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1.
Diabetes Obes Metab ; 26(6): 2257-2266, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38497233

RESUMO

AIM: Non-alcoholic fatty liver is the most common cause of chronic liver disease. GPR40 is a potential therapeutic target for energy metabolic disorders. GPR40 is a potential therapeutic target for energy metabolic disorders. SZZ15-11 is a newly synthesized GPR40 agonist. In this study, we estimate the potency of SZZ15-11 in fatty liver treatment. METHODS: In vivo, diet-induced obese (DIO) mice received SZZ15-11 (50 mg/kg) and TAK875 (50 mg/kg) for 6 weeks. Blood glucose and lipid, hepatocyte lipid and liver morphology were analysed. In vitro, HepG2 cells and GPR40-knockdown HepG2 cells induced with 0.3 mM oleic acid were treated with SZZ15-11. Triglyceride and total cholesterol of cells were measured. At the same time, the AMPK pathway regulating triglycerides and cholesterol esters synthesis was investigated via western blot and quantitative polymerase chain reaction in both liver tissue and HepG2 cells. RESULTS: SZZ15-11 was found to not only attenuate hyperglycaemia and hyperlipidaemia but also ameliorate fatty liver disease in DIO mice. At the same time, SZZ15-11 decreased triglyceride and total cholesterol content in HepG2 cells. Whether examined in the liver of DIO mice or in HepG2 cells, SZZ15-11 upregulated AMPKα phosphorylation and then downregulated the expression of the cholesterogenic key enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibited acetyl-CoA carboxylase activity. Furthermore, SZZ15-11 promotes AMPK activity via [cAMP]i accumulation. CONCLUSION: This study confirmed that SZZ15-11, a novel GPR40 agonist, improves hyperlipidaemia and fatty liver, partially via Gs signalling and the AMPK pathway in hepatocytes.


Assuntos
Proteínas Quinases Ativadas por AMP , Homeostase , Hepatopatia Gordurosa não Alcoólica , Obesidade , Receptores Acoplados a Proteínas G , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Dieta Hiperlipídica , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triglicerídeos/metabolismo
2.
Acta Radiol ; 65(7): 681-688, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38715339

RESUMO

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with an extended Tofts linear (ETL) model for tissue and tumor evaluation has been established, but its effectiveness in evaluating the pancreas remains uncertain. PURPOSE: To understand the pharmacokinetics of normal pancreas and serve as a reference for future studies of pancreatic diseases. MATERIAL AND METHODS: Pancreatic pharmacokinetic parameters of 54 volunteers were calculated using DCE-MRI with the ETL model. First, intra- and inter-observer reliability was assessed through the use of the intra-class correlation coefficient (ICC) and coefficient of variation (CoV). Second, a subgroup analysis of the pancreatic DCE-MRI pharmacokinetic parameters was carried out by dividing the 54 individuals into three groups based on the pancreatic region, three groups based on age, and two groups based on sex. RESULTS: There was excellent agreement and low variability of intra- and inter-observer to pancreatic DCE-MRI pharmacokinetic parameters. The intra- and inter-observer ICCs of Ktrans, kep, ve, and vp were 0.971, 0.952, 0.959, 0.944 and 0.947, 0.911, 0.978, 0.917, respectively. The intra- and inter-observer CoVs of Ktrans, kep, ve, vp were 9.98%, 5.99%, 6.47%, 4.76% and 10.15%, 5.22%, 6.28%, 5.40%, respectively. Only the pancreatic ve of the older group was higher than that of the young and middle-aged groups (P = 0.042, 0.001), and the vp of the pancreatic head was higher than that of the pancreatic body and tail (P = 0.014, 0.043). CONCLUSION: The application of DCE-MRI with an ETL model provides a reliable, robust, and reproducible means of non-invasively quantifying pancreatic pharmacokinetic parameters.


Assuntos
Meios de Contraste , Imageamento por Ressonância Magnética , Pâncreas , Humanos , Meios de Contraste/farmacocinética , Imageamento por Ressonância Magnética/métodos , Masculino , Feminino , Pâncreas/diagnóstico por imagem , Reprodutibilidade dos Testes , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Aumento da Imagem/métodos , Variações Dependentes do Observador
3.
Eur Radiol ; 33(3): 1928-1937, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36219237

