Palladium-Catalyzed ß-C(sp3)-H Bond Arylation of Tertiary Aldehydes Facilitated by 2-Pyridone Ligands.

2-Pyridone ligand-facilitated palladium-catalyzed direct C-H bond functionalization via the transient directing group strategy has become an attractive topic. Here, we report a Pd-catalyzed direct ß-C(sp3)-H arylation reaction of tertiary aliphatic aldehydes by using an α-amino acid as a transient directing group in combination with a 2-pyridone ligand.

Combinatorial Ligand Assisted Simultaneous Control of Axial and Central Chirality in Highly Stereoselective C-H Allylation.

The significance of stereoselective C-H bond functionalization thrives on its direct application potential to pharmaceuticals or complex chiral molecule synthesis. Complication arises when there are multiple stereogenic elements such as a center and an axis of chirality to control. Over the years cooperative assistance of multiple chiral ligands has been applied to control only chiral centers. In this work, we harness the essence of cooperative ligand approach to control two different stereogenic elements in the same molecule by atroposelective allylation to synthesize axially chiral biaryls from its racemic precursor. The crucial roles played by chiral phosphoric acid and chiral amino acid ligand in concert helped us to obtain one major stereoisomer out of four distinct possibilities.

Disrupting of IGF2BP3-stabilized HK2 mRNA by MYO16-AS1 competitively binding impairs LUAD migration and invasion.

Since invasive cancer is associated with poor clinical outcomes, exploring the molecular mechanism underlying LUAD progression is crucial to improve the prognosis of patients with advanced disease. Herein, we found that MYO16-AS1 is expressed mainly in lung tissue but is notably downregulated in LUAD tissues. Overexpression of MYO16-AS1 inhibited the migration and invasion of LUAD cells. Mechanistic studies indicated that H3K27Ac modification mediated MYO16-AS1 transcription. Furthermore, we found that MYO16-AS1 competitively bound to the IGF2BP3 protein and in turn reduced IGF2BP3 protein binding to HK2 mRNA, decreasing HK2 mRNA stability and inhibiting glucose metabolism reprogramming and LUAD cell invasion in vitro and in vivo. The finding that the MYO16-AS1/IGF2BP3-mediated glucose metabolism reprogramming mechanism regulates HK2 expression provides novel insight into the process of LUAD invasion and suggests that MYO16-AS1 may be a therapeutic target for LUAD.

Access to unsaturated bicyclic lactones by overriding conventional C(sp3)-H site selectivity.

Transition metal catalysis plays a pivotal role in transforming unreactive C-H bonds. However, regioselective activation of distal aliphatic C-H bonds poses a tremendous challenge, particularly in the absence of directing templates. Activation of a methylene C-H bond in the presence of methyl C-H is underexplored. Here we show activation of a methylene C-H bond in the presence of methyl C-H bonds to form unsaturated bicyclic lactones. The protocol allows the reversal of the general selectivity in aliphatic C-H bond activation. Computational studies suggest that reversible C-H activation is followed by ß-hydride elimination to generate the Pd-coordinated cycloalkene that undergoes stereoselective C-O cyclization, and subsequent ß-hydride elimination to provide bicyclic unsaturated lactones. The broad generality of this reaction has been highlighted via dehydrogenative lactonization of mid to macro ring containing acids along with the C-H olefination reaction with olefin and allyl alcohol. The method substantially simplifies the synthesis of important bicyclic lactones that are important features of natural products as well as pharmacoactive molecules.

Circular RNA circ-FIRRE interacts with HNRNPC to promote esophageal squamous cell carcinoma progression by stabilizing GLI2 mRNA.

