Histone Deacetylase 3 Couples Mitochondria to Drive IL-1ß-Dependent Inflammation by Configuring Fatty Acid Oxidation.

Immune cell function depends on specific metabolic programs dictated by mitochondria, including nutrient oxidation, macromolecule synthesis, and post-translational modifications. Mitochondrial adaptations have been linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Here we reveal that histone deacetylase 3 (HDAC3) is essential for shaping mitochondrial adaptations for IL-1ß production in macrophages through non-histone deacetylation. In vivo, HDAC3 promoted lipopolysaccharide-induced acute inflammation and high-fat diet-induced chronic inflammation by enhancing NLRP3-dependent caspase-1 activation. HDAC3 configured the lipid profile in stimulated macrophages and restricted fatty acid oxidation (FAO) supported by exogenous fatty acids for mitochondria to acquire their adaptations and depolarization. Rather than affecting nuclear gene expression, HDAC3 translocated to mitochondria to deacetylate and inactivate an FAO enzyme, mitochondrial trifunctional enzyme subunit α. HDAC3 may serve as a controlling node that balances between acquiring mitochondrial adaptations and sustaining their fitness for IL-1ß-dependent inflammation.

Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages.

Cholesterol metabolism has been linked to immune functions, but the mechanisms by which cholesterol biosynthetic signaling orchestrates inflammasome activation remain unclear. Here, we have shown that NLRP3 inflammasome activation is integrated with the maturation of cholesterol master transcription factor SREBP2. Importantly, SCAP-SREBP2 complex endoplasmic reticulum-to-Golgi translocation was required for optimal activation of the NLRP3 inflammasome both in vitro and in vivo. Enforced cholesterol biosynthetic signaling by sterol depletion or statins promoted NLPR3 inflammasome activation. However, this regulation did not predominantly depend on changes in cholesterol homeostasis controlled by the transcriptional activity of SREBP2, but relied on the escort activity of SCAP. Mechanistically, NLRP3 associated with SCAP-SREBP2 to form a ternary complex which translocated to the Golgi apparatus adjacent to a mitochondrial cluster for optimal inflammasome assembly. Our study reveals that, in addition to controlling cholesterol biosynthesis, SCAP-SREBP2 also serves as a signaling hub integrating cholesterol metabolism with inflammation in macrophages.

Nucleobase-Coupled Xanthones with Anti-ROS Effects from Marine-Derived Fungus Aspergillus sydowii.

A MS/MS-based molecular networking approach compared to the Global Natural Product Social Molecular Networking library, in association with genomic annotation of natural product biosynthetic gene clusters within a marine-derived fungus, Aspergillus sydowii, identified a suite of xanthone metabolites. Chromatographic techniques applied to the cultured fungus led to the isolation of 11 xanthone-based alkaloids, dubbed sydoxanthones F-M. The structures of these alkaloids were elucidated using extensive spectroscopic data, including electronic circular dichroism and single-crystal X-ray diffraction data for configurational assignments. Among these analogues, sydoxanthones F-K exhibit structure features typical of nucleobase-coupled xanthones, with sydoxanthone H being an N-bonded xanthone dimer. Notably, (±)sydoxanthones F (1a/1b), (±)sydoxanthones H (3b/3a), and (±)sydoxanthones J (5b/5a) are enantiomeric pairs, while sydoxanthones G (2), I (4), and K (6) are stereoisomers of 1, 3, and 5, respectively. Furthermore, (+)sydoxanthone H (3a) demonstrated significant rescue of cell viability in H2O2-injuried SH-SY5Y cells by inhibiting reactive oxygen species production, suggesting its potential for neuroprotection.

Toxicity of common biocides used in aquaculture to embryos and larvae of Brachymystax tsinlingensis Li.

