Unraveling the 2,3-diketo-L-gulonic acid-dependent and -independent impacts of L-ascorbic acid on somatic cell reprogramming.

BACKGROUND: L-ascorbic acid (Asc) plays a pivotal role in regulating various biological processes, including somatic cell reprogramming, through multiple pathways. However, it remains unclear whether Asc regulates reprogramming directly or functions through its metabolites. RESULTS: Asc exhibited dual capabilities in promoting reprogramming through both 2,3-diketo-L-gulonic acid (DKG), a key metabolite during Asc degradation, dependent and independent routes. On the one hand, Asc facilitated reprogramming by promoting cell proliferation and inducing the conversion from pre-induced pluripotent stem cells (pre-iPSCs) to iPSCs through DKG-independent pathways. Additionally, Asc triggered mesenchymal-epithelial transition (MET) and activated glycolysis via DKG-dependent mechanisms. Notably, DKG alone activated a non-canonical tricarboxylic acid cycle characterized by increased succinate, fumarate, and malate. Consequently, this shift redirected oxidative phosphorylation toward glycolysis and induced MET. Moreover, owing to its antioxidant capabilities, Asc directly inhibited glycolysis, thereby preventing positive feedback between glycolysis and epithelial-mesenchymal transition, ultimately resulting in a higher level of MET. CONCLUSION: These findings unveil the intricate functions of Asc in the context of reprogramming. This study sheds light on the DKG-dependent and -independent activities of Asc during reprogramming, offering novel insights that may extend the application of Asc to other biological processes.

Nuclear localization of TET2 requires ß-catenin activation and correlates with favourable prognosis in colorectal cancer.

Mutation-induced malfunction of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is widely reported in haematological malignancies. However, the role of TET2 in solid cancers, including colorectal cancer (CRC), is unclear. Here, we found that TET2 malfunction in CRC is mostly due to decreased nuclear localization and that nuclear localization of TET2 is correlated with better survival of patients. To explore the underlying mechanisms, 14 immortalized solid tumour cell lines and 12 primary CRC cell lines were used. TET2 was mostly detected in the nucleus, and it induced significant DNA demethylation and suppressed cell growth by demethylating RORA and SPARC in cell lines like SW480. While in cell lines like SW620, TET2 was observed in the cytosol and did not affect DNA methylation or cell growth. Further examination with immunoprecipitation-mass spectrometry illustrated that ß-catenin activation was indispensable for the nuclear localization and tumour suppression effects of TET2. In addition, the ß-catenin pathway activator IM12 and the TET2 activator vitamin C were used simultaneously to enhance the effects of TET2 under low-expression conditions, and synergistic inhibitory effects on the growth of cancer were observed both in vitro and in vivo. Collectively, these data suggest that ß-catenin-mediated nuclear localization of TET2 is an important therapeutic target for solid tumours.

An Asymmetric Cross-Linked Ionic Copolymer Hybrid Solid Electrolyte with Super Stretchability for Lithium-Ion Batteries.

Composite solid electrolytes are recommended to be the most promissing strategy for solid-state batteries because they combine the advantages of inorganic ceramics and polymers. However, the huge interfacial resistance between the inorganic ceramic and polymer results in low ionic conductivity, which is still the major impediment that limits their applications. Herein, a novel highly elastic and weakly coordinated ionic copolymer hybrid electrolyte with asymmetric structure based on surface-modified Li1.5 Al0.5 Ge1.5 (PO4 )3 by "in situ" polymerization is proposed to improve ionic conductivity and mechanical properties simultaneously. The all-solid hybrids electrolytes exhibit room-temperature ionic conductivity up to 2.61 × 10-4 S cm-1 and lithium-ion transference number of 0.41. The hybrids electrolytes can be repeatedly stretching-releasing-stretching, showing a super stretchability with the elongation at break up to 496%. The Li symmetrical cells assembled with the hybrid electrolytes can continuously operate for 800 h at 0.1 mA cm-2 without discernable dendrites, indicating good interfacial compatibility between the hybrid electrolytes and lithium electrodes. The Li|LiFePO4 batteries assembled with the hybrid electrolytes deliver an initial discharge specific capacity of 165.5 mAh g-1 with an initial coulombic efficiency of 94.8% and 154 mAh g-1 after 100 cycles at 0.1 C, and maintain 95.4% capacity retention after 100 cycles at 0.5 C.