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1.
Small ; 20(29): e2310768, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38342671

RESUMO

There is a noticeable gap in the literature regarding research on halogen-substitution-regulated ferroelectric semiconductors featuring multiple phase transitions. Here, a new category of 1D perovskite ferroelectrics (DFP)2SbX5 (DFP+ = 3,3-difluoropyrrolidium, X- = I-, Br-, abbreviated as I-1 and Br-2) with twophase transitions (PTs) is reported. The first low-temperature PT is a mmmFmm2 ferroelectric PT, while the high-temperature PT is a counterintuitive inverse temperature symmetry-breaking PT. By the substitution of iodine with bromine, the Curie temperature (Tc) significantly increases from 348 K of I-1 to 374 K of Br-2. Their ferroelectricity and pyroelectricity are improved (Ps value from 1.3 to 4.0 µC cm-2, pe value from 0.2 to 0.48 µC cm-2 K-1 for I-1 and Br-2), while their optical bandgaps increased from 2.1 to 2.7 eV. A critical slowing down phenomenon is observed in the dielectric measurement of I-1 while Br-2 exhibits the ferroelastic domain. Structural and computational analyses elucidate that the order-disorder movement of cations and the distortion of the chain perovskite [SbX5]2- anions skeleton lead to PT. The semiconductor properties are determined by [SbX5]2- anions. The findings contribute to the development of ferroelectric semiconductors and materials with multiple PTs and provide materials for potential applications in the optoelectronic field.

2.
Environ Sci Technol ; 58(8): 3702-3713, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38356452

RESUMO

Microplastics are found in various human tissues and are considered harmful, raising concerns about human exposure to microplastics in the environment. Existing research has analyzed indoor and occupational scenarios, but long-term monitoring of ambient atmospheric microplastics (AMPs), especially in highly polluted urban regions, needs to be further investigated. This study estimated human environmental exposure to AMPs by considering inhalation, dust ingestion, and dermal exposure in three urban functional zones within a megacity. The annual exposure quantity was 7.37 × 104 items for children and 1.06 × 105 items for adults, comparable with the human microplastic consumption from food and water. Significant spatiotemporal differences were observed in the characteristics of AMPs that humans were exposed to, with wind speed and rainfall frequency mainly driving these changes. The annual human AMP exposure quantity in urban green land spaces, which were recognized as relatively low polluted zones, was comparable with that in public service zones and residential zones. Notably, significant positive correlations between the AMP characteristics and the pathogenicity of the airborne bacterial community were discovered. AMP size and immune-mediated disease risks brought by atmospheric microbes showed the most significant relationship, where Sphingomonas might act as the potential key mediator.


Assuntos
Microplásticos , Poluentes Químicos da Água , Criança , Adulto , Humanos , Plásticos , Monitoramento Ambiental , Poeira/análise , Exposição Ambiental , Poluentes Químicos da Água/análise
3.
BMC Public Health ; 24(1): 2426, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39243077

