Gd(III)-Catalyzed Regio-, Diastereo-, and Enantioselective [4 + 2] Photocycloaddition of Naphthalene Derivatives.

Catalytic asymmetric dearomatization (CADA) reactions have evolved into an efficient strategy for accessing chiral polycyclic and spirocyclic scaffolds from readily available planar aromatics. Despite the significant developments, the CADA reaction of naphthalenes remains underdeveloped. Herein, we report a Gd(III)-catalyzed asymmetric dearomatization reaction of naphthalene with a chiral PyBox ligand via visible-light-enabled [4 + 2] cycloaddition. This reaction features application of a chiral Gd/PyBox complex, which regulates the reactivity and selectivity simultaneously, in excited-state catalysis. A wide range of functional groups is compatible with this protocol, giving the highly enantioenriched bridged polycycles in excellent yields (up to 96%) and selectivity (up to >20:1 chemoselectivity, >20:1 dr, >99% ee). The synthetic utility is demonstrated by a 2 mmol scale reaction, removal of directing group, and diversifications of products. Preliminary mechanistic experiments are performed to elucidate the reaction mechanism.

Network pharmacology analysis and molecular mechanism of paeoniflorin and its metabolite in prolactinoma cells.

Prolactinoma was the most common functional pituitary neuroendocrine tumor tissue type, which was caused by excessive proliferation of pituitary prolactin (PRL) cells. Drug therapy of dopamine receptor agonists was generally considered as the prior treatment for prolactinoma patients. However, there were still prolactinoma patients who were resistant to dopamine agonists. Studies have been reported that paeoniflorin can inhibit the secretion of PRL in prolactinoma cells lacking dopamine D2 receptor (D2R) expression, and paeoniflorin can be metabolized into albiflorin by intestinal flora in rats. The effect of albiflorin on prolactinoma has not been reported yet. In this study, network pharmacology was used to analyze the mechanism of paeoniflorin and its metabolite albiflorin as multi-target therapy for prolactinoma, and the experimental verification was carried out. In order to clarify the complex relationship among paeoniflorin, albiflorin and prolactinoma, we constructed a component-target-disease network, and further constructed interaction network, MMP9, EGFR, FGF2, FGFR1 and LGALS3 were screened as the core targets. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that paeoniflorin and albiflorin may be involved in various pathways in the treatment of prolactinoma, included relaxin signaling pathway and PI3K-Akt signaling pathway. Molecular docking analysis showed that paeoniflorin and albiflorin had good binding activity with MMP9. Western blotting results showed that paeoniflorin and albiflorin could significantly reduce the expression of MMP9, and ELISA results showed that paeoniflorin and albiflorin could significantly reduce the concentration of PRL in GH3 cells, and the reduce degree of albiflorin was stronger than paeoniflorin at 50 µM, which indicated that albiflorin might be a potential drug to treat prolactinoma, which can regulate prolactinoma through MMP9 and reduce the concentration of PRL. Our study provided a new therapeutic strategy for prolactinoma.

Extracellular loop 2 of G protein-coupled olfactory receptors is critical for odorant recognition.

G protein-coupled olfactory receptors (ORs) enable us to detect innumerous odorants. They are also ectopically expressed in nonolfactory tissues and emerging as attractive drug targets. ORs can be promiscuous or highly specific, which is part of a larger mechanism for odor discrimination. Here, we demonstrate that the OR extracellular loop 2 (ECL2) plays critical roles in OR promiscuity and specificity. Using site-directed mutagenesis and molecular modeling, we constructed 3D OR models in which ECL2 forms a lid over the orthosteric pocket. We demonstrate using molecular dynamics simulations that ECL2 controls the shape and volume of the odorant-binding pocket, maintains the pocket hydrophobicity, and acts as a gatekeeper of odorant binding. Therefore, we propose the interplay between the specific orthosteric pocket and the variable, less specific ECL2 controls OR specificity and promiscuity. Furthermore, the 3D models created here enabled virtual screening of new OR agonists and antagonists, which exhibited a 70% hit rate in cell assays. Our approach can potentially be generalized to structure-based ligand screening for other G protein-coupled receptors that lack high-resolution 3D structures.

