Neurochemical Research最新文献

The study investigated the mechanism of ALDH2 in mitochondrial dysfunction and blood-brain barrier (BBB) damage arising from chronic cerebral hypoperfusion (CCH). A rat model of bilateral common carotid artery occlusion (BCCAO) was established and treated with AAV-ALDH2. ALDH2 expression, cognitive function, and levels of inflammation- and oxidative stress-related factors, were examined, followed by observing changes in BBB and mitochondrial functions. A rat neuron model of oxygen glucose deprivation/re-oxygenation (OGD/R) was constructed and treated with AAV-ALDH2 and the SIRT1 inhibitor Sirtinol. 4-HNE, SIRT1, ROS levels, mitochondrial membrane potential (MMP), and ATP production were detected, followed by oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) assays. ALDH2 was down-regulated in BCCAO-modeled rats. In BCCAO-modeled rats, ALDH2 overexpression repressed learning/memory deficits and BBB leakage, elevated SOD and GSH levels, decreased the levels of inflammation-related factors, ROS, 4-HNE, and MDA, and improved mitochondrial morphology. In OGD/R-stimulated neurons, ALDH2 overexpression diminished ROS and 4-HNE levels and ECAR and increased MMP, OCR, and ATP production, which was abrogated by Sirtinol. Overall, ALDH2 up-regulation exerts suppressive effects on BBB damage and mitochondrial dysfunction in CCH via the SIRT1/ROS axis.

The Warburg effect serves as a crucial aspect of tumor metabolism, where tumor cells preferentially rely on glycolysis, despite its lower efficiency, over oxidative phosphorylation for energy production even under aerobic conditions. This reprogramming of glucose metabolism confers glioma cells with the capacity for survival and proliferation. Serving as a messenger for regulating transforming growth factor beta, intracellular pH, cell metabolism maintaining cellular bioenergetic homeostasis, SMAD family member 5 (SMAD5) plays a pivotal role in the malignant progression of glioma cells and aerobic glycolysis. Hence, we have identified the expression and function of SMAD5 in human glioma cells, aiming to clarify its role in glycolysis. qRT-PCR and Western blot, reveal that SMAD5 is significantly overexpressed in glioma cells. Knocking down SMAD5 can effectively suppress the proliferation and invasion of glioma cells, while promoting apoptosis, furthermore, downregulation of SMAD5 in vivo has been shown to significantly reduce the growth of xenograft tumors. Conversely, overexpressing SMAD5 enhances the proliferative and invasive capabilities of glioma cells, while suppressing apoptosis. Concurrently, alterations in the expression level of SMAD5 exert an impact on the expression of glucose transporter GLUT1 and crucial enzymes involved in glycolysis, namely HK2 and PKM2, ultimately influencing the glycolytic capability of glioma cells. Specifically, knockdown of SMAD5 suppresses glycolysis, whereas its overexpression enhances glycolytic activity. In conclusion, our data demonstrate that SMAD5 can influence the proliferation, invasion, and apoptosis of glioma cells by modulating glycolysis. This finding holds potential for the development of novel metabolic treatment strategies for glioma.

Glioblastoma stem like cells (GSCs) are a group of cells with strong tumorigenicity that exist in glioblastoma (GBM). Wilms tumor 1-associated protein (WTAP) is thought to promote the malignant process of GBM. However, whether WTAP regulates GSCs function to mediate GBM process is still unclear. The expression levels of WTAP and CCAAT/enhancer-binding protein delta (CEBPD) were examined by qRT-PCR and western blot. GSCs stemness, proliferation, apoptosis, and migration were assessed using sphere formation assay, CCK8 assay, EdU assay, colony formation assay, flow cytometry and transwell assay. Cell glycolysis was evaluated by testing glucose consumption and lactification. The regulation of CEBPD on WTAP was confirmed by ChIP assay and dual-luciferase reporter assay. In vivo experiments were performed to explore the effect of CEBPD/WTAP on the tumorigenicity of GSCs. WTAP and CEBPD had increased expression in GBM tissues and GSCs. Silencing of WTAP suppressed GSCs stemnness, proliferation, migration, glycolysis and promoted apoptosis. CEBPD could bind to WTAP promoter region to enhance its transcription. Besides, WTAP overexpression reversed the suppressive effect of CEBPD knockdown on GSCs stemnness, growth, migration and glycolysis in vitro, as well as the reducing effect on tumorigenicity of GSCs in vivo. CEBPD/WTAP axis played a vital role in regulating GSCs function, providing a potential therapy target for GBM.

