Neurochemical Research最新文献

This study aimed to investigate the role of urocanic acid (UCA) modulates cognitive impairment in a D-galactose (DG)-induced aging model, providing new insights and a theoretical foundation for the treatment of related diseases. Mouse senescence and astrocyte model was created by DG-induced stimuli to assess the effects of UCA. Molecular docking was utilized to confirm potential targets of UCA, and the interaction was validated using the Drug Affinity Responsive Target Stability assay combined with Western blot analysis. The molecular mechanism of UCA was elucidated through in vivo and in vitro experiments. The result showed that UCA treatment ameliorated learning and memory capabilities in DG-induced mice, maintains astrocyte morphology while reducing apoptosis and senescent cells, and inflammatory factors. Additionally, UCA treatment alleviated cell cycle arrest. Molecular docking revealed direct binding between UCA and the ZCCHC3 protein. ZCCHC3 overexpression exacerbated cellular senescence, increased apoptosis and senescent cells, and inflammatory factor levels, while simultaneously activating the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. UCA treatment reversed the effects of ZCCHC3 overexpression. Mechanistically, UCA inhibited the cGAS/STING pathway by binding to ZCCHC3, thereby alleviating cellular senescence. In vivo experiments further confirmed that ZCCHC3 overexpression or exogenous cGAS activation negated the cognitive protective effects of UCA. The study demonstrates that UCA alleviates cognitive impairment and astrocyte senescence by directly binding to ZCCHC3 to suppress the cGAS‑STING pathway. These results identify ZCCHC3 as a novel therapeutic target and clarify the molecular basis of related disorders.raci.

Parkinson's disease (PD) is a neurodegenerative condition distinguished by both motor and non-motor signs. Currently, therapeutic interventions effectively mitigate motor symptoms; however, they fail to impede the progression of neurodegeneration. Enzymatically modified isoquercitrin (EMIQ) is a variant of isoquercitrin with enhanced bioavailability and potentially greater health benefits. Sodium R-Lipoate (NaRLA) is a modified form of lipoic acid with improved stability and efficacy. The current work assessed EMIQ and NaRLA neuroameliorative properties in a rotenone (ROT) model of PD in rats. The study employed open field and hanging tests to evaluate motor effects, and used dopamine (DA) estimation and tyrosine hydroxylase (TH) immunoreactivity to confirm motor abnormalities and neurodegeneration. Furthermore, neuroinflammation was evaluated through ELISA of proinflammatory cytokines (IL-1β, IL-6), expression of Toll-like receptor 4 (TLR4) via qRT-PCR, and immunoreactivity of ionized calcium-binding adaptor molecule 1 (IBA1). The findings indicated that the use of EMIQ and NaRLA with ROT reduced the neuroinflammation via decreasing: the expression level of TLR4, IL-1β and IL-6 levels, and the number of IBA1⁺ microglial cells. Moreover, EMIQ and NaRLA ameliorated motor impairments induced with ROT through the enhancement of rats' behavior, increasing DA concentration and TH immunoreactivity in the striatum. In the light of the findings of the current investigation, EMIQ and NaRLA exerted neuroameliorative effects against the ROT-induced PD model. These results provide support for the potential impact of EMIQ and NaRLA in the treatment of PD and other diseases related to mitochondrial dysfunction and neuroinflammation.

The pathophysiology of depression is associated with inflammation. This study aims to investigate the mechanism by which Yin Yang 1 (YY1) participates in microglial inflammatory activation and M1 polarization in depression. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to quantify Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) mRNA in serum from depressed patients and healthy controls. A chronic unpredictable mild stress (CUMS) depression mouse model was established, and proteins were detected by Western blot (WB). Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic value of TRAF6 for depression. Depressive-like behaviors were assessed by behavioral tests. Inflammatory factors were detected via Enzyme-linked immunosorbent assay (ELISA), M1 polarization markers were analyzed via flow cytometry, and WB, respectively. CHX stability and WB-based ubiquitination assays were used to examine the regulatory effect of Ubiquitin-Specific Protease 19 (USP19) on TRAF6 ubiquitination. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted to verify the transcriptional activation effect of YY1 on USP19. TRAF6 was highly expressed in patient serum and mouse hippocampi, with potential diagnostic value for depression. Silencing TRAF6 improved depressive-like behaviors and reduced inflammation. USP19 was highly expressed in mouse hippocampi, and stabilized TRAF6 via deubiquitination. TRAF6 overexpression reversed inflammation and M1 polarization inhibition from USP19 silencing. YY1 was also highly expressed in mouse hippocampi and activated USP19 transcription. USP19 overexpression reversed the inhibition from YY1 silencing. YY1 activates USP19 to promote TRAF6 deubiquitination and its stabilization, thereby enhancing microglial inflammation and M1 polarization that exacerbates depression progression. This axis may provide a novel direction for depression diagnosis and treatment.

