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BACKGROUND: Inner Mongolia cashmere goat (IMCG), renowned for its superior cashmere quality, is a Chinese indigenous goat breed that has been developed through natural and artificial selection over a long period. However, recently, the genetic resources of IMCGs have been significantly threatened by the introduction of cosmopolitan goat breeds and the absence of adequate breed protection systems. RESULTS: In order to assess the conservation effectiveness of IMCGs and efficiently preserve and utilize the purebred germplasm resources, this study analyzed the genetic diversity, kinship, family structure, and inbreeding of IMCGs utilizing resequencing data from 225 randomly selected individuals analyzed using the Plink (v.1.90), GCTA (v.1.94.1), and R (v.4.2.1) software. A total of 12,700,178 high-quality SNPs were selected through quality control from 34,248,064 SNP sites obtained from 225 individuals. The average minor allele frequency (MAF), polymorphic information content (PIC), and Shannon information index (SHI) were 0.253, 0.284, and 0.530, respectively. The average observed heterozygosity (Ho) and the average expected heterozygosity (He) were 0.355 and 0.351, respectively. The analysis of the identity by state distance matrix and genomic relationship matrix has shown that most individuals' genetic distance and genetic relationship are far away, and the inbreeding coefficient is low. The family structure analysis identified 10 families among the 23 rams. A total of 14,109 runs of homozygosity (ROH) were identified in the 225 individuals, with an average ROH length of 1014.547 kb. The average inbreeding coefficient, calculated from ROH, was 0.026 for the overall population and 0.027 specifically among the 23 rams, indicating a low level of inbreeding within the conserved population. CONCLUSIONS: The IMCGs exhibited moderate polymorphism and a low level of kinship with inbreeding occurring among a limited number of individuals. Simultaneously, it is necessary to prevent the loss of bloodline to guarantee the perpetuation of the IMCGs' germplasm resources.
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Variação Genética , Cabras , Polimorfismo de Nucleotídeo Único , Animais , Cabras/genética , Sequenciamento Completo do Genoma , Frequência do Gene , Endogamia , ChinaRESUMO
Objective: This study aimed to assess the current status of early enteral nutrition (EN) support among patients diagnosed with acute pancreatitis (AP) and analyze the factors influencing its duration. The findings aimed to provide guidance for the development of tailored EN support protocols for pancreatitis patients. Methods: A convenience sampling method was employed, and 51 patients diagnosed with acute pancreatitis (AP) were enrolled from the Gastroenterology Department of Zhoushan Hospital between May 2020 and June 2021. Data analysis included the categorization of patients based on their early enteral nutrition (EN) support duration, followed by thorough statistical analysis, including logistic regression, to identify the factors impacting EN duration. Results: The mean duration of early EN support among AP patients was (93.57 ± 43.29) hours. A mere 13.73% of patients initiated EN within 48 hours of admission. Upon categorizing patients by the median duration of EN support, multiple logistic regression analysis revealed several significant risk factors influencing the duration of EN in AP patients, including patient age, underlying medical conditions, severity of pancreatitis, nutritional status, and blood lipase levels (P < .05). Conclusion: The study highlights the significant influence of disease severity and patients' functional status on the duration of early EN support in AP cases. It emphasizes the importance of a comprehensive patient assessment by medical professionals to determine the optimal timing for initiating EN support.
