Regulation of hepatocyte phospholipid peroxidation signaling by a Chinese patent medicine against psychological stress-induced liver injury.

BACKGROUND: Psychological stress is associated with various diseases including liver dysfunction, yet effective intervention strategies remain lacking due to the unrevealed pathogenesis mechanism. PURPOSE: This study aims to explore the relevance between BMAL1-controlled circadian rhythms and lipoxygenase 15 (ALOX15)-mediated phospholipids peroxidation in psychological stress-induced liver injury, and to investigate whether hepatocyte phospholipid peroxidation signaling is involved in the hepatoprotective effects of a Chinese patent medicine, Pien Tze Huang (PZH). METHODS: Restraint stress models were established to investigate the underlying molecular mechanisms of psychological stress-induced liver injury and the hepatoprotective effects of PZH. Redox lipidomics based on liquid chromatography-tandem mass spectrometry was applied for lipid profiling. RESULTS: The present study discovered that acute restraint stress could induce liver injury. Notably, lipidomic analysis confirmed that phospholipid peroxidation was accumulated in the livers of stressed mice. Additionally, the essential core circadian clock gene Brain and Muscle Arnt-like Protein-1 (Bmal1) was altered in stressed mice. Circadian disruption in mice, as well as BMAL1-overexpression in human HepaRG cells, also appeared to have a significant increase in phospholipid peroxidation, suggesting that stress-induced liver injury is closely related to circadian rhythm and phospholipid peroxidation. Subsequently, arachidonate 15-lipoxygenase (ALOX15), a critical enzyme that contributed to phospholipid peroxidation, was screened as a potential regulatory target of BMAL1. Mechanistically, BMAL1 promoted ALOX15 expression via direct binding to an E-box-like motif in the promoter. Finally, this study revealed that PZH treatment significantly relieved pathological symptoms of psychological stress-induced liver injury with a potential mechanism of alleviating ALOX15-mediated phospholipid peroxidation. CONCLUSION: Our findings illustrate the critical role of BMAL1-triggered phospholipid peroxidation in psychological stress-induced liver injury and provide new insight into treating psychological stress-associated liver diseases by TCM intervention.

Metastable precipitation and ion-extractant transport in liquid-liquid separations of trivalent elements.

The extractant-assisted transport of metal ions from aqueous to organic environments by liquid-liquid extraction has been widely used to separate and recover critical elements on an industrial scale. While current efforts focus on designing better extractants and optimizing process conditions, the mechanism that underlies ionic transport remains poorly understood. Here, we report a nonequilibrium process in the bulk aqueous phase that influences interfacial ion transport: the formation of metastable ion-extractant precipitates away from the liquid-liquid interface, separated from it by a depletion region without precipitates. Although the precipitate is soluble in the organic phase, the depletion region separates the two and ions are sequestered in a long-lived metastable state. Since precipitation removes extractants from the aqueous phase, even extractants that are sparingly soluble in water will continue to be withdrawn from the organic phase to feed the aqueous precipitation process. Solute concentrations in both phases and the aqueous pH influence the temporal evolution of the process and ionic partitioning between the precipitate and organic phase. Aqueous ion-extractant precipitation during liquid-liquid extraction provides a reaction path that can influence the extraction kinetics, which plays an important role in designing advanced processes to separate rare earths and other minerals.

Large two-photon cross sections and low-threshold multiphoton lasing of CdS/CdSe/CdS quantum shells.