Epilepsy is a chronic neurological disorder characterized by recurrent seizures and frequently accompanied by cognitive deficits for which effective treatments are lacking. Neuroinflammation, particularly microglia-mediated immune responses, is pivotal in epileptogenesis. Although the stimulator of interferon genes (STING) pathway is a key cytosolic DNA-sensing mechanism driving innate immunity, its specific role in epilepsy-related cognitive dysfunction remains unclear. This study investigated the function of the STING pathway in epilepsy pathology and its therapeutic potential. Adult male Sprague-Dawley rats (250-300 g) were subjected to lithium chloride-pilocarpine-induced status epilepticus (SE). The study consisted of two parts. In the first part, the temporal expression of hippocampal STING was examined at 1, 3, 7, 14, and 30 days after SE. In the second part, rats were randomly divided into control (Con+Vehicle), epilepsy (EP+Vehicle), and C-176-treated (EP + C-176) groups. Vehicle (1000 µL) or C-176 (2 mg/rat in 1000 µL) was administered intraperitoneally once daily from 1 day before SE to 6 days after SE. Seizure severity was assessed using the Racine scale. Hippocampal tissues were collected on day 7 after SE for analysis, and cognitive function was evaluated by the Morris water maze test on days 30-35 after SE. The results showed that hippocampal STING expression peaked on day 7 after SE compared with the control group, accompanied by cytosolic double-stranded DNA (dsDNA) accumulation and a shift of microglia toward a pro-inflammatory M1 phenotype. C-176 treatment significantly inhibited STING expression, reduced p-TBK1 and p-NF-κB p65 levels, reversed M1 microglial polarization with decreased iNOS and increased Arg-1 expression, decreased levels of pro-inflammatory cytokines (including IL-6, cleaved IL-1β, and TNF-α), attenuated neuronal damage, and improved learning and memory in SE rats. Our findings suggest that status epilepticus induces neuronal injury and dsDNA release, activating the STING pathway in microglia and driving neuroinflammation via the TBK1/NF-κB axis, leading to cognitive dysfunction. Inhibiting STING alleviates these effects by promoting microglial phenotypic switching from M1 to M2 via regulation of the TBK1/NF-κB pathway. This study identifies STING as a critical regulator of neuroinflammation and a novel therapeutic target for epilepsy-related cognitive dysfunction.

The objective of this study is to determine the binding and functional activity of a variety of ibogalogs and their pyridoindole homologs at the serotonin subtype 2 A receptor (5-HT_2AR) and compare the molecular mechanisms with that at the 5-HT_2BR. The binding results showed that ibogalos and their pyridoindole homologs (2MePI, 8MeO-2MePI) have affinities in the nM concentration range. In contrast, ibogalogs and PNU-22,394, but not catharanthalog (CAG) or pyridoindole homologs, activated the 5-HT_2AR with relatively high potency and high efficacy. Subsequently, we determined the inhibitory activity of the least potent partial agonists, CAG and pyridoindole homologs, via functional competition experiments. Functionally, 2MePI and 8MeO-2MePI, but not CAG, behaved as relatively more potent competitive antagonists than agonists. To assess the mechanistic differences between agonists (ibogalogs) and antagonits (pyridoindole homologs) at the 5-HT_2AR as well as the differences with the 5-HT_2BR, molecular docking and molecular dynamics simulations were performed. The results showed that ibogalogs induce coordinated conformational changes across multiple microswitch networks in the 5-HT_2AR, stabilizing the active state characterized by an outward movement of TM6 and inward movement of TM7. In the 5-HT_2BR, most ibogalogs (except DM506 and PNU-22394) behave as competitive antagonists by promoting the ionic lock, characterized by a reduced distance between TM3 and TM6.