Liver injury due to endothelin receptor antagonists: a real-world study based on post-marketing drug monitoring data.

BACKGROUND: Liver injury is the hallmark adverse reaction of endothelin receptor antagonist (ERA). Since the first drug, bosentan has been widely used in clinical practice, hepatotoxicity has been accompanied by the history of ERA. The new ERA has been proven to have a lower liver risk but the current research findings are inconsistent. ERA-based targeted drug combinations are commonly used in the treatment of pulmonary arterial hypertension, where the risk of liver injury is difficult to estimate. OBJECTIVES: This study aimed to compare the correlation between ERA and different ERA combination regimens with liver injury in the real world. DESIGN: This is a retrospective study using data from the Adverse Event Reporting System (Food and Drug Administration AERS, FAERS). METHODS: The study used proportional imbalance and Bayesian analysis to mine FAERS data from January 2004 to December 2022 to determine the association of three ERAs with liver injury and to further mine the risk of liver injury due to the combination of ERAs with other targeted drugs. In addition, we analyzed the onset time, mortality, and hospitalization rate of liver injury caused by different ERA combination regimens. RESULTS: We screened out 3581 ERA-related liver injury events, of which bosentan (59.82%) had the largest number of cases. The patients with liver injury were mainly female (60.63%), and the age was concentrated between 61 and 75 years (26.75%). According to different signal mining methods, reporting odds ratio (ROR; 3.38, 95% confidence interval = 3.23-3.53), proportional reporting ratio (PRR; 3.22, χ2 = 37.84), Bayesian confidence propagation neural network (BCPNN; 1.68, 95% confidence interval = 1.61), multi-item gamma Poisson shrinker (MGPS; 3.21, 95% confidence interval = 3.09), bosentan had the strongest association with liver injury compared to ambrisentan and macitentan. Furthermore, bosentan + sildenafil [ROR (2.52, 95% confidence interval = 2.23-2.84), PRR (2.44, χ2 = 15.92), BCPNN (1.29, 95% confidence interval = 1.14), MGPS (2.44, 95% confidence interval = 2.21)], bosentan + epoprostenol [ROR (5.39, 95% confidence interval = 4.29-6.77), PRR (4.94, χ2 = 65.18), BCPNN (2.30, 95% confidence interval = 1.83), MGPS (4.94, 95% confidence interval = 4.08)], bosentan + iloprost [ROR (2.70, 95% confidence interval = 2.11-3.45), PRR (2.61, χ2 = 31.03), BCPNN (1.38, 95% confidence interval = 1.08), MGPS (2.61, 95% confidence interval = 2.12)] had a higher risk of liver injury caused by the three ERA combination regimens. The median time to onset of hepatotoxicity associated with all ERA combination regimens was 259 days (interquartile range: 58-716.5 days). Finally, the hospitalization rate for patients experiencing hepatotoxicity with ERA combination regimens was 47.86% and the mortality rate was 12.67%. CONCLUSION: By mining the FAERS, we analyzed and compared the risk of liver injury related to different ERA and ERA combination regimens, and the onset time and adverse reaction outcomes of all ERA combination regimens. According to the results of the study, bosentan had the highest risk of liver injury and the combination regimens bosentan + sildenafil, bosentan + epoprostenol, and bosentan + iloprost had a stronger risk of liver injury. From the early stages of treatment, we need to regularly monitor the liver function of patients, especially for females and the elderly, and discontinue the suspected drug as soon as the liver injury occurs.

Can glucagon-like peptide-1 receptor agonists cause acute kidney injury? An analytical study based on post-marketing approval pharmacovigilance data.

Clinical studies after marketing have shown that the use of glucagon-like peptide-1 receptor agonist(GLP-1RA) may lead to acute kidney injury(AKI). However, few epidemiological studies have investigated the risk, clinical features, and outcomes of AKI caused by different GLP-1RA. In this study, Adverse Event Reporting System (FAERS) data were used to compare the association between different GLP-1RA and AKI in the real world. Methods: FAERS data from January 2004 to December 2021 were mined using disproportionality analysis and Bayesian analysis to determine the correlation between different GLP-1RA and AKI, and the onset time, mortality, and hospitalization rate of different GLP-1RA were analyzed. Results: We identified 2670 cases of AKI events associated with GLP-1RA, of which liraglutide was the most commonly reported (34.98%). The patients with AKI were mainly males (47.94%), and the age group was mainly 45-84 years old (73.15%). obese patients with weight more than 99kg (24.42%) were more likely to have AKI. According to different signal mining methods, reporting odds ratio (ROR) (1.50, 95% confidence interval =1.41-1.60) and Bayesian confidence Propagation neural network (0.57, 95% confidence interval =0.54), liraglutide was more strongly associated with AKI than other GLP-1RA. The median time to onset of AKI was 63 days [quartile range (IQR): 15-458.5 days]. In addition, the hospitalization rate and fatality rate of patients with GLP-1RA-related AKI were 45.28% and 4.23% respectively. Conclusions: Based on the data in the FAERS database, we analyzed the risk, onset time, and adverse reaction outcomes of GLP-1RA-induced AKI in detail. The results showed that liraglutide had the highest risk of AKI. From the early stage of treatment, we need to monitor patients' renal function regularly, especially for patients with high kidney risks such as obesity and age.

