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1.
Aging Cell ; 19(2): e13095, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31880094

RESUMO

To determine whether 1,25-dihydroxyvitamin D (1,25(OH)2 D) can exert an anti-osteoporosis role through anti-aging mechanisms, we analyzed the bone phenotype of mice with 1,25(OH)2 D deficiency due to deletion of the enzyme, 25-hydroxyvitamin D 1α-hydroxylase, while on a rescue diet. 1,25(OH)2 D deficiency accelerated age-related bone loss by activating the p16/p19 senescence signaling pathway, inhibiting osteoblastic bone formation, and stimulating osteoclastic bone resorption, osteocyte senescence, and senescence-associated secretory phenotype (SASP). Supplementation of exogenous 1,25(OH)2 D3 corrected the osteoporotic phenotype caused by 1,25(OH)2 D deficiency or natural aging by inhibiting the p16/p19 pathway. The proliferation, osteogenic differentiation, and ectopic bone formation of bone marrow mesenchymal stem cells derived from mice with genetically induced deficiency of the vitamin D receptor (VDR) were significantly reduced by mechanisms including increased oxidative stress, DNA damage, and cellular senescence. We also demonstrated that p16 deletion largely rescued the osteoporotic phenotype caused by 1,25(OH)2 D3 deficiency, whereas 1,25(OH)2 D3 could up-regulate the enzyme Ezh2 via VDR-mediated transcription thereby enriching H3K27me3 and repressing p16/p19 transcription. Finally, we demonstrated that treatment with 1,25(OH)2 D3 improved the osteogenic defects of human BM-MSCs caused by repeated passages by stimulating their proliferation and inhibiting their senescence via the VDR-Ezh2-p16 axis. The results of this study therefore indicate that 1,25(OH)2 D3 plays a role in preventing age-related osteoporosis by up-regulating Ezh2 via VDR-mediated transcription, increasing H3K27me3 and repressing p16 transcription, thus promoting the proliferation and osteogenesis of BM-MSCs and inhibiting their senescence, while also stimulating osteoblastic bone formation, and inhibiting osteocyte senescence, SASP, and osteoclastic bone resorption.

2.
Nano Lett ; 19(11): 8049-8058, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31558023

RESUMO

Pyroptosis is a lytic and inflammatory form of programmed cell death and could be induced by chemotherapy drugs via caspase-3 mediation. However, the key protein gasdermin E (GSDME, translated by the DFNA5 gene) during the caspase-3-mediated pyroptosis process is absent in most tumor cells because of the hypermethylation of DFNA5 (deafness autosomal dominant 5) gene. Here, we develop a strategy of combining decitabine (DAC) with chemotherapy nanodrugs to trigger pyroptosis of tumor cells by epigenetics, further enhancing the immunological effect of chemotherapy. DAC is pre-performed with specific tumor-bearing mice for demethylation of the DFNA5 gene in tumor cells. Subsequently, a commonly used tumor-targeting nanoliposome loaded with cisplatin (LipoDDP) is used to administrate drugs for activating the caspase-3 pathway in tumor cells and trigger pyroptosis. Experiments demonstrate that the reversal of GSDME silencing in tumor cells is achieved and facilitates the occurrence of pyroptosis. According to the anti-tumor activities, anti-metastasis results, and inhibition of recurrence, this pyroptosis-based chemotherapy strategy enhances immunological effects of chemotherapy and also provides an important insight into tumor immunotherapy.

3.
Math Biosci Eng ; 16(5): 5877-5896, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31499743

RESUMO

Embryonic development is widely studied due to its application in disease treatment. The published literature demonstrated that Krüppel-like factor 8(KLF8) plays an important role in modulating mesendoderm to definitive endoderm (DE) differentiation. However, it is not clear how KLF8 interacts with other key genes and affects the differentiation process. To qualitatively and quantitatively explore the molecular mechanisms of KLF8 during the differentiation of human embryonic stem cells (hESCs) in detail, we developed a mathematical model to describe the dynamics between KLF8 and two other significant genes, E-cadherin(CDH1) and Zinc-finger E-box-binding homeobox1(ZEB1). Based on the single-cell RNA-seq data, the model structure and parameters were obtained using particle swarm optimization (PSO). The bifurcation analysis and simulation results reveal that the system can exhibit a complex tristable transition, which corresponds to the three states of embryonic development at the single-cell level. We further predict that the novel important gene KLF8 promotes the formation of DE cells by reciprocal inhibition between CDH1 and KLF8 and promotion of the expression of ZEB1. These results may help to shed light on the biological mechanism in the differentiation process of hESCs.

