Glutamatergic neurons in lateral hypothalamus play a vital role in acupuncture preconditioning to alleviate MIRI.

Myocardial ischemia-reperfusion injury (MIRI) has high morbidity and mortality worldwide. Increasing evidence has shown that electroacupuncture (EA) plays a critical role in alleviating MIRI. The aim of this study is to investigate whether glutamatergic neurons in the lateral hypothalamus (LH) have vital effect on MIRI as well as the underlying mechanism during the EA pretreatment. The MIRI model was established by ligating the left anterior descending (LAD) coronary artery for 30 min followed by reperfusion for 2 h. Chemogenetics, electrocardiogram (ECG) recording, ELISA, multichannel physiology recording, and immunofluorescence staining methods were combined to demonstrate that firing frequencies of neurons in the LH and expression of c-Fos decreased by EA pretreatment. Meanwhile, EA preconditioning significantly reduced the percentage of infarct size and the levels of cardiac troponin I (cTnI) and creatine kinase isoenzymes (CK-MB) were similar to inhibition of glutamatergic neurons in LH, also attenuated morphology of myocardial tissue was induced by MIRI. However, activation of glutamatergic neurons in LH weakened the above effects of EA pretreatment.NEW & NOTEWORTHY This study demonstrates that EA preconditioning can attenuate myocardial injury for MIRI, which is similar to inhibition of glutamatergic neurons in LH. However, chemical activation of glutamatergic neurons in LH attenuates the protective effect of EA pretreatment. These findings help better understand the mechanisms of EA to regulate cardiac function.

NUCKS1 promotes the progression of colorectal cancer via activating PI3K/AKT/mTOR signaling pathway.

Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) is highly expressed in a variety of malignant tumors and functions as an oncogene; however, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the function and regulatory mechanisms of NUCKS1 and potential therapeutic agents targeting NUCKS1 in CRC. We knocked down and overexpressed NUCKS1 in CRC cells and explored its effects in vitro and in vivo. Flow cytometry, CCK-8, Western blotting, colony formation, immunohistochemistry, in vivo tumorigenic, and transmission electron microscopy analyses were performed to determine the effects of NUCKS1 on CRC cell function. LY294002 was used to examine the mechanism of NUCKS1 expression in CRC cells. Potential therapeutic agents for NUCKS1-high CRC patients were analyzed using the CTRP and PRISM datasets, and the function of selected agents was determined by CCK-8 and Western blotting. We revealed that NUCKS1 was highly expressed in CRC tissues and clinically correlated with poor prognosis in CRC patients. NUCKS1 knockdown induces cell cycle arrest, inhibits CRC cell proliferation, and promotes apoptosis and autophagy. These results were reversed when NUCKS1 was overexpressed. Mechanistically, NUCKS1 exerts a cancer-promoting function by activating the PI3K/AKT/mTOR signaling pathway. This was reversed when LY294002 was used to inhibit the PI3K/AKT pathway. Furthermore, we determined that mitoxantrone exhibited high drug sensitivity in NUCKS1-overexpressing CRC cells. This work demonstrated NUCKS1 plays a crucial role in CRC progression via the PI3K/AKT/mTOR signaling pathway. Additionally, mitoxantrone may be a potential therapeutic agent for CRC treatment. Therefore, NUCKS1 represents a promising anti-tumor therapeutic target.

An Iridium/Aluminum Cooperative Strategy for the ß-C(sp3 )-H Borylation of Saturated Cyclic Amines.

Despite the widespread success in the functionalization of C(sp2 )-H bonds, the deliberate functionalization of C(sp3 )-H bonds in a highly site- and stereoselective manner remains a longstanding challenge. Herein, we report an iridium/aluminum cooperative catalytic system that enables the ß-selective C-H borylation of saturated cyclic amines and lactams. Furthermore, we have accomplished an enantioselective variant using binaphthol-derived chiral aluminum catalysts to forge C-B bonds with high levels of stereocontrol. Computational studies suggest that the formation of a Lewis pair with the substrates is crucial to lower the energy of the transition state for the rate-determining reductive elimination step.

