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1.
Endocr J ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790062

RESUMO

Bilateral inferior petrosal sinus sampling (BIPSS) is the current gold standard test for differentially diagnosing ACTH-dependent Cushing's syndrome (CS). However, BIPSS is an invasive procedure, and its availability is limited. We retrospectively analysed the 24-hour urinary free cortisol (UFC) level during the high-dose dexamethasone suppression test (HDDST) and plasma ACTH/cortisol levels after the desmopressin stimulation test (DDAVP test) in subjects with confirmed Cushing's disease (CD) (n = 92) and ectopic ACTH-dependent CS (EAS) (n = 16), and evaluated the positive predictive value (PPV) of the two combined-tests in the aetiological diagnosis of ACTH-dependent CS. The percent changes in UFC levels after the HDDST and in ACTH/cortisol levels after DDAVP administration relative to the corresponding basal levels and the area under the receiver operating characteristic (ROC) curve (AUC) were analysed. UFC suppression below 62.7% suggested a pituitary origin with a sensitivity (SE) of 80% (95% CI: 70-88) and a specificity (SP) of 80% (95% CI: 52-96). A threshold increase in the ACTH level after DDAVP stimulation of 44.6% identified CD with an SE of 91% (95% CI: 83-97) and an SP of 75% (95% CI: 48-93). The combination of both tests yielded an SE of 95.5% and PPV of 98.4% for CD, and significantly improved the efficiency of the differential diagnosis between CD and EAS. These dual non-invasive endocrine tests may substantially reduce the need for BIPSS in the etiological investigation of ACTH-dependent CS.

2.
Front Endocrinol (Lausanne) ; 12: 627395, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790859

RESUMO

Objective: Growth differentiation factor 15 (GDF-15) is a member of the TGF-ß superfamily that has anti-inflammatory properties. The objective of this study was to evaluate the relationship between circulating GDF-15 levels and diabetic retinopathy (DR) in patients with type 2 diabetes. Materials/Methods: A case-control study was performed in which 402 patients with type 2 diabetes were enrolled. Of these, 171 patients had DR and the remaining 231 patients without DR acted as controls. The plasma GDF-15 levels were measured using ELISA, while DR was diagnosed using the canon ophthalmic digital imaging system and the Canon EOS 10D digital camera (Canon, Tokyo, Japan) through a non-pharmacologically dilated pupil. Results: The levels of GDF-15 were significantly higher in patients with DR [168.9 (112.9-228.3) pg/ml vs. 127.8 (96.1-202.8) pg/ml, P < 0.001] compared to controls. Results of the Spearman correlation analysis showed that the GDF-15 levels were positively associated with the duration of diabetes morbidity, fasting plasma glucose, systolic blood pressure, albumin/creatinine ratio, creatinine, and liver enzymes, but negatively associated with eGFR (both P < 0.001). The participants in the highest GDF-15 quartile had a significantly increased risk for DR (OR = 2.15, 95% CI 1.53-3.02) after adjusting for potential cofounders. Conclusions: The circulating GDF-15 levels are positively associated with DR independent of potential cofounders.

3.
Sci Total Environ ; 781: 146730, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33798882

RESUMO

Previous studies demonstrated that microcystin-leucine-arginine (MC-LR) disrupted testosterone (T) synthesis, but the underlying mechanisms are not entirely elucidated. This study aims to explore the role of reactive oxygen species (ROS)-mediated GCN2/eIF2α activation on MC-LR-induced disruption of testicular T synthesis. Male mice were intraperitoneally injected with MC-LR (0 or 20 µg/kg) daily for 5 weeks. Serum T was decreased in MC-LR-exposed mice (0.626 ± 0.122 vs 24.565 ± 8.486 ng/ml, P < 0.01), so did testicular T (0.667 ± 0.15 vs 8.317 ± 1.387 ng/mg protein, P < 0.01). Steroidogenic proteins including StAR, CYP11A1 and CYP17A1 were downregulated in MC-LR-exposed mouse testes and TM3 cells. Mechanistically, p-GCN2 and p-eIF2α were elevated in MC-LR-exposed TM3 cells. GCN2iB attenuated MC-LR-induced GCN2 and eIF2α phosphorylation in TM3 cells. Moreover, GCN2iB attenuated MC-LR-induced downregulation of steroidogenic proteins in TM3 cells. Further analysis found that cellular ROS were elevated and HO-1 was upregulated in MC-LR-exposed TM3 cells. PBN rescued MC-LR-induced activation of GCN2/eIF2α signaling in TM3 cells. Additionally, pretreatment with PBN attenuated MC-LR induced downregulation of steroidogenic proteins and synthases in TM3 cells. These results suggest that ROS-mediated GCN2/eIF2α activation contributes partially to MC-LR-caused downregulation of steroidogenic proteins and synthases. The present study provides a new clue for understanding the mechanism of MC-LR-induced endocrine disruption.

