Visible-light-enabled stereoselective synthesis of functionalized cyclohexylamine derivatives via [4 + 2] cycloadditions.

An unprecedented intermolecular [4 + 2] cycloaddition of benzocyclobutylamines with α-substituted vinylketones, enabled by photoredox catalysis, has been developed. The current method enables facile access to highly functionalized cyclohexylamine derivatives that were otherwise inaccessible, in moderate to good yields with excellent diastereoselectivities. This protocol has some excellent features, such as full atom economy, good functional-group compatibility, mild reaction conditions, and an overall redox-neutral process. Additionally, an asymmetric version of this cycloaddition was preliminarily investigated via the incorporation of a chiral phosphoric acid (CPA), and moderate to good enantioselectivity could be effectively realized with excellent diastereoselectivity. Synthetic applications were demonstrated via a scale-up experiment and elaborations to access amino alcohol and cyclobutene derivatives. Based on the results of control experiments, a reasonable reaction mechanism was proposed to elucidate the reaction pathway.

Restricted responses of AcMYB68 and AcERF74/75 enhanced waterlogging tolerance in kiwifruit.

Most of kiwifruit cultivars (e.g. Actinidia chinensis cv. Donghong, "DH") were sensitive to waterlogging, thus, waterlogging resistant rootstocks (e.g. Actinidia valvata Dunn, "Dunn") were widely used for kiwifruit industry. Those different species provided ideal materials to understand the waterlogging responses in kiwifruit. Compared to the weaken growth and root activities in "DH", "Dunn" maintained the relative high root activities under the prolonged waterlogging. Based on comparative analysis, transcript levels of pyruvate decarboxylase (PDCs) and alcohol dehydrogenase (ADHs) showed significantly difference between these two species. Both PDCs and ADHs had been significantly increased by waterlogging in "DH", while they were only limitedly triggered by 2 days stress and subsided during the prolonged waterlogging in "Dunn". Thus, 19 differentially expressed transcript factors (DETFs) had been isolated using weighted gene co-expression network analysis combined with transcriptomics and transcript levels of PDCs and ADHs in waterlogged "DH". Among these DETFs, dual luciferase and electrophoretic mobility shift assays indicated AcMYB68 could bind to and trigger the activity of AcPDC2 promoter. The stable over-expression of AcMYB68 significantly up-regulated the transcript levels of PDCs but inhibited the plant growth, especially the roots. Moreover, the enzyme activities of PDC in 35S::AcMYB68 were significantly enhanced during the waterlogging response than that in wild type plants. Most interestingly, comparative analysis indicated that the expression patterns of AcMYB68 and the previously characterized AcERF74/75 (the direct regulator on ADHs) either showed no responses (AcMYB68 and AcERF74) or very limited response (AcERF75) in "Dunn". Taken together, the restricted responses of AcMYB68 and AcERF74/75 in "Dunn" endow its waterlogging tolerance.

Oxidative stress mediated decrement of spinal endomorphin-2 contributes to lumbar disc herniation sciatica in rats.

Increasing evidence supported that oxidative stress induced by herniated lumbar disc played important role in the formation of lumbar disc herniation sciatica (LDHS), however, the neural mechanisms underlying LDHS need further clarification. Endomorphin-2 (EM2) is the endogenous ligand for mu-opioid receptor (MOR), and there is increasing evidence implicating the involvement of spinal EM2 in neuropathic pain. In this study, using an nucleus pulposus implantation induced LDHS rat model that displayed obvious mechanical allodynia, it was found that the expression of EM2 in dorsal root ganglion (DRG) and spinal cord was significantly decreased. It was further found that oxidative stress in DRG and spinal cord was significantly increased in LDHS rats, and the reduction of EM2 in DRG and spinal cord was determined by oxidative stress dominated increment of dipeptidylpeptidase IV activity. A systemic treatment with antioxidant could prevent the forming of mechanical allodynia in LDHS rats. In addition, MOR expression in DRG and spinal cord remained unchanged in LDHS rats. Intrathecal injection of MOR antagonist promoted pain behavior in LDHS rats, and the analgesic effect of intrathecal injection of EM2 was stronger than that of endomorphin-1 and morphine. Taken together, our findings suggest that oxidative stress mediated decrement of EM2 in DRG and spinal cord causes the loss of endogenous analgesic effects and enhances the pain sensation of LDHS.

