Bempedoic Acid Unveils Therapeutic Potential in Non-Alcoholic Fatty Liver Disease: Suppression of the Hepatic PXR-SLC13A5/ACLY Signaling Axis.

The hepatic SLC13A5/SLC25A1-ATP-dependent citrate lyase (ACLY) signaling pathway, responsible for maintaining the citrate homeostasis, plays a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Bempedoic acid (BA), an ACLY inhibitor commonly used for managing hypercholesterolemia, has shown promising results in addressing hepatic steatosis. This study aimed to elucidate the intricate relationships in processes of hepatic lipogenesis among SLC13A5, SLC25A1, and ACLY and to examine the therapeutic potential of BA in NAFLD, providing insights into its underlying mechanism. In murine primary hepatocytes and HepG2 cells, the silencing or pharmacological inhibition of SLC25A1/ACLY resulted in significant upregulation of SLC13A5 transcription and activity. This increase in SLC13A5 activity subsequently led to enhanced lipogenesis, indicating a compensatory role of SLC13A5 when the SLC25A1/ACLY pathway was inhibited. However, BA effectively counteracted this upregulation, reduced lipid accumulation, and ameliorated various biomarkers of NAFLD. The disease-modifying effects of BA were further confirmed in NAFLD mice. Mechanistic investigations revealed that BA could reverse the elevated transcription levels of SLC13A5 and ACLY, and the subsequent lipogenesis induced by PXR activation in vitro and in vivo. Importantly, this effect was diminished when PXR was knocked down, suggesting the involvement of the hepatic PXR-SLC13A5/ACLY signaling axis in the mechanism of BA action. In conclusion, SLC13A5-mediated extracellular citrate influx emerges as an alternative pathway to SLC25A1/ACLY in the regulation of lipogenesis in hepatocytes, BA exhibits therapeutic potential in NAFLD by suppressing the hepatic PXR-SLC13A5/ACLY signaling axis, while PXR, a key regulator in drug metabolism may be involved in the pathogenesis of NAFLD. SIGNIFICANCE STATEMENT: This work describes that bempedoic acid, an ATP-dependent citrate lyase (ACLY) inhibitor, ameliorates hepatic lipid accumulation and various hallmarks of non-alcoholic fatty liver disease. Suppression of hepatic SLC25A1-ACLY pathway upregulates SLC13A5 transcription, which in turn activates extracellular citrate influx and the subsequent DNL. Whereas in hepatocytes or the liver tissue challenged with high energy intake, bempedoic acid reverses compensatory activation of SLC13A5 via modulating the hepatic PXR-SLC13A5/ACLY axis, thereby simultaneously downregulating SLC13A5 and ACLY.

Multipartite Entanglement Generation in a Structured Environment.

In this paper, we investigate the entanglement generation of n-qubit states in a model consisting of n independent qubits, each coupled to a harmonic oscillator which is in turn coupled to a bath of N additional harmonic oscillators with nearest-neighbor coupling. With analysis, we can find that the steady multipartite entanglement with different values can be generated after a long-time evolution for different sizes of the quantum system. Under weak coupling between the system and the harmonic oscillator, multipartite entanglement can monotonically increase from zero to a stable value. Under strong coupling, multipartite entanglement generation shows a speed-up increase accompanied by some oscillations as non-Markovian behavior. Our results imply that the strong coupling between the harmonic oscillator and the N additional harmonic oscillators, and the large size of the additional oscillators will enhance non-Markovian dynamics and make it take a very long time for the entanglement to reach a stable value. Meanwhile, the couplings between the additional harmonic oscillators and the decay rate of additional harmonic oscillators have almost no effect on the multipartite entanglement generation. Finally, the entanglement generation of the additional harmonic oscillators is also discussed.

Soybean protein isolate-sodium alginate double network emulsion gels: Mechanism of formation and improved freeze-thaw stability.

