Ab initio prediction of key parameters and magneto-structural correlation of tetracoordinated lanthanide single-ion magnets.

Single-molecule magnets (SMMs) have great potential in becoming revolutionary materials for micro-electronic devices. As one type of SMM and holding the performance record, lanthanide single-ion magnets (Ln-SIMs) stand at the forefront of the family. Lowering the coordination number (CN) is an important strategy to improve the performance of Ln-SIMs. Here, we report a theoretical study on a typical group of low-CN Ln-SIMs, i.e., tetracoordinated structures. Our results are consistent with those of experiments and they identify the same three best Ln-SIMs via a concise criterion, i.e., the co-existence of long τQTM and high Ueff. Compared to the record-holding dysprosocenium systems, the best SIMs here possess τQTM values that are shorter by several orders of magnitude and Ueff values that are lower by ∼1000 Kelvin (K). These are important reasons for the fact that the tetracoordinated Ln-SIMs are clearly inferior to dysprosocenium. A simple but intuitive crystal-field analysis leads to several routes to improve the performance of a given Ln-SIM, including compression of the axial bond length, widening the axial bond angle, elongation of the equatorial bond length and usage of weaker equatorial donor ligands. Although these routes are not brand-new, the most efficient option and the degree of improvement resulting from it are not known in advance. Consequently, a theoretical magneto-structural study, covering various routes, is carried out for the best Ln-SIM here and the most efficient route is shown to be widening the axial ∠O-Dy-O angle. The most optimistic case, having a ∠O-Dy-O of 180°, could have a τQTM (up to 103 s) and Ueff (∼2400 K) close to those of the record-holders. Subsequently, a blocking temperature (TB) of 64 K is predicted to be possible for it. A more practical case, with ∠O-Dy-O being 160°, could have a τQTM of up to 400 s, Ueff of around 2200 K and the possibility of a TB of 57 K. Although having an inherent precision limit, these predictions provide a guide to performance improvement, starting from an existing system.

Capsaicin functions as a selective degrader of STAT3 to enhance host resistance to viral infection.

Although STAT3 has been reported as a negative regulator of type I interferon (IFN) signaling, the effects of pharmacologically inhibiting STAT3 on innate antiviral immunity are not well known. Capsaicin, approved for the treatment of postherpetic neuralgia and diabetic peripheral nerve pain, is an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), with additional recognized potencies in anticancer, anti-inflammatory, and metabolic diseases. We investigated the effects of capsaicin on viral replication and innate antiviral immune response and discovered that capsaicin dose-dependently inhibited the replication of VSV, EMCV, and H1N1. In VSV-infected mice, pretreatment with capsaicin improved the survival rate and suppressed inflammatory responses accompanied by attenuated VSV replication in the liver, lung, and spleen. The inhibition of viral replication by capsaicin was independent of TRPV1 and occurred mainly at postviral entry steps. We further revealed that capsaicin directly bound to STAT3 protein and selectively promoted its lysosomal degradation. As a result, the negative regulation of STAT3 on the type I IFN response was attenuated, and host resistance to viral infection was enhanced. Our results suggest that capsaicin is a promising small-molecule drug candidate, and offer a feasible pharmacological strategy for strengthening host resistance to viral infection.

TRAF6 promotes osteogenesis in ADSCs through Raf-Erk-Merk-Hif1-a pathway.

Critical-size defects (CSDs) are challenging oral clinical issues that need to be solved. Adipose-derived mesenchymal stem cells (ADSCs) and gene therapy offer a new target to solve these issues. Consequently, ADSCs attract more and more attention because of advantages such as easy obtainability and no ethical concerns. TNF receptor-associated factor 6 (TRAF6) is a significant binding protein both of tumour necrosis factor superfamily and of the toll/interleukin-1 receptor superfamily. Evidence is accumulating that TRAF6 inhibited osteoclast formation and promoted the proliferation of multiple myeloma cell lines and bone resorption. Here, we reported that overexpression of TRAF6 enhanced the proliferation, migration and osteogenesis of ADSCs through Raf-Erk-Merk-Hif1a pathway. Cell sheet of ADSCs combined with TRAF6 accelerated the healing of CSDs. In a word, TRAF6 enhanced osteogenesis, migration and proliferation through Raf-Erk-Merk-Hif1a pathway.

Evaluating the causal relationship between human blood metabolites and gastroesophageal reflux disease.

