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1.
Free Radic Biol Med ; 221: 273-282, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38740102

RESUMO

Defective mitochondria and autophagy, as well as accumulation of lipid and iron in WDR45 mutant fibroblasts, is related to beta-propeller protein-associated neurodegeneration (BPAN). In this study, we found that enlarged lysosomes in cells derived from patients with BPAN had low enzyme activity, and most of the enlarged lysosomes had an accumulation of iron and oxidized lipid. Cryo-electron tomography revealed elongated lipid accumulation, and spectrometry-based elemental analysis showed that lysosomal iron and oxygen accumulation superimposed with lipid aggregates. Lysosomal lipid aggregates superimposed with autofluorescence as free radical generator, lipofuscin. To eliminate free radical stress by iron accumulation in cells derived from patients with BPAN, we investigated the effects of the iron chelator, 2,2'-bipyridine (bipyridyl, BIP). To study whether the defects in patient-derived cells can be rescued by an iron chelator BIP, we tested whether the level of iron and reactive oxygen species (ROS) in the cells and genes related to oxidative stress were rescued BIP treatment. Although BIP treatment decreased some iron accumulation in the cytoplasm and mitochondria, the accumulation of iron in the lysosomes and levels of cellular ROS were unaffected. In addition, the change of specific RNA levels related to free radical stress in patient fibroblasts was not rescued by BIP. To alleviate free radical stress, we investigated whether l-serine can regulate abnormal structures in cells derived from patients with BPAN through the regulation of free radical stress. l-serine treatment alleviated increase of enlarged lysosomes and iron accumulation and rescued impaired lysosomal activity by reducing oxidized lipid accumulation in the lysosomes of the cells. Lamellated lipids in the lysosomes of the cells were identified as lipofuscin through correlative light and electron microscopy, and l-serine treatment reduced the increase of lipofuscin. These data suggest that l-serine reduces oxidative stress-mediated lysosomal lipid oxidation and iron accumulation by rescuing lysosomal activity.

2.
Diabetes Metab J ; 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38311058

RESUMO

Background: We aimed to evaluate whether composite blood biomarkers including aldo-keto reductase family 1 member B10 (AKR1B10) and cytokeratin 18 (CK-18; a nonalcoholic steatohepatitis [NASH] marker) have clinically applicable performance for the diagnosis of NASH, advanced liver fibrosis, and high-risk NASH (NASH+significant fibrosis). Methods: A total of 116 subjects including healthy control subjects and patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) were analyzed to assess composite blood-based and imaging-based biomarkers either singly or in combination. Results: A composite blood biomarker comprised of AKR1B10, CK-18, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) showed excellent performance for the diagnosis of, NASH, advanced fibrosis, and high-risk NASH, with area under the receiver operating characteristic curve values of 0.934 (95% confidence interval [CI], 0.888 to 0.981), 0.902 (95% CI, 0.832 to 0.971), and 0.918 (95% CI, 0.862 to 0.974), respectively. However, the performance of this blood composite biomarker was inferior to that various magnetic resonance (MR)-based composite biomarkers, such as proton density fat fraction/MR elastography- liver stiffness measurement (MRE-LSM)/ALT/AST for NASH, MRE-LSM+fibrosis-4 index for advanced fibrosis, and the known MR imaging-AST (MAST) score for high-risk NASH. Conclusion: Our blood composite biomarker can be useful to distinguish progressive forms of NAFLD as an initial noninvasive test when MR-based tools are not available.

