Neurochem. Res. [JOURNAL]
Sun
200 papers
A Primary Spinal Cord Mixed Culture Method for In Vitro Analysis of Glial Heterogeneity and Inflammatory Responses.
de Oliveira Santos Costa CC, de Jesus Nunes C, Pedreira ACNR … +2 more , Costa SL, do Nascimento RP
Neurochem Res · 2026 May · PMID 42166112 · Full text
Traditional in vitro models used in spinal cord research often rely on simplified cell systems, such as PC-12 cells, which do not reproduce the mixed cellular environment or glia-neuron interactions of spinal cord tissue...
Traditional in vitro models used in spinal cord research often rely on simplified cell systems, such as PC-12 cells, which do not reproduce the mixed cellular environment or glia-neuron interactions of spinal cord tissue. Although primary spinal cord cultures have been described, many protocols focus on purified populations and require technically demanding or costly procedures. In this study, we established a low-cost mixed primary spinal cord culture from neonatal Wistar rats and characterized its cellular composition and inflammatory responsiveness in vitro. At 7 days in vitro, immunofluorescence analysis showed the presence of neurons (42.5%), astrocytes (17.2%), and microglia (4.4%), together with an unresolved non-labeled cell population (35.9%). GFAP-positive astrocytes displayed marked morphological heterogeneity, including process-bearing, flattened, and ramified forms. To examine the inflammatory responsiveness of the preparation, cultures were exposed to lipopolysaccharide (LPS, 5 µg/mL for 12 h), which increased nitrite levels and was associated with a higher abundance of amoeboid-like cells and increased Iba1-positive and CD68-positive cell labeling. The culture could also be maintained for prolonged periods in vitro, although its biological interpretation changed over time as non-neuronal cells became more prominent. These findings support the use of this preparation as an accessible mixed primary spinal cord platform for studying glial-associated inflammatory responses in vitro and for future screening of anti-inflammatory compounds.
Maraviroc Attenuates Neuronal Apoptosis by Inhibiting CCR5-Mediated Microglial Activation After Subarachnoid Hemorrhage.
Ye J, Li H, Peng Z … +5 more , Duan Z, Chen Q, Jiang Y, Tu T, Peng J
Neurochem Res · 2026 May · PMID 42159851 · Publisher ↗
Subarachnoid hemorrhage (SAH) triggers robust neuroinflammatory responses that contribute to secondary brain injury, with microglia acting as central mediators; however, the upstream regulators governing microglial activ...
Subarachnoid hemorrhage (SAH) triggers robust neuroinflammatory responses that contribute to secondary brain injury, with microglia acting as central mediators; however, the upstream regulators governing microglial activation remain incompletely understood. To address this, we investigated the role of C-C chemokine receptor 5 (CCR5) using a murine endovascular perforation SAH model. Expression profiling revealed that CCR5 is rapidly upregulated after SAH, with prominent expression in microglia in the cortex and perilesional region. We then evaluated the therapeutic efficacy of pharmacological inhibition using the intranasal CCR5 antagonist maraviroc (MVC). MVC treatment successfully shifted microglia toward an anti-inflammatory phenotype and reduced pro-inflammatory cytokines. This inflammatory modulation attenuated brain edema, suppressed neuronal apoptosis, and significantly improved both early and long-term neurological outcomes. Furthermore, in vitro experiments confirmed that MVC reverses oxyhemoglobin-induced pro-inflammatory microglial polarization, indirectly protecting neurons from microglia-dependent injury. Collectively, these findings identify CCR5 as an important regulator of microglia-associated neuroinflammation after SAH and suggest that MVC exerts neuroprotection, at least in part, through modulation of the CCR5-related inflammatory microenvironment.
Inosine Ameliorates the Injurious Microenvironment for Oligodendrocyte Precursor Cells by Suppressing Microglial Activation and Neuroinflammation In Vitro.
Han Y, Chen J, Wang P … +3 more , Sun J, Niu J, Ma Q
Neurochem Res · 2026 May · PMID 42159816 · Publisher ↗
Neonatal white matter injury (WMI), a leading cause of cerebral palsy, results from microglial-driven neuroinflammation that affects oligodendrocyte precursor cell (OPC) survival and differentiation. Our prior in vivo re...
