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Background: Physical activity (PA) exerts an important influence on glycemic control in type 2 diabetes (T2D) patients. Alterations in body composition in patients with T2D may be involved in the overall pathophysiologic process, but PAs and alterations in body composition have been poorly studied. Methods: A total of 615 patients with T2D were selected by convenient sampling. The patients were investigated with the International Physical Activity Questionnaire (IPAQ-S). Moreover, biochemical indices were collected, and the progression of the body composition of the subjects was determined via dual-energy X-ray absorptiometry (DXA). The variables included lumbar bone mineral density (LSBMD), femoral neck bone mineral density (FNBMD), hip bone mineral density (HBMD), whole-body bone mineral density (TBMD), limb skeletal muscle mass index (ASMI), whole-body fat percentage (B-FAT) and trunk fat percentage (T-FAT). Moreover, the levels of physical activity (high level of physical activity [H-PA], medium level of physical activity [M-PA] and low level of physical activity [L-PA]) were divided into three groups to analyze the changes in patient body composition with changes in physical activity level. Results: One-way analysis of variance showed that ß-CTX, TP1NP, HbA1c, B-FAT and T-FAT increased significantly (p<0.05), while 25(OH)D, LSBMD, FNBMD, HBMD, TBMD and ASMI decreased significantly (p<0.001) with the decrease of physical activity. However, there was no significant difference in serum lipids between lnHOMA-ir and lnHOMA-ß (p>0.05). Multiple linear regression model was established to gradually adjust for clinical confounding factors. It was found that physical activity level was independently positively correlated with LSBMD, FNBMD, HBMD, TBMD, and ASMI, and was independently negatively correlated with B-FAT and T-FAT in patients with type 2 diabetes. Conclusion: A lack of physical activity is an independent risk factor for decreased bone mineral density, decreased skeletal muscle content and increased fat content in patients with T2D.
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Polian vesicle is thought to produce coelomocytes and contribute to the sea cucumber's immune system. Our previous work has indicated that polian vesicle was responsible for cell proliferation at 72 h post pathogenic challenge. However, the transcription factors related to the activation of effector factors and the molecular process behind this remained unknown. In this study, to reveal the early functions of polian vesicle in response to the microbe, a comparative transcriptome sequencing of polian vesicle in V. splendidus-challenged Apostichopus japonicus, including normal group (PV 0 h), pathogen challenging for 6 h (PV 6 h) and 12 h (PV 12 h) was performed. Compared PV 0 h to PV 6 h, PV 0 h to PV 12 h, and PV 6 h to PV 12 h, we found 69, 211, and 175 differentially expressed genes (DEGs), respectively. KEGG enrichment analysis revealed the DEGs, including several transcription factors such as fos, FOS-FOX, ATF2, egr1, KLF2, and Notch3 between PV 6 h and PV 12 h were consistently enriched in MAPK, Apelin and Notch3 signaling pathways related to cell proliferation compared with that in PV 0 h. Important DEGs involved in cell growth were chosen, and their expression patterns were almost the same as the transcriptome profile analysis by qPCR. Protein interaction network analysis indicated that two DEGs of fos and egr1 were probably significant as key candidate genes controlling cell proliferation and differentiation in polian vesicle after pathogenic infection in A. japonicus. Overall, our analysis demonstrates that polian vesicles may play an essential role in regulating proliferation via transcription factors-mediated signaling pathway in A. japonicus and provide new insights into hematopoietic modulation of polian vesicles in response to pathogen infection.
