Activation of the p62-Keap1-Nrf2 pathway improves pulmonary arterial hypertension in MCT-induced rats by inhibiting autophagy.

Autophagy is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate whether the p62-Keap1-Nrf2 pathway affects the development of PAH by mediating autophagy. A PAH rat model was established using monocrotaline (MCT). Pulmonary artery smooth muscle cells (PASMCs) were extracted, and the changes in proliferation, migration, autophagy, and oxidative stress were analyzed following overexpression or knockdown of p62. The impact of p62 on the symptoms of PAH rats was assessed by the injection of an adenovirus overexpressing p62. We found that the knockdown of p62 increased the proliferation and migration of PASMCs, elevating the oxidative stress of PASMCs and upregulating gene expression of NADPH oxidases. Co-IP assay results demonstrated that p62 interacted with Keap1. p62 knockdown enhanced Keap1 protein stability and Nrf2 ubiquitination. LC3II/I and ATG5 were expressed more often when p62 was knocked down. Treating with an inhibitor of autophagy reversed the impact of p62 knockdown on PASMCs. Nrf2 inhibitor treatment reduced the expression of Nrf2 and p62, while increasing the expression of Keap1, LC3II/I, and ATG5 in PASMCs. However, overexpressing p62 diminished mRVP, SPAP, and Fulton index in PAH rats and attenuated pulmonary vascular wall thickening. Overexpression of p62 also decreased the expression of Keap1, LC3II/I, and ATG5 and increased the nuclear expression of Nrf2 in PAH rats. Importantly, overexpression of p62 reduced oxidative stress and the NADPH oxidase expression in PAH rats. Overall, activation of the p62-Keap1-Nrf2 positive feedback signaling axis reduces the proliferation and migration of PASMCs and alleviates PAH by inhibiting autophagy and oxidative stress.

Integrating hydrogen utilization in CO2 electrolysis with reduced energy loss.

Electrochemical carbon dioxide reduction reaction using sustainable energy is a promising approach of synthesizing chemicals and fuels, yet is highly energy intensive. The oxygen evolution reaction is particularly problematic, which is kinetically sluggish and causes anodic carbon loss. In this context, we couple CO2 electrolysis with hydrogen oxidation reaction in a single electrochemical cell. A Ni(OH)2/NiOOH mediator is used to fully suppress the anodic carbon loss and hydrogen oxidation catalyst poisoning by migrated reaction products. This cell is highly flexible in producing either gaseous (CO) or soluble (formate) products with high selectivity (up to 95.3%) and stability (>100 h) at voltages below 0.9 V (50 mA cm-2). Importantly, thanks to the "transferred" oxygen evolution reaction to a water electrolyzer with thermodynamically and kinetically favored reaction conditions, the total polarization loss and energy consumption of our H2-integrated CO2 reduction reaction, including those for hydrogen generation, are reduced up to 22% and 42%, respectively. This work demonstrates the opportunity of combining CO2 electrolysis with the hydrogen economy, paving the way to the possible integration of various emerging energy conversion and storage approaches for improved energy/cost effectiveness.

Development and validation of risk prediction and neural network models for dilated cardiomyopathy based on WGCNA.

Background: Dilated cardiomyopathy (DCM) is a progressive heart condition characterized by ventricular dilatation and impaired myocardial contractility with a high mortality rate. The molecular characterization of DCM has not been determined yet. Therefore, it is crucial to discover potential biomarkers and therapeutic options for DCM. Methods: The hub genes for the DCM were screened using Weighted Gene Co-expression Network Analysis (WGCNA) and three different algorithms in Cytoscape. These genes were then validated in a mouse model of doxorubicin (DOX)-induced DCM. Based on the validated hub genes, a prediction model and a neural network model were constructed and validated in a separate dataset. Finally, we assessed the diagnostic efficiency of hub genes and their relationship with immune cells. Results: A total of eight hub genes were identified. Using RT-qPCR, we validated that the expression levels of five key genes (ASPN, MFAP4, PODN, HTRA1, and FAP) were considerably higher in DCM mice compared to normal mice, and this was consistent with the microarray results. Additionally, the risk prediction and neural network models constructed from these genes showed good accuracy and sensitivity in both the combined and validation datasets. These genes also demonstrated better diagnostic power, with AUC greater than 0.7 in both the combined and validation datasets. Immune cell infiltration analysis revealed differences in the abundance of most immune cells between DCM and normal samples. Conclusion: The current findings indicate an underlying association between DCM and these key genes, which could serve as potential biomarkers for diagnosing and treating DCM.

