Photoinduced Copper-Catalyzed Asymmetric Three-Component Radical 1,2-Azidooxygenation of 1,3-Dienes.

Radical-involved multicomponent difunctionalization of 1,3-dienes has recently emerged as a promising strategy for rapid synthesis of valuable allylic compounds in one-pot operation. However, the expansion of radical scope and enantiocontrol remain two major challenges. Herein, we describe an unprecedented photoinduced copper-catalyzed highly enantioselective three-component radical 1,2-azidooxygenation of 1,3-dienes with readily available azidobenziodazolone reagent and carboxylic acids. This mild protocol exhibits a broad substrate scope, high functional group tolerance, and exceptional control over chemo-, regio- and enantioselectivity, providing practical access to diverse valuable azidated chiral allylic esters. Mechanistic studies imply that the chiral copper complex is implicated as a bifunctional catalyst in both the photoredox catalyzed azidyl radical generation and enantioselective radical C-O cross-coupling.

A wide-range ratiometric sensor mediating fluorescence and scattering based on carbon dots/metal-organic framework composites for the detection of bisulfite/sulfite in sugar.

Bisulfite (HSO3-) and sulfite (SO32-) are commonly employed in food preservatives and are also significant environmental pollutants. Thus, developing an effective method for detecting HSO3-/SO32- is crucial for food safety and environment monitoring. In this work, based on carbon dots (CDs) and zeolitic imidazolate framework-90 (ZIF-90), a composite probe (named CDs@ZIF-90) is constructed. The fluorescence signal and the second-order scattering signal of CDs@ZIF-90 are employed to ratiometricly detect HSO3-/SO32-. This proposed strategy exhibits a broad linear range for HSO3-/SO32- determination (10 µM to 8.5 mM) with a limit of detection of 2.74 µM. This strategy is successfully applied for evaluating HSO3-/SO32- in sugar with satisfactory recoveries. Therefore, this work has uniquely combined the fluorescence and second-order scattering signals to establish a novel sensing system with a wide linear range, which is applicable for ratiometric sensing of HSO3-/SO32- in actual samples.

Disturbance of Fatty Acid Metabolism Promoted Vascular Endothelial Cell Senescence via Acetyl-CoA-Induced Protein Acetylation Modification.

Endothelial cell senescence is the main risk factor contributing to vascular dysfunction and the progression of aging-related cardiovascular diseases. However, the relationship between endothelial cell metabolism and endothelial senescence remains unclear. The present study provides novel insight into fatty acid metabolism in the regulation of endothelial senescence. In the replicative senescence model and H2O2-induced premature senescence model of primary cultured human umbilical vein endothelial cells (HUVECs), fatty acid oxidation (FAO) was suppressed and fatty acid profile was disturbed, accompanied by downregulation of proteins associated with fatty acid uptake and mitochondrial entry, in particular the FAO rate-limiting enzyme carnitine palmitoyl transferase 1A (CPT1A). Impairment of fatty acid metabolism by silencing CPT1A or CPT1A inhibitor etomoxir facilitated the development of endothelial senescence, as implied by the increase of p53, p21, and senescence-associated ß-galactosidase, as well as the decrease of EdU-positive proliferating cells. In the contrary, rescue of FAO by overexpression of CPT1A or supplement of short chain fatty acids (SCFAs) acetate and propionate ameliorated endothelial senescence. In vivo, treatment of acetate for 4 weeks lowered the blood pressure and alleviated the senescence-related phenotypes in aortas of Ang II-infused mice. Mechanistically, fatty acid metabolism regulates endothelial senescence via acetyl-coenzyme A (acetyl-CoA), as implied by the observations that suppression of acetyl-CoA production using the inhibitor of ATP citrate lyase NDI-091143 accelerated senescence of HUVECs and that supplementation of acetyl-CoA prevented H2O2-induced endothelial senescence. Deficiency of acetyl-CoA resulted in alteration of acetylated protein profiles which are associated with cell metabolism and cell cycle. These findings thus suggest that improvement of fatty acid metabolism might ameliorate endothelial senescence-associated cardiovascular diseases.

CRISPR/Cas9 from bench to bedside: what clinicians need to know before application?