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Nutrição Enteral , Pancreatite , Humanos , Nutrição Enteral/métodos , Pancreatite/terapia , Doença Aguda , Apoio Nutricional , Estado NutricionalRESUMO
Progressive degeneration of retinal ganglion cells (RGCs) is a major characteristic of glaucoma, whose underlying mechanisms are still largely unknown. An E50K mutation in the Optineurin (OPTN) gene is a leading cause of normal tension glaucoma (NTG), directly affecting RGCs without high intraocular pressure and causing severe glaucomatous symptoms in clinical settings. A systematic analysis of the NTG mouse model is crucial for better understanding of the underlying pathological mechanisms for glaucoma. To elucidate proteomic and biochemical pathway alterations during NTG development, we established an OPTN E50K mutant mouse model through CRISPR/Cas9. Retinal proteins from resulting mice exhibiting glaucomatous phenotypes were subject to tandem mass tag-labeled quantitative proteomics and then analyzed through bioinformatics methods to characterize the molecular and functional signatures of NTG. We identified 6364 quantitative proteins in our proteomic analysis. Bioinformatics analysis revealed that OPTN E50K mice experienced protein synthesis dysregulation, age-dependent energy defects and autophagy-lysosome pathway dysfunction. Certain biological features, including amyloid deposition, RNA splicing, microglia activation and reduction of crystallin production, were similar to Alzheimer's disease. Our study is the first to describe proteomic and biochemical pathway alterations in NTG pathogenesis during disease advancement. Several proteomic signatures overlapped with retinal changes found in the ad mice model, suggesting the presence of common mechanisms between age-related degenerative disorders, as well as prospective new targets for diagnostic and therapeutic strategies.
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Proteínas de Ciclo Celular/genética , Glaucoma de Baixa Tensão/genética , Proteínas de Membrana Transportadoras/genética , Retina/metabolismo , Animais , Autofagia/genética , Sistemas CRISPR-Cas/genética , Modelos Animais de Doenças , Humanos , Glaucoma de Baixa Tensão/metabolismo , Glaucoma de Baixa Tensão/patologia , Camundongos , Mutação/genética , Fenótipo , Proteômica , Retina/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Fator de Transcrição TFIIIARESUMO
BACKGROUND: Polarization of microglia, the resident retinal immune cells, plays important roles in mediating both injury and repair responses post-retinal ischemia-reperfusion (I/R) injury, which is one of the main pathological mechanisms behind ganglion cell apoptosis. Aging could perturb microglial balances, resulting in lowered post-I/R retinal repair. Young bone marrow (BM) stem cell antigen 1-positive (Sca-1+) cells have been demonstrated to have higher reparative capabilities post-I/R retinal injury when transplanted into old mice, where they were able to home and differentiate into retinal microglia. METHODS: Exosomes were enriched from young Sca-1+ or Sca-1- cells, and injected into the vitreous humor of old mice post-retinal I/R. Bioinformatics analyses, including miRNA sequencing, was used to analyze exosome contents, which was confirmed by RT-qPCR. Western blot was then performed to examine expression levels of inflammatory factors and underlying signaling pathway proteins, while immunofluorescence staining was used to examine the extent of pro-inflammatory M1 microglial polarization. Fluoro-Gold labelling was then utilized to identify viable ganglion cells, while H&E staining was used to examine retinal morphology post-I/R and exosome treatment. RESULTS: Sca-1+ exosome-injected mice yielded better visual functional preservation and lowered inflammatory factors, compared to Sca-1-, at days 1, 3, and 7 days post-I/R. miRNA sequencing found that Sca-1+ exosomes had higher miR-150-5p levels, compared to Sca-1- exosomes, which was confirmed by RT-qPCR. Mechanistic analysis found that miR-150-5p from Sca-1+ exosomes repressed the mitogen-activated protein kinase kinase kinase 3 (MEKK3)/JNK/c-Jun axis, leading to IL-6 and TNF-α downregulation, and subsequently reduced microglial polarization, all of which contributes to reduced ganglion cell apoptosis and preservation of proper retinal morphology. CONCLUSION: This study elucidates a potential new therapeutic approach for neuroprotection against I/R injury, via delivering miR-150-5p-enriched Sca-1+ exosomes, which targets the miR-150-5p/MEKK3/JNK/c-Jun axis, thereby serving as a cell-free remedy for treating retinal I/R injury and preserving visual functioning.