Brachymystax tsinlingensis Li is a threatened fish species endemic to China. With the problems of environmental factors and seeding breeding diseases, it is important to further improve the efficiency of seeding breeding and the basis of resource protection. This study investigated the acute toxicity of copper, zinc and methylene blue (MB) on hatching, survival, morphology, heart rate (HR) and stress behaviour of B. tsinlingensis. Eggs (diameter: 3.86 ± 0.07 mm, weight: 0.032 ± 0.004 g) of B. tsinlingensis were selected randomly from artificial propagation and developed from eye-pigmentation-stage embryos to yolk-sac stage larvae (length: 12.40 ± 0.02 mm, weight: 0.03 ± 0.001 g) and exposed to different concentrations of Cu, Zn and MB for 144 h in a series of semi-static toxicity tests. The acute toxicity tests indicated that the 96-h median lethal concentration (LC50 ) values of the embryos and larvae were 1.71 and 0.22 mg l-1 for copper and 2.57 and 2.72 mg l-1 for zinc, respectively, whereas the MB LC50 after 144-h exposure for embryos and larvae were 67.88 and 17.81 mg l-1 , respectively. The safe concentrations of copper, zinc and MB were 0.17, 0.77 and 6.79 mg l-1 for embryos and 0.03, 0.03 and 1.78 mg l-1 for larvae, respectively. Copper, zinc and MB treatments with concentrations greater than 1.60, 2.00 and 60.00 mg l-1 , respectively, led to a significantly low hatching rate and significantly high embryo mortality (P < 0.05), and copper and MB treatments with concentrations greater than 0.2 and 20 mg l-1 led to significantly high larvae mortality (P < 0.05). Exposure to copper, zinc and MB resulted in developmental defects, including spinal curvature, tail deformity, vascular system anomalies and discolouration. Moreover, copper exposure significantly reduced the HR of larvae (P < 0.05). The embryos exhibited an obvious change in behaviour, converting from the normal behaviour of emerging from the membrane head first to emerging tail first, with probabilities of 34.82%, 14.81% and 49.07% under copper, zinc and MB treatments, respectively. The results demonstrated that the sensitivity of yolk-sac larvae to copper and MB was significantly higher than that of embryos (P < 0.05) and that B. tsinlingensis embryos or larvae might be more resistant to copper, zinc and MB than other members of the Salmonidae family, which benefits their resource protection and restoration.

Insight into Polishing Slurry and Material Removal Mechanism of Photoassisted Chemical Mechanical Polishing of YAG Crystals.

Yttrium aluminum garnet (YAG) crystals are an important gain medium in thin-sheet solid-state lasers, and their processing quality directly affects the performance of solid-state lasers. But it is difficult to achieve high efficiency and high quality of YAG crystals by traditional chemical mechanical polishing (CMP). In this study, we developed a new polishing slurry for photoassisted chemical mechanical polishing (PCMP) of YAG crystals. The polishing slurry is composed of peroxymonosulfate (PMS), manganese ferrite (MnFe2O4), alumina (Al2O3) abrasives, and deionized water. PCMP is conducted in an ultraviolet (UV) light environment. When employing this polishing slurry for PCMP processing of YAG crystals, the material removal rate (MRR) achieved 250 nm/min and the surface roughness achieved 0.35 nm Sa. The experiments verified that both UV light and MnFe2O4 can effectively activate PMS to produce active free radicals and further enhance the chemical action of the polishing slurry. X-ray photoelectron spectroscopy (XPS) analysis results indicated that active radicals reacted with the surface structure of the crystal and removed the aluminum-oxygen octahedron in large quantities from it. The structural defects reduced the surface hardness of the crystal, which means that active free radicals can modify the crystal surface materials.

Indoloquinazoline alkaloids suppress angiogenesis and inhibit metastasis of melanoma cells.