Neonatal white matter injury (WMI), a leading cause of cerebral palsy, results from microglial-driven neuroinflammation that affects oligodendrocyte precursor cell (OPC) survival and differentiation. Our prior in vivo research indicated that inosine may protect against maternal inflammation-induced WMI by modulating microglial polarization and inhibiting TLR4/MyD88/NF-κB signaling, but its direct effects on microglia are unknown. This in vitro study used a microglia-conditioned medium (MCM)-OPC approach to explore this question. Primary microglia were stimulated with lipopolysaccharide (LPS) and treated with inosine, followed by the measurement of inflammatory cytokines (TNF-α, IL-1β, IL-6) and TLR4 pathway proteins via ELISA and Western blot. MCM derived from differentially treated microglia was then applied to OPC cultures, where OPC viability, death, proliferation, and differentiation were assessed using CCK-8 assay, propidium iodide (PI) staining, immunofluorescence, and Western blot. Inosine co-treatment significantly decreased LPS-induced secretion of TNF-α, IL-1β, and IL-6 from microglia (P < 0.05) and downregulated TLR4, MyD88, and p-NF-κB p65 expression (P < 0.001, P < 0.01). MCM from inosine-treated microglia mitigated OPC damage caused by activated microglia, as demonstrated by enhanced OPC viability (P < 0.01), reduced apoptosis (evidenced by decreased PI positivity and Cleaved Caspase-3 expression, P < 0.01, P < 0.05), increased proliferation (indicated by elevated Ki67 positivity and NG2 expression, P<0.001, P < 0.01), and improved differentiation (reflected by increased expression of CNPase, Olig2, and MBP, P < 0.001, P < 0.01). These findings suggest that inosine can directly inhibit the overactivation and inflammatory response of microglia in vitro, an effect associated with TLR4/MyD88/NF-κB downregulation. Furthermore, it can indirectly ameliorate the injurious microenvironment for OPC, thereby providing cellular-level mechanistic clues for explaining its neuroprotective role in vivo.
The Molecular Mechanism of LncRNA LUCAT1 Regulating HSPB8 Expression via miR-337-3p in Modulating Neurological Damage After Cerebral Infarction.
Lei L, Guo M, Zou Q
Neurochem Res · 2026 May · PMID 42159812 · Publisher ↗
This study aims to investigate the role of the lncRNA LUCAT1 in cerebral infarction-induced neurological damage. In vitro experiments employed N2a cells to establish an OGD/R model, while in vivo experiments utilized mal...
This study aims to investigate the role of the lncRNA LUCAT1 in cerebral infarction-induced neurological damage. In vitro experiments employed N2a cells to establish an OGD/R model, while in vivo experiments utilized male C57BL/6 mice to construct a MCAO model. Cell viability and apoptosis were assessed via the CCK-8 assay and flow cytometry, respectively. RT-qPCR measured mRNA expression of LUCAT1, miR-337-3p, and HSPB8. The molecular targeting relationship was validated using dual luciferase reporter assays and RNA pull-down experiments. ELISA was used to measure the levels of IL-6, IL-1β, and TNF-α. DCFH-DA fluorescent probes and commercial kits were employed to measure ROS levels, MDA and SOD activity. Neurological function assessment included Longa score, Bederson score, adhesive removal test, and modified neurological severity score. In both OGD/R and MCAO models, LUCAT1 expression was downregulated while miR-337-3p expression was upregulated. LUCAT1 was found to directly bind to miR-337-3p. Under OGD/R conditions, LUCAT1 overexpression enhanced cell viability, inhibited apoptosis, and alleviated inflammation and oxidative stress, with these protective effects being reversed by miR-337-3p overexpression. Animal experiments further confirmed that LUCAT1 overexpression improved neuroinflammation, oxidative stress, and neurological deficits in MCAO mice, an effect that was attenuated by co-expression of miR-337-3p. HSPB8 was identified as a direct target gene of miR-337-3p; inhibition of miR-337-3p exerted protective effects by upregulating HSPB8, whereas HSPB8 knockdown counteracted this protective effect. The long noncoding RNA LUCAT1 exerts neuroprotective effects in cerebral infarction by sponging miR-337-3p and relieving its inhibitory action on HSPB8.
Treml4 Drives Microglial Activation via the Lyn/Syk/ERK Pathway in Sepsis-Associated Encephalopathy.
