Tuning the Pyridine Units in Vinylene-Linked Covalent Organic Frameworks Boosting 2e- Oxygen Reduction Reaction.

The N-doped carbon materials are supposed to be the efficient oxygen reduction reaction (ORR) catalysts with the undefined N-doped carbon ring groups. It is essential to well define the role of the nitrogen atoms of these carbon structures in active behavior. Even though, the covalent organic frameworks (COFs) with precise structures are well developed, but unable to exclude the polar linkages influence. This study presents a series of pyridine-containing COFs linked via nonpolar carbon-carbon double bonds (C = C). Their catalytic activity and selectivity for 2e- ORR are successfully modulated by locating the embedded pyridine nitrogen in the backbones through the linking modes of pyridine moieties within the frameworks. Such phenomena can be attributed to their different binding abilities toward O2, leading to the different binding strength of the intermediate OH* to the catalytic sites, also verified by the theoretical calculation. This work provides us a new insight to design high-efficiency ORR catalysts through the exact location of pyridine nitrogen.

Optical Information Transmission and Multimode Fluorescence Anticounterfeiting of Ca2-xMgxGe7O16:Mn2.

Multimode emission of Mn2+ for multimode fluorescence anticounterfeiting is achieved by cation site and interstitial occupancy in Ca2-xMgxGe7O16. The rings in Ca2-xMgxGe7O16 have a significant distortion for Mn2+ ions to enter the ring interstitials with a luminescence center at 665 nm, which is supported by XRD refinement results and first-principles calculations. The interstitial Mn2+ ion has good thermal stability with an activation energy of 0.36 eV. Surprisingly, these two luminescence centers, the cation site Mn and the interstitial Mn, have an obvious afterglow, and the disappearing afterglow will reappear by heating or irradiating with the 980 nm laser. The afterglow is significantly enhanced, as MnO2 is used as the manganese source, which is explained in detail by the thermal luminescence spectrum. Finally, Ca2-xMgxGe7O16:Mn2+ fully demonstrates its excellent prospects in fluorescent anticounterfeiting, information encryption, and optical information storage.

The discovery of a new potent FXR agonist based on natural product screening.

FXR agonistic activity screening was conducted based on natural product resources containing 38 structurally diverse sesquiterpenoids isolated from Xylopia vielana. Among them, 34 undescribed sesquiterpenoids with 5 different skeleton types were first characterized by HRESIMS, NMR data, ECD calculations and X-ray crystallographic analysis. High-content screening for FXR agonistic activity of these compounds demonstrated that 13 compounds could activate FXR. Then molecular docking results suggested that hydrogen bonding and hydrophobic interactions might contribute to the main interaction of active compounds with FXR. The preliminary structure-activity relationships (SARs) of those isolates were also discussed. The most potent compound 27 significantly elevated the transcriptional activity of the FXR target gene BSEP promoter (EC50 = 14.26 µM) by a dual-luciferase reporter assay. Western blotting indicated that compound 27 activated the FXR-associated pathway, thereby upregulating SHP and BSEP expression, and downregulating CYP7A1 and NTCP expression. We further revealed that FXR was the target protein of compound 27 through diverse target validation methods, including CETSA, SIP, and DARTS under the intervention of temperature, organic reagents and protease. Pharmacological in vivo experiments showed that compound 27 effectively ameliorated α-naphthyl isothiocyanate (ANIT)-induced cholestasis in mice, as evidenced by the ameliorative histopathology of the liver and the decrease in biochemical markers: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), and total bile acid (TBA). This work showed a practical strategy for the discovery of new FXR agonists from natural products and provided potential insights for sesquiterpenoids as FXR agonist lead compounds.

(±)-Hypernumqulins A-H: Eight pairs of unexpected [2+2] cycloaddition sesquiterpenoid alkaloid with 6/6/6/4/10 ring system from Hypericum monogynum L.