Many studies in the open literature have highlighted the critical roles of endoplasmic reticulum stress and ferroptosis in neurological diseases such as neurodegenerative diseases, brain injuries, and depression, indicating that they are involved in the onset and progression of these diseases. Therefore, it is essential to explore the regulatory mechanisms and potential interventions targeting endoplasmic reticulum stress and ferroptosis in neurological diseases. However, most existing research has primarily focused on the unidirectional mechanisms of endoplasmic reticulum stress and ferroptosis within the nervous system, with a lack of in-depth investigations into their interactions. In this paper, we first present an overview of the pathogenesis of endoplasmic reticulum stress and ferroptosis, along with their roles in neurological diseases. We then summarize the latest findings on the interaction mechanism between endoplasmic reticulum stress and ferroptosis from the perspectives of calcium iron homeostasis, reactive oxygen species, microenvironment, and related factors. Finally, we explore the potential molecular mechanisms and targeted interventions associated with endoplasmic reticulum stress and ferroptosis in neurological diseases.

The intricate pathophysiological cascades following spinal cord injury (SCI), encompassing cellular demise, axonal degeneration, and the formation of glial scars, pose formidable barriers to neural regeneration and restoration. Notably, neuroinflammation and glial scars emerge as pivotal barrier to post-SCI repair. Formyl peptide receptors (FPRs) emerge as critical regulators of immune responses, exerting significant influence over inflammatory modulation and nerve regeneration subsequent to SCI. Beyond their classical expression in myeloid cells, FPRs demonstrate a pronounced presence within the central nervous system (CNS) with roles in the progression of neurodegenerative disorders and neurological malignancies. Post-SCI, the equilibrium of the inflammatory microenvironment is recalibrated through the strategic modulation of FPRs, including facilitating a balance in microglial polarization, stimulating neural stem cells (NSCs) migration, and promoting neural axon elongation. These observations enlighten the potential of FPRs as innovative targets for neuronal regenerations bolstering SCI repair. This review endeavors to delineate the distribution and function of FPRs in the aftermath of SCI, with a special attention to their roles in inflammatory regulation, NSCs mobilization, and synaptic growth. By elucidating these mechanisms, we aspire to contribute novel insights and strategies for SCI therapy.

Between the neurotransmission systems modulated by alcohol, the opioid system has been receiving attention in studies that seek to understand its relationship to the effects of addictive substances and different neuropsychiatric disorders. The use of naltrexone stands out in determining the mechanisms of the opioid system, as it acts as an opioid antagonist and consequently generates neurochemical responses. This study aimed to evaluate the pharmacological modulation of opioids on behavioral and neurobiological aspects in adult zebrafish submitted to the protocol of repeated exposure to ethanol and treated with naltrexone. Opioid modulation using naltrexone has been shown to modulate anxiety-like behavior, presenting anxiolytic properties in isolation, in addition to reversing the anxiogenic effect of ethanol through the Novel tank and Light/dark test. Naltrexone increased serotonin and dopamine levels, while ethanol antagonized these effects. In contrast, the interaction between ethanol and naltrexone raised noradrenaline levels. Naltrexone altered glutamate levels, however, ethanol reversed it. Ethanol acted on glutamate transporters increasing their activities, while naltrexone treatment reduced activities. No significant results were found in the pro-oxidant parameters, however, ethanol reduced SOD activity while naltrexone reversed. The same occurred in CAT activity. Also, naltrexone up-regulated the expression of genes related to the dopaminergic, glutamatergic, and opioid systems. The genes used as markers of the inflammatory process and glial activity were modulated by ethanol and together with naltrexone, respectively. Taken together, our findings reinforce the importance of opioid signaling on biochemical and molecular bases related to neuropsychiatric behaviors and diseases, such as anxiety and substance dependence.

