A Multitask Approach to Learn Molecular Properties.

The endeavors to pursue a robust multitask model to resolve intertask correlations have lasted for many years. A multitask deep neural network, as the most widely used multitask framework, however, experiences several issues such as inconsistent performance improvement over the independent model benchmark. The research aims to introduce an alternative framework by using the problem transformation methods. We build our multitask models essentially based on the stacking of a base regressor and classifier, where the multitarget predictions are realized from an additional training stage on the expanded molecular feature space. The model architecture is implemented on the QM9, Alchemy, and Tox21 datasets, by using a variety of baseline machine learning techniques. The resultant multitask performance shows 1 to 10% enhancement of forecasting precision, with the task prediction accuracy being consistently improved over the independent single-target models. The proposed method demonstrates a notable superiority in tackling the intertarget dependence and, moreover, a great potential to simulate a wide range of molecular properties under the transformation framework.

Biological activity and health promoting effects of psoralidin.

Psoralidin, a prenylated coumestrol isolated from the seed of a traditional Chinese medicine Psoralea corylifolia L., has been demonstrated to exhibit anti-inflammatory, anti-cancer, anti-oxidative, estrogenic, neuroprotective, anti-bacterial, and anti-parasite activities. Due to prenylation, psoralidin exhibits stronger estrogenic activity with no obvious adverse effects and shows a close association with management of osteoporosis and some cancers. However, the hydrophobicity and low bioavailability of psoralidin limit its clinical application, although recent investigation has gained valuable data. This review will discuss the biological activities of psoralidin in health.

The Key Roles of GSK-3ß in Regulating Mitochondrial Activity.

Glycogen synthase kinase-3ß (GSK-3ß), a serine/threonine protein kinase, has been reported to show essential roles in molecular pathophysiology of many diseases. Mitochondrion is a dynamic organelle for producing cellular energy and determining cell fates. Stress-induced translocated GSK-3ß may interact with mitochondrial proteins, including PI3K-Akt, PGC-1α, HK II, PKCε, components of respiratory chain, and subunits of mPTP. Mitochondrial pool of GSK-3ß has been implicated in mediation of mitochondrial functions. GSK-3ß exhibits the regulatory effects on mitochondrial biogenesis, mitochondrial bioenergetics, mitochondrial permeability, mitochondrial motility, and mitochondrial apoptosis. The versatile functions of GSK-3ß might be associated with its wide range of substrates. Accumulative evidence demonstrates that GSK-3ß inactivation may be potentially developed as the promising strategy in management of many diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Intensive efforts have been made for exploring GSK-3ß inhibitors. Natural products provide us a great source for screening new lead compounds in inactivation of GSK-3ß. The key roles of GSK-3ß in mediation of mitochondrial functions are discussed in this review.

A functional polymorphism in ADAR1 gene affects HBsAg seroclearance both spontaneously and interferon induced.

BACKGROUND & AIMS: Our previous study found that rs4845384 in ADAR1 gene to be associated with HBeAg seroconversion. However, the effect of rs4845384 on HBsAg seroclearance is unknown. To assess the relationship between rs4845384 and HBsAg seroclearance. METHODS: Two independent case-control studies were conducted to test whether rs4845384 in ADAR1 was associated with HBsAg clearance. Reporter gene assays and quantitative PCR experiments were also carried out to verify the functional significances of this polymorphism. RESULTS AND CONCLUSIONS: The rs4845384 polymorphism was associated with HBsAg seroclearance both spontaneously (P = 0.028, OR = 1.36, 95% CI = 1.03-1.78) and interferon induced (P = 0.013, OR = 1.83, 95% CI = 1.13-2.96), in a total of 725 subjects. Luciferase assays showed that pGL3-rs4845384G constructs had higher expression level than pGL3-rs4845384A constructs, especially in HepG2. 2.15 cell line. Quantitative real-time RT-PCR showed that chronic hepatitis B (CHB) patients had lower ADAR1 mRNA level than healthy individuals. The AA carriers of rs4845384 had lower ADAR1 mRNA expression than non-AA carriers. The non-response susceptible allele rs4845384A was functional for regulation of ADAR1 expression, so as to influence HBsAg seroclearance of CHB patients.

Facile fabrication of porous CL-20 for low sensitivity high explosives.