4.
J Biochem Mol Toxicol ; : e22787, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33830595

RESUMO

Local anesthetic with bupivacaine (BV) administration may cause severe neurotoxicity and neurological complications in developing neurons. Any substances that can mitigate the toxic effects of BV are of great importance in surgical procedures and pain management. The present study attempted to investigate if hesperidin (HN) could inhibit or prevent BV-induced neurotoxicity in SH-SY5Y cells. Exposure of BV at 5 mM resulted in a significant decrease of cell viability and a remarkable increase of lactate dehydrogenase release via the induction of apoptosis and production of reactive oxygen species. Moreover, a loss of mitochondrial membrane potential, decreased Bcl-2 protein expression, as well as increased expression of cytoplasmic cytochrome c, Bax, and cleaved caspase-3 protein was also observed in BV-stimulated SH-SY5Y cells. In addition, BV stimulation impaired the balance of oxidation-reduction and inflammation system, as evidenced by the increased malondialdehyde content, decreased superoxide dismutase and catalase activity, and reduced level of reduced glutathione, interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α. However, these iatrogenic changes were all reversed by the HN (5, 10, and 20 µM) supplement for 48 h in a concentration-dependent manner. In conclusion, HN can protect SH-SY5Y cells against BV-stimulated neurotoxicity via the inhibition of apoptosis, oxidative stress, and inflammation response. The present findings suggested that HN may be an effective alternative agent to inhibit or prevent BV-induced neurotoxicity in human patients.

5.
EMBO Rep ; : e52079, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33769671

RESUMO

Quaking (QKI) proteins belong to the signal transduction and activation of RNA (STAR) family of RNA-binding proteins that have multiple functions in RNA biology. Here, we show that QKI-5 is dramatically decreased in metastatic lung adenocarcinoma (LUAD). QKI-5 overexpression inhibits TGF-ß-induced epithelial-mesenchymal transition (EMT) and invasion, whereas QKI-5 knockdown has the opposite effect. QKI-5 overexpression and silencing suppresses and promotes TGF-ß-stimulated metastasis in vivo, respectively. QKI-5 inhibits TGF-ß-induced EMT and invasion in a TGFßR1-dependent manner. KLF6 knockdown increases TGFßR1 expression and promotes TGF-ß-induced EMT, which is partly abrogated by QKI-5 overexpression. Mechanistically, QKI-5 directly interacts with the TGFßR1 3' UTR and causes post-transcriptional degradation of TGFßR1 mRNA, thereby inhibiting TGF-ß-induced SMAD3 phosphorylation and TGF-ß/SMAD signaling. QKI-5 is positively regulated by KLF6 at the transcriptional level. In LUAD tissues, KLF6 is lowly expressed and positively correlated with QKI-5 expression, while TGFßR1 expression is up-regulated and inversely correlated with QKI-5 expression. We reveal a novel mechanism by which KLF6 transcriptionally regulates QKI-5 and suggest that targeting the KLF6/QKI-5/TGFßR1 axis is a promising targeting strategy for metastatic LUAD.