Operando Studies of Electrochemical Denitrogenation and Its Mitigation of N-Doped Carbon Catalysts in Alkaline Media.

N-doped carbons (NCs) have excellent electrocatalytic performance in oxygen reduction reaction, particularly in alkaline conditions, showing great promise of replacing commercial Pt/C catalysts in fuel cells and metal-air batteries. However, NCs are vulnerable when biased at high potentials, which suffer from denitrogenation and carbon corrosion. Such material degradation drastically undermines the activity, yet its dynamic evolution in response to the applied potentials is challenging to examine experimentally. In this work, we used differential electrochemical mass spectroscopy coupled with an optimized cell and observed the dynamic behaviors of NCs under operando conditions in KOH electrolyte. The corrosion of carbon occurred at ca. 1.2 V vs RHE, which was >0.3 V below the measured onset potential of water oxidation. Denitrogenation proceeded in parallel with carbon corrosion, releasing both NO and NO2. Combined with the ex situ characterizations and density-functional theory calculations, we identified that the pyridinic nitrogen moieties were particularly in peril. Three denitrogenation pathways were also proposed. Finally, we demonstrated that transferring the oxidation reaction sites to the well-deposited metal hydroxide with optimized loading was effective in suppressing the N leaching. This work showed the dynamic evolution of NC under potential bias and might cast light on understanding and mitigating NC deactivation for practical applications.

High-Rate Alkaline Water Electrolysis at Industrially Relevant Conditions Enabled by Superaerophobic Electrode Assembly.

Alkaline water electrolysis (AWE) is among the most developed technologies for green hydrogen generation. Despite the tremendous achievements in boosting the catalytic activity of the electrode, the operating current density of modern water electrolyzers is yet much lower than the emerging approaches such as the proton-exchange membrane water electrolysis (PEMWE). One of the dominant hindering factors is the high overpotentials induced by the gas bubbles. Herein, the bubble dynamics via creating the superaerophobic electrode assembly is optimized. The patterned Co-Ni phosphide/spinel oxide heterostructure shows complete wetting of water droplet with fast spreading time (≈300 ms) whereas complete underwater bubble repelling with 180° contact angle is achieved. Besides, the current collector/electrode interface is also modified by coating with aerophobic hydroxide on Ti current collector. Thus, in the zero-gap water electrolyzer test, a current density of 3.5 A cm-2 is obtained at 2.25 V and 85 °C in 6 m KOH, which is comparable with the state-of-the-art PEMWE using Pt-group metal catalyst. No major performance degradation or materials deterioration is observed after 330 h test. This approach reveals the importance of bubble management in modern AWE, offering a promising solution toward high-rate water electrolysis.

Role of thioredoxin-interacting protein in mediating endothelial dysfunction in hypertension.

