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2.
Sci Rep ; 10(1): 16690, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028924

RESUMO

We evaluated the feasibility and image quality of prospective electrocardiography (ECG)-triggered coronary computed tomography angiography (CCTA) using a body surface area (BSA) protocol for contrast-medium (CM) administration on both second- and third-generation scanners (Flash and Force CT), without using heart rate control. One-hundred-and-eighty patients with suspected coronary heart disease undergoing CCTA were divided into groups A (BSA protocol for CM on Flash CT), B (body mass index (BMI)-matched patients; BMI protocol for CM on Flash CT), and C (BMI-matched patients; BSA protocol for CM on Force CT). Patient characteristics, quantitative and qualitative measures, and radiation dose were compared between groups A and B, and A and C. Of the 180 patients, 99 were male (median age, 62 years). Average BSA in groups A, B, and C was 1.80 ± 0.17 m2, 1.74 ± 0.16 m2, and 1.64 ± 0.17 m2, respectively, with groups A and C differing significantly (P < 0.001). Contrast volume (50.50 ± 8.57 mL vs. 45.00 ± 6.18 mL) and injection rate (3.90 ± 0.44 mL/s vs. 3.63 ± 0.22 mL/s) differed significantly between groups A and C (P < 0.001). Groups A and C (both: all CT values > 250 HU, average scores > 4) achieved slightly lower diagnostic image quality than group B. The BSA protocol for CM administration was feasible in both Flash and Force CT, and therefore may be valuable in clinical practice.

3.
Radiother Oncol ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33039427

RESUMO

BACKGROUND AND PURPOSE: To propose a novel machine learning-based method for reliable and accurate modeling of linac beam data applicable to the processes of linac commissioning and QA. MATERIALS AND METHODS: We hypothesize that the beam data is a function of inherent linac features and percentage depth doses (PDDs) and profiles of different field sizes are correlated with each other. The correlation is formulated as a multivariable regression problem using a machine learning framework. Varian TrueBeam beam data sets (n=43) acquired from multiple institutions were used to evaluate the framework. The data sets included PDDs and profiles across different energies and field sizes. A multivariate regression model was trained for prediction of beam specific PDDs and profiles of different field sizes using a 10x10cm2 field as input. RESULTS: Predictions of PDDs were achieved with a mean absolute percent relative error (%RE) of 0.19-0.35% across the different beam energies investigated. The maximum mean absolute %RE was 0.93%. For profile prediction, the mean absolute %RE was 0.66-0.93% with a maximum absolute %RE of 3.76%. The largest uncertainties in the PDD and profile predictions were found at the build-up region and at the field penumbra, respectively. The prediction accuracy increased with the number of training sets up to around 20 training sets. CONCLUSIONS: Through this novel machine learning-based method we have shown accurate and reproducible generation of beam data for linac commissioning for routine radiation therapy. This method has the potential to simplify the linac commissioning procedure, save time and manpower while increasing the accuracy of the commissioning process.

4.
Allergy ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33040337

RESUMO

BACKGROUND: The missing asymptomatic COVID-19 infections have been overlooked because of the imperfect sensitivity of the nucleic acid testing (NAT). Globally understanding the humoral immunity in asymptomatic carriers will provide scientific knowledge for developing serological tests, improving early identification, and implementing more rational control strategies against the pandemic. MEASURE: Utilizing both NAT and commercial kits for serum IgM and IgG antibodies, we extensively screened 11,766 epidemiologically suspected individuals on enrollment and 63 asymptomatic individuals were detected and recruited. 63 healthy individuals and 51 mild patients without any preexisting conditions were set as controls. Serum IgM and IgG profiles were further probed using a SARS-CoV-2 proteome microarray and neutralizing antibody was detected by a pseudotyped virus neutralization assay system. The dynamics of antibodies were analyzed with exposure time or symptoms onset. RESULTS: A combination test of NAT and serological testing for IgM antibody with discovered 55.5% of the total of 63 asymptomatic infections, which significantly raises the detection sensitivity when compared with the NAT alone (19%). Serum proteome microarray analysis demonstrated that asymptomatics mainly produced IgM and IgG antibodies against S1 and N proteins out of 20 proteins of SARS-CoV-2. Different from strong and persistent N specific antibodies, S1 specific IgM responses, which evolved in asymptomatic individuals as early as the seventh day after exposure, peaked on days from 17d to 25d, and then disappeared in two months, might be used as an early diagnostic biomarker. 11.8% (6/51) mild patients and 38.1% (24/63) asymptomatic individuals did not produce neutralizing antibody. In particular, neutralizing antibody in asymptomatics gradually vanished in two months. CONCLUSION: Our findings might have important implications for the definition of asymptomatic COVID-19 infections, diagnosis, serological survey, public health and immunization strategies.