RESUMO

OBJECTIVES: To evaluate the potential of multi b-value DWI in predicting the prognosis of patients with locally advanced rectal cancer (LARC). METHODS: From 2015 to 2019, a total of 161 patients with LARC were enrolled and randomly sampled into a training set (n = 113) and validation set (n = 48). Multi b-value DWI (b = 0~1500 s/mm2) scans were postprocessed to generate functional parameters, including apparent diffusion coefficient (ADC), Dt, Dp, f, distributed diffusion coefficient (DDC), and α. Histogram features of each functional parameter were submitted into Least absolute shrinkage and selection operator (LASSO) and stepwise multivariate COX analysis to generate DWI_score based on the training set. The prognostic model was constructed with functional parameter, DWI_score, and clinicopathologic factors by using univariate and multivariate COX analysis on the training set and verified on the validation set. RESULTS: Multivariate COX analysis revealed that DWI_score was an independent indicator for 5-year progression-free survival (PFS, HR = 5.573, p < 0.001), but not for overall survival (OS, HR = 2.177, p = 0.051). No mean value of functional parameters was correlated with PFS or OS. Prognostic model for 5-year PFS based on DWI_score, TNM-stage, mesorectal fascia (MRF), and extramural venous invasion (EMVI) showed good performance both in the training set (AUC = 0.819) and validation set (AUC = 0.815). CONCLUSIONS: The DWI_score based on histogram features of multi b-value DWI functional parameters was an independent factor for PFS of LARC and the prognostic model with a combination of DWI_score and clinicopathologic factors could indicate the progression risk before treatment. KEY POINTS: • Mean value of functional parameters obtained from multi b-value DWI might not be useful to assess the prognosis of LARC. • The DWI_score based on histogram features of multi b-value DWI functional parameters was an independent prognosis factor for PFS of LARC. • Prognostic model based on DWI_score and clinicopathologic factors could indicate the progression risk of LARC before treatment.


Assuntos
Neoplasias Retais , Humanos , Prognóstico , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/terapia , Neoplasias Retais/patologia , Reto/patologia , Imagem de Difusão por Ressonância Magnética , Terapia Neoadjuvante , Estudos Retrospectivos
4.
BMC Palliat Care ; 22(1): 201, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38097993

RESUMO

BACKGROUND: Hemodialysis holds the highest incidence and prevalence rate in Taiwan globally. However, the implementation of advance care planning (ACP), advance directives (AD), and patient self-determination acts (PSDA) remains limited. Our objective was to examine the current status of ACP, AD and PSDA and potential opportunities for enhancement. METHODS: We developed a novel questionnaire to assess individuals' knowledge, attitudes, and intentions regarding ACP, AD, and PSDA. We also collected baseline characteristics and additional inquiries for correlation analysis to identify potential factors. Student's t-test and Analysis of Variance were employed to assess significance. RESULTS: Initially, a cohort of 241 patients was initially considered for inclusion in this study. Subsequently, 135 patients agreed to participate in the questionnaire study, resulting in 129 valid questionnaires. Among these respondents, 76 were male (59.9%), and 53 were female (41.1%). Only 13.2% had signed AD. A significant portion (85.3%) indicated that they had not discussed their dialysis prognosis with healthcare providers. Additionally, a mere 14% engaged in conversations about life-threatening decisions. Ninety percent believed that healthcare providers had not furnished information about ACP, and only 30% had discussed such choices with their families. The findings revealed that the average standardized score for ACP and AD goals was 84.97, while the attitude towards PSDA received a standardized score of 69.94. The intention score stood at 69.52 in standardized terms. Potential candidates for ACP initiation included individuals aged 50 to 64, possessing at least a college education, being unmarried, and having no history of diabetes. CONCLUSION: Patients undergoing hemodialysis exhibited a significant knowledge gap concerning ACP, AD, and the PSDA. Notably, a substantial number of dialytic patients had not received adequate information on these subjects. Nevertheless, they displayed a positive attitude, and a considerable proportion expressed a willingness to sign AD. It is imperative for nephrologists to take an active role in initiating ACP discussions with patients from the very beginning.


Assuntos
Planejamento Antecipado de Cuidados , Patient Self-Determination Act , Estados Unidos , Humanos , Masculino , Feminino , Intenção , Conhecimentos, Atitudes e Prática em Saúde , Diretivas Antecipadas , Diálise Renal
5.
Radiol Med ; 128(5): 520-527, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37101062

RESUMO

OBJECTIVE: To explore the relationship between unambiguous radiologic extranodal extension (rENE) and M1 staging in patients with metastatic PCa. METHODS: A respective analysis of 1073 patients of PCa N1 staging from January 2004 to May 2022 was retrospectively enrolled. They were divided into rENE + and rENE - groups and retrospectively analyzed the M staging with nuclear medicine data. The correlation index between unambiguous rENE and M1b staging was calculated. Logistic regression was used to evaluate the predictive performance of unambiguous rENE in M1b staging. ROC curves were used to investigate the relationship between unambiguous rENE and M staging in patients who underwent 68 Ga-PSMA PET/CT. RESULTS: A total of 1073 patients were included. Seven hundred and eighty patients were classified into the rENE + group (mean age, 69.6 years ± 8.7 [standard deviation]), and 293 were classified into rENE - group (mean age, 66.7 years ± 9.4 [standard deviation]). Relationship between unambiguous rENE and M1b existed (r = 0.58, 95%CI: 0.52-0.64, P < 0.05). Unambiguous rENE could be an independent predictor for M1b (OR = 13.64, 95%CI: 9.23-20.14, P < 0.05). The AUC of unambiguous rENE in predicting M1b and M staging was 0.835 and 0.915, respectively, in patients who underwent 68 Ga-PSMA PET/CT. CONCLUSIONS: Unambiguous rENE could be a strong biomarker to predict M1b and M staging in patients with PCa. When rENE came up, patients should perform nuclear medicine immediately, and a systematic treatment should be considered.


