Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity.

The gut-brain axis is implicated in depression development, yet its underlying mechanism remains unclear. We observed depleted gut bacterial species, including Bifidobacterium longum and Roseburia intestinalis, and the neurotransmitter homovanillic acid (HVA) in individuals with depression and mouse depression models. Although R. intestinalis does not directly produce HVA, it enhances B. longum abundance, leading to HVA generation. This highlights a synergistic interaction among gut microbiota in regulating intestinal neurotransmitter production. Administering HVA, B. longum, or R. intestinalis to mouse models with chronic unpredictable mild stress (CUMS) and corticosterone (CORT)-induced depression significantly improved depressive symptoms. Mechanistically, HVA inhibited synaptic autophagic death by preventing excessive degradation of microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1/p62 proteins, protecting hippocampal neurons' presynaptic membrane. These findings underscore the role of the gut microbial metabolism in modulating synaptic integrity and provide insights into potential novel treatment strategies for depression.

Acidity-Biodegradable Iridium-Coordinated Nanosheets for Amplified Ferroptotic Cell Death Through Multiple Regulatory Pathways.

Ferroptosis-based treatment strategies display the potential to suppress some malignant tumors with intrinsic apoptosis resistance. However, current related cancer treatments are still hampered by insufficient intracellular reactive oxygen species (ROS) levels and Fe2+ contents, posing considerable challenges for their clinical translation. Herein, an intracellular acid-biodegradable iridium-coordinated nanosheets (Ir-Hemin) with sonodynamic therapy (SDT) properties to effectively induce ferroptosis in tumor cells through multiple regulatory pathways are proposed. Under ultrasound (US) irradiation, Ir-Hemin nanosheets act as nanosonosensitizers to effectively generate ROS, subsequently causing the accumulation of lipid peroxides (LPO) and inducing ferroptotic cell death. Furthermore, these Ir-Hemin nanosheets decompose quickly to release hemin and Ir(IV), which deplete intracellular glutathione (GSH) to deactivate the enzyme glutathione peroxidase 4 (GPX4) and initiate the ferroptosis pathway. Specifically, the released hemin enables heme oxygenase 1 (HO-1) upregulation for endogenous ferrous ion supplementation, which compensates for the toxicity concerns brought about by the large uptake of exogenous iron. Surprisingly, Ir-Hemin nanosheets exhibit high tumor accumulation and trigger effective ferroptosis for tumor therapy. These Ir-Hemin nanosheets display pronounced synergistic anticancer efficacy under US stimulation both in vitro and in vivo, providing a strong rationale for the application of ferroptosis in cancer treatment.

Bioactive Iridium Nanoclusters with Glutathione Depletion Ability for Enhanced Sonodynamic-Triggered Ferroptosis-Like Cancer Cell Death.

Ferroptosis is a regulated form of necrotic cell death that involves the accumulation of lipid peroxide (LPO) species in an iron- and reactive oxygen species (ROS)-dependent manner. Previous investigations have reported that ferroptosis-based cancer therapy can overcome the limitations of traditional therapeutics targeting the apoptosis pathway. However, it is still challenging to enhance the antitumor efficacy of ferroptosis due to intrinsic cellular regulation. In this study, a ferroptosis-inducing agent, i.e., chlorin e6 (Ce6)-conjugated human serum albumin-iridium oxide (HSA-Ce6-IrO2 , HCIr) nanoclusters, is developed to achieve sonodynamic therapy (SDT)-triggered ferroptosis-like cancer cell death. The sonosensitizing role of both Ce6 and IrO2 within the HCIr nanoclusters exhibits highly efficient 1 O2 generation capacity upon ultrasound stimulation, which promotes the accumulation of LPO and subsequently induces ferroptosis. Meanwhile, the HCIr can deplete glutathione (GSH) by accelerating Ir (IV)-Ir (III) transition, which further suppresses the activity of glutathione peroxidase 4 (GPX4) to enhance the ferroptosis efficacy. Through in vitro and in vivo experiments, it is demonstrated that HCIr possesses tremendous capacity to reduce the intracellular GSH content, which enhances SDT-triggered ferroptosis-like cancer cell death. Thus, an iridium-nanoclusters-based ferroptosis-inducing agent is developed, providing a promising strategy for inducing ferroptosis-like cancer cell death.