Atropisomeric Phosphine Ligands Bearing C-N Axial Chirality: Applications in Enantioselective Suzuki-Miyaura Cross-Coupling Towards the Assembly of Tetra-ortho-Substituted Biaryls.

Biaryl phosphines bearing C(Ar)-C(Ar) axial chirality are commonly known and have been successfully applied in many asymmetric catalyses. Nevertheless, the development of a chiral ligand having an axially chiral C(Ar)-N backbone remains elusive due to its undesirable less restricted rotational barrier. In fact, it is highly attractive to overcome this challenge in ligand development as the incorporation of an N-donor component at the chiral axis is more favorable toward the transient metal coordination, and thus, a better outcome of stereocommunication is anticipated to the approaching substrates. Herein, we present a rational design of a new collection of chiral phosphines featuring a C-N axial chirality and their applications in enantioselective Suzuki-Miyaura cross-coupling for accessing highly steric hindered tetra-ortho-substituted biaryls (26 examples up to 98:2 er). It is worth noting that the embodied carbazolyl framework is crucial to succeed the reaction, by the fruitful steric relief of bulky substrate coordination and transmetalation via a fleeting Pd-N jumping to Pd-π fashion. DFT calculation reveals an interesting Pd-arene-walking characteristic across the carbazolyl plane for attaining a lower energy-preferred route in a catalytic cycle. The theoretical study successfully predicts the stereooutcome and matches the enantioselectivity with the experimental results.

Theoretical Insight into the Multiple Roles of LiHMDS in Pd-Catalyzed Borylation of Fluorobenzene.

Pd-catalyzed borylation of fluorobenzene was theoretically studied. DFT calculations revealed that the reaction occurs through an unprecedented 3 + 6-membered ring transition state, in which one LiHMDS (HMDS = hexamethyldisilazane) acts as a ligand and another LiHMDS is essential to provide Li···N and Li···F interactions, overcoming the large destabilization of the strong phenyl-F bond distortion. The characteristic feature of LiHMDS was elucidated by comparing it with HMDS and NaHMDS analogues.

Treatment of vitiligo with 308-nm light emitting diode: Our experience from a two-year follow-up of Chinese patients.

BACKGROUND: A light emitting diode (LED), with a wavelength of 308 nm, has been utilized in the dermatologic treatment of vitiligo. OBJECTIVES: We investigated the efficacy and safety of 308-nm LED for use in the treatment of vitiligo. METHODS: We conducted a retrospective study of 70 stable-stage vitiligo patients (with a total of 99 lesions) who received 308-nm LED treatment at the Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College from June 2018 to June 2020. Treatment efficacy was evaluated after 8 treatment sessions, 16 treatment sessions, and the final treatment session, to estimate the percentage of re-pigmentation in the treated area. The Kruskal-Wallis test was used for data analysis. RESULTS: Based on the final treatment session analysis of all 99 lesions, 0 lesions showed no response, 21 lesions showed poor response, 29 lesions showed moderate response, 23 lesions showed good response, and 26 lesions showed excellent response. The efficacy rate was 49.49%, and there was a significant correlation between the six distinct anatomical regions treated and re-pigmentation grade (χ2  = 13.419, p = .009). Among these regions, facial lesions showed the best response to treatment, while the hands and feet lesions showed the poorest response. CONCLUSIONS: The clinical efficacy of 308-nm LED treatment is limited based on the treatment area. It demonstrated significant practical application in the treatment of vitiligo.

Efficient Electron Transfer from Electron-Sponge Polyoxometalate to Single-Metal Site Metal-Organic Frameworks for Highly Selective Electroreduction of Carbon Dioxide.