(±)-Hypernumqulins A-H (1-8), eight pairs of enantiomeric quinoline alkaloids fused with an isopentenyl and a germacrane-type sesquiterpenoid, featuring an unprecedented skeleton with 6/6/6/4/10 ring system, were isolated from Hypericum monogynum L. under the guidance of molecular networking strategy. Their structures including absolute configuration were elucidated by NMR spectroscopy analysis, X-ray crystallography and quantum chemical calculation. The proposed [2+2] cycloaddition may play a key biogenic step in building the unexpected skeleton. Most of the isolates exhibited cytotoxicity with IC50 values ranging from 2.82 ± 0.03 to 45.25 ± 1.26 µM against MCF-7, A549 or SGC7901 cells. Furthermore, compounds (±)-1 and (-)-1 could induce apoptosis by upregulating the protein expression level of Bax and downregulating of Bcl-2 in MCF-7 cells. These findings provided the first example of germacrane sesquiterpene quinoline alkaloids, and supported the possibilities for the development of new anti-tumor agents.

The Alterations in the Brain Corresponding to Low Back Pain: Recent Insights and Advances.

Low back pain (LBP) is a leading cause of global disabilities. Numerous molecular, cellular, and anatomical factors are implicated in LBP. Current issues regarding neurologic alterations in LBP have focused on the reorganization of peripheral nerve and spinal cord, but neural mechanisms of exactly what LBP impacts on the brain required further researches. Based on existing clinical studies that chronic pain problems were accompanying alterations in brain structures and functions, researchers proposed logical conjectures that similar alterations occur in LBP patients as well. With recent extensive studies carried out using noninvasive neuroimaging technique, increasing number of abnormalities and alterations has been identified. Here, we reviewed brain alterations including white matters, grey matters, and neural circuits between brain areas, which are involved in chronic LBP. Moreover, brain structural and functional connectivity abnormalities are correlated to the happening and transition of LBP. The negative emotions related to back pain indicate possible alterations in emotional brain regions. Thus, the aim of this review is to summarize current findings on the alterations corresponding to LBP in the brain. It will not only further our understanding of etiology of LBP and understanding of negative emotions accompanying with back pain but also provide ideas and basis for new accesses to the diagnosis, treatment, and rehabilitation afterward based on integral medicine.

Pyridazine-Promoted Construction of Vinylene-Linked Covalent Organic Frameworks with Exceptional Capability of Stepwise Water Harvesting.

In this study, we successfully developed two novel vinylene-linked covalent organic frameworks (COFs) using 2-connected 3,6-dimethylpyridazine through Knoevenagel condensation. These COFs featured finely tailored micro-/nano-scale pore sizes, high surface areas and stable non-polar vinylene linkages. Finely resolved powder X-ray diffraction patterns demonstrated highly crystalline structures with a hexagonal lattice in the AA layer stacking. The resulting one-dimensional channels possess strong hydrogen-bond accepting sites arising from the decorated cis-azo/azine units with two pairs of fully exposed lone pair electrons, endowing the as-prepared COFs with exceptional water absorption properties. The g-DZPH-COF exhibited successive steep water uptake steps starting from low relative pressures (P/PSTA=0.1), with the remarkable water uptake capacity of 0.26 g/g at P/PSTA=0.2 (25 °C), which is the optimal value recorded among the reported COFs. Dynamic vapour sorption measurements revealed the fast kinetics of these COFs, even in the cluster formation process. Water uptake and release cycling tests demonstrated their outstanding hydrolytic stability, durability, and adsorption-desorption retention ability.

Mesoporous Vinylene-Linked Covalent Organic Frameworks with Heteroatom-Tuned Crystallinity and Photocatalytic Behaviors.