Increasing evidence has shown that circular RNAs (circRNAs) interact with RNA-binding proteins (RBPs) and promote cancer progression. However, the function and mechanism of the circRNA/RBP complex in esophageal squamous cell carcinoma (ESCC) are still largely unknown. Herein, we first characterized a novel oncogenic circRNA, circ-FIRRE, by RNA sequencing (Ribo-free) profiling of ESCC samples. Furthermore, we observed marked circ-FIRRE overexpression in ESCC patients with high TNM stage and poor overall survival. Mechanistic studies indicated that circ-FIRRE, as a platform, interacts with the heterogeneous nuclear ribonucleoprotein C (HNRNPC) protein to stabilize GLI2 mRNA by directly binding to its 3'-UTR in the cytoplasm, thereby resulting in elevated GLI2 protein expression and subsequent transcription of its target genes MYC, CCNE1, and CCNE2, ultimately contributing to ESCC progression. Moreover, HNRNPC overexpression in circ-FIRRE knockdown cells notably abolished circ-FIRRE knockdown-mediated Hedgehog pathway inhibition and ESCC progression impairment in vitro and in vivo. Clinical specimen results showed that circ-FIRRE and HNRNPC expression was positively correlated with GLI2 expression, which reveals the clear significance of the circ-FIRRE/HNRNPC-GLI2 axis in ESCC. In summary, our results indicate that circ-FIRRE could serve as a valuable biomarker and potential therapeutic target for ESCC and highlight a novel mechanism of the circ-FIRRE/HNRNPC complex in ESCC progression regulation.

Photoinduced meta-Selective C-H Oxygenation of Arenes.

The merger of photocatalysis and transition-metal catalysis has recently emerged as an adaptable platform for the development of innovative and environmentally benign synthetic methodologies. In contrast to classical transformation by Pd complexes, photoredox Pd catalysis operates through a radical pathway in the absence of a radical initiator. Using the synergistic merger of photoredox and Pd catalysis, we have developed a highly efficient, regioselective, and general meta-oxygenation protocol for diverse arenes under mild reaction conditions. The protocol showcases the meta-oxygenation of phenylacetic acids and biphenyl carboxylic acids/alcohols and is also amenable for a series of sulfonyls and phosphonyl-tethered arenes, irrespective of the nature and position of the substituents. Unlike thermal C-H acetoxylation which operates through the PdII/PdIV catalytic cycle, this metallaphotocatalytic C-H activation involves PdII/PdIII/PdIV intermediacy. The radical nature of the protocol is established through radical quenching experiments and EPR analysis of the reaction mixture. Furthermore, the catalytic path of this photoinduced transformation is established through control reactions, absorption spectroscopy, luminescence quenching, and kinetic studies.

Site-Selective C-H Functionalization of Carbazoles.

Carbazole alkaloids hold great potential in pharmaceutical and material sciences. However, the current approaches for C1 functionalization of carbazoles rely on the use of a pre-installed directing group, severely limiting their applicability and hindering their overall efficiency. Herein, we report for the first time the development of direct Pd-catalyzed C-H alkylation and acylation of carbazoles assisted by norbornene (NBE) as a transient directing mediator. Notably, the involvement of a six-membered palladacycle intermediate was suggested in this case, representing the first example of such intermediacy within the extensively studied Pd/norbornene reactions realm.

Identification of a transcription factor­cyclin family genes network in lung adenocarcinoma through bioinformatics analysis and validation through RT­qPCR.

Lung adenocarcinoma (LUAD) is the predominant pathological subtype of lung cancer, which is the most prevalent and lethal malignancy worldwide. Cyclins have been reported to regulate the physiology of various types of tumors by controlling cell cycle progression. However, the key roles and regulatory networks associated with the majority of the cyclin family members in LUAD remain unclear. In total, 556 differentially expressed genes were screened from the GSE33532, GSE40791 and GSE19188 mRNA microarray datasets by R software. Subsequently, protein-protein interaction network containing 499 nodes and 4,311 edges, in addition to a significant module containing 76 nodes and 2,631 edges, were extracted through the MCODE plug-in of Cytoscape. A total of four cyclin family genes [cyclin (CCNA2, CCNB1, CCNB2 and CCNE2] were then found in this module. Further co-expression analysis and associated gene prediction revealed forkhead box M1 (FOXM1), the common transcription factor of CCNB2, CCNB1 and CCNA2. In addition, using GEPIA database, it was found that the high expression of these four genes were simultaneously associated with poorer prognosis in patients with LUAD. Experimentally, it was proved that these four hub genes were highly expressed in LUAD cell lines (Beas-2B and H1299) and LUAD tissues through qPCR, western blot analysis and immunohistochemical studies. The diagnostic value of these 4 hub genes in LUAD was analyzed by logistic regression, CCNA2 was deleted, following which a nomogram diagnostic model was constructed accordingly. The area under the curve values of CCNB1, CCNB2 and FOXM1 diagnostic models were calculated to be 0.92, 0.91 and 0.96 in the training set (Combined dataset of GSE33532, GSE40791 and GSE19188) and two validation sets (GSE10072 and GSE75037), respectively. To conclude, data from the present study suggested that the FOXM1/cyclin (CCNA2, CCNB1 and/or CCNB2) axis may serve a regulatory role in the development and prognosis of LUAD. Specifically, CCNB1, CCNB2 and FOXM1 have potential as diagnostic markers and/or therapeutic targets for LUAD treatment.