BACKGROUND: Gastroesophageal reflux disease (GERD) affects approximately 13% of the global population. However, the pathogenesis of GERD has not been fully elucidated. The development of metabolomics as a branch of systems biology in recent years has opened up new avenues for the investigation of disease processes. As a powerful statistical tool, Mendelian randomization (MR) is widely used to explore the causal relationship between exposure and outcome. AIM: To analyze of the relationship between 486 blood metabolites and GERD. METHODS: Two-sample MR analysis was used to assess the causal relationship between blood metabolites and GERD. A genome-wide association study (GWAS) of 486 metabolites was the exposure, and two different GWAS datasets of GERD were used as endpoints for the base analysis and replication and meta-analysis. Bonferroni correction is used to determine causal correlation features (P < 1.03 × 10-4). The results were subjected to sensitivity analysis to assess heterogeneity and pleiotropy. Using the MR Steiger filtration method to detect whether there is a reverse causal relationship between metabolites and GERD. In addition, metabolic pathway analysis was conducted using the online database based MetaboAnalyst 5.0 software. RESULTS: In MR analysis, four blood metabolites are negatively correlated with GERD: Levulinate (4-oxovalerate), stearate (18:0), adrenate (22:4n6) and p-acetamidophenylglucuronide. However, we also found a positive correlation between four blood metabolites and GERD: Kynurenine, 1-linoleoylglycerophosphoethanolamine, butyrylcarnitine and guanosine. And bonferroni correction showed that butyrylcarnitine (odd ratio 1.10, 95% confidence interval: 1.05-1.16, P = 7.71 × 10-5) was the most reliable causal metabolite. In addition, one significant pathways, the "glycerophospholipid metabolism" pathway, can be involved in the pathogenesis of GERD. CONCLUSION: Our study found through the integration of genomics and metabolomics that butyrylcarnitine may be a potential biomarker for GERD, which will help further elucidate the pathogenesis of GERD and better guide its treatment. At the same time, this also contributes to early screening and prevention of GERD. However, the results of this study require further confirmation from both basic and clinical real-world studies.

Novel Bisamide Alkaloids Enantiomers from Pepper Roots (Piper nigrum L.) with Acetylcholinesterase Inhibitory and Anti-Neuroinflammatory Effects.

The roots of Piper nigrum L., a seasoning for cooking various types of broths, are renowned for their high nutritional content and potential medicinal benefits. In this study, nine pairs of novel cyclohexene-type bisamide alkaloids (1a/1b-9a/9b) were isolated from the pepper roots using molecular network analysis strategies. Their structures were determined by extensive spectroscopic data, electronic circular dichroism (ECD) calculations, and X-ray diffraction analyses. Using an intermolecular Diels-Alder reaction, a strategy for the synthesis of bisamide alkaloids from different monomeric amide alkaloids was developed. Furthermore, these compounds were chirally separated for the first time, and compounds 3a and 5a/5b showed significant anti-neuroinflammation effects in the models of lipopolysaccharide(LPS)-induced BV2 microglial cells. Meanwhile, compounds 6b and 7a displayed concentration-dependent inhibitory activities against acetylcholinesterase with IC50 values of 6.05 ± 1.10 and 3.81 ± 0.10 µM, respectively. These findings confirmed that these bisamide alkaloids could be applied in functional food formulations and pharmaceutical products as well as facilitate the further development and usage of pepper roots.

Oxidative Elimination and Reductive Addition of Thiol-Terminated Polymer Ligands to Metal Nanoparticles.

Metal nanoparticles (NPs) stabilized with thiol- (HS-) terminated polymers have applications in medicine, optoelectronics, and catalysis. It is assumed that upon exposure to oxidants or even air, these NPs lose colloidal stability, due to the oxidation of the HS-end-group and elimination of polymer ligands from the NP surface, however, this mechanism does not explain the unsuccessful recovery of the NP stability by adding fresh HS-terminated polymers. Here we propose the oxidation of the surface metal atoms as a mechanism for the oxidative elimination of polymer from the NP surface. Based on this mechanism, we reversed NP aggregation by reducing the oxidized metal surface and re-attaching HS-terminated polymer ligands. This mechanism is general for various metal NPs and different HS-terminated polymers. We show that oxidative elimination and reductive addition reactions can improve the colloidal stability of polymer-capped metal NPs and control their redox stimuli-responsive self-assembly.