RESUMO

BACKGROUND: Intracerebral hemorrhage (ICH) results from the rupture of blood vessels causing bleeding within the brain and is one of the major causes of death and long-term disability globally, particularly in low- and middle-income countries. Despite having a lower incidence than ischemic stroke, ICH imposes a greater social and economic burden. To our knowledge, since the release of the 2021 Global Burden of Disease (GBD) report, there has been no comprehensive update on the epidemiology and trends of ICH. This study aims to analyze the impact of gender, age, and the Sociodemographic Index (SDI) on the burden of ICH at global, regional, and national levels. METHODS: Data on the incidence, deaths, and disability-adjusted life years (DALYs) of ICH and its related risk factors from 1990 to 2021 were extracted from the GBD 2021 project, encompassing 203 countries and regions. Furthermore, temporal trends of the global intracerebral hemorrhage burden were assessed through Joinpoint analysis. RESULTS: In 2021, there were 3.444 million new cases of ICH worldwide, with an age-standardized prevalence rate of 40.8 per 100,000 people, representing a 31.4% decrease compared to 1990. In 2021, ICH caused 3.308 million deaths, with an age-standardized mortality rate of 39.1 per 100,000 people, a reduction of 36.6% since 1990. Globally, ICH accounted for 79.457 million DALYs, with an age-standardized DALY rate of 92.4 per 100,000 people, representing a 39.1% decrease since 1990. Regionally, Central Asia, Oceania, and Southeast Asia had the highest age-standardized prevalence rates of ICH, whereas Australasia, high-income North America, and Western Europe had the lowest rates. Nationally, the Solomon Islands, Mongolia, and Kiribati had the highest age-standardized prevalence rates, whereas Switzerland, New Zealand, and Australia had the lowest. Hypertension, smoking, and environmental pollution were identified as the primary risk factors for ICH. This study also validated the significant association between SDI and the burden of ICH, with the age-standardized DALY rate of ICH decreasing significantly as SDI increased. CONCLUSION: Despite the decreasing burden of intracerebral hemorrhage, it remains a significant public health issue in countries with a lower SDI. Prevention strategies should prioritize hypertension management, air quality improvement, and smoking control to further mitigate the impact of intracerebral hemorrhage.


Assuntos
Hemorragia Cerebral , Anos de Vida Ajustados por Deficiência , Carga Global da Doença , Saúde Global , Humanos , Hemorragia Cerebral/epidemiologia , Carga Global da Doença/tendências , Masculino , Fatores de Risco , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Saúde Global/estatística & dados numéricos , Incidência , Adulto Jovem , Idoso de 80 Anos ou mais , Adolescente , Pré-Escolar
4.
EMBO J ; 38(19): e96659, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31454099

RESUMO

Loss of the histone H3.3-specific chaperone component ATRX or its partner DAXX frequently occurs in human cancers that employ alternative lengthening of telomeres (ALT) for chromosomal end protection, yet the underlying mechanism remains unclear. Here, we report that ATRX/DAXX does not serve as an immediate repressive switch for ALT. Instead, ATRX or DAXX depletion gradually induces telomere DNA replication dysfunction that activates not only homology-directed DNA repair responses but also cell cycle checkpoint control. Mechanistically, we demonstrate that this process is contingent on ATRX/DAXX histone chaperone function, independently of telomere length. Combined ATAC-seq and telomere chromatin immunoprecipitation studies reveal that ATRX loss provokes progressive telomere decondensation that culminates in the inception of persistent telomere replication dysfunction. We further show that endogenous telomerase activity cannot overcome telomere dysfunction induced by ATRX loss, leaving telomere repair-based ALT as the only viable mechanism for telomere maintenance during immortalization. Together, these findings implicate ALT activation as an adaptive response to ATRX/DAXX loss-induced telomere replication dysfunction.


Assuntos
Proteínas Correpressoras/genética , Chaperonas Moleculares/genética , Homeostase do Telômero , Telômero/metabolismo , Proteína Nuclear Ligada ao X/genética , Linhagem Celular , Reparo do DNA , Deleção de Genes , Células HEK293 , Humanos , Telomerase/metabolismo
5.
Anticancer Drugs ; 34(6): 715-724, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36729998

RESUMO

As a vital oncogene, a variety of inhibitors targeting Stat3 and its various upstream signaling pathways has been explored. Since small molecules, peptidomimetics and other peptide inhibitors usually lead to side effects and difficult administration, gene therapeutics that have characteristics of low toxicity and high targeting, make them an attractive alternative for targeting Stat3. A major challenge to this approach is the lack of safe delivery systems for in-vivo applications. Among the various siRNA delivery systems, nanoparticles emerge as a new tool for gene delivery with high biocompatibility, low cost, and minimal toxicity. In this study, we developed a graphene oxide (GO)-based nanocarrier, GO-polyethyleneimine (PEI)-polyethylene glycol (PEG)-folic acid (FA), as a tool targeting for Stat3-specific shRNA to mouse hepatoma cells in vitro and in vivo . Infrared photothermal therapy was combined in vivo since GO has the characteristic of infrared absorbability. Our results suggest a significant tumor growth inhibition after treatment with GO-PEI-PEG-FA- sh-Stat3 combined with infrared photothermal therapy. Thus, GO-PEI-PEG-FA appears to be a novel nano-transformer that could be used in the clinics in future.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Ácido Fólico , Terapia Genética/métodos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Polietilenoglicóis/química , Polietilenoimina/química , RNA Interferente Pequeno/genética , Fator de Transcrição STAT3/genética
6.
J Environ Manage ; 345: 118710, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37536136