Iridium-catalyzed asymmetric cascade dearomative allylation/acyl transfer rearrangement: access to chiral N-substituted 2-pyridones.

Iridium-catalyzed dearomative allylation/acyl transfer rearrangement has been developed using easily available 2-pyridinyl benzoates and vinyl ethylene carbonate. This protocol enabled the expedient synthesis of a variety of chiral N-substituted 2-pyridones in good to high yields with excellent enantioselectivity. It has the advantages of high atom economy, wide substrate scope, gram-scale synthesis, and versatile synthetic transformations.

Modular access to chiral bridged piperidine-γ-butyrolactones via catalytic asymmetric allylation/aza-Prins cyclization/lactonization sequences.

Chiral functionalized piperidine and lactone heterocycles are widely spread in natural products and drug candidates with promising pharmacological properties. However, there remains no general asymmetric methodologies that enable rapid assemble both critical biologically important units into one three-dimensional chiral molecule. Herein, we describe a straightforward relay strategy for the construction of enantioenriched bridged piperidine-γ-butyrolactone skeletons incorporating three skipped stereocenters via asymmetric allylic alkylation and aza-Prins cyclization/lactonization sequences. The excellent enantioselectivity control in asymmetric allylation with the simplest allylic precursor is enabled by the synergistic Cu/Ir-catalyzed protocol; the success of aza-Prins cyclization/lactonization can be attributed to the pivotal role of the ester substituent, which acts as a preferential intramolecular nucleophile to terminate the aza-Prins intermediacy of piperid-4-yl cation species. The resulting chiral piperidine-γ-butyrolactone bridged-heterocyclic products show impressive preliminary biological activities against a panel of cancer cell lines.

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides.

An atom- and step-economical and redox-neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2-amino-5-hydroxyvaleric acid esters or peptides bearing 1,4-non-adjacent stereogenic centers have been prepared in high yields with excellent enantio- and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α-epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.

An unprecedented pair of Z/E isomeric pyridinium compound from the aqueous extract of Aspongopus chinensis Dallas / 药学学报

A novel pair of Z/E isomeric compounds with unprecedented carbon skeleton were isolated from an aqueous extract of Aspongopus chinensis Dallas by macroporous resin, silica gel, and semi-preparative high performance liquid chromatography (HPLC). Their structures were identified by nuclear magnetic resonance (NMR), Infrared spectroscopy (IR), Mass spectroscopy (MS) and other spectroscopic methods as (Z)-3-(but-1″-en-1″-yl)-1-(2ʹ-hydroxyethyl)-4-propylpyridin-1-ium, namely aspongopyridine A, and (E)-3-(but-1″-en-1″-yl)-1-(2ʹ-hydroxyethyl)-4-propylpyridin-1-ium, namely aspongopyridine B, respectively. Besides, the anti-inflammatory, anti-tumor, acetylcholinesterase inhibition and butyrylcholinesterase inhibition activities of the compounds 1 and 2 were evaluated. The results showed that compounds 1 and 2 have no anti-inflammatory, anti-tumor, and butyrylcholinesterase inhibition activities instead of weak acetylcholinesterase inhibition activity.

Effectiveness and the nomogram of small incision lenticule extraction in the correction of myopic anisometropia in adults.