5.
Ann Palliat Med ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-33040540

RESUMO

Aggressive angiomyxoma (AAM) is rare. AAM is characterized by invasion and recurrence. Improving the detection rate of AAM through ultrasonic inspection technology. There is very little literature reported on AAM. And the literature on the ultrasonic performance of AAM is rare. Therefore, this article describes the ultrasound manifestation of a 54-year-old woman whose pathology is confirmed to be AAM, and summarizes the common ultrasound manifestations of AAM. The unique feature is that the ultrasound performance does not explore the typical "vortex". So we need to diagnose this case through other ultrasound findings. The patient initially had no obvious cause of pain in the right hip. Transvaginal ultrasound examination of the pelvic was performed on the patient, and pathological sections were examined. The result suggested mesenchymal tumor. After surgical resection of the tumor, the pathology was again confirmed as AAM. The tumor is composed of well-differentiated spindle-shaped stellate cells with interstitial mucus degeneration, and vascular proliferation can be seen, which is consistent with deep AAM. Through this case we found that pathology is the gold standard for AAM, but early screening of AAM by ultrasound is feasible.

6.
Cell Mol Biol (Noisy-le-grand) ; 66(5): 98-104, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33040821

RESUMO

Diabetic ketoacidosis (DKA) is a very serious disease that can occur in both types of diabetes (type 1 and 2). It is caused by a combination of high blood sugar and low insulin levels, which can cause the body to produce too much ketone. Ketones are toxic to human organs. This research aimed to investigate the clinical efficacy of low-dose insulin combined with electrolyte in the treatment of pediatric DKA and its effect on serum inflammatory factors. For this purpose, a total of 122 children with DKA admitted to our hospital from April 2013 to May 2016 were selected as research objects. They were divided into group A with 60 cases and group B with 62 cases. Group B was treated with supplemental electrolytes, and group A was treated with low-dose insulin based on group B. The serum levels of TNF-α, IL-6, and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA) before and after treatment, and the blood sugar, sodium, and potassium levels were measured by an automatic biochemical analyzer. The time when blood sugar reached the standard level when acidosis was corrected and hospitalization time was compared between the two groups. The total effective rate of group A was significantly higher than that of group B (p< 0.05). There was no significant difference in blood glucose, sodium, potassium, TNF-α, IL-6, and IL-18 levels between the two groups before treatment. (all p > 0.05). But the blood glucose, sodium and potassium levels in group A were significantly better than those in group B (all p< 0.001). The levels of serum TNF-α, IL-6, and IL-18 in group A were significantly lower than those in group B after treatment (all p< 0.001). After treatment, the time when blood sugar reached the standard level when acidosis was corrected and hospitalization time in group A were significantly shorter than those in group B (all p< 0.001). Low-dose insulin combined with electrolyte supplementation is effective in the treatment of DKA in children, which can effectively control blood sugar, sodium, potassium level, and inflammatory factor concentration.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33010408

RESUMO

BACKGROUND AND AIMS: Programmatic colorectal cancer (CRC) screening increases uptake, but the design and resources utilized for such models are not well known. We characterized program components and participation at each step in a large program that used mailed fecal immunochemical testing (FIT) with opportunistic colonoscopy. METHODS: Mixed-methods with site visits and retrospective cohort analysis of 51-75-year-old adults during 2017 in the Kaiser Permanente Northern California integrated health system. RESULTS: Among 1,023,415 screening-eligible individuals, 405,963 (40%) were up to date with screening at baseline, and 507,401 of the 617,452 not up-to-date were mailed a FIT kit. Of the entire cohort (n=1,023,415), 206,481 (20%) completed FIT within 28 days of mailing, another 61,644 (6%) after a robocall at week 4, and 40,438 others (4%) after a mailed reminder letter at week 6. There were over 800,000 medical record screening alerts generated and about 295,000 FIT kits distributed during patient office visits. About 100,000 FIT kits were ordered during direct-to-patient calls by medical assistants and 111,377 people (11%) completed FIT outside of the automated outreach period. Another 13,560 (1.3%) completed a colonoscopy, sigmoidoscopy, or fecal occult blood test unrelated to FIT. Cumulatively, 839,463 (82%) of those eligible were up to date with screening at the end of the year and 12,091 of 14,450 patients (83.7%) with positive FIT had diagnostic colonoscopy. CONCLUSIONS: The >82% screening participation achieved in this program resulted from a combination of prior endoscopy (40%), large initial response to mailed FIT kits (20%), followed by smaller responses to automated reminders (10%) and personal contact (12%).