Metastasis is the leading cause of cancer-related mortality, targeting angiogenesis emerges as a therapeutic strategy for the treatment of melanoma metastasis. Discovery of new antiangiogenic compounds with specific mechanism of action is still desired. In present study, a bioassay-guidance uncovers the EtOAc extract of a marine-derived fungus Aspergillus clavutus LZD32-24 with significant inhibitory activity against the angiogenesis in Tg (fli1a: EGFP) zebrafish model. Extensive chromatographic fractionation led to the isolation of 48 indoloquinazoline alkaloids, including 21 new analogues namely clavutoines A-U (1-21). Their structures were determined by the spectroscopic data, including the ECD, single crystal X-ray diffraction and quantum chemical calculation for the configurational assignments. Among the bioactive analogues, quinadoline B (QB) showed the most efficacy to suppress the zebrafish vascular outgrowth in zebrafish embryos. QB markedly inhibited the migration, invasion and tube formation with weak cytotoxicity in human umbilical vein endothelial cells (HUVECs). Investigation of the mode of action revealed QB suppressed the ROCK/MYPT1/MLC2/coffin and FAK /Src signaling pathways, and subsequently disrupted actin cytoskeletal organization. In addition, QB reduced the number of new vessels sprouting from the ex vivo chick chorioallantoic membrane (CAM), and inhibited the metastasis of B16F10 melanoma cells in lung of C57BL/6 mice through suppressing angiogenesis. These findings suggest that QB is a potential lead for the development of new antiangiogenic agent to inhibit melanoma metastasis.

Concise Biosynthesis of Tropone-Containing Spiromaterpenes by a Sesquiterpene Cyclase and a Multifunctional P450 from a Deep-Sea-Derived Spiromastix sp. Fungus.

Spiromaterpenes are a group of rare tropone-containing sesquiterpenes with antineuroinflammatory activity. Herein, we elucidate their biosynthetic pathway in a deep-sea-derived Spiromastix sp. fungus by heterologous expression, biochemical characterization, and incubation experiments. The sesquiterpene cyclase SptA was first characterized to catalyze the production of guaia-1(5),6-diene, and a multifunctional cytochrome P450 catalyzed the tropone ring formation. These results provide important clues for the rational mining of bioactive guaiane-type sesquiterpenes and expand the repertoire of P450 activities to synthesize unique building blocks of natural products.

Epigenetic Manipulation to Trigger Production of Guaiane-Type Sesquiterpenes from a Marine-Derived Spiromastix sp. Fungus with Antineuroinflammatory Effects.

Epigenetic manipulation of a deep-sea sediment-derived Spiromastix sp. fungus using suberoylanilide hydroxamic acid (SAHA) induction resulted in the activation of a terpene-related biosynthetic gene cluster, and nine new guaiane-type sesquiterpenes, spiromaterpenes A-I (1-9), were isolated. Their structures were determined using various spectroscopic techniques, in association with the modified Mosher's method, computed electronic circular dichroism (ECD) spectra, and chemical conversion for configurational assignments. Compounds 4-6 exhibited significant effects against the NO production on lipopolysaccharide (LPS)-induced microglia cells BV2, and the preliminary SAR analyses demonstrated that a 2(R),11-diol unit is favorable. The most active 5 abolished LPS-induced NF-κB translocation from the cytosol to the nucleus in BV-2 microglial cells, accompanied by the marked reduction of the transcription levels of pro-inflammatory cytokines, including IL-1ß, IL-6, and TNF-α dose-dependently in both LPS-induced BV-2 and BV-2 cells, as well as the protein and mRNA levels of iNOS and COX-2. This study complements the gap in knowledge regarding the anti-neuroinflammatory activity of guaiane-type sesquiterpenoids at the cellular level and suggests that 5 is promising for further optimization as a multifunctional agent for antineuroinflammation.

Briarane-type diterpenoids suppress osteoclastogenisis by regulation of Nrf2 and MAPK/NF-kB signaling pathway.

Excess osteoclastic activity leads to an imbalance in bone remodeling and causes most adult skeletal diseases. Natural products are a promising source to attenuate the osteoporosis and relevant diseases of bone loss. Herein, a bioassay-guided detection of gorgonian corals resulted in junceellolide D (JD), a briarane-type diterpenoid from gorgonian Dichotella gemmacea, showing significant inhibition against the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs) in vitro. To extend the investigation for structure-activity relationship (SAR), a total of 39 briarane-type analogues were isolated including 28 new compounds, and their structures were determined by extensive analyses of spectroscopic data. The SAR data indicated that JD is the most active to inhibit osteoclast development due to the decreased number of multinucleated tartrate-resistance acid phosphatase positive cells, suppression of the actin ring formation, blockage of bone resorption, and downregulation of osteoclast-specific marker genes. Mechanistically, JD increased the protein stability of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2) and promoted Nrf2 nuclear translocation followed by activation its downstream antioxidant enzymes, which strongly abolished RANKL-induced generation of reactive oxygen species (ROS). Furthermore, JD inhibits the RANKL-stimulated activation of NF-κB and MAPK signaling pathways. Hence, JD is considered as a promising lead compound for anti-osteoclastogenesis via activating Nrf2 and suppressing NF-κB and MAPK signaling pathways to prevent osteoclast-mediated bone destructive diseases.