Enantioselective Synthesis of Cyclobutane Derivatives via Cascade Asymmetric Allylic Etherification/[2 + 2] Photocycloaddition.

Chiral cyclobutane presents as a popular motif in natural products and biologically active molecules, and its derivatives have been extensively used as key synthons in organic synthesis. Herein, we report an efficient synthetic method toward enantioenriched cyclobutane derivatives. The reaction proceeds in a cascade fashion involving Ir-catalyzed asymmetric allylic etherification and visible-light induced [2 + 2] cycloaddition. Readily available branched allyl acetates and cinnamyl alcohols are directly used as the substrates under mild reaction conditions, providing a broad range of chiral cyclobutanes in good yields with excellent diastereo- and enantioselectivities (up to 12:1 dr, >99% ee). It is worth noting that all substrates and catalysts were simultaneously added without any separated step in this approach. The gram-scale reaction and diverse transformations of product further enhance the potential utility of this method.

Interactions among key residues regulate mammalian odorant receptor trafficking.

Odorant receptors (ORs) expressed in mammalian olfactory sensory neurons are essential for the sense of smell. However, structure-function studies of many ORs are hampered by unsuccessful heterologous expression. To understand and eventually overcome this bottleneck, we performed heterologous expression and functional assays of over 80 OR variants and chimeras. Combined with literature data and machine learning, we found that the transmembrane domain 4 (TM4) and its interactions with neighbor residues are important for OR functional expression. The data highlight critical roles of T4.62 therein. ORs that fail to reach the cell membrane can be rescued by modifications in TM4. Consequently, such modifications in MOR256-3 (Olfr124) also alter OR responses to odorants. T1614.62 P causes the retention of MOR256-3 in the endoplasmic reticulum (ER), while T1614.62 P/T1484.49 A reverses the retention and makes receptor trafficking to cell membrane. This study offers new clues toward wide-range functional studies of mammalian ORs.

Ruthenium-Catalyzed Activation of Nonpolar C-C Bonds via π-Coordination-Enabled Aromatization.

Activation of C-C bonds allows editing of molecular skeletons, but methods for selective activation of nonpolar C-C bonds in the absence of a chelation effect or a driving force derived from opening of a strained ring are scarce. Herein, we report a method for ruthenium-catalyzed activation of nonpolar C-C bonds of pro-aromatic compounds by means of π-coordination-enabled aromatization. This method was effective for cleavage of C-C(alkyl) and C-C(aryl) bonds and for ring-opening of spirocyclic compounds, providing an array of benzene-ring-containing products. The isolation of a methyl ruthenium complex intermediate supports a mechanism involving ruthenium-mediated C-C bond cleavage.

Rhodium-Catalyzed Benzylic Addition Reactions of Alkylarenes to Michael Acceptors.

The use of alkylarenes as nucleophile precursors in benzylic addition is challenging because the benzylic hydrogen atoms of these compounds are inert to deprotonation. Herein, we report Rh-catalyzed benzylic addition of alkylarenes to Michael acceptors for the formation of C(sp3 )-C(sp3 ) bonds. The catalyst is proposed to activate the aromatic ring via η6 -coordination, dramatically facilitating deprotonation of the unactivated benzylic C-H bond and addition of the resulting carbanion to the α,ß-unsaturated double bond in the absence of bases. Notably, this byproduct-free method provides an access to all-carbon quaternary centers through the development of ligands.

Visible-Light-Induced Dearomatization of Indoles/Pyrroles with Vinylcyclopropanes: Expedient Synthesis of Structurally Diverse Polycyclic Indolines/Pyrrolines.