All-optical tunable high-order Gaussian beam splitter based on a periodic dielectric atomic structure.

Beam splitting of high-order Gaussian (HOG) beams increases the channel capacity and improves the processing speed of the incoming information. Here a novel all-optical tunable multi-port HOG beam splitter under a periodic dielectric atomic structure is proposed and demonstrated. The original HOG beam is replicated in the output beams. A distinguishable five-port output beam is observed in the experiment, which is beneficial for high-speed optical communications. By tuning the optical properties of this periodic dielectric structure, the spatial position and intensity distribution of each output port are precisely controllable. The splitting ratio δ can be finely adjusted in the range 0 - 4.8. This work provides a new approach for multi-port HOG beam splitters and the basis for all-optical communication.

Efficient all-optical modulator based on a periodic dielectric atomic lattice.

All-optical devices used to process optical signals without electro-optical conversion plays a vital role in the next generation of optical information processing systems. We demonstrate an efficient all-optical modulator that utilizes a periodic dielectric atomic lattice produced in a gas of 85Rb vapor. Four orders of diffraction patterns are observed when a probe laser is passed through the lattice. The frequency shift of the peak of each diffraction order can be tuned by adjusting the control laser power and two-photon detuning, enabling this device to be used as a multi-channel all-optical modulator. Both theoretical simulations and experimental results demonstrate that this modulator can operate over a frequency band extending from about 0 to 60 MHz. This work may pave the way for studying quantum information processing and quantum networking proposed in atomic ensembles.

High-performance flexible resistive random access memory devices based on graphene oxidized with a perpendicular oxidation gradient.

The conventional strategy of fabricating resistive random access memory (RRAM) based on graphene oxide is limited to a resistive layer with homogeneous oxidation, and the switching behavior relies on its redox reaction with an active metal electrode, so the obtained RRAMs are typically plagued by inferior performance and reliability. Here, we report a strategy to develop high-performance flexible RRAMs by using graphene oxidized with a perpendicular oxidation gradient as the resistive layer. In contrast to a homogeneous oxide, this graphene together with its distinctive inter-layer oxygen diffusion path enables excellent oxygen ion/vacancy diffusion. Without an interfacial redox reaction, oxygen ions can diffuse to form conductive filaments with two inert metal electrodes by applying a bias voltage. Compared with state-of-the-art graphene oxide RRAMs, these graphene RRAMs have shown superior performance including a high on-off current ratio of ∼105, long-term retention of ∼106 s, reproducibility over 104 cycles and long-term flexibility at a bending strain of 0.6%, indicating that the material has great potential in wearable smart data-storage devices.

Pushing the conductance and transparency limit of monolayer graphene electrodes for flexible organic light-emitting diodes.

Graphene has emerged as an attractive candidate for flexible transparent electrode (FTE) for a new generation of flexible optoelectronics. Despite tremendous potential and broad earlier interest, the promise of graphene FTE has been plagued by the intrinsic trade-off between electrical conductance and transparency with a figure of merit (σDC/σOp) considerably lower than that of the state-of-the-art ITO electrodes (σDC/σOp <123 for graphene vs. ∼240 for ITO). Here we report a synergistic electrical/optical modulation strategy to simultaneously boost the conductance and transparency. We show that a tetrakis(pentafluorophenyl)boric acid (HTB) coating can function as highly effective hole doping layer to increase the conductance of monolayer graphene by sevenfold and at the same time as an anti-reflective layer to boost the visible transmittance to 98.8%. Such simultaneous improvement in conductance and transparency breaks previous limit in graphene FTEs and yields an unprecedented figure of merit (σDC/σOp ∼323) that rivals the best commercial ITO electrode. Using the tailored monolayer graphene as the flexible anode, we further demonstrate high-performance green organic light-emitting diodes (OLEDs) with the maximum current, power and external quantum efficiencies (111.4 cd A-1, 124.9 lm W-1 and 29.7%) outperforming all comparable flexible OLEDs and surpassing that with standard rigid ITO by 43%. This study defines a straightforward pathway to tailor optoelectronic properties of monolayer graphene and to fully capture their potential as a generational FTE for flexible optoelectronics.