6.
Environ Pollut ; 279: 116921, 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33751944

RESUMO

Vehicular emissions are known to be major contributors of airborne polycyclic aromatic hydrocarbons (PAHs) in cities. In order to assess the long-term contamination of PAHs along roads, we collected organic films from vehicle windows (26 private cars and 4 buses, in Shanghai, China) and used mathematical models to convert the film-bound PAH concentrations to the airborne PAH concentrations. The field measurements of airborne PAHs revealed that the partitioning and Level III fugacity model was suitable to estimate the airborne concentrations of high and low volatile PAHs (expect for naphthalene), respectively. The total airborne PAH concentrations along roads in Shanghai ranged from 0.83 to 3.37 µg m-3 and the incremental lifetime cancer risks (ILCRtotal) by exposure to PAHs along roads were greater than the USEPA lower guideline of 10-6, indicating non-negligible carcinogenic risks to drivers and passengers, especially via ingestion processes. This study provided a practicable method to investigate long-term air contamination of PAHs in vehicles and along roads based on film-bound PAH on vehicle windows. In addition, it was also possible to investigate the health risk in vehicles as a result of exposure to PAHs. Comparisons of PAHs between roads and shipping lanes also facilitated the delineation of vehicular and shipping PAH inventories. A capsule that summarizes the main finding of the work: Investigating film-bound PAH on vehicle windows is a practicable pathway to investigate the long-term contamination of PAHs in vehicles and along roads. This method can not only simplify the sampling processes, but the model calculations. The results also enabled investigations into ILCR in vehicles and specified source apportionment of traffic PAHs.

7.
Gut Microbes ; 13(1): 1-27, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33691599

RESUMO

Atherosclerosis (AS) is exacerbated in the perimenopausal period, which significantly increases the incidence rate of cardiovascular disease. The disruption of the gut microbiota has been associated with AS or menopause, but the specific changes of AS-associated gut microbiota in the perimenopausal period remain largely unknown. As lipid abnormalities are mainly responsible for AS, the relationship between lipid metabolism abnormalities and gut microbiota disruptions during menopause is rarely reported hitherto. In the present study, ApoE-/- mice fed with a high-fat diet (HFD) were subjected to ovariectomy and supplemented with estrogen. The ovariectomized HFD-fed ApoE-/- mice underwent significant AS damage, hepatic lipid damage, hyperlipidemia, and changes of lipid metabolism- and transport-related enzymes. There was significantly higher abundance of some lipid metabolites in the plasma of ovariectomized HFD-fed ApoE-/- mice than in non-ovariectomized ones, including cholesterol esters, triglycerides, phospholipids, and other types of lipids (free fatty acids, acylcarnitine, sphingomyelins, and ceramides). The administration of estrogen significantly reduced the contents of most lipid metabolites. The diversity and composition of gut microbiota evidently changed in ovariectomized HFD-fed ApoE-/- mice, compared to HFD-fed ApoE-/- mice without ovariectomy. In contrast, with estrogen supplementation, the diversity and composition of gut microbiota were restored to approach that of non-ovariectomized HFD-fed ApoE-/- mice, and the relative abundances of some bacteria were even like those of C57BL/6 mice fed with a normal diet. On the other hand, the transplantation of feces from C57BL/6 mice fed with normal diet to ovariectomized HFD-fed ApoE-/- mice was sufficient to correct the hyperlipidemia and AS damage, and to reverse the characteristics changing of lipid metabolomics in ovariectomized HFD-fed ApoE-/- mice. These phenomena were also been observed after transplantation of feces from estrogen-treated ovariectomized HFD-fed ApoE-/- mice to ovariectomized HFD-fed ApoE-/- mice. Moreover, the gut microbiota and lipid metabolites were significantly correlated, demonstrating that the changes of serum lipids may be associated with the gut microbiota disruptions in the perimenopausal period. In conclusion, the gut microbiota during the progression of AS in the perimenopausal period showed specific compositional changes and significant correlations with circulating lipid metabolites. Estrogen supplementation may exert beneficial effects on gut bacteria and lipid metabolism.