Visible-light-induced cycloaddition reactions initiated via energy-transfer processes have recently evolved as powerful methods for the construction of strained cyclic molecules that are not easily accessed using known ground-state synthetic methods. Particularly, the reactions initiated by the excitation of aromatic rings provide an alternative solution to the direct transformations of aromatic feedstocks under the scheme of dearomatization. Vinylcyclopropanes (VCPs) are well-known reagents in radical clock experiments, working as a probe to detect transient radical intermediates. However, the synthetic applications in this regard still remain limited due to uncontrollable selectivities. Herein, we report visible-light-induced dearomatization of indole- or pyrrole-tethered VCPs, in which several competitive reaction pathways, including [5 + 2], [2 + 2], interrupted [5 + 2], and [5 + 4] cycloadditions, can be well regulated by engineering substrate structures and tuning reaction conditions. The reaction mechanism has been explored by combined experimental and computational investigations. These reactions provide a convenient method to synthesize structurally diverse polycyclic molecules with high efficiency and good selectivity.

Impact of H-Type Hypertension on Pericarotid Adipose Tissue and Plaque Characteristics Based on Computed Tomography (CT) Angiography: A Propensity Score Matching Study.

BACKGROUND We analyzed the correlation among the inflammatory changes in pericarotid adipose tissue (PCAT), plaque characteristics, and H-type hypertension on CT angiography (CTA) and explored the utility of CTA in the prevention and treatment of carotid atherosclerosis. MATERIAL AND METHODS A total of 135 patients who underwent head and neck CTA to investigate carotid artery atherosclerosis were retrospectively analyzed. The plaque characteristic parameters (plaque burden and remodeling index), PCAT attenuation value, and net enhancement value around the carotid artery, where the plaques were located, were recorded, and confounding factors were matched by propensity score analysis. A paired t test was used to compare the differences in fat tissue inflammatory changes and plaque characteristic parameters between the 2 groups, and logistic regression analysis was used to evaluate the relationship between plaque characteristics and the attenuation values and net enhancement values of PCAT. The correlation coefficient was calculated between type H hypertension and plaque risk grade. RESULTS The results of the experiment indicate that PCAT attenuation values and net enhancement values gradually increased as the degree of hypertension increased. Compared with those of patients in the normal Hcy group, these values increased more clearly in patients with high Hcy (HHcy) (r=0.641, P<0.001, r=0.581, P<0.001), although, regardless of whether the Hcy value increased, there were significant differences between the groups. However, this effect was more pronounced in patients with H-type hypertension. Logistic regression analysis of risk factors for carotid atherosclerotic plaque suggests that Hcy (OR=1.391, 95% CI 1.146-1.689, P=0.001), PCAT attenuation values (OR=1.212, 95% CI 1.074-1.367, P=0.002), and net enhancement values (OR=1.201, 95% CI 1.042-1.383, P=0.011) were independent risk factors for plaque vulnerability. CONCLUSIONS Our results suggest that H-type hypertension is significantly associated with PCAT attenuation and net enhancement and that PCAT net enhancement values are useful in predicting plaque risk as attenuation.

Catalytic SN Ar Hydroxylation and Alkoxylation of Aryl Fluorides.

Nucleophilic aromatic substitution (SN Ar) is a powerful strategy for incorporating a heteroatom into an aromatic ring by displacement of a leaving group with a nucleophile, but this method is limited to electron-deficient arenes. We have now established a reliable method for accessing phenols and phenyl alkyl ethers via catalytic SN Ar reactions. The method is applicable to a broad array of electron-rich and neutral aryl fluorides, which are inert under classical SN Ar conditions. Although the mechanism of SN Ar reactions involving metal arene complexes is hypothesized to involve a stepwise pathway (addition followed by elimination), experimental data that support this hypothesis is still under exploration. Mechanistic studies and DFT calculations suggest either a stepwise or stepwise-like energy profile. Notably, we isolated a rhodium η5 -cyclohexadienyl complex intermediate with an sp3 -hybridized carbon bearing both a nucleophile and a leaving group.

Presenilin1 exerts antiproliferative effects by repressing the Wnt/ß-catenin pathway in glioblastoma.

