Highly efficient electrocatalytic CO2 reduction by a CrIII quaterpyridine complex.

Design tactics and mechanistic studies both remain as fundamental challenges during the exploitations of earth-abundant molecular electrocatalysts for CO2 reduction, especially for the rarely studied Cr-based ones. Herein, a quaterpyridyl CrIII catalyst is found to be highly active for CO2 electroreduction to CO with 99.8% Faradaic efficiency in DMF/phenol medium. A nearly one order of magnitude higher turnover frequency (86.6 s-1) over the documented Cr-based catalysts (<10 s-1) can be achieved at an applied overpotential of only 190 mV which is generally 300 mV lower than these precedents. Such a high performance at this low driving force originates from the metal-ligand cooperativity that stabilizes the low-valent intermediates and serves as an efficient electron reservoir. Moreover, a synergy of electrochemistry, spectroelectrochemistry, electron paramagnetic resonance, and quantum chemical calculations allows to characterize the key CrII, CrI, Cr0, and CO-bound Cr0 intermediates as well as to verify the catalytic mechanism.

Boosting CO2 photoreduction by π-π-induced preassembly between a Cu(I) sensitizer and a pyrene-appended Co(II) catalyst.

The design of a highly efficient system for CO2 photoreduction fully based on earth-abundant elements presents a challenge, which may be overcome by installing suitable interactions between photosensitizer and catalyst to expedite the intermolecular electron transfer. Herein, we have designed a pyrene-decorated Cu(I) complex with a rare dual emission behavior, aiming at additional π-interaction with a pyrene-appended Co(II) catalyst for visible light-driven CO2-to-CO conversion. The results of 1H NMR titration, time-resolved fluorescence/absorption spectroscopies, quantum chemical simulations, and photocatalytic experiments clearly demonstrate that the dynamic π-π interaction between sensitizer and catalyst is highly advantageous in photocatalysis by accelerating the intermolecular electron transfer rate up to 6.9 × 105 s-1, thus achieving a notable apparent quantum yield of 19% at 425 nm with near-unity selectivity. While comparable to most earth-abundant molecular systems, this value is over three times of the pyrene-free system (6.0%) and far surpassing the benchmarking Ru(II) tris(bipyridine) (0.3%) and Ir(III) tris(2-phenylpyridine) (1.4%) photosensitizers under parallel conditions.

Subcellular Translocation of Yorkie through the PRP4K-CRM1 Axis Regulates Antimicrobial Peptides Transcription and Defense against Bacterial Infection in Crab.

The Hippo signaling pathway plays important roles in innate immunity. In the current study, we found that bacterial infection did not influence mRNA and protein levels of yorkie (Yki), which is an important terminal molecule of the Hippo signaling pathway. However, bacterial infection promoted the translocation of Yki from the nucleus to the cytoplasm in Chinese mitten crab (Eriocheir sinensis), thus attenuating Yki-suppressed transcription of antimicrobial peptides through Cactus. Chromosome region maintenance 1 (CRM1)-silenced crab hemocytes significantly suppressed Yki translocation from the nucleus to the cytoplasm upon bacterial infection, resulting in significantly increased expression of Cactus, decreased expression of antimicrobial peptides, and higher bacterial susceptibility, which demonstrated the regulatory role of CRM1 in subcellular localization of Yki. However, RNA interference of Scalloped (Sd) exhibited no effect on the subcellular localization of Yki and its regulation of Cactus/antimicrobial peptides. Moreover, we elucidated that both CRM1 and Sd could interact with Yki and that the PRP4K-mediated phosphorylation of a conserved serine amino acid residue in the nuclear export signal of Yki is essential for interaction between Yki and CRM1; however, the phosphorylation did not affect the binding of Yki with Sd. We also found that bacterial infection significantly promoted the expression of PRP4K in hemocytes; RNA interference of PRP4K and phosphatase inhibitor suppressed Yki translocation from the nucleus to the cytoplasm, promoting Cactus expression and inhibiting antimicrobial peptide expression. Thus, subcellular localization of Yki regulates antibacterial infection through both PRP4K and CRM1 in crabs.