8.
J Clin Invest ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33016929

RESUMO

ARID1A, a component of the chromatin-remodeling complex SWI/SNF, is one of the most frequently mutated genes in human cancer. We sought to develop rational combination therapy to potentiate the efficacy of immune checkpoint blockade in ARID1A-deficient tumors. In a proteomic analysis of a data set from The Cancer Genomic Atlas, we found enhanced expression of Chk2, a DNA damage checkpoint kinase, in ARID1A-mutated/deficient tumors. Surprisingly, we found that ARID1A targets the nonchromatin substrate Chk2 for ubiquitination. Loss of ARID1A increased the Chk2 level through modulating autoubiquitination of the E3-ligase RNF8 and thereby reducing RNF8-mediated Chk2 degradation. Inhibition of the ATM/Chk2 DNA damage checkpoint axis led to replication stress and accumulation of cytosolic DNA, which subsequently activated the DNA sensor STING-mediated innate immune response in ARID1A-deficient tumors. As expected, tumors with mutation or low expression of both ARID1A and ATM/Chk2 exhibited increased tumor-infiltrating lymphocytes and were associated with longer patient survival. Notably, an ATM inhibitor selectively potentiated the efficacy of immune checkpoint blockade in ARID1A-depleted tumors but not in WT tumors. Together, these results suggest that ARID1A's targeting of the nonchromatin substrate Chk2 for ubiquitination makes it possible to selectively modulate cancer cell-intrinsic innate immunity to enhance the antitumor activity of immune checkpoint blockade.

9.
Micromachines (Basel) ; 11(10)2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33008018

RESUMO

The rapid spread of the novel coronavirus disease, COVID-19, and its resulting situation has garnered much effort to contain the virus through scientific research. The tragedy has not yet fully run its course, but it is already clear that the crisis is thoroughly global, and science is at the forefront in the fight against the virus. This includes medical professionals trying to cure the sick at risk to their own health; public health management tracking the virus and guardedly calling on such measures as social distancing to curb its spread; and researchers now engaged in the development of diagnostics, monitoring methods, treatments and vaccines. Recent advances in non-contact sensing to improve health care is the motivation of this study in order to contribute to the containment of the COVID-19 outbreak. The objective of this study is to articulate an innovative solution for early diagnosis of COVID-19 symptoms such as abnormal breathing rate, coughing and other vital health problems. To obtain an effective and feasible solution from existing platforms, this study identifies the existing methods used for human activity and health monitoring in a non-contact manner. This systematic review presents the data collection technology, data preprocessing, data preparation, features extraction, classification algorithms and performance achieved by the various non-contact sensing platforms. This study proposes a non-contact sensing platform for the early diagnosis of COVID-19 symptoms and monitoring of the human activities and health during the isolation or quarantine period. Finally, we highlight challenges in developing non-contact sensing platforms to effectively control the COVID-19 situation.

10.
Biomater Sci ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001086

RESUMO

Anti-angiogenic tyrosine kinase inhibitors (TKIs) have been proved to be effective in prolonging progression-free survival in advanced osteosarcoma. However, osteosarcoma stem-like cells persist for a long time and ultimately cause disease recurrence and therapy resistance. Here, we reveal that inefficient accumulation of Apatinib, an anti-angiogenic TKI, induces the expression of ribosome-associated genes in osteosarcoma, and confers apoptosis resistance. An engineered nanoscale delivery system based on hydrophobic poly(ester amide) has been established to effectively deliver Apatinib to improve the treatment. Notably, the considerable uptake by osteosarcoma cells enables this nanodrug to distribute increasingly inside the tumor. Furthermore, the delivered nano-Apatinib can suppress osteosarcoma stemness and enhance osteosarcoma stem-like cell apoptosis, and overcomes the crucial bottleneck of the unfavorable stem-like cell residue for TKI therapy. Importantly, nano-Apatinib significantly inhibits the osteosarcoma stem-like cell-derived tumor growth in contrast with free Apatinib, with minimal side effects. These results suggest that this Apatinib-loaded nano delivery system may serve as a promising strategy to solve the issue of TKI therapeutic resistance existing in advanced osteosarcoma.