4.
Aging (Albany NY) ; 11(16): 6358-6370, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31437127

RESUMO

GP IIb/IIIa receptor activation plays an important role in thrombosis. The mechanism of early activation of GP IIb/IIIa receptors in diabetic conditions remains unknown. The purpose of this study was to investigate the release of Endothelial microparticle (EMP)-associated protein disulfide isomerase (PDI) after endothelial cell injury induced in diabetes and the changes in platelet activation. We produced an animal model of type 2 diabetes mellitus using ApoE-/- mice. Normal ApoE-/- and diabetic mice were allocated to four groups (n = 15): normal diet, normal diet plus rutin, diabetic, and diabetes plus rutin. The EMP-PDI content and GP IIb/IIIa expression of mice platelets were determined. In addition, EMPs obtained from the four groups were pretreated with the PDI inhibitor rutin; then, their effects on the platelets of normal C57 mice were characterized. Compared with the normal diet group, the diabetic group had significantly increased plasma EMP-PDI content and accelerated platelet activation by increased GP IIb/IIIa expression. In conclusion, EMP-PDI promotes early platelet activation through glycoprotein (GP) IIb/IIIa receptors present on platelet surface in the diabetic state. However, this process could be partially suppressed by the administration of rutin.

5.
Nat Commun ; 10(1): 2152, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089140

RESUMO

The flexibility in structural design of organic semiconductors endows organic solar cells (OSCs) not only great function-tunabilities, but also high potential toward practical application. In this work, simple non-fused-ring electron acceptors are developed through two-step synthesis from single aromatic units for constructing efficient OSCs. With the assistance of non-covalent interactions, these rotatable non-fused acceptors (in solution) allow transiting into planar and stackable conformation in condensed solid, promoting acceptors not only feasible solution-processability, but also excellent film characteristics. As results, decent power conversion efficiencies of 10.27% and 13.97% can be achieved in single and tandem OSCs consisting of simple solution-cast blends, in which the fully unfused acceptors exhibit exceptionally low synthetic complexity index. In addition, the unfused acceptor and its based OSCs exhibit promising stabilities under continuous illumination. Overall, this work reveals valuable insights on the structural design of simple and effective electron acceptors with great practical perspectives.

6.
Int J Mol Sci ; 20(7)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959810

RESUMO

Leaf senescence is the last period of leaf growth and a dynamic procedure associated with its death. The adaptability of the plants to changing environments occurs thanks to leaf senescence. Hence, transcriptional profiling is important to figure out the exact mechanisms of inducing leaf senescence in a particular crop, such as rice. From this perspective, leaf samples of two different rice genotypes, the brown midrib leaf (bml) mutant and its wild type (WT) were sampled for transcriptional profiling to identify differentially-expressed genes (DEGs). We identified 2670 DEGs, among which 1657 genes were up- and 1013 genes were down-regulated. These DEGs were enriched in binding and catalytic activity, followed by the single organism process and metabolic process through gene ontology (GO), while the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the DEGs were related to the plant hormone signal transduction and photosynthetic pathway enrichment. The expression pattern and the clustering of DEGs revealed that the WRKY and NAC family, as well as zinc finger transcription factors, had greater effects on early-senescence of leaf compared to other transcription factors. These findings will help to elucidate the precise functional role of bml rice mutant in the early-leaf senescence.


Assuntos
Perfilação da Expressão Gênica , Mutação/genética , Oryza/genética , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/genética , Transcriptoma/genética , Análise por Conglomerados , Regulação da Expressão Gênica de Plantas , Ontologia Genética , Fenótipo
7.
Am J Transl Res ; 11(3): 1460-1472, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30972174

RESUMO

Accumulating evidence suggests that oxidative stress plays an important role in the progression of osteoarthritis (OA), and pyrroloquinoline quinone (PQQ) is considered a strong antioxidant. However, it is unclear whether PQQ can prevent the progression of OA by inhibiting oxidative stress. In this study, anterior cruciate ligament transection (ACLT)-induced OA mice received a diet supplemented with/without PQQ, and were compared with each other and with sham-operated mice. Our results showed that in PQQ-untreated OA mice, articular surfaces collapsed, while the thickness of articular cartilage and the abundance of cartilage matrix protein decreased significantly, whereas PQQ supplementation largely prevented these alterations. We also found that oxidative stress, DNA damage, cellular senescence and the secretion of senescence-associated inflammatory cytokines were increased in PQQ-untreated OA mice compared with sham-operated mice. However, these parameters were obviously rescued in PQQ-treated OA mice. This study demonstrated that PQQ supplementation can prevent ACLT-induced OA by inhibiting oxidative stress, DNA damage, cell senescence and the development of the senescence-associated secretory phenotype.

