N-Heterocyclic Carbene/Transition Metal Dual Catalysis.

N-heterocyclic carbene catalysis has been developed as a versatile method for the enantioselective synthesis of complex organic molecules in organic chemistry. Merging of N-heterocyclic carbene catalysis with transition metal catalysis holds the potential to achieve unprecedented transformations with broad substrate scope and excellent stereoselectivity, which are unfeasible with individual catalyst. Thus, this dual catalysis has attracted increasing attention, and numerous elegant dual catalytic systems have been established. In this review, we summarize the recent achievements of dual NHC/transition metal catalysis, including the reaction design, mechanistic studies and practical applications.

Enantioselective Synthesis of Axially Chiral Diaryl Ethers via NHC Catalyzed Desymmetrization and Following Resolution.

Axially chiral diaryl ethers are present in numerous natural products and bioactive molecules. However, only few catalytic enantioselective approaches have been established to access diaryl ether atropisomers. Herein, we report the N-heterocyclic carbene-catalyzed enantioselective synthesis of axially chiral diaryl ethers via desymmetrization of prochiral 2-aryloxyisophthalaldehydes with aliphatic alcohols, phenol derivatives, and heteroaromatic amines. This reaction features mild reaction conditions, good functional group tolerance, broad substrate scope and excellent enantioselectivity. The utility of this methodology is illustrated by late-stage functionalization, gram-scale synthesis, and diverse enantioretentive transformations. Control experiments and DFT calculations support the association of NHC-catalyzed desymmetrization with following kinetic resolution to enhance the enantioselectivity.

N-Heterocyclic Carbene-Catalyzed Atroposelective Synthesis of Axially Chiral α-Carbolinones via Heterocycle Formation.

An NHC-catalyzed atroposelective synthesis of axially chiral α-carbolinones from α,ß-unsaturated iminoindole derivatives and α-chloroaldehydes was developed. The reaction proceeds through a cascade process including [4 + 2] annulation and then oxidative dehydrogenation with concomitant central-to-axial chirality conversion under mild conditions. The developed method opens a new avenue to efficiently access axially chiral α-carbolinones in moderate to good enantioselectivities.

Bifunctional NHC-Catalyzed Remote Enantioselective Mannich-type Reaction of 5-(Chloromethyl)furfural via Trienolate Intermediates.

N-heterocyclic carbene (NHC)-catalyzed enantioselective Mannich-type reactions of the biomass-derived platform compound 5-(chloromethyl)furfural (CMF) with imines were developed. A series of high-value-added chiral amines were afforded in good to high yields with excellent regio- and enantioselectivities. The bifunctional NHC derived from ʟ-pyroglutamic acid efficiently steered the remote addition of the trienolate intermediate to the imine in a highly stereocontrolled manner. This represents the first enantioselective reaction proceeding via an NHC-bound trienolate intermediate.

Mfsd2a overexpression alleviates vascular dysfunction in diabetic retinopathy.

Diabetic retinopathy (DR) is one of the common complications in diabetic patients. Nowadays, VEGF pathway is subject to extensive research. However, about 27% of the patients have a poor visual outcome, with 50% still having edema after two years' treatment of diabetic macular edema (DME) with ranibizumab. Docosahexaenoic acid (DHA), the primary ω-3 long-chain polyunsaturated fatty acid (LC-PUFA), reduces abnormal neovascularization and alleviates neovascular eye diseases. A study reported that fish oil reduced the incidence of retinopathy of prematurity (ROP) by about 27.5% in preterm infants. Although ω-3 LC-PUFAs protects against pathological retinal neovascularization, the treatment effectiveness is low. It is interesting to investigate why DHA therapy fails in some patients. In human vitreous humor samples, we found that the ratio of DHA and DHA-derived metabolites to total fatty acids was higher in vitreous humor from DR patients than that from macular hole patients; however, the ratio of DHA metabolites to DHA and DHA-derived metabolites was lower in the diabetic vitreous humor. The expression of Mfsd2a, the LPC-DHA transporter, was reduced in the oxygen-induced retinopathy (OIR) model and streptozotocin (STZ) model. In vitro, Mfsd2a overexpression inhibited endothelial cell proliferation, migration and vesicular transcytosis. Moreover, Mfsd2a overexpression in combination with the DHA diet obviously reduced abnormal retinal neovascularization and vascular leakage, which is more effective than Mfsd2a overexpression alone. These results suggest that DHA therapy failure in some DR patients is linked to low expression of Mfsd2a, and the combination of Mfsd2a overexpression and DHA therapy may be an effective treatment.

Enantioselective Synthesis of Axially Chiral Benzothiophene/Benzofuran-Fused Biaryls by N-Heterocyclic Carbene Catalyzed Arene Formation.