Excessive oxidative stress is a major causative factor of endothelial dysfunction in hypertension. As an endogenous pro-oxidant, thioredoxin-interacting protein (TXNIP) contributes to oxidative damage in various tissues. The present study aimed to investigate the role of TXNIP in mediating endothelial dysfunction in hypertension. In vivo, an experimental model of acquired hypertension was established with two-kidney, one-clip (2K1C) surgery. The expression of TXNIP in the vascular endothelial cells of multiple vessels was significantly increased in hypertensive rats compared with sham-operated rats. Resveratrol, a TXNIP inhibitor, suppressed vascular oxidative damage and increased the expression and activity of eNOS in the aorta of hypertensive rats. Notably, impaired endothelium-dependent vasodilation was effectively improved by TXNIP inhibition in hypertensive rats. In vitro, we observed that Ang II increased the expression of TXNIP in primary human aortic endothelial cells (HAECs) and that TXNIP knockdown by RNA interference alleviated cellular oxidative stress damage and mitigated the impaired eNOS activation and intracellular nitric oxide (NO) production observed in Ang II-treated HAECs. However, inhibiting thioredoxin (TRX) with PX-12 completely blunted the protective effect of silencing TXNIP. In addition, TXNIP knockdown facilitated TRX expression and promoted TRX nuclear translocation to further activate AP1 and REF1. TRX overexpression exhibited favorable effects on eNOS/NO homeostasis in Ang II-treated HAECs. Thus, TXNIP contributes to oxidative stress and endothelial dysfunction in hypertension, and these effects are dependent on the antioxidant capacity of TRX, suggesting that targeting TXNIP may be a novel strategy for antihypertensive therapy.

Balance Cell Apoptosis and Pyroptosis of Caspase-3-Activating Chemotherapy for Better Antitumor Therapy.

Chemotherapy is a standard treatment modality in clinic that exerts an antitumor effect via the activation of the caspase-3 pathway, inducing cell death. While a number of chemotherapeutic drugs have been developed to combat various types of tumors, severe side effects have been their common limitation, due to the nonspecific drug biodistribution, bringing significant pain to cancer patients. Recently, scientists found that, besides apoptosis, chemotherapy could also cause cell pyroptosis, both of which have great influence on the therapeutic index. For example, cell apoptosis is, generally, regarded as the main mechanism of killing tumor cells, while cell pyroptosis in tumors promotes treatment efficacy, but in normal tissue results in toxicity. Therefore, significant research efforts have been paid to exploring the rational modulation mode of cell death induced by chemotherapy. This critical review aims to summarize recent progress in the field, focusing on how to balance cell apoptosis and pyroptosis for better tumor chemotherapy. We first reviewed the mechanisms of chemotherapy-induced cell apoptosis and pyroptosis, in which the activated caspase-3 is the key signaling molecule for regulating both types of cell deaths. Then, we systematically discussed the rationale and methods of switching apoptosis to pyroptosis for enhanced antitumor efficacy, as well as the blockage of pyroptosis to decrease side effects. To balance cell pyroptosis in tumor and normal tissues, the level of GSDME expression and tumor-targeting drug delivery are two important factors. Finally, we proposed potential future research directions, which may provide guidance for researchers in the field.

Construction of CoS2 /Zn0.5 Cd0.5 S S-Scheme Heterojunction for Enhancing H2 Evolution Activity Under Visible Light.

In the field of photocatalysis, building a heterojunction is an effective way to promote electron transfer and enhance the reducibility of electrons. Herein, the S-scheme heterojunction photocatalyst (CoS2 /Zn0.5 Cd0.5 S) of CoS2 nanospheres modified Zn0.5 Cd0.5 S solid solution was synthesized and studied. The H2 evolution rate of the composite catalyst reached 25.15 mmol g-1 h-1 , which was 3.26 times that of single Zn0.5 Cd0.5 S, whereas pure CoS2 showed almost no hydrogen production activity. Moreover, CoS2 /Zn0.5 Cd0.5 S had excellent stability and the hydrogen production rate after six cycles of experiments only dropped by 6.19 %. In addition, photoluminescence spectroscopy and photoelectrochemical experiments had effectively proved that the photogenerated carrier transfer rate of CoS2 /Zn0.5 Cd0.5 S was better than CoS2 or Zn0.5 Cd0.5 S single catalyst. In this study, the synthesized CoS2 and Zn0.5 Cd0.5 S were both n-type semiconductors. After close contact, they followed an S-scheme heterojunction electron transfer mechanism, which not only promoted the separation of their respective holes and electrons, but also retained a stronger reduction potential, thus promoting the reduction of H+ protons in photocatalytic experiments. In short, this work provided a new basis for the construction of S-scheme heterojunction in addition to being used for photocatalytic hydrogen production.

Downregulating the P2X3 receptor in the carotid body to reduce blood pressure via acoustic gene delivery in canines.