RESUMO

The widespread secondary microplastics (MPs) in urban freshwater, originating from plastic wastes, have created a new habitat called plastisphere for microorganisms. The factors influencing the structure and ecological risks of the microbial community within the plastisphere are not yet fully understood. We conducted an in-site incubation experiment in an urban river, using MPs from garbage bags (GB), shopping bags (SB), and plastic bottles (PB). Bacterial communities in water and plastisphere incubated for 2 and 4 weeks were analyzed by 16S high-throughput sequencing. The results showed the bacterial composition of the plastisphere, especially the PB, exhibited enrichment of plastic-degrading and photoautotrophic taxa. Diversity declined in GB and PB but increased in SB plastisphere. Abundance analysis revealed distinct bacterial species that were enriched or depleted in each type of plastisphere. As the succession progressed, the differences in community structure was more pronounced, and the decline in the complexity of bacterial community within each plastisphere suggested increasing specialization. All the plastisphere exhibited elevated pathogenicity at the second or forth week, compared to bacterial communities related to natural particles. These findings highlighted the continually evolving plastisphere in urban rivers was influenced by the plastic substrates, and attention should be paid to fragile plastic wastes due to the rapidly increasing pathogenicity of the bacterial community attached to them.


Assuntos
Microbiota , Microplásticos , Plásticos , Rios , Bactérias/genética
7.
J Asthma ; 59(10): 1989-1996, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34587470

RESUMO

BACKGROUND: The relationship between childbirth delivery methods and the risk of wheezing in children remains controversial. Few studies have explored it under different maternal conditions. OBJECTIVE: To explore the influence of childbirth delivery method on the onset of wheezing in children of different parity. METHODS: A total of 21716 patients were included in this retrospective observational study. Multivariable logistic regression was used to analyze the relationship between childbirth delivery method and wheezing in children under 18 years of age in Fujian Province. RESULTS: Wheezing differed statistically based on the child's sex, age, season of onset, parity, jaundice history, and feeding patterns (P < 0.05). After adjusting for confounding factors, in cases of parity greater than two, the risk of wheezing in cesarean section deliveries was higher than that in vaginal deliveries (OR: 1.107; 95% CI 1.010-1.214). In girls with parity greater than two (OR: 1.179; 95% CI 1.003-1.387) and normal-weight infants with parity greater than two (OR: 1.106; 95% CI 1.003-1.220), the risk of wheezing in cesarean section deliveries was higher. The interaction term between the mode of childbirth and parity was significant in girls (P = 0.014). CONCLUSION: The method of childbirth delivery and parity are related to the risk of wheezing and may be relevant to gender and birth weight. Parity and gender have synergistic effects on wheezing.


Assuntos
Asma , Sons Respiratórios , Adolescente , Asma/epidemiologia , Cesárea , Criança , China/epidemiologia , Feminino , Humanos , Lactente , Paridade , Gravidez , Sons Respiratórios/etiologia , Estudos Retrospectivos , Fatores de Risco
8.
J Nat Prod ; 85(4): 1141-1146, 2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35380836