11.
Phys Med Biol ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032267

RESUMO

The coronavirus disease 2019 (COVID-19) is now a global pandemic. Tens of millions of people have been confirmed infection, and more people are suspected. Chest computed tomography (CT) is recognized as an important tool for COVID-19 severity assessment. As the number of chest CT images increase rapidly, manual severity assessment becomes a labor-intensive task, delaying appropriate isolation and treatment. In this paper, a study of automatic severity assessment for COVID-19 is presented. Specifically, chest CT images of 118 patients (age 46.5±16.5 years, 64 male and 54 female) with confirmed COVID-19 infection are used, from which 63 quantitative features and 110 Radiomics features are derived. Besides the chest CT image features, 36 laboratory indices of each patient are also used, which can provide complementary information from a different view. A random forest (RF) model is trained to assess the severity (non-severe or severe) according to the chest CT image features and laboratory indices. Importance of each chest CT image feature and laboratory index, which reflects the correlation to the severity of COVID-19, is also calculated from the RF model. Using three-fold cross-validation, the RF model shows promising results: 0.910 (true positive ratio), 0.858 (true negative ratio) and 0.890 (accuracy), along with AUC of 0.98. Moreover, several chest CT image features and laboratory indices are found to be important to COVID-19 severity, which could be valuable for the clinical diagnosis of COVID-19.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33020163

RESUMO

Background: The pharmacological activity of ceftriaxone depends on unbound concentration. However, direct measurement of unbound concentration is obstructive, and high individual variability of the unbound fraction of ceftriaxone was shown in children. We aim to evaluate and validate a method to predict unbound ceftriaxone in pediatric patients.Methods: Ninety-five pairs of concentration (total and unbound) from 92 patients were measured by the bioanalysis method we developed. The predictive performance of the three equations (empirical in vivo equation, disease adapted equation and multiple linear regression equation) was assessed by mean absolute prediction error (MAPE), mean prediction error (MAE), the proportion of the prediction error within ± 30% (P30) and ± 50% (P50) and linear regression of predicted versus actual unbound levels (R2).Results: The average total and unbound ceftriaxone concentrations were 126.18 ± 81.46 µg/mL and 18.82 ± 21.75 µg/mL, and the unbound fraction varied greatly from 4.75% to 39.97%. The MPE, MAPE, P30, P50 and R2 of empirical in vivo equation, disease equation and multiple linear equation were -.0.17 vs 0.00 vs 0.06, 0.24 vs 0.15 vs 0.27, 63.2% vs 89.5% vs 74.7% and 96.8% vs 97.9% vs 86.3% and 0.8730 vs 0.9342 vs 0.9315. The disease adapted equation showed the best predictive performance.Conclusion: We have developed and validated a bioanalysis method with one-step extraction pre-treatment for the determination of total ceftriaxone, and a prediction equation of unbound concentration was recommended. The proposed method can facilitate the clinical practice and research of unbound ceftriaxone in children.

13.
Cancer Gene Ther ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33046820

RESUMO

The tumor-suppressive role of Farnesoid X receptor (FXR) in colorectal tumorigenesis supports restoring FXR expression as a novel therapeutic strategy. However, the complicated signaling network and tumor heterogeneity hinder the effectiveness of FXR agonists in the clinical setting. These difficulties highlight the importance of identifying drug combinations with potency and specificity to enhance the antitumor effects of FXR agonists. In this study, we found that the ß-catenin level affected the antitumor effects of the FXR agonist OCA on colon cancer cells. Mechanistic studies identified a novel FXR/ß-catenin complex in colon cancer cells. Furthermore, the depletion of ß-catenin expedited FXR nuclear localization and enhanced its occupancy of the SHP promoter and thereby sensitized colon cancer cells to OCA. Furthermore, we utilized a drug combination study and identified that the antiparasitic drug nitazoxanide (NTZ) abrogated ß-catenin expression and acted synergistically with OCA in colon cancer cells. The combination of OCA plus NTZ exerts synergistic tumor inhibition in CRC both in vitro and in vivo by cooperatively upregulating SHP expression. In conclusion, our study offers useful evidence for the clinical use of FXR agonists combined with ß-catenin inhibitors in combating CRC.