8.
Emerg Microbes Infect ; 8(1): 55-69, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30866760

RESUMO

Accumulating evidence indicates that bacterial metabolism plays an important role in virulence. Acetyl phosphate (AcP), the high-energy intermediate of the phosphotransacetylase-acetate kinase pathway, is the major acetyl donor in E. coli. PhoP is an essential transcription factor for bacterial virulence. Here, we show in Salmonella typhimurium that PhoP is non-enzymatically acetylated by AcP, which modifies its transcriptional activity, demonstrating that the acetylation of Lysine 102 (K102) is dependent on the intracellular AcP. The acetylation level of K102 decreases under PhoP-activating conditions including low magnesium, acid stress or following phagocytosis. Notably, in vitro assays show that K102 acetylation affects PhoP phosphorylation and inhibits its transcriptional activity. Both cell and mouse models show that K102 is critical to Salmonella virulence, and suggest acetylation is involved in regulating PhoP activity. Together, the current study highlights the importance of the metabolism in bacterial virulence, and shows AcP might be a key mediator.


Assuntos
Proteínas de Bactérias/metabolismo , Lisina/metabolismo , Organofosfatos/metabolismo , Salmonelose Animal/microbiologia , Salmonella typhimurium/patogenicidade , Acetilação , Animais , Proteínas de Bactérias/química , Feminino , Regulação Bacteriana da Expressão Gênica , Magnésio/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fagocitose , Fosforilação , Células RAW 264.7 , Salmonella typhimurium/metabolismo , Estresse Fisiológico , Virulência
9.
Gene ; 699: 62-72, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30858135

RESUMO

Plants with purple leave attain interest because of their biological importance. A new rice mutant, purple leaf (pl) was isolated from an indicia cultivar Zhenong 34, which was induced by ethyl methane sulfonate (EMS) mutagenesis. The genetic analyses substantiated that pl was corroborated by one recessive allele and confirmed by map based cloning using Insertion-Deletion (InDel) markers located on the long arm of chromosome 5. DNAseq data of the candidate part showed one bp insertion ('C' insertion) at +901 bp position in the 3rd exon of OsPL gene. The pl was characterized as purple leaves, sheaths and leaf senescence phenotype at late grain filling stage of growth cycle. It possessed abnormal cell with distorted chloroplasts, less chlorophyll, and increased anthocyanin content in leaves. The anthocyanin biosynthesis genes, OsPAL, OsCHS, OsANS, and OsMYB55 showed up-regulation in pl plants compared to wild type (WT). High super oxide dismutase enzyme (SOD), catalase enzyme activity (CAT), total soluble sugar (TSS) and malondialdehyde activity (MDA) were detected in the pl; contrastingly, photosynthesis linked genes were down-regulated. The germinated pl seeds showed comparatively higher temperature stress tolerance than WT. The phytohormones abscicic acid (ABA), jasmonic acid (JA) and indole acetic acid (IAA) content were increased significantly in the pl plants. This research work will be provided information on better understanding of the molecular mechanism toward the anthocyanin biosynthetic pathway in rice. Therefore, OsPL gene could be a good genetic tool in marker aided backcrossing or gene editing for improving the rice cultivation in future.


Assuntos
Antocianinas/genética , Regulação da Expressão Gênica de Plantas/genética , Resposta ao Choque Térmico/genética , Oryza/genética , Proteínas de Plantas/genética , Estresse Fisiológico/genética , Fatores de Transcrição/genética , Clorofila/genética , Cloroplastos/genética , Edição de Genes/métodos , Genes de Plantas/genética , Fotossíntese/genética , Folhas de Planta/genética , Regulação para Cima/genética
10.
Biochem Genet ; 57(3): 403-420, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30600409

