Cardiac-specific overexpression of Ndufs1 ameliorates cardiac dysfunction after myocardial infarction by alleviating mitochondrial dysfunction and apoptosis

Myocardial infarction (MI) is the leading cause of premature death among adults. Cardiomyocyte death and dysfunction of the remaining viable cardiomyocytes are the main pathological factors of heart failure after MI. Mitochondrial complexes are emerging as critical mediators for the regulation of cardiomyocyte function. However, the precise roles of mitochondrial complex subunits in heart failure after MI remain unclear. Here, we show that NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) expression is decreased in the hearts of heart failure patients and mice with myocardial infarction. Furthermore, we found that cardiac-specific Ndufs1 overexpression alleviates cardiac dysfunction and myocardial fibrosis in the healing phase of MI. Our results demonstrated that Ndufs1 overexpression alleviates MI/hypoxia-induced ROS production and ROS-related apoptosis. Moreover, upregulation of Ndufs1 expression improved the reduced activity of complex I and impaired mitochondrial respiratory function caused by MI/hypoxia. Given that mitochondrial function and cardiomyocyte apoptosis are closely related to heart failure after MI, the results of this study suggest that targeting Ndufs1 may be a potential therapeutic strategy to improve cardiac function in patients with heart failure.Subject terms: Heart failure, Myocardial infarction, Myocardial infarction     

Chemical Constituents from the Flowers of Carthamus tinctorius L. and Their Lung Protective Activity

A new flavonoid, saffloflavanside (1), a new sesquiterpene, safflomegastigside (2), and a new amide, saffloamide (3), together with twenty-two known compounds (4–25), were isolated from the flowers of Carthamus tinctorius L. Their structures were determined based on interpretation of their spectroscopic data and comparison with those reported in the literature. The protective effects against lipopolysaccharide (LPS)-stimulated damage on human normal lung epithelial (BEAS-2B) cells of the compounds were evaluated using MTT assay and cellular immunofluorescence assay. The results showed that compounds 2–3, 8–11, and 15–19 exhibited protective effects against LPS-induced damage to BEAS-2B cells. Moreover, compounds 2–3, 8–11, and 15–19 can significantly downregulate the level of nuclear translocation of NF-κB p-p65. In summary, this study revealed chemical constituents with lung protective activity from C. tinctorius, which may be developed as a drug for the treatment of lung injury.     

A MXene-derived redox homeostasis regulator perturbs the Nrf2 antioxidant program for reinforced sonodynamic therapy

Ultrasound (US)-mediated sonodynamic therapy (SDT) has emerged as a spatiotemporally controllable therapeutic modality in combating cancer because of its high tissue-penetration depth and minimal invasiveness. However, the elevated nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant program in cancer cells can serve as a chief reactive oxygen species (ROS) detoxification system to alleviate oxidative injury and promote tumorigenesis, and thus greatly antagonize the therapeutic efficacy of ROS-mediated anticancer therapies. Herein, we report that vanadium carbide MXene-derived carbon dots (PMQDs) can act as high-efficacy sonosensitizers to efficiently generate ROS upon US irradiation and simultaneously hinder the Nrf2 antioxidant program for enhanced sonodynamic therapy of cancer. These PMQDs show superior US-triggered ROS generating ability because of their efficient migration/separation of electron–hole pairs and narrow bandgap. Importantly, these PMQDs can serve as efficient redox homeostasis regulators to perturb the Nrf2 antioxidant mechanism and thus reduce its effects on ROS neutralization for enhanced SDT efficacy. Overall, the present study will not only provide a new paradigm to augment SDT by perturbing the Nrf2 antioxidant program, but also give valuable insights into developing high-efficacy MXene-derived nanoagents for cancer therapy.

A redox homeostasis regulator has been developed as a high-efficacy sonosensitizer to efficiently generate reactive oxygen species upon ultrasound irradiation and simultaneously hinder the Nrf2 antioxidant program for enhanced sonodynamic therapy.     