Li R, Xie J, Li Q … +4 more , Ouyang Y, Zhang Q, Wang JF, Deng XM
Neurochem Res · 2026 May · PMID 42159801 · Publisher ↗
Sepsis-associated encephalopathy (SAE) is one of the common and severe complications of sepsis, but the pathogenesis remains to be clarified. It has been reported that Treml4 was upregulated in myeloid cells of septic mi...
Sepsis-associated encephalopathy (SAE) is one of the common and severe complications of sepsis, but the pathogenesis remains to be clarified. It has been reported that Treml4 was upregulated in myeloid cells of septic mice, and inhibition of Treml4 was protective against sepsis-induced mortality. But the role of Treml4 on SAE remains unclear. Cecal ligation and puncture (CLP) was carried out to establish a murine sepsis model. The hippocampal tissues and blood samples of mice were collected for the detection of inflammatory factors (IL-1β, IL-6, TNF-α), oxidative stress damage (MDA, SOD), and WB analysis. Brain tissues were collected for immunofluorescence staining to localize the Treml4 receptor and assess the activation and polarization of microglia. Learning and memory abilities of mice were detected with the Morris water maze(MWM) test. In vitro experiments were conducted using small interfering RNA (siRNA) technology in LPS-stimulated microglia to explore the potential mechanism of Treml. Treml4 was upregulated in the hippocampus of CLP mice, associated with the activation of Lyn, Syk and ERK. Knockout of Treml4 significantly reversed the phosphorylation of Lyn, Syk, and ERK in the hippocampus, alleviated inflammation and oxidative stress damage, and protected against memory dysfunction caused by sepsis. Similarly, knockdown of Treml4 could inhibit LPS-induced BV-2 cell activation, and the Lyn agonist Tolimidone (CP-26154) could reverse this effect in vitro. Treml4-mediated inflammatory and oxidative stress injury is crucial in the development of sepsis encephalopathy, indicating the potential role of Treml4 as a target for preventing and treating SAE.
Loss-of-Function (G603R) Lrp10 Fails to Downregulate mRNA of Pathologic α-Synuclein and Causes Neurodegeneration of Substantia Nigra Dopaminergic Cells in Parkinson's Disease Knockin Mice.
Wang HL, Liu SY, Chiu CC … +6 more , Yeh TH, Chen WS, Chiu TJ, Yeh YC, Wu PR, Weng YH
Neurochem Res · 2026 May · PMID 42159631 · Publisher ↗
Heterozygous (G603R) LRP10 mutation causes autosomal dominant Parkinson's disease (PD). Heterozygous Lrp10 mice were prepared to unravel pathomechanisms underlying (G603R) Lrp10-induced death of substantia nigra (SN) dop...
Heterozygous (G603R) LRP10 mutation causes autosomal dominant Parkinson's disease (PD). Heterozygous Lrp10 mice were prepared to unravel pathomechanisms underlying (G603R) Lrp10-induced death of substantia nigra (SN) dopaminergic neurons. Lrp10 mouse exhibited PD movement deficits, neurodegeneration of SN dopaminergic cells and existence of SN phospho-α-synuclein-containing aggregates. Lrp10 was expressed in mouse SN dopaminergic neurons, and WT LRP10 exerted neuroprotection function on dopaminergic cells by repressing α-synuclein gene transcription and downregulating α-synuclein mRNA. (G603R) LRP10 failed to negatively regulate α-synuclein mRNA of dopaminergic neurons, and heterozygous (G603R) Lrp10 mutation elevated protein and mRNA of pathological α-synuclein or α-synuclein oligomers in SN dopaminergic cells of Lrp10 mouse. Macroautophagy activator rapamycin reversed (G603R) Lrp10-induced increment of α-synuclein, death of SN dopaminergic cells and PD locomotor disability in Lrp10 mouse. (G603R) Lrp10 upregulation of α-synuclein increased ER α-synuclein and activated ER stress and UPR, resulting in excitation of ER stress pro-apoptotic pathway in SN of Lrp10 mouse. Upregulated α-synuclein within SN dopaminergic cells increased mitochondrial α-synuclein and induced mitochondrial detriment and oxidative insult in SN of Lrp10 mouse. (G603R) Lrp10-evoked overexpression of Puma, Noxa or Bim and mitochondrial abnormality excited mitochondrial apoptotic process in SN of Lrp10 mouse. Elevated α-synuclein oligomers excited NLRP3 inflammasome and microglia in SN of Lrp10 mouse, leading to incremented IL-1β-, IL-18- or TNF-α-triggered MKK4-JNK-c-Jun/ATF-2 degeneration and RIPK1-RIPK3-MLKL necroptotic pathways. Our data propose that heterozygous loss-of-function (G603R) mutation of LRP10 debilitates WT LRP10-mediated downregulation of α-synuclein mRNA, leading to elevated α-synuclein-evoked neurodegeneration of SN dopaminergic cells and autosomal dominant PD.