BACKGROUND: Glioblastoma and Alzheimer's disease (AD) are the most common and devastating diseases in the central nervous system. The dysfunction of Presenilin1 is the main reason for AD pathogenesis. However, the molecular function of Presenilin1 and its relative mechanism in glioblastoma remain unclear. METHODS: Expression of presenilin1 in glioma was determined by IHC. CCK-8, colony formation, Flow cytometry, Edu staining were utilized to evaluate functions of presenilin1 on glioblastoma proliferation. The mechanism of above process was assessed by Western blotting and cell immunofluorescence. Mouse transplanting glioblastoma model and micro-MRI detection were used to verified presenilin1 function in vivo. RESULTS: In this study, we found that all grades of glioma maintained relatively low Presenilin1 expression and that the expression of Presenilin1 in high-grade glioma was significantly lower than that in low-grade glioma. Moreover, the Presenilin1 level had a positive correlation with glioma and glioblastoma patient prognosis. Next, we determined that Presenilin1 inhibited the growth and proliferation of glioblastoma cells by downregulating CDK6, C-myc and Cyclin D1 to arrest the cell cycle at the G1/S phase. Mechanistically, Presenilin1 promoted the direct phosphorylation of ß-catenin at the 45 site and indirect phosphorylation at the 33/37/41 site, then decreased the stabilized part of ß-catenin and hindered its translocation from the cytoplasm to the nucleus. Furthermore, we found that Presenilin1 downregulation clearly accelerated the growth of subcutaneous glioblastoma, and Presenilin1 overexpression significantly repressed the subcutaneous and intracranial transplantation of glioblastoma by hindering ß-catenin-dependent cell proliferation. CONCLUSION: Our data implicate the antiproliferative effect of Presenilin1 in glioblastoma by suppressing Wnt/ß-catenin signaling, which may provide a novel therapeutic agent for glioblastoma. Video Abstract.

Antimicrobial Meroterpenoids and Erythritol Derivatives Isolated from the Marine-Algal-Derived Endophytic Fungus Penicillium chrysogenum XNM-12.

One new meroterpenoid-type alkaloid, oxalicine C (1), and two new erythritol derivatives, penicierythritols A (6) and B (7), together with four known meroterpenoids (2-5), were isolated from the marine algal-derived endophytic fungus Penicillium chrysogenum XNM-12. Their planar structures were determined by means of spectroscopic analyses, including UV, 1D and 2D NMR, and HRESIMS spectra. Their stereochemical configurations were established by comparing the experimental and calculated electronic circular dichroism (ECD) spectra for compound 1, as well as by comparison of the optical rotations with literature data for compounds 6 and 7. Notably, oxalicine C (1) represents the first example of an oxalicine alkaloid with a cleaved α-pyrone ring, whereas penicierythritols A (6) and B (7) are the first reported from the Penicillium species. The antimicrobial activities of compounds 1-7 were evaluated. Compounds 1 and 6 exhibited moderate antibacterial effects against the plant pathogen Ralstonia solanacearum with minimum inhibitory concentration (MIC) values of 8 and 4 µg/mL, respectively. Compound 6 also possesses moderate antifungal properties against the plant pathogen Alternaria alternata with a MIC value of 8 µg/mL.

Intermolecular Dearomatization of Naphthalene Derivatives by Photoredox-Catalyzed 1,2-Hydroalkylation.

An intermolecular hydroalkylative dearomatization of naphthalenes with commercially available α-amino acids is achieved via visible-light photoredox catalysis. With an organic photocatalyst, a series of multi-substituted 1,2-dihydronaphthalenes are obtained in good-to-excellent yields. Intriguingly, by tuning the substituents at the C2 position of naphthalenes, formal dearomative [3+2] cycloadditions occur exclusively via a hydroalkylative dearomatization-cyclization sequence. This overall redox-neutral method features mild reaction conditions, good tolerance of functionalities, and operational simplicity. Diverse downstream elaborations of the products are demonstrated. Preliminary mechanistic studies suggest the involvement of a radical-radical coupling pathway.