Assuntos
Extensão Extranodal , Neoplasias da Próstata , Masculino , Humanos , Idoso , Extensão Extranodal/patologia , Estudos Retrospectivos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Imageamento por Ressonância Magnética , Biomarcadores , Estadiamento de Neoplasias
6.
Plant Foods Hum Nutr ; 78(2): 320-328, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36947370

RESUMO

Antioxidative and antiaging abilities of probiotic fermented ginseng (PG) were evaluated in Caenorhabditis elegans (C. elegans). Lifespan and effect on heat stress and acute oxidative stress in C. elegans were significantly enhanced by PG. Antioxidative enzymes such as T-SOD, GSH-PX, CAT were significantly up-regulated, and MDA, ROS and apoptosis levels were significantly down-regulated. At the same time, PG exerted antioxidant and anti-aging activities by reducing the expression of DAF-2 mRNA and increasing the expression of SKN-1 and SOD-3 mRNA in C. elegans. In addition, the mechanism of antioxidative and antiaging activities of PG was explored through gut microbiota sequencing and untargeted metabolomics. The results of gut microbiota indicated that PG could significantly improve the composition and structure of microbes in the gut of C. elegans, and the relative abundance of beneficial bacteria was up-regulated. Untargeted metabolomic results elucidated that PG modulated antioxidant and antiaging activities through neuroactive ligand-receptor interaction, Citrate cycle (TCA cycle), pyruvate metabolism, ascorbate and aldarate metabolism and D-Arginine and D-ornithine metabolism of C. elegans. These results indicated that PG had excellent antioxidant and anti-aging activities, providing research value for the development of functional foods and improvement of aging-related diseases.


Assuntos
Proteínas de Caenorhabditis elegans , Microbioma Gastrointestinal , Panax , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/farmacologia , Envelhecimento , Estresse Oxidativo , Longevidade/fisiologia , Superóxido Dismutase/metabolismo , RNA Mensageiro , Espécies Reativas de Oxigênio/metabolismo
7.
Bioorg Chem ; 129: 106203, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36265352

RESUMO

Farnesoid X receptor (FXR) ligands have been actively pursued to treat metabolic disorders, liver and bile diseases, among others. Starting from a widely occurring natural product, oleanolic acid (OA), we discovered potent and selective FXR modulator from the 12ß-oxygenated OA alkyl esters, with the assistance of molecular modeling. The representative compound 7b modulated some FXR downstream genes involved in glucose and lipid metabolism in cells, and significantly improved hyperglycemia in KKay fat mice fed with high fat diet, through the reduction of mRNA expression of gluconeogenesis genes PEPCK and G6Pase. This study provides a new series of selective FXR modulator, as well as the in vitro and in vivo evidence for their potential to improve hyperglycemia in diabetic mice through FXR antagonism.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hiperglicemia , Hipoglicemiantes , Ácido Oleanólico , Receptores Citoplasmáticos e Nucleares , Animais , Camundongos , Ácidos e Sais Biliares/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ésteres/química , Ésteres/farmacologia , Ésteres/uso terapêutico , Hiperglicemia/tratamento farmacológico , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gluconeogênese/efeitos dos fármacos
8.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36232514

RESUMO

Hyperglycemia, oxidative stress, and inflammation play key roles in the onset and development of diabetic complications such as diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple organic selenium compound with anti-hyperglycemic, anti-inflammatory, and anti-oxidative activities. Nevertheless, in vitro, the role and molecular mechanism of DPDS on DN remains unknown. Therefore, we investigated the effects of DPDS on tert-butyl hydrogen peroxide (t-BHP)-induced oxidative stress and lipopolysaccharide (LPS)-induced inflammation in rat glomerular mesangial (HBZY-1) cells and explored the underlying mechanisms. DPDS attenuated t-BHP-induced cytotoxicity, concurrent with decreased intracellular ROS and MDA contents and increased SOD activity and GSH content. Moreover, DPDS augmented the protein and mRNA expression of Nrf2, HO-1, NQO1, and GCLC in t-BHP-stimulated HBZY-1 cells. In addition, DPDS suppressed LPS-induced elevations of intracellular content and mRNA expression of interleukin (IL)-6, IL-1ß and TNF-α. Furthermore, LPS-induced NFκB activation and high phosphorylation of JNK and ERK1/2 were markedly suppressed by DPDS in HBZY-1 cells. In summary, these data demonstrated that DPDS improves t-BHP-induced oxidative stress by activating the Nrf2/Keap1 pathway, and also improves LPS-induced inflammation via inhibition of the NFκB/MAPK pathways in HBZY-1 cells, suggesting that DPDS has the potential to be developed as a candidate for the prevention and treatment of DN.