In this work, by combining the superiority of polyoxometalates (POMs) and catalytic single-metal site Co of metalloporphyrin, a series of mixed-valence POM-based metal-organic frameworks (MOFs) composites is synthesized by a post-modification method. The electron-transfer property of POM@PCN-222(Co) composite is significantly enhanced owing to the directional electron-transfer from POM to single-metal site Co in PCN-222(Co). In particular, H-POM@PCN-222(Co) gives a high Faradaic efficiency of 96.2% for electroreduction of CO2 into CO and good stability over 10 h. DFT calculations confirm that the directional electron transfer, which accelerates the multi-electron transfer from the electrode to active single-metal site Co, enriches the electron density of the Co center, and ultimately reduces the energy of the rate-determining step, thus increasing the catalytic activity of CO2 reduction reaction (CO2 RR). This work therefore suggests some new insight for the design of efficient electrocatalysts for CO2 RR.

Diterpenoids from the whole plants of Croton yunnanensis and their bioactivities.

Four new 19-nor-clerodane diterpenoids (1-4), one new 15,16-dinor-ent-pimarane diterpenoid (5) together with four known diterpenoids (6-9) were isolated from whole plants of Croton yunnanensis. The structures of these compounds were determined by extensive spectroscopic methods including 1D, 2D NMR, HR-ESI-MS, and by comparing their NMR data with those of previously reported compounds. The experimental and calculated electronic circular dichroism data were used to define their absolute configurations. The 1H and 13C NMR spectra of 6 were completely assigned for the first time. All isolated compounds (1-9) were evaluated for their cytotoxic activities against five human cancer cell lines (including SMMC-7721, HL-60, A-549, MCF-7, and SW-480), and anti-inflammatory activities in LPS-induced RAW264.7 macrophages. Crotonyunnan E (5) exhibited selective cytotoxicities against three tumor cell lines, SMMC-7721 (human hepatoma cells, IC50 4.47 ± 0.39 µM), HL-60 (human premyelocytic leukemia, IC50 14.38 ± 1.19 µM), and A-549 (human lung cancer cells, IC50 27.42 ± 0.48 µM), while none of the compounds showed obviously anti-inflammatory activities at 50 µM level.

Acupuncture for functional gastrointestinal disorders: A systematic review and meta-analysis.

OBJECTIVES: The therapeutic effect of acupuncture treatments (AT) on functional gastrointestinal disorders (FGIDs) is contentious. A meta-analysis was conducted to assess the efficacy and safety of acupuncture for FGIDs. METHODS: The Cochrane Library, EMBASE, PUBMED, Web of Science, Wanfang Database, China National Knowledge Infrastructure, and VIP Database were searched through December 31, 2019 with no language restrictions. Risk ratio (RR) with 95% confidence interval (CI) was calculated to determine the improvement in symptom severity after treatment. RESULTS: A total of 61 randomized controlled trials (RCTs) on FGIDs were included. The pooled results illustrated the following: compared to pharmacotherapy (RR 1.13, 95% CI 1.09-1.17), placebo acupuncture (RR 1.69, 95% CI 1.37-2.08), no specific treatment (RR 1.86, 95% CI 1.31-2.62), and AT as an adjuvant intervention to other active treatments (RR 1.25, 95% CI 1.21-1.30), AT had more favorable improvements in symptom severity; sub-group analysis results classified according to functional dyspepsia, irritable bowel syndrome, and functional constipation also supported this finding; and the incidence of adverse events was lower in AT than in other treatments (RR 0.75, 95% CI 0.56-0.99). CONCLUSIONS: This meta-analysis found that AT was significantly associated with relief of FGIDs symptoms; however, the evidence level was moderate or low. Further data from rigorously designed and well powered RCTs are needed to verify the effectiveness and safety of AT as a FGIDs treatment. PROSPERO PROTOCOL NUMBER: CRD42020169508.

Methane Borylation Catalyzed by Ru, Rh, and Ir Complexes in Comparison with Cyclohexane Borylation: Theoretical Understanding and Prediction.