8.
Int J Nanomedicine ; 16: 1849-1867, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33707943

RESUMO

Background: With the development of bacterial resistance, the range of effective antibiotics is increasingly becoming more limited. The effective use of nanoscale antimicrobial peptides (AP) in therapeutic and diagnostic methods is a strategy for new antibiotics. Methods: Combining both AP and cadmium selenide (CdSe) into a composite material may result in a reagent with novel properties, such as enhanced antibacterial activity, fluorescence and favorable stability in aqueous solution. Results: AP-loaded CdSe NPs (AP-CdSe NPs) showed strong antibacterial activity against multidrug-resistant (MDR) Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) in vitro and in vivo. Colony-forming unit (CFU) and minimum inhibitory concentration (MIC) assays showed that AP-CdSe NPs have highly effective antibacterial activity. The quantitative analysis of apoptosis by flow cytometry analysis further confirmed that MDR E. coli and S. aureus treated with AP-CdSe NPs had death rates of 98.76% and 99.13%, respectively. Also, AP-CdSe NPs was found to inhibit bacterial activity in an in vivo bacteremia model in mice infected with S. aureus. In addition, the antibacterial mechanism of AP-CdSe NPs was determined by RNA sequencing analysis. Gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed the molecular mechanism of the antibacterial effect of AP-CdSe NPs. Importantly, histopathology analysis, and hematological toxicity analysis indicated that AP-CdSe NPs had few side effects. Conclusion: These results demonstrate that AP loaded on CdSe NPs had a higher water solubility, bioavailability and antibacterial effect compared with raw AP. This study reports findings that are helpful for the design and development of antibacterial treatment strategies based on AP.


Assuntos
Antibacterianos/farmacologia , Compostos de Cádmio/química , Luminescência , Nanopartículas/química , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Pontos Quânticos/química , Compostos de Selênio/química , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Bacteriemia/microbiologia , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/ultraestrutura , Feminino , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Camundongos Nus , Testes de Sensibilidade Microbiana , Microscopia de Fluorescência , Nanopartículas/ultraestrutura , Proteínas Citotóxicas Formadoras de Poros/efeitos adversos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/ultraestrutura
9.
Front Cell Infect Microbiol ; 11: 643092, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33768014

RESUMO

Rheumatic heart disease refers to the long-term damage of heart valves and results from an autoimmune response to group A Streptococcus infection. This study aimed to analyze the microbiota composition of patients with rheumatic heart disease and explore potential function of microbiota in this disease. First, we revealed significant alterations of microbiota in feces, subgingival plaques, and saliva of the patients compared to control subjects using 16S rRNA gene sequencing. Significantly different microbial diversity was observed in all three types of samples between the patients and control subjects. In the gut, the patients possessed higher levels of genera including Bifidobacterium and Eubacterium, and lower levels of genera including Lachnospira, Bacteroides, and Faecalibacterium. Coprococcus was identified as a super-generalist in fecal samples of the patients. Significant alterations were also observed in microbiota of subgingival plaques and saliva of the patients compared to control subjects. Second, we analyzed microbiota in mitral valves of the patients and identified microbes that could potentially transmit from the gut or oral cavity to heart valves, including Streptococcus. Third, we further analyzed the data using random forest model and demonstrated that microbiota in the gut, subgingival plaque or saliva could distinguish the patients from control subjects. Finally, we identified gut/oral microbes that significantly correlated with clinical indices of rheumatic heart disease. In conclusion, patients with rheumatic heart disease manifested important alterations in microbiota that might distinguish the patients from control subjects and correlated with severity of this disease.

10.
Nat Commun ; 12(1): 1812, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33753739

RESUMO

Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. The binding of hexokinase 2 to the outer membrane of mitochondria is critical for its oncogenic activity. However, the regulation of hexokinase 2 binding to mitochondria remains unclear. Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492. SUMO-specific protease SENP1 mediates the de-SUMOylation of hexokinase 2. SUMO-defective hexokinase 2 preferably binds to mitochondria and enhances both glucose consumption and lactate production and decreases mitochondrial respiration in parallel. This metabolic reprogramming supports prostate cancer cell proliferation and protects cells from chemotherapy-induced cell apoptosis. Moreover, we demonstrate an inverse relationship between SENP1-hexokinase 2 axis and chemotherapy response in prostate cancer samples. Our data provide evidence for a previously uncovered posttranslational modification of hexokinase 2 in cancer cells, suggesting a potentially actionable strategy for preventing chemotherapy resistance in prostate cancer.