Apoptosis induction effect of Apocynum venetum polyphenol on human U87 glioma cells via NF-κB pathway.

Aim: Apocynum venetum polyphenol (AVP) was used in in vitro glioma cells culture to prove the growth inhibitory effect of AVP on human U87 glioma cells via NF-κB pathway. Materials & methods: The MTT assay, DAPI morphology, quantitative PCR and western blot experiments were used for determination in vitro. Results & conclusion: AVP can also induce U87 cancer cells apoptosis illustrated by DAPI morphology. AVP could enhance the mRNA and protein expression of IκB-α, TNF-α, TRAIL, caspase-3 and caspase-9 in U87 cancer cells and reduce those of NF-κBp65, cIAP-1, cIAP-2, TGF-ß2, CyclinD1, VEGF and IL-8. After ammonium pyrrolidine dithiocarbamate (PDTC) treatment, the NF-κBp65 expression was reduced in U87 cells, and AVP could raise these effects. The results of HPLC indicate that AVP mainly contains six constituents. The growth inhibitory effects of AVP on U87 glioma cells are predominantly from these natural active constituents.

Total Synthesis of (±)-Cephanolides B and C via a Palladium-Catalyzed Cascade Cyclization and Late-Stage sp3 C-H Bond Oxidation.

Herein, we report the first total syntheses of complex cephalotaxus diterpenoids cephanolide B and C from commercially available 5-bromo-2-methylanisole. Key to the success of this synthetic route is a palladium-catalyzed cascade cyclization reaction, which allowed us to efficiently forge the 6-5-6 cis-fused tricyclic ring systems found in the entire family of cephalotaxus diterpenoids. Additionally, site-selective late-stage sp3 C-H bond oxidation served as a key strategic element in the chemical synthesis of cephanolide C.

Monitoring Dynamic Morphological Changes With Electrocardiography-Gated Dynamic 4-Dimensional Computed Tomography Angiography to Predict Intraoperative Rupture of Intracranial Aneurysms.

OBJECTIVE: This study aims to evaluate dynamic morphological changes of intracranial aneurysms to predict intraoperative aneurysm rupture (IAR) during clipping. METHODS: Included in this study were 153 patients, who had ruptured and microsurgical-clipped aneurysms. All patients underwent dual-source computed tomography examination of electrocardiography-gated dynamic 4-dimensional computed tomography angiography before clipping. Original scanning data were reconstructed to produce 20 data sets of cardiac cycles with 5% time intervals. The aneurysm neck, transverse and longitudinal diameters, and volume from the 20 groups of images were measured to calculate their respective change rates. In addition, other data and clinical characteristics were recorded. Data were analyzed by logistic regression to identify factors associated with IAR. RESULTS: Of the 153 patients, 24 patients experienced IAR. Multivariable analysis revealed that the aneurysm neck change rate (P = 0.0001; odds ratio, 1.276) and aspect ratio (height/neck ratio, P = 0.025; odds ratio, 2.387) are predictors for IAR. When the change rate was greater than or equal to 60%, and the sensitivity and specificity were 91.7% and 76.7%, respectively. CONCLUSIONS: Aneurysm neck change rate is independent predictor of IAR.

WIP1 phosphatase is a critical regulator of adipogenesis through dephosphorylating PPARγ serine 112.

WIP1, as a critical phosphatase, plays many important roles in various physiological and pathological processes through dephosphorylating different substrate proteins. However, the functions of WIP1 in adipogenesis and fat accumulation are not clear. Here, we report that WIP1-deficient mice show impaired body weight growth, dramatically decreased fat mass, and significantly reduced triglyceride and leptin levels in circulation. This dysregulation of adipose development caused by the deletion of WIP1 occurs as early as adipogenesis. In contrast, lentivirus-mediated WIP1 phosphatase overexpression significantly increases the adipogenesis of pre-adipocytes via an enzymatic activity-dependent mechanism. PPARγ is a master gene of adipogenesis, and the phosphorylation of PPARγ at serine 112 strongly inhibits adipogenesis; however, very little is known about the negative regulation of this phosphorylation. Here, we show that WIP1 phosphatase plays a pro-adipogenic role by interacting directly with PPARγ and dephosphorylating p-PPARγ S112 in vitro and in vivo.

miR-210 protects renal cell against hypoxia-induced apoptosis by targeting HIF-1 alpha.