Methane borylation catalyzed by Cp*M(Bpin)n (M = Ru or Rh; HBpin = pinacolborane; n = 2 or 3) and (TMPhen)Ir(Bpin)3 (TMPhen = 3,4,7,8-tetramethyl-1,10-phenanthroline) was investigated by DFT in comparison with cyclohexane borylation. Because Ru-catalyzed borylation has not been theoretically investigated yet, its reaction mechanism was first elucidated; Cp*Ru(Bpin)3 1-Ru is an active species, and Cp*Ru(Bpin)3(H)(CH3) 4-Ru is a key intermediate. In 4-Ru, the Ru is understood to have an ambiguous oxidation state between +IV and +VI because it has a H··Bpin bonding interaction with a bond order of about 0.5. Methane borylation occurs through oxidative addition of methane C-H bond followed by reductive elimination of borylmethane in all of these catalysts. The catalytic activity for methane borylation increases following the order Cp*Ru(Bpin)3 < (TMPhen)Ir(Bpin)3 < Cp*Rh(Bpin)2. Cyclohexane borylation occurs in the same mechanism except for the presence of isomerization of a key intermediate. Chemoselectivity of methane over cyclohexane increases following the order Ir < Ru < Rh. In all of these catalysts, the rate-determining step (RDS) of cyclohexane borylation needs a larger ΔG°‡ than the RDS of methane borylation because the more bulky cyclohexyl group induces larger steric repulsion with the ligand than methyl. One reason for the worse chemoselectivity of the Ir catalyst is its less congested transition state of the reductive elimination of borylcyclohexane. Herein, use of a strongly electron-donating ligand consisting of pyridine and N-heterocyclic carbene with bulky substituents is computationally proposed as a good ligand for the Ir catalyst; actually, the Ir complex of this ligand is calculated to be more active and more chemoselective than Cp*Rh(Bpin)2 for methane borylation.

sp3 C-H Borylation Catalyzed by Iridium(III) Triboryl Complex: Comprehensive Theoretical Study of Reactivity, Regioselectivity, and Prediction of Excellent Ligand.

Iridium-catalyzed C-H borylation of THF was theoretically investigated as example of sp3 C-H functionalization. DFT computations show that ß-regioselective borylation occurs more easily than does α-regioselective, as reported experimentally, through oxidative addition of C-H bond to iridium(III) species and reductive elimination of B-C bond. The reductive elimination is both a rate-determining step and a regioselectivity-determining step. The lower energy transition state (TS) of the reductive elimination of ß-boryloxolane arises from the Ir···(ß-oxolanyl) interaction at TS being stronger than the Ir···(α-oxolanyl) one. The Ir···(ß-oxolanyl) interaction being stronger than the Ir···(α-oxolanyl) one is a result of the valence orbital energy of the α-oxolanyl group being higher than that of the ß-oxolanyl group due to antibonding overlap of the valence orbital with O 2p orbital, where SOMO of oxolanyl radical is taken as valence orbital hereinafter. Reactivity of substrate decreases following the order primary (ß) C-H of ethyl ether > primary C-H of n-pentane ∼ secondary (ß) C-H of THF > secondary C-H of cyclopentane > secondary (α) C-H of THF ∼ secondary C-H of n-pentane > secondary (α) C-H of ethyl ether. The primary C-H bond is more reactive than the secondary one because of its smaller steric repulsion and lower energy valence orbital of the primary alkyl group. The ß-C-H bond of THF is more reactive than the secondary C-H bond of cyclopentane because of valence orbital energy of the ß-oxolanyl group being lower than that of the cyclopentyl group. Both steric and electronic factors are important for determining reactivity of substrate. Bidentate ligand consisting of pyridine and N-heterocyclic carbene is predicted to be better than 3,4,7,8-tetramethyl-1,10-phenanthroline used experimentally.

Strong Pancake 2e/12c Bond in π-Stacking Phenalenyl Derivatives Avoiding Bond Conversion.