RESUMO

Clostridioides difficile is a commensal Gram-positive gut bacterium that causes C. difficile-associated diarrhea. Currently available antibacterial therapeutic treatment options are effective except for the repeated recurrences significantly burdening the health care system and causing mortality. The development of new therapeutic modalities including new effective antibiotics with a low rate of recurrence has been unpredictive and exceedingly challenging, requiring continued profiling of many new classes of antibiotics. Nocathiacins and thiazomycins are a class of thiazolyl peptides exhibiting potent and selective broad-spectrum Gram-positive activity including activity against the anaerobe C. difficile. These compounds showed MIC values of 0.015-0.06 µg/mL against C. difficile with more than 100-200-fold selectivity versus commensurate Gram-negative Bacteroides fragilis. Nocathiacin I and one of its analogs exhibited potent in vivo efficacy in the gold-standard hamster model of C. difficile infection, providing 100% protection in this lethal model at 6.25 mg/kg orally twice daily. The efficacy was corroborated by robust reduction of cecum C. difficile burden and proportionate exposure of the compounds in the cecum contents without any systemic absorption. In this paper, details of the results of in vitro, in vivo, pharmacodynamics, and pharmacokinetic studies have been described.


Assuntos
Clostridioides difficile , Clostridioides , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Cricetinae , Bactérias Gram-Positivas , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos , Tiazóis
9.
Minerva Pediatr ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33438852

RESUMO

BACKGROUND: Wheezing is a common clinical manifestation in children with pneumonia. However, the risk factors associated with the development of wheezing pneumonia and its clinical features are not fully characterized, especially in children with severe pneumonia. METHODS: We retrospectively recruited 1434 pediatric patients diagnosed with severe pneumonia between April 2012 and September 2019 in Fujian Maternity and Child Health Hospital. The medical records regarding demographic information, clinical manifestations, radiographic/laboratory findings, and complications were collected. Based on the presence or absence of wheezing symptoms and signs, subjects were divided into wheezing cohort (n=684) and non-wheezing cohort (n=750), and their clinical data were compared. Multivariate cox regression analysis was performed to identify independent risk factors of wheezing. RESULTS: Demographic features including gender, weigh, onset season, birth weight, full-term birth or not, history of pneumonia were significantly associated with the occurrence of wheezing in severe CAP (P<0.05). Specifically, male gender, onset seasons in autumn/winter, and absence of a history of pneumonia were identified as independent risk factors of wheezing in multivariate analysis (P<0.05). As for clinical features, wheezing cohort differed from the non-wheezing one in terms of clinical manifestation (higher incidence of cough and breathless, but lower incidence of fever), laboratory finding (higher levels of red blood cells, hemoglobin, and albumin and lower levels of total or indirect bilirubin and creatine), pathogen detection (higher incidence of respiratory syncytial viral infection), and clinical complications (lesser risk of sepsis and hydrothorax) (P<0.05). CONCLUSIONS: Severe CAP with wheezing is a special clinical entity of severe pneumonia in children, which has specific risk factors and differ from non-wheezing pneumonia in terms of clinical features and etiologic pathogens.

10.
Financ Res Lett ; 38: 101872, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36569655

RESUMO

We investigate the dynamic responses of stock return to the unexpected changes in the COVID-19 cases and the uncertainty associated with the pandemic. Using daily data from Canada and the US, we find there is a negative effect of an increase in the COVID-19 cases on the stock market in general. Moreover, the stock return responses are asymmetric in the increase and decrease in the cases in Canada. The asymmetry is caused by the negative impact of uncertainty about the pandemic. We also find that uncertainty adversely affects the US stock market. However, the magnitude is small.

11.
BMC Pregnancy Childbirth ; 20(1): 127, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093673

RESUMO

BACKGROUND: To establish age-standardized charts of weight gain for term twin pregnancies in Southeast China. METHODS: We designed a retrospective study on data from women pregnant with twins, a gestational age beyond 36 weeks and an average weight ≥ 2500 g. We established hierarchical linear regression models to express gestational weight gain patterns. RESULTS: We analyzed data from 884 women pregnant with twins (151 underweight, 597 normal weight, and 136 overweight). Our final models fit the crude weight measurement data well. The means of weight gain generally decreased as the pre-pregnancy BMI increased. For each BMI category, the mean weight gains increased with the gestational age and the standard deviation increased slightly. The mean weight gains were 18.82 ± 6.73, 18.53 ± 6.74, and 16.97 ± 6.95 kg at 37 weeks in underweight, normal weight, and overweight women, respectively. CONCLUSION: The weight gain chart can be used to estimate maternal weight gain to be gestational age-standardized z scores by pre-pregnancy BMI and may serve as an innovative tool for perinatal care providers to guide the weight gain of women pregnant with twins.