The purinergic P2X3 receptor in the carotid body (CB) is considered a new target for treating hypertension, although approaches for targeted regulating P2X3 receptor expression are lacking. Here, we explored the feasibility of targeted P2X3 receptor down-regulation in CBs by localized low-intensity focused ultrasound (LIFU)-mediated gene delivery to reduce the blood pressure. Thirty-two Kunming canines were randomly assigned to the treatment group (n = 14), negative control group (n = 10), LIFU + cationic microbubbles group (n = 4), and LIFU-only group (n = 4). Plasmid-loaded cationic microbubbles were injected and bilateral CBs were irradiated with a LIFU-based transducer. Flow cytometry showed that 33.15% of transfected cells expressed the green fluorescent protein reporter gene. T7 endonuclease I assays showed an insertion-deletion rate of 8.30%. The P2X3 receptor mRNA- and protein-expression levels in CBs decreased by 56.31% and 45.10%, respectively, in the treatment group. Mean systolic (152.5 ± 3.0 vs 138.0 ± 2.9 mm Hg, P = 0.003) and diastolic (97.8 ± 1.5 vs 87.2 ± 2.3 mm Hg, P= 0.002) blood pressures reduced on day 14 in the treatment group, compared with the baseline values, whereas no effects were observed with LIFU treatment or cationic microbubbles injection alone. Canines treated with this strategy exhibited no local or systemic adverse events. Thus, LIFU-mediated gene delivery to CBs successfully modulated CB function and reduced blood pressure in a canine model, suggesting a new possibility for treating hypertension and further clinical translation.

Protonated g-C3N4 cooperated with Co-MOF doped with Sm to construct 2D/2D heterojunction for integrated dye-sensitized photocatalytic H2 evolution.

A dye-sensitive photocatalytic H2 evolution reaction (HER) system with photogenerated carrier directed conduction was constructed. The protonated g-C3N4 combines with the sheet-like Co MOF to form a 2D/2D heterojunction via electrostatic self-assembly. The protonated g-C3N4 and 2D Co-MOF directionally adsorb Eosin Y (EY) and triethanolamine (TEOA) molecules through hydrogen bond and complexation to achieve a whole photocatalytic system. The integral structure effectively facilitates the utilization of dye sensitizer and hole sacrificial agent to achieve the effective and stable photocatalytic H2 evolution capacity. The photocatalytic hydrogen evolution rate of g-C3N4 after protonation is 1.88 times as high as that of the original g-C3N4. On the basis of 2D/2D heterojunction, Co MOF is doped with rare earth element Sm. The 4f electrons and the difference valences (Sm3+ and Co2+) further suppress the reorganization of photogenerated excitons to achieve highly efficient photocatalytic HER. The directional coupling of sensitizer and electron sacrificial agent combined with rare earth element doping makes the photocatalytic HER rate of the composite material reached 73.42 µmol.h-1 within 5 h under simulated sunlight.

A bimetallic sulfide CuCo2S4 with good synergistic effect was constructed to drive high performance photocatalytic hydrogen evolution.

In order to further improve the photocatalytic performance of the semiconductor photocatalyst, a photocatalytic hydrogen production performance was measured using a bimetallic sulfide photocatalyst. On this basis, the hydrogen production performance of the bimetallic sulfide CuCo2S4 (CCS-3) was compared with that of the single metal sulfides Cu31S16 and CoS2. The results showed that the bimetallic sulfide CCS-3 significantly improved the photocatalytic hydrogen production performance. The unique structure of the bimetallic sulfide CCS-3 made the photocatalytic activity of H2 2.47 times and 178.08 times higher than that of Cu31S16 and CoS2, respectively. In addition, the hydrogen production activity in CCS-3 was also very stable after XRD comparison before and after the reaction. The results of UV-visible diffuse reflectance spectroscopy showed that the visible light response range was significantly expanded, and the forbidden band width was smaller than that of Cu31S16 and CoS2. Photoluminescence spectroscopy results showed that CCS-3 had the best quenching effect because of its unique structure, which improved the separation efficiency and electron transfer efficiency of photogenerated electrons and holes. This article demonstrated new design strategies that would bring new insights into hydrogen evolution photocatalysts.