The nature of the 2e/12c bond and its conversion to a carbon-carbon single bond in phenalenyl dimers have prompted a great deal of interests recently. In this work, we theoretically investigated a series of π-stacking phenalenyl derivatives with 2e/12c bonding character by density functional theory (DFT) calculations to elucidate origin of this unusual bond conversion. Results show that bond-conversion of the phenalenyl dimer easily occurs at room-temperature both dynamically and thermodynamically. However, bond-conversion of hetero π-stacking adducts, in which the two center carbon atoms were substituted by boron and nitrogen atoms, respectively, is much more difficult, because the 2e/12c bond is stabilized by its charge transfer character. Consequently, the bond-conversion is an endothermic process, albeit with a low conversion barrier. Interestingly, Lewis acid-base interactions would be induced by substitution of the center nitrogen atom to phosphorus atom. The 2e/12c bond is further stabilized by 5.9 kcal mol-1 and its conversion is also thermodynamically unfavorable.

Constructing Stable π-Dimers: Two Parallel Pancake π-π Bonds.

Stable phenalenyl (PLY) radical π-dimers still play an important role for new multifunctional materials owing to their intriguing molecular structure and unusual pancake π-π bonding mode. Herein, we design a new biphenalenyl biradicaloid (1) consisting of two PLYs and one benzene ring linkage tethered by single bonds, which presents an open-shell character. Further, three π-dimers (a1, b1, and c1) combined with 1 and conventional biphenalenyl biradicaloid (a, b, and c), which are capable of forming two staggered PLY dimers, exhibiting a short interlayer distance between the monomers. Interestingly, the analysis of the frontier molecular orbital reveals that two bonding orbitals, namely, the two highest occupied molecular orbitals (HOMO and HOMO-1) are doubly occupied. The results reveal that three π-dimers display two parallel pancake bonds. Moreover, they have small diradical and tetraradical characters, large interaction energies, and strong aromaticity, which indicate the stability of these π-dimers. The present work creates a new class of strong pancake bonding and might be utilized in devising an array of materials.

Quarter-mode spoof plasmonic resonator for a microfluidic chemical sensor.

In this paper, we propose a microfluidic chemical sensor based on quarter-mode spoof plasmonic resonators with more compact overall size and higher sensitivity. First, a microfluidic channel engraved on polydimethylsiloxane is aligned to the upper part of the spoof plasmonic metal-insulator-metal (MIM) ring resonator where the strongest electric fields are observed at resonance. Although a resonant frequency shift of 270 MHz has been observed when the microfluidic channel is filled with pure ethanol, there is no resonant frequency shift when the ethanol concentration is changed from 40% to 60%. Then the spoof localized surface plasmons modes on the quarter corrugated MIM ring are analyzed, and a microfluidic sensor based on the quarter-mode spoof plasmonic resonator has been proposed. The proposed microfluidic sensor requires a very small amount (3.9 µL) of liquid for testing. After infilling the microfluidic channel with pure ethanol, the resonant frequency shift of 940 MHz has been observed on account of the dielectric changes. It is observed that the resonant frequency of the proposed sensor shifts from 5.07 to 6.62 GHz when the ethanol concentration is varied from 10% to 90%. It has been demonstrated that such quarter-mode spoof plasmonic resonator is well suited to a highly sensitive and compact microfluidic chemical sensor.

Transcription Factor Trps1 Promotes Tubular Cell Proliferation after Ischemia-Reperfusion Injury through cAMP-Specific 3',5'-Cyclic Phosphodiesterase 4D and AKT.