Impacts of pro-inflammatory cytokines variant on cardiometabolic profile and premature coronary artery disease: A systematic review and meta-analysis.

Interleukin-6 (IL-6), a pivotal pro-inflammatory cytokine, is closely linked to vascular wall thickening and atherosclerotic lesion. Since serum IL-6 levels are largely determined by the genetic variant in IL-6, this study was conducted to investigate whether the IL-6 variant impacts cardiometabolic profile and the risk of premature coronary artery disease (PCAD). PubMed, Cochrane Library, Central, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and ClinicalTrials.gov were searched from May 13, 2022 to June 28, 2023. In total, 40 studies (26,543 individuals) were included for the analysis. The rs1800795 (a function variant in the IL-6 gene) C allele was linked to higher levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), fasting plasma glucose (FPG), body mass index (BMI), and waist circumference (WC), and a lower levels of high-density lipoprotein cholesterol (HDL-C). However, no significant association was observed of rs1800795 with triglycerides (TG), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Interestingly, a significant association was detected between rs1800795 and PCAD. Subgroup analyses indicted that the impacts of rs1800795 on cardiometabolic risk factors were significant in Caucasians but stronger in obese patients. In contrast, the impact of rs1800795 on PCAD was significant in brown race population. In summary, rs1800795 had a slight but significant impact on cardiometabolic risk factors and PCAD. IL-6 inhibition with ziltivekimab or canakinumab may benefit high-risk populations (e.g. brown race population, Caucasians, obese patients, etc.) with rs1800795 to prevent PCAD.

Homocysteine concentration in coronary artery disease and severity of coronary lesions.

Our previous study reckons that the impact of the rs1801133 variant of 5,10-methylenetetrahydrofolate reductase (MTHFR) on coronary artery disease (CAD) is possibly mediated by cardiometabolic disorder. This study is performed to verify this hypothesis. Four hundred and thirty CAD patients and 216 CAD-free individuals were enrolled in this case-control study. The rs1801133 variant was genotyped by PCR-RFLP. Severity of coronary lesions was evaluated by number of stenotic coronary vessels and extent of coronary stenosis. The rs1801133 T allele significantly increased homocysteine levels in patients with CAD and CAD-free individuals. Individuals with the T allele of rs1801133 had an increased risk of developing CAD. In contrast, individuals with the TT genotype of rs1801133 were at high risk of multiple vessel lesions. The carriers of CT genotype had higher levels of systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), and high-sensitivity C-reactive protein (hs-CRP), and lower levels of apolipoprotein A1 (APOA1) than those with CC genotype in male patients with CAD. The receiver operating characteristic (ROC) curve and precision-recall (PR) curve indicated that hyperhomocysteinemia was sensitive to predict the severity of CAD. Multivariate logistic regression revealed that homocysteine, rs1801133, age, smoking, weight, body mass index (BMI), lipoprotein(a) [Lp(a)], and hs-CRP were independent risk factors for CAD. The increased risk of CAD and severity of coronary lesions associated with rs1801133 in the Chinese Han population were attributed, at least partly, to high homocysteine levels. Hyperhomocysteinemia had a high predictive value for severe CAD or multiple vessel lesions.

Highly Efficient, Noble-Metal-Free, Fully Aqueous CO2 Photoreduction Sensitized by a Robust Organic Dye.

The development of efficient, selective, and durable CO2 photoreduction systems presents a long-standing challenge in full aqueous solutions owing to the presence of scarce CO2 and the fierce competition against H2 evolution, which is even more challenging when noble metals are not utilized. Herein, we present the facile decorations of four phosphonic acid groups on a donor-acceptor-type organic dye to obtain a water-soluble photosensitizer (4P-DPAIPN), which succeeds the excellent photophysical and photoredox properties of its prototype, exhibiting long-lived delayed fluorescence (>10 µs) in aqueous solutions. Combining 4P-DPAIPN with a cationic cobalt porphyrin catalyst has accomplished record-high apparent quantum yields of 9.4-17.4% at 450 nm for CO2-to-CO photoconversion among the precedented systems (maximum 13%) in fully aqueous solutions. Remarkable selectivity of 82-93% and turnover number of 2700 for CO production can also be achieved with this noble-metal-free system, outperforming a benchmarking ruthenium photosensitizer and a commercial organic dye under parallel conditions. Such high performances of 4P-DPAIPN can be well maintained under real sunlight. More impressively, no significant decomposition of 4P-DPAIPN was detected during the long-term photocatalysis. Eventually, the photoinduced electron transfer pathways were proposed.

