Neurochemistry international最新文献

Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.

The term "circadian rhythm" refers to the 24-h oscillations found in various physiological processes in organisms, responsible for maintaining bodily homeostasis. Many neurological diseases mainly involve the process of demyelination, and remyelination is crucial for the treatment of neurological diseases. Current research mainly focuses on the key role of circadian clocks in the pathophysiological mechanisms of multiple sclerosis. Various studies have shown that the circadian rhythm regulates various cellular molecular mechanisms and signaling pathways involved in remyelination. The process of remyelination is primarily mediated by oligodendrocyte precursor cells (OPCs), oligodendrocytes, microglia, and astrocytes. OPCs are activated, proliferate, migrate, and ultimately differentiate into oligodendrocytes after demyelination, involving many key signaling pathway and regulatory factors. Activated microglia secretes important cytokines and chemokines, promoting OPC proliferation and differentiation, and phagocytoses myelin debris that inhibits remyelination. Astrocytes play a crucial role in supporting remyelination by secreting signals that promote remyelination or facilitate the phagocytosis of myelin debris by microglia. Additionally, cell-to-cell communication via gap junctions allows for intimate contact between astrocytes and oligodendrocytes, providing metabolic support for oligodendrocytes. Therefore, gaining a deeper understanding of the mechanisms and molecular pathways of the circadian rhythm at various stages of remyelination can help elucidate the fundamental characteristics of remyelination and provide insights into treating demyelinating disorders.

Glutamate-induced neuronal death is associated with neurodegeneration including cerebral ischemia. Several μ-opioid receptor antagonists exhibit a neuroprotective activity and have been considered as a potential therapeutic option for neurodegenerative disorders. For the first time, our current study unveiled the neuroprotective activity of selective δ-opioid receptor antagonists. A potent, selective δ-opioid receptor antagonist naltriben, also known as a potent TRPM7 agonist, displayed the prominent protective effect against glutamate-induced toxicity through opioid receptor-independent, TRPM7-independent mechanisms in HT22 cells. Naltriben activated Nrf2 pathway, and alleviated glutamate-induced Ca²⁺ influx, ROS production, and apoptosis. Moreover, intraperitoneal administration of naltriben at 20 mg/kg greatly reduced the infarct volume in the subcortical photothrombotic ischemia mouse model in vivo. The neuroprotective activity of naltriben was enhanced by a longer pretreatment, indicating that like Nrf2 activators, naltriben also requires the cellular priming for its full protective effects. Together, these results suggested naltriben as a potential therapeutic agent in conditions related with glutamate-induced neurotoxicity.

Neurosteroids have a crucial role in physiological intrinsic regulations of the Central Nervous System functions. They are derived from peripheral steroidogenic sources and from the de novo neurosteroidogenic capacity of brain cells. Significant alterations of neurosteroid levels have been frequently observed in neuroinflammation and neurodegenerative diseases. Such level fluctuations may be useful for both diagnosis and treatment of these pathological conditions. Beyond steroid administration, enhancing the endogenous production by Translocator Protein (TSPO) targeting has been proposed to restore these altered pathological levels. However, the neurosteroid quantification and the prediction of their final effects are often troublesome, sometimes controversial and context dependent, due to the complexity of neurosteroid biosynthetic pathway and to the low produced amounts. The aim of this review is to report recent advances, and technical limitations, in neurosteroid-related strategies against neuroinflammation.

As the incidence of Alzheimer's disease (AD) continues to rise, the need for an effective PET radiotracer to facilitate early diagnosis has become more pressing than ever before in modern medicine. Phosphodiesterase (PDE) is closely related to cognitive impairment and neuroinflammatory processes in AD. Current research progress shows that specific PDE4D inhibitors radioligands can bind specifically to the PDE4D enzyme in the brain, thereby showing pathology-related signal enhancement in AD animal models, indicating the potential of these ligands as effective radiotracers. At the same time, we need to pay attention to the important role computer aided drug design (CADD) plays in advancing AD drug design and PET imaging. Future research will verify the potential of these ligands in clinical applications through computer simulation techniques, providing patients with timely intervention and treatment, which is of great significance.

The disturbances in thyroid hormones lead to altered brain metabolism, function, and cognition. Neuroimaging studies have shown structural and functional changes in hypothyroidism. Present study investigates the neuro-metabolite changes in dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex (PPC) and associated decline cognitive function in hypothyroid patients before and after thyroxine treatment. We performed neuropsychological test and ¹H MRS in hypothyroid patients (n = 25) and controls (n = 30). In addition, follow-up data was also collected from 19 patients treated with levo-thyroxine for 32 weeks. The concentration of the neurometabolites were calculated using LCModel. MRS data were analyzed using analysis of covariance (ANCOVA), with age and gender as covariates. A paired t-test was conducted to compare the baseline hypothyroid with the follow-up. Partial correlations were utilised to assess possible associations between neuropsychological scores and neurometabolites with age and gender as covariates. Spearman correlation was performed between thyroid hormone levels and neurometabolites. Hypothyroid patients showed an impairment in delayed recall, immediate recall of semantic, visual retention, recognition of objects memory, attention, and motor function at baseline, which improved significantly after thyroxine therapy. At baseline, patients with hypothyroidism exhibited significantly higher levels of choline compounds (GPC + PCh) [Cho]. No significant normalization of Cho levels was observed, despite achieving euthyroidism with thyroxine treatment. Cho levels showed a positive correlation with TSH in PPC and a negative correlation with T4 in DLPFC and PCC. Cho levels also showed negative correlations with delayed recall, immediate recall of semantic, visual retention memory and MMSE scores. The MRS findings show increased levels of Cho in hypothyroid patients compared to healthy controls. These Cho levels are not reversible within 32 weeks of treatment, suggesting that a longer follow-up may be needed to see if levels can be normalized.