Dopamine Functionalized Polyethylene Glycol for Improving Stability of Gold Nanoparticles against Reactive Oxygen Species in Serum.

PEGylation is the most effective antifouling method for the surface modification of gold nanoparticles (AuNPs). However, thiol-terminated polyethylene glycol (PEG) ligands tethered on the AuNPs are instable in serum and can detach from the AuNP surface, resulting in a significant reduce of their antifouling properties. Herein, it is reported that reactive oxygen species (ROS) is a major factor causing the detachment of PEG ligands from AuNP surfaces. By covalently backfilling dopamine-functionalized PEG on the AuNPs, the stability of PEG ligands on AuNP surface and the antifouling ability of AuNPs can be effectively improved. Tuning the balance between ROS and dopamine-functionalized PEG can be used as a new strategy to control the self-assembly of AuNPs and serum proteins.

Structure reassignment of two triterpenes with CASE algorithms and DFT chemical shift predictions.

Two triterpenes (14S,17S,20S,24R)-25-hydroxy-14,17-cyclo-20,24-epoxy-malabarican-3-one (CEM, 1a) and (14S,17S,20S,24R)-20,24,25-trihydroxy-14,17-cyclomalabarican-3-one (CM, 2a) with a cyclobutane ring were reported, which have the same NMR data as ocotillone (1b) and gardaubryone C (2b), respectively. An incorrect structure might be reported. Therefore, the structure reanalysis of these triterpenes was achieved by CASE algorithm and DFT chemical shift predictions, and the results showed that the structures of CEM and CM might be incorrect. To further verify the structure of compound 1, the HMBC, 1H-1H COSY and HSQC-TOCSY spectra were employed. Herein, we revised the structure of CEM and CM, and our study also showed that CASE algorithm and DFT chemical shift predictions can hold the post of effective structure reassignment method.

Association between HO­1 gene promoter polymorphisms and diseases (Review).

Heme oxygenase­1 (HO­1) is an inducible cytoprotective enzyme that degrades heme into free iron, carbon monoxide and biliverdin, which is then rapidly converted into bilirubin. These degradation products serve an important role in the regulation of inflammation, oxidative stress and apoptosis. While the expression level of HO­1 is typically low in most cells, it may be highly expressed when induced by a variety of stimulating factors, a process that contributes to the regulation of cell homeostasis. In the 5'­non­coding region of the HO­1 gene, there are two polymorphic sites, namely the (GT)n dinucleotide and T(­413)A single nucleotide polymorphism sites, which regulate the transcriptional activity of HO­1. These polymorphisms have been shown to be closely associated with the occurrence and progression of numerous diseases, including cardiovascular, pulmonary, liver and kidney, various types of cancer and viral diseases. The present article reviews the progress that has been made in research on the association between the two types of polymorphisms and these diseases, which is expected to provide novel strategies for the diagnosis, treatment and prognosis of various diseases.

Phototropin 1 Mediates High-Intensity Blue Light-Induced Chloroplast Accumulation Response in a Root Phototropism 2-Dependent Manner in Arabidopsis phot2 Mutant Plants.

Phototropins, namely, phototropin 1 (phot1) and phototropin 2 (phot2), mediate chloroplast movement to maximize photosynthetic efficiency and prevent photodamage in plants. Phot1 primarily functions in chloroplast accumulation process, whereas phot2 mediates both chloroplast avoidance and accumulation responses. The avoidance response of phot2-mediated chloroplasts under high-intensity blue light (HBL) limited the understanding of the function of phot1 in the chloroplast accumulation process at the HBL condition. In this study, we showed that the phot2 mutant exhibits a chloroplast accumulation response under HBL, which is defective when the root phototropism 2 (RPT2) gene is mutated in the phot2 background, mimicking the phenotype of the phot1 phot2 double mutant. A further analysis revealed that the expression of RPT2 was induced by HBL and the overexpression of RPT2 could partially enhance the chloroplast accumulation response under HBL. These results confirmed that RPT2 also participates in regulating the phot1-mediated chloroplast accumulation response under HBL. In contrast, RPT2 functions redundantly with neural retina leucine zipper (NRL) protein for chloroplast movement 1 (NCH1) under low-light irradiation. In addition, no chloroplast accumulation response was detected in the phot2 jac1 double mutant under HBL, which has been previously observed in phot2 rpt2 and phot1 phot2 double mutants. Taken together, our results indicated that phot1 mediates the HBL-induced chloroplast accumulation response in an RPT2-dependent manner and is also regulated by j-domain protein required for chloroplast accumulation response 1 (JAC1).