Candidate Mechanisms of Cerebral Ischemia/Hypoxia Tolerance: Insights from Hibernating Rodents.
Li R, Ren H, Tan B … +4 more , Wang P, Chen Y, Liu R, Xu B
Neurochem Res · 2026 May · PMID 42159620 · Publisher ↗
Cerebral ischemia/hypoxia constitutes a central pathological process in ischemic stroke and a range of neurological disorders, yet effective and safe neuroprotective strategies remain scarce in clinical practice. Hiberna...
Cerebral ischemia/hypoxia constitutes a central pathological process in ischemic stroke and a range of neurological disorders, yet effective and safe neuroprotective strategies remain scarce in clinical practice. Hibernating rodents repeatedly undergo extreme physiological fluctuations, including marked reductions in cerebral blood flow and subsequent reperfusion, during torpor-arousal cycles, yet they do not exhibit overt neurological deficits upon emergence from hibernation. This unique phenotype renders them a valuable natural model for investigating endogenous tolerance to cerebral ischemia/hypoxia. In this narrative review, we systematically summarize the physiological characteristics of hibernating rodents and their differential tolerance to cerebral ischemia/hypoxia under euthermic versus hibernating conditions. We further focus on several candidate mechanisms, including suppression of excitotoxicity, regulation of sulfide metabolism, global inhibition of protein synthesis, and enhanced SUMOylation. Current evidence suggests that these mechanisms may contribute to hibernation-associated tolerance; however, the quality of evidence and the strength of causal inferences remain inconsistent or limited. Overall, hibernating rodents provide a novel perspective for understanding tolerance to cerebral ischemia/hypoxia, and the underlying mechanisms may offer valuable insights for future basic research and potential translational applications.
BMSC-Derived Exosomal miR-874-3p Protects against OGD/R-Induced Neuronal Injury in PC12 Cells via Regulating KPNA4.
Dai G, Li Y, Feng B
Neurochem Res · 2026 May · PMID 42149376 · Publisher ↗
BACKGROUND: Sciatic nerve injury was considered to be one of the most common peripheral nerve injuries, posing a major threat to patients. miR-874-3p previously reported to modulate key biological processes including cel...
BACKGROUND: Sciatic nerve injury was considered to be one of the most common peripheral nerve injuries, posing a major threat to patients. miR-874-3p previously reported to modulate key biological processes including cell proliferation, immune response, and apoptosis. However, its specific role and underlying mechanism in sciatic nerve injury remain largely uncharacterized. In this study, we demonstrated that exosomal miR‑874‑3p derived from bone marrow mesenchymal stem cells (BMSCs) alleviates key pathological features of sciatic nerve injury in a cellular model. METHODS: BMSCs were isolated from Sprague Dawley rats and identified by Flow Cytometry (FCM). Exosomes were extracted from BMSCs using differential centrifugation. The morphology of BMSCs-derived exosomes was observed via TEM. The related gene and protein expression were respectively determined by qPCR and western blot. Cell viability and apoptosis were respectively assessed by CCK-8 kits and FCM. The level of ROS, MDA, SOD and GSH-Px were respectively detected using corresponding kit. Inflammatory factors were measured by ELISA. The dual-luciferase reporter assay served to determine the connection of miR-874-3p with KPNA4. RESULTS: miR-874-3p was markedly upregulated in BMSCs-derived exosomes. The supplementation of BMSCs-Exos miR-874-3p maintained cell viability and diminished apoptosis. Moreover, it modulated the intracellular levels of oxidative stress-associated proteins within cells and concurrently suppressed the release of inflammatory factor, consequently decelerating neuronal impairment. Furthermore, the regulatory effects of BMSC-Exos miR-874-3p on cell proliferation, apoptosis, cytokine release, and oxidative stress were mediated by the inhibition of KPNA4, as evidenced by the fact that KPNA4 overexpression abolished these effects. CONCLUSION: Exosomal miR‑874‑3p from BMSCs alleviated OGD/R‑induced neuronal injury by targeting KPNA4.