Assuntos
Nefropatias Diabéticas , Selênio , Animais , Anti-Inflamatórios/farmacologia , Derivados de Benzeno , Nefropatias Diabéticas/metabolismo , Peróxido de Hidrogênio/metabolismo , Hipoglicemiantes/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/toxicidade , Células Mesangiais/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Compostos Organosselênicos , Estresse Oxidativo , RNA Mensageiro/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Selênio/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , terc-Butil Hidroperóxido/farmacologia
9.
Int J Mol Sci ; 23(24)2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36555580

RESUMO

Voglibose is an α-glycosidase inhibitor that improves postprandial hyperglycemia and increases glucagon-like peptide-1 (GLP-1) secretion in patients with type 2 diabetes. Recently, there has been increasing interest in the anti-inflammatory effects of voglibose on the intestine, but the underlying mechanism is not clear. This study evaluated the effects and mechanisms of voglibose on glycemic control and intestinal inflammation. Type 2 diabetic KKAy mice were treated with voglibose (1 mg/kg) by oral gavage once daily. After 8 weeks, glucose metabolism, levels of short-chain fatty acids (SCFAs), systematic inflammatory factors, intestinal integrity and inflammation were evaluated using hematoxylin and eosin staining, immunohistochemistry, immunofluorescence and Western blot analysis. Voglibose ameliorated glucose metabolism by enhancing basal- and glucose-dependent GLP-1 secretion. Several beneficial SCFAs, such as acetic acid and propionic acid, were increased by voglibose in the fecal sample. Additionally, voglibose notably decreased the proportion of pro-inflammatory macrophages and the expression of nuclear factor kappa B but increased the expression of tight junction proteins in the ileum, thus markedly improving intestinal inflammatory damage and reducing the systematic inflammatory factors. Ileal genomics and protein validation suggested that voglibose attenuated inositol-requiring protein 1α-X-box binding protein 1-mediated endoplasmic reticulum stress (ERS). Together, these results showed that voglibose enhanced the secretion of GLP-1, which contributed to the glycemic control in KKAy mice at least in part by regulating intestinal inflammation and the expression of ERS factors.


Assuntos
Diabetes Mellitus Tipo 2 , Camundongos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Inositol/farmacologia , Íleo/metabolismo , Glucose
10.
Int J Mol Sci ; 23(19)2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36233031

RESUMO

CXCR4 antagonists have been claimed to reduce mortality after myocardial infarction in myocardial infarction (MI) animals, presumably due to suppressing inflammatory responses caused by myocardial ischemia-reperfusion injury, thus, subsequently facilitating tissue repair and cardiac function recovery. This study aims to determine whether a newly designed CXCR4 antagonist DBPR807 could exert better vascular-protective effects than other clinical counterparts (e.g., AMD3100) to alleviate cardiac damage further exacerbated by reperfusion. Consequently, we find that instead of traditional continuous treatment or multiple-dose treatment at different intervals of time, a single-dose treatment of DBPR807 before reperfusion in MI animals could attenuate inflammation via protecting oxidative stress damage and preserve vascular/capillary density and integrity via mobilizing endothelial progenitor cells, leading to a desirable fibrosis reduction and recovery of cardiac function, as evaluated with the LVEF (left ventricular ejection fraction) in infarcted hearts in rats and mini-pigs, respectively. Thus, it is highly suggested that CXCR4 antagonists should be given at a single high dose prior to reperfusion to provide the maximal cardiac functional improvement. Based on its favorable efficacy and safety profiles indicated in tested animals, DBPR807 has a great potential to serve as an adjunctive medicine for percutaneous coronary intervention (PCI) therapies in acute MI patients.


Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Intervenção Coronária Percutânea , Receptores CXCR4 , Animais , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/etiologia , Ratos , Receptores CXCR4/antagonistas & inibidores , Volume Sistólico , Suínos , Porco Miniatura , Função Ventricular Esquerda
11.
J Biomed Sci ; 28(1): 81, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34819065

RESUMO

BACKGROUND: RAD51-dependent homologous recombination (HR) is one of the most important pathways for repairing DNA double-strand breaks (DSBs), and its regulation is crucial to maintain genome integrity. Elp1 gene encodes IKAP/ELP1, a core subunit of the Elongator complex, which has been implicated in translational regulation. However, how ELP1 contributes to genome maintenance is unclear. METHODS: To investigate the function of Elp1, Elp1-deficient mouse embryonic fibroblasts (MEFs) were generated. Metaphase chromosome spreading, immunofluorescence, and comet assays were used to access chromosome abnormalities and DSB formation. Functional roles of Elp1 in MEFs were evaluated by cell viability, colony forming capacity, and apoptosis assays. HR-dependent DNA repair was assessed by reporter assay, immunofluorescence, and western blot. Polysome profiling was used to evaluate translational efficiency. Differentially expressed proteins and signaling pathways were identified using a label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics approach. RESULTS: Here, we report that Elp1 depletion enhanced genomic instability, manifested as chromosome breakage and genotoxic stress-induced genomic DNA fragmentation upon ionizing radiation (IR) exposure. Elp1-deficient cells were hypersensitive to DNA damage and exhibited impaired cell proliferation and defective HR repair. Moreover, Elp1 depletion reduced the formation of IR-induced RAD51 foci and decreased RAD51 protein levels. Polysome profiling analysis revealed that ELP1 regulated RAD51 expression by promoting its translation in response to DNA damage. Notably, the requirement for ELP1 in DSB repair could be partially rescued in Elp1-deficient cells by reintroducing RAD51, suggesting that Elp1-mediated HR-directed repair of DSBs is RAD51-dependent. Finally, using proteome analyses, we identified several proteins involved in cancer pathways and DNA damage responses as being differentially expressed upon Elp1 depletion. CONCLUSIONS: Our study uncovered a molecular mechanism underlying Elp1-mediated regulation of HR activity and provides a novel link between translational regulation and genome stability.


Assuntos
Quebra Cromossômica , Dano ao DNA/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Biossíntese de Proteínas/genética , Rad51 Recombinase/genética , Reparo de DNA por Recombinação/genética , Animais , Fibroblastos , Instabilidade Genômica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Rad51 Recombinase/metabolismo
12.
Toxicol Appl Pharmacol ; 406: 115189, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800772

RESUMO

The potential therapeutic effect of histone deacetylase 3 (HDAC3) pharmacologic inhibition on diabetes has been focused recently. RGFP966, as a highly-selective HDAC3 inhibitor, its possible roles and underlying mechanism in the treatment of diabetes needs to be clarified. In this study, low-dose streptozotocin (STZ)-induced pre-diabetic mice were used to test the regulatory ability of RGFP966 in blood glucose and insulin. We isolated the islets both from normal C57BL/6 J mice and KKAy mice with spontaneous type 2 diabetes to determine the potency of RGFP966 on glucose-stimulated insulin secretion. NIT-1 pancreatic ß-cells induced by sodium palmitate (PA) were applied to identify the protective effects of RGFP966 against ß-cell apoptosis. The results showed that administration of RGFP966 in the pre-diabetic mice not only significantly reduced hyperglycemia, promoted phase I insulin secretion, improved morphology of islets, but also increased glucose infusion rate (GIR) during hyperglycemic clamp test. When treated in vitro, RGFP966 enhanced insulin secretion and synthesis in islets of normal C57BL/6J mice and diabetic KKAy mice. In addition, it partially attenuated PA-induced apoptosis in NIT-1 cells. Therefore, our research suggests that RGFP966, probably through selective inhibition of HDAC3, might serve as a novel potential preventive and therapeutic candidate for diabetes.


Assuntos
Acrilamidas/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Intolerância à Glucose/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Hipoglicemiantes/uso terapêutico , Fenilenodiaminas/uso terapêutico , Acrilamidas/farmacologia , Animais , Linhagem Celular , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Hipoglicemiantes/farmacologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Fenilenodiaminas/farmacologia
13.
J Chem Inf Model ; 60(3): 1202-1214, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32050066

RESUMO

Farnesoid X receptor (FXR) agonists can reverse dysregulated bile acid metabolism, and thus, they are potential therapeutics to prevent and treat nonalcoholic fatty liver disease. The low success rate of FXR agonists' R&D and the side effects of clinical candidates such as obeticholic acid make it urgent to discover new chemotypes. Unfortunately, structure-based virtual screening (SBVS) that can speed up drug discovery has rarely been reported with success for FXR, which was likely hindered by the failure in addressing protein flexibility. To address this issue, we devised human FXR (hFXR)-specific ensemble learning models based on pose filters from 24 agonist-bound hFXR crystal structures and coupled them to traditional SBVS approaches of the FRED docking plus Chemgauss4 scoring function. It turned out that the hFXR-specific pose filter ensemble (PFE) was able to improve ligand enrichment significantly, which rendered 3RUT-based SBVS with its PFE the ideal approach for FXR agonist discovery. By screening of the Specs chemical library and in vitro FXR transactivation bioassay, we identified a new class of FXR agonists with compound XJ034 as the representative, which would have been missed if the PFE was not coupled. Following that, we performed in-depth biological studies which demonstrated that XJ034 resulted in a downtrend of intracellular triglyceride in vitro, significantly decreased the serum/liver TG in high fat diet-induced C57BL/6J obese mice, and more importantly, showed metabolic stabilities in both plasma and liver microsomes. To provide insight into further structure-based lead optimization, we solved the crystal structure of hFXR complexed with compound XJ034, uncovering a unique hydrogen bond between compound XJ034 and residue Y375. The current work highlights the power of our pose filter-based ensemble learning approach in terms of scaffold hopping and provides a promising lead compound for further development.