3.
J Immunol ; 212(1): 7-11, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-38038390

RESUMO

The 2'3'-cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of IFN genes (STING) pathway can sense infection and cellular stress by detecting cytosolic DNA. Upon ligand binding, cGAS produces the cyclic dinucleotide messenger cGAMP, which triggers its receptor STING. Active STING initiates gene transcription through the transcription factors IFN regulatory factor 3 (IRF3) and NF-κB and induces autophagy, but whether STING can cause changes in the metabolism of macrophages is unknown. In this study, we report that STING signaling activates ATP-citrate lyase (ACLY) by phosphorylation in human macrophages. Using genetic and pharmacologic perturbation, we show that STING targets ACLY via its prime downstream signaling effector TANK (TRAF family member-associated NF-κB activator)-binding kinase 1 (TBK1). We further identify that TBK1 alters cellular metabolism upon cGAMP treatment. Our results suggest that STING-mediated metabolic reprogramming adjusts the cellular response to DNA sensing in addition to transcription factor activation and autophagy induction.


Assuntos
NF-kappa B , Proteínas Serina-Treonina Quinases , Humanos , ATP Citrato (pro-S)-Liase/metabolismo , DNA , Fator Regulador 3 de Interferon/metabolismo , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Nucleotidiltransferases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo
4.
Sci Rep ; 13(1): 5998, 2023 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-37045895

RESUMO

Social jetlag refers to the discrepancy between social time and the body's internal rhythm, which can lead to unfavorable health outcomes. However, no study has directly explored the relation between social jetlag and chronic kidney disease (CKD). This study aims to investigate the relationship between social jetlag and CKD in a representative population of South Korea. This study included 8259 currently economically active Korean population in the Korea National Health and Nutrition Examination Survey. Social jetlag was calculated as the difference between the midpoint of sleep time on weekdays and free days. The estimated glomerular filtration rate (eGFR) was calculated the by using the serum creatinine value according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Participants with an eGFR less than 60 ml/min/1.73 m2 were defined as CKD cases. The estimated glomerular filtration rate decreased as social jetlag increased. Multiple logistic regression analysis showed that the adjusted odds ratio (95% confidence interval) of CKD for 1-2 h of social jetlag was 0.926 (0.660-1.299), while the odds ratio for more than 2 h was 2.042 (1.328-3.139) when less than 1 h was used as reference. This study found that social jetlag and risk of CKD were significantly related in the Korean working population.


Assuntos
Insuficiência Renal Crônica , Humanos , Inquéritos Nutricionais , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/diagnóstico , Sono , República da Coreia/epidemiologia , Taxa de Filtração Glomerular , Creatinina
5.
Epidemiol Health ; 45: e2023016, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36758962

RESUMO

Korean Community Health Status Indicators (K-CHSI) is a model-based database containing annual data on health outcomes and determinants at the municipal level (si/gun/gu-level regions, including mid-sized cities, counties, and districts). K-CHSI's health outcomes include overall mortality, disease incidence, prevalence rates, and self-reported health. Health determinants were measured in 5 domains: socio-demographic factors, health behaviors, social environment, physical environment, and the healthcare system. The data sources are 71 public databases, including Causes of Death Statistics, Cancer Registration Statistics, Community Health Survey, Population Census, and Census on Establishments and Statistics of Urban Plans. This dataset covers Korea's 17 metropolitan cities and provinces, with data from approximately 250 municipal regions (si/gun/gu). The current version of the database (DB version 1.3) was built using 12 years of data from 2008 to 2019. All data included in K-CHSI may be downloaded via the Korea Community Health Survey site, with no login requirement (https://chs.kdca.go.kr/chs/recsRoom/dataBaseMain.do). K-CHSI covers extensive health outcomes and health determinants at the municipal level over a period of more than 10 years, which enables ecological and time-series analyses of the relationships among various health outcomes and related factors.


Assuntos
Meio Ambiente , Indicadores Básicos de Saúde , Humanos , Bases de Dados Factuais , Inquéritos Epidemiológicos , República da Coreia/epidemiologia , Saúde Pública
6.
Int J Mol Sci ; 23(9)2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35563425