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Stichopus , Animais , Stichopus/genética , Fatores de Transcrição/genética , Perfilação da Expressão Gênica , Transcriptoma , Proliferação de Células , Imunidade InataRESUMO
BACKGROUND: Western medicine is beneficial for the recovery of neurological function in patients with depression, but some patients experience side effects such as headaches, dizziness, nausea, gastrointestinal symptoms, insomnia, and cardiac dysfunction. In recent years, integrative medicine has achieved positive results in the treatment of various diseases. AIM: To study Chuanjin Qinggan decoction combined with selective serotonin reuptake inhibitors (SSRIs) in patients with herpes zoster complicated by depression. METHODS: Patients with herpes zoster complicated by depression who were treated at the Yantai Hospital of Traditional Chinese Medicine from January 2021 to December 2022 were retrospectively selected as research participants. Among them, 43 patients with herpes zoster complicated by depression who received SSRI treatment between January and December 2021 were assigned to the Western medicine group, while those who received combined treatment of traditional Chinese and Western medicine between January and December 2022 were assigned to the combined group. Both groups were treated for eight weeks. The degree of pain, effect of herpes zoster treatment, degree of improvement in depressive symptoms, serum neurotransmitter levels, sleep quality, and occurrence of adverse reactions were compared between the two groups. RESULTS: We found that after eight weeks of drug treatment, the two treatment schemes achieved differing efficacy. In further comparison, we found that, compared with patients treated with SSRIs alone, patients treated with Chuanjin Qinggan decoction combined with SSRIs showed more significant improvement in depression and a greater increase in dopamine and 5-hydroxytryptamine levels after treatment (P < 0.05). Patients treated with Chuanjin Qinggan decoction combined with SSRIs also experienced lower pain, better treatment efficacy for herpes zoster, better sleep quality, and a lower incidence of adverse reactions compared to those treated with SSRIs alone (P < 0.05). All minor adverse reactions occurring during treatment were resolved after symptomatic treatment. CONCLUSION: The treatment scheme of Chuanjin Qinggan decoction combined with SSRIs can improve the psychological state of patients with herpes zoster complicated by depression and alleviate adverse reactions.
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CONCLUSION: Oxycodone hydrochloride injection could be safely and effectively applied to negative pressure aspiration, and a 0.08 mg/kg dose could significantly reduce postoperative uterine contraction pain of patients with dysmenorrhea.
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Oxicodona , Contração Uterina , Analgésicos Opioides/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Oxicodona/efeitos adversos , Medição da Dor , Dor Pós-Operatória/tratamento farmacológico , Dor Pélvica/tratamento farmacológico , Resultado do TratamentoRESUMO
PURPOSE: Wear debris particle-induced periprosthetic osteolysis is a severe complication of total joint replacement that results in aseptic loosening and subsequent arthroplasty failure. No effective therapeutic agents or drugs have been approved to prevent or treat osteolysis; thus, revision surgery is often needed. Extracellular vesicles (EVs) are vital nanosized regulators of intercellular communication that can be directly applied to promote tissue repair and regeneration. In this study, we assessed the therapeutic potential of EVs from human urine-derived stem cells (USCs) (USC-EVs) in preventing ultrahigh-molecular-weight polyethylene (UHMWPE) particle-induced osteolysis. METHODS: USCs were characterized by measuring induced multipotent differentiation and flow cytometry. USC-EVs were isolated and characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS) and Western blotting. RAW264.7 cells and bone marrow mesenchymal stem cells (BMSCs) were cultured with USC-EVs to verify osteoclast differentiation and osteoblast formation, respectively, in vitro. The effects of USC-EVs were investigated on a UHMWPE particle-induced murine calvarial osteolysis model by assessing bone mass, the inflammatory reaction, and osteoblast and osteoclast formation. RESULTS: USCs differentiated into osteogenic, adipogenic and chondrogenic cells in vitro and were positive for CD44, CD73, CD29 and CD90 but negative for CD34 and CD45. USC-EVs exhibited a cup-like morphology with a double-layered membrane structure and were positive for CD63 and TSG101 and negative for calnexin. In vitro, USC-EVs promoted the osteogenic differentiation of BMSCs and reduced proinflammatory factor production and osteoclastic activity in RAW264.7 cells. In vivo, local injection of USC-EVs around the central sites of the calvaria decreased inflammatory cytokine generation and osteolysis compared with the control groups and significantly increased bone formation. CONCLUSION: Based on our findings, USC-EVs prevent UHMWPE particle-induced osteolysis by decreasing inflammation, suppressing bone resorption and promoting bone formation.
