USP14 increases the sensitivity of retinoblastoma to cisplatin by mediating the ferroptosis.

The aim of this study is to explore the function of USP14 on the sensitivity of retinoblastoma (RB) to cisplatin (DDP) and the underlying mechanism. USP14 was knockdown in Y79 cells by transfecting three siRNAs (si-USP14-1, si-USP14-2, and si-USP14-3), with si-USP14 NC as the negative control. si-USP14-3 was selected by results of Western blotting. The CCK-8 assay was used to detect the IC50 of Y79 cells and the growth curve. The cell cycle, cell apoptosis, and ROS level were measured by flow cytometry. The expression level of P-GP, ERCC1, survivin, GPX4, FTH1, ACSL4, NOX1, COX2, and FASN was determined by the Western blotting assay. CO-IP assay was utilized to evaluate the interaction between USP14 and FASN. The IC50 of DDP in Y79 cells and Y79/DDP cells was 7.83 µM and 24.67 µM, respectively. Compared to control and si-USP14 NC groups, increased apoptotic rate and ROS level, and arrested cell cycle in S phase were observed in USP14-knockdown Y79 cells. Compared to control and si-USP14 NC groups, increased apoptotic rate and arrested cell cycle in G0/G1 phase were observed in USP14-knockdown Y79/DDP cells. Compared to control, increased ROS level was observed in USP14-knockdown Y79/DDP cells. Compared to the si-USP14 NC groups, extremely downregulated P-GP, ERCC1, survivin, GPX4, FTH1, NOX1, COX2, and FASN were observed in USP14-knockdown Y79 cells or Y79/DDP cells, accompanied by the elevated expression of ACSL4. The interaction between USP14 and FASN was identified according to the result of CO-IP assay. By silencing USP14 in Y79 and Y79/DDP cells, levels of resistance-related proteins (P-GP, ERCC1, and survivin), ferroptosis-related proteins (FTH1 and GPX4), and lipid metabolism-related proteins (NOX1, COX2, and FASN) were dramatically reduced, accompanied by enhanced ROS level, increased apoptosis, and restrained DNA content, indicating that USP14 might suppress the DDP resistance in RB by mediating ferroptosis, which is an important target for treating RB.

Cardiovascular toxicities following the use of tyrosine kinase inhibitors in hepatocellular cancer patients: a retrospective, pharmacovigilance study.

BACKGROUND: Cardiac adverse events (AEs) are common in tyrosine kinase inhibitors(TKIs). This study explored the cardiac AEs of TKIs through the Food and Drug Administration's Adverse Event Reporting System (FAERS). METHODS: Disproportionality analysis and Bayesian analysis were utilized for data mining of the suspected cardiac AEs of TKIs, based on FAERS data from January 2004 to December 2021. RESULTS: A total of 4708 cardiac AEs reports of sorafenib, regorafenib, lenvatinib, and cabozantinib were identified. Hypertension accounts for the most reported cardiac AE. Lenvatinib appears to induce cardiac failure with the highest signals strength [ROR = 7.7 (3.46,17.17)]. Acute myocardial infarction was detected in lenvatinib [ROR = 7.91 (5.64,11.09)] and sorafenib [ROR = 2.22 (1.74, 2.84)]. Acute coronary syndrome was detected in lenvatinib [ROR = 11.57 (6.84, 19.58)] and sorafenib [ROR = 2.81 (1.87,4.24)]. Atrial fibrillation was detected in sorafenib [ROR = 1.82 (1.55,2.14)] and regorafenib [ROR = 1.36 (1.03,1.81)]. Meanwhile, aortic dissections were detected in sorafenib [ROR = 5.08 (3.31,7.8)] and regorafenib [ROR = 3.39 (1.52,7.56)]. Most patients developed hypertension and cardiac failure within 30 days of initiating TKI treatments. Patients taking lenvatinib had an increased incidence of developing acute coronary syndrome after 180 days of treatment. CONCLUSION: Analysis of FAERS data provides a precise profile on the characteristics of cardiac AEs associated with different TKI regimens. Distinct monitoring and appropriate management are needed in the care of TKI recipients.