Monocyte-derived extracellular vesicles upon treated by palmitate promote endothelial migration and monocytes attachment to endothelial cells.

AIM: High circulating free fatty acid (FFA) concentration has a critical role in the development of obesity associated vascular comorbidities. Ample previous findings revealed that FFA, especially saturated, induce endothelial dysfunction throught multiple mechanisms (summarized as lipotoxicity). As a mediator that transfers information among cells, extracellular vesicles(EVs) participate in pathologic processes of many diseases, including angiocardiopathy, insulin resistance, autoimmunity disease. However, how lipotoxicity changed the proportion of EVs secreted from monocytes, furthermore, the effect of the EVs exerts on endothelial cells, haven't been demonstrated. METHOD: In our experience, differential ultracentrifugation was used to extract EVs from condition medium (CM) of THP-1 monocytes under given treatments. Then we co-incubated the EVs derived from palmitate-treated monocytes with HUVECs for 24 h, after which molecular and phenotypic assays were conducted. RESULT: Palmitate-treated monocytes EVs promote the production of adhesion associated proteins of endothelial cells, such as VCAM-1, ICAM-1. Meanwhile, palmitate-stimulation may play a promoter role in the pro-migration capacity of monocytes-EVs. In brief, EVs could be the new pathological junction between FFA and endothelial damage.

Briarane-type diterpenoids from a gorgonian coral Ellisella sp. with anti-HBV activities.

Chemical investigation of a gorgonian coral Ellisella sp. resulted in the isolation of 12 briarane-type diterpenoids, including eight new congeners namely ellisellolides A-H (1-8). Their structures were determined by extensive spectroscopic analysis, aided the calculated ECD data to support the configurational assignment. All compounds were evaluated for the in vitro anti-HBV activities in HepAD38 cell line, while preliminary analyses of the structure-activity relationship demonstrated that junceellolide C featured an 3E,5(16)-diene and a chlorine-substitution at C-6 is the most active congener. Junceellolide C exhibited efficient reduction against the HBV DNA, HBV RNA and HBeAg production with a dose-dependent manner. It also significantly reduced the HBV cccDNA replenishment and promoted the existed HBV cccDNA degradation. These findings suggest junceellolide C to be a transcription inhibitor of cccDNA and a promising lead for the development of new anti-HBV agent.

Absolute Configurations and Chitinase Inhibitions of Quinazoline-Containing Diketopiperazines from the Marine-Derived Fungus Penicillium polonicum.

Three new quinazoline-containing diketopiperazines, polonimides A-C (1-3), along with four analogues (4-7), were obtained from the marine-derived fungus Penicillium polonicum. Among them, 2 and 4, 3 and 5 were epimers, respectively, resulting the difficulty in the determination of their configurations. The configurations of 1-3 were determined by 1D nuclear overhauser effect (NOE), Marfey and electron circular dichroism (ECD) methods. Nuclear magnetic resonance (NMR) calculation with the combination of DP4plus probability method was used to distinguish the absolute configurations of C-3 in 3 and 5. All of 1-7 were tested for their chitinase inhibitory activity against OfHex1 and OfChi-h and cytotoxicity against A549, HGC-27 and UMUC-3 cell lines. Compounds 1-7 exhibited weak activity towards OfHex1 and strong activity towards OfChi-h at a concentration of 10.0 µM, with the inhibition rates of 0.7%-10.3% and 79.1%-95.4%, respectively. Interestingly, 1-7 showed low cytotoxicity against A549, HGC-27 and UMUC-3 cell lines, suggesting that good prospect of this cluster of metabolites for drug discovery.