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Vesículas Extracelulares , Osteólise , Animais , Humanos , Camundongos , Osteoclastos , Osteogênese , Osteólise/induzido quimicamente , Polietileno , Células-TroncoRESUMO
Cancer-derived exosomes or their specific components hold great promise for early diagnosis and precise staging of cancers. This work aimed to construct a novel enzyme-activatable fluorescent substrate for real-time detection and in situ imaging of a key exosomal surface protein CD26 in various biological systems, as well as to reveal the relevance of exosomal CD26 to the tumorigenesis. For these purposes, a group of Gly-Pro amides deriving from several near-infrared fluorophores were designed on the basis of the unique prolyl-cleaving dipeptidease activity of CD26, while molecular docking simulations were applied to assess the possibility of the designed amides as CD26 specific substrates. Following virtual screening and experimental validation, it was observed that GP-ACM displayed the best combination of high sensitivity and excellent specificity to CD26. The sensing and imaging ability of GP-ACM towards CD26 were examined in a range of biological systems, such as living cells, in situ tissues, and the exosomes secreted from cancer cells. Under physiological conditions, GP-ACM can be readily hydrolyzed by CD26 to release the fluorescent product ACM. The fluorescent product emits strong near-infrared fluorescence signals around 660 nm, which can be easily captured by the devices equipped with a fluorescence detector. GP-ACM prolyl-cleaving reaction shows excellent specificity and rapid response towards CD26, while its fluorescent product ACM displays good chemical stability and outstanding photostability. With the help of GP-ACM, CD26 in living cells, tissues and the tumor-secreted exosomes can be real-time monitored and in-situ imaged, while further investigations reveal that the exosomal CD26 activities are abnormally elevated with the progression of colon tumor. Collectively, the present study offers a practical optical assay for real-time monitoring CD26 activities in multiple complex biological systems including the exosomes secreted by tumor cells. The simplicity and effectiveness of this assay hold great potential for facilitating fundamental researches and clinical diagnosis of exosomal CD26 associated diseases.
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Neoplasias Colorretais , Exossomos , Neoplasias Colorretais/diagnóstico por imagem , Dipeptidil Peptidase 4 , Corantes Fluorescentes , Humanos , Simulação de Acoplamento MolecularRESUMO
Health risk analysis can predict and control the risks posed by heavy metals, especially in drinking water, which is a highly sensitive environmental receptors. In order to evaluate heavy metal pollution in drinking water, the monthly average concentrations of As, Cd, Cu, Hg, Ni, and Zn were used to assess the health risk between January 2015 and December 2018 in a drinking water source. Furthermore, Spearman rank correlation coefficient and the ARIMA model were used to analyze temporal variations. The results showed that the monthly average concentrations of heavy metals exceeded the class â ¢ values as specified by Chinese environmental quality standard for surface water(GB 3838-2002), especially Hg with a minimum monthly average four times more than that set by the standard limits. Overall, the order of carcinogenic risk of As and Cd was decreased; the non-carcinogenic risk of Zn, Cu, Ni, Pb, and Hg was increased. Further, the comprehensive non-carcinogenic risk for adults was lower than 1 throughout the study period except February 2015, when the comprehensive non-carcinogenic risk for children was lower than or close to 1 after October 2017, and the comprehensive carcinogenic risk for children was more than 10-4. Meanwhile, the children's health risks are higher than that for adults, with the main health risk characteristic factors of As, Cd, and Hg. The Spearman rank correlation coefficient were -0.714069, -0.773122, and -0.62234, indicating the significant downward trend from 2015 to 2018. However, the children's comprehensive carcinogenic risk, whose average value was 0.000234 much more than 10-4, had significant upward trend in 2018 with Spearman rank correlation coefficient 0.902098. The ARIMA(3,1,3) model was able to predict the comprehensive carcinogenic risk for children from heavy metals in drinking water, and the result indicated the children comprehensive carcinogenic risk should be monitored to ensure levels between 0.000200 and 0.000302. The study has positive significance for risk warning and environmental management compared to the analysis and prediction of health risk from heavy metals in drinking water sources based on time series models.