Assuntos
Fígado , Receptores Citoplasmáticos e Nucleares , Animais , Ligantes , Aprendizado de Máquina , Camundongos , Camundongos Endogâmicos C57BL
14.
BMC Med Imaging ; 20(1): 97, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32799809

RESUMO

BACKGROUND: To testify whether multi-b-values diffusion-weighted imaging (DWI) can be used to ultra-early predict treatment response of concurrent chemoradiotherapy (CCRT) in cervical cancer patients and to assess the predictive ability of concerning parameters. METHODS: Fifty-three patients with biopsy proved cervical cancer were retrospectively recruited in this study. All patients underwent pelvic multi-b-values DWI before and at the 3rd day during treatment. The apparent diffusion coefficient (ADC), true diffusion coefficient (Dslow), perfusion-related pseudo-diffusion coefficient (Dfast), perfusion fraction (f), distributed diffusion coefficient (DDC) and intravoxel diffusion heterogeneity index(α) were generated by mono-exponential, bi-exponential and stretched exponential models. Treatment response was assessed based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1) at 1 month after the completion of whole CCRT. Parameters were compared using independent t test or Mann-Whitney U test as appropriate. Receiver operating characteristic (ROC) curves was used for statistical evaluations. RESULTS: ADC-T0 (p = 0.02), Dslow-T0 (p <  0.01), DDC-T0 (p = 0.03), ADC-T1 (p <  0.01), Dslow-T1 (p <  0.01), ΔADC (p = 0.04) and Δα (p <  0.01) were significant lower in non-CR group patients. ROC analyses showed that ADC-T1 and Δα exhibited high prediction value, with area under the curves of 0.880 and 0.869, respectively. CONCLUSIONS: Multi-b-values DWI can be used as a noninvasive technique to assess and predict treatment response in cervical cancer patients at the 3rd day of CCRT. ADC-T1 and Δα can be used to differentiate good responders from poor responders.


Assuntos
Quimiorradioterapia/métodos , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Curva ROC , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias do Colo do Útero/patologia
15.
Phytother Res ; 34(5): 1166-1174, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31833107

RESUMO

Berberine (BBR), a small alkaloid, is used as a hypoglycemic agent in China. Stachyose (Sta), a Rehmannia glutinosa oligosaccharide, acts as a prebiotic. This study aimed to evaluate whether BBR combined with Sta produced better glycometabolism than BBR alone, and explored the effects on gut microbiota and metabolomics. Type-2 diabetic db/db mice were administered BBR (100 mg/kg), Sta (200 mg/kg), or both by gavage once daily. Glucose metabolism, the balance of α- and ß-cells, and mucin-2 expression were ameliorated by combined treatment of BBR and Sta, with stronger effects than upon treatment with BBR alone. The microbial diversity and richness were altered after combined treatment and after treatment with BBR alone. The abundance of Akkermansia muciniphila was increased by combined treatment compared to treatment with BBR alone, while the levels of the metabolite all-trans-heptaprenyl diphosphate were decreased and the levels of fumaric acid were increased, which both showed a strong correlation with A. muciniphila. In summary, BBR combined with Sta produced better glycometabolism than BBR alone through modulating gut microbiota and fecal metabolomics, and may aid in the development of a novel pharmaceutical strategy for treating Type 2 diabetes mellitus.


Assuntos
Berberina/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Fezes/química , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolômica/métodos , Oligossacarídeos/uso terapêutico , Animais , Berberina/farmacologia , Masculino , Camundongos , Oligossacarídeos/farmacologia
16.
Diabetes Obes Metab ; 21(11): 2553-2563, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31364797