Assuntos
Pesos e Medidas Corporais/normas , Ganho de Peso na Gestação/fisiologia , Gravidez de Gêmeos/fisiologia , Adulto , Índice de Massa Corporal , China , Feminino , Idade Gestacional , Humanos , Sobrepeso/epidemiologia , Gravidez , Estudos Retrospectivos , Magreza/epidemiologia
12.
J Clin Lab Anal ; 34(8): e23313, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32222021

RESUMO

BACKGROUND: Accurate prediction of preterm birth (PTB) is still difficult, mostly because of the multifactorial etiology of PTB. Previous studies have been mostly focused on the prediction of PTB in symptomatic women or those presenting with threatened preterm labor. We aimed to study whether complete blood count (CBC) parameters at 20-30 weeks of pregnancy can predict asymptomatic PTB. METHODS: In this retrospective case-control study, the preterm and term delivery groups were matched by propensity score-matched (PSM) analysis. Baseline data and the CBC parameters examined at 20-30 weeks of gestation were recorded. RESULTS: The combined marker of neutrophil-to-lymphocyte ratio (NLR), hemoglobin (HGB), and platelet distribution width (PDW) accurately predicts PTB at a cutoff value of 0.25, with sensitivity and specificity of 88.6% and 40.5% and negative and positive predictive value of 97.9% and 10.2%, respectively. CONCLUSION: The combined marker of CBC parameters can supplement other markers to predict PTB about 10 weeks in advance. This combined marker had a very high negative predictive value for PTB. Therefore, in subjects with normal combined marker value, further screening tests for PTB may be eliminated unless clinical suspicion is high.


Assuntos
Contagem de Células Sanguíneas , Trabalho de Parto Prematuro , Nascimento Prematuro , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Trabalho de Parto Prematuro/diagnóstico , Trabalho de Parto Prematuro/epidemiologia , Valor Preditivo dos Testes , Gravidez , Nascimento Prematuro/diagnóstico , Nascimento Prematuro/epidemiologia , Pontuação de Propensão , Estudos Retrospectivos
13.
Sensors (Basel) ; 20(16)2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32824353

RESUMO

When the inverse finite element method (inverse FEM) is used to reconstruct the deformation field of a multi-element structure with strain measurements, strain measurement errors can lower the reconstruction accuracy of the deformation field. Furthermore, the calibration ability of a self-structuring fuzzy network (SSFN) is weak when few strain samples are used to train the SSFN. To solve this problem, a novel two-step calibration method for improving the reconstruction accuracy of the inverse FEM method is proposed in this paper. Initially, the errors derived from measured displacements and reconstructed displacements are distributed to the degrees of freedom (DOFs) of nodes. Then, the DOFs of nodes are used as knots, in order to produce non-uniform rational B-spline (NURBS) curves, such that the sample size employed to train the SSFN can be enriched. Next, the SSFN model is used to determine the relationship between the measured strain and the DOFs of the end nodes. A loading deformation experiment using a three-element structure demonstrates that the proposed algorithm can significantly improve the accuracy of reconstruction displacement.