Axially chiral biaryl scaffolds are prevalent in natural products, chiral ligands, and organocatalysts. However, N-heterocyclic carbene (NHC) catalyzed de novo construction of an aromatic ring with concomitant axial chirality induction for the synthesis of biaryl atropisomers is far less developed, and the efficient synthesis of axially chiral tetra-ortho-substituted biaryls remains an unsolved problem under NHC catalysis. Reported here is an NHC-catalyzed de novo synthesis of axially chiral benzothiophene/benzofuran-fused biaryls from enals and 2-benzyl-benzothiophene/benzofuran-3-carbaldehydes through a [2+4] annulation, decarboxylation, and oxidative aromatization cascade with central-to-axial chirality conversion. The developed method provides efficient and general access to novel axially chiral benzothiophene/benzofuran-fused biaryls in high enantioselectivities and works well for the synthesis of tetra-ortho-substituted biaryls.

The role of semaphorins in small vessels of the eye and brain.

Small vessel diseases, such as ischemic retinopathy and cerebral small vessel disease (CSVD), are increasingly recognized in patients with diabetes, dementia and cerebrovascular disease. The mechanisms of small vessel diseases are poorly understood, but the latest studies suggest a role for semaphorins. Initially identified as axon guidance cues, semaphorins are mainly studied in neuronal morphogenesis, neural circuit assembly, and synapse assembly and refinement. In recent years, semaphorins have been found to play important roles in regulating vascular growth and development and in many pathophysiological processes, including atherosclerosis, angiogenesis after stroke and retinopathy. Growing evidence indicates that semaphorins affect the occurrence, perfusion and regression of both the macrovasculature and microvasculature by regulating the proliferation, apoptosis, migration, barrier function and inflammatory response of endothelial cells, vascular smooth muscle cells (VSMCs) and pericytes. In this review, we concentrate on the regulatory effects of semaphorins on the cell components of the vessel wall and their potential roles in microvascular diseases, especially in the retina and cerebral small vessel. Finally, we discuss potential molecular approaches in targeting semaphorins as therapies for microvascular disorders in the eye and brain.

Analyzing the Interactions of mRNAs and ncRNAs to Predict Competing Endogenous RNA Networks in Osteosarcoma Chemo-Resistance.

Chemo-resistance is a huge obstacle encountered in the osteosarcoma (OS) treatment. Protein-coding mRNAs, as well as non-coding RNAs (ncRNAs), including long ncRNA (lncRNA), circular RNA (circRNA), and microRNA (miRNA), have been demonstrated to play an essential role in the regulation of cancer biology. However, the comprehensive expression profile and competing endogenous RNA (ceRNA) regulatory network between mRNAs and ncRNAs in the OS chemo-resistance still remain unclear. In the current study, we developed whole-transcriptome sequencing (RNA sequencing [RNA-seq]) in the three paired multi-drug chemo-resistant and chemo-sensitive OS cell lines to comprehensively identify differentially expressed lncRNAs, circRNAs, miRNAs, and mRNAs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for mRNAs with significantly different expression. Then the ceRNA networks combining lncRNAs, circRNAs, miRNAs, and mRNAs were predicted and constructed on the basis of the authoritative miRanda and TargetScan databases combined with the widely accepted vital drug resistance-related genes and signal transduction pathways. In addition, two constructed ceRNA regulatory pathways, lncRNAMEG3/hsa-miR-200b-3p/AKT2 and hsa_circ_0001258/hsa-miR-744-3p/GSTM2, were randomly selected and validated by real-time qPCR, RNA immunoprecipitation (RIP), RNA pull-down assay, and dual luciferase reporter gene system. Taken together, our findings may provide new evidence for the underlying mechanism of OS chemo-resistance and uncover some novel targets for reversing it.

N-Heterocyclic Carbene-Catalyzed Annulation of α-Chloroaldehydes with γ-/δ-Amino-α,ß-Unsaturated Ketones: Enantioselective Synthesis of Pyrrolidones and Piperidones.

The N-heterocyclic carbene-catalyzed [2+3] and [2+4] annulations of α-chloroaldehydes with γ-/δ-amino-α,ß-unsaturated ketones were developed, giving the corresponding pyrrolidones and piperidones in good yields with exclusive trans-selectivities and excellent enantioselectivities.

DBU-Mediated Construction of 1,3,5-Trisubstituted Benzenes via Annulation of α,ß-Unsaturated Carboxylic Acids and α-Cyano-ß-methylenones.

A DBU-mediated synthesis of 1,3,5-trisubstituted benzenes was developed via the [2 + 4] annulation of in situ activated α,ß-unsaturated carboxylic acids and α-cyano-ß-methylenones. The dual role of DBU as Brønsted base and nucleophilic Lewis base is the key for the success of the reaction.