RESUMO

AIMS: To evaluate a novel tetrahydroisoquinoline derivative YR4-42 as a selective peroxisome proliferator-activated receptor γ (PPARγ) modulator (SPPARM) and explore its anti-diabetic effects in vitro and in vivo. MATERIALS AND METHODS: Using two standard full PPARγ agonists rosiglitazone and pioglitazone as controls, the PPARγ binding affinity and transactivation action of YR4-42 were evaluated using biochemical and cell-based reporter gene assays. The capacity of YR4-42 to recruit coactivators of PPARγ was also assessed. The effects of YR4-42 on adipogenesis and glucose consumption and PPARγ Ser273 phosphorylation were investigated in 3T3-L1 adipocytes. The effects of YR4-42 and pioglitazone, serving as positive control, on glucose and lipids metabolism were investigated in high-fat diet-induced obese (DIO) C57BL/6J mice. The expression of PPARγ target genes involved in glucose and lipid metabolism was also assessed in vitro and in vivo. RESULTS: In vitro biochemical and cell-based functional assays showed that YR4-42 has much weaker binding affinity, transactivation, and recruitment to PPARγ of the coactivators thyroid hormone receptor-associated protein complex 220 kDa component (TRAP220) and PPARγ coactivator 1-α (PGC1α) compared to full agonists. In 3 T3-L1 adipocytes, YR4-42 significantly improved glucose consumption without a lipogenesis effect, while blocking tumour necrosis factor α-mediated phosphorylation of PPARγ at Ser273, thereby upregulating the expression of the PPARγ Ser273 phosphorylation-dependent genes. Furthermore, in DIO mice, oral administration of YR4-42 ameliorated the hyperglycaemia, with a similar insulin sensitization effect to that of pioglitazone. Importantly, YR4-42 also improved hyperlipidaemia-associated hepatic steatosis without weight gain, which avoids a major side effect of pioglitazone. Thus, YR4-42 appeared to selectively modulate PPARγ responses. This finding was supported by the gene expression analysis, which showed that YR4-42 selectively targets PPARγ-regulated genes mapped to glucose and lipid metabolism in DIO mice. CONCLUSIONS: We conclude that YR4-42 is a novel anti-diabetic drug candidate with significant advantages compared to standard PPARγ agonists. YR4-42 should be further investigated in preclinical and clinical studies.


Assuntos
Dislipidemias/metabolismo , Hiperglicemia/metabolismo , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Tetra-Hidroisoquinolinas/farmacologia , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Fígado Gorduroso/metabolismo , Células HEK293 , Humanos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos
17.
Eur Radiol ; 29(2): 857-865, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30039224

RESUMO

OBJECTIVES: To determine and validate alanine aminotransferase (ALT)-adapted dual cut-offs of liver stiffness measurements (LSMs) for assessing liver fibrosis with two-dimensional shear wave elastography (2D-SWE) in patients with chronic hepatitis B (CHB) infection. METHODS: Patients with CHB infection who underwent liver biopsy to assess liver fibrosis were consecutively included. 2D-SWE confirmation thresholds with a positive likelihood ratio ≥10 and 2D-SWE exclusion thresholds with a negative likelihood ratio ≤0.1 were identified to rule in or rule out significant fibrosis and cirrhosis, respectively. RESULTS: The first 515 patients (index cohort) and the next 421 patients (validation cohort) were included in the final analysis. The low and high cut-offs to rule out and rule in patients with significant fibrosis (≥ F2) were 5.4 kPa and 9.0 kPa, respectively, in patients with ALT levels ≤ 2 × the upper limit of normal (ULN) and 7.1 kPa and 11.2 kPa in patients with ALT levels > 2 × ULN. For cirrhosis (F4), the corresponding values were 8.1 kPa and 12.3 kPa in patients with ALT levels ≤ 2 × ULN and 11.9 kPa and 24.7 kPa in patients with ALT levels > 2 × ULN. The dual cut-off values showed an overall accuracy of more than 90% for diagnosis of the presence or absence of significant fibrosis and cirrhosis in the index and validation cohorts. There were no significant differences in the accuracy values between the cohorts (all p>0.05). CONCLUSION: The ALT-adapted dual cut-offs of LSMs showed high accuracy for diagnosis of the presence or absence of significant fibrosis and cirrhosis in patients with CHB infection. KEY POINTS: • The ALT-adapted dual cut-off values of LSMs showed high accuracy for diagnosis of the presence or absence of significant fibrosis and cirrhosis. • ALT levels did not influence the overall diagnostic accuracy for predicting significant fibrosis and cirrhosis. • The ALT-adapted dual cut-offs in patients with ALT levels > 2 × ULN were markedly higher than those in patients with ALT levels ≤ 2 × ULN.