14.
Int J Med Sci ; 16(12): 1573-1582, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839745

RESUMO

Colorectal cancer is one of the most common cancers worldwide with a high incidence rate. Therefore, the molecular basis of colorectal tumorigenesis and evolution must be clarified. Structure-specific recognition protein 1 (SSRP1) is involved in transcriptional regulation, DNA damage repair, and cell cycle regulation and has been confirmed to be highly expressed in various tumor tissues, including colorectal cancer. However, the role of SSRP1 in the development of colorectal cancer remains unclear. Therefore, this study explored the role of SSRP1 in the occurrence and development of colorectal cancer. Using bioinformatics databases, including samples from the Cancer Genome Atlas (TCGA), we confirmed high SSRP1 expression in human colorectal adenocarcinoma tissues. We demonstrated that SSRP1 knockdown via small interfering RNA significantly inhibited the proliferation of colorectal cancer cells and promoted apoptosis through the AKT signaling pathway, suppressing the invasion and migration of colorectal cancer cells in vitro and in vivo. In conclusion, this study demonstrated that SSRP1 silencing influenced the proliferation and apoptosis of colorectal cancer cells via the AKT signaling pathway.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Proteínas de Grupo de Alta Mobilidade/genética , Invasividade Neoplásica/genética , Proteína Oncogênica v-akt/genética , Fatores de Elongação da Transcrição/genética , Apoptose/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Biologia Computacional , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/patologia , Transdução de Sinais/genética
15.
Bioorg Med Chem Lett ; 27(9): 2069-2073, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28284804

RESUMO

Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic ß-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03mg/kg led to robust blood glucose lowering efficacy in 3week high fat diet-fed mice.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/química , Ativadores de Enzimas/uso terapêutico , Glucoquinase/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Indóis/química , Indóis/uso terapêutico , Regulação Alostérica/efeitos dos fármacos , Animais , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/farmacocinética , Ativadores de Enzimas/farmacologia , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Indóis/farmacocinética , Indóis/farmacologia , Insulina/sangue , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
16.
Bioorg Med Chem Lett ; 27(9): 2063-2068, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28284809

RESUMO

Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic ß-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Hipoglicemiantes/farmacologia , Piridinas/farmacologia , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Descoberta de Drogas , Ativadores de Enzimas/química , Ativadores de Enzimas/farmacocinética , Ativadores de Enzimas/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Piridinas/química , Piridinas/farmacocinética , Piridinas/uso terapêutico
17.
Tumour Biol ; 37(9): 12023-12032, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27164937

RESUMO

Prostate carcinoma (PC) is one of the most common cancers for males. However, the molecular mechanisms of PC progression are still to be uncovered. MicroRNA (miRNA) has been shown to be associated with the initiation and progression of prostate cancer. Among the identified tumor-promoting miRNAs, miR-96 has been well established to contribute to PC by reducing FOXO1 expression. This study is aimed to study if miR-96 can promote the progression of PC through other pathways. Our data reinforced the finding that the level of miR-96 was higher in PC samples and cell lines than in non-cancerous tissues and normal prostate epithelial cells. In addition, serum miR-96 abundance was also found to be elevated in PC patients. Decreasing miR-96 expression was able to suppress the proliferation, clonogenicity, and invasion of PC cells. Overexpressing miR-96 led to increased proliferation and colony formation of normal prostate epithelial cells. miR-96 level was found to be inversely associated with the abundance of metastasis suppressor protein 1 (MTSS1) messenger RNA (mRNA), which has been proved to be a tumor suppressor for PC. Predictive analysis indicated that there was a potential miRNA response elements (MREs) located within 3'UTR of MTSS1 mRNA. The changes in miR-96 expression can affect the levels of MTSS1 both at mRNA and protein levels. miR-96 also suppressed the activity of luciferase reporter under the regulation of 3'UTR of MTSS1. Further studies showed that MTSS1 restoration accounted for the effect of miR-96 reduction on PC cells. The overexpression of a recombinant MTSS1 resistant against miRNA regulation was also demonstrated to abolish the transforming effect of miR-96 on prostate epithelial cells. Taken together, we found that miR-96 has a higher abundance in serum samples of PC patients than healthy controls, implying that it may be used as a prognostic marker. MTSS1 is a new authentic target of miR-96 in PC. The above findings suggested that targeting miR-96 may be a promising strategy for PC treatment.