RING-Finger Protein 6 promotes Drug Resistance in Retinoblastoma via JAK2/STAT3 Signaling Pathway.

Chemotherapy is the first-line treatment for human retinoblastoma (RB), but the occurrence of drug resistance greatly limited its efficacy in practice. RING-finger protein 6 (RNF6) is an E3 ubiquitin ligase that is aberrantly upregulated in a range of cancers and plays important roles in cancer progression. However, the role of RNF6 in RB is largely unknown. In this study, we investigated the role of RNF6 in RB drug resistance. Two carboplatin-resistant RB cells, Y-79/CR and SO-Rb50/CR, were generated based on Y-79 and SO-Rb50 cells. RT-PCR and western blot analyses showed that RNF6 expression on both mRNA and protein levels was significantly increased in Y-79/CR and SO-Rb50/CR cells comparing to their parental cells. Knockdown of RNF6 using siRNA in Y-79/CR and SO-Rb50/CR cells resulted in cells sensitive to carboplatin on a RNF6 siRNA dose dependent manner. Similarly, RNF6 overexpression in parental Y-79 and SO-Rb50 cells could help cells gain resistance to carboplatin on a RNF6 expression dependent manner. Signaling pathway analyses revealed that JAK2/STAT3 pathway was involved in the RNF6-induced carboplatin resistance in RB cells. We further revealed that RNF6 expression in both Y-79 and SO-Rb50 cells could render cells resistant to multiple anti-cancer drugs including carboplatin, vincristine and etoposide, an implication of RNF6 as a biomarker for RB drug resistance. Taken together, our study has revealed that RNF6 is upregulated in drug-resistant RB cells and RNF6 promotes drug resistance through JAK2/STAT3 signaling pathway. The importance of RNF6 in RB cells drug resistance may represent this protein as a potential biomarker and treatment target for drug resistance in RB.

Corrigendum to "Vanillic Acid Alleviates Acute Myocardial Hypoxia/Reoxygenation Injury by Inhibiting Oxidative Stress".

[This corrects the article DOI: 10.1155/2020/8348035.].

Vanillic Acid Alleviates Acute Myocardial Hypoxia/Reoxygenation Injury by Inhibiting Oxidative Stress.

Oxidative stress is an important factor of myocardial hypoxia/reoxygenation (H/R) injury. Our research focuses on how to reduce the cardiac toxicity caused by oxidative stress through natural plant extracts. Vanillic acid (VA) is a phenolic compound found in edible plants and rich in the roots of Angelica sinensis. Experimental studies have provided evidence for this compound's effectiveness in cardiovascular diseases; however, its mechanism is still unclear. In this study, molecular mechanisms related to the protective effects of VA were investigated in H9c2 cells in the context of H/R injury. The results showed that pretreatment with VA significantly increased cell viability and decreased the percentage of apoptotic cells, as well as lactate dehydrogenase and creatine phosphokinase activity, in the supernatant, accompanied by reduced levels of reactive oxygen species and reduced caspase-3 activity. VA pretreatment also restored mitochondrial membrane potentials. Moreover, preincubation with VA significantly attenuated mitochondrial permeability transition pore activity. VA administration upregulated adenosine monophosphate-activated protein kinase α2 (AMPKα2) protein expression, and interestingly, pretreatment with AMPKα2-siRNA lentivirus effectively attenuated the cardioprotective effects of VA in response to H/R injury.

Comparison of pregabalin with ondansetron in treatment of uraemic pruritus in dialysis patients: a prospective, randomized, double-blind study.