RESUMO

Rice tillering ability and plant height are two of the important traits determining the grain yield. A novel rice (Oryza sativa L.) mutant dhta-34 from an Indica cultivar Zhenong 34 treated by ethyl methy1 sulfonate (EMS) was investigated in this study. The dhta-34 mutant significantly revealed thrifty tillers with reduced plant height, smaller panicles and lighter grains. It also exhibited late-maturing (19.80 days later than the wild type) and withered leaf tip during the mature stage. The length of each internode was reduced compared to the wild type, belonging to the dn type (each internode of the plant stem decreased in the same ratio). The longitudinal section of dhta-34 internodes showed that the length of cells was reduced leading to the dwarfism of the mutant. The F2 population derived from a cross between dhta-34 and an Japonica cultivar Zhenongda 104 were used for gene mapping by using the map-based cloning strategy. The gene DHTA-34 was fine mapped in 183.8kb region flanked by markers 3R-7 and 3R-10. The cloning and sequencing of the target region from the mutant revealed that there was a substitution of G to A in the second exon of LOC_Os03g10620, which resulted in an amino acid substitution arginine to histidine. DHTA-34 encoded a protein of the α/ß-fold hydrolase superfamily, which could suppress the tillering ability of rice. DHTA-34 was a strong loss-of-function allele of the Arabidopsis thaliana D14 gene, which was involved in part of strigolactones (SLs) perception and signaling. Moreover, the relative expression of DHTA-34 gene in leaf was higher than that in bud, internode, root or sheath. This study revealed that DHTA-34 played an important role in inhabiting tiller development in rice and further identifying the function of D14.


Assuntos
Genes de Plantas , Lactonas/farmacologia , Mutação , Oryza/genética , Sequência de Aminoácidos , Clonagem Molecular , Metanossulfonato de Etila/farmacologia , Filogenia , Reguladores de Crescimento de Planta/metabolismo , Folhas de Planta/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Homologia de Sequência de Aminoácidos , Transdução de Sinais
11.
J Plant Physiol ; 231: 110-123, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30253267

RESUMO

Semi-dwarfism is one of the most important agronomic traits for many cereal crops. In the present study, a mutant with semi-dwarf and short flag leaf 1, sdsfl1, was identified and characterized. The sdsfl1 mutant demonstrated some distinguished structural alterations, including shorter plant height and flag leaf length, increased tiller numbers and flag leaf width, and decreased panicle length compared with those of wild type (WT). Genetic analysis suggested that the mutant traits were completely controlled by a single recessive gene. The SDSFL1 gene was mapped to the long arm of chromosome 3 within a region of 44.6 kb between InDel markers A3P8.3 and A3P8.4. The DNA sequence analysis revealed that there was only a T to C substitution in the coding region of LOC_Os03g63970, resulting in the substitution of Tryptophan (Try) to Arginine (Arg) and encoding a GA 20 oxidase 1 protein of 372 amino acid residues. Photosynthesis analysis showed that the photosynthetic rate (Pn), stomatal conductance (Gs), and intercellular CO2 concentration (Ci) were significantly increased in sdsfl1. Chlorophyll a (Chl a), total Chl, and carotenoid contents were significantly increased in sdsfl1 compared with those in WT. sdsfl1 carried a reduced level of GA3 but reacted to exogenously applied gibberellins (GA). Moreover, the levels of abscisic acid (ABA), indole 3-acetic acid (IAA), and salicylic acid (SA) were notably improved in sdsfl1, whereas there was no noteworthy change in jasmonic acid (JA). The results thus offer a visible foundation for the molecular and physiological analysis of the SDSFL1 gene, which might participate in various functional pathways for controlling plant height and leaf length in rice breeding.


Assuntos
Genes de Plantas/fisiologia , Oryza/genética , Reguladores de Crescimento de Planta/fisiologia , Clorofila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica de Plantas/genética , Genes de Plantas/genética , Microscopia Eletrônica de Varredura , Oryza/crescimento & desenvolvimento , Oryza/fisiologia , Oryza/ultraestrutura , Fotossíntese , Filogenia , Folhas de Planta/ultraestrutura , Reação em Cadeia da Polimerase em Tempo Real , Alinhamento de Sequência
12.
Genes (Basel) ; 9(6)2018 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891831