A New Sythetic Hybrid (A1D5) between Gossypium herbaceum and G. raimondii and Its Morphological, Cytogenetic, Molecular Characterization.

The diploid species G. herbaceum (A1) and G. raimondii (D5) are the progenitors of allotetraploid cotton, respectively. However, hybrids between G. herbaceum and G. raimondii haven't been reported. In the present study, hybridization between G. herbaceum and G. raimondii was explored. Morphological, cytogenetic and molecular analyses were used to assess the hybridity. The interspecific hybrid plants were successfully obtained. Most of the morphological characteristics of the hybrids were intermediate between G. herbaceum and G. raimondii. However, the color of glands, anther cases, pollen and corolla, and the state of bracteoles in hybrids were associated with the G. herbaceum. The color of staminal columns and filaments in hybrids were associated with G. raimondii. Cytogenetic analysis confirmed abnormal meiotic behavior existed in hybrids. The hybrids couldn't produce boll-set. Simple sequence repeat results found that besides the fragments inherited from the two parents, some novel bands were amplified in hybrids, indicating that potential mutations and chromosomal recombination occurred between parental genomes during hybridization. These results may provide some novel insights in speciation, genome interaction, and evolution of the tetraploid cotton species.

[Protective effect of ligustilide against low potassium induced apoptosis in cultured rat cerebellar granule neurons].

OBJECTIVE: To investigate the effect of ligustilide (LIG) on low potassium-induced apoptosis in primary cultured cerebellar granule neurons (CGN). METHODS: Apoptosis was induced by low potassium in cultured neonatal rat CGN in vitro. The CGN was divided into control/model/CGP54626 + LIG and LIG group. The neuronal viability of each group was measured by MTT assay. The protein expression levels of the key insulin-like growth factor 1 (IGF)-1 signaling effectors,including the phosphorylated IGF-1 receptor (IGF-1R), Akt, ERK1/2, CREB and activated caspase 3 were examined by Western blot analysis. RESULTS: LIG ranging from 2.5 to 20 micromol/L could protect against low potassium-induced apoptosis of CGN ini a concentration-dependent manner. 20 micromol/L LIG significantly induced upregulation of the phosphorylated levels of IGF-1, Akt, ERK1/2 and CREB, and downregulation of cleaved-caspase 3 expression, which could be blocked by a selective gamma-aminobutyric acid B (GABAs) receptor antagonist CGP54626. CONCLUSION: LIG concentration-dependently protects against low potassium-induced apoptosis in CGN at least partly through GABAa receptor activation and its downstream IGF-1 signaling pathway.

Klotho upregulation contributes to the neuroprotection of ligustilide in an Alzheimer's disease mouse model.

Klotho, an aging-suppressor gene, encodes a protein that potentially acts as a neuroprotective factor by modulating insulin-like growth factor 1 signaling and oxidative stress. In the present study, we investigated the potential role of Klotho in the therapeutic effect of ligustilide against Alzheimer's disease (AD)-like neuropathologies and memory impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. Ligustilide treatment (10 and 40 mg/kg for 8 weeks, intragastrically) in 10-month-old SAMP8 mice reduced memory deficits, amyloid-ß(1)-42 accumulation, tau phosphorylation, and neuron loss, increased mitochondrial manganese-superoxide dismutase and catalase expression and activity, and decreased malondialdehyde, protein carbonyl, and 8-hydroxydesoxyguanosine levels in the brain. Ligustilide upregulated Klotho expression in the cerebral choroid plexus and serum, decreased Akt and Forkhead box class O1 phosphorylation. Moreover, ligustilide inhibited the insulin-like growth factor 1 pathway and induced Forkhead box class O1 activation in 293T cells along with Klotho upregulation. An inverse correlation was found between Klotho expression and the AD phenotype, suggesting that Klotho might be a novel therapeutic target for age-related AD, and Klotho upregulation might contribute to the neuroprotective effect of ligustilide against AD.