Neuronal ferroptosis and ferroptosis-mediated endoplasmic reticulum stress: Implications in cognitive dysfunction induced by chronic intermittent hypoxia in mice.

Obstructive sleep apnea, typically characterized by chronic intermittent hypoxia (CIH), is linked to cognitive dysfunction in children. Ferroptosis, a novel form of cell death characterized by lethal iron accumulation and lipid peroxidation, is implicated in neurodegenerative diseases and ischemia-reperfusion injuries. Nevertheless, its contribution to CIH-induced cognitive dysfunction and its interaction with endoplasmic reticulum stress (ERS) remain uncertain. In this study, utilizing a CIH model in 4-week-old male mice, we investigated ferroptosis and its potential involvement in ERS regulation during cognitive dysfunction. Our findings indicate ferroptosis activation in prefrontal cortex neurons, leading to neuron loss, mitochondrial damage, decreased levels of GPX4, SLC7A11, FTL, and FTH, increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), Fe2+, ACSL4, TFRC, along with the activation of ERS-related PERK-ATF4-CHOP pathway. Treatment with the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) effectively mitigated the neuron injury and cognitive dysfunction induced by CIH, significantly reducing Fe2+ and partly restoring expression levels of ferroptosis-related proteins. Furhermore, the use of Lip-1 and DFO downregulated p-PERK, ATF4 and CHOP, and upregulated Nrf2 expression, suggesting that inhibiting ferroptosis reduce ERS and that the transcription factor Nrf2 is involved in the process. In summary, our findings indicate that cognitive impairment in CIH mice correlates with the induction of neuronal ferroptosis, facilitated by the System xc - GPX4 functional axis, lipid peroxidation, and the iron metabolism pathway, along with ferroptosis-mediated ERS in the prefrontal cortex. Nrf2 has been identified as a potential regulator of ferroptosis and ERS involved in the context of CIH.

Evaluation of the novel endophytic fungus Chaetomium ascotrichoides 1-24-2 from Pinus massoniana as a biocontrol agent against pine wilt disease caused by Bursaphelenchus xylophilus.

BACKGROUND: Bursaphelenchus xylophilus, the causative agent of pine wilt disease (PWD), is an ever-increasing threat to Pinus forests worldwide. This study aimed to develop biological control of PWD by the application of endophytic fungi isolated from healthy pine trees. RESULTS: We successfully isolated a novel endophytic fungal strain 1-24-2 from branches of healthy Pinus massoniana. The culture filtrates (CFs) of strain 1-24-2 exhibited strong nematicidal activity against Bursaphelenchus xylophilus, with a corrected mortality rate of 99.00%. Based on the morphological and molecular characteristics, the isolated strain 1-24-2 was identified as Chaetomium ascotrichoides. In the in-planta assay, pine seedlings (2-years-old) treated with 1-24-2 CFs + pine wood nematode (T2) showed a significant control effect of 80%. A total of 24 toxic compounds were first identified from 1-24-2 CFs through gas chromatography-mass spectrometry (GC-MS) analysis, from which O-methylisourea, 2-chlorobenzothiazole, and 4,5,6-trihydroxy-7-methylphthalide showed robust binding sites at Tyr119 against phosphoethanolamine methyltransferase (PMT) protein of Bursaphelenchus xylophilus by molecular docking approach and could be used as potential compounds for developing effective nematicides. Interestingly, strain 1-24-2 produces toxic volatile organic compounds (VOCs), which disturb the natural development process of B. xylophilus, whose total number decreased by up to 83.32% in the treatment group as compared to control and also reduced Botrytis cinerea growth by up to 71.01%. CONCLUSION: Our results highlight the potential of C. ascotrichoides 1-24-2 as a promising biocontrol agent with solid nematicidal activity against B. xylophilus. This is the first report of C. ascotrichoides isolated from P. massoniana exhibiting strong biocontrol potential against B. xylophilus in the world. © 2024 Society of Chemical Industry.

Small molecules targeting c-Myc oncogene: promising anti-cancer therapeutics.

The nuclear transcription factor c-Myc is a member of the Myc gene family with multiple functions and located on band q24.1 of chromosome 8. The c-Myc gene is activated by chromosomal translocation, rearrangement, and amplification. Its encoded protein transduces intracellular signals to the nucleus, resulting in the regulation of cell proliferation, differentiation, and apoptosis, and has the ability to transform cells and bind chromosomal DNA. c-Myc also plays a critical role in malignant transformation. The abnormal over-expression of c-Myc is frequently observed in some tumors, including carcinomas of the breast, colon, and cervix, as well as small-cell lung cancer, osteosarcomas, glioblastomas, and myeloid leukemias, therefore making it a possible target for anticancer therapy. In this minireview, we summarize unique characteristics of c-Myc and therapeutic strategies against cancer using small molecules targeting the oncogene, and discuss the prospects in the development of agents targeting c-Myc, in particular G-quadruplexes formed in c-Myc promoter and c-Myc/Max dimerization. Such information will be of importance for the research and development of c-Myc-targeted drugs.

The C-kit receptor-mediated signal transduction and tumor-related diseases.

As an important member of tyrosine kinase family, c-kit receptor causes specific expression of certain genes, regulates cell differentiation and proliferation, resists cell apoptosis, and plays a key role in tumor occurrence, development, migration and recurrence through activating the downstream signaling molecules following interaction with stem cell factor (SCF). The abnormality of SCF/c-kit signaling pathway is closely related to some certain tumors. The discovery of c-kit receptor-targeted drugs has promoted clinical-related cancer's diagnosis and treatment. In this paper, we review recent research progress on c-kit receptor-mediated signal transduction and its potential therapeutic application as a target in tumor-related diseases.