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Exossomos , MicroRNAs , Traumatismo por Reperfusão , Camundongos , Animais , Microglia/metabolismo , MicroRNAs/metabolismo , Exossomos/metabolismo , Traumatismo por Reperfusão/metabolismo , Células da Medula Óssea/metabolismoRESUMO
BACKGROUND: Prostaglandin analogs (PGAs) are the first-line treatment for primary open-angle glaucoma (POAG) and ocular hypertension (OH). This study aimed to confirm the effectiveness and safety of Tapros® (0.0015% tafluprost eye drops) in Chinese patients with POAG and OH. METHODS: This phase IV, multicenter, non-comparative, prospective study enrolled patients with POAG and OH in China between 12/27/2017 and 04/15/2020. Patients who were treatment-naïve or untreated within one month (group A) or with unreached intraocular pressure (IOP) target after previous monotherapy of other PGAs (group B) or non-PGA IOP-lowering drugs (group C) were treated with 0.0015% tafluprost for three months. The IOP reduction, response rate, and safety were observed. RESULTS: There were 165, 89, and 31 patients in groups A, B, and C, with baseline IOPs of 22.4 ± 4.7, 21.0 ± 3.5, and 22.5 ± 3.2 mmHg, respectively. The least-square means and percentages of IOP reduction at 3 months for groups A, B, and C were 4.7 (19.8%), 1.6 (6.1%), and 4.6 mmHg (20.3%), respectively. A significant reduction in IOP was observed at each visit compared with baseline (all P < 0.05). At the final visit, 57.0% of the participants in group A achieved an IOP reduction of ≥ 20%, while 40.4% and 77.4% in groups B and C achieved an IOP reduction of ≥ 10%. Fifty-eight treatment-related adverse events occurred in 46 participants (15.7%), of which the most common one was conjunctival hyperemia (34/293, 11.6%). CONCLUSIONS: Tafluprost showed a sustained and significant effect with tolerable adverse events in Chinese patients with POAG and OH who were treatment-naïve or untreated within one month or received prior treatments with unsatisfying outcomes.
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Glaucoma de Ângulo Aberto , Glaucoma , Hipertensão Ocular , Hipotensão Ocular , Anti-Hipertensivos/efeitos adversos , Glaucoma/tratamento farmacológico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Humanos , Pressão Intraocular , Marketing , Hipotensão Ocular/tratamento farmacológico , Estudos Prospectivos , Prostaglandinas F , Prostaglandinas Sintéticas , Resultado do TratamentoRESUMO
BACKGROUND: Although moderate weight loss improves outcomes of type 2 diabetes mellitus (T2DM) in young and middle-aged adults, there is a lack of high-quality evidence to support the strong relationship between obesity and T2DM in older people. This study aims to investigate whether the association of obesity with T2DM changes with aging. METHODS: In this cross-sectional study, we recruited 63,180 Chinses and US subjects from 3 datasets. Subjects were divided into young & middle-aged (≤59 years), young-old (60-75 years), and old-old (≥75 years). Logistic regression was used to determine the odds ratio (OR) and 95% confidence intervals (95% CI) for the association between obesity and T2DM, stratified by common confounders. A sliding-window based algorithm and restricted cubic splines were used to smoothly estimate the changes with aging. RESULTS: The OR (95% CI) for the associations between general obesity and T2DM were decreased from the young & middle-aged group (OR, 5.91; 95% CI, 5.33-6.56) to the young-old group (OR, 3.98; 95% CI, 3.56-4.45) and then to the old-old group (OR, 3.06; 95% CI, 2.57-3.66). The trend for this reduced association with aging persisted after stratification by obesity type, region, gender, recruiting time, hypertension, and hyperlipidemia in both Chinese and Americans. We also identified a weakened gender disparity for this association between the young & middle-aged subjects (P for disparity < 0.001) and the old-old group (P for disparity = ~ 0.36). CONCLUSIONS: The obesity-T2DM association is clearly reduced with aging, which indicates that the elderly may gain fewer potential benefits in weight lose than the younger patients. Considering this attenuated association, as well as the increased incidence of geriatric syndrome in the elderly, clinicians should comprehensively balance the benefits and side effects of weight loss in geriatric T2DM interventions.
