Tao Ma

FOXO/DAF-16 is involved in stress resistance and metabolic regulation, but the molecular mechanisms of its interaction with hypoxia remain unclear. This study aimed to evaluate the anti-hypoxic effects of Poecilobdella manillensis bioactive peptide (PMP) and to investigate whether IIS/FOXO acts as a key node in mediating the regulation of oxidative stress and metabolic reprogramming. In the chemical hypoxia model of Caenorhabditis elegans (C. elegans) induced by sodium sulfite, PMP treatment improved the survival status and movement, feeding, and reproductive ability of hypoxic C. elegans, and significantly increased their survival rate. It also reduced reactive oxygen species (ROS) and lipofuscin levels in C. elegans, enhancing their tolerance to oxidative and heat stress. In the terminal normobaric hypoxia mice model, PMP intervention prolonged the survival time of hypoxic mice, alleviated the damage of heart, lung, and brain tissues, and increased superoxide dismutase (SOD) activity and glutathione (GSH) levels, and decreased malondialdehyde (MDA) concentrations and lactate dehydrogenase (LDH) activity in serum and tissues of mice. ¹H-NMR metabolomics analysis showed that PMP treatment reversed hypoxia-induced abnormalities in key metabolites such as glucose, lactic acid, glutamic acid, and taurine. Next, we utilized C. elegans mutants deficient in daf-2, age-1, akt-1, daf-16, and hsp-16.2, and further observed the nuclear translocation of DAF-16 in DAF-16::GFP C. elegans. The results showed PMP induced DAF-16 nuclear translocation and upregulated the expression of downstream SOD-3. Key metabolites representing antioxidant and energy metabolism were measured in the daf-16 mutant C. elegans. The results showed that PMP intervention failed to restore the levels of glucose, lactic acid, glutamic acid, and taurine in the mutant. Finally, 12 peptides containing antioxidant-related bioactive amino acid residues in PMP were screened by UPLC-Q-Exactive-MS and peptide biological activity prediction. Among them, molecular docking showed that KPPGP had a good binding with FOXO1. In conclusion, in C. elegans, PMP activated DAF-16/FOXO by inhibiting the Insulin/insulin-like growth factor-1 signaling (IIS) pathway and regulated redox homeostasis and metabolic reprogramming to resist hypoxia injury, and this protective effect was also observed in mouse models. IIS/FOXO can be used as a key node to regulate oxidative stress and energy metabolism under hypoxic conditions, and the identification of KPPGP provides insights into the screening and study of bioactive peptides in natural products.

Traditional antiviral strategies primarily rely on vaccines and virus protein-targeting drugs, which adopt a virus-targeting approach. However, the rapid mutation of viruses often leads to vaccine failure and drug resistance, highlighting the limitations of these conventional methods. Consequently, the development of novel broad-spectrum, host-targeting antiviral strategies has become a major research focus. Itaconate, an endogenous immunomodulatory metabolite, inhibits viral replication via post-translational modifications; however, its mechanism in suppressing viral endocytosis remains unclear. This study demonstrates that itaconate inhibits viral endocytosis by covalently modifying the Cys128 site of the adaptor-related protein complex 1 gamma 1 subunit (AP1G1), thereby providing a new target for host-directed antiviral drug development. It was found that itaconate binds to AP1G1 at Cys128, impairing its interaction with clathrin, which inhibits clathrin-mediated viral particle uptake and reduces cellular susceptibility to infection (i.e., the likelihood of cells being infected by viruses and undergoing infection). Furthermore, the natural product Licochalcone B was identified as targeting the same site as itaconate. In both BEAS-2B cell models and mouse infection models, Licochalcone B reduced pulmonary viral loads by over 95%. This study is the first to propose and validate the feasibility of inhibiting broad-spectrum viral infection by targeting AP1G1, elucidating a novel molecular mechanism of itaconate-mediated regulation, offering a new target for broad-spectrum antiviral drug development, and identifying Licochalcone B as a promising broad-spectrum antiviral agent.

Magnolol (M), a hydroquinone containing an allyl side chain, is one of the major active components of Houpoea officinalis for antioxidation and anti-aging. To enhance the antioxidant activity of magnolol, the different sites of magnolol were structurally modified in this experiment, and a total of 12 magnolol derivatives were obtained. Based on the preliminary exploration of the anti-aging effect of magnolol derivatives in a Caenorhabditis elegans (C. elegans) model. Our results indicate that the active groups of magnolol exerting anti-aging effects were allyl groups and hydroxyl on the phenyl. Meanwhile, the anti-aging effect of the novel magnolol derivative M27 was found to be significantly superior to that of magnolol. To investigate the effect of M27 on senescence and the potential mechanism of action, we investigated the effect of M27 on senescence in C. elegans. In this study, we investigated the effect of M27 on C. elegans physiology by examining body length, body curvature and pharyngeal pumping frequency. The effect of M27 on stress resistance in C. elegans was explored by acute stress experiments. The mechanism of M27 anti-aging was investigated by measuring ROS content, DAF-16 nuclear translocation, sod-3 expression, and lifespan of transgenic nematodes. Our results indicate that M27 prolonged the lifespan of C. elegans. Meanwhile, M27 improved the healthy lifespan of C. elegans by improving pharyngeal pumping ability and reducing lipofuscin accumulation in C. elegans. M27 increased resistance to high temperature and oxidative stress in C. elegans by reducing ROS. M27 induced DAF-16 translocation from cytoplasm to nucleus in transgenic TJ356 nematodes and upregulated the expression of sod-3 (a gene downstream of DAF-16) in CF1553 nematodes. Furthermore, M27 did not extend the lifespan of daf-16, age-1, daf-2, and hsp-16.2 mutants. This work suggests that M27 may ameliorate aging and extend lifespan in C. elegans through the IIS pathway.

Alzheimer’s disease (AD) is a common geriatric disease with a complex pathogenesis and challenging treatment options. Wuling capsule is a single herbal formula mainly composed of Xylarianigripes powder, which has sedative and neuroprotective effects on the central nervous system. This study aimed to explore various potential pathways and targets of Wuling capsules for the treatment of AD.

A novel route for ortho-selective C–H borylation of 2-phenylthiopyridines using BBr₃ as the boron source under metal-free conditions has been reported. The reaction exhibited site exclusivity, and the synthesized aryl boronates were freely converted to various useful intermediates. Thus, this facile method would be beneficial to synthesize structurally diversified phenylthioethers derivatives and other materials containing boron-nitrogen coordination.