Assuntos
Carcinogênese/metabolismo , Hexoquinase/metabolismo , Mitocôndrias/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Docetaxel/farmacologia , Hexoquinase/genética , Humanos , Masculino , Camundongos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Ligação Proteica , Sumoilação , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
Front Endocrinol (Lausanne) ; 12: 615913, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746900

RESUMO

Background: Cathepsin S, as an adipokine, was reported to play a critical role in various disease, including atherosclerosis and diabetes. The present study aims to elucidate the relationship between circulating cathepsin S and cardiovascular disease (CVD) in patients with type 2 diabetes. Methods: A total of 339 type 2 diabetes individuals were enrolled in this cross-sectional community-based study. Basic information, medical and laboratory data were collected. Serum cathepsin S levels were assessed by ELISA. Results: Compared to the CVD (-) group, levels of serum cathepsin S were significantly higher in the CVD (+) group, with the median 23.68 ng/ml (18.54-28.02) and 26.81 ng/ml (21.19-37.69) respectively (P < 0.001). Moreover, patients with acute coronary syndrome (ACS) had substantially higher levels of serum cathepsin S than those with stable angina pectoris (SAP), with the median 34.65 ng/ml (24.33-42.83) and 25.52 ng/ml (20.53-31.47) respectively (P < 0.01). The spearman correlation analysis showed that circulating cathepsin S was correlated with several cardiovascular risk factors. The univariate and multivariate logistic regression analysis revealed that circulating cathepsin S was an independent risk factor for CVD (all P < 0.001) after adjustment for potential confounders. Restricted cubic spline analysis showed circulating cathepsin S had a linearity association with CVD. In addition, receiver operating characteristic (ROC) curve analysis demonstrated that the area under curve (AUC) values of cathepsin S was 0.80 (95% CI: 0.75-0.84, P < 0.001), with the optimal cutoff value of cathepsin 26.28 ng/ml. Conclusion: Circulating cathepsin S was significantly higher in the CVD (+) group than that in the CVD (-) one among type 2 diabetes. The increased serum cathepsin S levels were associated with increased risks of CVD, even after adjusting for potential confounders. Thus, cathepsin S might be a potential diagnostic biomarker for CVD.

12.
Cogn Res Princ Implic ; 6(1): 17, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33710497

RESUMO

Cognition and action are often intertwined in everyday life. It is thus pivotal to understand how cognitive processes operate with concurrent actions. The present study aims to assess how simple physical effort operationalized as isometric muscle contractions affects visual attention and inhibitory control. In a dual-task paradigm, participants performed a singleton search task and a handgrip task concurrently. In the search task, the target was a shape singleton among distractors with a homogeneous but different shape. A salient-but-irrelevant distractor with a unique color (i.e., color singleton) appeared on half of the trials (Singleton distractor present condition), and its presence often captures spatial attention. Critically, the visual search task was performed by the participants with concurrent hand grip exertion, at 5% or 40% of their maximum strength (low vs. high physical load), on a hand dynamometer. We found that visual search under physical effort is faster, but more vulnerable to distractor interference, potentially due to arousal and reduced inhibitory control, respectively. The two effects further manifest in different aspects of RT distributions that can be captured by different components of the ex-Gaussian model using hierarchical Bayesian method. Together, these results provide behavioral evidence and a novel model for two dissociable cognitive mechanisms underlying the effects of simple muscle exertion on the ongoing visual search process on a moment-by-moment basis.

13.
Carbohydr Polym ; 260: 117842, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33712176

RESUMO

The development of effective and environment-friendly corrosion inhibitors is of great significance for the protection of mild steel in hydrochloric acid media. Accordingly, a natural polysaccharide mixture inhibitor composed of chondroitin sulfate derived from pig cartilage (CS-PC) and sodium alginate (SA) is developed here, and the synergistic effect of the two polysaccharides towards adsorption on mild steel in 1 M HCl is studied. The inhibition performance has been studied using weight loss test, electrochemical investigations, SEM, SECM and UV methods. The results indicate that the mixtures of CS-PC and SA strongly inhibit the corrosion of mild steel compared to individual inhibitors (i.e., 95.18 % versus 72.78 %), and show a synergistic inhibition effect. The structure-activity relationship between the molecular structure of the CS-PC + SA mixture and its corrosion inhibition performance has been discussed by using the quantum chemistry calculation and molecular dynamics simulations. It is believed that these results have certain guiding significance for the rational design of efficient corrosion inhibitor.