Visible light promoted coupling of alkynyl bromides and Hantzsch esters for the synthesis of internal alkynes.

A metal-free visible light promoted C(sp3)-C(sp) coupling reaction of alkynyl bromides and Hantzsch esters was developed, giving internal alkynes with primary, secondary, tertiary alkyl or other functional groups in good to high yields.

LncRNA ODRUL Contributes to Osteosarcoma Progression through the miR-3182/MMP2 Axis.

Recent findings have shown that lncRNA dysregulation is involved in many cancers, including osteosarcoma (OS). In a previous study, we reported a novel lncRNA, ODRUL, that could promote doxorubicin resistance in OS. We now report the function and underlying mechanism of ODRUL in regulating OS progression. We show that ODRUL is upregulated in OS tissues and cell lines and correlates with poor prognosis. ODRUL knockdown significantly inhibits OS cell proliferation, migration, invasion, and tumor growth in vitro and in vivo by decreasing matrix metalloproteinase (MMP) expression. A microarray screen combined with online database analysis showed that miR-3182 is upregulated and MMP2 is downregulated in sh-ODRUL-expressing MG63 cells and that miR-3182 harbors potential binding sites for ODRUL and the 3' UTR of MMP2 mRNA. In addition, miR-3182 expression and function are inversely correlated with ODRUL expression in vitro and in vivo. A luciferase reporter assay demonstrated that ODRUL could directly interact with miR-3182 and upregulate MMP2 expression via its competing endogenous RNA activity on miR-3182 at the posttranscriptional level. Taken together, our study has elucidated the role of oncogenic ODRUL in OS progression and may provide a new target in OS therapy.

A long non-coding RNA contributes to doxorubicin resistance of osteosarcoma.

Long non-coding RNAs (lncRNAs) are emerging in molecular biology as crucial regulators of cancer. Although the aberrant expression of lncRNAs has been observed in osteosarcoma (OS), the molecular mechanisms underlying lncRNAs in doxorubicin resistance of OS still unknown. In the current study, we investigated a novel lncRNA, termed ODRUL (osteosarcoma doxorubicin-resistance related up-regulated lncRNA), and evaluated its role in the occurrence of doxorubicin resistance in OS. LncRNA microarray revealed that lncRNA ODRUL was the most up-regulated expressed in the doxorubicin-resistant OS cell line. Quantitative real-time PCR (qRT-PCR) confirmed that lncRNA ODRUL was higher in different doxorubicin-resistant OS cell lines and lower in different doxorubicin-sensitive OS cell lines. Moreover, we showed that lncRNA ODRUL was increased in specimens of OS patients with a poor chemoresponse and lung metastasis. We further demonstrated that lncRNA ODRUL inhibition could inhibit OS cell proliferation, migration, and partly reversed doxorubicin resistance in vitro. In addition, we found that the expression of classical drug resistance-related ATP-binding cassette, subfamily B, member 1 (ABCB1) gene was decreased after the lncRNA ODRUL knockdown. Thus, we concluded that lncRNA ODRUL may act as a pro-doxorubicin-resistant molecule through inducing the expression of the classical multidrug resistance-related ABCB1 gene in osteosarcoma cells .These findings may provide a novel target for reversing doxorubicin resistance in OS.

N-Heterocyclic carbene-catalyzed [3 + 2] annulation of bromoenals with 3-aminooxindoles: highly enantioselective synthesis of spirocyclic oxindolo-γ-lactams.

The chiral N-heterocyclic carbene-catalyzed [3 + 2] annulation of α-bromoenals and 3-aminooxindoles was developed, giving the corresponding spirocyclic oxindolo-γ-lactams in good yields with high diastereoselectivities and enantioselectivities.

Enantioselective N-heterocyclic carbene-catalyzed synthesis of saccharine-derived dihydropyridinones with cis-selectivity.

The enantioselective N-heterocyclic carbene-catalyzed [2 + 4] cyclocondensation of α-chloroaldehydes and saccharine-derived 1-azadienes was developed, giving the corresponding saccharine-derived dihydropyridinones in good yields with exclusive cis-selectivities and excellent enantioselectivities.

Surgical Anatomy of the Radial Nerve at the Elbow and in the Forearm: Anatomical Basis for Intraplexus Nerve Transfer to Reconstruct Thumb and Finger Extension in C7 - T1 Brachial Plexus Palsy.

