst ROX index within 30 minutes before intubation was the largest negative influencing factor for the timing of tracheal intubation in SAP patients [odds ratio (OR) = 0.723, 95% confidence interval (95%CI) was 0.568-0.896, P = 0.000], followed by PaO2 (OR = 0.872, 95%CI was 0.677-1.105, P < 0.001). PCT was the positive influencing factor (OR = 1.605, 95%CI was 1.240-2.089, P < 0.001). ROC curve analysis showed that the area under the ROC curve (AUC) of PaO2, PCT, the worst ROX index within 30 minutes before intubation and the combination to evaluate the tracheal intubation time of patients with SAP were 0.715, 0.702, 0.722 and 0.808, the sensitivity was 78.1%, 75.0%, 81.5% and 89.3%, the specificity was 66.7%, 59.0%, 73.2% and 86.4%, and the best cut-off value was 60.23 mmHg (1 mmHg ≈ 0.133 kPa), 2.72 µg/L, 4.85, and 0.58, respectively. The AUC of the combination of PaO2, PCT and the worst ROX index within 30 minutes before intubation predicted the timing of tracheal intubation in patients with SAP was significantly greater than using each index alone (all P < 0.01). CONCLUSIONS: The worst ROX index within 30 minutes before intubation combined with PaO2 and PCT is helpful for clinicians to make a decision for tracheal intubation in patients with SAP.


Assuntos
Pancreatite , Pró-Calcitonina , Humanos , Oxigênio , Estudos de Casos e Controles , Pressão Parcial , Estudos Retrospectivos , Pancreatite/terapia , Intubação Intratraqueal , Prognóstico , Curva ROC
12.
Eur J Med Chem ; 259: 115673, 2023 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-37487305

RESUMO

Histone deacetylases, as a new class of anticancer targets, could maintain homeostasis by catalyzing histone deacetylation and play important roles in regulating the expression of target genes. Due to the fact that simultaneous intervention with dual tumor related targets could improve treatment effects, researches on innovative design of dual-target drugs are underway. HDAC is known as a "sensitizer" for the synergistic effects with other anticancer-target drugs because of its flexible structure design. The synergistic effects of HDAC inhibitor and other target inhibitors usually show enhanced inhibitory effects on tumor cells, and also provide new strategies to overcome multidrug resistance. Many research groups have reported that simultaneously inhibiting HDAC and other targets, such as tubulin, EGFR, could enhance the therapeutic effects. The o-aminobenzamide group is often used as a ZBG group in the design of HDAC inhibitors with potent antitumor effects. Given the prolonged inhibitory effects and reduced toxic side effects of HDAC inhibitors using o-aminobenzamide as the ZBG group, the o-aminobenzamide group is expected to become a more promising alternative to hydroxamic acid. In fact, o-aminobenzamide-based dual inhibitors of HDAC with different chemical structures have been extensively prepared and reported with synergistic and enhanced anti-tumor effects. In this work, we first time reviewed the rational design, molecular docking, inhibitory activities and potential application of o-aminobenzamide-based HDAC inhibitors with dual targeting capabilities in cancer therapy, which might provide a reference for developing new and more effective anticancer drugs.


Assuntos
Antineoplásicos , Neoplasias , Inibidores de Histona Desacetilases/química , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Antineoplásicos/química , Tubulina (Proteína) , Proliferação de Células , Neoplasias/tratamento farmacológico
13.
J Enzyme Inhib Med Chem ; 38(1): 2237701, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37489043

RESUMO

In this work, a series of novel arylamide derivatives containing piperazine moiety were designed and synthesised as tubulin polymerisation inhibitors. Among 25 target compounds, compound 16f (MY-1121) exhibited low nanomolar IC50 values ranging from 0.089 to 0.238 µM against nine human cancer cells. Its inhibitory effects on liver cancer cells were particularly evident with IC50 values of 89.42 and 91.62 nM for SMMC-7721 and HuH-7 cells, respectively. Further mechanism studies demonstrated that compound 16f (MY-1121) could bind to the colchicine binding site of ß-tubulin and directly act on ß-tubulin, thus inhibiting tubulin polymerisation. Additionally, compound 16f (MY-1121) could inhibit colony forming ability, cause morphological changes, block cell cycle arrest at the G2 phase, induce cell apoptosis, and regulate the expression of cell cycle and cell apoptosis related proteins in liver cancer cells. Overall, the promising bioactivities of compound 16f (MY-1121) make the novel arylamide derivatives have the value for further development as tubulin polymerisation inhibitors with potent anticancer activities.