Electroacupuncture Promotes Synaptic Recovery After Cerebral Ischemia-Reperfusion by Activating SIRT1 to Inhibit the NF-κB Pathway and Regulate Astrocyte Phenotypic Transformation.
Song Q, Zhao MM, Sun WQ … +4 more , Xie QY, Zhang Y, Tang W, Li MX
Neurochem Res · 2026 May · PMID 42149357 · Publisher ↗
Functional recovery after cerebral ischemia-reperfusion injury (CIRI) depends on synaptic plasticity, which is profoundly modulated by astrocyte phenotypes-the neurotoxic A1 phenotype exacerbates damage, while the A2 phe...
Functional recovery after cerebral ischemia-reperfusion injury (CIRI) depends on synaptic plasticity, which is profoundly modulated by astrocyte phenotypes-the neurotoxic A1 phenotype exacerbates damage, while the A2 phenotype supports repair. Electroacupuncture (EA) is neuroprotective, yet whether it promotes synaptic repair by orchestrating this phenotypic switch remains elusive. We hypothesized that EA drives this switch via the SIRT1-NF-κB axis to enhance synaptic recovery. Mice that underwent middle cerebral artery occlusion/reperfusion (MCAO/R) were randomly assigned to the following experimental groups: MCAO/R, EA, EA + SIRT1 inhibitor (Selisistat), or MCAO/R + NF-κB inhibitor (PDTC). Sham-operated mice served as Sham group. EA at GV20 and GV16 was applied daily for 7 days. Neurological function, cerebral blood flow, SIRT1 activity, NF-κB pathway, astrocyte markers (C3, S100A10), inflammatory cytokines, and synaptic proteins were assessed using behavioral tests, imaging, Western blotting, immunofluorescence, ELISA, and transmission electron microscopy. EA significantly improved neurological function and cerebral blood flow. Notably, EA upregulated both the protein level and deacetylase activity of SIRT1 while concurrently suppressing NF-κB phosphorylation, indicating a shift toward anti-inflammatory signaling. This molecular change was accompanied by a significant reduction in the A1 astrocytic marker C3 and pro-inflammatory cytokines, alongside a pronounced increase in the A2 marker S100A10 and anti-inflammatory mediators. Furthermore, EA restored synaptic protein expression and preserved synaptic ultrastructural integrity. The SIRT1 inhibitor Selisistat reversed all these beneficial effects, whereas the NF-κB inhibitor PDTC phenocopied EA‑induced astrocyte phenotype modulation. EA drives astrocyte phenotypic switching from A1 to A2 via the SIRT1-NF-κB axis, reshaping the inflammatory microenvironment to promote synaptic repair and functional recovery after CIRI.
Electroacupuncture Ameliorates Depressive-Like Behaviors by Enhancing Autophagy to Attenuate Hippocampal Neuroinflammation via the VEGF/AKT1/ERK Pathway in CUMS Rats.
Lin L, He Q, Su H … +10 more , Qin L, Pan M, Wei G, Wang T, Li L, Lin L, Cai H, Zhang X, Cen K, Su S
Neurochem Res · 2026 May · PMID 42149321 · Publisher ↗
The high prevalence of depression and limitations of current antidepressants necessitate alternative therapies. Electroacupuncture (EA) shows promise, but its mechanisms remain unclear. Hippocampal impairment in depressi...