Background C7 - T1 palsy results in complete loss of finger motion and poses a surgical challenge. This study investigated the anatomy of the radial nerve in the elbow and forearm and the feasibility of intraplexus nerve transfer to restore thumb and finger extension. Methods The radial nerves were dissected in 28 formalin-fixed upper extremities. Branching pattern, length, diameter, and number of myelinated fibers were recorded. Results Commonly, the branching pattern (from proximal to distal) was to the brachioradialis, extensor carpi radialis longus, superficial sensory proximal to the lateral epicondyle, extensor carpi radialis brevis, supinator, extensor digitorum communis, extensor digiti minimi, extensor carpi ulnaris, abductor pollicis longus, extensor pollicis brevis, extensor pollicis longus, and extensor indicis distal to the lateral epicondyle. Conclusions Branches to the brachioradialis, extensor carpi radialis longus, and supinator can be transferred to the posterior interosseous nerve to restore hand movement in patients with C7 - T1 brachial plexus palsies; the supinator branch is probably the best choice in this regard.

N-Heterocyclic carbene-catalyzed [3 + 3] cyclocondensation of bromoenals with hydrazones: highly enantioselective synthesis of dihydropyridazones.

The N-heterocyclic carbene-catalyzed [3 + 3] cyclocondensation of bromoenals and hydrazones is developed to give the corresponding chiral 4,5-dihydropyridazones in good yields with excellent enantioselectivities.

Investigation of uterine arterial chemoembolization and uterine arterial infusion chemotherapy for advanced cervical cancer before radical radiotherapy: a long-term follow-up study.

PURPOSE: To investigate the contribution of uterine arterial chemoembolization (UACE) and uterine arterial infusion chemotherapy (UAIC) to advanced cervical cancer before radical radiotherapy. METHODS: A total of 735 patients with primary advanced cervical cancer were retrospectively studied; of these patients, 299 were classified as FIGO stage II, 359 as stage III and 77 as stage IVa. 126 underwent UACE, 103 underwent UAIC before radiotherapy, and 506 received radical radiotherapy alone (RT). Disease-specific survival (DSS), pelvic control (PC), distant metastasis-free survival (MFS), and risk factors of late toxicity were analyzed. RESULTS: The 1-, 2-, 5-, and 8-year DSS of all patients was 94.4, 82.1, 50.2, and 30.7 %, respectively. The DSS of the UACE group was 96.0, 83.4, 39.6, 18.3 %; UAIC group was 95.6, 84.3, 59.6, 42.7 % and RT group was 93.7, 80.8, 51.5, 31.5 % (χ (2) = 10.236, P = 0.006). The 1- and 2-year DSS of the UAIC and UACE groups was higher than those of the RT group (χ (2) = 2.510, P = 0.285; χ (2) = 2.822, P = 0.244). The 5- and 8-year DSS of the UACE group was obviously decreased (χ (2) = 14.962, P = 0.001; χ (2) = 14.043, P = 0.001). PC and MFS were highest in the UAIC group and lowest in the UACE group. The incidence of late radiation toxicity of the small intestine and rectosigmoid was similar. The bladder injury was highest in the UACE group (UACE:UAIC:RT = 11.1:4.8:4.2 %, χ (2) = 9.579, P = 0.008). UACE is a risk factor for late radiation toxicity of the urinary bladder. CONCLUSIONS: The use of UAIC before radical radiotherapy could improve the treatment outcome and prognosis of patients with advanced cervical cancer, while the UACE would significantly decrease long-time survival. UACE is an important risk factor for late radiation toxicity.

N-heterocyclic carbene catalyzed cyclocondensation of α,ß-unsaturated carboxylic acids: enantioselective synthesis of pyrrolidinone and dihydropyridinone derivatives.

The catalytic cyclocondensation of in situ activated α,ß-unsaturated carboxylic acids was developed. N-heterocyclic carbenes efficiently catalyzed the generation of α,ß-unsaturated acyl azolium intermediates from α,ß-unsaturated carboxylic acids via in situ generated mixed anhydrides for the enantioselective [3+2] and [3+3] cyclocondensation with α-amino ketones and alkyl(aryl)imines, respectively. The corresponding pyrrolidinones and dihydropyridinones were isolated in good yields with high to excellent enantioselectivities.

Stereoselective Fluoroalkylacylation of Alkynes via Cooperative N-Heterocyclic Carbene/Palladium Catalysis.

Herein, a cooperative N-heterocyclic carbene- and palladium-catalyzed three-component reaction of alkynes with aldehydes and fluoroalkyl iodides is developed. A series of biologically valuable CF2R-incorporated α-substituted enones was obtained in moderate to good yields. This mild catalytic method exhibits exclusive regio- and stereoselectivity, excellent functional group tolerance, and a broad substrate scope including terminal and internal alkynes. Mechanistic investigations disclose that this alkyne fluoroalkylacylation proceeds via a radical relay process in which vinyl iodides serve as putative reaction intermediates.