Detoxified pneumolysin derivative ΔA146Ply inhibits autophagy and induces apoptosis in acute myeloid leukemia cells by activating mTOR signaling

Leukemia is caused by the malignant clonal expansion of hematopoietic stem cells, and in adults, the most common type of leukemia is acute myeloid leukemia (AML). Autophagy inhibitors are often used in preclinical and clinical models in leukemia therapy. However, clinically available autophagy inhibitors and their efficacy are very limited. More effective and safer autophagy inhibitors are urgently needed for leukemia therapy. In a previous study, we showed that ΔA146Ply, a mutant of pneumolysin that lacks hemolytic activity, inhibited autophagy of triple-negative breast cancer cells by activating mannose receptor (MR) and toll-like receptor 4 (TLR4) and that tumor-bearing mice tolerated ΔA146Ply well. Whether this agent affects AML cells expressing TLR4 and MR and the related mechanisms remain to be determined. In this study, we found that ΔA146Ply inhibited autophagy and induced apoptosis in AML cells. A mechanistic study showed that ΔA146Ply inhibited autophagy by activating mammalian target of rapamycin signaling and induced apoptosis by inhibiting autophagy. ΔA146Ply also inhibited autophagy and induced apoptosis in a mouse model of AML. Furthermore, the combination of ΔA146Ply and chloroquine synergistically inhibited autophagy and induced apoptosis in vitro and in vivo. Overall, this study provides an alternative effective autophagy inhibitor that may be used for leukemia therapy.Subject terms: Translational research, Acute myeloid leukaemia     

Sargassum fusiforme Polysaccharide-Based Hydrogel Microspheres Enhance Crystal Violet Dye Adsorption Properties

In this study, a polysaccharide-based hydrogel microsphere (SFP/SA) was prepared using S. fusiforme polysaccharide (SFP) and sodium alginate (SA). Fourier transform infrared spectroscopy (FT-IR) demonstrated that SFP was effectively loaded onto the hydrogel microsphere. Texture profile analysis (TPA) and differential scanning calorimetry (DSC) showed that, with the increase of SFP concentration, the hardness of SFP/SA decreased, while the springiness and cohesiveness of SFP/SA increased, and the thermal stability of SFP/SA improved. The equilibrium adsorption capacity of SFP/SA increased from 8.20 mg/g (without SFP) to 67.95 mg/g (SFP accounted 80%) without swelling, and from 35.05 mg/g (without SFP) to 81.98 mg/g (SFP accounted 80%) after 24 h swelling. The adsorption of crystal violet (CV) dye by SFP/SA followed pseudo-first order and pseudo-second order kinetics (both with R² > 0.99). The diffusion of intraparticle in CV dye was not the only influencing factor. Moreover, the adsorption of CV dye for SFP/SA (SFP accounted 60%) fit the Langmuir and Temkin isotherm models. SFP/SA exhibited good regenerative adsorption capacity. Its adsorption rate remained at > 97% at the 10th consecutive cycle while SFP accounted for 80%. The results showed that the addition of Sargassum fusiforme polysaccharide could increase the springiness, cohesiveness and thermal stability of the hydrogel microsphere, as well as improve the adsorption capacity of crystal violet dye.     

Optimized Green Extraction of Polyphenols from Cassia javanica L. Petals for Their Application in Sunflower Oil: Anticancer and Antioxidant Properties

The total phenolic content (TPC) from Cassia javanica L. petals were extracted using ethanolic solvent extraction at concentrations ranging from 0 to 90% and an SCF-CO₂ co-solvent at various pressures. Ultrasound-assisted extraction parameters were optimized using response surface methodology (RSM). Antioxidant and anticancer properties of total phenols were assessed. An SCF-CO₂ co-solvent extract was nano-encapsulated and applied to sunflower oil without the addition of an antioxidant. The results indicated that the best treatment for retaining TPC and total flavonoids content (TFC) was SCF-CO₂ co-solvent followed by the ultrasound and ethanolic extraction procedures. Additionally, the best antioxidant activity by β-carotene/linoleic acid and DPPH free radical-scavenging test systems was observed by SCF-CO₂ co-solvent then ultrasound and ethanolic extraction methods. SCF-CO₂ co-solvent recorded the highest inhibition % for PC3 (76.20%) and MCF7 (98.70%) and the lowest IC₅₀ value for PC3 (145 µ/mL) and MCF7 (96 µ/mL). It was discovered that fortifying sunflower oil with SCF-CO₂ co-solvent nanoparticles had a beneficial effect on free fatty acids and peroxide levels. The SCF-CO₂ method was finally found to be superior and could be used in large-scale processing.     