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Diabetes Mellitus Tipo 2 , Idoso , China/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Humanos , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/terapia , Fatores de Risco , Redução de PesoRESUMO
Human longevity is a complex phenotype influenced by both genetic and environmental factors. It is also known to be associated with various types of age-related diseases, such as Alzheimer's disease (AD) and cardiovascular disease (CVD). The central dogma of molecular biology demonstrates the conversion of DNA to RNA to the encoded protein. These proteins interact to form complex cell signaling pathways, which perform various biological functions. With prolonged exposure to the environment, the in vivo homeostasis adapts to the changes, and finally, humans adopt the phenotype of longevity or aging-related diseases. In this review, we focus on two different states: longevity and aging-related diseases, including CVD and AD, to discuss the relationship between genetic characteristics, including gene variation, the level of gene expression, regulation of gene expression, the level of protein expression, both genetic and environmental influences and homeostasis based on these phenotypes shown in organisms.
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PURPOSE: To investigate the prevalence of refractive error in adults 40 years of age and older in Kailu, Inner Mongolia. METHODS: A population-based, cross-sectional study was conducted in Chinese adults. Spherical equivalent (S.E.) refractive error was determined from the right eye. Myopia and hyperopia were defined as a spherical equivalent (S.E.) < -0.5 dioptres (D) and >0.5 D, respectively. Since the prevalence of high myopia will vary with the precise criterion chosen, the prevalence of this condition was calculated for thresholds of both <-5.0 D and <6.0 D. Astigmatism was defined as cylinder power >0.5 D. Anisometropia was defined as a difference in S.E. between the two eyes >1.0 D. RESULTS: The prevalence of myopia, high myopia (<-5.0 D/<-6.0 D) and hyperopia in Kailu adults was 60.3% (95%CI: 58.95-61.71), 5.5% (95%CI: 4.82-6.10) /4.0% (95%CI: 3.47-4.57) and 12.2% (95%CI: 11.26-13.11), respectively. The age- and gender-standardised prevalence of myopia, high myopia (-5.0 D/-6.0 D) and hyperopia were 62.5% (95%CI: 61.05-63.99), 5.0% (95%CI: 4.34-5.61) /3.5% (95%CI: 2.99-4.04) and 10.6% (95%CI: 9.71-11.49), respectively. 52.9% had refractive astigmatism >0.5 D and 18.8% of subjects had clinically significant anisometropia. Age was significantly associated with hyperopia, high myopia, astigmatism and anisometropia. Myopia was more prevalent in females. Individuals with a higher educational level had a greater and lesser likelihood of myopia and astigmatism, respectively. CONCLUSIONS: Myopia affects around two-thirds of the rural Chinese population over 40 years of age in Kailu. This high prevalence highlights that rural populations should be included in epidemiological studies of refractive error. Further investigations are needed to clarify the role of environmental factors in myopia development.
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Povo Asiático/estatística & dados numéricos , Erros de Refração/epidemiologia , População Rural/estatística & dados numéricos , Adulto , Distribuição por Idade , Idoso , Astigmatismo/epidemiologia , China/epidemiologia , Estudos Transversais , Escolaridade , Feminino , Humanos , Hiperopia/epidemiologia , Masculino , Pessoa de Meia-Idade , Miopia/epidemiologia , Prevalência , Fatores de Risco , Distribuição por SexoRESUMO
BACKGROUND: Excessive copper (Cu) has risky effect on insulin resistance (IR), oxidative stress and inflammation. Instead, some studies reported serum Cu to be protective for non-alcoholic fatty liver disease (NAFLD). The aim of this study was to reevaluate the evidence for a potential risky correlation of serum Cu to NAFLD in large-scale and non-institutionalized American subjects. METHODS: A cross-sectional study of 3211 subjects was from the National Health and Nutrition Examination Survey (NHANES). Logistic regression and cubic spline-based curve-fitting analyses were used to estimate the independent risky effect of Cu to hepatic steatosis index (HSI), US fatty liver index (USFLI) and NAFLD and their dose-effect relationship. Moreover, this association was analyzed in stratification of HOMA-IR, Metabolic syndrome (MetS) and severity of NAFLD, besides age and gender. RESULTS: The average level of serum Cu was 18.67 µmol/L and the prevalence of NAFLD was 54.53% and 32.60%, respectively defined by HSI and USFLI. Generally, the level of Cu was higher in females than males. Serum Cu was positively associated with higher HSI, USFLI index and risk of NAFLD. In fully adjusted models, compared with the lowest quartile, the risk of NAFLD increased 97% in the highest quartile of Cu. Interestingly, stratified analysis showed that the risky effect of Cu to NAFLD was more prominent in the middle-aged, females and subjects with improved status of IR (lower HOMA-IR and non-Mets) compared with their counterparts. Moreover, we further found that circulating copper was correlated to severity of NAFLD only in males. CONCLUSION: Excess serum Cu is significantly associated with risk of NAFLD, which is prominent in females, middle-aged and subjects with improved status of IR, and seems to be related to the severity of NAFLD, additionally. It is necessary to be cautious of the toxic effect of Cu and prospective cohort and mechanism studies are needed to verify the causal effect of Cu to NAFLD.