Mechanochemical Fabrication of Full-Color Luminescent Materials from Aggregation-Induced Emission Prefluorophores for Information Storage and Encryption.

The development of luminescent materials via mechanochemistry embodies a compelling yet intricate frontier within materials science. Herein, we delineate a methodology for the synthesis of brightly luminescent polymers, achieved by the mechanochemical coupling of aggregation-induced emission (AIE) prefluorophores with generic polymers. An array of AIE moieties tethered to the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) radical are synthesized as prefluorophores, which initially exhibit weak fluorescence due to intramolecular quenching. Remarkably, the mechanical coupling of these prefluorophores with macromolecular radicals, engendered through ball milling of generic polymers, leads to substantial augmentation of fluorescence within the resultant polymers. We meticulously evaluate the tunable emission of the AIE-modified polymers, encompassing an extensive spectrum from the visible to the near-infrared region. This study elucidates the potential of such materials in stimuli-responsive systems with a focus on information storage and encryption displays. By circumventing the complexity inherent to the conventional synthesis of luminescent polymers, this approach contributes a paradigm to the field of AIE-based polymers with implications for advanced technological applications.

Determinants of the interaction between the 5'-leader of HIV-1 genome and human lysyl-tRNA synthetase in reverse transcription primer release process.

Reverse transcription of human immunodeficiency virus type 1 (HIV-1) initiates from the 3' end of human tRNALys3. The primer tRNALys3 is selectively packaged into the virus in the form of a complex with human lysyl-tRNA synthetase (LysRS). To facilitate reverse transcription initiation, part of the 5' leader (5'L) of HIV-1 genomic RNA (gRNA) evolves a tRNA anticodon-like element (TLE), which binds LysRS and releases tRNALys3 for primer annealing and reverse transcription initiation. Although TLE has been identified as a key element in 5'L responsible for LysRS binding, how the conformations and various hairpin structures of 5'L regulate 5'L-LysRS interaction is not fully understood. Here, these factors have been individually investigated using direct and competitive fluorescence anisotropy binding experiments. Our data showed that the conformation of 5'L significantly influences its binding affinity with LysRS. The 5'L conformation favoring gRNA dimerization and packaging exhibits much weaker binding affinity with LysRS compared to the alternative 5'L conformation that is not selected for packaging. Additionally, dimerization of 5'L impairs LysRS-5'L interaction. Furthermore, among various regions of 5'L, both the primer binding site/TLE domain and the stem-loop 3 are important for LysRS interaction, whereas the dimerization initiation site and the splicing donor plays a minor role. In contrast, the presence of the transacting responsive and the polyadenylation signal hairpins slightly inhibit LysRS binding. These findings reveal that the conformation and various regions of the 5'L of HIV-1 genome regulate its interaction with human LysRS and the reverse transcription primer release process.

DSEATM: drug set enrichment analysis uncovering disease mechanisms by biomedical text mining.

Disease pathogenesis is always a major topic in biomedical research. With the exponential growth of biomedical information, drug effect analysis for specific phenotypes has shown great promise in uncovering disease-associated pathways. However, this method has only been applied to a limited number of drugs. Here, we extracted the data of 4634 diseases, 3671 drugs, 112 809 disease-drug associations and 81 527 drug-gene associations by text mining of 29 168 919 publications. On this basis, we proposed a 'Drug Set Enrichment Analysis by Text Mining (DSEATM)' pipeline and applied it to 3250 diseases, which outperformed the state-of-the-art method. Furthermore, diseases pathways enriched by DSEATM were similar to those obtained using the TCGA cancer RNA-seq differentially expressed genes. In addition, the drug number, which showed a remarkable positive correlation of 0.73 with the AUC, plays a determining role in the performance of DSEATM. Taken together, DSEATM is an auspicious and accurate disease research tool that offers fresh insights.