Optically tunable grating in a V+Ξ configuration involving a Rydberg state.

A novel tunable all-optical grating is realized experimentally in a V+Ξ configuration coherent rubidium thermal vapor. This new energy level structure employs a Rydberg level as the uppermost level and contains two typical electromagnetically induced transparency energy level configurations with the same probe field. Compared with the traditional V-type three-level grating, a significant improvement of the diffraction efficiency of this novel grating was observed. Its improvement was then also demonstrated experimentally by the transition spectrum and theoretically by a comprehensive simulation. The diffraction efficiency gain introduced by the control laser field was tuned with several experimental parameters, such as the atomic density and the control field intensity. And the maximum enhancement rate of first-order diffraction efficiency is proved to be as high as 30%. Such a novel all-optical tunable grating promises to be the new driving force in the advancement of all-optical communications and information technology.

UV-Epoxy-Enabled Simultaneous Intact Transfer and Highly Efficient Doping for Roll-to-Roll Production of High-Performance Graphene Films.

Flexible graphene transparent conductive films (TCFs) prepared by chemical vapor deposition hold great promise for next-generation wearable optoelectronic devices, but the lack of low-cost scalable intact transfer and highly efficient doping greatly limits their commercialization. Here, we report a UV-epoxy adhesive as a robust multifunctional layer for the low-cost scalable production of high-performance flexible graphene TCF. Its high solvent stability, sufficient adhesion force, and conformal contact with graphene enable the intact bubbling transfer of graphene. More importantly, a highly strong and stable p-dopant, superacid HSbF6, is in situ generated from UV-epoxy. HSbF6 substantially increases the hole concentration of pristine graphene by more than 10 times and consequently reduces its sheet resistance by up to 95% with high stability. Furthermore, it can be readily integrated with the roll-to-roll transfer process. These features enable continuous production of graphene TCFs with overall performances superior to those produced by common transfer methods and typical dopants. As an example, we demonstrate the use of this film in the capacitive multitouch panel of tablet computers.

Probiotic Lactobacillus casei Zhang reduces pro-inflammatory cytokine production and hepatic inflammation in a rat model of acute liver failure.

PURPOSE: In this study, we sought to find the effects and mechanisms of probiotic Lactobacillus casei Zhang (L. casei Zhang) on the pro-inflammatory cytokine production and hepatic inflammatory response in a rat model of acute liver failure induced by lipopolysaccharide (LPS) and d-galactosamine (GalN). METHODS: Male Wistar rats were orally administrated with or without L. casei Zhang for 30 days prior to challenge with LPS and GalN. Dexamethasone administrated group serving as a positive anti-inflammation control. Serum, intestinal and liver samples were collected 8 h after LPS/GalN challenge for histological, molecular and biochemical analysis. RESULTS: LPS/GalN challenge alone resulted in significantly increased production of endotoxin, tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1ß) and nitric oxide as compared to the normal control rats. Pretreatment with L. casei Zhang not only reduced these changes, but also attenuated hepatic inflammation as shown by improved histological assessment, decreased myeloperoxidase activity and reduced expression of IL-1ß and inducible nitric oxide synthase in the liver. L. casei Zhang supplementation significantly inhibited LPS/GalN-triggered phosphorylation of ERK, JNK and p-38 MAPK, but increased the expression of TLR2, TLR9 and PPAR-γ. Moreover, L. casei Zhang treatment prevented intestinal injury and modulated the intestinal ecology by increasing the fecal Lactobacillus and Bifidobacterium levels. CONCLUSIONS: Probiotic L. casei Zhang reduces LPS/GalN-induced pro-inflammatory cytokine and hepatic inflammation through modulating the TLR-MAPK-PPAR-γ signaling pathways and intestinal microbiota.