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Água Potável , Metais Pesados , Poluentes Químicos da Água , Adulto , Criança , China , Água Potável/análise , Monitoramento Ambiental , Humanos , Metais Pesados/análise , Medição de Risco , Poluentes Químicos da Água/efeitos adversos , Poluentes Químicos da Água/análiseRESUMO
Pyroglutamate (pE) modification, catalyzed mainly by glutaminyl cyclase (QC), is prevalent throughout nature and is particularly important in mammals including humans for the maturation of hormones, peptides, and proteins. In humans, the upregulation of QC is involved in multiple diseases and conditions including Alzheimer's disease, Huntington's disease, melanomas, thyroid carcinomas, accelerated atherosclerosis, septic arthritics, etc. This upregulation catalyzes the generation of modified mediators such as pE-amyloid beta (Aß) and pE-chemokine ligand 2 (CCL2) peptides. Not surprisingly, QC has emerged as a reasonable target for the development of therapeutics to combat these diseases and conditions. In this manuscript the deleterious effects of upregulated QC resulting in disease manifestation are reviewed, along with progress on the development of QC inhibitors.
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Aminoaciltransferases/antagonistas & inibidores , Inibidores Enzimáticos/química , Aminoaciltransferases/metabolismo , Peptídeos beta-Amiloides/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Humanos , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Ácido Pirrolidonocarboxílico/metabolismo , Regulação para CimaRESUMO
The human UDP-glucuronosyltransferase 1A1 (UGT1A1), one of the most essential conjugative enzymes, is responsible for the metabolism and detoxification of bilirubin and other endogenous substances, as well as many different xenobiotic compounds. Deciphering UGT1A1 relevance to human diseases and characterizing the effects of small molecules on the activities of UGT1A1 requires reliable tools for probing the function of this key enzyme in complex biological matrices. Herein, an easy-to-use assay for highly-selective and sensitive monitoring of UGT1A1 activities in various biological matrices, using liquid chromatography with fluorescence detection (LC-FD), has been developed and validated. The newly developed LC-FD based assay has been confirmed in terms of sensitivity, specificity, precision, quantitative linear range and stability. One of its main advantages is lowering the limits of detection and quantification by about 100-fold in comparison to the previous assay that used the same probe substrate, enabling reliable quantification of lower amounts of active enzyme than any other method. The precision test demonstrated that both intra- and inter-day variations for this assay were less than 5.5%. Furthermore, the newly developed assay has also been successfully used to screen and characterize the regulatory effects of small molecules on the expression level of UGT1A1 in living cells. Overall, an easy-to-use LC-FD based assay has been developed for ultra-sensitive UGT1A1 activities measurements in various biological systems, providing an inexpensive and practical approach for exploring the role of UGT1A1 in human diseases, interactions with xenobiotics, and characterization modulatory effects of small molecules on this conjugative enzyme.
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Pancreatic lipase (PL), a crucial enzyme in the digestive system of mammals, has been proven as a therapeutic target to prevent and treat obesity. The purpose of this study is to evaluate and characterize the PL inhibition activities of the major constituents from Fructus Psoraleae (FP), one of the most frequently used Chinese herbs with lipid-lowering activity. To this end, a total of eleven major constituents isolated from Fructus Psoraleae have been obtained and their inhibition potentials against PL have been assayed by a fluorescence-based assay. Among all tested compounds, isobavachalcone, bavachalcone and corylifol A displayed strong inhibition on PL (IC50 < 10 µmol·L-1). Inhibition kinetic analyses demonstrated that isobavachalcone, bavachalcone and corylifol A acted as mixed inhibitors against PL-mediated 4-methylumbelliferyl oleate (4-MUO) hydrolysis, with the Ki values of 1.61, 3.77 and 10.16 µmol·L-1, respectively. Furthermore, docking simulations indicated that two chalcones (isobavachalcone and bavachalcone) could interact with the key residues located in the catalytic cavity of PL via hydrogen binding and hydrophobic interactions. Collectively, these finding provided solid evidence to support that Fructus Psoraleae contained bioactive compounds with lipid-lowering effects via targeting PL, and also suggested that the chalcones in Fructus Psoraleae could be used as ideal leading compounds to develop novel PL inhibitors.