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BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer morbidity and mortality in men worldwide; however, PCa incidence and mortality rates vary widely across geographic regions and ethnic groups. The current study was designed to elucidate the pivotal factors involved in PCa occurrence and development. METHODS: We performed RNA sequencing on the prostate tumor and adjacent normal tissues from Chinese PCa patients. Genes identified via genome-wide expression profile analysis were validated by quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. Hypermethylation of CpG islands was assessed by nested methylation-specific PCR. Whole genome microarray analysis was performed using an Affymetrix GeneChip. RESULTS: We identified nine possible abnormally expressed genes (P < .05) and then revealed TWIST2 as having strikingly lower expression in tumors than in control tissues (P < .01). Low messenger RNA expression levels of TWIST2 were associated with hypermethylation of CpG islands in its promoter region. In accordance with these findings, PCa tumor tissues showed markedly decreased TWIST2 protein expression compared to that in both normal and prostatic intraepithelial neoplasia tissues by immunohistochemical staining. Ectopic expression of TWIST2 in LNCap cells not only inhibited cell proliferation and colony formation in vitro and tumor growth in vivo but also induced transcriptional repression of a cell proliferation-related gene cohort, including androgen receptor signaling mediators, cyclins, homeobox genes, forkhead box genes, and SOX2. CONCLUSIONS: Our results suggest that TWIST2 could function as a tumor suppressor involved in the pathogenesis of PCa by influencing the expression of target genes and that hypermethylation of the TWIST2 promoter in prostate tumors may be an underlying mechanism for TWIST2 transcriptional silencing.
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Neoplasias da Próstata/genética , Proteínas Supressoras de Tumor , Proteína 2 Relacionada a Twist/genética , China , Ilhas de CpG , Metilação de DNA , Epigênese Genética , Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise em Microsséries , Regiões Promotoras Genéticas , Neoplasia Prostática Intraepitelial/química , Neoplasias da Próstata/química , RNA Mensageiro/análise , Análise de Sequência de RNA , Células Tumorais Cultivadas , Proteína 2 Relacionada a Twist/análise , Proteína 2 Relacionada a Twist/fisiologiaRESUMO
The human rhomboid family-1 gene (RHBDF1) is an oncogene in breast and head and neck squamous cancers. Here, we show that RHBDF1 plays a significant role in colorectal cancer (CRC) formation and that the RHBDF1 expression level is higher in CRC than in corresponding normal tissues. Moreover, RHBDF1 promotes cell proliferation, invasion and migration in vitro. Furthermore, through overexpression and silencing of RHBDF1 and the mediator complex, our study demonstrates that RHBDF1 may positively regulate adenomatous polyposis coli (APC) in the Wnt/ß-catenin signalling pathway to increase the expression levels of MMP-14 and Twist, which act as important epithelial-to-mesenchymal transition (EMT) stimulating factors. Additionally, RHBDF1 may regulate c-myc and CyclinD1 expression to influence cell proliferation. Finally, RHBDF1 overexpression and silencing influence CRC growth in BALB/c nude mice. In summary, our findings demonstrate that the regulatory effects of RHBDF1 on EMT and on cell proliferation are partially attributable to the Wnt/ß-catenin signalling pathway.