RESUMO

We found several blood biomarkers through computational secretome analyses, including aldo-keto reductase family 1 member B10 (AKR1B10), which reflected the progression of nonalcoholic fatty liver disease (NAFLD). After confirming that hepatic AKR1B10 reflected the progression of NAFLD in a subgroup with NAFLD, we evaluated the diagnostic accuracy of plasma AKR1B10 and other biomarkers for the diagnosis of nonalcoholic steatohepatitis (NASH) and fibrosis in replication cohort. We enrolled healthy control subjects and patients with biopsy-proven NAFLD (n = 102) and evaluated the performance of various diagnostic markers. Plasma AKR1B10 performed well in the diagnosis of NASH with an area under the receiver operating characteristic (AUROC) curve of 0.834 and a cutoff value of 1078.2 pg/mL, as well as advanced fibrosis (AUROC curve value of 0.914 and cutoff level 1078.2 pg/mL), with further improvement in combination with C3. When we monitored a subgroup of obese patients who underwent bariatric surgery (n = 35), plasma AKR1B10 decreased dramatically, and 40.0% of patients with NASH at baseline showed a decrease in plasma AKR1B10 levels to below the cutoff level after the surgery. In an independent validation study, we proved that plasma AKR1B10 was a specific biomarker of NAFLD progression across varying degrees of renal dysfunction. Despite perfect correlation between plasma and serum levels of AKR1B10 in paired sample analysis, its serum level was 1.4-fold higher than that in plasma. Plasma AKR1B10 alone and in combination with C3 could be a useful noninvasive biomarker for the diagnosis of NASH and hepatic fibrosis.


Assuntos
Membro B10 da Família 1 de alfa-Ceto Redutase , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica , Membro B10 da Família 1 de alfa-Ceto Redutase/sangue , Membro B10 da Família 1 de alfa-Ceto Redutase/metabolismo , Biomarcadores , Fibrose , Humanos , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia
7.
BMC Public Health ; 22(1): 188, 2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-35086510

RESUMO

BACKGROUND: Although unintentional pregnancy loss is common, national representative statistics are lacking in high-income East Asian countries undergoing rapid demographic changes. It is necessary to confirm the income inequality of pregnancy loss even in universal national health insurance. METHOD: Using National Health Insurance Service data between 2008 and 2014, the annual prevalence of pregnancy loss was enumerated, and differences in pregnancy loss according to age and income levels were assessed by multivariable Poisson regression. Joint-point regression was used to examine the trend of pregnancy loss. RESULT: On average, there was a 15.0% annual pregnancy loss among 3,941,020 pregnancy cases from 2008 to 2014. Pregnancy loss inequality increased stepwise with income levels except for the highest income group. After adjusting for income levels, the annual percent change of age-standardized prevalence significantly increased by 2.6% every year since 2011. CONCLUSION: Even in high-income countries with universal national health insurance, income inequality in pregnancy loss is observed. Further appraisal is needed to explain the increasing trend of pregnancy loss between 2011 and 2014 even after adjusting income.


Assuntos
Aborto Espontâneo , Renda , Aborto Espontâneo/epidemiologia , Feminino , Humanos , Programas Nacionais de Saúde , Gravidez , Prevalência , República da Coreia/epidemiologia , Cobertura Universal do Seguro de Saúde
8.
Int J Mol Sci ; 22(21)2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34769084

RESUMO

Iron overload in the brain, defined as excess stores of iron, is known to be associated with neurological disorders. In neurodegeneration accompanied by brain iron accumulation, we reported a specific point mutation, c.974-1G>A in WD Repeat Domain 45 (WDR45), showing iron accumulation in the brain, and autophagy defects in the fibroblasts. In this study, we investigated whether fibroblasts with mutated WDR45 accumulated iron, and other effects on cellular organelles. We first identified the main location of iron accumulation in the mutant fibroblasts and then investigated the effects of this accumulation on cellular organelles, including lipid droplets, mitochondria and lysosomes. Ultrastructure analysis using transmission electron microscopy (TEM) and confocal microscopy showed structural changes in the organelles. Increased numbers of lipid droplets, fragmented mitochondria and increased numbers of lysosomal vesicles with functional disorder due to WDR45 deficiency were observed. Based on correlative light and electron microscopy (CLEM) findings, most of the iron accumulation was noted in the lysosomal vesicles. These changes were associated with defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed remarkable changes in lipid metabolism, mitochondrial function, and autophagy-related genes. These data suggested that functional and structural changes resulted in impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, caused by iron overload.