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Medicamentos de Ervas Chinesas/química , Inibidores Enzimáticos/química , Lipase/antagonistas & inibidores , Psoralea/química , Animais , Chalconas/química , Flavonas/química , Frutas/química , Lipase/química , Pancrelipase/metabolismo , SuínosRESUMO
BACKGROUND: Lymphangioma is a benign lesion that rarely involves the gastrointestinal tract, especially in adults. Small bowel lymphangioma is a rare cause of gastrointestinal bleeding. Here, we report a case of an adult diagnosed with jejunal lymphangioma presenting with melena, anemia and hypogammaglobulinemia. We also summarize and analyze all 23 reported cases from 1961 to 2019, and propose an algorithm for identification and management of small bowel lymphangioma. CASE SUMMARY: A case of a 29-year-old woman presented with persistent melena and iron-deficiency anemia, accompanied by hypogammaglobulinemia. No lesions were found in the initial workup with esophagogastroduodenoscopy, colonoscopy and computed tomography (CT) enterography. Ultimately, capsule endoscopy and double-balloon enteroscopy revealed a 3 cm × 2 cm primary lesion with intensive white lymphatic dilatatory changes and visible fresh blood stains, accompanied by a small satellite lesion. The patient underwent complete surgical resection of these lesions, and histopathological examination confirmed a diagnosis of cavernous lymphangioma of the jejunum. The patient showed no evidence of disease at the time of this report. CONCLUSION: We recommend CT, capsule endoscopy and enteroscopy to identify the lesions of lymphangioma. Laparoscopic surgery with histological diagnosis is an ideal curative method.
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PURPOSE: Tumor drug resistance limits the response to chemotherapy. Interestingly, sequential combination therapy enhances the anticancer efficacy of drugs like cisplatin (CDDP) via synergistic effects. We assayed the synergistic effects of combined photodynamic therapy programmed death receptor-ligand 1 (PDT) and chemotherapy in malignant Hep-2 cells. METHODS: In the cultured Hep-2 cells, meta-tetra(hydroxyphenyl)chlorin (m-THPC) and CDDP were administered separately or in combination. The cellular viability and apoptosis were assessed, accompanied by measurement of the expression of Bax, Bcl-2, ATG-7, and LC3 (LC3-I and LC3-II). Additionally, nuclear chromatin changes, drug retention, and PD-L1 expression were further investigated following different treatments. RESULTS: The sequential treatment significantly diminished cell viability and induced cell apoptosis, in consistency with the usage of single therapeutic strategies, as reflected by an increase in Bax expression and decrease of Bcl-2 expression. Moreover, ATG-7 and LC3-II/LC3-I ratio were reduced after administration of the sequential treatment. Synergetic effect of nuclear chromatin configuration, negative effects of cellular drug retention, and a decrease in PD-L1 expression were observed following the sequential treatment. CONCLUSION: The application of sequential treatment of PDT in combination with chemotherapy offers a promising therapeutic option for cancer treatment, by regulating the PD-L1 expression, autophagy, and non-mitochondrial pathways.