AIM: To evaluate the safety, effectiveness, and predictability of small incision lenticule extraction (SMILE) for the treatment of anisometropia, and to explore the personalized design scheme of SMILE in correcting adult myopia anisometropia based on the nomogram. METHODS: It's a prospective cohort study. Patients with anisometropic myopia of refractive difference ≥ 2.0 diopters (D) who underwent SMILE between September 2020 and March 2021 were enrolled. Clinical features and visual function were assessed preoperatively and at 1wk, 1, 3, and 6mo after the operation. The examination included tests for uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refractive errors, effectiveness index (preoperative CDVA/postoperative UDVA), safety index (postoperative CDVA/preoperative CDVA), nomogram and stereoscopic function. Paired t-test, Wilcoxon signed-rank test and repeated-measures analyses of variance were used for continuous variables, and Pearson Chi-squared test was used for categorical variables. RESULTS: The study involved 45 consecutive patients (average age: 25.0±6.9y; 82 out of 90 eyes underwent SMILE, while 8 eyes were not operated). The average preoperative spherical equivalent (SE) was -4.74±0.22 D. Six months after surgery, the effectiveness index was 1.05±0.12, and the safety index was 1.09±0.11. Seventy eyes (85.4%) exhibited SE correction error within ±0.5 D. The percentage of eyes with Titmus stereoscopic function equal to or less than 200″ significantly increased from 55.6% preoperatively to 88.9% postoperatively (P<0.05). There was statistically significant difference between higher myopia eyes and contralateral eyes in average nomogram value/spherical refraction ratio. CONCLUSION: SMILE is safe, effective and predictable in correcting myopic anisometropia, and it improves stereoscopic visual function of anisometropia patients. The precise and individualized design of the nomogram is a vital element to ensure the balance of both eyes after SMILE.

Organocatalytic atroposelective synthesis of axially chiral N,N'-pyrrolylindoles via de novo indole formation.

The first organocatalytic atroposelective synthesis of axially chiral N,N'-pyrrolylindoles based on o-alkynylanilines was successfully established via de novo indole formation catalyzed by chiral phosphoric acid (CPA). This new synthetic strategy introduced CPA-catalyzed asymmetric 5-endo-dig cyclization of new well-designed o-alkynylanilines containing a pyrrolyl unit, resulting in a wide range of axially chiral N,N'-pyrrolylindoles in high yields with exclusive regioselectivity and excellent enantioselectivity (up to 99% yield, >20 : 1 rr, 95 : 5 er). Considering the potential biological significance of N-N atropisomers, preliminary biological activity studies were performed and revealed that these structurally important N,N'-pyrrolylindoles had a low IC50 value with promising impressive cytotoxicity against several kinds of cancer cell lines. DFT studies reveal that the N-nucleophilic cyclization mediated by CPA is the rate- and stereo-determining step, in which ligand-substrate dispersion interactions facilitate the axial chirality of the target products.

Cascade NH3 Oxidation and N2O Decomposition via Bifunctional Co and Cu Catalysts.

The selective catalytic oxidation of NH3 (NH3-SCO) to N2 is an important reaction for the treatment of diesel engine exhaust. Co3O4 has the highest activity among non-noble metals but suffers from N2O release. Such N2O emissions have recently been regulated due to having a 300× higher greenhouse gas effect than CO2. Here, we design CuO-supported Co3O4 as a cascade catalyst for the selective oxidation of NH3 to N2. The NH3-SCO reaction on CuO-Co3O4 follows a de-N2O pathway. Co3O4 activates gaseous oxygen to form N2O. The high redox property of the CuO-Co3O4 interface promotes the breaking of the N-O bond in N2O to form N2. The addition of CuO-Co3O4 to the Pt-Al2O3 catalyst reduces the full NH3 conversion temperature by 50 K and improves the N2 selectivity by 20%. These findings provide a promising strategy for reducing N2O emissions and will contribute to the rational design and development of non-noble metal catalysts.

Boosting reactivity of water-gas shift reaction by synergistic function over CeO2-x/CoO1-x/Co dual interfacial structures.