Ligand-promoted palladium-catalyzed ß-methylene C-H arylation of primary aldehydes.

The transient directing group (TDG) strategy allowed long awaited access to the direct ß-C(sp3)-H functionalization of unmasked aliphatic aldehydes via palladium catalysis. However, the current techniques are restricted to terminal methyl functionalization, limiting their structural scopes and applicability. Herein, we report the development of a direct Pd-catalyzed methylene ß-C-H arylation of linear unmasked aldehydes by using 3-amino-3-methylbutanoic acid as a TDG and 2-pyridone as an external ligand. Density functional theory calculations provided insights into the reaction mechanism and shed light on the roles of the external and transient directing ligands in the catalytic transformation.

Ligand-Enabled δ-C(sp3 )-H Borylation of Aliphatic Amines.

Directed C-H functionalization has been realized as a complimentary technique to achieve borylation at a distal position of aliphatic amines. Here, we demonstrated the oxidative borylation at the distal δ-position of aliphatic amines using various borylating agents, a palladium catalyst, and a rightly tuned ligand in the presence of a cheap oxidant. Moreover, an organopalladium δ-C(sp3 )-H-activated intermediate has been isolated and crystallographically characterized to get mechanistic insight.

The mediation effect of maternal glucose on the association between ambient air pollution and birth weight in Foshan, China.

Maternal blood glucose level is associated with fetal growth, therefore, its role in the associations between air pollution and birth weight deserves investigation. We examined the mediation effect of maternal blood glucose on the associations between maternal air pollution exposure and birth weight. A total of 10,904 pregnant women in Foshan, China during 2015-2019 were recruited. Oral glucose tolerance test (OGTT) was administered to each participant after late trimester 2. Air pollution data at the monitoring stations in residential districts was used to estimate exposures of each participant during trimester 1 and trimester 2. Mixed-effects linear models were used to estimate the associations between air pollution and birth weight. After controlling for ten covariates, the direct effect of PM2.5 and SO2 (each 10 µg/m3 increment) on birth weight was -15.7 g (95% CI: -29.4, -4.8 g) and -83.6 g (95% CI: -134.8, -33.0 g) during trimester 1. The indirect effect of PM2.5 and SO2 (each 10 µg/m3 increment) on birth weight by increasing maternal fasting glucose level was 6.6 g (95% CI: 4.6, 9.1 g) and 22.0 g (95% CI: 4.1, 44.0 g) during trimester 1. Our findings suggest that air pollution might affect the birth weight through direct and indirect pathway, and the indirect effect might be mediated by maternal blood glucose.

Clinical efficacy of Baihe Gujin decoction combined with anti-tuberculosis therapy for pulmonary tuberculosis with Yin-deficiency and Fire-hyperactivity syndrome.

OBJECTIVE: To evaluate the clinical efficacy of Baihe Gujin decoction combined with anti-tuberculosis therapy in mitigating the symptoms of pulmonary tuberculosis and to measure the effect on the CD4+ CD25+ regulatory T cell (Treg) ratio. METHODS: This randomized study enrolled patients with pulmonary tuberculosis and randomly assigned them to one of two treatment groups: an anti-tuberculosis treatment group and a combined treatment group. Bronchoalveolar lavage was performed before and 2 weeks after treatment. The ratio of CD4+ CD25+ Treg cells and the levels of tumour necrosis factor (TNF)-α, interleukin (IL)-4, IL-6 and IL-12 in peripheral blood and bronchoalveolar lavage fluid were measured. Symptoms were recorded before and after treatment. RESULTS: A total of 100 patients were enrolled and assigned to the anti-tuberculosis (n = 58) and combined treatment groups (n = 42). In the combined treatment group, Leicester Cough Questionnaire score, erythrocyte sedimentation rate, CD4+ CD25+ Treg cell ratio in bronchoalveolar lavage fluid, cytokine levels, chest pain score and sleep disorder score were significantly decreased compared with the anti-tuberculosis treatment group after treatment. The leukocyte count, haemoglobin level, platelet and alanine aminotransferase levels did not differ significantly between the two groups after treatment. The creatinine level in the combined treatment group was significantly lower than that in the anti-tuberculosis treatment group. CONCLUSION: Baihe Gujin decoction combined with anti-tuberculosis treatment can effectively alleviate the symptoms of pulmonary tuberculosis, enhance the host immune function and protect renal function.