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Thrombin inhibitor therapy is one of the most effective therapeutic strategies for the prevention and treatment of cardiovascular and thrombotic diseases. Although several marketed direct thrombin inhibitors (DTIs) have been widely used in clinic, the potentially serious complications of these DTIs prompted the researchers to find more DTIs with improved safety profiles. Herein, we report that natural anthraquinones in Cassiae semen (the seed of Cassia obtusifolia L. or C. tora L.), including obtusifolin, obtusin, aurantio-obtusin and chryso-obtusin, display strong to moderate inhibition on human thrombin, with the IC50 values ranging from 9.08⯵M to 27.88⯵M. Further investigation on the inhibition kinetics demonstrates that these anthraquinones are mixed inhibitors against thrombin-mediated Z-GGRAMC acetate hydrolysis, while obtusifolin and aurantio-obtusin show strong thrombin inhibition capacity, with the Ki values of 9.63⯵M and 10.30⯵M, respectively. Docking simulations demonstrate that both obtusifolin and aurantio-obtusin can simultaneously bind on the catalytic cavity and the two anion binding exosites (ABE1 and ABE2), while the hydroxyl group at the C-7 site and the methoxyl group at the C-8 site can create key interactions with the amino acids surrounding the catalytic cavity via hydrogen bonding. All these findings suggest that obtusifolin and aurantio-obtusin are strong thrombin inhibitors possessing a unique anthraquinone skeleton, and could be used as lead compounds for the development of new thrombin inhibitors with improved properties.
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Antraquinonas/farmacologia , Cassia/química , Simulação de Acoplamento Molecular , Inibidores de Serina Proteinase/farmacologia , Trombina/antagonistas & inibidores , Antraquinonas/química , Antraquinonas/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/isolamento & purificação , Relação Estrutura-Atividade , Trombina/metabolismoRESUMO
Human carboxylesterase 1 (CES1), primarily expressed in the liver and adipocytes, is responsible for the hydrolysis of endogenous esters (such as cholesteryl esters and triacylglycerols) and the metabolism of xenobiotic esters (such as clopidogrel and oseltamivir), thus participates in physiological and pathological processes. In this study, a series of natural pentacyclic triterpenoids were collected and their inhibitory effects against CES1 and CES2 were assayed using D-luciferin methyl ester (DME) and N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-benzo[de] isoquinolin- 6-yl)- 2-chloroacetamide (NCEN) as specific optical substrate for CES1, and CES2, respectively. To this end, betulinic acid (BA) was found with strong inhibitory effect on CES1 (IC50, 15â¯nM) and relative high selectivity over CES2 (>2400-fold). Primary structure-activity relationships (SAR) analysis and docking simulations revealed that the carboxyl group at the C-28 site of BA is very essential for CES1 inhibition. The inhibition kinetic analyses demonstrated that BA was a potent competitive inhibitor against CES1-mediated DME hydrolysis. Further investigation on the inhibitory effect of BA in living cells (HepG2) based assays demonstrated that BA displayed potent inhibitory effects on intracellular CES1 activities, with the low IC50 value of 1.30⯵M. These results demonstrated that BA is potent and highly selective CES1 inhibitor, which might be used as the promising tool for exploring the biological functions of CES1 in complex biological systems.
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Hidrolases de Éster Carboxílico/antagonistas & inibidores , Triterpenos/farmacologia , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Matrix metalloproteinases (MMPs) and the epithelial-mesenchymal transition (EMT) contribute to metastasis. As shown in our previous studies, interleukin-6 (IL-6) induces ATM phosphorylation to increase MMP expression and metastasis in lung cancer. However, the exact roles of ATM activation in the IL-6-induced epithelial-mesenchymal transition and lung cancer metastasis are currently unclear. Here, ATM phosphorylation exerts its pro-metastatic effect via vimentin-mediated epithelial-mesenchymal transition, which was supported by the evidence described below. Firstly, IL-6 treatment increases vimentin expression via the ATM-NF-κB pathway. Second, ATM inactivation not only abolishes IL-6-induced increases in vimentin expression but also inhibits IL-6-induced nest formation in a xenograft lung metastasis model. Moreover, close positive correlations were observed between ATM phosphorylation and vimentin upregulation, IL-6 levels and metastasis in lung cancer specimens. Hence, ATM modulates vimentin expression to facilitate IL-6-induced epithelial-mesenchymal transition and metastasis in lung cancer, indicating that ATM and vimentin might be potential therapeutic targets for inflammation-associated lung cancer metastasis.