A facile solvent/non-solvent co-crystallization technology is applied to fabricate porous CL-20, which exhibits interesting morphologies and low sensitivity with ß-cyclodextrin as a crystal modifier.

TMF inhibits extracellular matrix degradation by regulating the C/EBPß/ADAMTS5 signaling pathway in osteoarthritis.

Osteoarthritis (OA) is a chronic joint disease, characterized by degenerative destruction of articular cartilage. Chondrocytes, the unique cell type in cartilage, mediate the metabolism of extracellular matrix (ECM), which is mainly constituted by aggrecan and type II collagen. A disintegrin and metalloproteinase with thrombospondin 5 (ADAMTS5) is an aggrecanase responsible for the degradation of aggrecan in OA cartilage. CCAAT/enhancer binding protein ß (C/EBPß), a transcription factor in the C/EBP family, has been reported to mediate the expression of ADAMTS5. Our previous study showed that 5,7,3',4'-tetramethoxyflavone (TMF) could activate the Sirt1/FOXO3a signaling in OA chondrocytes. However, whether TMF protected against ECM degradation by down-regulating C/EBPß expression was unknown. In this study, we found that aggrecan expression was down-regulated, and ADAMTS5 expression was up-regulated. Knockdown of C/EBPß could up-regulate aggrecan expression and down-regulate ADAMTS5 expression in IL-1ß-treated C28/I2 cells. TMF could compromise the effects of C/EBPß on OA chondrocytes by activating the Sirt1/FOXO3a signaling. Conclusively, TMF exhibited protective activity against ECM degradation by mediating the Sirt1/FOXO3a/C/EBPß pathway in OA chondrocytes.

De novo creation of fluorescent molecules via adversarial generative modeling.

The development of AI for fluorescent materials design is technologically demanding due to the issue of accurately forecasting fluorescent properties. Besides the huge efforts made in predicting the photoluminescent properties of organic dyes in terms of machine learning techniques, this article aims to introduce an adversarial generation paradigm for the rational design of fluorescent molecules. Molecular SMILES is employed as the input of a GRU based autoencoder, where the encoding and decoding of the string information are processed. A generative adversarial network is applied on the latent space with a generator to generate samples to mimic the latent space, and a discriminator to distinguish samples from the latent space. It is found that the excited state property distributions of generated molecules fully match those of the original samples, with the molecular synthesizability being accessible as well. Further screening of the generated samples delivers a remarkable luminescence efficiency of molecules epitomized by the significant oscillator strength and charge transfer characteristics, demonstrating the great potential of the adversarial model in enriching the fluorescent library.

Efficient Adversarial Generation of Thermally Activated Delayed Fluorescence Molecules.

Adversarial generative models are becoming an essential tool in molecular design and discovery due to their efficiency in exploring the desired chemical space with the assistance of deep learning. In this article, we introduce an integrated framework by combining the modules of algorithmic synthesis, deep prediction, adversarial generation, and fine screening for the purpose of effective design of the thermally activated delayed fluorescence (TADF) molecules that can be used in the organic light-emitting diode devices. The retrosynthetic rules are employed to algorithmically synthesize the D-A complex based on the empirically defined donor and acceptor moieties, which is followed by the high-throughput labeling and prediction with the deep neural network. The new D-A molecules are subsequently generated via the adversarial autoencoder, with the excited-state property distributions perfectly matching those of the original samples. Fine screening of the generated molecules, including the spin-orbital coupling calculation and the excited-state optimization, is eventually implemented to select the qualified TADF candidates within the novel chemical space. Further investigation shows that the created structures fully mimic the original D-A samples by maintaining a significant charge transfer characteristic, a minimal adiabatic singlet-triplet gap, and a moderate spin-orbital coupling that are desirable for the delayed fluorescence.

7-Ketocholesterol Induces Oxiapoptophagy and Inhibits Osteogenic Differentiation in MC3T3-E1 Cells.

