Role of Nrf2 in chronic liver disease Tang, Wei; Jiang, Yong-Fang; Ponnusamy, Murugavel ...
World journal of gastroenterology,
09/2014, Volume:
20, Issue:
36
Journal Article
Open access
Nuclear erythroid 2-related factor 2(Nrf2) is a central regulator of antioxidative response elements-mediated gene expression. It has a significant role in adaptive responses to oxidative stress by ...interacting with the antioxidant response element, which induces the expression of a variety of downstream targets aimed at cytoprotection. Previous studies suggested oxidative stress and associated damage could represent a common link between different forms of diseases. Oxidative stress has been implicated in various liver diseases, including viral hepatitis, nonalcoholic fatty liver disease/steatohepatitis, alcoholic liver disease and drug-induced liver injury. Nrf2 activation is initiated by oxidative or electrophilic stress, and aids in the detoxification and elimination of potentially harmful exogenous chemicals and their metabolites. The expression of Nrf2 has been observed throughout human tissue, with high expression in detoxification organs, especially the liver. Thus, Nrf2 may serve as a major regulator of several cellular defense associated pathways by which hepatic cells combat oxidative stress. We review the relevant literature concerning the crucial role of Nrf2 and its signaling pathways against oxidative stress to protect hepatic cell from oxidative damage during development of common chronic liver diseases. We also review the use of Nrf2 as a therapeutic target to prevent and treat liver diseases.
A ceruloplasmin (CP) concentration <200 mg/L is conventionally considered as one of the major diagnostic criteria for Wilson's disease (WD). However, the diagnostic accuracy of this threshold has ...never been investigated in a sufficiently large group of patients. This study aims to present the results of serum CP measurements in various patients and to identify the optimal cutoff value of CP for the diagnosis of WD.
We identified patients whose CP levels were evaluated from January 1, 2016 to December 31, 2016 using a laboratory information database. Data related to CP measurement were retrieved. We carefully reviewed patients' electronic medical records to correct errors and to obtain other necessary data. Data related to WD were retrieved from a special document containing medical records of patients with WD, which were created, modified, and maintained by authors.
CP level was determined in 4048 patients (WD, 297; non-WD, 3751). The mean serum CP level in patients with WD was 50.6±44.2 mg/L, which was significantly lower than that in non-WD patients (293.2±117.3 mg/L, p<0.001). Only 1.0% of patients with WD had CP ≥200 mg/L. The sensitivity and specificity of CP for the diagnosis of WD were 99.0 and 80.9%, respectively, for the conventional cutoff value <200 mg/L and 95.6 and 95.5%, respectively, for the cutoff value <150 mg/L; the latter provided a higher diagnostic accuracy for WD. 53.0% of patients with liver failure, 37.7% of patients with nephrotic syndrome, and 23.0% of patients age 1 to 6 months had serum CP <200 mg/L. Patients who were pregnant and those with malignant tumors, and infectious and inflammatory diseases had significantly higher mean serum CP levels.
The optimal cutoff value of CP for the diagnosis of WD in China is 150 mg/L, with a sensitivity of 95.6% and specificity of 95.5%, thereby providing the highest diagnostic accuracy for WD.
High-molecular-weight glutenin subunits (HMW-GSs) are the most critical grain storage proteins that determine the unique processing qualities of wheat. Although it is a part of the superior HMW-GS ...pair (Dx5+Dy10), the contribution of the Dy10 subunit to wheat processing quality remains unclear. In this study, we elucidated the effect of Dy10 on wheat processing quality by generating and analyzing a deletion mutant (with the Dy10-null allele), and by elucidating the changes to wheat flour following the incorporation of purified Dy10. The Dy10-null allele was transcribed normally, but the Dy10 subunit was lacking. These findings implied that the Dy10-null allele reduced the glutenin:gliadin ratio and negatively affected dough strength (i.e., Zeleny sedimentation value, gluten index, and dough development and stability times) and the bread-making quality; however, it positively affected the biscuit-making quality. The incorporation of various amounts of purified Dy10 into wheat flour had a detrimental effect on biscuit-making quality. The results of this study demonstrate that the Dy10 subunit is essential for maintaining wheat dough strength. Furthermore, the Dy10-null allele may be exploited by soft wheat breeding programs.