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Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Interleucina-6/farmacologia , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Vimentina/genética , Células A549 , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética , Vimentina/metabolismoRESUMO
Coronary artery disease has become a major health concern over the past several decades. We aimed to explore the association of single nucleotide polymorphisms (SNPs) in the ATP-binding cassette subfamily A member 1 (ABCA1) and lifestyle factors with coronary artery disease (CAD) in dyslipidemia. This nested case-control study included 173 patients with CAD and 500 matched control individuals (1:3, case: control) from a district in southern China. We collected medical reports, lifestyle details, and blood samples of individuals with dyslipidemia and used the polymerase chain reaction-ligase detection reaction method to genotype the SNPs. The CC genotype of the additive and recessive models of rs4149339, together with regular intake of fried foods or dessert, increased the risk of CAD (adjusted odd ratio (OR) = 1.91, p = 0.030; adjusted OR = 1.97, p = 0.017; adjusted OR = 1.80, p = 0.002; adjusted OR = 1.98, p = 0.001). The AT + AA genotype of the dominant model of rs4743763 and moderate/heavy physical activity reduced the risk of CAD (adjusted OR = 0.66, p = 0.030; adjusted OR = 0.44, p = 0.001). The CT + CC genotype of the dominant model of rs2472386 reduced the risk of CAD only in males (adjusted OR = 0.36, p = 0.001). The interaction between rs4149339 and rs4743763 of ABCA1 and haplotype CTT (comprising rs4149339, rs4743763, and rs2472386) appeared to increase the risk of CAD (relative excess risk due to interaction (RERI) = 3.19, p = 0.045; OR = 1.49, p = 0.019). Polymorphisms of rs4149339, rs4743763 and rs2472386 in ABCA1 and three lifestyle factors (physical activity, fried food intake, and dessert intake) were associated with CAD in people with dyslipidemia in southern China. These results provide the theoretical basis for gene screening and the prevention of chronic cardiovascular diseases.
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Transportador 1 de Cassete de Ligação de ATP/genética , Povo Asiático/genética , Doença da Artéria Coronariana/genética , Dislipidemias/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , China/epidemiologia , Doença da Artéria Coronariana/epidemiologia , Dislipidemias/epidemiologia , Ingestão de Alimentos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Cervical cancer is a deadly gynecological malignancy in need of innovative treatment strategies. Emerging preclinical data has suggested the benefits of nanocarriers over the traditional chemotherapy for cancer treatment. In particular, gold nanoparticles are gaining popularity due to gold's inert nature, limited side effects, good cytocompatibility, and flexibility in preparation/modification. We conjugated polyethylene glycol (PEG) with hollow gold nanospheres (HGNs) and loaded the pegylated HGNs with an anticancer drug, cisplatin to target cervical cancer. HGNs were irradiated with noninfrared laser to increase the penetration of drug into tumor tissue and improve the delivery of cisplatin. We investigated the comparative characterization studies of prepared cisplatin loaded pegylated HGNs (cis PEG-HGNs), free cisplatin, cisplatin loaded HGNs (cis-HGNs), cis PEG-HGNs without laser, and cis PEG-HGNs with laser and its effects over cervical cancer cells. Transmission electron microscopy photomicrographs confirmed the integrity of prepared HGNs. While no significant difference was observed between encapsulation efficiency and drug loading of cis-HGNs (84.6%) and cis PEG-HGNs (86.7%), the encapsulation efficiency increased almost twice in HGNs, compared with control gold nanoparticles (GNs) because of the hollow cavity in HGNs. In-vitro cytotoxicity was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using HeLa cells. With irradiation, HGNs induced much elevated cytotoxicity. Not only HGNs were internalized by HeLa cells, they were retained in the cellular compartment. We also tested formulations in vivo and observed that the irradiated cis-HGNs and cis PEG-HGNs were most effective in regressing tumors in mice.