In October 2020, Dr. Emmanuelle Charpentier and Dr. Jennifer Doudna won the Nobel Prize in Chemistry for their pioneering work in precise genome editing using the CRISPR technology. Although CRISPR technology has developed rapidly in the last decade, there are still many uncertainties before eventual use in clinical settings. In this mini review, we summarize the current efforts in addressing the limitations of CRISPR technology and future directions.

mTORC2 facilitates endothelial cell senescence by suppressing Nrf2 expression via the Akt/GSK-3ß/C/EBPα signaling pathway.

Vascular endothelial cell senescence is a leading cause of age-associated and vascular diseases. Mammalian target of rapamycin complex 2 (mTORC2) is a conserved serine/threonine (Ser/Thr) protein kinase that plays an important regulatory role in various cellular processes. However, its impact on endothelial senescence remains controversial. In this study we investigated the role and molecular mechanisms of mTORC2 in endothelial senescence. A replicative senescence model and H2O2-induced premature senescence model were established in primary cultured human umbilical vein endothelial cells (HUVECs). In these senescence models, the formation and activation of mTORC2 were significantly increased, evidenced by the increases in binding of Rictor (the essential component of mTORC2) to mTOR, phosphorylation of mTOR at Ser2481 and phosphorylation of Akt (the effector of mTORC2) at Ser473. Knockdown of Rictor or treatment with the Akt inhibitor MK-2206 attenuated senescence-associated ß-galactosidase (ß-gal) staining and expression of p53 and p21 proteins in the senescent endothelial cells, suggesting that mTORC2/Akt facilitates endothelial senescence. The effect of mTORC2/Akt on endothelial senescence was due to suppression of nuclear factor erythroid 2-related factor 2 (Nrf2) at the transcriptional level, since knockdown of Rictor reversed the reduction of Nrf2 mRNA expression in endothelial senescence. Furthermore, mTORC2 suppressed the expression of Nrf2 via the Akt/GSK-3ß/C/EBPα signaling pathway. These results suggest that the mTORC2/Akt/GSK-3ß/C/EBPα/Nrf2 signaling pathway is involved in both replicative and inducible endothelial senescence. The deleterious role of mTORC2 in endothelial cell senescence suggests therapeutic strategies (targeting mTORC2) for aging-associated diseases and vascular diseases.

Early administration of tumor necrosis factor-alpha antagonist promotes survival of transplanted neural stem cells and axon myelination after spinal cord injury in rats.

Neural stem cell (NSC) transplantation has been reported to be a leading strategy to stimulate neuroplasticity, repair neuronal loss and promote the morphologic and functional recovery of spinal cord injury (SCI). However, massive death of transplanted NSCs is still a problem, which is considered to be related to a series of pro-inflammatory cytokines that induce apoptosis, extensive demyelination and axonal destruction. Tumor necrosis factor alpha (TNF-α), as one of the major inflammation initiators, contributes to secondary neural cell death. We previously found that the administration of the TNF-α antagonist etanercept during the acute phase of SCI can reduce the apoptosis of neurons and oligodendrocytes. To investigate whether etanercept can suppress transplanted NSC apoptosis and promote NSC survival, axon myelination and functional recovery, we tested the combination strategy of the early administration of etanercept and NSC transplantation. First we observed that etanercept suppressed the TNF-α expression and apoptosis of transplanted NSCs by Western blot, TUNEL and immunofluorescence staining. The Basso, Beattle and Bresnahan scale and motor-evoked potential were used to evaluate functional recovery. The results suggest significantly better recovery after combination therapy. Further, histopathological alterations were evaluated by hematoxylin and eosin staining and Nissl staining. These procedures showed that the early administration of etanercept improved survival of neurons in the ventral horn, restored neural morphology and produced a smaller cavity area. We observed most abundant NF-positive fibers after the combination treatment, indicating that combination therapy retained and promoted neural regeneration. Finally, the early suppression of TNF-α reduced the occurrence of demyelination, and the combination therapy led to more myelinated axons, as shown by electron microscopy. These data suggest that this strategy significantly protected transplanted NSCs via the anti-inflammation and anti-apoptosis effects of etanercept, promoting re-myelination, neural regeneration and locomotor function.