Alzheimer’s disease (AD) is the most common neurodegenerative disease. Currently, it has shown a trend of earlier onset, with most patients experiencing a progressive decline in cognitive function following the disease’s onset, which places a heavy burden on society and family. Since no drug cure for AD exists, exploring new ways for its treatment and prevention has become critical. Early vascular damage is an initial trigger for neuronal injury in AD, underscoring the importance of vascular health in the early stages of the disease. Patients with early AD experience abnormal blood-brain barrier transport of amyloid-β (Aβ) peptides, with excess Aβ being deposited in the cerebral vasculature. The toxic effects of Aβ lead to abnormalities in cerebrovascular structure and function. Fibroblast growth factor21 (FGF21) is an endocrine factor that positively regulates energy homeostasis and glucose-lipid metabolism. Notably, it is one of the effective targets for metabolic disease prevention and treatment. Recent studies have found that FGF21 has anti-aging and vasoprotective effects, with receptors for FGF21 present in the brain. Exercise stimulates the liver to produce large amounts of FGF21, which enters the blood-brain barrier with the blood to exert neurovascular protection. Therefore, we review the biological properties of FGF21, its role in the cerebrovascular structure and function in AD, and the mechanism of exercise-regulated FGF21 action on AD-related cerebrovascular changes, aiming to provide a new theoretical basis for using exercise to ameliorate degenerative neurological diseases.

Although it is well documented that the striatal GABAergic projection neurons receive excitatory and inhibitory dopaminergic innervation via D1 and D2 receptors, the trace amine-associated receptor 1 (TAAR1)-mediated regulation of this neural connection is much less studied. The presence of TAAR1 was originally detected in brain aminergic neurons, with recent evidence indicating its presence in striatal GABAergic neurons as well. The objective of the present study was to demonstrate the role of TAAR1 and signaling in dopaminergic-GABAergic interaction in the neural circuitry of the striatum. Besides trace amines, which are considered natural ligands for TAAR1, series of different exogenous drugs were identified to act on this receptor. Using the dopaminergic activity enhancer compound (-)BPAP ((-)-1-(benzofuran-2-yl)-2-propylaminopentane HCl), a potential agonist for TAAR1, we have found that it increased the electrical stimulation-induced [³H]dopamine release in rat striatal slices. This effect of (-)BPAP occurred parallel with increases of [³H]GABA release in striatum when used in 10^–13–10^–11 mol/L concentrations. The effects of (-)BPAP on the release of both neurotransmitters were bell-shaped. We speculated that the rising phase of the concentration-effect curves was evoked by an agonist effect of (-)BPAP on TAAR1 whereas the declining phase was a result of heterodimerization of TAAR1 with pre- and postsynaptic dopamine D2 receptors. The bell-shaped curves suggest that the (-)BPAP-induced heterodimerization of TAAR1 with dopamine D2 receptors may switch off TAAR1 signaling and switch on transduction coupled to D2 receptors. We also suggest that (-)BPAP increases synaptic strength in a hypothetical quadrilateral neuronal organization consisting of dopaminergic nerve ending, GABAergic neurons, trace amine-producing D cells, and supportive glial cell processes.

Yin Yang 1 is a ubiquitously expressed transcription factor that has been extensively studied given its particular dual transcriptional regulation. Yin Yang 1 is involved in various cellular processes like cell cycle progression, cell differentiation, DNA repair, cell survival and apoptosis among others. Its malfunction or alteration leads to disease and even to malignant transformation. This transcription factor is essential for the proper central nervous system development and function. The activity of Yin Yang 1 depends on its interacting partners, promoter environment and chromatin structure, however, its mechanistic activity is not completely understood. In this review, we briefly discuss the Yin Yang 1 structure, post-translational modifications, interactions, mechanistic functions and its participation in neurodevelopment. We also discuss its expression and critical involvement in the physiology and physiopathology of glial cells, summarizing the contribution of Yin Yang 1 on different aspects of cellular function.

Neuropathic pain (NP), a chronic pain condition, is the result of abnormalities in both central and peripheral pain conduction pathways. Here, we investigated the underlying mechanisms associated with this effect. We found that following chronic constriction injury (CCI) surgery, there was an increase of mTOR in astrocytes and an activation of astrocytes within the spinal cord. Pharmacological inhibition of mTOR reversed CCI-induced hyperalgesia and neuroinflammation. Moreover, knockdown of astrocytic mTOR rescued the downregulation of spinal glutamate metabolism-related protein expression, underscoring the pivotal role of mTOR in modulating this pathway. Intriguingly, we observed that overexpression of mTOR, achieved via intrathecal administration of TSC2-shRNA, led to an upregulation of RIP3. Notably, pharmacological inhibition of RIP3, while ineffective in modulating mTOR activation, effectively eliminated the mTOR-induced astrocyte activation. Mechanistically, we found that mTOR controlled the expression of RIP3 in astrocytes through ITCH-mediated ubiquitination and an autophagy-dependent degradation. Taken together, our results reveal an unanticipated link between mTOR and RIP3 in promoting astrocyte activation, providing new avenues of investigation directed toward the management and treatment of NP.