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Polipose Adenomatosa do Colo/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transformação Celular Neoplásica/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , beta Catenina/metabolismoRESUMO
BACKGROUND: CDK8 is associated with the transcriptional Mediator complex and has been shown to regulate several transcription factors implicated in cancer. As a pancreatic cancer oncogene, the role of CDK8 in cancer angiogenesis remains unclear. Here, we investigated the contribution of CDK8 in pancreatic cancer angiogenesis and examined the underlying molecular mechanisms. METHODS: CDK8 expression was evaluated via immunohistochemistry, western blotting, and qRT-PCR in relation to the clinicopathological characteristics of pancreatic cancer patients. The effects of silencing or overexpressing CDK8 on cancer angiogenesis were assessed in vitro by western blotting assays in pancreatic cancer cell lines and in vivo with nude mice xenograft models. RESULTS: Compared with adjacent normal tissues, pancreatic cancer tissues showed upregulation of CDK8 expression, which was inversely correlated with T grade, liver metastasis, size, lymph node metastasis and poor survival. CDK8 overexpression promoted angiogenesis in pancreatic cancer via activation of the CDK8-ß-catenin-KLF2 signaling axis, as demonstrated by the upregulation and downregulation of signals representing the rate-limiting steps in angiogenesis. Silencing CDK8 inhibited angiogenesis in pancreatic cancer in vitro. Additionally, these results were confirmed in nude mice xenograft models in vivo. CONCLUSIONS: CDK8 promotes angiogenesis in pancreatic cancer via activation of the CDK8-ß-catenin-KLF2 signaling axis, thus providing valid targets for the treatment of pancreatic cancer.
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Quinase 8 Dependente de Ciclina/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Neovascularização Patológica/metabolismo , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/metabolismo , beta Catenina/metabolismo , Idoso , Animais , Linhagem Celular Tumoral , Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Quinase 8 Dependente de Ciclina/genética , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Neoplasias Pancreáticas/genética , RNA Interferente Pequeno/genética , Transdução de Sinais , Regulação para Cima , beta Catenina/antagonistas & inibidores , beta Catenina/genéticaRESUMO
Retinal ganglion cell apoptosis and optic nerve degeneration are prevalent in aged patients, which may be related to the decrease in bone marrow (BM) stem cell number/function because of the possible cross-talk between the two organs. This pathological process is accelerated by retinal ischaemia-reperfusion (I/R) injury. This study investigated whether young BM stem cells can regenerate and repair the aged retina after acute I/R injury. Young BM stem cell antigen 1 positive (Sca-1+ ) or Sca-1- cells were transplanted into lethally irradiated aged recipient mice to generate Sca-1+ and Sca-1- chimaeras, respectively. The animals were housed for 3 months to allow the young Sca-1 cells to repopulate in the BM of aged mice. Retinal I/R was then induced by elevation of intraocular pressure. Better preservation of visual function was found in Sca-1+ than Sca-1- chimaeras 7 days after injury. More Sca-1+ cells homed to the retina than Sca-1- cells and more cells differentiated into glial and microglial cells in the Sca-1+ chimaeras. After injury, Sca-1+ cells in the retina reduced host cellular apoptosis, which was associated with higher expression of fibroblast growth factor 2 (FGF2) in the Sca-1+ chimaeras. Young Sca-1+ cells repopulated the stem cells in the aged retina and diminished cellular apoptosis after acute I/R injury through FGF2 and Akt signalling pathways.
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Antígenos Ly/genética , Fator 2 de Crescimento de Fibroblastos/genética , Proteínas de Membrana/genética , Traumatismo por Reperfusão/terapia , Transplante de Células-Tronco , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Apoptose/genética , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Nervo Óptico/metabolismo , Nervo Óptico/patologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Retina/crescimento & desenvolvimento , Retina/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologiaRESUMO
The article is withdrawn by the authors request.