Molecules with luminescence have been extensively investigated, but the luminescence of a stable molecule with a triplet ground state has not been observed. Synthesis of boron-containing radicals has ...attracted lots of interest because of their unique electronic structures and potential applications in organic semiconductors. Though some boron-based diradicals have been reported, neutral boron-containing diradicals with triplet ground states are rare. Herein two borocyclic diradicals with different substituents (
3
and
4
) have been isolated. Their electronic structures were investigated by EPR and UV spectroscopy, and SQUID magnetometry, in conjunction with DFT calculations. Both experiment and calculation suggest that
3
is an open shell singlet diradical while
4
is a triplet ground state diradical with a large singlet-triplet gap (0.25 kcal mol
−1
). Both diradicals show multi fluorescence peaks (
3
: 414, 431, and 470 nm;
4
: 420, 433, and 495 nm).
3
displays multiple redox steps and is a potential material towards the design of high-density memory devices.
4
represents the first example of a neutral triplet boron-containing diradical with a strong ferromagnetic interaction, and also is the first stable triplet diradical emitter.
Stable borocyclic diradical emitters with a tunable ground state.
Aims
Voriconazole is a broad‐spectrum antifungal agent for the treatment of invasive fungal infections. There is limited information about the pharmacokinetics and appropriate dosage of voriconazole ...in patients with liver dysfunction. This study aimed to explore the relationship between voriconazole trough concentration (Ctrough) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised voriconazole dosing regimen for patients with liver dysfunction.
Methods
The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic curves were used to explore the relationship between voriconazole Ctrough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed‐effects method. Dosing simulations stratified by total bilirubin (TBIL, TBIL‐1: TBIL < 51 μmol/L; TBIL‐2: 51 μmol/L ≤ TBIL < 171 μmol/L; TBIL‐3: TBIL ≥ 171 μmol/L) were performed.
Results
Receiver operating characteristic curve analysis revealed that voriconazole Ctrough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A 1‐compartment pharmacokinetic model with first‐order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance, volume of distribution and oral bioavailability were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole clearance was significantly associated with TBIL and platelet count. The volume of distribution increased with body weight. Patients with TBIL‐1 could be treated with a loading dose of 400 mg every 12 hours (q12h) for first day, followed by a maintenance dose of 100 mg q12h administered orally or intravenously. TBIL‐2 and TBIL‐3 patients could be treated with a loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily and 50 mg once daily orally or intravenously, respectively.
Conclusions
Lower doses and longer dosing intervals should be considered for patients with liver dysfunction. TBIL‐based dosing regimens provide a practical strategy for achieving voriconazole therapeutic range and therefore maximizing treatment outcomes.
Abstract
We describe 4 cases of Chlamydia psittaci pneumonia among medical staff in a coronavirus disease 2019 (COVID-19) screening ward, as well as the experience of dealing with this nosocomial ...infection event. Atypical pneumonia, in addition to COVID-19, should be considered when clustering cases occur, even during a COVID-19 pneumonia pandemic.
Hepatic copper determination is an important test for the diagnosis of Wilson's disease (WD). However, the method has not been standardized, the diagnostic accuracy has not been evaluated ...prospectively, and the optimal cut‐off value remains controversial. Accordingly, we aimed to prospectively evaluate the diagnostic accuracy of hepatic copper content, as determined using the entire core of a liver biopsy sample. Patients for whom a liver biopsy was indicated were consecutively enrolled. Hepatic copper content was determined with atomic absorption spectroscopy. All assays were performed using careful quality control by a single technician. WD diagnosis was based on WD score or its combination with clinical follow‐up results. A total of 3,350 consecutive patients underwent liver biopsy. Six hundred ninety‐one patients, including 178 with WD, underwent two passes of liver biopsy with hepatic copper determination. Mean hepatic content in WD patients was 770.6 ± 393.2 μg/g dry weight (wt). Sensitivity, specificity, and positive and negative predictive values of hepatic copper content for WD diagnosis in the absence of primary biliary cirrhosis (PBC) or primary sclerosing cholangitis at the cut‐off value of 250 μg/g dry wt. were 94.4%, 96.8%, 91.8%, and 97.8%, respectively. The most useful cut‐off value was 209 μg/g dry wt, with a sensitivity and specificity of 99.4% and 96.1%, respectively. A total of 23.3% of patients without WD and PBC had hepatic copper content >75 μg/g dry wt. Conclusion: A liver biopsy sample of more than 1 mg dry wt may reliably reflect hepatic copper content and should be used for hepatic copper determination. Hepatic copper determination is a very valid procedure for the diagnosis of WD, and the most useful cut‐off value is 209 μg/g dry wt.(Hepatology 2015;62:1731–1741)