Assuntos
Alanina Transaminase/sangue , Técnicas de Imagem por Elasticidade/métodos , Hepatite B Crônica/diagnóstico por imagem , Hepatite B Crônica/patologia , Cirrose Hepática/diagnóstico por imagem , Adolescente , Adulto , Idoso , Biópsia/métodos , Feminino , Hepatite B Crônica/enzimologia , Humanos , Cirrose Hepática/enzimologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Adulto Jovem
18.
Exp Cell Res ; 371(1): 205-213, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30098330

RESUMO

Recently, SIRT5 was reported to be a predominant desuccinylase and demalonylase in mitochondria. Ablation of SIRT5 enhances the systemic succinylation and malonylation of mitochondrial proteins, including various metabolic enzymes; however, its function in pancreatic ß cells has not yet been clarified. In this study, we evaluated the effects of SIRT5 overexpression on glucolipotoxicity-induced apoptosis in ß cell lines. Full-length SIRT5, which preferentially targeted to mitochondria and partially to the nucleus and cytoplasm, was overexpressed in NIT-1 cells. Chronic exposure to excess palmitate and glucose (High-PA-G) induced apoptosis and suppressed glucose-stimulated insulin secretion in ß cells. SIRT5 overexpression significantly alleviated apoptosis under the High-PA-G condition, accompanied by suppressed Caspase 3 activity and reduced malondialdehyde levels. SIRT5 overexpression also improved ß cell secretory capacity in response to glucose under the High-PA-G condition, suggesting its protective role in ß cell function. Furthermore, SIRT5 overexpression reversed the decreasing trend of anti-apoptotic factors BCL-2 and BCL-XL expression under High-PA-G condition. Further regulation mechanisms between SIRT5 and these anti-apoptotic factors remains to be explored in future studies. Our data reveal that SIRT5 is a potentially protective factor for pancreatic ß cells against glucolipotoxicity-induced apoptosis and cell dysfunction.


Assuntos
Diabetes Mellitus Experimental/genética , Regulação da Expressão Gênica , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Mitocôndrias/metabolismo , Sirtuínas/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Glucose/farmacologia , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Malondialdeído/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Ácido Palmítico/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Transdução de Sinais , Sirtuínas/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína de Morte Celular Associada a bcl/genética , Proteína de Morte Celular Associada a bcl/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
19.
J Cell Mol Med ; 22(8): 3768-3781, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29754422

RESUMO

The zinc finger E-box-binding homeobox 1 (ZEB1) induced the epithelial-mesenchymal transition (EMT) and altered ZEB1 expression could lead to aggressive and cancer stem cell (CSC) phenotypes in various cancers. Tissue specimens from 96 prostate cancer patients were collected for immunohistochemistry and CD34/periodic acid-Schiff double staining. Prostate cancer cells were subjected to ZEB1 knockdown or overexpression and assessment of the effects on vasculogenic mimicry formation in vitro and in vivo. The underlying molecular events of ZEB1-induced vasculogenic mimicry formation in prostate cancer were then explored. The data showed that the presence of VM and high ZEB1 expression was associated with higher Gleason score, TNM stage, and lymph node and distant metastases as well as with the expression of vimentin and CD133 in prostate cancer tissues. Furthermore, ZEB1 was required for VM formation and altered expression of EMT-related and CSC-associated proteins in prostate cancer cells in vitro and in vivo. ZEB1 also facilitated tumour cell migration, invasion and clonogenicity. In addition, the effects of ZEB1 in prostate cancer cells were mediated by Src signalling; that is PP2, a specific inhibitor of the Src signalling, dose dependently reduced the p-Src527 level but not p-Src416 level, while ZEB1 knockdown also down-regulated the level of p-Src527 in PC3 and DU-145 cells. PP2 treatment also significantly reduced the expression of VE-cadherin, vimentin and CD133 in these prostate cancer cells. Src signalling mediated the effects of ZEB1 on VM formation and gene expression.

20.
Int J Cancer ; 142(10): 2130-2138, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29238974

RESUMO

To further assess the efficacy and safety of recombinant human endostatin (rh-endostatin), a Phase III, multicenter, prospective, randomized, controlled clinical trial was conducted. Patients to be treated with neoadjuvant docetaxel and epirubicin (DE) or DE plus rh-endostatin (DEE) were eligible for this trial. The primary endpoint was clinical/pathological response. Secondary endpoints included adverse events and quality of life (QOL). Finally, 803 patients were enrolled and randomly assigned to receive DE (n = 402) or DEE (n = 401) regimen. After three cycles of neoadjuvant therapy, "complete response" achieved in 14.2% of patients in DEE group versus 6.7% in DE group, "partial response" achieved in 76.8% versus 71.1%, while "stable disease" in 6.0% versus 18.9%, "progressive disease" in 3.0% versus 3.2% of patients. The rate of objective response in DEE and DE group was 91.0% and 77.9%, respectively (p < 0.001). In spite of a relatively higher pathological complete response achieved following the combination therapy, no significant difference was found between two arms. Adverse events were mostly of Grades 1-2. No significant difference in adverse event and QOL was found between the two arms. In conclusion, the combination of chemotherapy and rh-endostatin achieved better outcomes than chemotherapy alone, and thus can be considered as a promising therapeutic strategy for breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Docetaxel/administração & dosagem , Endostatinas/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neovascularização Patológica/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Prospectivos , Qualidade de Vida
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