AIM: Pruritus is common among patients with end-stage renal disease undergoing dialysis, and the pathogenesis can be explained by several mechanisms. However, there is no definite evidence supporting them, which limits the relative efficacy of any individual treatment option. In this paper, we aimed to compare pregabalin with ondansetron in treatment of uraemic pruritus (UP) in dialysis patients. METHODS: In this 12-week prospective, randomized, and double-blind trial, we assessed the efficacy and side effects in UP patients undergoing dialysis. Patients were randomly assigned to receive 12 weeks of 75 mg twice-weekly pregabalin or 8 mg/day ondansetron or a placebo. Visits were scheduled at 0, 2, 4, 6, 8, and 12 weeks after treatment. The severity of pruritus was evaluated using Visual Analogue Scale and modified Duo's VAG Scale. Quality of sleep was evaluated using the Pittsburgh sleep quality index. The effect of UP on health-related quality of life was assessed using the Chinese version of the 12-item short-form (SF-12) general health survey. Baseline laboratory data and demographic characteristics were recorded from patient charts. RESULTS: Finally, 179 (108 males, 71 females, aged 54.7±11.3 years old) out of the 188 patients completed the 12-week study. Of five patients who stopped pregabalin treatment due to side effects, two patients reported an improvement in nausea and vomiting among those receiving ondansetron. Two patients dropped out for renal transplantation. The 179 patients included 62 cases from the pregabalin group, 60 from the ondansetron group, and 57 from the placebo group. Over the 12 weeks, only pregabalin improved UP significantly. The severity of pruritus was reduced significantly in the pregabalin group compared with the ondansetron and the placebo groups. The final pruritus scores were not different between the ondansetron and the placebo groups. Pruritus absolutely disappeared in two patients following renal transplantation. CONCLUSIONS: Pregabalin is an effective alternative for treatment of uraemic pruritus. Ondansetron has negligible effect on uremic pruritus and is expensive. A larger sample size may be needed to demonstrate the effect of ondansetron in uraemic pruritus.

Tannic acid functionalized N-doped graphene modified glassy carbon electrode for the determination of bisphenol A in food package.

A rapid, environmental friendly, and sensitive sensor for the detection of bisphenol A (BPA) was developed at glassy carbon electrode (GCE) modified with Tannic acid functionalized N-doped graphene (TA/N-G) immobilized by Nafion. Compared with other sensors, the proposed sensor greatly enhanced the response signal of BPA due to the active surface area of N-G and high absorption efficiency of TA. Under the optimal conditions, the oxidation current increased linearly with increasing the concentration of BPA in the range of 0.05-13 µM with the detection limit of 4.0 nM. The fabricated electrode showed good reproducibility, stability and anti-interference. The developed electrochemical sensor was successfully applied to determine BPA in food package.

Fluorescent blood glucose monitor by hemin-functionalized graphene quantum dots based sensing system.

In the present work, a highly sensitive and specific fluorescent biosensor for blood glucose monitoring is developed based on hemin-functionalized graphene quantum dots (GQDs) and glucose oxidase (GOx) system. The GQDs which are simply prepared by pyrolyzing citric acid exhibit strong fluorescence and good water-solubility. Due to the noncovalent assembly between hemin and GQDs, the addition of hemin can make hydrogen peroxide (H2O2) to destroy the passivated surface of GQDs, leading to significant fluorescence quenching of GQDs. Based on this effect, a novel fluorescent platform is proposed for the sensing of glucose. Under the optimized conditions, the linear range of glucose is from 9 to 300µM, and the limit of detection is 0.1µM. As unique properties of GQDs, the proposed biosensor is green, simple, cost-efficient, and it is successfully applied to the determination of glucose in human serum. In addition, the proposed method provides a new pathway to further design the biosensors based on the assembly of GQDs with hemin for detection of biomolecules.

Single Pt nanowire electrode: preparation, electrochemistry, and electrocatalysis.