Soybean protein isolate (SPI) is widely used in the food industry. However, SPI-based emulsion gels tend to aggregate and undergo oiling-off during freeze-thawing. In this study, emulsion gels were prepared by a combination of heat treatment and ionic cross-linking using SPI and sodium alginate (SA) as raw materials. The focus was on exploring the mechanistic effects of the SPI-SA double network structure on the freeze-thaw stability of emulsion gels. The results showed that the addition of SA could form different types of network structures with SPI, due to different degrees of phase separation. In addition, SA appearing on the SPI network indicated that the addition of Ca2+ shielded the electrostatic repulsion between SPI and SA to form SPI-SA complexes. The disappearance of the characteristic peaks of SA and SPI in Fourier transform infrared spectroscopy analysis also confirmed this view. Low-field nuclear magnetic resonance data revealed that SA played a role in restricting water migration within the emulsion gels, increasing bound water content, and thereby improving the water-holding capacity of the emulsion gels. Therefore, the incorporation of SA improved the freeze-thaw stability of SPI emulsion gels. These findings offer a theoretical basis and technical support for SPI application in frozen products.

Deciphering the interaction mechanism between soy protein isolate and fat-soluble anthocyanin on experiments and molecular simulations.

In this work, the acylated anthocyanin (Ca-An) was prepared by enzymatic modification of black rice anthocyanin with caffeic acid, and the binding mechanism of Ca-An to soybean protein isolate (SPI) was investigated by experiments and computer simulation to expand the potential application of anthocyanin in food industry. Multi-spectroscopic studies revealed that the stable binding of Ca-An to SPI induced the folding of protein polypeptide chain, which transformed the secondary structure of SPI trended to be flexible. The microenvironment of protein was transformed from hydrophobic to hydrophilic, while tyrosine played dominant role in quenching process. The binding sites and forces of the complexes were determined by computer simulation for further explored. The protein conformation of the 7S and 11S binding regions to Ca-An changed, and the amino acid microenvironment shifted to hydrophilic after binding. The results showed that more non-polar amino acids existed in the binding sites, while in binding process van der Waals forces and hydrogen bonding played a major role hydrophobicity played a minor role. Based on MM-PBSA analysis, the binding constants of 7S-Ca-An and 11S-Ca-An were 0.518 × 106 mol-1 and 5.437 × 10-3 mol-1, respectively. This information provides theoretical guidance for further studying the interaction between modified anthocyanins and biomacromolecules.

Discovery of Novel Aminobutanoic Acid-Based ASCT2 Inhibitors for the Treatment of Non-Small-Cell Lung Cancer.

Alanine-serine-cysteine transporter 2 (ASCT2) is up-regulated in lung cancers, and inhibiting it could potentially lead to nutrient deprivation, making it a viable strategy for cancer treatment. In this study, we present a series of ASCT2 inhibitors based on aminobutanoic acids, which exhibit potent inhibitory activity. Two compounds, 20k and 25e, were identified as novel and potent ASCT2 inhibitors, with IC50 values at the micromolar level in both A549 and HEK293 cells, effectively blocking glutamine (Gln) uptake. Additionally, these compounds regulated amino acid metabolism, suppressed mTOR signaling, inhibited non-small-cell lung cancer (NSCLC) growth, and induced apoptosis. In vivo, experiments showed that 20k and 25e suppressed tumor growth in an A549 xenograft model, with tumor growth inhibition (TGI) values of 65 and 70% at 25 mg/kg, respectively, while V9302 only achieved a TGI value of 29%. Furthermore, both compounds demonstrated promising therapeutic potential in patient-derived organoids. Therefore, these ASCT2 inhibitors based on aminobutanoic acids are promising therapeutic agents for treating NSCLC by targeting cancer Gln metabolism.

Sliding mode control with an adaptive switching power reaching law.

This paper proposes a adaptive reaching law-based sliding mode control (SMC) method for maintaining favorable velocity control performance of permanent magnet synchronous motors (PMSMs) under internal and external perturbations. An adaptive switching power reaching law (ASPRL) is designed, which contains adaptive terms and state variables of the sliding mode surface function. This augmented reaching law decreases the chatter of the control system and increases the rate at which the state variables of the system reach the sliding mode surface. Additionally, a Luenberger observer load torque (LOLT) is designed to observe the external load and provide feedback to the velocity controller, reducing the impact of load disturbances and improving the jamming performance of the controller. Simulation experiments confirm that ASPRL reduces buffeting, decreases overshoot, and shortens response time, demonstrating its advantages in PMSM control.