Assuntos
Neoplasias Hepáticas , Tubulina (Proteína) , Humanos , Apoptose , Sítios de Ligação , Piperazina , Moduladores de Tubulina
14.
Bioorg Chem ; 137: 106580, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37149948

RESUMO

As a class of microtubule targeting agents, colchicine binding site inhibitors (CBSIs) are considered as promising drug candidates for cancer therapy. However, due to adverse reactions, there are currently no CBSIs approved by FDA for cancer treatment. Therefore, extensive efforts are still encouraged to find novel CBSIs with different chemical structures and better anticancer efficacies. In this work, we designed and synthesized a new coumarin-dihydroquinoxalone derivative, MY-673, and evaluated its anticancer potency in vitro and in vivo. We confirmed that MY-673 was a potent CBSI that it not only inhibited tubulin polymerization, but also exhibited significant inhibitory potency on the growth of 13 cancer cells with IC50 values from 11.7 nM to 395.9 nM. Based on the results of kinase panel screening, MY-673 could inhibit ERK (extracellular regulated protein kinases) pathways-related kinases. We further confirmed that MY-673 could inhibit ERK signaling pathway in MGC-803 and HGC-27 cells, and then affected the expression level of SMAD4 protein in TGF-ß (transforming growth factor ß) /SMAD (small mother against decapentaplegic) signaling pathway using the western blotting assay. In addition, compound MY-673 could effectively inhibit cell proliferation, migration and induce cell apoptosis. We also further confirmed the in vivo efficacy of MY-673 in inhibiting tumor growth using the MGC-803 xenograft tumor model. At 20 mg/kg, the TGI rate was 85.9%, and it did not cause obvious toxicity to the main organs of mice. Together, the results we report here indicated that MY-673 was a promising CBSI for cancer treatment, which was capable of inhibiting the ERK pathway with potent antiproliferative activities in vitro and in vivo.


Assuntos
Antineoplásicos , Neoplasias Gástricas , Humanos , Animais , Camundongos , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico , Moduladores de Tubulina/química , Sistema de Sinalização das MAP Quinases , Tubulina (Proteína)/metabolismo , Microtúbulos , Colchicina/metabolismo , Proliferação de Células , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade
15.
Mol Hum Reprod ; 29(6)2023 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-37068378

RESUMO

Strategies to maximize individual fertility chances are constant requirements of ART. In vitro folliculogenesis may represent a valid option to create a large source of immature ovarian follicles in ART. Efforts are being made to set up mammalian follicle culture protocols with suitable FSH stimuli. In this study, a new type of recombinant FSH (KN015) with a prolonged half-life is proposed as an alternative to canonical FSH. KN015 supports the in vitro development of mouse follicles from primary to preovulatory stage with higher efficiency than canonical FSH and enhanced post-fertilization development rates of the ovulated oocytes. The use of KN015 also allows us to compare the dynamic transcriptome changes in oocytes and granulosa cells at different stages, in vivo and in vitro. In particular, KN015 facilitates mRNA accumulation in growing mouse oocytes and prevents spontaneous luteinization of granulosa cells in vitro. Novel analyses of transcriptome changes in this study reveal that the in vivo oocytes were more efficient than in vitro oocytes in terms of maternal mRNA clearing during meiotic maturation. KN015 promotes the degradation of maternal mRNA during in vitro oocyte maturation, improves cytoplasmic maturation and, therefore, enhances embryonic developmental potential. These findings establish new transcriptome data for oocyte and granulosa cells at the key stages of follicle development, and should help to widen the use of KN015 as a valid and commercially available hormonal support enabling optimized in vitro development of follicles and oocytes.