Dual-interfacial structure within catalysts is capable of mitigating the detrimentally completive adsorption during the catalysis process, but its construction strategy and mechanism understanding remain vastly lacking. Here, a highly active dual-interfaces of CeO2-x/CoO1-x/Co is constructed using the pronounced interfacial interaction from surrounding small CeO2-x islets, which shows high activity in catalyzing the water-gas shift reaction. Kinetic evidence and in-situ characterization results revealed that CeO2-x modulates the oxidized state of Co species and consequently generates the dual active CeO2-x/CoO1-x/Co interface during the WGS reaction. A synergistic redox mechanism comprised of independent contribution from dual functional interfaces, including CeO2-x/CoO1-x and CoO1-x/Co, is authenticated by experimental and theoretical results, where the CeO2-x/CoO1-x interface alleviates the CO poison effect, and the CoO1-x/Co interface promotes the H2 formation. The results may provide guidance for fabricating dual-interfacial structures within catalysts and shed light on the mechanism over multi-component catalyst systems.

Electron-rich benzofulvenes as effective dipolarophiles in copper(i)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides.

A series of benzofulvenes without any electron-withdrawing substituents were employed as 2π-type dipolarophiles for the first time to participate in Cu(i)-catalyzed asymmetric 1,3-dipolar cycloaddition (1,3-DC) reactions of azomethine ylides. An intrinsic non-benzenoid aromatic characteristic from benzofulvenes serves as a key driving force for activation of the electron-rich benzofulvenes. Utilizing the current methodology, a wide range of multi-substituted chiral spiro-pyrrolidine derivatives containing two contiguous all-carbon quaternary centers were formed in good yield with exclusive chemo-/regioselectivity and high to excellent stereoselectivity. Computational mechanistic studies elucidate the origin of the stereochemical outcome and the chemoselectivity, in which the thermostability of these cycloaddition products is the major factor.

Effects of dietary supplementation with a carvacrol-cinnamaldehyde-thymol blend on growth performance and intestinal health of nursery pigs.

BACKGROUND: Stress, herd transfer, and food changes experienced by nursery and fattening pigs can lead to reduced performance, reduced digestion and absorption, and impaired intestinal health. Given the role of essential oils in relieving stress and improving animal welfare, we hypothesized that essential oils may improve pig performance via promoting gut health and gut homeostasis laid by EOs supplementation during nursery continuously impacts performance in fattening pigs. RESULTS: A total of 100 piglets (Landrace × Large White; weighted 8.08 ± 0.34 kg, weaned at d 28) were randomly selected and divided into 2 treatments: (1) basal diet (Con); (2) basal diet supplement with 0.1% complex essential oils (CEO). The experiment period was 42 days. Then weaned piglets' growth performance and indications of intestinal health were assessed. Compared to the Con group, dietary supplemented CEO enhanced BW at 14 d (P < 0.05), and increased ADG during 1 ~ 14 d and 1 ~ 42 d (P < 0.05). Furthermore, CEO group had lower FCR during 1 ~ 42 d (P < 0.05). The CEO group also showed higher VH and VH:CD in duodenum and ileum (P < 0.05). Additionally, dietary CEO supplementation improved gut barrier function, as manifested by increased the mRNA expression of tight-junction protein and decreased serum DAO, ET and D-LA levels (P < 0.05). Finally, CEO supplementation alleviated gut inflammation, increased the activity of digestive enzymes. Importantly, piglets supplemented with CEOs during nursery also had better performance during fattening, suggesting that the establishment of intestinal health will also continuously affect subsequent digestion and absorption capacity. In short, dietary supplemented CEO improved performance and gut health via modulating increased intestine absorptive area, barrier integrity, digestive enzyme activity, and attenuating intestine inflammation. Meanwhile, essential oil supplementation during the nursery period also had a favorable effect on the performance of growing pigs. CONCLUSIONS: Therefore, the strategy of adding CEO to pig diets as a growth promoter and enhancing intestinal health is feasible.

Comprehensive analysis and molecular map of Hippo signaling pathway in lower grade glioma: the perspective toward immune microenvironment and prognosis.