Colloidal quantum shells are spherical semiconductor quantum wells, which have shown strong promise as optical materials, particularly in classes of experiments requiring multiple excitons. The two-photon properties of CdS/CdSe/CdS quantum shell samples are studied here to demonstrate large non-linear absorption cross-sections while retaining advantageous multiexciton physics conferred by the geometrical structure. The quantum shells have large two-phonon cross sections (0.4-7.9 × 106 GM), which highlights their potential use in upconversion imaging in which large per particle two-photon absorption is critical. Time-resolved measurements confirmed that the quantum shells have long biexciton lifetime (>10 ns in the largest core samples reported here) and large gain bandwidth (>300 meV). The combination of these attributes with large two-photon cross sections makes the CdS/CdSe/CdS quantum shells excellent gain media for two-photon excitation. With a broad gain bandwidth and long gain lifetime, quantum shell solids support multimodal amplified spontaneous emission from excitons, biexcitons, and higher excited states. Thresholds for amplified spontaneous emission and lasing, which are as low as 1 mJ cm-2, are comparable to, or lower than, the thresholds reported for other colloidal materials.

Surface premelting of ice far below the triple point.

Premelting of ice, a quasi-liquid layer (QLL) at the surface below the melting temperature, was first postulated by Michael Faraday 160 y ago. Since then, it has been extensively studied theoretically and experimentally through many techniques. Existing work has been performed predominantly on hexagonal ice, at conditions close to the triple point. Whether the same phenomenon can persist at much lower pressure and temperature, where stacking disordered ice sublimates directly into water vapor, remains unclear. Herein, we report direct observations of surface premelting on ice nanocrystals below the sublimation temperature using transmission electron microscopy (TEM). Similar to what has been reported on hexagonal ice, a QLL is found at the solid-vapor interface. It preferentially decorates certain facets, and its thickness increases as the phase transition temperature is approached. In situ TEM reveals strong diffusion of the QLL, while electron energy loss spectroscopy confirms its amorphous nature. More significantly, the premelting observed in this work is thought to be related to the metastable low-density ultraviscous water, instead of ambient liquid water as in the case of hexagonal ice. This opens a route to understand premelting and grassy liquid state, far away from the normal water triple point.

Membrane phospholipid peroxidation promotes loss of dopaminergic neurons in psychological stress-induced Parkinson's disease susceptibility.

Parkinson's disease (PD) is a neurodegenerative disorder associated with α-synuclein aggregation and dopaminergic neuron loss in the midbrain. There is evidence that psychological stress promotes PD progression by enhancing glucocorticoids-related oxidative damage, however, the mechanisms involved are unknown. The present study demonstrated that plasma membrane phospholipid peroxides, as determined by phospholipidomics, triggered ferroptosis in dopaminergic neurons, which in turn contributed to stress exacerbated PD-like motor disorder in mice overexpressing mutant human α-synuclein. Using hormonomics, we identified that stress stimulated corticosteroid release and promoted 15-lipoxygenase-1 (ALOX15)-mediated phospholipid peroxidation. ALOX15 was upregulated by α-synuclein overexpression and acted as a fundamental risk factor in the development of chronic stress-induced parkinsonism and neurodegeneration. Further, we demonstrated the mechanism by which corticosteroids activated the PKC pathway and induced phosphatidylethanolamine-binding protein-1 (PEBP1) to form a complex with ALOX15, thereby facilitating ALOX15 to locate on the plasma membrane phospholipids. A natural product isolated from herbs, leonurine, was screened with activities of inhibiting the ALOX15/PEBP1 interaction and thereby attenuating membrane phospholipid peroxidation. Collectively, our findings demonstrate that stress increases the susceptibility of PD by driving membrane lipid peroxidation of dopaminergic neurons and suggest the ALOX15/PEBP1 complex as a potential intervention target.

Kinetics of Shear-Induced Structural Ordering in Dense Colloids.

The macroscopic rheological response of a colloidal solution is highly correlated with the local microscopic structure, as revealed by an in situ Rheo-SAXS experiment with a high temporal resolution. Oscillatory shear can induce a strain-controlled ordering-to-disorder transition, resulting in a shear-thickening process that is different from the normal shear-thickening behavior that is driven by hydrodynamics and particle friction. We reveal that there is a complex time-dependent kinetics toward structural ordering under different applied strains. When the strain amplitude reaches a critical value that starts to induce disordering in the system, the pathway toward the dynamic equilibrium can also become highly non-monotonic. Within the same oscillatory cycle, there is a strong correlation of ordering with different phases of the oscillation, with the system oscillating between two dynamic metastable states.