Assuntos
RNA Mensageiro Estocado , Transcriptoma , Feminino , Camundongos , Animais , RNA Mensageiro Estocado/metabolismo , Oogênese/genética , Oócitos/metabolismo , Células da Granulosa , Hormônio Foliculoestimulante/genética , Hormônio Foliculoestimulante/farmacologia , Hormônio Foliculoestimulante/metabolismo , Meiose , Mamíferos
16.
Front Endocrinol (Lausanne) ; 14: 1135973, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37020592

RESUMO

Human fertilization begins when a capacitated spermatozoon binds to the zona pellucida (ZP) surrounding a mature oocyte. Defective spermatozoa-ZP interaction contributes to male infertility and is a leading cause of reduced fertilization rates in assisted reproduction treatments (ARTs). Human ejaculate contains millions of spermatozoa with varying degrees of fertilization potential and genetic quality, of which only thousands of motile spermatozoa can bind to the ZP at the fertilization site. This observation suggests that human ZP selectively interacts with competitively superior spermatozoa characterized by high fertilizing capability and genetic integrity. However, direct evidence for ZP-mediated sperm selection process is lacking. This study aims to demonstrate that spermatozoa-ZP interaction represents a crucial step in selecting fertilization-competent spermatozoa in humans. ZP-bound and unbound spermatozoa were respectively collected by a spermatozoa-ZP coincubation assay. The time-course data demonstrated that ZP interacted with a small proportion of motile spermatozoa. Heat shock 70 kDa protein 2 (HSPA2) and sperm acrosome associated 3 (SPACA 3) are two protein markers associated with the sperm ZP-binding ability. Immunofluorescent staining indicated that the ZP-bound spermatozoa had significantly higher expression levels of HSPA2 and SPACA3 than the unbound spermatozoa. ZP-bound spermatozoa had a significantly higher level of normal morphology, DNA integrity, chromatin integrity, protamination and global methylation when compared to the unbound spermatozoa. The results validated the possibility of applying spermatozoa-ZP interaction to select fertilization-competent spermatozoa in ART. This highly selective interaction might also provide diagnostic information regarding the fertilization potential and genetic qualities of spermatozoa independent of those derived from the standard semen analysis.


Assuntos
Interações Espermatozoide-Óvulo , Zona Pelúcida , Humanos , Masculino , Zona Pelúcida/metabolismo , Sêmen/metabolismo , Espermatozoides/metabolismo , Fertilização
17.
J Transl Med ; 21(1): 293, 2023 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-37121999

RESUMO

BACKGROUND: Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. METHODS: A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. RESULTS: PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. CONCLUSION: This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI.


Assuntos
Lesão Pulmonar Aguda , Ferroptose , Sepse , Animais , Camundongos , Antígenos CD59 , Ciclo-Oxigenase 2 , Lipopolissacarídeos/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Sepse/complicações , Fator 2 Ativador da Transcrição
18.
Environ Pollut ; 329: 121676, 2023 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-37098367

RESUMO

At a global scale, organisms are under threat due to various kinds of environmental changes, such as artificial light at night (ALAN), noise, climatic change and vegetation destruction. Usually, these changes co-vary in time and space and may take effect simultaneously. Although impacts of ALAN on biological processes have been well documented, our knowledge on the combined effects of ALAN and other environmental changes on animals remains limited. In this study, we conducted field experiments in semi-natural enclosures to explore the combined effects of ALAN and vegetation height on foraging behavior, vigilance, activity patterns and body weight in dwarf striped hamsters (Cricetulus barabensis), a nocturnal rodent widely distributed in East Asia. We find that ALAN and vegetation height affected different aspects of behavior. ALAN negatively affected search speed and positively affected handling speed, while vegetation height negatively affected giving-up density and positively affected body weight. ALAN and vegetation height also additively shaped total time spent in a food patch. No significant interactive effect of ALAN and vegetation height was detected. C. barabensis exposed to ALAN and short vegetation suffered a significant loss in body weight, and possessed a much narrower temporal niche (i.e. initiated activity later but became inactive earlier) than those under other combinations of treatments. The observed behavioral responses to ALAN and changes in vegetation height may bring fitness consequences, as well as further changes in structure and functioning of local ecosystems.