7-Ketocholesterol (7KC) is one of the oxysterols produced by the auto-oxidation of cholesterol during the dysregulation of cholesterol metabolism which has been implicated in the pathological development of osteoporosis (OP). Oxiapoptophagy involving oxidative stress, autophagy, and apoptosis can be induced by 7KC. However, whether 7KC produces negative effects on MC3T3-E1 cells by stimulating oxiapoptophagy is still unclear. In the current study, 7KC was found to significantly decrease the cell viability of MC3T3-E1 cells in a concentration-dependent manner. In addition, 7KC decreased ALP staining and mineralization and down-regulated the protein expression of OPN and RUNX2, inhibiting osteogenic differentiation. 7KC significantly stimulated oxidation and induced autophagy and apoptosis in the cultured MC3T3-E1 cells. Pretreatment with the anti-oxidant acetylcysteine (NAC) could effectively decrease NOX4 and MDA production, enhance SOD activity, ameliorate the expression of autophagy-related factors, decrease apoptotic protein expression, and increase ALP, OPN, and RUNX2 expression, compromising 7KC-induced oxiapoptophagy and osteogenic differentiation inhibition in MC3T3-E1 cells. In summary, 7KC may induce oxiapoptophagy and inhibit osteogenic differentiation in the pathological development of OP.

Geniposide ameliorated dexamethasone-induced endoplasmic reticulum stress and mitochondrial apoptosis in osteoblasts.

ETHNOPHARMACOLOGICAL RELEVANCE: Eucommia ulmoides Oliver has been traditionally used for treatment of various diseases, including osteoporosis, knee pain, and paralysis. The extract of Eucommia ulmoides has been reported to stimulate the bone formation and suppress the bone resorption, leading to protection against osteoporosis (OP). Geniposide (GEN) has been considered as one of the effective compounds responsible for the therapeutic efficacy of Eucommia ulmoides against OP. AIM OF THE STUDY: To explore whether GEN protected against dexamethasone (DEX)-induced osteoporosis (OP) by activating NRF2 expression and inhibiting endoplasmic reticulum (ER) stress. MATERIALS AND METHODS: The DEX-induced rat OP models were duplicated. The pathological changes were examined by histological/immunohistochemical evaluation and micro-computed tomography (micro-CT) assessment. Apoptosis was detected by a flow cytometer. Mitochondrial Ca2+ concentrations and mitochondrial membrane potential were detected. Western blot assays were used to detect the protein expression. RESULTS: GEN effectively reversed DEX-induced pathological changes of trabecular bone in rats. In addition, the DEX-increased expression of ATF4/CHOP was also ameliorated. In MC3T3-E1 cells, DEX promoted endoplasmic reticulum (ER) stress and mitochondrial apoptosis. Inhibition of ER stress abolished the induction of apoptosis by DEX. Similarly, GEN significantly ameliorated DEX-induced mitochondrial apoptosis. The possible underlying mechanism might be associated with the pharmacological effects of GEN on activating the expression of NRF2 and alleviating ER stress in DEX-treated MC3T3-E1 cells. CONCLUSION: GEN ameliorated DEX-induced ER stress and mitochondrial apoptosis in osteoblasts.

Correction: Zheng et al. Geniposide Ameliorated Dexamethasone-Induced Cholesterol Accumulation in Osteoblasts by Mediating the GLP-1R/ABCA1 Axis. Cells 2021, 10, 3424.

The authors wish to make the following changes to their paper [...].

5,7,3',4'-tetramethoxyflavone ameliorates cholesterol dysregulation by mediating SIRT1/FOXO3a/ABCA1 signaling in osteoarthritis chondrocytes.

Dyslipidemia has been associated with the development of osteoarthritis. Our previous study found that 5,7,3',4'-tetramethoxyflavone (TMF) exhibited protective activities against the pathological changes of osteoarthritis. Aim: To investigate the roles of TMF in regulating ABCA1-mediated cholesterol metabolism. Methods: Knockdown and overexpression were employed to study gene functions. Protein-protein interaction was investigated by co-immunoprecipitation, and the subcellular locations of proteins were studied by immunofluorescence. Results: IL-1ß decreased ABCA1 expression and induced apoptosis. Therapeutically, TMF ameliorated the effects of IL-1ß. FOXO3a knockdown expression abrogated the effects of TMF, and FOXO3a overexpression increased ABCA1 expression by interacting with LXRα. TMF promoted FOXO3a nuclear translocation by activating SIRT1 expression. Conclusions: TMF ameliorates cholesterol dysregulation by increasing the expression of FOXO3a/LXRα/ABCA1 signaling through SIRT1 in C28/I2 cells.

Light-driven selective aerobic oxidation of (iso)quinoliniums and related heterocycles.