Owing to its prominent π-delocalization and stability, vinylene linkage holds great merits in the construction of covalent organic frameworks (COFs) with promising semiconducting properties. However, carbon-carbon double bond formation reaction always exhibits relatively low reversibility, unfavorable for the formation of high crystalline frameworks through self-error correction and assembling processes. In this work, we report a heteroatom-tuned strategy to build up a series of two-dimensional (2D) vinylene-linked COFs by Knoevenagel condensation of an electron-deficient methylthiazolyl-based monomer with different triformyl substituted (hetero-)aromatic derivatives. The resulting COFs show high-quality periodic mesoporous structures with high surface areas. Embedding heteroatoms into the backbones enables significantly improving their crystallinity, and finely tailoring their semiconducting structures. Upon visible light stimulation, one of the as-prepared COFs with donor-π-acceptor structure could deliver a nearly seven-fold increase in the catalytic activity of hydrogen generation as compared with the other two. Meanwhile, in combination with high crystallinity and the matched conduction band energy level, such kind of COFs can be able to selectively generate singlet oxygen and superoxide radicals in a high ratio of up to 30:1, allowing for catalyzing aerobic thioanisole oxidation in distinctly tunable activities through the substituent electronic effect of the substrates.

Hexatopic Vertex-Directed Approach to Vinylene-Linked Covalent Organic Frameworks with Heteroporous Topologies.

A D3h-symmetric hexatopic monomer was first prepared by attaching the three-fold ditopic moiety 2,6-dimethylpyridine to the meta-positions of a phenyl ring. It was further condensed at its six pyridylmethyl carbons with linear ditopic aromatic dialdehydes, resulting in two vinylene-linked COFs with heteroporous topologies, as revealed by powder X-ray diffraction (PXRD), nitrogen sorption, and pore-size distribution analyses, as well as transmission electron microscopy (TEM) image. The linear- and cross-conjugations, respectively, arising from the 2,6-linked pyridines and meta-linked phenylenes in the hexatopic nodes rendered the resultant COFs with well-patterned π-delocalization, allowing for efficiently catalyzing the bromination of aromatic derivatives with the pore-size-dependent conversion yields and regioselectivity under the irradiation of green light.

Combined pembrolizumab and bevacizumab therapy effectively inhibits non-small-cell lung cancer growth and prevents postoperative recurrence and metastasis in humanized mouse model.

Antibodies targeting the programmed cell death protein 1/programmed cell death ligand-1 (PD-1/PD-L1) pathway have dramatically changed the treatment landscape of advanced non-small cell lung cancer (NSCLC). However, combination approaches are required to extend this benefit beyond a subset of patients. In addition, it is of equal interest whether these combination therapy can be applied to neoadjuvant therapy of early-stage NSCLC. In this study, we hypothesized that combining immunotherapy with anti-angiogenic therapy may have a synergistic effect in local tumor control and neoadjuvant therapy. To this end, the effect of combination of bevacizumab and pembrolizumab in humanized mouse models was evaluated. Furthermore, we innovatively constructed a neoadjuvant mouse model that can simulate postoperative recurrence and metastasis of NSCLC to perform neoadjuvant study. Tumor growth and changes in the tumor vasculature, along with the frequency and phenotype of tumor-infiltrating lymphocytes, were examined. Additionally, in vivo imaging system (IVIS) was used to observe the effect of neoadjuvant therapy. Results showed that combination therapy could inhibited tumor growth by transforming tumor with low immunoreactivity into inflamed ('hot') tumor, as demonstrated by increased CD8+granzyme B+ cytotoxic T cell infiltration. Subsequent studies revealed that this process is mediated by vascular normalization and endothelial cell activation. IVIS results showed that neoadjuvant therapy can effectively prevent postoperative recurrence and metastasis. Taken together, these preclinical studies demonstrated that the combination of bevacizumab and pembrolizumab had a synergistic effect in both advanced tumor therapy and neoadjuvant setting and therefore provide a theoretical basis for translating this basic research into clinical applications.

Schisanwilsonins H and I, two new dibenzocyclooctane lignans from the fruits of Schisandra wilsoniana.

Two new dibenzocyclooctane lignans, schisanwilsonins H (1) and I (2), together with eight known compounds gomisin J (3), wulignan A1 (4), gomisin S (5), tigloylgomisin P (6), gomisin O (7), (-)-gomisin K1 (8), rubschisantherin (9) and wuweizisu C (10) were isolated from the 95% ethanol extract of the fruits of Schisandra wilsoniana. 7 exhibited anti-HBV activity with potency against HBsAg and HBeAg secretion by 37.1% and 32.6%, respectively, at 50 µg/ml. 10 exhibited anti-HIV activity with EC50 and therapeutic index (TI) values of 2.10 µg/ml and 11.98, respectively.