Solvent-Evaporation Induced and Mechanistic Entropy-Enthalpy-Balance Controlled Polymer Patch Formation on Nanoparticle Surfaces.

The formation of polymer-patch nanoparticles (PNPs) involves a condensation process of grafted chains on a nanoparticle (NP) surface, which is conventionally achieved via a fine-tuning of the solvent quality. However, such a critical solvent condition differs dramatically between polymers, and the formation mechanism of different patchy structures remains under debate. In this study, we demonstrate by a combined simulation and experimental study that such a surface-patterning process can be easily achieved via a simple solvent evaporation process, which creates a natural nonsolvent condition and is, in principle, adaptable for all polymers. More importantly, we find that patchy structures are controlled by a delicate balance between enthalpic interaction and the entropy penalty of grafted chains. A small variation of cohesive energy density can lead to a dramatic change in patch structure. This work offers a robust yet easy approach for the fabrication of PNPs and provides new insights into polymer segregation on spherical surfaces.

Polymers via Reversible Addition-Fragmentation Chain Transfer Polymerization with High Thiol End-Group Fidelity for Effective Grafting-To Gold Nanoparticles.

End-group fidelity is the most important property for end-functional polymers. Compared to other controlled living polymerization methods, reversible addition-fragmentation chain transfer (RAFT) polymerization often yields polymers with a lower end-group fidelity, which greatly affects their applications. Herein, we report a staged-thermal-initiation RAFT polymerization for the synthesis of polymers with high thiol end-group fidelity and their high efficiencies for grafting to various gold nanoparticles (GNPs). We experimentally prove that the decrease of end-group fidelity with their molecular weight is caused by the gradual decomposition of the initiator rather than the degradation of chain-transfer agents. We show that the staged-thermal-initiation RAFT polymerization is more effective for synthesis of polymers with high thiol end-group fidelity. The grafting-to assays for various GNPs illustrate the positive correlation between the end-group fidelity of polymers and grafting-to efficiency. This work highlights the prospects for synthesis of high end-group fidelity polymers and their application in the preparation of nanoparticles-polymer hybrid materials.

Quassinoids: Phytochemistry and antitumor prospect.

Quassinoids, originating from the oxidative degradation of tetracyclic tirucallane triterpene, are a diverse class of secondary metabolites identifying from nature mostly in Simaroubaceae family. The crucial pharmacological activities and structural complexity of quassinoids have long fascinated scientists due to their medicinal uses, infamous toxicity, and unique biosynthesis. In the past few decades, 482 quassinoids, assigned to 6 skeletons, have been isolated and identified from plants. The names, classes, molecular formula, and plant sources of these secondary metabolites are collated here. This review will be a detailed update of the naturally occurring quassinoids reported from the plant kingdom, providing an in-depth discussion of their diversity, antitumor activities, structure-activity relationship.

Structural insights into targeting of the colchicine binding site by ELR510444 and parbendazole to achieve rational drug design.

Microtubules consisting of α- and ß-tubulin heterodimers have proven to be an efficient drug target for cancer therapy. A broad range of agents, including ELR510444 and parbendazole, can bind to tubulin and interfere with microtubule assembly. ELR510444 and parbendazole are colchicine binding site inhibitors with antiproliferative activities. However, the lack of structural information on the tubulin-ELR510444/parbendazole complex has hindered the design and development of more potent drugs with similar scaffolds. Therefore, we report the crystal structures of tubulin complexed with ELR510444 at a resolution of 3.1 Å and with parbendazole at 2.4 Å. The structure of these complexes revealed the intermolecular interactions between the two colchicine binding site inhibitors and tubulin, thus providing a rationale for the development of novel benzsulfamide and benzimidazole derivatives targeting the colchicine binding site.

Two new guaiane sesquiterpenes from the fruiting bodies of Lactarius Deliciosus.

Two new guaiane sesquiterpenes, 7-(1-hydroxyethyl)-4-methyl-1-azulenecarboxaldehyde (1) and 7-isopropenyl-4-methyl-1-azulenecarboxylic acid (2), together with 5 known sesquiterpenes, were isolated from the fruiting bodies of Lactarius deliciosus. All structures were elucidated based on extensive spectroscopic methods, including 1 D and 2 D-NMR spectroscopy and high resolution mass spectrometry.