Trichorhinophalangeal 1 (Trps1) is a transcription factor essential for epithelial cell morphogenesis during kidney development, but the role of Trps1 in AKI induced by ischemia-reperfusion (I/R) remains unclear. Our study investigated Trps1 expression during kidney repair after acute I/R in rats and explored the molecular mechanisms by which Trps1 promotes renal tubular epithelial cell proliferation. Trps1 expression positively associated with the extent of renal repair after I/R injury. Compared with wild-type rats, rats with knockdown of Trps1 exhibited significantly delayed renal repair in the moderate I/R model, with lower GFR levels and more severe morphologic injury, whereas rats overexpressing Trps1 exhibited significantly accelerated renal repair after severe I/R injury. Additionally, knockdown of Trps1 inhibited and overexpression of Trps1 enhanced the proliferation of renal tubular epithelial cells in rats. Chromatin immunoprecipitation sequencing assays and RT-PCR revealed that Trps1 regulated cAMP-specific 3',5'-cyclic phosphodiesterase 4D (Pde4d) expression. Knockdown of Trps1 decreased the renal protein expression of Pde4d and phosphorylated Akt in rats, and dual luciferase analysis showed that Trps1 directly activated Pde4d transcription. Furthermore, knockdown of Pde4d or treatment with the phosphatidylinositol 3 kinase inhibitor wortmannin significantly inhibited Trps1-induced tubular cell proliferation in vitro Trps1 may promote tubular cell proliferation through the Pde4d/phosphatidylinositol 3 kinase/AKT signaling pathway, suggesting Trps1 as a potential therapeutic target for kidney repair after I/R injury.

Maternal expression and early induction of histone gene transcription factor Hinfp sustains development in pre-implantation embryos.

Fidelity of histone gene expression is important for normal cell growth and differentiation that is stringently controlled during development but is compromised during tumorigenesis. Efficient production of histones for packaging newly replicated DNA is particularly important for proper cell division and epigenetic control during the initial pre-implantation stages of embryonic development. Here, we addressed the unresolved question of when the machinery for histone gene transcription is activated in the developing zygote to accommodate temporal demands for histone gene expression. We examined induction of Histone Nuclear Factor P (HINFP), the only known transcription factor required for histone H4 gene expression, that binds directly to a unique H4 promoter-specific element to regulate histone H4 transcription. We show that Hinfp gene transcripts are stored in oocytes and maternally transmitted to the zygote. Transcripts from the paternal Hinfp gene, which reflect induction of zygotic gene expression, are apparent at the 4- to 8-cell stage, when most maternal mRNA pools are depleted. Loss of Hinfp expression due to gene ablation reduces cell numbers in E3.5 stage embryos and compromises implantation. Reduced cell proliferation is attributable to severe reduction in histone mRNA levels accompanied by reduced cell survival and genomic damage as measured by cleaved Caspase 3 and phospho-H2AX staining, respectively. We conclude that transmission of maternal Hinfp transcripts and zygotic activation of the Hinfp gene together are necessary to control H4 gene expression in early pre-implantation embryos in order to support normal embryonic development.

The Suzuki-Miyaura Coupling of Nitroarenes.

Synthesis of biaryls via the Suzuki-Miyaura coupling (SMC) reaction using nitroarenes as an electrophilic coupling partners is described. Mechanistic studies have revealed that the catalytic cycle of this reaction is initiated by the cleavage of the aryl-nitro (Ar-NO2) bond by palladium, which represents an unprecedented elemental reaction.

Highly expressed long non-coding RNA FOXD2-AS1 promotes non-small cell lung cancer progression via Wnt/ß-catenin signaling.

Non-small cell lung cancer (NSCLC) is one of the most common and aggressive tumors around the world. Long-noncoding RNAs (lncRNAs) have been recently shown to play important roles in regulating numerous biological processes including tumor progression. However, the role of lncRNA FOXD2-AS1 in NSCLC remains unclear. In this study, we found that lncRNA FOXD2-AS1 is significantly up-regulated in NSCLC tissues. Loss- and gain-function assays revealed that FOXD2-AS1 promotes NSCLC cell growth and NSCLC tumor progression. Furthermore, we also revealed that FOXD2-AS1 modulates Wnt/ß-catenin signaling in NSCLC cells. Taken together, we conclude that lncRNA FOXD2-AS1 promotes NSCLC progression though Wnt/ß-catenin signaling. These results suggest that lncRNA FOXD2-AS1 might act as a novel therapeutic target for NSCLC treatment.