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BACKGROUND The main aim of the current investigation was to study the antiproliferative activity of gingerol in RB355 human retinoblastoma cancer cells. The effects of gingerol on apoptosis induction, cell cycle arrest, and PI3K/Akt signaling pathway were also evaluated. MATERIAL AND METHODS MTT cell viability assay was used to assess the cytotoxic effects of gingerol in these cells while. To study apoptotic effects in these cells, we used inverted microscopy along with fluorescence microscopy using acridine orange/propidium iodide and Hoechst 33258 as staining dyes. Flow cytometry was used to study cell cycle phase distribution and Western blot assay indicated effects on PI3K/Akt protein expression levels. RESULTS Results showed that gingerol exerted dose-dependent and time-dependent growth inhibitory effects in these retinoblastoma cells. However, the growth inhibitory effects of gingerol were less pronounced against normal fr2 cells. As compared to the untreated control cells, gingerol-treated cells at concentrations of 25, 75, and 150 µM had drastic changes in cell morphology, including rounding and withering of cells, with disorganized cell layers. Gingerol-treated cells exhibited bright fluorescence, indicating rupture of the cell membrane. These results were further confirmed by acridine orange/propidium iodide staining, in which untreated cells showed normal green fluorescence and gingerol-treated cells showed yellow/red fluorescence. Gingerol also led to dose-dependent G2/M phase cell cycle arrest in RB355 retinoblastoma cells, as well as concentration-dependent activation of PI3K-related protein expressions. CONCLUSIONS Gingerol exhibits potent anticancer effects in RB355 human retinoblastoma cancer cells and these effects were mediated via apoptosis induction, cell cycle arrest, and modulation of the PI3K/Akt signaling pathway.
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Catecóis/farmacologia , Álcoois Graxos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias da Retina/enzimologia , Neoplasias da Retina/patologia , Retinoblastoma/enzimologia , Retinoblastoma/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
In the present work, several MEEKC systems are studied to assess their suitability for lipophilicity determination of acidic, neutral, and basic compounds. Thus, several microemulsion compositions over a wide range of pH values (from 2.0 to 12.0), containing heptane, 1-butanol and different types and amounts of surfactant (SDS or sodium cholate: from 1.3 to 3.3%) are characterized using Abraham's solvation model. The addition of acetonitrile (up to 10%) is also studied, since it increases the resolution of the technique for the most lipophilic compounds. The system coefficients obtained are very similar to those of the 1-octanol/water, used as the reference lipophilicity index, allowing simple and linear correlations between the 1-octanol/water partition values (log Po/w ) and MEEKC mass distribution ratios (log kMEEKC ). Variations in the microemulsion composition (aqueous buffer, surfactant, concentration of ACN) did not significantly affect the similarity of the MEEKC systems to log Po/w partition.
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Cromatografia Capilar Eletrocinética Micelar/métodos , Emulsões , Concentração de Íons de Hidrogênio , Lipídeos/química , Modelos QuímicosRESUMO
Multiple mechanisms contribute to progressive cardiac dysfunction after myocardial infarction (MI) and inflammation is an important mediator. Mast cells (MCs) trigger inflammation after MI by releasing bio-active factors that contribute to healing. c-Kit-deficient (Kit(W/W-v) ) mice have dysfunctional MCs and develop severe ventricular dilatation post-MI. We explored the role of MCs in post-MI repair. Mouse wild-type (WT) and Kit(W/W-v) MCs were obtained from bone marrow (BM). MC effects on fibroblasts were examined in vitro by proliferation and gel contraction assays. MCs were implanted into infarcted mouse hearts and their effects were evaluated using molecular, cellular and cardiac functional analyses. In contrast to WT, Kit(W/W-v) MC transplantation into Kit(W/W-v) mice did not improve cardiac function or scar size post-MI. Kit(W/W-v) MCs induced significantly reduced fibroblast proliferation and contraction compared to WT MCs. MC influence on fibroblast proliferation was Basic fibroblast growth factor (bFGF)-dependent and MC-induced fibroblast contractility functioned through transforming growth factor (TGF)-ß. WT MCs transiently rescue cardiac function early post-MI, but the benefits of BM cell implantation lasted longer. MCs induced increased inflammation compared to the BM-injected mice, with increased neutrophil infiltration and infarct tumour necrosis factor-α (TNF-α) concentration. This augmented inflammation was followed by increased angiogenesis and myofibroblast formation and reduced scar size at early time-points. Similar to the functional data, these beneficial effects were transient, largely vanishing by day 28. Dysfunctional Kit(W/W-v) MCs were unable to rescue cardiac function post-MI. WT MC implantation transiently enhanced angiogenesis and cardiac function. These data suggest that increased inflammation is beneficial to cardiac repair, but these effects are not persistent.