La- and Mn-doped cobalt spinel oxygen evolution catalyst for proton exchange membrane electrolysis.

Discovery of earth-abundant electrocatalysts to replace iridium for the oxygen evolution reaction (OER) in a proton exchange membrane water electrolyzer (PEMWE) represents a critical step in reducing the cost for green hydrogen production. We report a nanofibrous cobalt spinel catalyst codoped with lanthanum (La) and manganese (Mn) prepared from a zeolitic imidazolate framework embedded in electrospun polymer fiber. The catalyst demonstrated a low overpotential of 353 millivolts at 10 milliamperes per square centimeter and a low degradation for OER over 360 hours in acidic electrolyte. A PEMWE containing this catalyst at the anode demonstrated a current density of 2000 milliamperes per square centimeter at 2.47 volts (Nafion 115 membrane) or 4000 milliamperes per square centimeter at 3.00 volts (Nafion 212 membrane) and low degradation in an accelerated stress test.

Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual loss of midbrain dopaminergic neurons in association with aggregation of α-synuclein. Oxidative damage has been widely implicated in this disease, though the mechanisms involved remain elusive. Here, we demonstrated that preferential accumulation of peroxidized phospholipids and loss of the antioxidant enzyme glutathione peroxidase 4 (GPX4) were responsible for vulnerability of midbrain dopaminergic neurons and progressive motor dysfunctions in a mouse model of PD. We also established a mechanism wherein iron-induced dopamine oxidation modified GPX4, thereby rendering it amenable to degradation via the ubiquitin-proteasome pathway. In conclusion, this study unraveled what we believe to be a novel pathway for dopaminergic neuron degeneration during PD pathogenesis, driven by dopamine-induced loss of antioxidant GPX4 activity.

Catalytic divergent synthesis of imidazoles via reaction condition-dependent [3 + 2] cyclization of TosMIC.

A base-catalyzed divergent synthesis of multisubstituted imidazoles through TosMIC-based [3 + 2] cyclization reaction has been developed. In the presence of ketenimines and tBuONa, 1,4,5-trisubstituted imidazoles were obtained. Nonetheless, in the absence of ketenimines, 1,4-disubstituted imidazole was produced through cyclodimerization of TosMIC.

Construction of IL-13 Receptor α2-Targeting Resveratrol Nanoparticles against Glioblastoma Cells: Therapeutic Efficacy and Molecular Effects.

Glioblastoma multiforme (GBM) is the most common lethal primary brain malignancy without reliable therapeutic drugs. IL-13Rα2 is frequently expressed in GBMs as a molecular marker. Resveratrol (Res) effectively inhibits GBM cell growth but has not been applied in vivo because of its low brain bioavailability when administered systemically. A sustained-release and GBM-targeting resveratrol form may overcome this therapeutic dilemma. To achieve this goal, encapsulated Res 30 ± 4.8 nm IL-13Rα2-targeting nanoparticles (Pep-PP@Res) were constructed. Ultraviolet spectrophotometry revealed prolonged Res release (about 25%) from Pep-PP@Res in 48 h and fluorescent confocal microscopy showed the prolonged intracellular Res retention time of Pep-PP@Res (>24 h) in comparison with that of free Res (<4 h) and PP@Res (<4 h). MTT and EdU cell proliferation assays showed stronger suppressive effects of Pep-PP@Res on rat C6 GBM cells than that of PP@Res (p = 0.024) and Res (p = 0.009) when used twice for 4 h/day. Pep-PP@Res had little toxic effect on normal rat brain cells. The in vivo anti-glioblastoma effects of Res can be distinctly improved in the form of Pep-PP@Res nanoparticles via activating JNK signaling, upregulating proapoptosis gene expression and, finally, resulting in extensive apoptosis. Pep-PP@Res with sustained release and GBM-targeting properties would be suitable for in vivo management of GBMs.