Periodically tunable multimode soliton pulsation in a spatiotemporal mode-locked fiber laser.

Multimode fiber lasers have become a new platform for investigating nonlinear phenomena since the report on spatiotemporal mode-locking. In this work, the multimode soliton pulsation with a tunable period is achieved in a spatiotemporal mode-locked fiber laser. It demonstrates that the pulsation period drops while increasing the pump power. Moreover, it is found that different transverse modes have the same pulsation period, asynchronous pulsation evolution and different dynamical characteristics through the spatial sampling technique and the dispersive Fourier transform technique. To further verify the experimental results, we numerically investigate the influences of the gain and the loss on the pulsation properties. It is found that within a certain parameter range, the pulsation period drops and rises linearly with the increase of the gain and the loss, respectively. The obtained results contribute to understanding the formation and regulating of soliton pulsations in fiber lasers.

Impact of third-order dispersion on the dynamics of dissipative solitons in an ultrafast fiber laser.

Dissipative solitons (DSs), due to the complex interplay among dispersion, nonlinear, gain and loss, illustrate abundant nonlinear dynamics behaviors. Especially, dispersion plays an important role in the research of DS dynamics in ultrafast fiber lasers. Previous studies have mainly focused on the effect of even-order dispersion, i.e., group velocity dispersion (GVD) and fourth-order dispersion. In fact, odd-order dispersions, such as third-order dispersion (TOD), also significantly influences the dynamics of DSs. However, due to the lack of dispersion engineering tools, few experimental researches in this domain have been reported. In this work, by employing a pulse shaper in ultrafast fiber laser, an in-depth exploration of the DS dynamics influenced by TOD was conducted. With the increase of TOD value, the stable single DS undergoes a splitting into two solitons and then enters explosion state, and ultimately evolves into a chaotic state. The laser operation state is correlated to dispersion profile, which could be controlled by TOD. Here, the positive dispersion at long-wavelength side will be gradually shifted to negative dispersion by increasing the TOD, where soliton effect will drive the transitions. These findings offer valuable insights into the nonlinear dynamics of ultrafast lasers and may also foster applications involving higher-order dispersion.

Protease SfpB plays an important role in cell membrane stability and immune system evasion in Streptococcus agalactiae.

Bacteria possess the ability to develop diverse and ingenious strategies to outwit the host immune system, and proteases are one of the many weapons employed by bacteria. This study sought to identify S. agalactiae additional serine protease and determine its role in virulence. The S. agalactiae THN0901 genome features one S8 family serine peptidase B (SfpB), acting as a secreted and externally exposed entity. A S8 family serine peptidase mutant strain (ΔsfpB) and complement strain (CΔsfpB) were generated through homologous recombination. Compared to the wild-type strain THN0901, the absorption of EtBr dyes was significantly reduced (P < 0.01) in ΔsfpB, implying an altered cell membrane permeability. In addition, the ΔsfpB strain had a significantly lower survival rate in macrophages (P < 0.01) and a 61.85 % lower adhesion ability to the EPC cells (P < 0.01) compared to THN0901. In the in vivo colonization experiment using tilapia as a model, 210 fish were selected and injected with different bacterial strains at a concentration of 3 × 106 CFU/tail. At 6, 12, 24, 48, 72 and 96 h post-injection, three fish were randomly selected from each group and their brain, liver, spleen, and kidney tissues were isolated. Subsequently, it was demonstrated that the ΔsfpB strain exhibited a markedly diminished capacity for colonization in tilapia. Additionally, the cumulative mortality of ΔsfpB in fish after intraperitoneal injection was reduced by 19.92-23.85 %. In conclusion, the findings in this study have demonstrated that the SfpB plays a significant role in S. agalactiae cell membrane stability and immune evasion. The immune evasion is fundamental for the development and transmission of invasive diseases, the serine protease SfpB may be a promising candidate for the development of antimicrobial agents to reduce the transmission of S. agalactiae.

Sub-50†fs, 0.5†W average power Nd-doped fiber amplifier at 920†nm.