Assuntos
Proteínas de Transporte/genética , Fibroblastos/metabolismo , Ferro/metabolismo , Proteínas de Transporte/metabolismo , Células Cultivadas , Fibroblastos/citologia , Humanos , Ferro/análise , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/metabolismo , Gotículas Lipídicas/metabolismo , Lisossomos/genética , Lisossomos/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação Puntual , Polimorfismo de Nucleotídeo Único
9.
Pharmaceuticals (Basel) ; 14(11)2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34832960

RESUMO

Inflammation and immunity are linked to the onset and development of obesity and metabolic disorders. Pattern recognition receptors (PRRs) are key regulators of inflammation and immunity in response to infection and stress, and they have critical roles in metainflammation. In this study, we investigated whether RIG-I (retinoic acid-inducible gene I)-like receptors were involved in the regulation of obesity-induced metabolic stress in RIG-I knockout (KO) mice fed a high-fat diet (HFD). RIG-I KO mice fed an HFD for 12 weeks showed greater body weight gain, higher fat composition, lower lean body mass, and higher epididymal white adipose tissue (eWAT) weight than WT mice fed HFD. In contrast, body weight gain, fat, and lean mass compositions, and eWAT weight of MDA5 (melanoma differentiation-associated protein 5) KO mice fed HFD were similar to those of WT mice fed a normal diet. RIG-I KO mice fed HFD exhibited more severely impaired glucose tolerance and higher HOMA-IR values than WT mice fed HFD. IFN-ß expression induced by ER stress inducers, tunicamycin and thapsigargin, was abolished in RIG-I-deficient hepatocytes and macrophages, showing that RIG-I is required for ER stress-induced IFN-ß expression. Our results show that RIG-I deficiency promotes obesity and insulin resistance induced by a high-fat diet, presenting a novel role of RIG-I in the development of obesity and metabolic disorders.

10.
Int J Mol Sci ; 22(22)2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34830464

RESUMO

The genus Fragaria encompass fruits with diverse colors influenced by the distribution and accumulation of anthocyanin. Particularly, the fruit colors of strawberries with different ploidy levels are determined by expression and natural variations in the vital structural and regulatory genes involved in the anthocyanin pathway. Among the regulatory genes, MYB10 transcription factor is crucial for the expression of structural genes in the anthocyanin pathway. In the present study, we performed a genome wide investigation of MYB10 in the diploid and octoploid Fragaria species. Further, we identified seven quantitative trait loci (QTLs) associated with fruit color in octoploid strawberry. In addition, we predicted 20 candidate genes primarily influencing the fruit color based on the QTL results and transcriptome analysis of fruit skin and flesh tissues of light pink, red, and dark red strawberries. Moreover, the computational and transcriptome analysis of MYB10 in octoploid strawberry suggests that the difference in fruit colors could be predominantly influenced by the expression of MYB10 from the F. iinumae subgenome. The outcomes of the present endeavor will provide a platform for the understanding and tailoring of anthocyanin pathway in strawberry for the production of fruits with aesthetic colors.


Assuntos
Fragaria/genética , Proteínas de Plantas/genética , Locos de Características Quantitativas/genética , Fatores de Transcrição/genética , Antocianinas/genética , Cor , Fragaria/crescimento & desenvolvimento , Frutas/genética , Frutas/crescimento & desenvolvimento , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/genética , Estudo de Associação Genômica Ampla , Poliploidia
11.
Cells ; 10(3)2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806593

RESUMO

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.


