Para-selective nitrobenzene amination lead by C(sp2)-H/N-H oxidative cross-coupling through aminyl radical.

Arylamines, serving as crucial building blocks in natural products and finding applications in multifunctional materials, are synthesized on a large scale via an electrophilic nitration/reduction sequence. However, the current methods for aromatic C-H amination have not yet attained the same level of versatility as electrophilic nitration. Here we show an extensively investigated transition metal-free and regioselective strategy for the amination of nitrobenzenes, enabling the synthesis of 4-nitro-N-arylamines through C(sp2)-H/N-H cross-coupling between electron-deficient nitroarenes and amines. Mechanistic studies have elucidated that the crucial aspects of these reactions encompass the generation of nitrogen radicals and recombination of nitrobenzene complex radicals. The C(sp2)-N bond formation is demonstrated to be highly effective for primary and secondary arylamines as well as aliphatic amines under mild conditions, exhibiting exceptional tolerance towards diverse functional groups in both nitroarenes and amines (>100 examples with yields up to 96%). Notably, this C(sp2)-H/N-H cross-coupling exhibits exclusive para-selectivity.

Targeting FoxO proteins induces lytic reactivation of KSHV for treating herpesviral primary effusion lymphoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus consisting of both latent and lytic life cycles. Primary effusion lymphoma (PEL) is an aggressive B-cell lineage lymphoma, dominantly latently infected by KSHV. The latent infection of KSHV is persistent and poses an obstacle to killing tumor cells. Like the "shock and kill" strategy designed to eliminate latent HIV reservoir, methods that induce viral lytic reactivation in tumor latently infected by viruses represent a unique antineoplastic strategy, as it could potentially increase the specificity of cytotoxicity in cancer. Inspired by this conception, we proposed that the induction of KSHV lytic reactivation from latency could be a potential therapeutic stratagem for KSHV-associated cancers. Oxidative stress, the clinical hallmark of PEL, is one of the most prominent inducers for KSHV reactivation. Paradoxically, we found that hydrogen peroxide (H2O2) triggers robust cytotoxic effects on KSHV-negative rather than KSHV-positive B lymphoma cells in a dose-dependent manner. Mechanistically, we identified forkhead box protein O1 (FoxO1) and FoxO3 as irrevocable antioxidant defense genes and both of them are upregulated by KSHV latent infection, which is essential for the promoted ROS scavenging in KSHV-positive B lymphoma cells. Pharmacological inhibition or functional knockdown of either FoxO1 or FoxO3 is sufficient to ablate the antioxidant ability and therefore increases the intracellular ROS level that further reverses KSHV from latency to active lytic replication in PEL cells, resulting in tremendous cell death both in vitro and in vivo. Additionally, the elevated level of ROS by inhibiting FoxO proteins further sensitizes PEL cells to ROS-induced apoptosis. Our study therefore demonstrated that the lytic reactivation of KSHV by inhibiting FoxO proteins is a promising therapeutic approach for PEL, which could be further extended to other virus-associated diseases.

The Central Role of mTORC1 in Amino Acid Sensing.

The mTOR is a master regulator of cell growth that controls cell homeostasis in response to nutrients, growth factors, and other environmental cues. Recent studies have emphasized the importance of lysosomes as a hub for nutrient sensing, especially amino acid sensing by mTORC1. This review highlights recent advances in understanding the amino acid-mTORC1 signaling axis and the role of mTORC1 in cancer.

Paternal Zn-deficiency abolishes metabolic effects in offspring induced by diet type.

Accumulating evidence implicates that offspring are susceptible to paternal alterations in numerous fetal disorders, such as growth and metabolic defects. However, less study has been conducted to define the relationship between paternal zinc deficiency (ZnD) and energy metabolism of offspring. In the present study, we used a paternal ZnD exposure (Zn at 0.3 µg/g) model to test energy metabolism of male and female offspring with the intervention of diet type (high-fat diet and low-fat diet). Our results demonstrated that paternal ZnD decreased body weight (BW) gain per week (P < 0.01) and ME intake per week (P < 0.05) at 11 weeks in male offspring with high-fat diet intervention but not in female offspring. Further, anabolism and catabolism of hepatic energy products also exhibited alterations. ZnD attenuated liver glucose but increased lipids content accompanied with elevated adiponectin and reduction in leptin level in serum, which exhibited lipid metabolic disturbance and smaller ratio of liver weight to BW in male but not female offspring. The qRT-PCR and liver energy metabolites analysis revealed that paternal ZnD mainly induced reduction in glucose tolerance and lowered glucose uptaking ability in male offspring and thereby alleviated glycolysis and the tricarboxylic acid cycle (TCA) cycle, which displayed a male gender-dependency. Therefore, we propose that paternal ZnD abolishes metabolic effects in male offspring induced by diet type intervention. Our findings reveal a novel link between paternal Zn-D and offspring energy metabolism.