We develop an all polarization-maintaining (PM) 920 nm Nd-doped fiber amplifier delivering a train of pulses with ∼0.53 W average power and sub-50 fs duration. The sub-50 fs pulse benefits from the pre-chirping management method that allows for over 60 nm broadening spectrum without pulse breaking in the amplification stage. By virtue of the short pulse duration, the pulse peak power can reach to ∼0.31 MW in spite of the moderate average power. These results represent a key step in developing high-peak-power pulse Nd-doped fiber laser systems at 920 nm, which will find important applications in fields such as biomedical imaging, ultrafast optical spectroscopy, and excitation of quantum-dot single photon sources.

Spatiotemporal dual-periodic soliton pulsation in a multimode fiber laser.

Spatiotemporal mode-locked (STML) fiber lasers have become a new platform for investigating nonlinear phenomena. In this work, spatiotemporal dual-periodic soliton pulsation (SDSP) is firstly observed in an STML fiber laser. It is found that in the SDSP, the long-period pulsations (LPPs) of different transverse modes are synchronous, while the short-period pulsations (SPPs) exhibit asynchronous modulations. The numerical simulation confirms the experimental results and further reveals that the proportion of transverse mode components can manipulate the periods of the LPP and SPP but does not affect the synchronous and asynchronous pulsations of different transverse modes. The obtained results bring the study of spatiotemporal dissipative soliton pulsation into the multi-period modulation stage, which helps to understand the complex spatiotemporal dynamics in STML fiber lasers and discover new dynamics in high-dimensional nonlinear systems.

Ip3r-Grp75-Vdac and Relevant Ca2+ Signaling Regulate Dietary Palmitic Acid-Induced De Novo Lipogenesis by Mitochondria-Associated ER Membrane (MAM) Recruiting Seipin in Yellow Catfish.

BACKGROUND: The mitochondria-associated endoplasmic reticulum membrane (MAM) is the central hub for endoplasmic reticulum and mitochondria functional communication. It plays a crucial role in hepatic lipid homeostasis. However, even though MAM has been acknowledged to be rich in enzymes that contribute to lipid biosynthesis, no study has yet investigated the exact role of MAM on hepatic neutral lipid synthesis. OBJECTIVES: To address these gaps, this study investigated the systemic control mechanisms of MAM on neutral lipids synthesis by recruiting seipin, focusing on the role of the inositol trisphosphate receptor-1,4,5(Ip3r)-75 kDa glucose-regulated protein (Grp75)-voltage-dependent anion channel (Vdac) complex and their relevant Ca2+ signaling in this process. METHODS: To this end, a model animal for lipid metabolism, yellow catfish (Pelteobagrus fulvidraco), were fed 6 different diets containing a range of palmitic acid (PA) concentrations from 0-150 g/kg in vivo for 10 wk. In vitro, experiments were also conducted to intercept the MAM-mediated Ca2+ signaling in isolated hepatocytes by transfecting them with si-mitochondrial calcium uniporter (mcu). Because mcu was placed in the inner mitochondrial membrane (IMM), si-mcu cannot disrupt MAM's structural integrity. RESULTS: 1. Hepatocellular MAM subproteome analysis indicated excessive dietary PA intake enhanced hepatic MAM structure joined by activating Ip3r-Grp75-Vdac complexes. 2. Dietary PA intake induced hepatic neutral lipid accumulation through MAM recruiting Seipin, which activated lipid droplet biogenesis. Our findings also revealed a previously unidentified mechanism whereby MAM-recruited seipin and controlled hepatic lipid homeostasis, depending on Ip3r-Grp75-Vdac-controlled Ca2+ signaling and not only MAM's structural integrity. CONCLUSIONS: These results offer a novel insight into the MAM-recruited seipin in controlling hepatic lipid synthesis in a MAM structural integrity-dependent and Ca2+ signaling-dependent manner, highlighting the critical contribution of MAM in maintaining hepatic neutral lipid homeostasis.

P38γ modulates the lipid metabolism in non-alcoholic fatty liver disease by regulating the JAK-STAT signaling pathway.