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Diabetic nephropathy (DN) is one of the leading causes of death in diabetes mellitus (DM). Early warning and therapy has significant clinical value for DN. This research sought to find biomarkers to predict the occurrence and development of DN and the intervention of Ginkgo biloba leaves extract (GBE) by quantifying fatty acids, amino acids, and nucleosides and nucleobases in rat plasma. Samples were respectively collected at the weekend of 5-10 weeks after diabetic rats induced by streptozotocin were defined. Plasma fasting blood-glucose, kidney index, blood urea nitrogen, creatinine, urine albumin excretion and ultrastructural morphology of kidney were measured or observed. Fatty acids, amino acids and nucleosides and nucleobases in rat plasma were analyzed by gas chromatography or liquid phase chromatography and mass spectrometry, respectively. From the biochemical index and morphological change of kidney, the rats from the 5th to 7th week were in the stage of DM while from the begin of 8th week the rats were suggested in the early stage of DN. The results of quantitative metabolomics showed that 16 differential metabolites were related to the progression of DN, and oleic acid, glutamate and guanosine might be the potential biomarkers of kidney injury. 14 differential metabolites were related to GBE against the progression of DN, while oleic acid and glutamate might be the potential biomarkers of GBE against kidney injury. Those findings potentially promote the understanding of the pathogenic progression of DN and reveal the therapeutic mechanism of GBE against DN.
Assuntos
Aminoácidos/sangue , Nefropatias Diabéticas/sangue , Ácidos Graxos/sangue , Metabolômica , Nucleosídeos/sangue , Extratos Vegetais/uso terapêutico , Albuminúria , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/tratamento farmacológico , Ginkgo biloba , Rim/patologia , Rim/ultraestrutura , Masculino , RatosRESUMO
BACKGROUND: Increased production of estrogen in human placenta during pregnancy closely associates with parturition. Aromatase, encoded by CYP19A1 gene, is an enzyme critical for biosynthesis of estrogen. Despite numerous efforts in the past few decades ascribed to characterizing the mechanisms of transcriptional control of aromatase, the posttranscriptional control of CYP19A1 remains poorly understood. OBJECTIVE: In this study, we sought to investigate the role of microRNA, let-7g, in posttranscriptional regulation of aromatase in human trophoblast choriocarcinoma cell line, JEG3. METHODS AND RESULTS: We show that the expression of let-7g was downregulated in JEG3 cell line, but upregulated in primary term trophoblast; conversely, aromatase was upregulated in JEG3 but downregulated in primary trophoblast. We further show that let-7g antagomirs and mimics increased and decreased aromatase expression, respectively; and let-7g directly targeted 3'-untranslated region of CYP19A1 mRNA by using dual luciferase assay. Using ELISA, we also demonstrate that let-7g antagomirs and mimics robustly increased and decreased production of estradiol, respectively. DISCUSSION: Our results suggest that aromatase expression is regulated at multiple molecular layers in the placenta. These results further suggest that JEG3 cell line is a valuable tool to study additional mechanisms associated with human birth.
RESUMO
BACKGROUND: Choriocarcinoma is the most aggressive gestational trophoblastic disease, with massive local trophoblast invasion and vascular percolation, resulting in multiple organ metastases. Recent evidence has shown that long noncoding RNAs (lncRNAs) play an important role in tumor progression. This study aimed to investigate the expression and role of lncRNA PCA3 in the progression of choriocarcinoma. METHODS: First, the expression of lncRNA PCA3 in choriocarcinoma cells was detected using quantitative real-time PCR (qRT-PCR). Then functional assays such as cell proliferation assay, wound healing assay, and invasion assay were conducted to determine the role of PCA3. In addition, the specific molecular mechanism was studied using western blot, luciferase assay, and rescue experiment. RESULTS: We demonstrated that the expression of PCA3 is significantly higher in choriocarcinoma cells in contrast to normal human chorionic trophoblast cells. Furthermore, PCA3 could promote cell proliferation, migration and invasion in gestational choriocarcinoma cells and facilitated epithelial to mesenchymal transition (EMT) in vitro. In addition, PAC3 could directly bind to miR-106b and effectively liberate the expression of its endogenous target matrix metallopeptidase 2 (MMP2). CONCLUSION: Our results suggest that PCA3 contributes to the progression of choriocarcinoma by acting as a ceRNA against miR-106b.