Triterpenes from Archidendron clypearia (Jack) I.C.N. with anti-ß-amyloid aggregation activity.

A new triterpene as well as five known compounds were isolated from the twigs and leaves of Archidendron clypearia (Jack) I.C.N. Their structures were established by comprehensive spectroscopic analyses including 1D, 2D NMR and HRESIMS data. The ability of all isolated compounds to inhibit ß-amyloid aggregation was investigated by a ThT-based fluorometric assay. Among them, compounds 3 (67.8%) and 6 (77.7%) exhibited higher inhibitory activity than the positive (48.0%). In addition, molecular dynamics and molecular docking have been utilized to predict the detailed binding interaction between ligands and Aß1-42.

A new dilignan from the twigs and leaves of Archidendron clypearia.

Previous work has shown that the lignans from the twigs and leaves of Archidendron clypearia (Jack) I.C.N. possess anti-ß-amyloid aggregation activity. Here we report a new dilignan, archidendronin A (1), along with one known sesquilignan (2). Their structures were determined by extensive spectroscopic methods, including UV, HRESIMS, 1 D and 2 D NMR data. The inhibitory activity on Aß1-42 aggregation was screened by ThT assay with curcumin as the positive control, and compounds 1 and 2 showed inhibition rate of 60.0% and 64.4% at 20 µM, respectively.[Formula: see text].

Fetal growth restriction mice are more likely to exhibit depression-like behaviors due to stress-induced loss of dopaminergic neurons in the VTA.

Fetal growth restriction (FGR) is a severe perinatal complication that can increase risk for mental illness. To investigate the mechanism by which FGR mice develop mental illness in adulthood, we established the FGR mouse model and the FGR mice did not display obvious depression-like behaviors, but after environmental stress exposure, FGR mice were more likely to exhibit depression-like behaviors than control mice. Moreover, FGR mice had significantly fewer dopaminergic neurons in the ventral tegmental area but no difference in serotoninergic neurons in the dorsal raphe. RNA-seq analysis showed that the downregulated genes in the midbrain of FGR mice were associated with many mental diseases and were especially involved in the regulation of NMDA-selective glutamate receptor (NMDAR) activity. Furthermore, the NMDAR antagonist memantine can relieve the stress-induced depression-like behaviors of FGR mice. In summary, our findings provide a theoretical basis for future research and treatment of FGR-related depression.

Lignans and neolignans with isovaleroyloxy moiety from Solanum lyratum Thunb.: Chiral resolution, configurational assignment and neuroprotective effects.

Eight pairs of enantiomeric lignans and neolignans including thirteen undescribed compounds, along with an undescribed meso compound, were isolated from the herbs of Solanum lyratum Thunb.(Solanaceae). Their structures and relative configurations were determined by extensive spectroscopic analyses of HRESIMS and nuclear magnetic resonance. The absolute configurations of the pure isomers were established based on the cooperative comparison between the experimental and calculated electronic circular dichroism (ECD) and optical rotation (OR). It is interesting that we obtained several naturally occurring stereoisomers with the identical gross structure possessing several stereogenic carbons from S. lyratum. Additionally, all isolates were assessed for neuroprotective effects toward human neuroblastoma SH-SY5Y cells injury induced by H2O2.

Phenolics from Archidendron clypearia (Jack) I.C.Nielsen protect SH-SY5Y cells against H2O2-induced oxidative stress.

Five undescribed phenolics named pithecellobiumin C-G, along with thirteen known ones were isolated from the twigs and leaves of Archidendron clypearia (Jack) I.C.Nielsen. Their structures were elucidated based on comprehensive spectroscopic analyses, combined with computer-assisted structure elucidation software (ACD/Structure Elucidator) and gauge-independent atomic orbitals (GIAO) NMR chemical shift calculations. The absolute configurations were determined by comparison of experimental and calculated specific rotation and ECD curves. These compounds were tested for their neuroprotective activities against H2O2-induced injury in human neuroblastoma SH-SY5Y cells by MTT assay. Pithecellobiumin C-E exhibited noticeable neuroprotective effect. Further pharmacological study demonstrated that they could prevent cell death through inhibiting the apoptosis induction. Flow cytometry assays also proved that these compounds could attenuate reactive oxygen species (ROS) level and mitochondrial dysfunction in SH-SY5Y cells.