RESUMO

Panicle architecture and grain size are two important agronomic traits which determine grain yield directly in rice. In the present study, a mutant named ltbsg1 (longer top branch and shorter grain 1) was isolated from the cultivar “Zhenong 34” (Oryza sativa L. ssp. indica) by ethyl methane sulfonate (EMS) mutagenesis. The target gene was studied through phenotype observation, genetic analysis, map-based cloning and functional analysis. The histocytological analysis indicated that the elongated top branch and shorter grain of mutant ltbsg1 were caused from the defects of cell elongation. The ltbsg1 gene in mutant revealed a single nucleotide substitution (G-A) in the exon 2 of LOC_Os10g25780, causing an amino acid variation (Glycine-Arginine) in the FAD (Flavin-adenine dinucleotide)-binding domain of delta (24)-sterol reductase, which was involved in the brassinosteroid (BR) biosynthesis. LTBSG1 was constitutively expressed and the protein was widely localized in chloroplast, nucleus and cytomembrane. The ltbsg1 seedlings had a lower endogenous BR level and could be restored to the phenotype of wild type by exogenous BR. The LTBSG1 knock-out lines showed similar phenotype defects as mutant ltbsg1, which confirmed that LTBSG1 was responsible for top branch elongation and grain size reduction. Furthermore, LTBSG1 along with other BR-related genes were feedback-regulated due to their obvious altered expression in mutant ltbsg1. This study demonstrated that LTBSG1 could play a new role in regulating panicle and grain development by BR biosynthetic pathway.

13.
Genes (Basel) ; 9(4)2018 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-29642546

RESUMO

Isolating and characterizing mutants with altered senescence phenotypes is one of the ways to understand the molecular basis of leaf aging. Using ethyl methane sulfonate mutagenesis, a new rice (Oryza sativa) mutant, brown midrib leaf (bml), was isolated from the indica cultivar 'Zhenong34'. The bml mutants had brown midribs in their leaves and initiated senescence prematurely, at the onset of heading. The mutants had abnormal cells with degraded chloroplasts and contained less chlorophyll compared to the wild type (WT). The bml mutant showed excessive accumulation of reactive oxygen species (ROS), increased activities of superoxide dismutase, catalase, and malondialdehyde, upregulation of senescence-induced STAY-GREEN genes and senescence-related transcription factors, and down regulation of photosynthesis-related genes. The levels of abscisic acid (ABA) and jasmonic acid (JA) were increased in bml with the upregulation of some ABA and JA biosynthetic genes. In pathogen response, bml demonstrated higher resistance against Xanthomonas oryzae pv. oryzae and upregulation of four pathogenesis-related genes compared to the WT. A genetic study confirmed that the bml trait was caused by a single recessive nuclear gene (BML). A map-based cloning using insertion/deletion markers confirmed that BML was located in the 57.32kb interval between the L5IS7 and L5IS11 markers on the short arm of chromosome 5. A sequence analysis of the candidate region identified a 1 bp substitution (G to A) in the 5'-UTR (+98) of bml. BML is a candidate gene associated with leaf senescence, ROS regulation, and disease response, also involved in hormone signaling in rice. Therefore, this gene might be useful in marker-assisted backcrossing/gene editing to improve rice cultivars.

14.
Plant Cell Rep ; 37(6): 933-946, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29572657

RESUMO

KEY MESSAGE: A rice receptor-like kinase gene OSBBS1/OsRLCK109 was identified; this gene played vital roles in leaf senescence and the salt stress response. Early leaf senescence can cause negative effects on rice yield, but the underlying molecular regulation is not fully understood. bilateral blade senescence 1 (bbs1), an early leaf senescence mutant with a premature senescence phenotype that occurs mainly performing at the leaf margins, was isolated from a rice mutant population generated by ethylmethane sulfonate (EMS) treatment. The mutant showed premature leaf senescence beginning at the tillering stage and exhibited severe symptoms at the late grain-filling stage. bbs1 showed accelerated dark-induced leaf senescence. The OsBBS1 gene was cloned by a map-based cloning strategy, and a guanine (G) insertion was found in the first exon of LOC_Os03g24930. This gene encodes a receptor-like cytoplasmic kinase and was named OsRLCK109 in a previous study. Transgenic LOC_Os03g24930 knockout plants generated by a CRISPR/Cas9 strategy exhibited similar early leaf senescence phenotypes as did the bbs1 mutant, which confirmed that LOC_Os03g24930 was the OsBBS1 gene. OsBBS1/OsRLCK109 was expressed in all detected tissues and was predominantly expressed in the main vein region of mature leaves. The expression of OsBBS1 could be greatly induced by salt stress, and the bbs1 mutant exhibited hypersensitivity to salt stress. In conclusion, this is the first identification of OsRLCKs participating in leaf senescence and playing critical roles in the salt stress response in rice (Oryza sativa L.).