Assuntos
Autofagia/fisiologia , Cromatografia Líquida/métodos , Fosfolipídeos/metabolismo , Espectrometria de Massas em Tandem/métodos , Humanos , Metástase Neoplásica , Estresse Oxidativo , Microambiente Tumoral
12.
Molecules ; 25(22)2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33187365

RESUMO

Watermelon (Citrulus lantus) is an important horticultural crop which belongs to the Curcubitaceae family. The nutraceutical potential of watermelon has been illustrated by several researchers, which makes it a better choice of functional food. Watermelon has been used to treat various ailments, such as cardio-vascular diseases, aging related ailments, obesity, diabetes, ulcers, and various types of cancers. The medicinal properties of watermelon are attributed by the presence of important phytochemicals with pharmaceutical values such as lycopene, citrulline, and other polyphenolic compounds. Watermelon acts as vital source of l-citrulline, a neutral-alpha amino acid which is the precursor of l-arginine, an essential amino acid necessary for protein synthesis. Supplementation of l-citrulline and lycopene displayed numerous health benefits in in vitro and in vivo studies. Similarly, the dietary intake of watermelon has proven benefits as functional food in humans for weight management. Apart from the fruits, the extracts prepared from the seeds, sprouts, and leaves also evidenced medicinal properties. The present review provides a comprehensive overview of benefits of watermelon for the treatment of various ailments.


Assuntos
Citrullus/química , Suplementos Nutricionais , Compostos Fitoquímicos/química , Extratos Vegetais/farmacologia , Aminoácidos/química , Animais , Antioxidantes/química , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Citrulina/química , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/prevenção & controle , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/prevenção & controle , Dieta , Frutas/química , Alimento Funcional , Horticultura , Humanos , Licopeno/química , Óxido Nítrico/metabolismo , Obesidade/tratamento farmacológico , Obesidade/prevenção & controle , Plantas Medicinais/metabolismo
13.
Plants (Basel) ; 9(11)2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33143243

RESUMO

The epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen and a potential target for tumor vaccine. The EpCAM is a cell-surface glycoprotein highly expressed in colorectal carcinomas. The objective of the present study is to develop an edible vaccine system through Agrobacterium-mediated transformation in Chinese cabbage (Brassica rapa). For the transformation, two plant expression vectors containing genes encoding for the EpCAM recombinant protein along with the fragment crystallizable (Fc) region of immunoglobulin M (IgM) and Joining (J)-chain tagged with the KDEL endoplasmic reticulum retention motif (J-chain K) were constructed. The vectors were successfully transformed and expressed in the Chinese cabbage individually using Agrobacterium. The transgenic Chinese cabbages were screened using genomic polymerase chain reaction (PCR) in T0 transgenic plant lines generated from both transformants. Similarly, the immunoblot analysis revealed the expression of recombinant proteins in the transformants. Further, the T1 transgenic plants were generated by selfing the transgenic plants (T0) carrying EpCAM-IgM Fc and J-chain K proteins, respectively. Subsequently, the T1 plants generated from EpCAM-IgM Fc and J-chain K transformants were crossed to generate F1 plants carrying both transgenes. The presence of both transgenes was validated using PCR in the F1 plants. In addition, the expression of Chinese cabbage-derived EpCAM-IgM Fc × J-chain K was evaluated using immunoblot and ELISA analyses in the F1 plants. The outcomes of the present study can be utilized for the development of a potential anti-cancer vaccine candidate using Chinese cabbage.

