Addictive substances transform environmental cues into potent conditioned cues through reward-based associative learning. While visual cues are known to amplify drug-seeking behavior and trigger relapse, the neural circuits mediating their motivational salience remain incompletely understood. Here, we identified the superior colliculus (SC) as a critical encoder of drug-related visual information via gating reinstatement through a defined SC-VTA-NAcore pathway. We established a methamphetamine (MA) self-administration model in mice with fiber photometry, optogenetic, and chemogenetic techniques. Using fiber photometry, we discovered that the monosynaptic SC-VTA pathway exhibited selective activation during exposure to drug-paired visual cues, which demonstrated a stable cue encoding. Optogenetic inhibition of SC-VTA projections completely abolished cue-induced reinstatement, while activation potentiated reinstatement. Transsynaptic tracing confirmed a SCGlu+-VTADA+-NAcore circuit. Bidirectional manipulation of this pathway demonstrated its necessity and sufficiency for controlling cue-triggered reinstatement. Our results establish the SC as a sensory-motivational hub that transforms visual drug cues into relapse-promoting signals through a hardwired midbrain circuit. The discovery of this SC-VTA-NAcore pathway provides both a mechanistic framework for understanding cue-driven addiction and concrete targets for interventions.
Epigenetic modulating drugs are emerging as promising cancer treatments. We previously showed that a natural compound, nordihydroguaiaretic acid (NDGA), exerted anti-prostate cancer effects in vitro and in vivo. In this study, we elucidated the anticancer mechanisms of NDGA against prostate cancer. Using integrating bioinformatics analysis and proteomic research, we identified 12 differentially expressed proteins in NDGA-treated PC3 cells that were associated with EZH2, a histone methyltransferase and a catalytic component of polycomb repressive complex 2 (PRC2), which catalyzed the trimethylation of histone H3 at Lys27 (H3K27me3). We showed that NDGA (5, 10, 20 μmol/L) dose-dependently inhibited EZH2 expression in PC3 cells by increasing its degradation and inhibiting its transcription. We demonstrated that NDGA targeted neuropilin 1 (NRP1) in PC3 cells, inhibiting the EZH2/H3K27me3 and PI3K/AKT/mTOR pathways and the expression of E2F1. NDGA blocked E2F1 binding to the EZH2 promoter, decreasing EZH2 and H3K27me3 levels. On the other hand, NDGA inhibited CBP/p300, decreased H3K27ac levels, and synergized with the EZH2 inhibitor EPZ6438 against PC3 cells. In conclusion, NDGA is a potential epigenetic antineoplastic agent that downregulates EZH2 and H3K27me3 through the NRP1 and PI3K/AKT/mTOR pathways and exerts a synergistic antitumor effect with H3K27ac and EZH2 inhibitors, suggesting that it could be a valuable therapeutic option for prostate cancer.
Environmental toxicants such as MPTP and rotenone induce Parkinsonism in both humans and animals. Lactate-driven histone lactylation has recently been implicated in microglial activation and broader CNS pathology. However, its role in dopaminergic (DA) neurons and Parkinson’s disease (PD)-related toxicant responses remains unclear. In this study, we investigated whether neurotoxicant-induced histone lactylation contributes to PD pathogenesis. SH-SY5Y cells were exposed to MPP+ (5 mM) or rotenone (5 μM) for 24 h. A mouse model of PD was established by injection of MPTP (25 mg/kg) for 5 days. We showed that PD-related neurotoxicants increased intracellular lactate levels, promoting histone lactylation in SH-SY5Y cells by suppressing PDH complex activity. By integrating RNA-seq and ChIP-seq analyses, we identified the DDIT4 gene as a lactylation target in response to MPP+ and rotenone. A pharmacological reduction in lactate production or inhibition of lactylation with sodium dichloroacetate (DCA) suppressed DDIT4 promoter lactylation and expression, reduced MPP+- and rotenone-induced cell death in SH-SY5Y cells in vitro and partially protected against MPTP-induced TH-positive DA neuron loss in the brains of MPTP-treated mice in vivo. We demonstrated that DDIT4 was upregulated in the AGTR1/SOX6-positive dopaminergic subpopulation that was highly susceptible to loss in PD patients. These results provide the first evidence that environmental toxicity-induced metabolic alterations drive histone lactylation of the DDIT4 promoter, directly linking a known PD stress effector gene to a lactate-epigenetic signal underlying DA neuron loss. This study reveals a lactate-epigenetic axis that contributes to environmental toxicant-induced Parkinsonism and identifies lactate metabolism and histone lactylation as promising targets for further preclinical investigation.
Triptolide has demonstrated potent immunosuppressive properties in multiple autoimmune disorders, but its severe toxicity has greatly hampered clinical application. Here, we synthesized a triptolide derivative STP1, which exhibits remarkably reduced toxicity compared with triptolide. Immune dysfunction plays a critical role in systemic lupus erythematosus (SLE), an archetypical and refractory autoimmune disorder with limited therapeutic options and suboptimal outcomes. To elucidate the drugability and effect, we investigated the therapeutic potential, safety, regulatory mechanism and target of STP1 on SLE. Our data indicated that STP1 significantly ameliorates imiquimod-induced murine SLE by reducing anti-IgG, anti-dsDNA IgG, proteinuria, and renal pathological injury. Mechanistically, STP1 exerts markedly immunosuppressive roles by modulating the differentiation of B cell into plasma cells and T cell into Tfh cells. Further investigation showed that STP1 regulates B-cell receptor and T-cell receptor signaling by directly targeting Fyn kinase responsible for its immunosuppressive activity. For safety of STP1, our findings indicated that the STP1 did not show any toxicity in biochemical parameters and organ pathological analysis in subacute toxicity experiment. The findings suggested that STP1 is an attractive novel candidate for SLE and other autoimmune diseases for thorough evaluation. STP1, a structurally modified derivative of triptolide with improved safety, alleviates murine systemic lupus erythematosus by targeting and inhibiting Fyn, a Src kinase family member that regulates B- and T- cell responses.
Abdominal aortic aneurysm (AAA) is a chronic, inflammatory and degenerative vascular disease. Previous studies have demonstrated that stimulator of interferon genes (STING) is involved in multiple inflammatory diseases. However, the role of STING in AAA formation and its possible mechanisms have yet to be investigated. Here, we investigated the role of STING in the development of AAA using two murine AAA models induced by porcine pancreatic elastase (PPE)/β-aminopropionitrile (BAPN) or angiotensin II (Ang II). The STING signaling pathway was significantly activated in AAA tissues from both mice and patients. Sting mutation slowed AAA formation, as confirmed by reduced AAA incidence, maximal abdominal aortic diameter, elastin disruption, collagen deposition, and inhibited immune cell infiltration in AAA mice. RNA-sequencing analysis revealed that compared with the control, Sting mutation inhibited inflammatory and immune responses in AAA tissues. Similar effects were observed after pharmacological inhibition of STING in Ang II infused ApoE-/- mice. Besides, STING signaling pathway was also activated in TNFα treated MOVAS. Sting knockdown suppressed inflammatory response and oxidative stress in vitro. Finally, colchicine protected against AAA formation in mice partially through inhibition of the STING signaling pathway. Our study demonstrated that Sting mutation and pharmacological inhibition could limit AAA progression possibly through inhibition of inflammation and oxidative stress. Colchicine could slow AAA formation in a partially STING-dependent manner in AAA mice. These findings suggest that STING might be a potential pharmacological target for the treatment of AAA.