Protective effects of sea buckthorn polysaccharide extracts against LPS/d-GalN-induced acute liver failure in mice via suppressing TLR4-NF-κB signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn (Hippophae rhamnoides L.) berries have been traditionally used to treat gastric disorders, cardiovascular problems, and liver injuries in oriental medicinal system. This study aimed to explore the protective effects and mechanisms of the polysaccharide extracts of Sea buckthorn (HRP) berries against lipopolysaccharide (LPS) and d-galactosamine hydrochloride (d-GalN)-induced acute liver failure in mice. MATERIALS AND METHODS: HRP was isolated by hot-water extraction and characterized by HPLC and infrared spectrum analysis. The total carbohydrate, uronic acid and protein contents of HRP were measured by a spectrophotometric method. Mice were orally administrated with HRP (50, 100, 200mg/kg) once daily for 14 consecutive days prior to the challenge with LPS (50 µg/kg) and d-GalN (300 mg/kg). Animals of positive control group were intraperitoneally injected with dexamethasone (10mg/kg). Mice were sacrificed at 8h after LPS/d-GalN injection. RESULTS: Pretreatment with HRP significantly inhibited LPS/d-GalN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, which were accompanied by alleviated liver injuries and reduced production of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). HRP was also found to reduce malondialdehyde (MDA) content and to restore superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities. Furthermore, HRP supplementation dose-dependently inhibited the expression of Toll-like receptor 4 (TLR4), phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated c-Jun N-terminal kinase (p-JNK), and phosphorylated mitogen activated protein kinase 38 (p-p38 MAPK) in the liver of LPS/d-GalN challenged mice. Pretreatment with HRP also inhibited LPS/d-GalN-induced activation and translocation of nuclear factor-κB (NF-κB). CONCLUSIONS: This study indicates that pretreatment with HRP protects against LPS/d-GalN-induced liver injury in mice via suppressing the TLR4-NF-κB signaling pathway. Sea buckthorn may be a hopeful drug for prevention of acute live injury.

Introducing confinement effects into ultraweak chemiluminescence for an improved sensitivity.

So-called confinement effects at the interface of nanomaterials could spring up unique properties in catalytical activities and optical amplifiers. There is apparently no good reason to disregard confinement effect-amplified chemiluminescence (CL). In this work, confinement effects were first introduced into CL field using cetyltrimethylammonium bromide (CTAB) bilayer aggregates confined at the interface of the CTAB-carbon dots, which were prepared by one-step microwave irradiation using glycerol as carbon source in the presence of CTAB. Interestingly, it was found that the CTAB bilayer confined at the interface of carbon dots can amplify H2O2 induced ultraweak CL emissions, such as the Co(II)-triggered Fenton-like reaction, the peroxynitrous acid (ONOOH) system, and the peroxymonocarbonate (HCO4(-)) system. The study of fluorescent properties of the as-prepared CTAB-carbon dots and the comparison with the CL efficiency of their analogues indicated that the CTAB bilayer confined in carbon dots could act as a special micelle microenvironment, helping the access of reactive intermediates to the central carbon core. Our findings opened up new possibilities in confinement-enhanced CL emissions.

A new approach for bisphenol A detection employing fluorosurfactant-capped gold nanoparticle-amplified chemiluminescence from cobalt(II) and peroxymonocarbonate.

In this work, we utilized the nonionic fluorosurfactant-capped gold nanoparticles (GNPs) as a novel chemiluminescence (CL) probe for the determination of trace bisphenol A. Bisphenol A can induce a sharp decrease in CL intensity from the GNP-Co(2+)-peroxymonocarbonate (HCO4(-)) system. Under the selected experimental conditions, a linear relationship was obtained between the CL intensity and the logarithm of concentration of bisphenol A in the range of 0.05-50 µM (R(2) = 0.9936), and the detection limit at a signal-to-noise ratio of 3 for bisphenol A was 10 nM. The applicability of the proposed method has been validated by determining bisphenol A in real polycarbonate samples with satisfactory results. The recoveries for bisphenol A in spiked samples were found to be between 94.4% and 105.0%. The relative standard deviation (RSD) for 12 repeated measurements of 0.5 µM bisphenol A was 2.2%. The proposed method described herein was simple, selective and obviated the need of extensive sample pretreatment.

Organo-modified hydrotalcite-quantum dot nanocomposites as a novel chemiluminescence resonance energy transfer probe.

In this work, we fabricate an oriented luminescent quantum dot (QD)-layered double hydroxide (LDH) nanocomposite material by the highly orderly and alternate assembly of trace CdTe QDs in dodecylbenzene sulfonate bilayer bunches on the organo-modified LDH exterior surfaces. Interestingly, the novel QD-LDH nanocomposites can remarkably amplify chemiluminescence (CL) of the luminol-H2O2 system, which is attributed to an inhibition of QD oxidation by H2O2, an increase in the radiative decay rate, and an inhibition in the nonradiative relaxation of QDs. In addition, a novel flow-through column-based CL resonance energy transfer is fabricated using luminol as energy donors and the solid luminescent QD-LDH nanocomposites as energy acceptors for signal amplification. The applicability of this flow-through column is evaluated by determining H2O2 using luminol-H2O2 CL system. The CL intensity exhibits a stable response to H2O2 over a concentration range from 0.5 to 60 µM with a detection limit as low as 0.3 µM. Finally, the proposed method has been successfully applied to detect H2O2 in snow samples, and the results agreed with those obtained by the standard spectrophotometric method. Our findings indicate that the new luminescent QD-LDH nanocomposite material would be used for high throughput screening of complex systems with different sized QDs.