Selective C1-H/C4-H carbonylation of N-methylene iminium salts, catalyzed by visible-light photoredox and oxygen in the air, has been reported. A ruthenium complex acts as a chemical switch to conduct two different reaction pathways and to afford two different kinds of products. In the absence of the ruthenium complex, the Csp2-H bonds adjacent to the nitrogen atoms are oxidized to α-lactams by the N-methyleneiminium substrates themselves as photosensitizers. In the presence of the ruthenium complex, the oxidation reaction site of quinoliniums is switched to the C4 region, resulting in the formation of 4-quinolones. The use of two transformations directly introduces oxygen into the nitrogen heterocyclic skeletons under an air atmosphere.

Geniposide Ameliorated Dexamethasone-Induced Cholesterol Accumulation in Osteoblasts by Mediating the GLP-1R/ABCA1 Axis.

BACKGROUND: Overexposure to glucocorticoid (GC) produces various clinical complications, including osteoporosis (OP), dyslipidemia, and hypercholesterolemia. Geniposide (GEN) is a natural iridoid compound isolated from Eucommia ulmoides. Our previous study found that GEN could alleviate dexamethasone (DEX)-induced differentiation inhibition of MC3T3-E1 cells. However, whether GEN protected against Dex-induced cholesterol accumulation in osteoblasts was still unclear. METHODS: DEX was used to induce rat OP. Micro-CT data was obtained. The ALP activity and mineralization were determined by the staining assays, and the total intracellular cholesterol was determined by the ELISA kits. The protein expression was detected by western blot. RESULTS: GEN ameliorated Dex-induced micro-structure damages and cell differentiation inhibition in the bone trabecula in rats. In MC3T3-E1 cells, Dex enhanced the total intracellular cholesterol, which reduced the activity of cell proliferation and differentiation. Effectively, GEN decreased DEX-induced cholesterol accumulation, enhanced cell differentiation, and upregulated the expression of the GLP-1R/ABCA1 axis. In addition, inhibition of ABAC1 expression reversed the actions of GEN. Treatment with Exendin9-39, a GLP-1R inhibitor, could abrogate the protective activity of GEN. CONCLUSIONS: GEN ameliorated Dex-induced accumulation of cholesterol and inhibition of cell differentiation by mediating the GLP-1R/ABCA1 axis in MC3T3-E1 cells.

Ag-Si Co-doped TiO2 photocatalyst synthesized via a nonaqueous method.

Ag-Si/TiO2 photocatalysts were synthesized in a nonaqueous system at 140 degrees C, and then annealed at different temperatures. The obtained photocatalysts were characterized by XRD, TEM, BET, TG-DTA, XPS, as well as UV-vis DRS. The results showed that All Ag-Si/TiO2 held an anatase phase and high thermal stability and the phase transformation from anatase to rutile was retarded to about 900 degrees C. The Ag-Si/TiO2 particles were highly mono-dispersed and the particles size became smaller compared to TiO2. Additionally, UV-vis light absorption shifted to visible region after Ag doping. Si weaved into the matrix of TiO2, while Ag dispersed on the surface of TiO2 particles. The visible light photocatalytic activity was evaluated by Rhodamine B (RhB) degradation in an aqueous solution under visible light irradiation. It was found that the photccatalytic activities of the obtained Ag-Si/TiO2 samples were all higher than those of pure TiO2 and Ag/TiO2, reaching the maximum at the Ag and Si content of 0.5 mol% and 20.0 mol%, respectively. The enhanced visible photocatalytic activity may be attributed to the simultaneous effects of silver and silicon co-doping.

Oxysophocarpine protects airway epithelial cells against inflammation and apoptosis by inhibiting miR-155 expression.

Oxysophocarpine (OSC) has been documented for anti-inflammatory activity. However, the mechanisms of OSC in anti-inflammation are unclear. Aim: To investigate the protective effects of OSC on inflammation and apoptosis induced by lipopolysaccharide in NCI-H292 and human primary airway epithelial cells. Materials & methods: MTT and Annexin V-FITC/PI staining were used to detect cells viability. Inflammatory responses were determined by ELISA. The quantitative real-time PCR (qRT-PCR) and western blot were used to detect mRNA/miRNA and protein expressions respectively. Co-immunoprecipitation was investigated for protein interactions. Results & conclusion: miR-155 mimics significantly induced cell apoptosis, inflammatory responses and MAPK and NF-κB pathways. NDFIP1 was identified as the target of miR-155. OSC protected cells against apoptosis and inflammatory responses and compromised miR-155 activity by attenuating MAPK and NF-κB pathways.