Assuntos
Inflamação/metabolismo , Mastócitos/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Animais , Vasos Sanguíneos/metabolismo , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Ensaio de Imunoadsorção Enzimática , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Inflamação/fisiopatologia , Inflamação/terapia , Mastócitos/transplante , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Miocárdio/patologia , Miofibroblastos/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In this paper, the gaseous and electrochemical hydrogen storage properties of 200 nm Mg-Pd thin films with different morphologies have been investigated. The results show that Mg-Pd films become porous with the increase of substrate temperature. Porous Mg-Pd films exhibit superior gaseous and electrochemical hydrogen storage behaviors under mild conditions, including rapid hydrogen sorption kinetics, a large hydrogen storage amount, high electrochemical discharge capacity, and a fast hydrogen diffusion rate. The excellent behaviors of porous Mg-Pd films might be ascribed to the significantly shortened hydrogen diffusion paths and the large contact areas between the hydrogen gas and the solid Mg phases, which are elucidative for the development and applications of thick Mg-Pd films.
RESUMO
PURPOSE: Prostate cancer (PCa) is one of the most common malignancies in males, and multiple genetic studies have confirmed association with susceptibility to PCa. However, the risk conferred in men living in China is unkown. We selected 6 previously identified variants as candidates to define their association with PCa in Chinese men. METHODS: We genotyped 6 single nucleotide polymorphisms (SNPs) (rs1465618, rs1983891, rs339331, rs16901966, rs1447295 and rs10090154) using high resolution melting (HRM) analysis and assessed their association with PCa risk in a case-control study of 481 patients and 480 controls in a Chinese population. In addition, the individual and cumulative contribution for the risk of PCa and clinical covariates were analysed. RESULTS: We found that 5 of the 6 genetic variants were associated with PCa risk. The T allele of rs339331 and the G allele of rs16901966 showed a significant association with PCa susceptibility: OR (95%CI)= 0.78 (0.64-0.94), p<0.009 and OR (95%CI)= 0.66 (0.54-0.81), p<0.0001, as well as A allele of rs1447295 (OR [95%CI]=1.46 (1.17-1.84), p<0.001) and T allele of rs10090154 (OR [95%CI]= 0.58 (0.46-0.74), p<0.0001). rs339331(T) was associated with a 0.71-fold and 1.42-fold increase of PCa risk by dominant model (p=0.007) and recessive model (p=0.007). rs16901966 (G) was associated with a 0.51-fold and 1.98-fold increase of PCa risk by dominant model (p=0.006) and recessive model (p=0.0058). rs10090154 (T) was associated with a 1.89-fold and 0.53-fold increase of PCa risk by dominant model (p=0.000006) and recessive model (p=0.000006). And, rs1983891(C) was associated with a 0.77-fold increase of PCa risk by recessive model (p=0.045). rs1447295 was associated with a 1.57-fold increase of PCa risk by dominant model (p=0.008). rs1465618 showed no significant association with PCa. The cumulative effects test of risk alleles (rs rs1983891, rs339331, rs16901966, rs1447295 and rs10090154) showed an increasing risk to PCa in a frequency-dependent manner (ptrend=0.001), and men with more than 3 risk alleles had the most significant susceptibility to PCa (OR=1.99, p=0.001), compared with those who had one risk allele (OR=1.17, p=0.486). CONCLUSION: Our results provide further support for association of the THADA, FOXP4, GPRC6A/RFX6 and 8q24 genes with Pca in Asian populations. Further work is still required to determine the functional variations and finally clarify the underlying biological mechanisms.