Recent Advances in the Application of Selectfluor as a "Fluorine-free" Functional Reagent in Organic Synthesis.

Selectfluor, [1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate)], is not only an important electrophilic fluorinating agent but also a facile and efficient "fluorine-free" functional reagent in other organic reactions. In this Minireview, we will present a brief history of Selectfluor as a transition metal oxidant, fluorine cation and radical initiator in "fluorine-free" functionalizations over the last five years.

Maternal air pollution exposure associated with risk of congenital heart defect in pre-pregnancy overweighted women.

OBJECTIVES: Prenatal exposure to air pollutant has been associated with congenital heart defect (CHD). However, no study has investigated this effect in pre-pregnancy overweighted women. This study aimed to evaluate gestational exposure to particulate pollutant (PM2.5) and gaseous air pollutants (O3 and NO2) on the risk of CHD, and explore the potential effect modifiers including maternal age, pre-pregnancy BMI and pregestational diseases. METHODS: In this birth cohort study, a total of 63,213 pregnant women in Foshan, China were initially recruited and followed from their first hospital visit for pregnancy to delivery during 2015-2019. CHD cases were confirmed by the records in hospital- and population- based birth defect surveillance systems. Air pollutant exposures were estimated by the daily concentrations measured in air monitoring stations in each participant's residential county. Mixed-effects regression models, adjusted for potential confounding factors were applied to estimate the associations between air pollutant and CHD during the first three months of the pregnancy. RESULTS: A total of 985 (1.6%) newborns were identified as CHD cases. For each 10 µg/m3 increase in ambient O3 during the 1st month, the OR values for CHD were 1.03 (95% CI: 0.94, 1.13) in pre-pregnancy normal weighted women and 1.24 (95% CI: 1.01, 1.53) in pre-pregnancy overweighted women. For each 10 µg/m3 increase in NO2 during the 3rd month, the OR values for CHD were 1.09 (95% CI: 1.01, 1.18) in pre-pregnancy normal weighted women and 1.27 (95% CI: 1.07, 1.51) in pre-pregnancy overweighted women. No significant associations were found between PM2.5 exposure and CHD in our analysis. CONCLUSIONS: This study demonstrates that gaseous air pollutants (O3 and NO2) exposure during the cardiac embryogenesis period is associated with an increased risk of CHD, particularly for pre-pregnancy overweighted women.

Lack of association between polymorphism of IL-2 -330T/G and pulmonary tuberculosis among Caucasians.

This meta-analysis was conducted to assess the consistency and strength of the relationship between polymorphism of IL-2 -330T/G and susceptibility to pulmonary tuberculosis (TB). PubMed, Web of Knowledge and CNKI were searched to find eligible studies about the relationship between IL-2 -330T/G polymorphism and susceptibility to pulmonary TB. A total of eight studies comprising 971 cases and 1519 controls were grouped together for the purpose of elucidating the relationship between polymorphism of IL-2 -330T/G and pulmonary TB susceptibility. The allele model (G vs. T: odds ratio (OR) = 1.34; 95% confidence interval (CI) 1.05-1.71, Phet = 0.001) and the recessive model (GG+GT vs. TT: OR = 1.60; 95% CI 1.08-2.38, Phet = 0.0001) showed an increased risk of development of pulmonary TB. However, the homozygous model (GG vs. TT: OR = 1.74; 95% CI 0.98-3.09, Phet = 0.0005) and the dominant model (GG vs. TT + TG: OR = 1.30; 95% CI = 0.80-2.14, Phet = 0.001) failed to show an increased incidence of pulmonary TB. When analysis was stratified by ethnicity, no obvious associations were identified in the Caucasian subgroup under all four genetic models. Additionally, heterogeneity disappeared in the analysis of Caucasian subgroup. Our combined data suggested that there was no association between IL-2 -330T/G polymorphism and pulmonary TB among Caucasians.