14.
Nanotechnology ; 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711826

RESUMO

Doxorubicin (DOX) is a commonly used anticancer drug, but is inefficient as a therapeutic due to a lack of targeting. Peptide-tuned self-assembly of DOX offers a strategy to improve targeting for greater efficacy. In this work, we designed and prepared an amphiphilic tumor cell targeting peptide, P14 (AAAAFFFHHHGRGD), able to encapsulate DOX by self-assembly to form tumor cell targeting and pH-sensitive nano-micelles. The results showed that a critical P14-micelle concentration of 1.758 mg/L and an average particle size of micelles of 121.64 nm, with entrapment and drug loading efficiencies of 28.02% ± 1.35% and 12.06% ± 0.59%, respectively. The prepared micelles can release 73.52 ± 1.27% DOX within 24 hours in pH 4.5 medium, and the drug cumulative release profile of micelle can be described by first-order model. Compared with free DOX, the micelles exhibited increased ability to inhibit tumor cell growth and cause tumor apoptosis in vitro, with IC50 values of DOX and P14-DOX micelles against human breast cancer cells (MCF-7) of 0.91 ± 0.07 and 0.75 ± 0.06 µg/mL, respectively, and cellular apoptotic rates of DOX and P14-DOX micelles of 70.3% and 42.4%, respectively. Cellular uptake experiments revealed high concentrations of micelles around and inside MCF-7 cells, demonstrating that micelles can target tumor cells. These results indicate the excellent potential for the application of this amphiphilic peptide as a carrier for small-molecule drugs and suggest a strategy for the design of effective anti-tumor drugs.

15.
Mech Ageing Dev ; 196: 111475, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33781783

RESUMO

Kidney ageing, which is always accompanied by renal fibrosis, drives the progression of renal fibrosis. Thioredoxin-interacting protein (TXNIP) is an endogenous suppressor of the reactive oxygen species-scavenging protein thioredoxin, which has been implicated in the ageing of some organs and is involved in renal fibrosis. However, the expression of TXNIP in ageing kidneys has not been examined, and the relationship between TXNIP and ageing-related renal fibrosis is unclear. We found that TXNIP expression was upregulated in aged mouse kidneys, and this upregulation was accompanied by ageing-related renal fibrosis phenotypes. We demonstrated that the ageing biomarkers were downregulated in TXNIP-knockout mice, and these effects resulted in the alleviation of renal fibrosis and impairments in kidney function. TXNIP overexpression in tubular cells upregulated senescence markers, promoted a profibrotic response and activated STAT3 signalling, and these parameters were inhibited by the silencing of TXNIP. Similarly, the TXNIP-mediated profibrotic response was significantly suppressed by a STAT3 inhibitor. By coimmunoprecipitation, we verified that TXNIP directly bound to STAT3, which suggested that TXNIP exacerbates renal tubular epithelial fibrosis by activating the STAT3 pathway. In summary, TXNIP plays an important role in age-related renal fibrosis and might be a therapeutic target for preventing ageing-associated renal fibrosis.

16.
FEMS Yeast Res ; 21(2)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33620449

RESUMO

Improving yeast tolerance toward isobutanol is a critical issue enabling high-titer industrial production. Here, we used EMS mutagenesis to screen Saccharomyces cerevisiae with greater tolerance toward isobutanol. By this method, we obtained EMS39 with high-viability in medium containing 16 g/L isobutanol. Then, we metabolically engineered isobutanol synthesis in EMS39. About 2µ plasmids carrying PGK1p-ILV2, PGK1p-ILV3 and TDH3p-cox4-ARO10 were used to over-express ILV2, ILV3 and ARO10 genes, respectively, in EMS39 and wild type W303-1A. And the resulting strains were designated as EMS39-20 and W303-1A-20. Our results showed that EMS39-20 increased isobutanol titers by 49.9% compared to W303-1A-20. Whole genome resequencing analysis of EMS39 showed that more than 59 genes had mutations in their open reading frames or regulatory regions. These 59 genes are enriched mainly into cell growth, basal transcription factors, cell integrity signaling, translation initiation and elongation, ribosome assembly and function, oxidative stress response, etc. Additionally, transcriptomic analysis of EMS39-20 was carried out. Finally, reverse engineering tests showed that overexpression of CWP2 and SRP4039 could improve tolerance of S.cerevisiae toward isobutanol. In conclusion, EMS mutagenesis could be used to increase yeast tolerance toward isobutanol. Our study supplied new insights into mechanisms of tolerance toward isobutanol and enhancing isobutanol production in S. cerevisiae.