Assuntos
Ecossistema , Roedores , Animais , Poluição Luminosa , Fotoperíodo , Peso Corporal
19.
Exp Neurol ; 363: 114374, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36907352

RESUMO

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system and is marked by inflammation and damage to the myelin sheath surrounding nerve fibers. Recent studies have highlighted the therapeutic value of exosomes (Exos) obtained from bone marrow mesenchymal stem cells (BMSCs) in MS treatment. These BMSC-Exos contain biologically active molecules that show promising results in preclinical evaluations. The aim of this study was to investigate the mechanism of BMSC-Exos containing miR-23b-3p in both LPS-stimulated BV2 microglia and in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Exos were isolated from BMSCs, and their effects were evaluated in vitro by co-culturing with BV2 microglia. The interaction between miR-23b-3p and its downstream targets was also explored. The efficacy of BMSC-Exos was further verified in vivo by injecting the Exos into EAE mice. The results showed that BMSC-Exos containing miR-23b-3p reduced microglial pyroptosis in vivo by specifically binding to and suppressing the expression of NEK7. In vivo, BMSC-Exos containing miR-23b-3p alleviated the severity of EAE by decreasing microglial inflammation and pyroptosis via the repression of NEK7. These findings provide new insights into the therapeutic potential of BMSC-Exos containing miR-23b-3p for MS.


Assuntos
Encefalomielite Autoimune Experimental , Células-Tronco Mesenquimais , MicroRNAs , Esclerose Múltipla , Camundongos , Animais , Microglia/metabolismo , Encefalomielite Autoimune Experimental/terapia , Encefalomielite Autoimune Experimental/metabolismo , Piroptose , Células-Tronco Mesenquimais/metabolismo , Inflamação/metabolismo , Esclerose Múltipla/terapia , MicroRNAs/genética , MicroRNAs/metabolismo
20.
Biomed Pharmacother ; 162: 114593, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37001184

RESUMO

Multiple sclerosis (MS) is an autoimmune, inflammatory demyelinating disorder of the central nervous system. Accumulating evidence has underscored the therapeutic potential of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (BMSC-Exos) containing bioactive compounds in MS. Herein, the current study sought to characterize the mechanism of BMSC-Exos harboring miR-367-3p both in BV2 microglia by Erastin-induced ferroptosis and in experimental autoimmune encephalomyelitis (EAE), a typical animal model of MS. Exosomes were firstly isolated from BMSCs and identified for further use. BV2 microglia were co-cultured with miR-367-3p-containing BMSC-Exos, followed by an assessment of cell ferroptosis. Mechanistic exploration was furthered by the interaction of miR-367-3p and its downstream regulators. Lastly, BMSC-Exos harboring miR-367-3p were injected into EAE mice for in vivo validation. BMSC-Exos carrying miR-367-3p restrained microglial ferroptosis in vitro. Mechanistically, miR-367-3p could bind to Enhancer of zeste homolog 2 (EZH2) and restrain EZH2 expression, leading to the over-expression of solute carrier family 7 member 11 (SLC7A11). Meanwhile, over-expression of SLC7A11 resulted in Glutathione Peroxidase 4 (GPX4) activation and ferroptosis suppression. Ectopic expression of EZH2 in vitro negated the protective effects of BMSC-Exos. Furthermore, BMSC-Exos containing miR-367-3p relieved the severity of EAE by suppressing ferroptosis and restraining EZH2 expression in vivo. Collectively, our findings suggest that BMSC-Exos carrying miR-367-3p brings about a significant decline in microglia ferroptosis by repressing EZH2 and alleviating the severity of EAE in vivo, suggesting a possible role of miR-367-3p overexpression in the treatment strategy of EAE. AVAILABILITY OF DATA AND MATERIALS: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.


Assuntos
Encefalomielite Autoimune Experimental , Proteína Potenciadora do Homólogo 2 de Zeste , Ferroptose , Células-Tronco Mesenquimais , MicroRNAs , Animais , Camundongos , Encefalomielite Autoimune Experimental/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Células-Tronco Mesenquimais/metabolismo , Microglia/metabolismo , MicroRNAs/metabolismo
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