Palladium-catalyzed direct asymmetric C-H bond functionalization enabled by the directing group strategy.

In the past decade, selective C-C and C-heteroatom bond construction through palladium-catalyzed direct C-H bond functionalization has been extensively studied by employing a variety of directing groups. Within this category, direct asymmetric C(sp2)-H and C(sp3)-H activation for the construction of highly enantiomerically enriched skeletons still progressed at a slow pace. This minireview briefly introduces the major advances in the field for palladium-catalyzed direct asymmetric C-H bond functionalization via the directing group strategy.

Ligand-Controlled Direct γ-C-H Arylation of Aldehydes.

The first example of PdII -catalyzed γ-C(sp3 )-H functionalization of aliphatic and benzoheteroaryl aldehydes has been developed using a transient ligand and an external ligand, concurrently. A wide array of γ-arylated aldehydes were readily accessed without preinstalling internal directing groups. The catalytic mechanism was studied by performing deuterium-labelling experiments, which indicated that the γ-C(sp3 )-H bond cleavage is the rate-limiting step during the reaction process. This reaction could be performed on a gram scale, and also demonstrated its potential application in the synthesis of new mechanofluorochromic materials with blue-shifted mechanochromic properties.

Silver-Promoted Site-Selective Intramolecular Cyclization of 2-Methylthiobenzamide Through α-C(sp3)-H Functionalization.

Silver-mediated intramolecular α-C(sp3)-H bond functionalization of the methylthio group has been established in the presence of Selectfluor as an additive. This novel strategy provides efficient access to various diverse sulfur-based heterocycles with good yields and functional group compatibility. It is noteworthy that the completely novel benzooxathiin-4-imine skeletons were reported for the first time in this study.

AMMECR1 Inhibits Apoptosis and Promotes Cell-cycle Progression and Proliferation of the A549 Human Lung Cancer Cell Line.

AIM: The aim of this study was to characterize the role of Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis chromosomal region gene 1 (AMMECR1) in human lung cancer cell lines. MATERIALS AND METHODS: AMMECR1 gene expression was evaluated in four lung cell lines, with A549 then selected for further in-depth examination. To characterize the role of AMMECR1, silencing was achieved utilizing lentivirus-mediated RNA interference, and confirmed by quantitative real-time polymerase chain reaction and western blotting. The impact of AMMECR1 silencing on cellular proliferation was assessed using Celigo-based and MTT assays. Apoptosis was determined using the annexin V-allophycocyanin single staining method. Cell-cycle arrest was assessed by flow cytometry. Finally, colony formation was assessed using Giemsa staining. RESULTS: In A549 cells, AMMECR1 silencing was found to significantly suppress cell proliferation, reduce colony formation, promote apoptosis, and arrest cells in the S and G2/M phases. CONCLUSION: AMMECR1 plays a critical role in cell proliferation, cell-cycle progression, and apoptosis of human lung cancer cells, and may serve as a potential therapeutic target for non-small-cell lung cancer.

Highly selective electrochemical hydrogenation of alkynes: Rapid construction of mechanochromic materials.

Electrochemical hydrogenation has emerged as an environmentally benign and operationally simple alternative to traditional catalytic reduction of organic compounds. Here, we have disclosed for the first time the electrochemical hydrogenation of alkynes to a library of synthetically important Z-alkenes under mild conditions with great selectivity and efficiency. The deuterium and control experiments of electrochemical hydrogenation suggest that the hydrogen source comes from the solvent, supporting electrolyte, and base. The scanning electron microscopy and x-ray diffraction experiments demonstrate that palladium nanoparticles generated in the electrochemical reaction act as a chemisorbed hydrogen carrier. Moreover, complete reduction of alkynes to saturated alkanes can be achieved through slightly modified conditions. Furthermore, a series of novel mechanofluorochromic materials have been efficiently constructed with this protocol that showed blue-shifted mechanochromism. This discovery represents the first example of cis-olefins-based organic mechanochromic materials.