Narrow-Pore Engineering of Vinylene-Linked Covalent Organic Frameworks with Weak Interaction-Triggered Multiple Responses.

Vinylene-linked covalent organic frameworks (COFs) are emerging as promising crystalline materials, but their narrow pore engineering is severely impeded by the weak reversibility of the carbon-carbon double bond formation reaction, which has led to less exploration of their ultramicroporous structures and properties. Herein, we developed a single aromatic ring-based tetratopic monomer, tetramethylpyrazine, which undergoes a smooth Knoevenegal condensation at its four arylmethly carbon atoms with linear aromatic dialdehyde monomers upon the self-catalyzed activation of pyridine nitrogen-containing monomers in the presence of an organic anhydride. This has resulted in the formation of two vinylene-linked COFs, which both crystallized in orthorhombic lattices, and layered in AA stacking fashions along the vertical directions. They exhibit high surface areas and well-tailored ultramicropore sizes up to 0.5 nm. The unique cross-linking mode at two pairs of para-positions of each pyrazine unit through carbon-carbon double bonds afford them with π-extended conjugation over the in-plane backbones and substantial semiconducting characters. The resultant COFs can be well-dispersed in water to form stable sub-microparticles with negative charges (zeta potentials: ca. -30 mV), and exhibiting tunable aggregation behaviors through protonation/deprotonation. As a consequence, they exhibit pore-size-dependent colorimetric responses to various anions with different pKa values in high selectivity.

Synthesis of Vinylene-Linked Covalent Organic Frameworks by Monomer Self-Catalyzed Activation of Knoevenagel Condensation.

Reticular chemistry based on thermodynamically controlled linking modes and numerous organic building blocks has constituted versatile crystalline frameworks in molecular-level precision. However, vinylene-linked covalent organic frameworks (COFs) are still quite far from flexible tailoring in either their structures or topologies, due to the lack of monomers with sufficient activities. Herein, we establish a strategy to synthesize vinylene-linked COFs via Knoevenagel condensation between a tetratopic monomer 2,2',6,6'-tetramethyl-4,4'-bipyridine (TMBP) and linear aromatic dialdehydes in a mixed solvent of benzoic anhydride and benzoic acid. Mechanistic investigation suggests that the condensation was promoted by a pyridine self-catalyzed benzoylation upon the cleavage of benzoic anhydride solvent molecules. The layered structures of the resultant COFs are highly crystallized into orthorhombic lattices with vertically aligned AA stacking modes, delivering high surface areas up to 1560 m2 g-1. The π-extended conjugated skeletons comprising para-bipyridyl units and vinylene linkages endow these COFs with substantial semiconducting properties, releasing visible-light-stimulated catalytic activity in water-splitting hydrogen evolution with a rate as high as 3230 µmol g-1 h-1.

Multi-Strategy Architecture of High-Efficiency Electrocatalysts for Underwater Zn-H2 O2 Batteries with Superior Power Density of 442 mW cm-2.

A facile multistage regulated strategy is reported to synthesize ZnCo-NC based carbon nanotubes including DMEA induced crystallization, Zn ion activation, and magnetic control growth of carbon nanotubes. Uniform Co distribution and the modulation of Zn, and their catalytic properties are carefully investigated by X-ray absorption spectroscopy and X-ray photoelectron spectroscopy. The surface contents of pyridinic N for the oxygen-reduction reaction (ORR) and the surface contents of CoNx and high valence Co for the oxygen-evolution reaction (OER) can be significantly modulated by Zn content in precursors and the sintering temperature. Furthermore, the catalyst also contains high specific surface areas, high porosity, and high electrochemical active surfaces. Therefore, the ZnCo-NC based catalyst exhibits outstanding bifunctional electrocatalytic activities for ORR with a high Eonset (1.02 V) and E1/2 (0.91 V) and OER with low Ej=10 (1.56 V), better than Pt/C and RuO2 . Importantly, the ZnCo-NC based Zn-H2 O2 batteries achieve the superior power density of 442 mW cm-2 , much higher than 238 and 198 mW cm-2 of Zn-air batteries with ZnCo-NC based catalyst and Pt/C respectively. More importantly, the high-power Zn-H2 O2 batteries can work well in underwater conditions while Zn-air batteries are out of work.