Background: The activation of YAP/TAZ transcriptional co-activators, downstream effectors of the Hippo/YAP pathway, is commonly observed in human cancers, promoting tumor growth and invasion. The aim of this study was to use machine learning models and molecular map based on the Hippo/YAP pathway to explore the prognosis, immune microenvironment and therapeutic regimen of patients with lower grade glioma (LGG). Methods: SW1783 and SW1088 cell lines were used as in vitro models for LGG, and the cell viability of the XMU-MP-1 (a small molecule inhibitor of the Hippo signaling pathway) treated group was evaluated using a Cell Counting Kit-8 (CCK-8). Univariate Cox analysis on 19 Hippo/YAP pathway related genes (HPRGs) was performed to identify 16 HPRGs that exhibited significant prognostic value in meta cohort. Consensus clustering algorithm was used to classify the meta cohort into three molecular subtypes associated with Hippo/YAP Pathway activation profiles. The Hippo/YAP pathway's potential for guiding therapeutic interventions was also investigated by evaluating the efficacy of small molecule inhibitors. Finally, a composite machine learning models was used to predict individual patients' survival risk profiles and the Hippo/YAP pathway status. Results: The findings showed that XMU-MP-1 significantly enhanced the proliferation of LGG cells. Different Hippo/YAP Pathway activation profiles were associated with different prognostic and clinical features. The immune scores of subtype B were dominated by MDSC and Treg cells, which are known to have immunosuppressive effects. Gene Set Variation Analysis (GSVA) indicated that subtypes B with a poor prognosis exhibited decreased propanoate metabolic activity and suppressed Hippo pathway signaling. Subtype B had the lowest IC50 value, indicating sensitivity to drugs that target the Hippo/YAP pathway. Finally, the random forest tree model predicted the Hippo/YAP pathway status in patients with different survival risk profiles. Conclusions: This study demonstrates the significance of the Hippo/YAP pathway in predicting the prognosis of patients with LGG. The different Hippo/YAP Pathway activation profiles associated with different prognostic and clinical features suggest the potential for personalized treatments.

Enantio- and diastereodivergent synthesis of fused indolizines enabled by synergistic Cu/Ir catalysis.

Highly diastereo-/enantioselective assembly of 2,3-fused indolizine derivatives could be easily available through a cascade allylation/Friedel-Crafts type reaction enabled by a synergistic Cu/Ir catalysis. This designed protocol provides an unprecedented and facile route to enantioenriched indolizines bearing three stereogenic centers in moderate to high yields with excellent stereoselective control, which also featured broad substrate generality. Remarkably, four stereoisomers of the 2,3-fused indolizine products could be efficiently constructed in a predictable manner through the pairwise combination of copper and iridium catalysts. The synthetic utility of this method was readily elaborated by a gram-scale reaction, and synthetic transformations to other important chiral indolizine derivatives. Quantum mechanical explorations constructed a plausible synergetic catalytic cycle, revealed the origins of stereodivergence, and rationalized the protonation-stimulated stereoselective Friedel-Crafts type cyclization to form the indolizine products.

In Vitro Hypoglycemic Diterpenoids from the Roots of Croton yunnanensis.

Fifteen compounds including nine new diterpenes were isolated from the roots of Croton yunnanensis. By HRESIMS, NMR, ECD data, and X-ray diffraction analysis, the new compounds were characterized as eight neo-clerodane diterpenes (compounds 1-8) and one 15,16-dinor-ent-pimarane diterpene (9). All diterpenes were assayed for their hypoglycemic activities. Compounds 1-4, 6, 7, and 10 promoted glucose uptake activity in insulin-resistant 3T3-L1 adipocytes. Compounds 1 and 6 showed insulin sensitizing activity, potentiating conspicuously their glucose uptake activity at a concentration of 20 µM when treated synergistically with low-concentration insulin at 1 nM.

Enantio- and Diastereoselective De Novo Synthesis of 3-Substituted Proline Derivatives via Cooperative Photoredox/Brønsted Acid Catalysis and Epimerization.