Assuntos
Guanina , Oryza/fisiologia , Proteínas de Plantas/metabolismo , Mutagênese Insercional , Mutação , Oryza/genética , Fenótipo , Folhas de Planta/genética , Folhas de Planta/fisiologia , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas , Sais , Estresse Fisiológico , Fatores de Tempo
15.
Chin Med J (Engl) ; 131(1): 56-62, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29271381

RESUMO

BACKGROUND: Klebsiella pneumoniae (KP) is a pathogen commonly causing nosocomial infection. Carbapenem-resistant KP (CRKP) is more resistant to multiple antimicrobial drugs than carbapenem-susceptible KP (CSKP) isolates. The aim of the present study was to identify the risk factors for CRKP infection and the predictors of mortality among KP-infected adult patients. METHODS: Patients with CRKP and CSKP infection were categorized as the case group and control group, respectively, and we conducted a 1:1 ratio case-control study on these groups. The CRKP isolates collected were tested for antimicrobial susceptibility and presence of KP carbapenemase (KPC) gene. Clinical data were collected to identify risk factors for CRKP infection and mortality of KP infection. Risk factors were analyzed under univariable and multivariable logistic regression model. RESULTS: The independent risk factors for CRKP infection were admission to Intensive Care Unit (odds ratio [OR]: 15.486, 95% confidence interval [CI]: 3.175-75.541, P < 0.001); use of ß-lactams and ß-lactamase inhibitor combination (OR: 4.765, 95% CI: 1.508-15.055, P = 0.008); use of cephalosporins (OR: 8.033, 95% CI: 1.623-39.763, P = 0.011); fluoroquinolones (OR: 6.090, 95% CI: 1.343-27.613, P = 0.019); and indwelling of urethral catheter (OR: 6.164, 95% CI: 1.847-20.578, P = 0.003). However, older age (OR: 1.079, 95% CI: 1.005-1.158, P = 0.036), Charlson comorbidity index (OR: 4.690, 95% CI: 2.094-10.504, P = 0.000), and aminoglycoside use (OR: 670.252, 95% CI: 6.577-68,307.730, P = 0.006) were identified as independent risk factors for patient deaths with KP infection. The mortality of CRKP group was higher than that of the CSKP group. KPC gene did not play a role in the CRKP group. CRKP mortality was high. CONCLUSION: Implementation of infection control measures and protection of the immunefunction are crucial.


Assuntos
Antibacterianos/uso terapêutico , Carbapenêmicos/uso terapêutico , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Farmacorresistência Bacteriana , Quimioterapia Combinada , Feminino , Humanos , Unidades de Terapia Intensiva , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/mortalidade , Fatores de Risco , Inibidores de beta-Lactamases/uso terapêutico
16.
J Cachexia Sarcopenia Muscle ; 9(1): 106-118, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29152896

RESUMO

BACKGROUND: Exercise rehabilitation is demonstrated to improve the prognosis of patients with coronary heart disease (CHD). Statins, as the key medicine to lower cholesterol in CHD, result in skeletal muscle injury and impair exercise training adaptation. Energy metabolism dysfunction is identified as the potential mechanism underlying statin-induced skeletal muscle injury. In this study, we investigated the effects of the metabolic modulator trimetazidine on skeletal muscle energy metabolism and statin-associated exercise intolerance. METHODS: High-fat fed apolipoprotein E knockout (ApoE-/- ) mice were given aerobic exercise and administrated simvastatin, trimetazidine, or simvastatin plus trimetazidine by gavage. Exercise capacity was evaluated at the end of the treatment by hanging grid test, forelimb grip strength, and running tolerance test. Plasma glucose, lipid, and creatine kinase concentrations were measured at the end of the treatment. After sacrifice, gastrocnemii were stored for assessment of muscle morphology and fibre type. Energy metabolism was estimated by plasma lactic acid concentration, ragged red fibres, and glycogen stores. Activities of mitochondrial complex III, citrate synthase activity, and membrane potential were measured to assess mitochondrial function. Oxidative stress was also evaluated by superoxide in mitochondria, superoxide dismutase activity, and glutathione redox state. RESULTS: In high-fat fed ApoE-/- mice, exercise training had no effect on lipid concentrations. Lower lipid concentrations with increased creatine kinase were observed with additional simvastatin treatment. Exercise capacity increased significantly in response to exercise training alone but was blunted by the addition of simvastatin. Similarly, cross-sectional area of muscle fibres and the proportion of slow-twitch fibres increased in the exercise group but decreased in the simvastatin plus exercise group. Additionally, simvastatin increased centronucleated fibres and induced energy metabolism dysfunction by inhibiting complex III activity and thus promoted oxidative stress in gastrocnemius. We demonstrated that trimetazidine could reverse simvastatin-induced exercise intolerance and muscle damages. We also found the ability of trimetazidine in restoration of muscle fibre hypertrophy and facilitating fast-to-slow type shift. The energy metabolism dysfunction and oxidative stress in gastrocnemii were rescued by trimetazidine. CONCLUSIONS: Trimetazidine alleviated statin-related skeletal muscle injury by restoration of oxidative phenotype and increasing fibre cross-sectional areas in response to exercise training. Correspondingly, the exercise training adaptation were improved in high-fat fed ApoE-/- mice. Moreover, trimetazidine is able to exert its positive effects without affecting the beneficial lipid-lowering properties of the statins. Thus, trimetazidine could be prescribed to remedy the undesirable statins-induced exercise intolerance during cardiac rehabilitation in patients with CHD.