High-quality joints between titanium alloys and stainless steels have found applications for nuclear, petrochemical, cryogenic, and aerospace industries due to their relatively low cost, lightweight, ...high corrosion resistance, and appreciable mechanical properties. This article reviews diffusion bonding between titanium alloys and stainless steels with or without interlayers. For diffusion bonding of a titanium alloy and a stainless steel without an interlayer, the optimized temperature is in the range of 800–950°C for a period of 60–120 min. Sound joint can be obtained, but brittle FeTi and Fe-Cr-Ti phases are formed at the interface. The development process of a joint mainly includes three steps: matching surface closure, growth of brittle intermetallic compounds, and formation of the Kirkendall voids. Growth kinetics of interfacial phases needs further clarification in terms of growth velocity of the reacting layer, moving speed of the phase interface, and the order for a new phase appears. The influence of Cu, Ni (or nickel alloy), and Ag interlayers on the microstructures and mechanical properties of the joints is systematically summarized. The content of FeTi and Fe-Cr-Ti phases at the interface can be declined significantly by the addition of an interlayer. Application of multi-interlayer well prevents the formation of intermetallic phases by forming solid solution at the interface, and parameters can be predicted by using a parabolic diffusion law. The selection of multi-interlayer was done based on two principles: no formation of brittle intermetallic phases and transitional physical properties between titanium alloy and stainless steel.
Blocking vascular endothelial growth factor pathway can enhance the efficacy of EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC. ACTIVE is the first phase 3 study conducted in the People’s ...Republic of China evaluating apatinib, a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, plus gefitinib as first-line therapy in EGFR-mutant NSCLC.
Treatment-naive patients with stage IIIB or IV nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and EGFR exon 19 deletion or exon 21 L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/d), plus apatinib (500 mg/d; apatinib A + gefitinib G group), or placebo (placebo P + gefitinib G group). Stratification factors were mutation type, sex, and performance status. The primary end point was progression-free survival (PFS) by blinded independent radiology review committee (IRRC). Secondary end points were investigator-assessed PFS, overall survival, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance.
A total of 313 patients were assigned to the A + G (n = 157) or P + G group (n = 156). Median IRRC PFS in the A + G group was 13.7 months versus 10.2 months in the P + G group (hazard ratio 0.71, p = 0.0189). Investigator- and IRRC-assessed PFS were similar. Overall survival was immature. The most common treatment-emergent adverse events greater than or equal to grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A + G group and increased alanine aminotransferase (10.4%) and aspartate aminotransferase (3.2%) in the P + G group. QoL in the two groups had no statistical differences. Post hoc analysis revealed PFS benefits tended to favor the A + G group in patients with TP53 exon 8 mutation.
Apatinib + gefitinib as first-line therapy had superior PFS in advanced EGFR-mutant NSCLC versus placebo + gefitinib. Combination therapy brought more adverse events but did not interfere QoL.
NCT02824458.
Mitochondria are high dynamic organelles with frequent fission and fusion. Here, we found hypoxia stimulated Drp1 expression, mitochondrial fission and migration in metastatic MDA-MB‑231 cells, but ...not in non-metastatic MCF-7 cells. Inhibition of Drp1-dependent mitochondrial fission by Mdivi-1 or silencing Drp1 attenuated hypoxia-induced mitochondrial fission and migration in MDA-MB‑231 cells. On the other hand, cisplatin induced significant apoptosis and mitochondrial fission in MDA-MB‑231 cells, but not in MCF-7 cells. Mdivi-1 and silencing Drp1 also efficiently prevented cisplatin-induced MMP decrease, ROS production and apoptosis in MDA-MB‑231 cells. Our data suggest that Drp1-dependent mitochondrial fission not only regulates hypoxia-induced migration of breast cancer cells, but also facilitates its sensitivity to chemotherapeutic agents. Thus, targeting Drp1-dependent mitochondrial dynamics may provide a novel strategy to suppress breast cancer metastasis and improve the chemotherapeutic effect in the future.
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