A novel nomogram for predicting the risk of epilepsy occurrence after operative in gliomas patients without preoperative epilepsy history.

OBJECTIVE: Epilepsy is a common complication in glioma patients after undergoing brain tumor surgery combined with chemotherapy and/or radiotherapy. Whether antiepileptic drug prophylaxis could be used in these patients remains an open question. The purpose of this study was to produce a model for predicting the risk of epilepsy occurrence in such patients. METHODS: The clinicopathologic data of glioma patients after tumor treatment were reviewed in this study. Univariate and multivariate logistic regression analyses were carried out to analyze the correlation between the clinicopathologic data and the risk of epilepsy occurrence. A nomogram was built according to the multivariate logistic regression model results. RESULTS: A total of 219 patients with gliomas were reviewed. Univariate analyses revealed that age, WHO glioma classification, CD34, EGFR, Ki67, MGMT, P53 and VIM were significantly associated with the risk of epilepsy occurrence. Multivariate analyses revealed that age, WHO glioma classification, CD34, EGFR, MGMT, and VIM were predictors of risk of epilepsy occurrence. A nomogram of the risk of epilepsy occurrence was built based on statistically significant variables from the multivariate logistic regression analysis. The c-index of the nomogram was 0.755 (95 % confidence interval (CI), 0.742-0.769). SIGNIFICANCE: This nomogram model provides reliable information about the risk of epilepsy occurrence for oncologists and neurological physicians.

A novel electrochemical biosensor for exosomal microRNA-181 detection based on a catalytic hairpin assembly circuit.

Exosomal microRNAs (miRNAs) derived from different cells are proposed to be important noninvasive biomarkers for the diagnosis of cardiovascular disease. Recently, sensitive and reliable sensing of exosomal miRNAs has been garnered significant attention. Herein, a novel electrochemical biosensor based on a step polymerization catalytic hairpin assembly (SP-CHA) circuit is designed for exosomal miR-181 detection. Exosomal miR-181 as a trigger, induced SP-CHA process and generated a large number of T shaped concatemers with different length on the electrode surface. These ultra-concatemers could provide a much enhanced signal-to-noise ratio with the linear range from 10 fM to 100 nM and the detection limit of 7.94 fM. Furthermore, this assay was successfully applied to the detection of exosomal miR-181 in serum samples of normal healthy controls and patients with coronary heart disease (CHD) and the results were consistent with those analysis collected from qRT-PCR. The assembly demonstrated great performance in differentiating CHD patients from healthy controls (AUC:0.9867). Collectively, this sensing system possessed high stability and sensitivity with ease of operation and cost efficiency, leading to great potential for exosomal miRNAs detection in cardiovascular disease.

LncRNA AC105942.1 Downregulates hnRNPA2/B1 to Attenuate Vascular Smooth Muscle Cells Proliferation.

The abnormal proliferation of vascular smooth muscle cells (VSMCs) is crucial in the atherosclerosis. Although long noncoding RNAs (lncRNAs) are implicated in a variety of diseases, their roles in activation of VSMCs proliferation and vascular disorder diseases are not well understood. In addition, heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) was reported to participate in lncRNAs-mediated function. Herein, we propose to investigate the role of lncRNA AC105942.1 and hnRNPA2/B1 in pathological VSMCs proliferation and the possible mechanisms in vitro. We have identified that lncRNA AC105942.1 was downregulated and hnRNPA2/B1 was upregulated in atherosclerotic plaques compared with normal artery tissues. Enhanced lncRNA AC105942.1 could noticeably inhibit Ang II-induced VSMCs proliferation. Further investigation suggested that lncRNA AC105942.1 could downregulate the expression of hnRNPA2/B1 and then regulate the level of CDK4 and p27. Taken together, our study indicated that lncRNA AC105942.1 downregulated hnRNPA2B1 to protect against the atherosclerosis by suppressing VSMCs proliferation. LncRNA AC105942.1 and hnRNPA2/B1 could represent potential therapeutic and diagnostic targets to atherosclerosis-related diseases.