14.
Clin Epigenetics ; 12(1): 160, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097085

RESUMO

BACKGROUND: Elderly patients with diffuse large B-cell lymphoma (DLBCL) present with poor clinical outcome and intolerance to intensive chemotherapy. Histone deacetylase inhibitors (HDACIs) show anti-lymphoma activities and can be applied to treat DLBCL. This study aimed to evaluate efficacy and safety of oral HDACI tucidinostat (formerly known as chidamide) plus R-CHOP (CR-CHOP) in elderly patients with newly diagnosed DLBCL (International Prognostic Index ≥ 2). RESULTS: Among 49 patients, the complete response rate was 86%, with overall response rate achieving 94%. The 2-year progression survival (PFS) and overall survival (OS) rates were 68% (95% CI 52-79) and 83% (95% CI 68-91). Comparing with historical control (NCT01852435), the 2-year PFS and OS rates of double-expressor lymphoma phenotype (DEL) were improved, and negative prognostic effect of histone acetyltransferases CREBBP/EP300 mutations was also mitigated by CR-CHOP. Grade 3-4 neutropenia was reported in 171, grade 3-4 thrombocytopenia in 27, and grade 3 anemia in 11 of 283 cycles. No grade 4 non-hematological adverse event was reported. CONCLUSION: CR-CHOP is effective and safe in elderly patients with newly diagnosed DLBCL. Relevance of DEL phenotype and molecular biomarkers on CR-CHOP response warrants further investigation in DLBCL. Trial registration ClinicalTrial.gov, NCT02753647. Registered on April 28, 2016.

15.
Med Sci Monit ; 26: e925709, 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33097682

RESUMO

BACKGROUND The objective of the present study was to test the hypothesis that intravenous dexmedetomidine is safe and effective when administered to women before and during cesarean section. MATERIAL AND METHODS The analysis included 392 women who received spinal anesthesia and no analgesia prior to undergoing elective cesarean delivery. Of them, 115 women received dexmedetomidine before anesthesia and during delivery (DX cohort), 109 received normal saline before anesthesia and during delivery and dexmedetomidine after delivery (SC cohort), and 168 received normal saline only before anesthesia and during delivery (CN cohort). Data about the women's consumption of sufentanil and ondansetron during hospitalization, onset of lactation, and hospital stays were retrospectively collected and analyzed. RESULTS Most of the women in the study were primiparous (362/392). The women in the DX cohort received less sufentanil during their hospital stays than those in either of the other 2 cohorts (SC comparison: 151.45±11.15 µg vs. 175.12±25.15 µg, P<0.0001, q=8.776; CN comparison: 151.45±11.15 µg vs. 185.42±37.45 µg, P<0.0001, q=13.911). Also, the women in the DX cohort received less ondansetron before discharge and had shorter times to first lactation and hospital stays than those in the SC and CN cohorts. CONCLUSIONS Administering dexmedetomidine before spinal anesthesia appears to be safe and effective for women undergoing elective cesarean delivery.

16.
Nat Commun ; 11(1): 5372, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097724

RESUMO

Chiral aldehyde catalysis is a burgeoning strategy for the catalytic asymmetric α-functionalization of aminomethyl compounds. However, the reaction types are limited and to date include no examples of stereodivergent catalysis. In this work, we disclose two chiral aldehyde-catalysed diastereodivergent reactions: a 1,6-conjugate addition of amino acids to para-quinone methides and a bio-inspired Mannich reaction of pyridinylmethanamines and imines. Both the syn- and anti-products of these two reactions can be obtained in moderate to high yields, diastereo- and enantioselectivities. Four potential reaction models produced by DFT calculations are proposed to explain the observed stereoselective control. Our work shows that chiral aldehyde catalysis based on a reversible imine formation principle is applicable for the α-functionalization of both amino acids and aryl methylamines, and holds potential to promote a range of asymmetric transformations diastereoselectively.

17.
Food Funct ; 11(10): 9048-9056, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33021614

RESUMO

Type-II diabetes mellitus (T2DM) has become one of the most prevalent diseases on Earth and some treatments have been developed to manage it. One intestinal enzyme α-amylase can break down starch to glucose. Inhibiting its activity will control blood glucose and provide an essential approach for the management of T2DM. Alpha-amylase inhibitor (α-AI) specifically inhibits the activity of α-amylase, and reduces the blood glucose level efficiently. To develop a novel α-AI, the red seaweed laver (Porphyra spp.) was exploited in this work, whose extracts contain polysaccharides showing an inhibitory effect against α-amylase. The crude polysaccharides were extracted using hot water (85 °C) and degraded to low-molecular-weight polysaccharides with 7% of H2O2. One polysaccharide PD-1 exhibiting a competitive binding mode with an IC50 of 12.72 mg mL-1 was separated from these degraded polysaccharides, showing approximately 98.78% of α-amylase inhibition activity. In vivo, PD-1 could efficiently suppress postprandial blood glucose levels in normal and diabetic rats. The polysaccharide inhibitor from red seaweed laver could be regarded as a novel functional food ingredient in T2DM management.

