Implications of GCLC in prognosis and immunity of lung adenocarcinoma and multi-omics regulation mechanisms.

BACKGROUND: Ferroptosis is an iron-dependent type of regulated cell death, and has been implicated in lung adenocarcinoma (LUAD). Evidence has proved the key role of glutamate-cysteine ligase catalytic subunit (GCLC) in ferroptosis, but its role in LUAD remains unclear. Herein, we explored the implications of GCLC and relevant genes in LUAD prognosis and immunity as well as underlying molecular mechanisms. METHODS: This work gathered mRNA, miRNA, DNA methylation, somatic mutation and copy-number variation data from TCGA-LUAD. WGCNA was utilized for selecting GCLC-relevant genes, and a GCLC-relevant prognostic signature was built by uni- and multivariate-cox regression analyses. Immune compositions were estimated via CIBERSORT, and two immunotherapy cohorts of solid tumors were analyzed. Multi-omics regulatory mechanisms were finally assessed. RESULTS: Our results showed that GCLC was overexpressed in LUAD, and potentially resulted in undesirable survival. A prognostic model was generated, which owned accurate and independent performance in prognostication. GCLC, and relevant genes were notably connected with immune compositions and immune checkpoints. High GCLC expression was linked with better responses to anti-PD-L1 and anti-CTLA-4 treatment. Their possible DNA methylation sites were inferred, e.g., hypomethylation in cg19740353 might contribute to GCLC up-regulation. Frequent genetic mutations also affected their expression. Upstream transcription factors (E2F1/3/4, etc.), post-transcriptional regulation of miRNAs (hsa-mir-30c-1, etc.), lncRNAs (C8orf34-AS1, etc.), and IGF2BP1-mediated m6A modification were identified. It was also found NOP58-mediated SUMOylation post-translational modification. CONCLUSIONS: Together, we show that GCLC and relevant genes exert crucial roles in LUAD prognosis and immunity, and their expression can be controlled by complex multi-omics mechanisms.

Three new MnII-[MoIII(CN)7]4- molecular magnets constructed from chiral bidentate chelating ligands.

Three new cyanide-bridged compounds {[Mn((S,S)-Dpen)]3[Mn((S,S)-Dpen)(H2O)][Mo(CN)7]2·4H2O·4C2H3N}n (1-SS), {[Mn((R,R)-Dpen)]3[Mn((R,R)-Dpen)(H2O)][Mo(CN)7]2·4.5H2O·4C2H3N}n (1-RR), and {[Mn(Chxn)][Mn(Chxn)(H2O)0.8][Mo(CN)7]·H2O·4C2H3N}n (2) (SS/RR-Dpen = (S,S)/(R,R)-1,2-diphenylethylenediamine and Chxn = 1,2-cyclohexanediamine) have been successfully synthesized from the self-assembly reaction of the [MoIII(CN)7]4- unit, the MnII ions, and two chiral bidentate chelating ligands. Single-crystal structure determinations show that compounds 1-SS and 1-RR containing ligands SS/RR-Dpen are enantiomers and crystallize in the chiral space group P21. On the other hand, compound 2 crystallizes in the achiral centrosymmetric space group P1̄ due to the racemization of the SS/RR-Chxn ligands during the growth of the crystals. Despite their different space groups and ligands, all three compounds exhibit similar framework structures consisting of cyano-bridged MnII-MoIII two-dimensional layers separated by the bidentate ligands. The circular dichroism (CD) spectra have further demonstrated the enantiopure character of compounds 1-SS and 1-RR. Magnetic measurements revealed that all three compounds display ferrimagnetic ordering with similar critical temperatures of about 40 K. The chiral enantiomers 1-SS and 1-RR exhibit the magnetic hysteresis loop with a coercive field of about 8000 Oe at 2 K, which is by far the highest for all known MnII-[MoIII(CN)7]4- magnets. Analyses of their structures and magnetic properties indicated that their magnetic properties depend on the anisotropic magnetic interactions between the MnII and MoIII centers, which are closely related to the C-N-M bond angles.

Effects of Fdft 1 gene silencing and VD3 intervention on lung injury in hypoxia-stressed rats.

BACKGROUND: Hypoxia can induce lung injury such as pulmonary arterial hypertension and pulmonary edema. And in the rat model of hypoxia-induced lung injury, the expression of Farnesyl diphosphate farnesyl transferase 1 (Fdft 1) was highly expressed and the steroid biosynthesis pathway was activated. However, the role of Fdft 1 and steroid biosynthesis pathway in hypoxia-induced lung injury remains unclear. OBJECTIVE: The study aimed to further investigate the relationship between Fdft1 and steroid biosynthesis pathway with hypoxia-induced lung injury. METHODS: A rat model of lung injury was constructed by hypobaric chamber with hypoxic stress, the adenovirus interference vector was used to silence the expression of Fdft 1, and the exogenous steroid biosynthesis metabolite Vitamin D3 (VD3) was used to treat acute hypoxia-induced lung injury in rats. RESULTS: Sh-Fdft 1 and exogenous VD3 significantly inhibited the expression of Fdft 1 and the activation of the steroid pathway in hypoxia-induced lung injury rats, which showed a synergistic effect on the steroid activation pathway. In addition, sh-Fdft 1 promoted the increase of pulmonary artery pressure and lung water content, the decrease of oxygen partial pressure and oxygen saturation, and leaded to the increase of lung cell apoptosis and the aggravation of mitochondrial damage in hypoxia-stressed rats. And VD3 could significantly improve the lung injury induced by hypoxia and sh-Fdft 1 in rats. CONCLUSIONS: Fdft 1 gene silencing can promote hypoxic-induced lung injury, and exogenous supplement of VD3 has an antagonistic effect on lung injury induced by Fdft 1 gene silencing and hypoxic in rats, suggesting that VD3 has a preventive and protective effect on the occurrence and development of hypoxia-induced lung injury.