Assuntos
Terapia por Exercício/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Debilidade Muscular/induzido quimicamente , Músculo Esquelético/patologia , Sinvastatina/efeitos adversos , Trimetazidina/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Feminino , Humanos , Masculino , Camundongos , Trimetazidina/farmacologia , Vasodilatadores/farmacologia
17.
Future Microbiol ; 12: 1045-1057, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28796533

RESUMO

AIM: Acid is an important environmental condition encountered frequently by Salmonella enterica serovar Typhimurium during its pathogenesis, but the role of small-noncoding RNAs (sRNAs) in response to acid stress is poorly understood. METHODS: We used RNA sequencing to explore acid-responsive sRNAs in S. Typhimurium. RESULTS: It identified that 6S RNA encoded by the ssrS was significantly upregulated at pH 3.0. The 6S RNA knockout strain showed a reduced ability to survive at pH 3.0. Additionally, genes in Salmonella pathogenicity island-1 were downregulated in the 6S RNA knockout strain. The loss of 6S RNA significantly reduced S. Typhimurium invasion ability in HeLa cells and virulence in a mouse model. CONCLUSION: These findings demonstrate that 6S RNA plays an important role in S. Typhimurium survival under extremely acid conditions and for invasion of epithelial cells.


Assuntos
Células Epiteliais/microbiologia , RNA Bacteriano/genética , RNA Bacteriano/fisiologia , RNA não Traduzido/genética , RNA não Traduzido/fisiologia , Salmonella typhimurium/genética , Sorogrupo , Virulência/genética , Animais , Modelos Animais de Doenças , Células Epiteliais/patologia , Regulação Bacteriana da Expressão Gênica , Técnicas de Inativação de Genes , Genes Bacterianos/genética , Ilhas Genômicas/genética , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , RNA Bacteriano/isolamento & purificação , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/fisiologia , Salmonella typhimurium/patogenicidade , Análise de Sequência de RNA/métodos , Estresse Fisiológico/genética
18.
Gene ; 627: 351-362, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28578018

RESUMO

A new mutant named sdl (stripe and drooping leaf) was characterized from indica cultivar Zhenong 34 by ethylmethane sulfonate (EMS) mutagenesis. The mutant sdl exhibited development defects including stripe and drooping leaf, dwarfism and deformed floral organs. The gene SDL was found allelic to RNRS1 by map-based cloning, which was homologous to Arabidopsis TSO2 encoding the small subunit of ribonucleotide reductase. The gDNA sequencing results of sdl in mutant showed that there was a repetitive sequence insertion of 138-bp at the 475th bp in the exon. The redundant sequence was conserved in SDL homologous proteins, which contained the active site (tyrosine), as well as two amino acids glutamate and histidine involved in the binding of iron. There were fewer chloroplasts and grana lamellas in sdl leaf compared with those of wild-type. Additionally, the stripe leaves of sdl seedlings were highly sensitive to temperature, since the chlorophyll content was increased with the temperature rising. The drooping leaf of sdl might be resulted from the disappearance of vascular bundles and mesophyll cells in both leaf midrib and lateral veins. Fittingly to the phenotypes of mutant sdl, the expression levels of genes associated with photosynthesis and chlorophyll synthesis were found to be down- or up-regulated at different temperatures in mutant sdl. Also, the transcriptional levels of genes related to plant height and floral organ formation showed obvious differences between wild-type and sdl. The "SDL/RNRS1" was, hence, required for the chlorophyll biosynthesis and also played pleiotropic roles in the regulation of plant development.