14.
BMJ Open ; 10(9): e039259, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912993

RESUMO

OBJECTIVES: We sought to examine occupational disparities in survival among Korean women diagnosed with cancer. DESIGN: Population-based, registry-linkage study. SETTING: South Korea. PARTICIPANTS: Our study population comprised female workers registered in the Korean national employment insurance programme during 1995-2000 and diagnosed with cancer between 1995 and 2008. A total of 61 110 women with cancer diagnoses was included in analysis. The occupation was categorised into four groups: (1) managers, professionals and technical workers, (2) clerks, (3) service/sales workers and (4) blue-collar workers. PRIMARY AND SECONDARY OUTCOME MEASURE: Study population were linked to the national death registry until 2009. HRs for mortality adjusting for age and year of diagnosis were calculated in the study sample and subgroups with 10 specific cancer sites including thyroid, breast, stomach, cervix, colon or lung cancer using managers, professionals and technical workers as the reference. RESULTS: Women in service/sales (HR 1.25, 95% CI 1.15 to 1.35) and blue-collar occupations (HR 1.34, 95% CI 1.25 to 1.44) had poorer survival for all cancer sites combined, while blue-collar workers showed poorer survival for lung (HR 1.41, 95% CI 1.14 to 1.77), breast (HR 1.28, 95% CI 1.06 to 1.54), cervical cancer (HR 1.42, 95% CI 1.02 to 2.06) and non-Hodgkin's lymphoma (HR 1.69, 95% CI 1.09 to 2.77) compared with women in professional and managerial positions. CONCLUSION: We found substantial and significant inequalities in overall survival by the occupational group among Korean women with cancer, even in the context of universal access to cancer screening and treatment.


Assuntos
Neoplasias , Ocupações , Emprego , Feminino , Humanos , Sistema de Registros , República da Coreia/epidemiologia
15.
Front Plant Sci ; 11: 1098, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849681

RESUMO

Many of the recessive virus-resistance genes in plants encode eukaryotic translation initiation factors (eIFs), including eIF4E, eIF4G, and related proteins. Notably, eIF4E and its isoform eIF(iso)4E are pivotal for viral infection and act as recessive resistance genes against various potyviruses in a wide range of plants. In this study, we used Clustered Regularly Interspaced Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated targeted mutagenesis to test whether novel sequence-specific mutations at eIF4E1 in Solanum lycopersicum (tomato) cv. Micro-Tom could confer enhanced resistance to potyviruses. This approach produced heritable homozygous mutations in the transgene-free E1 generation. Sequence analysis of eIF4E1 from E0 transgenic plants expressing Cas9 and eIF4E-sgRNA transcripts identified chimeric deletions ranging from 11 to 43 bp. Genotype analysis of the eIF4E1-edited lines in E0, E1, and E2 transgenic tomato plants showed that the mutations were transmitted to subsequent generations. When homozygous mutant lines were tested for resistance to potyviruses, they exhibited no resistance to tobacco etch virus (TEV). Notably, however, several mutant lines showed no accumulation of viral particles upon infection with pepper mottle virus (PepMoV). These results indicate that site-specific mutation of tomato eIF4E1 successfully conferred enhanced resistance to PepMoV. Thus, this study demonstrates the feasibility of the use of CRISPR/Cas9 approach to accelerate breeding for trait improvement in tomato plants.

16.
J Med Chem ; 63(13): 6821-6833, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32579356

RESUMO

Tumors adapt to hypoxia by regulating angiogenesis, metastatic potential, and metabolism. These adaptations mediated by hypoxia-inducible factor 1 (HIF-1) make tumors more aggressive and resistant to chemotherapy and radiation. Therefore, HIF-1 is a validated therapeutic target for cancer. In order to develop new HIF-1 inhibitors for cancer chemotherapy by harnessing the potential of the natural product manassantin A, we synthesized and evaluated manassantin A analogues with modifications in the tetrahydrofuran core region of manassantin A. Our structure-activity relationship study indicated that the α,α'-trans-configuration of the central ring of manassantin A is critical to HIF-1 inhibition. We also demonstrated that a combination of manassantin A with an epidermal growth factor receptor inhibitor shows cooperative antitumor activity (∼80% inhibition for combination vs ∼30% inhibition for monotherapy). Our findings will provide important frameworks for the future therapeutic development of manassantin A-derived chemotherapeutic agents.