BVES downregulation in non-syndromic tetralogy of fallot is associated with ventricular outflow tract stenosis.

BVES is a transmembrane protein, our previous work demonstrated that single nucleotide mutations of BVES in tetralogy of fallot (TOF) patients cause a downregulation of BVES transcription. However, the relationship between BVES and the pathogenesis of TOF has not been determined. Here we reported our research results about the relationship between BVES and the right ventricular outflow tract (RVOT) stenosis. BVES expression was significantly downregulated in most TOF samples compared with controls. The expression of the second heart field (SHF) regulatory network genes, including NKX2.5, GATA4 and HAND2, was also decreased in the TOF samples. In zebrafish, bves knockdown resulted in looping defects and ventricular outflow tract (VOT) stenosis, which was mostly rescued by injecting bves mRNA. bves knockdown in zebrafish also decreased the expression of SHF genes, such as nkx2.5, gata4 and hand2, consistent with the TOF samples` results. The dual-fluorescence reporter system analysis showed that BVES positively regulated the transcriptional activity of GATA4, NKX2.5 and HAND2 promoters. In zebrafish, nkx2.5 mRNA partially rescued VOT stenosis caused by bves knockdown. These results indicate that BVES downregulation may be associated with RVOT stenosis of non-syndromic TOF, and bves is probably involved in the development of VOT in zebrafish.

DMSO/t-BuONa/O2-Mediated Aerobic Dehydrogenation of Saturated N-Heterocycles.

Aromatic N-heterocycles such as quinolines, isoquinolines, and indolines are synthesized via sodium tert-butoxide-promoted oxidative dehydrogenation of the saturated heterocycles in DMSO solution. This reaction proceeds under mild reaction conditions and has a good functional group tolerance. Mechanistic studies suggest a radical pathway involving hydrogen abstraction of dimsyl radicals from the N-H bond or α-C-H of the substrates and subsequent oxidation of the nitrogen or α-aminoalkyl radicals.

The Functional Polymorphism R129W in the BVES Gene Is Associated with Sporadic Tetralogy of Fallot in the Han Chinese Population.

Background: Tetralogy of Fallot (TOF) accounts for ∼10% of congenital heart disease cases. The blood vessel epicardial substance (BVES) gene has been reported to play a role in the function of adult hearts. However, whether allelic variants in BVES contribute to the risk of TOF and its possible mechanism remains unknown. Methods: The open reading frame of the BVES gene was sequenced using samples from 146 TOF patients and 100 unrelated healthy controls. qRT-PCR and western blot assays were used to confirm the expression of mutated BVES variants in the TOF samples. The online software Polyphen2 and SIFT were used to predict the deleterious effects of the observed allelic variants. The effects of these allelic variants on the transcriptional activities of genes were examined using dual-fluorescence reporter assays. Results: We genotyped four single nucleotide polymorphisms (SNPs) in the BVES gene from each of the 146 TOF patients. Among them, the minor allelic frequencies of c.385C>T (p.R129W) were 0.035% in TOF, but ∼0.025% in 100 controls and the Chinese Millionome Database. This allelic variant was predicted to be a potentially harmful alteration by the Polyphen2 and SIFT softwares. qRT-PCR and western blot analyses indicated that the expression of BVES in the six right ventricular outflow tract samples with the c.385C>T allelic variant was significantly downregulated. A dual-fluorescence reporter system showed that the c.385C>T allelic variant significantly decreased the transcriptional activity of the BVES gene and also decreased transcription from the GATA4 and NKX2.5 promoters. Conclusions: c.385C>T (p.R129W) is a functional SNP of the BVES gene that reduces the transcriptional activity of BVES in vitro and in vivo in TOF tissues. This subsequently affects the transcriptional activities of GATA4 and NKX2.5 related to TOF. These findings suggest that c.385C>T may be associated with the risk of TOF in the Han Chinese population.