Assuntos
Clorofila/biossíntese , Oryza/genética , Proteínas de Plantas/genética , Ribonucleotídeo Redutases/genética , Clorofila/genética , Pleiotropia Genética , Mutação , Oryza/crescimento & desenvolvimento , Oryza/metabolismo , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Ligação Proteica , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Ribonucleotídeo Redutases/metabolismo
19.
J Cell Mol Med ; 21(12): 3298-3308, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28631352

RESUMO

The aim of this study was to investigate whether overexpression of STAMP2 improves insulin resistance by regulating angiogenesis in adipose tissues. The characteristics of diabetic mice were measured by serial metabolite and pathology tests. Samples were obtained from epididymal, subcutaneous and brown adipose tissues. Histological and morphological analysis demonstrated that STAMP2 gene overexpression reduced adipocyte size, angiogenesis in epididymal and brown adipose tissues. On aortic ring assay, microvessels sprouting from aortas were significantly inhibited after STAMP2 gene overexpression. The cellular effect of STAMP2 on angiogenesis was explored in human umbilical vein endothelial cells (HUVECs) model. Correlation of STAMP2 and angiogenesis was validated by Ad-STAMP2 transfection and STAMP2 siRNA inhibition. In vitro, overexpression of STAMP2 significantly inhibited endothelial cell migration, tube formation. The effects of Ad-STAMP2 transfection on HUVECs were abolished by treatment with PPARγ antagonist GW9662 (2.5 µM), and the roles of STAMP2 siRNA on HUVECs were also reversed by treatment with PPARγ agonist rosiglitazone (RSG) (0.1 mM). RT-PCR indicated that STAMP2 could regulate levels of adhesion molecules, vascular endothelial growth factor A and CD36. The expression of PPARγ and CD36 was decreased when STAMP2 was inhibited by siRNA, while PPARγ and CD36 were highly expressed after overexpression of STAMP2. Our results suggested that STAMP2 gene overexpression may improve insulin resistance via attenuating angiogenesis in epididymal and brown adipose tissues through the PPARγ/CD36 signalling pathway.


Assuntos
Tecido Adiposo/metabolismo , Antígenos CD36/genética , Diabetes Mellitus Experimental/terapia , Proteínas de Membrana/genética , Neovascularização Patológica/prevenção & controle , PPAR gama/genética , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/patologia , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Antígenos CD36/metabolismo , Movimento Celular , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Resistência à Insulina , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , PPAR gama/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Transdução de Sinais , Estreptozocina
20.
J Infect Dis ; 216(8): 1018-1026, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28329249

RESUMO

HilD, a dominant regulator of Salmonella pathogenicity island 1, can be acetylated by protein acetyltransferase (Pat) in Salmonella Typhimurium, and the acetylation is beneficial to its stability. However, the underlying mechanism of HilD stability regulated by acetylation is not clear. We show here that lysine 297 (K297) located in the helix-turn-helix motif, can be acetylated by Pat. Acetylation of K297 increases HilD stability, but reduces its DNA-binding affinity. In turn, the deacetylated K297 enhances the DNA-binding ability but decreases HilD stability. Under the Salmonella pathogenicity island 1-inducing condition, the acetylation level of K297 is down-regulated. The acetylated K297 (mimicked by glutamine substitution) causes attenuated invasion in HeLa cells, as well as impaired virulence in mouse model, compared with the deacetylated K297 (mimicked by arginine substitution), suggesting that deacetylation of K297 is essential for Salmonella virulence. These findings demonstrate that the acetylation of K297 can regulate both protein stability and DNA-binding ability. This regulation mediated by acetylation not only degrades redundant HilD to keep a moderate protein level to facilitate S. Typhimurium growth but also maintains an appropriate DNA-binding activity of HilD to ensure bacterial pathogenicity.


Assuntos
Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Infecções por Salmonella/imunologia , Salmonella typhimurium/patogenicidade , Fatores de Transcrição/metabolismo , Virulência , Acetilação , Animais , Proteínas de Bactérias/genética , Ilhas Genômicas , Células HeLa , Humanos , Camundongos , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Infecções por Salmonella/microbiologia , Fatores de Transcrição/genética
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