Chartarlactams Q-T, Dimeric Phenylspirodrimanes with Antibacterial and Antiviral Activities.

Four new phenylspirodrimane-type dimers, namely chartarlactams Q-T, along with stachyin B were isolated from the fermentation broth of a sponge-derived fungus Stachybotrys chartarum WGC-25 C-6. Chartarlactams Q-T were structurally featured by the dimerization of two units of phenylspirodrimane linked by a C-N bond. Their structures were determined on the basis of extensive spectroscopic analysis, while quantum ECD calculation and modified Mosher's method were used for the assignment of absolute configurations. Chartarlactams Q-S and stachyin B showed moderate inhibition against bacterial pathogen Staphylococcus aureus with MIC values ranging from 4 µg/mL to 16 µg/mL, and chartarlactam T exhibited significant inhibition toward ZIKV virus.

Human α defensins promote the expression of the inflammatory cytokine interleukin-8 under high-glucose conditions: Novel insights into the poor healing of diabetic foot ulcers.

Sustained infection and chronic inflammation are the most common features and complex mechanisms of diabetic foot disease. In this study, we examined the expression and functional roles of human endogenous α defensins in diabetic foot ulcer. The expression levels of human α defensins HNP1, HNP3, and HNP4 were significantly higher in the wound center than the edge of diabetic foot ulcers. And the inflammatory cytokine interleukin IL-8 (IL-8) was also highly expressed in wound exudates. In human foreskin fibroblasts, these human α defensins were found only slightly to affect IL-8 expression directly. hemoglobin A1C (HbA1c) is the main clinical indicator of diabetic foot disease. Advanced glycation end products of bovine serum albumin (AGE-BSA), as HbA1c analogue, was found to promote IL-8 expression. Human α defensins, in the presence of AGE-BSA, further significantly promoted IL-8 expression. These findings showed that human α defensins aggravated the inflammatory response in diabetic foot ulcers patients, providing new insights in to the poor healing of diabetic foot ulcers.

Axially chiral N,N'-dioxides ethers for catalysis in enantioselective allylation of aldehydes.

A series of axially chiral ethers synthesized from biscarboline N,N'-dioxides, (S)-1a to (S)-1n, was investigated in enantioselectivity addition reactions of allyltrichlorosilane with a series of substituted aldehydes, including bulky substituted aldehydes. High enantioselectivities (up to 96%ee) were achieved using the catalyst (S)-1k at 1 mol % loading.

Parental Burnout, Negative Parenting Style, and Adolescents' Development.

Research on parental burnout has focused more on its antecedents than on its consequences. Burned-out parents may experience a series of behavioral changes, negatively affecting their children's physical and mental development. This study examined the effects of primary caregivers' parental burnout on adolescents' development and the mediating role of negative parenting styles. This study used a time-lagged design, and data were collected at three different time points. Adolescents were asked to identify their primary caregivers, and parents were asked whether they were the primary caregivers of their children. Thereafter, paired data from the children and primary caregivers were collected. A total of 317 junior middle school students (178 boys, Mage = 14.20 ± 0.8 years) and primary caregivers (71 fathers, Mage = 42.20 ± 4.53 years) from Henan province participated. Primary caregivers' parental burnout was positively associated with negative parenting styles, and negative parenting styles mediated the relationship between parental burnout and adolescent development. From the perspective of prevention-focused interventions, it is necessary to focus on preventing the occurrence of parental burnout. Further, parents should try to avoid using abusive behaviors toward their children and neglecting them.

Comparative study on CeO2 catalysts with different morphologies and exposed facets for catalytic ozonation: performance, key factor and mechanism insight.