Resveratrol and its Nanoparticle suppress Doxorubicin/Docetaxel-resistant anaplastic Thyroid Cancer Cells in vitro and in vivo.

Background: Docetaxel and doxorubicin combination has been widely used in anaplastic thyroid cancer/ATC treatment but often results in serious adverse effects and drug resistance. Resveratrol effectively inhibits ATC cell proliferation in vitro without affecting the corresponding normal cells, while its in vivo anti-ATC effects especially on the ones with docetaxel/doxorubicin-resistance have not been reported due to its low bioavailability. Nanoparticles with sustained-release and cancer-targeting features may overcome this therapeutic bottleneck. Methods: The resveratrol nanoparticles with sustained-release and IL-13Rα2-targeting capacities (Pep-1-PEG3.5k-PCL4k@Res) were prepared to improve the in vivo resveratrol bioavailability. Human THJ-16T ATC cell line was employed to establish nude mice subcutaneous transplantation model. The tumor-bearing mice were divided into four groups as Group-1, without treatment, Group-2, treated by 30 mg/kg free resveratrol, Group-3, treated by 30 mg/kg Pep-1-PEG3.5k-PCL4k@Res and Group-4, treated by 5 mg/kg docetaxel/5 mg/kg doxorubicin combination. TUNEL staining was used to detect the apoptotic cells in the tumor tissues. Docetaxel/doxorubicin resistant xenografts named as THJ-16T/R were isolated and subjected to 2D and 3D culture. The docetaxel/doxorubicin and resveratrol sensitivities of the original THJ-16T and THJ-16T/R cells were analyzed by multiple methods. Results: Docetaxel/doxorubicin and Pep-1-PEG3.5k-PCL4k@Res but not free resveratrol significantly delayed tumor growth (P < 0.01) and caused extensive apoptosis. The mice in docetaxel/doxorubicin-treated group suffered from weight loss (> 10%) and 2/3 of them died within 3 times of treatment and the chemotherapy was stop to avoid further animal loss. One week after drug withdrawal, the subcutaneous tumors regrew and the tumor volume increased 55.28% within 14 days. The cells isolated from the regrowing tumors (THJ-16T/R) were successfully cultured under 2D and 3D condition and underwent drug treatments. Compared with THJ-16T, the death rate of docetaxel/doxorubicin-treated THJ-16T/R population was lower (39.3% vs 18.0%), which remained almost unchanged in resveratrol-treated group (45.3% vs 49.3%). Conclusion: Resveratrol sustained-release targeting nanoparticles effectively inhibit in vivo ATC growth. Docetaxel/doxorubicin suppresses ATC xenografts but causes obvious side effects and secondary drug resistance that can be overcome by resveratrol.

Synthesis of novel 9R/S-acyloxy derivatives of cinchonidine and cinchonine as insecticidal agents.

Endeavor to discover biorational natural products-based insecticides, two series (27) of novel 9R/S-acyloxy derivatives of cinchonidine and cinchonine were prepared and assessed for their insecticidal activity against Mythimna separata in vivo by the leaf-dipping method at 1 mg/mL. Among all the compounds, especially derivatives 6l and 6o exhibited the best insecticidal activity with final mortality rates of 75.0% and 71.4%, respectively. Overall, a free 9-hydroxyl group is not a prerequisite for insecticidal activity and C9-substitution is well tolerated; the configuration of C8/9 position is important for insecticidal activity, and 9S-configuration is optimal; 6'-OCH3 moiety is not necessary, removal of it is also acceptable. [Formula: see text].

Synthesis, anti-oomycete activity, and SAR studies of paeonol derivatives.