Intestinal Microbiota Is a Key Target for Load Swimming to Improve Anxiety Behavior and Muscle Strength in Shank 3-/- Rats.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social disorder and stereotypical behavior, and its incidence rate is increasing yearly. It is considered that acritical period for the prognosis of young children with ASD exists, thus early treatment is crucial. Swimming, due to its comforting effect, is often used to induce enthusiasm in young children for completing activities and has a good effect in the treatment of ASD, but the effective path of swimming has yet to be reported. The intestinal microbiota of ASD patients and animal models has been reported to be different from that of healthy controls, and these changes may affect the brain environment. Therefore, whether the intestinal microbiota is involved in the treatment of ASD by early swimming is our concern. In this study, we used 8-day old Shank3 gene knockout rats with 8 weeks of early load swimming training and conducted behavioral, small intestine morphology, and intestinal content sequencing after training. The results showed that early load swimming significantly reduced the stereotyped and anxious behaviors of Shank3-/- rats, increased their muscle strength, increased the length of intestinal villi and the width of the muscular layer after Shank3 knockout, and affected the abundance of intestinal microorganisms. The abundances with statistical significance were Lactobacillus, Lachnospiraceae, and Alloprevotella. To further confirm the role of intestinal microorganisms in it, we designed a 14-day intestinal stool transplantation experiment. Fecal microbiota transplantation demonstrated that load swimming can significantly reduce the anxiety behavior of Shank3 rats, increase their muscle strength, change the structure of the small intestine, and affect the abundance of intestinal contents. The abundance of Epsilonbateraeota, Prevotella, and Bacteroides significantly changed after transplantation. Our findings confirm the possibility of early load swimming therapy for individuals with ASD and explain that the intestinal microbiota is a key pathway for early exercise therapy for patients with ASD.

Performances of the Canadian Agility and Movement Skill Assessment (CAMSA), and validity of timing components in comparison with three commonly used agility tests in Chinese boys: an exploratory study.

BACKGROUND: The practical application of the Canadian Agility and Movement Skill Assessment (CAMSA) has been reported in some Western countries. However, a few studies reported the application of the CAMSA in Chinese children. In addition, given that the CAMSA was designing to incorporate both movement skills and agility assessment, the value and validity of the timing component of the CAMSA are worth discussing. METHODS: By choosing the Illinois Agility Test, Repeated Side Step-1 m distance, and the newly designed Repeated Side Step-half of height as the benchmark, we evaluate the performance of the CAMSA, further establish the concurrent validity of the CAMSA timing components (completion time and time score). In total, 149 male children (mean age 9.0 ± 0.8 years) from public schools in Shanghai, China, participated in the study. RESULTS: The mean CAMSA completion time was 19.3 ± 5.3 (s), and mean time score was 8.7 ± 3.9 (range of 1-14) for all participants (n = 149). After adjusted the sprint speed, older age was positively associated with the performance of the CAMSA. Being overweight was not associated with the performance of the CAMSA comparing with healthy body mass children, however, being obese was negatively associated with the CAMSA timing components and total score. Children having extracurricular sports activities (e.g., athletic experiences), mostly soccer, were more likely to demonstrated better performances of the CAMSA completion time, time score and total score. However, overweight and obese, also athletic experiences were not significantly contributed to the CAMSA skill score, although the association was slight (Adj R 2 = 0.13). Besides, the CAMSA completion time has a strong correlation with the IAT, r = 0.77; RSS-1MD, r =  - 0.76; and RSS-HHD, r =  - 0.77, p < 0.01. The same pattern of correlation was also found between the CAMSA time score and three agility tests: IAT, r =  - 0.79; RSS-1MD, r = 0.76; RSS-HHD, r = 0.78, p < 0.01. DISCUSSION: Overall, a few participants in the study were able to reach the recommended level of the total CAMSA score referring to the Canadian criterion. The strong concurrent validity was found between the CAMSA timing components and three selected agility tests, respectively.