Background and purpose: The field of hydrogen medicine has garnered extensive attention since Professor Ohsawa established that low concentrations of hydrogen (2%-4%) exert antioxidant effects. The present study aimed to evaluate the therapeutic effect of molecular hydrogen in a CUMS rat model.

Methods: A total of 40 SD rats were randomly divided into a control group, a model group, a hydrogen group, and a positive drug group. Four weeks post-modeling, hydrogen inhalation and other treatments were administered. Behavioral, biochemical, and immunohistochemical evaluations were performed after treatment.

Results: Hydrogen inhalation alleviated depressive behavior and hippocampal neuronal damage in CUMS rats, as well as restored the levels of neurotransmitters, inflammatory factors, and oxidative stress. Moreover, it maintained mitochondrial homeostasis and up-regulated the expression of PGC-1α, PINK1, and Parkin.

Conclusions: The results collectively indicated that hydrogen significantly attenuated CUMS-induced depressive-like behavior and monoamine neurotransmitter deficiency, as well as protected the brain from oxidative stress and inflammatory damage and effectively preserved mitochondrial homeostasis.

Phosphoinositide 3-kinase γ (PI3Kγ) is a signaling protein that is constitutively expressed in immune competent cells and plays a crucial role in cell proliferation, apoptosis, migration, deformation, and immunology. Several studies have shown that high expression of PI3Kγ can inhibit the occurrence of inflammation in microglia while also regulating the polarization of microglia to inhibit inflammation and enhance microglial migration and phagocytosis. It is well known that the regulation of microglial polarization, migration, and phagocytosis is key to the treatment of most neurodegenerative diseases. Therefore, in this article, we review the important regulatory role of PI3Kγ in microglia to provide a basis for the treatment of neurodegenerative diseases.

Background: Epilepsy causes a heavy disease burden, and the gut microbiota (GM) influences the progression of epilepsy, while plasma metabolites directly or indirectly associated with GM may play a mediating role. However, the causal relationships between epilepsy, GM, and potential metabolite mediators are lack of investigation.

Methods: Mendelian randomization (MR) analysis was applied to estimate the effects of GM and plasma metabolites on epilepsy. Genetic instruments were obtained from large-scale genome-wide meta-analysis of GM (n = 5959), plasma metabolites (n = 136,016), and epilepsy (Cases/controls = 12891/312803) of European ancestry. Epilepsy phenotypes included all epilepsy, generalized epilepsy and focal epilepsy from the Finn Gen R10 database. And two-step MR (TSMR) to discover the potential mediating metabolites.

Results: In total, we found 19 gut microbial taxa to be causally associated with the risk of epilepsy, among which Omnitrophota phylum had the strongest association (OR, 2.3; P = 0.009) with promoting effect. We also identified 21 plasma metabolites associated with epilepsy, the strongest ones of which are eastotal fatty acids (OR, 1.12; P = 0.001) that exhibited a facilitating effect. We observed indirect effects of free cholesterol to total lipids ratio in large LDL in associations between Fournierella massiliensis species and epilepsy, with a mediated proportion of -3.64% (95%CI, -7.22%∼-0.06%; P = 0.046).

Conclusion: This study supports a causal link between Fournierella massiliensis species, free cholesterol to total lipids ratio in large LDL and epilepsy, as well as a mediating effect of free cholesterol to total lipids ratio in large LDL in epilepsy.

In glioblastoma, glioma-associated microglia/macrophages (GAMs) represent the major population of tumor infiltrating cells, with up to one half of the cells of the tumor mass. Recent studies have shown that microglia are involved in the maintenance of immunological homeostasis and protection against autoimmunity. However, despite the growing body of evidence on the topic, many aspects are yet to be clarified. In our study, 3 different situations emerged concerning the markers of microglial/macrophage-related and other cell types in GBM patients: i) most of the markers (IBA1, TMEM119, CD206 and CD86) show an ascending gradient from the tumor center to the non-tumor/healthy area of the brain; ii) one marker (CD204) shows a descending gradient, going from the center of the tumor to the non-tumor/healthy brain area; iii) two markers (CD163 and P2RY12) show no gradient. These observations support the idea that the magnitude of the diverted inflammation is a 'extensive' rather than a 'local' phenomenon and that could possibly play a role in disease resistance and relapse.