Morphology and facet effects of metal oxides in heterogeneous catalytic ozonation (HCO) are attracting increasing interests. In this paper, the different HCO performances for degradation and mineralization of phenol of seven ceria (CeO2) catalysts, including four with different morphologies (nanorod, nanocube, nanooctahedron and nanopolyhedron) and three with the same nanorod morphology but different exposed facets, are comparatively studied. CeO2 nanorods with (110) and (100) facets exposed show the best performance, much better than that of single ozonation, while CeO2 nanocubes and nanooctahedra show performances close to single ozonation. The underlying reason for their different HCO performances is revealed using various experimental and density functional theory (DFT) calculation results and the possible catalytic reaction mechanism is proposed. The oxygen vacancy (OV) is found to be pivotal for the HCO performance of the different CeO2 catalysts regardless of their morphology or exposed facet. A linear correlation is discerned between the rate of catalytic decomposition of dissolved ozone (O3) and the density of Frenkel-type OV. DFT calculations and in-situ spectroscopic studies ascertain that the existence of OV can boost O3 activation on both the hydroxyl (OH) and Ce sites of CeO2. Conversely, various facets without OV exhibit similar O3 adsorption energies. The OH group plays an important role in activating O3 to produce hydroxyl radical (∙OH) for improved mineralization. This work may offer valuable insights for designing Facet- and OV-regulated catalysts in HCO for the abatement of refractory organic pollutants.

Intestinal Tissue, Digestive Enzyme, and Antioxidant Enzyme Activities in the Early Development Stage of Endangered Brachymystax tsinlingensis.

This work explores the digestive system characteristics of Brachymystax tsinlingensis during early developmental stages and aims to solve the problem of high lethality of fry during the transgression period, which is crucial for the artificial propagation and population conservation of endangered fishes. This study was carried out on intestinal tissue, digestive enzymes, and antioxidant enzyme activities in the early development stage of Brachymystax tsinlingensis. Ten random samples during endogenous nutrition (7, 10, and 11 days after hatching), mixed nutrition (13 and 19 DAH), and exogenous nutrition (31, 33, 39, 45, and 73 DAH) were collected by histological and biochemical analysis methods. The results showed that the intestine of Brachymystax tsinlingensis already has four layers initially at 7 DAH, and the intestinal gland tissue is evident at 73 DAH. The contents of total protein (TP) and the activities of lipase (LPS) and trypsin (TPS) were maximal at 39 DAH, and the activities were 3.20 ± 0.26 mg/mL, 2.52 ± 0.69 U/g, and 2717.45 ± 295.26 U/mg, respectively. Catalase (CAT) and glutathione peroxidase (GSH-PX) activities both showed the lowest values at 39 DAH, which were 0.57 ± 0.11 U/mg and 3.35 ± 0.94 U/mg, respectively. The activity of amylase (AMS) and the content of malonaldehyde (MDA) increased, and the highest values were reached at 45 DAH (1.32 ± 0.41 U/mg) and 73 DAH (1.29 ± 0.43 nmoL/mg), respectively. Superoxide dismutase (SOD) and GSH-PX activities both showed a peak value at 7 DAH (126.58 ± 20.13 U/mg and 6.47 ± 1.86 U/mg). Overall, the changes in intestinal tissue, digestive enzymes, and antioxidant enzyme activities at 39 DAH of Brachymystax tsinlingensis are inseparable from different vegetative stages during the developmental period, and these results can provide a reference for the proliferation and cultivation of Brachymystax tsinlingensis resources.

Interfering Josephson diode effect in Ta2Pd3Te5 asymmetric edge interferometer.

Edge states in topological systems have attracted great interest due to their robustness and linear dispersions. Here a superconducting-proximitized edge interferometer is engineered on a topological insulator Ta2Pd3Te5 with asymmetric edges to realize the interfering Josephson diode effect (JDE), which hosts many advantages, such as the high efficiency as much as 73% at tiny applied magnetic fields with an ultra-low switching power around picowatt. As an important element to induce such JDE, the second-order harmonic in the current-phase relation is also experimentally confirmed by half-integer Shapiro steps. The interfering JDE is also accompanied by the antisymmetric second harmonic transport, which indicates the corresponding asymmetry in the interferometer, as well as the polarity of JDE. This edge interferometer offers an effective method to enhance the performance of JDE, and boosts great potential applications for future superconducting quantum devices.