Metabolism and pharmacological activities of the natural health-benefiting compound diosmin.

Diosmin is a famous natural flavonoid for treating chronic venous insufficiency and varicose veins. Recently, extensive study has indicated that diosmin possesses diverse pharmacological activities, including anti-inflammation, anti-oxidation, anti-diabetes, anti-cancer, anti-microorganism, liver protection, neuro-protection, cardiovascular protection, renoprotection, and retinal protection activities. Due to its low water solubility, diosmin is dramatically limited in clinical application. Expectedly, many potential strategies have been developed for improving its pharmacokinetic values and bioavailability. This health-benefiting compound has been explored as the major component of Daflon and micronized purified flavonoid fraction (MPFF), which have been used in clinics to improve micro-circulation. However, no specific drug targets for diosmin are reported, although some potential factors have been involved in screening, such as P-glycoprotein (P-gp), IKKß, acetylcholinesterase (AChE), and aldose reductase (AR). More investigations on the underlying mechanisms of diosmin in mediating cellular processes with high specificity is still needed.

The roles of post-translational modifications and coactivators of STAT6 signaling in tumor growth and progression.

Signal transducers and activators of transcription 6 (STAT6) are highly expressed in various tumors and associated with tumorigenesis, immunosuppression, proliferation, metastasis and poor prognosis in human cancers. In response to IL-4/13, STAT6 is phosphorylated, dimerizes and triggers transcriptional regulation after recruitment of coactivators to transcriptosome, such as CBP/p300, SRC-1, PARP-14 and PSF. Post-translational modifications, including phosphorylation, ubiquitination, ADP-ribosylation and acetylation, have been explored for molecular mechanisms of STAT6 in tumor development and management. STAT6 has been developed as a specific biomarker for distinguishing and diagnosing tumor phenotypes, although it is observed to be frequently mutated in metastatic tumors. In this article, we focus mainly on the structural characteristics of STAT6 and its role in tumor growth and progression.

Preparation and Characterization of Edible Dialdehyde Carboxymethyl Cellulose Crosslinked Feather Keratin Films for Food Packaging.

The development of edible films based on the natural biopolymer feather keratin (FK) from poultry feathers is of great interest to food packaging. Edible dialdehyde carboxymethyl cellulose (DCMC) crosslinked FK films plasticized with glycerol were prepared by a casting method. The effect of DCMC crosslinking on the microstructure, light transmission, aggregate structure, tensile properties, water resistance and water vapor barrier were investigated. The results indicated the formation of both covalent and hydrogen bonding between FK and DCMC to form amorphous FK/DCMC films with good UV-barrier properties and transmittance. However, with increasing DCMC content, a decrease in tensile strength of the FK films indicated that plasticization, induced by hydrophilic properties of the DCMC, partly offset the crosslinking effect. Reduction in the moisture content, solubility and water vapor permeability indicated that DCMC crosslinking slightly reduced the moisture sensitivity of the FK films. Thus, DCMC crosslinking increased the potential viability of the FK films for food packaging applications, offering a value-added product.

The Multifunctional Benefits of Naturally Occurring Delphinidin and Its Glycosides.

Delphinidin (Del) and its glycosides are water-soluble pigments, belonging to a subgroup of flavonoids. They are health-promoting candidates for pharmaceutical and nutraceutical uses, as indicated by exhibiting antioxidation, anti-inflammation, antimicroorganism, antidiabetes, antiobesity, cardiovascular protection, neuroprotection, and anticancer properties. Glycosylation modification of Del is associated with increased stability and reduced biological activity. Del and its glycosides can be the alternative inhibitors of CBRs, ERα/ß, EGFR, BCRP, and SGLT-1, and virtual docking indicates that the sugar moiety may not effectively interact with the active sites of the targets. Structure-based characteristics confer the multifunctional properties of Del and its glycosides. Because of their health-promoting effects, Del and its glycosides are promising and have been developed as potential pharmaceuticals. However, more investigation on the underlying mechanisms of Del and its glycosides in mediating cellular processes with high specificity are still needed. The research progression of Del and its glycosides over the last 10 years is comprehensively reviewed in this article.