Three series of sulfonate derivatives of paeonol were synthesized and screened in vitro for their anti-oomycete activity against P. capsici, respectively. Among all the compounds, 4m displayed the best promising and pronounced anti-oomycete activity against P. capsici than zoxamide, with the EC50 values of 24.51 and 26.87 mg/L, respectively. The results show that acetyl and 4-OCH3 are two necessary groups. The existence of these two sites is closely related to the anti-oomycete activity. Relatively speaking, hydroxyl group is well tolerated, and the results showed that after modification of hydroxyl group with sulfonyl, the anti-oomycete activity was significantly increased. [Formula: see text].

Synthesis of sulfonate derivatives of carvacrol and thymol as anti-oomycetes agents.

Two series of sulfonate derivatives of carvacrol and thymol were synthesized and screened in vitro for their anti-oomycete activity against Phytophthora capsici, respectively. Among all of 32 derivatives, five compounds 3a, 4a, 4k, 3n, and 4n exhibited more potent anti-oomycete activity against P. capsici with EC50 values of 66.66, 62.94, 68.65, 61.24, and 52.91 mg/L, respectively. This suggested that introduction of different substitutions at the hydroxyl position of 1/2 could have remarkable effect on anti-oomycete activity. Overall, when R1 = isopropyl and R2 = methyl, the anti-oomycete activities of the compounds were higher than that of the corresponding compounds of R1 = methyl and R2 = isopropyl.[Formula: see text].

Ultrathin Porous Hydrocarbon Membranes Templated by Nanoparticle Assemblies.

Porous polymer membranes are widely desired as catalyst supports, sensors, and active layers for separation membranes. We demonstrate that electron beam irradiation of freely suspended gold or Fe3O4 nanoparticle (NP) monolayer sheets followed by wet chemical etching is a high-fidelity strategy to template two-dimensional (2D) porous cross-linked hydrocarbon membranes. This approach, which relies on secondary electrons generated by the NP cores, can further be used to transform three-dimensional (3D) terraced gold NP supercrystals into 3D porous hydrocarbon membranes. We utilize electron tomography to show how the number of NP layers (monolayer to pentalayer) controls attenuation and scattering of the primary e-beam, which in turn determines ligand cross-link density and 3D pore structure. Electron tomography also reveals that many nanopores are vertically continuous because of preferential sintering of NPs. This work demonstrates new routes for the construction of functional nanoporous media.

Biological implications of PTEN upregulation and altered sodium/iodide symporter intracellular distribution in resveratrol-suppressed anaplastic thyroid cancer cells.

Objective: Anaplastic thyroid cancer/ATC is a highly aggressive malignancy with extremely poor prognosis. Resveratrol/Res promotes re-differentiation of cancer cells and exerts inhibitory effects on ATC cells. Sodium/iodide symporter/NIS and phosphate and tension homology deleted on chromsome ten/PTEN levels are positively correlated with the grade of thyroid cancer differentiation, while the impact of Res on them remain unknown. Materials and Methods: The patterns of NIS and PTEN expression and intracellular distribution in THJ-16T and THJ-21T ATC and Nthy-ori 3-1 normal thyroid cells and their relevance with Res-caused ATC suppression were investigated via multiple experimental methods. E-cadherin was cited as a re-differentiation biomarker of ATC cells. Results: MTT and EdU cell proliferation assays showed distinct growth suppression in ATC cells after Res treatment. TUNEL staining revealed extensive apoptosis of Res-treated THJ-16T and THJ-21T rather than Nthy-ori 3-1 cells. Western blotting, immunocytochemical/ICC and double-labeled immunofluorescent/IF staining showed increased PTEN levels accompanied with distinct NIS and PTEN nuclear co-translocation in Res-treated THJ-16T and THJ-21T cells. E-cadherin but not NIS appeared on the outer membrane. Conclusion: PTEN upregulation and the concurrent NIS and PTEN nuclear translocation in Res-suppressed ATC cells may indicate the better therapeutic outcome and would be a group of beneficial prognostic factors of ATCs.