A single Pt nanowire electrode (SPNE) was fabricated through HF etching process from Pt disk nanoelectrode and an underpotential deposition (UPD) redox replacement technique. The electrochemical experiments showed that SPNE had steady-state electrochemical responses at redox species solution and the mass transfer rates were affected by the lengths and radii of SPNEs. The prepared SPNEs were utilized to examine the oxygen-reduction reaction in a KOH solution to explore the feasibility of electrocatalytic activity of single Pt nanowire and the results showed that the electrocatalytic activity of SPNE was dependent on the surface position of single Pt nanowire: the tip end position is more active than the sidewall position. Meanwhile, the electrocatalytic activity of SPNE was related to the radius of nanowire. These observations are not only important to understand the structure-function relationship in single nanowire level but have significant implications for the synthesis and selection of novel catalysts with high efficiency used in electrochemistry, energy, bioanalysis, etc.

Label-free electrochemical detection of DNA using ferrocene-containing cationic polythiophene and PNA probes on nanogold modified electrodes.

A label-free electrochemical method for the detection of DNA-PNA hybridization using a water-soluble, ferrocene-functionalized polythiophene transducer and single-stranded PNA probes on the nanogold modified electrode is investigated. Nanogold modified electrodes can largely increase the immobilization amount of ss-PNA capture probe and lead to an increase of the electrical signal. The ferrocene-containing cationic polythiophene do not interact electrostatically with the PNA probes due to the absence of the anionic phosphate groups on the PNA probes. But after DNA-PNA hybridization, cationic polythiophene is adsorbed on the DNA backbone, giving a clear hybridization detection signal in differential pulse voltammetry (DPV). Very good discrimination against non-complementary DNA and four-base mismatch DNA is observed. These studies show that the proposed method can provide an alternative for expanding the range of detection methods available for DNA hybridization.

Preparation of aminylferrocene/nanogold modified glassy carbon electrode and its electrocatalysis on dopamine.

Aminylferrocene(FcAI)-Nanogold(NG) modified glassy carbon electrode (FcAI/NG/GCE) was prepared by the Au-N bond between Au and FcAI. Electrochemical impedance spectroscopy (EIS) was employed to study the surface of the modified electrode. The electrochemical behavior of dopamine (DA) on the modified electrode was investigated and it was found that the modified electrode had an obvious electrocatalytic effect on DA. Compared with a bare GCE, the modified electrode exhibited an apparent shift of the oxidation peak potential in the negative potential direction and a marked enhancement in the current response for DA. We investigated the determination of DA on the modified electrode by differential pulse voltammetry (DPV). Linear calibration curve was obtained in the range of 7.0 x 10(-7) mol/L to 6x10(-4) mol/L of DA in 0.1 mol/L phosphate buffer solution (pH = 7.0) with a correlation coefficient of 0.9989. The detection limit (S/N = 3) of DA was estimated to be 1.0 x 10(-7) mol/L. Especially, by using the modified electrode, we can separate the oxidation peaks of ascorbic acid (AA) and DA in the PBS and it was satisfactory for the determination of DA with the interference of AA.

Simultaneous determination of uric acid and ascorbic acid at a ferrocenium-thioglycollate modified electrode.

Self-assembled monolayers (SAMS) of chemisorbed thioglycollate on a gold electrode surface have been used as a base interface for the electrostatic adsorption of ferrocenium ion. Electrochemical impedance spectra (EIS) and cyclic voltammetry (CV) were used to evaluate the electrochemical properties of the supramolecular film. The bare gold electrode failed to distinguish the oxidation peaks of ascorbic acid (AA) and uric acid (UA) in phosphate buffer solution (PBS, pH 7.0), while the ferrocenium-thioglycollate modified electrode could separate them efficiently. In differential pulse voltammetric measurements, the prepared gold electrode could separate AA and UA signals, allowing the simultaneous determination of AA and UA. Under optimal conditions and within the linear range of 1.0 x 10(-6) to 5.0 x 10(-4) M, the detection limits of AA and UA achieved were 2.0 x 10(-7) and 1.0 x 10(-7) M, respectively. The applicability of the prepared electrode was demonstrated by measuring AA and UA in human urine without any pretreatment.