Non-alcoholic fatty liver disease (NAFLD) is a major health problem in Western countries and has become the most common cause of chronic liver disease. Although NAFLD is closely associated with obesity, inflammation, and insulin resistance, its pathogenesis remains unclear. The disease begins with excessive accumulation of triglycerides in the liver, which in turn leads to liver cell damage, steatosis, inflammation, and so on. P38γ is one of the four isoforms of P38 mitogen-activated protein kinases (P38 MAPKs) that contributes to inflammation in different diseases. In this research, we investigated the role of P38γ in NAFLD. In vivo, a NAFLD model was established by feeding C57BL/6J mice with a methionine- and choline-deficient (MCD) diet and adeno-associated virus (AAV9-shRNA-P38γ) was injected into C57BL/6J mice by tail vein for knockdown P38γ. The results indicated that the expression level of P38γ was upregulated in MCD-fed mice. Furthermore, the downregulation of P38γ significantly attenuated liver injury and lipid accumulation in mice. In vitro, mouse hepatocytes AML-12 were treated with free fatty acid (FFA). We found that P38γ was obviously increased in FFA-treated AML-12 cells, whereas knockdown of P38γ significantly suppressed lipid accumulation in FFA-treated AML-12 cells. Furthermore, P38γ regulated the Janus Kinase-Signal transducers and activators of transcription (JAK-STAT) signaling pathway. Inhibition of P38γ can inhibit the JAK-STAT signaling pathway, thereby inhibiting lipid accumulation in FFA-treated AML-12 cells. In conclusion, our results suggest that targeting P38γ contributes to the suppression of lipid accumulation in fatty liver disease.

Effect of the Molecular Structure of 1,3-Diketones on the Realization of Oil-Based Superlubricity on Steel/Steel Friction Pairs.

In this article, five kinds of 1,3-diketones and their chelates with different molecular structures were prepared, and their tribological properties were tested. The experimental results show that the running-in time and friction coefficient of the friction pairs lubricated by 1,3-diketones containing a benzene ring increased with the increase of the carbon chain length. In addition, only the friction pair lubricated by 1-(4-ethylphenyl)-butane-1,3-dione (0201) and 1-(4-ethylphenyl)-nonane-1,3-dione (0206) could achieve stable superlubricity. When the benzene ring was replaced with a carbon six-membered ring, it was found that although the friction pair lubricated by this lubricant could achieve superlubricity, the wear of the friction pair was severe, and obvious abrasive wear occurred. In addition, the lubricants prepared by mixing 1,3-diketones and the corresponding chelates in a ratio of 4:6 had greatly improved lubricating properties compared to 1,3-diketones. Through X-ray photoelectron spectroscopy (XPS) analysis of the surface of the friction pair after the test and Fourier transform infrared (FT-IR) and nuclear magnetic resonance (NMR) analyses of 1,3-diketones before and after the experiment, we found that the necessary conditions for the friction pair lubricated by 1,3-diketone to achieve superlubricity were formation of tribochemical adsorption films and the presence of chelates in solution.

Choline-mediated hepatic lipid homoeostasis in yellow catfish: unravelling choline's lipotropic and methyl donor functions and significance of ire-1α signalling pathway.

Choline plays a crucial role in hepatic lipid homeostasis by acting as a major methyl-group donor. However, despite this well-accepted fact, no study has yet explored how choline's methyl-donor function contributes to preventing hepatic lipid dysregulation. Moreover, the potential regulatory role of Ire-1α, an ER-transmembrane transducer for the unfolded protein response (UPRer), in choline-mediated hepatic lipid homeostasis remains unexplored. Thus, this study investigated the mechanism by which choline prevents hepatic lipid dysregulation, focusing on its role as a methyl-donor and the involvement of Ire-1α in this process. To this end, a model animal for lipid metabolism, yellow catfish (Pelteobagrus fulvidraco) were fed two different diets (adequate or deficient choline diets) in vivo for 10 weeks. The key findings of studies are as follows: 1. Dietary choline, upregulated selected lipolytic and fatty acid ß-oxidation transcripts promoting hepatic lipid homeostasis. 2. Dietary choline ameliorated UPRer and prevented hepatic lipid dysregulation mainly through ire-1α signalling, not perk or atf-6α signalling. 3. Choline inhibited the transcriptional expression level of ire-1α by activating site-specific DNA methylations in the promoter of ire-1α. 4. Choline-mediated ire-1α methylations reduced Ire-1α/Fas interactions, thereby further inhibiting Fas activity and reducing lipid droplet deposition. These results offer a novel insight into the direct and indirect regulation of choline on lipid metabolism genes and suggests a potential crosstalk between ire-1α signalling and choline-deficiency-induced hepatic lipid dysregulation, highlighting the critical contribution of choline as a methyl-donor in maintaining hepatic lipid homeostasis.