Assuntos
MicroRNAs/fisiologia , Proteínas dos Microfilamentos/genética , Proteínas de Neoplasias/genética , Neoplasias da Próstata/patologia , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , MicroRNAs/sangue , Proteínas dos Microfilamentos/análise , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Neoplasias da Próstata/genética , RNA Mensageiro/análise
18.
Cell Biochem Funct ; 33(7): 495-502, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26486443

RESUMO

Gastric cancer remains one of the most prevalent and lethal malignancies in the world. Despite new advances in treatment and diagnosis, patients with advanced gastric cancer are still difficult to cure resulting in a high mortality rate and poor prognosis. Signal transducer and activator of transcription 3 (Stat3) is observed aberrant in multiple tumours, including gastric cancer. Stat3 overexpression was confirmed performing a vital role in tumorigenesis. In the present study, we constructed a pSi-Stat3 plasmid to silence Stat3 and investigated the effect of pSi-Stat3 on cell proliferation, apoptosis and cell cycle progression in gastric cancer cell line SGC-7901 and mice xenograft model. Downstream proteins of Stat3, including Cyclin-D1, Survivin and Bcl-2, were detected as well for the underlying mechanism exploration. It showed that pSi-Stat3 can effectively silence the expression of Stat3 and inhibits the growth of gastric tumour both in vitro and in vivo significantly via cell apoptosis and cell cycle shift induction. The findings suggest that Stat3 signal pathway might be a promising therapeutic target for tumour treatment, including gastric cancer.


Assuntos
Antineoplásicos/farmacologia , RNA Interferente Pequeno/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Feminino , Genes bcl-2 , Xenoenxertos , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Mensageiro/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Neoplasias Gástricas/metabolismo , Survivina
19.
Sensors (Basel) ; 15(3): 5344-75, 2015 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-25751076

RESUMO

With the quick development of RFID technology and the decreasing prices of RFID devices, RFID is becoming widely used in various intelligent services. Especially in the retail application domain, RFID is increasingly adopted to capture the shopping tracks and behavior of in-store customers. To further enhance the potential of this promising application, in this paper, we propose a unified framework for RFID-based path analytics, which uses both in-store shopping paths and RFID-based purchasing data to mine actionable navigation patterns. Four modules of this framework are discussed, which are: (1) mapping from the physical space to the cyber space, (2) data preprocessing, (3) pattern mining and (4) knowledge understanding and utilization. In the data preprocessing module, the critical problem of how to capture the mainstream shopping path sequences while wiping out unnecessary redundant and repeated details is addressed in detail. To solve this problem, two types of redundant patterns, i.e., loop repeat pattern and palindrome-contained pattern are recognized and the corresponding processing algorithms are proposed. The experimental results show that the redundant pattern filtering functions are effective and scalable. Overall, this work builds a bridge between indoor positioning and advanced data mining technologies, and provides a feasible way to study customers' shopping behaviors via multi-source RFID data.

20.
J Hazard Mater ; 465: 133428, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38198862

RESUMO

The plastisphere may act as reservoir of antibiotic resistome, accelerating global antimicrobial resistance dissemination. However, the environmental risks in the plastisphere of field microplastics (MPs) in farmland remain largely unknown. Here, antibiotic resistance genes (ARGs) and virulence factors (VFs) on polyethylene microplastics (PE-MPs) and polybutylene adipate terephthalate and polylactic acid microplastics (PBAT/PLA-MPs) from residues were investigated using metagenomic analysis. The results suggested that the profiles of ARG and VF in the plastisphere of PBAT/PLA-MPs had greater number of detected genes with statistically higher values of diversity and abundance than soil and PE-MP. Procrustes analysis indicated a good fitting correlation between ARG/VF profiles and bacterial community composition. Actinobacteria was the major host for tetracycline and glycopeptide resistance genes in the soil and PE-MP plastisphere, whereas the primary host for multidrug resistance genes changed to Proteobacteria in PBAT/PLA-MP plastisphere. Besides, three human pathogens, Sphingomonas paucimobilis, Lactobacillus plantarum and Pseudomonas aeruginosa were identified in the plastisphere. The PE-MP plastisphere exhibited a higher transfer potential of ARGs than PBAT/PLA-MP plastisphere. This work enhances our knowledge of potential environmental risks posed by microplastic in farmland and provides valuable insights for risk assessment and management of agricultural mulching applications.


Assuntos
Microplásticos , Plásticos , Humanos , Fazendas , Antibacterianos , Poliésteres , Solo
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