Herein, a novel strategy for the catalytic asymmetric synthesis of enantioenriched 3-cis- and 3-trans-substituted prolines has been successfully established via an unprecedented cascade radical addition/cyclization enabled by synergistic photoredox/Brønsted acid catalysis and subsequent base-assisted epimerization. The current protocol provides a unique de novo access to all four stereoisomers of 3-substituted prolines which are not readily achieved via currently established methods. This methodology could be further extended to the asymmetric synthesis of the full complement of stereoisomers of 3-substituted pipecolinic acids.

Promoting Molecular Exchange on Rare-Earth Oxycarbonate Surfaces to Catalyze the Water-Gas Shift Reaction.

It is highly desirable to fabricate an accessible catalyst surface that can efficiently activate reactants and desorb products to promote the local surface reaction equilibrium in heterogeneous catalysis. Herein, rare-earth oxycarbonates (Ln2O2CO3, where Ln = La and Sm), which have molecular-exchangeable (H2O and CO2) surface structures according to the ordered layered arrangement of Ln2O22+ and CO32- ions, are unearthed. On this basis, a series of Ln2O2CO3-supported Cu catalysts are prepared through the deposition precipitation method, which provides excellent catalytic activity and stability for the water-gas shift (WGS) reaction. Density functional theory calculations combined with systematic experimental characterizations verify that H2O spontaneously dissociates on the surface of Ln2O2CO3 to form hydroxyl by eliminating the carbonate through the release of CO2. This interchange efficiently promotes the WGS reaction equilibrium shift on the local surface and prevents the carbonate accumulation from hindering the active sites. The discovery of the unique layered structure provides a so-called "self-cleaning" active surface for the WGS reaction and opens new perspectives about the application of rare-earth oxycarbonate nanomaterials in C1 chemistry.

Cholesterol paradox in the community-living old adults: is higher better?

OBJECTIVE: To evaluate the associations of lipid indicators and mortality in Beijing Elderly Comprehensive Health Cohort Study. METHODS: A prospective cohort was conducted based on Beijing Elderly Comprehensive Health Cohort Study with 4499 community older adults. After the baseline survey, the last follow-up was March 31, 2021 with an average 8.13 years of follow-up. Cox proportional hazard model was used to estimate the hazard ratios (HR) with 95% CI for cardiovascular disease (CVD) death and all-cause death in associations with baseline lipid indicators. RESULTS: A total of 4499 participants were recruited, and the mean levels of uric acid, body mass index, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, total cholesterol (TC), triglyceride, and low-density lipoprotein cholesterol (LDL-C) showed an upward trend with the increasing remnant cholesterol (RC) quarters (Ptrend < 0.05), while the downward trend was found in high-density lipoprotein cholesterol (HDL-C). During the total 36,596 person-years follow-up, the CVD mortality and all-cause mortality during an average 8.13 years of follow-up was 3.87% (95% CI: 3.30%-4.43%) and 14.83% (95% CI: 13.79%-15.86%) with 174 CVD death participants and 667 all-cause death participants. After adjusting for confounders, the higher level of TC (HR = 0.854, 95% CI: 0.730-0.997), LDL-C (HR = 0.817, 95% CI: 0.680-0.982) and HDL-C (HR = 0.443, 95% CI: 0.271-0.724) were associated with lower risk of CVD death, and the higher level of HDL-C (HR = 0.637, 95% CI: 0.501-0.810) were associated with lower risk of all-cause death. The higher level of RC (HR = 1.276, 95% CI: 1.010-1.613) increase the risk of CVD death. Compared with the normal lipid group, TC ≥ 6.20 mmol/L group and LDL-C ≥ 4.10 mmol/L group were no longer associated with lower risk of CVD death, while RC ≥ 0.80 mmol/L group was still associated with higher risk of CVD death. In normal lipid group, the higher levels of TC, LDL-C and HDL-C were related with lower CVD death. CONCLUSIONS: In community older adults, higher levels of TC and HDL-C were associated with lower CVD mortality in normal lipid reference range. Higher RC was associated with higher CVD mortality, which may be a better lipid indicator for estimating the CVD death risk in older adults.