The kidney is vulnerable to hypoxia-induced injury. One of the mechanisms underlying this phenomenon is cell apoptosis triggered by hypoxia-inducible factor-1-alpha (HIF-1α) activation. MicroRNA-210 (miR-210) is known to be induced by HIF-1α and can regulate various pathological processes, but its role in hypoxic kidney injury remains unclear. Here, in both kinds of rat systemic hypoxia and local kidney hypoxia models, we found miR-210 levels were upregulated significantly in injured kidney, especially in renal tubular cells. A similar increase was observed in hypoxia-treated human renal tubular HK-2 cells. We also verified that miR-210 can directly suppress HIF-1α expression by targeting the 3' untranslated region (UTR) of HIF-1α mRNA in HK-2 cells in severe hypoxia. Accordingly, miR-210 overexpression caused significant inhibition of the HIF-1α pathway and attenuated apoptosis caused by hypoxia, while miR-210 knockdown exerted the opposite effect. Taken together, our findings verify that miR-210 is involved in the molecular response in hypoxic kidney lesions in vivo and attenuates hypoxia-induced renal tubular cell apoptosis by targeting HIF-1α directly and suppressing HIF-1α pathway activation in vitro.

Hypoxia augments LPS-induced inflammation and triggers high altitude cerebral edema in mice.

High altitude cerebral edema (HACE) is a life-threatening illness that develops during the rapid ascent to high altitudes, but its underlying mechanisms remain unclear. Growing evidence has implicated inflammation in the susceptibility to and development of brain edema. In the present study, we investigated the inflammatory response and its roles in HACE in mice following high altitude hypoxic injury. We report that acute hypobaric hypoxia induced a slight inflammatory response or brain edema within 24h in mice. However, the lipopolysaccharide (LPS)-induced systemic inflammatory response rapidly aggravated brain edema upon acute hypobaric hypoxia exposure by disrupting blood-brain barrier integrity and activating microglia, increasing water permeability via the accumulation of aquaporin-4 (AQP4), and eventually leading to impaired cognitive and motor function. These findings demonstrate that hypoxia augments LPS-induced inflammation and induces the occurrence and development of cerebral edema in mice at high altitude. Here, we provide new information on the impact of systemic inflammation on the susceptibility to and outcomes of HACE.

YTHDF1 promotes the osteolytic bone metastasis of breast cancer via inducing EZH2 and CDH11 translation.

Bone metastasis is common in breast cancer and more effective therapies are required, however, its molecular mechanism is poorly understood. Additionally, the role of the m6A reader YTHDF1 in bone metastasis of breast cancer has not been reported. Here, we reveal that the increased expression of YTHDF1 is clinically correlated with breast cancer bone metastases. YTHDF1 promotes migration, invasion, and osteoblast adhesion and induces osteoclast differentiation of cancer cells in vitro and vivo. Mechanically, RNA-seq, MeRIP-seq and RIP-seq analysis, and molecular biology experiments demonstrate that YTHDF1 translationally enhances EZH2 and CDH11 expression by reading m6A-enriched sites of their transcripts. Moreover, adeno-associated virus (AAV) was used to deliver shYTHDF1 (shYTHDF1-AAV) in intratibial injection models, eliciting a significant suppressive effect on breast cancer bone metastatic formation and osteolytic destruction. Overall, we uncovered that YTHDF1 promotes osteolytic bone metastases of breast cancer by inducing EZH2 and CDH11 translation.