Costunolide protects against alcohol-induced liver injury by regulating gut microbiota, oxidative stress and attenuating inflammation in vivo and in vitro.

Costunolide (cos) derived from the roots of Dolomiaea souliei (Franch.), which belongs to the Dolomiaea genus in the family Compositae, exert the anti-inebriation effect mainly by inhibiting the absorption of alcohol in the gastrointestinal tract. However, the protective effect of cos against alcohol-induced liver injury (ALI) remains obscure. The present study was aimed to evaluate the hepatoprotective effects of cos (silymarin was used as positive control) against ALI and its potential mechanisms. MTT was used to examine the effect of cos on the cell viability of L-02 cells. Plasma was separated from blood that used to test the levels of TNF-α, IL-6 and IL-12, and LPS while serum separated from blood which used to detect the level of ALT and AST. Liver tissues were obtained for histopathological examination and western blot analysis. Fresh mice feces samples were collected for the detection of bacterial composition. Cos exhibited protective effect against alcoholic-induced liver injury by regulating gut microbiota capacities (higher relative abundance of Firmicutes and Actinobacteria while lower in Bacteroidetes and Proteobacteria), adjusting oxidative stress (reduced the activities of MDA and ROS while promoted SOD, GSH and GSH-PX in L-02 cells) and attenuating inflammation (decreased the levels of ALT, AST, LPS, IL-6, IL-12 and TNF-α) via LPS-TLR4-NF-κB p65 signaling pathway, which might be an active therapeutic agent for treatment of ALI.

[Two new triterpeneoids from roots of Dolomiaea souliei].

The present study analyzed the chemical constituents in dried roots of Dolomiaea souliei. Chromatographic methods, such as normal-phase, and reversed-phase column chromatography, TLC, and preparative HPLC, were applied to separate and purify the petroleum ether extract of D. souliei. The structures of the purified constituents were identified by multiple spectroscopic methods including 1 D NMR, 2 D NMR, IR, UV, and HR-ESI-MS. Fourteen triterpenoids were obtained and identified as bauer-8-ene-3,11-dione-7α-ol(1), bauer-8-ene-3-one-7α,11α-diol(2), 3-oxo-11α-hydroxy-urs-12-ene(3), 3-oxour-12-ene-1ß,11α-diol(4), 3ß,11α-dihydroxy-urs-12-ene(5), taraxast-20-ene-3ß,30-diol(6), 28-hydroxy-3-oxo-12-ursene(7), 3ß-hydroxytaraxast-20-ene-30-aldehyde(8), urs-12-ene-2α,3ß,28-triol(9), 20-hydroxylupan-3-one(10), monogynol A(11), obtusalin(12), 3-oxo, 11α-hydroxy-olean-12-ene(13), and isocabralealactone(14). Among them, compounds 1 and 2 were new compounds. Compounds 4-10, 12, and 14 were isolated from this genus for the first time. Compounds 3 and 11 were obtained from D. souliei for the first time.

Heteroatom-Embedded Approach to Vinylene-Linked Covalent Organic Frameworks with Isoelectronic Structures for Photoredox Catalysis.

Embedding heteroatoms into the main backbones of polymeric materials has become an efficient tool for tailoring their structures and improving their properties. However, owing to comparatively harsh heteroatom-doping conditions, this has rarely been explored in covalent organic frameworks (COFs). Herein, upon aldol condensation of a trimethyl-substituted pyrylium salt with a tritopic aromatic aldehyde, a two-dimensional oxonium-embedded COF with vinylene linkages was achieved, which was further converted to a neutral pyridine-cored COF by in situ replacement of oxonium ions with nitrogen atoms under ammonia treatment. The two heteroatom-embedded COFs are conceptually isoelectronic with each other, featuring similar geometric structures but different electronic structures, rendering them capable of catalyzing the visible-light-promoted multi-component synthesis of tri-substituted pyridine derivatives with good recyclability.