Correlation between Irradiation Treatment and Metabolite Changes in Bactrocera dorsalis (Diptera: Tephritidae) Larvae Using Solid-Phase Microextraction (SPME) Coupled with Gas Chromatography-Mass Spectrometry (GC-MS)

The metabolites produced by the larvae of Bactrocera dorsalis (Diptera: Tephritidae) exposed to different doses of irradiation were analyzed using solid phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS), and a metabonomic analysis method of irradiated insects based on GC-MS was established. The analysis revealed 67 peaks, of which 23 peaks were identified. The metabolites produced by larvae treated with different irradiation doses were compared by multivariate statistical analysis, and eight differential metabolites were selected. Irradiation seriously influenced the fatty acid metabolic pathway in larvae. Using the R platform combined with the method of multivariate statistical analysis, changes to metabolite production under four irradiation doses given to B. dorsalis larvae were described. Differential metabolites of B. dorsalis larvae carried chemical signatures that indicated irradiation dose, and this method is expected to provide a reference for the detection of irradiated insects.     

Toxic Effect of Fullerene and Its Derivatives upon the Transmembrane β2-Adrenergic Receptors

Numerous experiments have revealed that fullerene (C₆₀) and its derivatives can bind to proteins and affect their biological functions. In this study, we explored the interaction between fullerine and the β₂-adrenergic receptor (β₂AR). The MD simulation results show that fullerene binds with the extracellular loop 2 (ECL2) and intracellular loop 2 (ICL2) of β₂AR through hydrophobic interactions and π–π stacking interactions. In the C₆₀_in1 trajectory, due to the π–π stacking interactions of fullerene molecules with PHE and PRO residues on ICL2, ICL2 completely flipped towards the fullerene direction and the fullerene moved slowly into the lipid membrane. When five fullerene molecules were placed on the extracellular side, they preferred to stack into a stable fullerene cluster (a deformed tetrahedral aggregate), and had almost no effect on the structure of β₂AR. The hydroxyl groups of fullerene derivatives (C₆₀(OH)_X, X represents the number of hydroxyl groups, X = 4, 8) can form strong hydrogen bonds with the ECL2, helix6, and helix7 of β₂AR. The hydroxyl groups firmly grasp the β₂AR receptor like several claws, blocking the binding entry of ligands. The simulation results show that fullerene and fullerene derivatives may have a significant effect on the local structure of β₂AR, especially the distortion of helix4, but bring about no great changes within the overall structure. It was found that C₆₀ did not compete with ligands for binding sites, but blocked the ligands’ entry into the pocket channel. All the above observations suggest that fullerene and its derivatives exhibit certain cytotoxicity.     

The Potential Antidepressant Action of Duloxetine Co-Administered with the TAAR1 Receptor Agonist SEP-363856 in Mice

Here, we explored the possible interaction between duloxetine and SEP-363856 (SEP-856) in depression-related reactions. The results showed that oral administration of duloxetine showed powerful antidepressant-like effects in both the forced swimming test (FST) and the suspension tail test (TST). SEP-856 orally administered alone also exerted an antidepressant-like effect in FST and TST, especially at doses of 0.3, 1, and 10 mg/kg. In addition, duloxetine (15 mg/kg) and SEP-856 (15 mg/kg) both showed antidepressant-like effects in the sucrose preference test (SPT). Most importantly, in the above experiments, compared with duloxetine alone, the simultaneous use of duloxetine and SEP-856 caused a more significant antidepressant-like effect. It is worth noting that doses of drug combination in FST and TST did not change the motor activities of mice in the open-field test (OFT). Thus, duloxetine and SEP-856 seem to play a synergistic role in regulating depression-related behaviors and might be beneficial for refractory depression.     

Asymmetric conductivity of the Kondo effect in cold atomic systems

Motivated by recent theoretical and experimental advances in quantum simulations using alkaline earth(AE)atoms,we put forward a proposal to detect the Kondo physics in a cold atomic system.It has been demonstrated that the intrinsic spin-exchange interaction in AE atoms can be significantly enhanced near a confinement-induced resonance(CIR),which facilitates the simulation of Kondo physics.Since the Kondo effect appears only for antiferromagnetic coupling,we find that the conductivity of such system exhibits an asymmetry across a resonance of spin-exchange interaction.The asymmetric conductivity can serve as the smoking gun evidence for Kondo physics in the cold atom context.When an extra magnetic field ramps up,the spin-exchange process near Fermi surface is suppressed by Zee-man energy and the conductivity becomes more and more symmetric.Our results can be verified in the current experimental setup.