18.
Molecules ; 25(20)2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33086565

RESUMO

The edible and medicinal part of Inula nervosa Wall. (Xiaoheiyao) is confined to its root without sufficient phytochemical and biological investigation. In this study, the secondary metabolites of root, stem, leaf, and flower of I. nervosa Wall. were visualized using Global Natural Products Social Molecular Networking (GNPS), MolNetEnhancer, XCMS(xcmsonline.scripps.edu) analysis, and `ili mapping based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) data to reveal their chemical differences. Among the 11 kinds of chemical repertoires annotated by MolNetEnhancer and 16 hits against the GNPS library, 10-isobutyryloxy-8,9-epoxythymol isobutyrate (1) was revealed as the most dominant and responsible marker between the roots and the other parts. Moreover, a battery of unique MS features as well as differential markers were discovered from different parts of the plant. The chemical differences contribute to the bioactivity differences, which presented in the 2,2-diphenyl-1-picryl-hydrazyl (DPPH)assay and H2O2-insulted HepG2 cells and were in significant correlations with the contents of 1. real-time reverse transcription polymerase chain reaction (RT-PCR)results demonstrated that I. nervosa Wall. extracts upregulated the mRNA expression of nuclear factor E2-related factor 2(Nrf2), heme oxygenase 1(HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), manganese superoxide dismutase (MnSOD), and glutamate-cysteine ligase catalytic subunit (GCLC) actors involved in antioxidative response in H2O2-challenged HepG2 cells. These findings support the roots of I. nervosa Wall. as active parts of Xiaoheiyao, and also indicate the potential antioxidant activities of other parts.

19.
Mech Ageing Dev ; 192: 111381, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33045248

RESUMO

Saccharomyces cerevisiae MED2/YDL005C is a subunit of the mediator complex (Mediator), which is responsible for tightly controlling the transcription of protein-coding genes by mediating the interaction of RNA polymerase II with gene-specific transcription factors. Although a high-throughput analysis in yeast showed that the MED2 protein exhibits altered cellular localization under hypoxic stress, no specific function of MED2 has been described to date. In this study, we first provided evidence that MED2 is involved in the endoplasmic reticulum (ER) stress response and modulation of the replicative life span. We showed that deletion of MED2 leads to sensitivity to the ER stress inducer tunicamycin (TM) as well as a shortened replicative lifespan (RLS), accompanied by increased intracellular ROS levels and hyperpolarization of mitochondria. On the other hand, overexpression of MED2 in wild-type (WT) yeast enhanced TM resistance and extended the RLS. In addition, the IRE1-HAC1 pathway was essential for the TM resistance of MED2-overexpressing cells. Moreover, we showed that MED2 deficiency enhances ER unfolded protein response (UPR) activity compared to that in WT cells. Collectively, these results suggest the novel role of MED2 as a regulator in maintaining ER homeostasis and longevity.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33079514

RESUMO

Smart transformable nanocarriers are promising to treat deep-seated diseases but require adaptable diagnostic/imaging potency to reflect the morphology change and therapeutic feedback, yet their design and synthesis remains challenging. Herein, stimuli-responsive polyprodrug nanoparticles (SPNs) are formulated from the co-assembly of negatively charged corona and positively charged polyprodrug cores, exhibiting high loading content of camptothecin (CPT, ∼28.6 wt %) tethered via disulfide linkages in the core. SPNs are sequentially sensitive to tumor acidic condition and elevated reductive milieu in the cytosol for deep-penetration drug delivery. Upon accumulation at acidic tumor sites, SPNs dissociate to release smaller positively charged polyprodrug nanoparticles, which efficiently enter deep-seated tumor cells to trigger high-dosage parent CPT release in the reductive cytosolic milieu. Meanwhile, the polyprodrug cores of SPNs labeled with DTPA(Gd), a magnetic resonance imaging contrast agent, can trace the cascade degradation and biodistribution of SPNs as well as the resulting intracellular CPT release. The longitudinal relaxivity of SPNs increases stepwise in the above two processes. The size-switchable polyprodrug nanoparticles exhibit remarkable tumor penetration and noteworthy tumor inhibition in vitro and in vivo, which are promising for endogenously activated precision diagnostics and therapy.

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