2,4,6-Trimethylpyridine-Derived Vinylene-Linked Covalent Organic Frameworks for Confined Catalytic Esterification.

Knoevenagel condensation is a powerful tool for the construction of vinylene-linked covalent organic frameworks. Herein, we established a concise approach to vinylene-linked COFs by Knoevenagel condensation at the multi-methyl groups of a pyridine ring through in situ formation of an N-acyl pyridinium cation in the presence of various acylating reagents. Following this strategy, two vinylene-linked COFs were constructed using 2,4,6-trimethylpyridine and multi-aldehyde-substituted aromatic derivatives as monomers. The resultant COFs are highly crystalline and assembled into hexagonal lattices with specific surface areas as large as 1915 m2 g-1 (vs. 1972 m2 g-1 of the theoretical value). The stable and abundant pyridine-decorated regular nanochannels within the COFs allow for catalyzing the esterification of several pharmaceutical intermediates with distinct spatially confined selectivity and recyclability, representing an environmentally friendly catalytic organic transformation.

[A novel alkaloid from Corydalis tomentella].

The chemical constituents in the ethyl acetate extract of Corydalis tomentella was isolated and purified with normal and reversed phase silica gel column chromatography, Sephadex LH-20, MCI, and semi-preparative HPLC. The compound structures were identified based on spectroscopic experiments and reported papers. Finally, eighteen compounds(1-18) were obtained from C. tomentella, including 17 alkaloids and 1 terpenoid. Among them, compound 1(tomentellaine A) was a novel alkaloid. Compounds 2-5, 7-14, and 16-18 were isolated from this plant for the first time.

Synthesis of Ionic Vinylene-Linked Covalent Organic Frameworks through Quaternization-Activated Knoevenagel Condensation.

We developed a simple approach to synthesizing ionic vinylene-linked two-dimensional covalent organic frameworks (COFs) through a quaternization-promoted Knoevenagel condensation at three aromatic methyl carbon atoms of N-ethyl-2,4,6-trimethylpyridinium halide with multitopic aromatic aldehyde derivatives. The resultant COFs exhibited a honeycomb-like structure with high crystallinity and surface areas as large as 1343 m2 g-1 . The regular shape-persistent nanochannels and the positively charged polymeric frameworks allowed the COFs to be uniformly composited with linear polyethylene oxide and lithium salt, displaying ionic conductivity as high as 2.72×10-3  S cm-1 .

Musculoskeletal Pain during the Menopausal Transition: A Systematic Review and Meta-Analysis.

Musculoskeletal pain (MSP) is one of the most severe complaints in women undergoing menopause. The prevalence of MSP varied when taking the menopausal state and age factor into consideration. This study investigated the prevalence of MSP in perimenopausal women and its association with menopausal state. The MEDLINE, Embase, Web of Science, and PubMed databases were searched from inception to July 2020, and 16 studies were retrieved for the current meta-analysis. The primary outcome measure was the MSP Odds Ratio (OR). The estimated overall prevalence of MSP among perimenopausal women was 71% (4144 out of 5836, 95% confidence interval (CI): 64%-78%). Perimenopausal women demonstrated a higher risk for MSP than premenopausal ones (OR: 1.63, 95% CI: 1.35-1.96, P = 0.008, I 2 = 59.7%), but similar to that in postmenopausal ones (OR: 1.07, 95% CI: 0.95-1.20, P = 0.316, I 2 = 13.4%). The postmenopausal women were at a higher risk of moderate/severe MSP than the premenopausal ones (OR: 1.45, 95% CI: 1.21-1.75, P = 0.302, I 2 = 16.5%) or the perimenopausal ones (OR: 1.40, 95% CI: 1.09-1.79, P = 0.106, I 2 = 55.4%). In conclusion, the perimenopause is a state during which women are particularly predisposed to develop MSP. As to moderate to severe degrees of MSP, the odds increase linearly with age, from premenopause to peri- and then to postmenopause.