17.
Int J Cancer ; 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33521930

RESUMO

The HOX genes are a group of highly conserved Homeobox-containing genes that control the body plan organization during development. However, their contributions to tumorigenesis and tumor progression remain uncertain and controversial. Here we provided evidence of tumor-suppressive activity of HOXD13 in prostate cancer. HOXD13 depletion contributes to more aggressiveness of prostate cancer cells in vitro and in vivo. These effects were corroborated in a metastatic mice model, where we observed more bone metastatic lesions formed by prostate cancer cells with HOXD13 ablation. Mechanistically, HOXD13 prevents BMP4-induced epithelial-mesenchymal transition (EMT) by inhibiting mothers against decapentaplegic homolog 1 (SMAD1) transcription. Both bioinformation and our tissue microarray cohort data show that HOXD13 expression inversely correlated in advanced prostate cancer patient specimens. Our findings establish HOXD13 as a negative regulator of prostate cancer progression and metastasis by preventing BMP4/SMAD1 signaling, and potentially suggest new strategies for targeting metastatic prostate cancer.

19.
Int J Clin Pharm ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33555498

RESUMO

Background Audits of antimicrobial prophylaxis is an essential strategy to identify practice gaps in antimicrobial prescribing in healthcare facilities. There is a lack of studies on the costs, quality, and antimicrobial use density of neurosurgical perioperative antimicrobial prophylaxis in China. Objectives Evaluate the appropriateness of perioperative antimicrobial prophylaxis in neurosurgeries and analyze the costs, quality, and antimicrobial use density of neurosurgical perioperative antimicrobial prophylaxis. Setting Beijing Tsinghua Changgung Hospital, a teaching hospital in Beijing. Methods This retrospective study was conducted among 262 neurosurgical patients without infections during 2017. The appropriateness of perioperative antimicrobial prophylaxis was determined based on relevant international and Chinese perioperative antimicrobial prophylaxis guidelines. Main outcome measures Discrepancy rates in perioperative antimicrobial prophylaxis, including indication, choice of antimicrobials, dose, route of administration, time of administration of the first dose, re-dosing, and duration, were analyzed. Results Discrepancies were observed between current practice and relevant guidelines. A total of 51 (32.1%) procedures failed to administer intraoperative re-dosing as needed, and the perioperative antimicrobial prophylaxis duration of 217 (82.8%) procedures was inappropriately prolonged. The choice of antimicrobial agents was optimal in 249 (95%) procedures, and the timing of perioperative antimicrobial prophylaxis was appropriate in all procedures. If perioperative antimicrobial prophylaxis was implemented according to guidelines, the defined daily dose per 100 procedures would decrease from 31.97 to 16.99, and the total cost would reduce from $2000 to $490. Conclusions Effective antimicrobial stewardship is urgently needed to promote the appropriateness of neurosurgical perioperative antimicrobial prophylaxis in China.

20.
Retina ; 41(3): 595-601, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33600135

RESUMO

PURPOSE: To propose a new clinical evaluation index, foveal avascular zone (FAZ) volume, and analyze its statistical significance. METHODS: A semiautomatic method is proposed to measure the FAZ volume in optical coherence tomography angiography images as follows: The region of interest was flattened and annotated axially. The labeled pixels in the restored region of interest were counted as the FAZ volume. Linear regression and the independent samples t-test were performed for the statistical analysis. RESULTS: Sixty-one normal, 64 high myopia, and 42 diabetic retinopathy eyes were imaged using optical coherence tomography angiography. For normal eyes, the FAZ volume correlates inversely with central macular thickness (superficial: P = 0.004; deep: P < 0.001) and positively with area (P < 0.001). For high myopia eyes, the deep plexus FAZ (P = 0.34) and total FAZ (P = 0.38) volumes show no significant difference, whereas the superficial plexus FAZ volume is significantly larger than control (P < 0.001). For diabetic retinopathy eyes, the superficial plexus FAZ (P = 0.001), deep plexus FAZ (P = 0.014), and total volumes (P = 0.002) are significantly larger than control. CONCLUSION: The FAZ volume is proposed for depicting the 3D structure of the FAZ. It shows greater sensitivity for vascular alteration that makes it meaningful for clinical analysis.

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