Assuntos
Receptores ErbB/antagonistas & inibidores , Furanos/química , Lignanas/química , Lignanas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Células HEK293 , Humanos
17.
Angew Chem Int Ed Engl ; 59(31): 12976-12983, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32337812

RESUMO

Chiral optical metamaterials with delicate structures are in high demand in various fields because of their strong light-matter interactions. Recently, a scalable strategy for the synthesis of chiral plasmonic nanoparticles (NPs) using amino acids and peptides has been reported. Reported herein, 3D chiral gold NPs were synthesized using dipeptide γ-Glu-Cys and Cys-Gly and analyzed crystallographically. The γ-Glu-Cys-directed NPs present a cube-like outline with a protruding chiral wing. In comparison, the NPs synthesized with Cys-Gly exhibited a rhombic dodecahedron-like outline with curved edges and elliptical cavities on each face. Morphology analysis of intermediates indicated that γ-Glu-Cys generated an intermediate concave hexoctahedron morphology, while Cys-Gly formed a concave rhombic dodecahedron. NPs synthesized with Cys-Gly are named 432 helicoid V because of their unique morphology and growth pathway.

18.
Saf Health Work ; 11(1): 41-49, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32206373

RESUMO

BACKGROUND: We performed this study to investigate the inequalities in site-specific cancer incidences among workers across different occupations in Korea. METHODS: Subjects included members of the national employment insurance. Incident cancers among 8,744,603 workers were followed from 1995 to 2007. Occupational groups were classified according to the Korean Standard Occupational Classification. Age-standardized incidence rate ratios were calculated. RESULTS: We found that men in service/sales and blue-collar occupations had elevated rates of esophageal, liver, laryngeal, and lung cancer. Among women, service/sales workers had elevated incidences of cervical cancer. Male prostate cancer, female breast, corpus uteri, and ovarian cancers, as well as male and female colorectal, kidney, and thyroid cancer showed lower incidences among workers in lower socioeconomic occupations. CONCLUSIONS: Substantial differences in cancer incidences were found depending on occupation reflecting socioeconomic position, in the Korean working population. Cancer prevention policy should focus on addressing these socioeconomic inequalities.

19.
Nat Commun ; 11(1): 263, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937767

RESUMO

Chiral plasmonic nanostructures have opened up unprecedented opportunities in optical applications. We present chirality evolution in nanoparticles focusing on the crystallographic aspects and elucidate key parameters for chiral structure formation. From a detailed understanding of chirality formation, we achieved a morphology (432 Helicoid IV) of three-dimensionally controlled chiral plasmonic nanoparticles based on the rhombic dodecahedral shape. The role of the synthesis parameters, seed, cysteine, cetyltrimethylammonium bromide and ascorbic acid on chiral formation are studied, and based on this understanding, the systematic control of the chiral structure is presented. The relation between the modulated chiral structure factors and optical response is further elucidated by electromagnetic simulation. Importantly, a new optical response is achieved by assembling chiral nanoparticles into a film. This comprehensive study of chiral nanoparticles will provide valuable insight for the further development of diverse chiral plasmonic nanostructures with fascinating properties.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31906362

RESUMO

Background: We aimed to describe inequalities in site-specific cancer survival across different occupational classes in Korean men. Methods: Subjects included cancer diagnosed members of the national employment insurance program during 1995-2008. A total of 134,384 male cases were followed by linking their data to the Death registry until 2009. Occupational classes were categorized according to the Korean Standard Occupational Classification (KSOC). Hazard ratio adjusting age and diagnosed year were calculated for each occupation by cancer sites. Results: Men in service/sales and blue-collar occupations had lower survival of all cancer sites combined and esophagus, stomach, colorectal, liver, larynx, lung, prostate, thyroid cancer and non-Hodgkin's lymphoma than men in professional and managerial positions. Cancer sites with good prognosis like prostate cancer showed wider gap across occupational class. Conclusions: Considerable inequalities in cancer survival were found by occupation among Korean men. Cancer control policy should more focus on lower socioeconomic occupational class.


Assuntos
Neoplasias , Ocupações , Adulto , Emprego , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/mortalidade , Ocupações/estatística & dados numéricos , Modelos de Riscos Proporcionais , Sistema de Registros , República da Coreia/epidemiologia , Fatores Socioeconômicos
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