Yinyu Wang, Lingjuan Gao, Yu Xu, Limei Niu, Xuan Tang, Yunxu Zhou, Xianhui Deng, Zhidan Bao
Neonatal hypoxic–ischemic encephalopathy (HIE) is a common severe neurological disorder following perinatal asphyxia and a leading cause of neonatal mortality and long-term neurodevelopmental impairments, including cerebral palsy, epilepsy, and cognitive and behavioral deficits. It remains one of the primary causes of death and disability in newborns, imposing a substantial burden on families and society. Although therapeutic hypothermia is currently recognized as an effective intervention, its narrow treatment window, limited patient eligibility, and the persistence of significant sequelae in some affected infants underscore the urgent need for adjunctive therapeutic strategies targeting novel mechanisms. In recent years, short-chain fatty acids (SCFAs), which are metabolites of the gut microbiota, have garnered considerable attention due to their neuroprotective effects via the gut–brain axis. This article systematically reviews the potential mechanisms and therapeutic prospects of SCFAs in neonatal HIE, focusing on their modulation of mitochondrial dysfunction and endoplasmic reticulum stress (ERS).
Glycine receptors (GlyRs) are chloride permeable ligand-gated ion channels that play an important role in synaptic transmission in the central nervous system. Besides glycine as neurotransmitter, cesium (Cs +) was shown to activate homomeric GlyRs with α2 and α3 subunits, and a recent study revealed the position D194 as essential for activation of RNA-edited GlyR α3 185L at the cell surface. This position in the N-terminal extracellular ligand-binding domain belongs to a series of amino acid positions (D141, E192, D194 and D91, D97, E110, D114, Y161) predicted to be involved in Cs + binding. In the present study, we mutated the negatively charged amino acids D91, D97, E110, and D114 as well as the neutral polar amino acid Y161 to code for alanine with a neutral hydrophobic side chain or lysine with a positively charged side chain and performed patch-clamp analysis as well as surface GlyR staining using transfected HEK293T cells. We found that substitutions D97A/K and Y161K resulted in a complete loss of receptor function in response to glycine or Cs +, whereas mutations at D91 and E110 retained detectable current responses, with E110A/K mainly affecting glycine-evoked currents. Y161A retained at least some Cs + -dependent GlyR responsiveness at concentrations above 5 mM, indicating that a positive charge (K) at position Y161 is detrimental to glycine-dependent GlyR activation. However, as no mutant was identified that responded to glycine while lacking Cs + -evoked activity, these findings suggest that Cs + -mediated GlyR activation involves the same structural framework required for glycine-induced channel opening.
Dopamine and norepinephrine regulate hippocampal plasticity through molecular, cellular and circuit mechanisms that shape which experiences are encoded and later remembered. Translating these mechanisms into human memory research remains challenging because direct measures of endogenous catecholaminergic activity are difficult to obtain during memory formation. This Perspective argues that pupillometry provides a non-invasive, temporally precise biomarker for bridging this translational gap. Rather than treating pupil dynamics as a simple proxy for locus coeruleus activity or general arousal, I consider whether pupil-linked memory effects can be better understood by relating them to concurrent neuromodulatory, autonomic and hippocampal processes. I further propose that dilation- and constriction-linked encoding profiles may be associated with different physiological configurations across encoding contexts, including conditions that favour model updating or integration with existing knowledge. I outline how multimodal approaches combining pupillometry with functional MRI, neuromelanin-sensitive imaging, pharmacology, magnetic resonance spectroscopy and computational modelling can test these hypotheses directly. Reframing pupillometry in this way provides a scalable route for linking dopamine and norepinephrine mechanisms with human hippocampal memory and for advancing translational research across ageing and disease.
Yeeun Kim, Myeongguk Jeong, Hyeokjin Kwon, Jungho Kim, Yeongdon Ju, Do-Young Kang, Aelee Jang, Go-Eun Choi
Chemotherapy is the most common cancer therapy due to its ability to effectively destroy cancer cells. However, peripheral neuropathy is a notable side effect, which has no clearly established prevention or treatment methods. Although various therapeutic strategies using microRNAs (miRNAs) have been developed for a wide range of diseases, the role of miRNAs in neuroregeneration has yet to be elucidated. Our group previously identified five differentially expressed miRNAs in the plasma of patients with gastric cancer receiving XELOX (capecitabine and oxaliplatin) chemotherapy. Among these, miR-378f alone showed a significant correlation with peripheral neuropathy severity, providing the rationale for the present study. Bioinformatic analysis further predicted calcium-binding protein 39 (CAB39), a regulator of autophagy, as a shared target of these miRNAs. The downregulation of miR-378f increased CAB39 expression, activated AMPK and inhibited mTOR. Furthermore, changes in autophagy-related markers were observed, including increased Beclin-1 expression, elevated LC3-I to LC3-II conversion, and decreased p62 expression. The findings of the present study suggest that autophagy regulation by miR-378f may be a novel diagnostic and therapeutic target for peripheral neuropathy.
Sleep deprivation suppresses the SIRT1/PGC-1α/Nrf2 signaling pathway, leading to oxidative stress, synaptic damage, and cognitive dysfunction. Glycosides of Cistanche (GCs) possess well-documented antioxidant and neuroprotective properties and have been reported to improve cognition in sleep-deprived animals, but the molecular mechanism remains unclear. We hypothesized that GCs alleviate sleep deprivation-induced cognitive dysfunction by activating the SIRT1/PGC-1α/Nrf2 signaling pathway. Sixty male Sprague Dawley rats were randomly assigned to six groups (n = 10): Control, Platform, Model, GCs, Control+GCs, and Estazolam (Est) groups. A 21-day sleep deprivation model was established using the modified multiple platform water method. Assessments included cognitive function by Morris water maze (MWM) test; Wake, non-rapid eye movement (NREM), rapid eye movement (REM), and total sleep time (TST) by Electroencephalogram (EEG); the serum levels of MDA, GSH-Px and SOD by ELISA, hippocampal CA1 neuronal morphology structure by Nissl staining and transmission electron microscopy (TEM), and the SIRT1/PGC-1α/Nrf2 signaling pathway and synaptic related proteins were detected by Western blot. In an additional cohort (n = 40), the SIRT1-specific inhibitor EX527 was used to validate the causal role of the pathway. Compared with the Control group, the Model group exhibited significantly prolonged escape latency, along with reduced the number of platform crossings and the percentage time in the target quadrant (p < 0.05). The proportion of Wake significantly increased, while NREM, REM, and TST all significantly decreased (all p < 0.01). The serum level of MDA elevated, while GSH-Px and SOD activities markedly reduced (all p < 0.01). Hippocampal CA1 neurons showed disorganized arrangement, decreased Nissl bodies, and mitochondrial damage. Moreover, the SIRT1/PGC-1α/Nrf2 signaling pathway and synaptic related proteins significantly downregulated (all p < 0.01). Nevertheless, GCs intervention ameliorated cognitive dysfunction, alleviated oxidative stress and neuronal damage, and upregulated the protein expression levels above mentioned (all p < 0.01). Notably, these protective effects of GCs were abrogated by the SIRT1 inhibitor EX527. GCs inhibited oxidative stress damage and improved synaptic plasticity, and thereby alleviated sleep deprivation induced cognitive dysfunction by activating the SIRT1/PGC-1α/Nrf2 signaling pathway.