Dietary chenodeoxycholic acid attenuates high-fat diet-induced growth retardation, lipid accumulation and bile acid metabolism disorder in the liver of yellow catfish Pelteobagrus fulvidraco.

This experiment was conducted to investigate whether dietary chenodeoxycholic acid (CDCA) could attenuate high-fat (HF) diet-induced growth retardation, lipid accumulation and bile acid (BA) metabolism disorder in the liver of yellow catfish Pelteobagrus fulvidraco. Yellow catfish (initial weight: 4·40 (sem 0·08) g) were fed four diets: the control (105·8 g/kg lipid), HF diet (HF group, 159·6 g/kg lipid), the control supplemented with 0·9 g/kg CDCA (CDCA group) and HF diet supplemented with 0·9 g/kg CDCA (HF + CDCA group). CDCA supplemented in the HF diet significantly improved growth performance and feed utilisation of yellow catfish (P < 0·05). CDCA alleviated HF-induced increment of hepatic lipid and cholesterol contents by down-regulating the expressions of lipogenesis-related genes and proteins and up-regulating the expressions of lipololysis-related genes and proteins. Compared with the control group, CDCA group significantly reduced cholesterol level (P < 0·05). CDCA significantly inhibited BA biosynthesis and changed BA profile by activating farnesoid X receptor (P < 0·05). The contents of CDCA, taurochenodeoxycholic acid and glycochenodeoxycholic acid were significantly increased with the supplementation of CDCA (P < 0·05). HF-induced elevation of cholic acid content was significantly attenuated by the supplementation of CDCA (P < 0·05). Supplementation of CDCA in the control and HF groups could improve the liver antioxidant capacity. This study proved that CDCA could improve growth retardation, lipid accumulation and BA metabolism disorder induced by HF diet, which provided new insight into understanding the physiological functions of BA in fish.

Repositioning baloxavir marboxil as VISTA agonist that ameliorates experimental asthma.

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA), a novel negative checkpoint regulator, plays an essential role in allergic pulmonary inflammation in mice. Treatment with a VISTA agonistic antibody could significantly improve asthma symptoms. Thus, for allergic asthma treatment, VISTA targeting may be a compelling approach. In this study, we examined the functional mechanism of VISTA in allergic pulmonary inflammation and screened the FDA-approved drugs for VISTA agonists. By using mass cytometry (CyTOF), we found that VISTA deficiency primarily increased lung macrophage infiltration in the OVA-induced asthma model, accompanied by an increased proportion of M1 macrophages (CD11b+F4/80+CD86+) and a decreased proportion of M2 macrophages (CD11b+F4/80+CD206+). Further in vitro studies showed that VISTA deficiency promoted M1 polarization and inhibited M2 polarization of bone marrow-derived macrophages (BMDMs). Importantly, we discovered baloxavir marboxil (BXM) as a VISTA agonist by virtual screening of FDA-approved drugs. The surface plasmon resonance (SPR) assays revealed that BXM (KD = 1.07 µM) as well as its active form, baloxavir acid (BXA) (KD = 0.21 µM), could directly bind to VISTA with high affinity. Notably, treatment with BXM significantly ameliorated asthma symptoms, including less lung inflammation, mucus secretion, and the generation of Th2 cytokines (IL-5, IL-13, and IL-4), which were dramatically attenuated by anti-VISTA monoclonal antibody treatment. BXM administration also reduced the pulmonary infiltration of M1 macrophages and raised M2 macrophages. Collectively, our study indicates that VISTA regulates pulmonary inflammation in allergic asthma by regulating macrophage polarization and baloxavir marboxil, and an old drug might be a new treatment for allergic asthma through targeting VISTA.