The high prevalence of depression and limitations of current antidepressants necessitate alternative therapies. Electroacupuncture (EA) shows promise, but its mechanisms remain unclear. Hippocampal impairment in depression involves neuroinflammation linked to defective autophagy. This study investigated whether EA alleviates depressive-like behaviors by enhancing autophagy via the VEGF/AKT1/ERK pathway to attenuate hippocampal neuroinflammation. Bioinformatic analysis of the GEO dataset GSE53987 was performed to identify autophagy- and neuroinflammation-related differentially expressed genes in depression. A chronic unpredictable mild stress (CUMS) rat model was used for validation. Rats were divided into control, CUMS, EA, EA + VEGFR2 inhibitor (SU5416) (EA+SU5416), EA + 3-methyladenine (3-MA), and FXL (fluoxetine) groups. Comprehensive assessments included behavioral tests, Nissl staining for histomorphology, transmission electron microscopy (TEM) for neuronal ultrastructure, immunofluorescence(IF), immunohistochemistry (IHC), Western blot (WB), enzyme-linked immunosorbent assay (ELISA), and reverse transcription quantitative polymerase chain reaction (RT-qPCR) to evaluate therapeutic effects and hippocampal alterations, focusing on VEGF/AKT1/ERK pathway expression and phosphorylation. AKT1 was identified as a key gene linking autophagy and inflammation. CUMS rats exhibited upregulation of hippocampal AKT1 transcription but decreased phosphorylation, along with enrichment of the VEGF pathway. EA at LI4/LR3 significantly ameliorated depressive-like behaviors and hippocampal damage in CUMS rats. Mechanistically, EA upregulated hippocampal VEGF expression and promoted synergistic phosphorylation of AKT1 and ERK. This was accompanied by enhanced autophagic activity (increased LC3-II/I ratio, decreased p62) and attenuated neuroinflammation (reduced IL-1β, TNF-α). Co-administration of the VEGFR2 inhibitor SU5416 largely abolished these therapeutic effects, including behavioral improvement, AKT1/ERK phosphorylation, autophagy enhancement, and anti-neuroinflammation. Furthermore, the autophagy inhibitor 3-MA also blocked EA's benefits, indicating autophagy as the essential downstream executor. EA ameliorated depressive-like behaviors in CUMS rats, suggesting that the mechanism may involve the activation of the VEGF/AKT1/ERK pathway, leading to enhanced autophagy and attenuated hippocampal neuroinflammation.
Unfolded Protein Response in Glioblastoma: Mechanisms of Proteostasis, Tumor Adaptation, and Therapeutic Relevance.
Caglar HO
Neurochem Res · 2026 May · PMID 42149316 · Full text
Glioblastoma (GBM) is an aggressive brain tumor that rapidly develops resistance to standard clinical therapies. The tumor microenvironment of GBM is highly hostile, characterized by hypoxia, elevated reactive oxygen spe...
Glioblastoma (GBM) is an aggressive brain tumor that rapidly develops resistance to standard clinical therapies. The tumor microenvironment of GBM is highly hostile, characterized by hypoxia, elevated reactive oxygen species, and severe metabolic stress. These conditions promote protein misfolding, particularly in the endoplasmic reticulum (ER), thereby triggering ER stress. The unfolded protein response (UPR) is an adaptive signaling pathway that mitigates ER stress, restores proteostasis, and promotes cellular survival. Activation of UPR signaling provides a survival advantage to GBM cells under these adverse conditions. This signaling is closely associated with drug resistance and malignant progression in GBM. Furthermore, inhibition of UPR sensors exhibits anticancer effects, highlighting their potential as therapeutic targets in GBM. This review describes the biological functions of UPR sensors and their roles in GBM pathogenesis and treatment response.
xCT (Slc7a11) Regulation: Lessons from Cancer Research.
Chirla S, Pandit R, Martinez-Lozada Z
Neurochem Res · 2026 May · PMID 42149253 · Publisher ↗
The cystine/glutamate antiporter, also known as system X, has two roles: (1) imports cystine used to form glutathione (GSH), (2) regulates the extracellular concentration of glutamate. These roles are essential for brain...
The cystine/glutamate antiporter, also known as system X, has two roles: (1) imports cystine used to form glutathione (GSH), (2) regulates the extracellular concentration of glutamate. These roles are essential for brain function, as GSH is the most important antioxidant in the brain, and glutamate is the main excitatory neurotransmitter. This antiporter is composed of two subunits: xCT (encoded by the gene Slc7a11) and a heavy chain, CD98 (encoded by the gene Slc3a2). xCT is the subunit responsible for cystine/glutamate transport, while CD98 is responsible for the translocation of system X to the membrane. The antioxidant function of xCT has been highlighted by the discovery of ferroptosis, a distinctive form of programmed cell death triggered by lipid peroxidation and the accumulation of reactive oxygen species. In addition, numerous types of cancers have been shown to overexpress xCT to evade ferroptosis. The mechanisms by which healthy cells regulate xCT expression, the mechanisms responsible for xCT overexpression in cancer cells, and whether different types of cancers employ identical mechanisms to upregulate xCT have not been systematically studied. To answer these questions, we conducted a systematic review to consolidate the regulatory mechanisms governing xCT expression. We found that xCT expression is regulated at nearly all known levels, including epigenetic, transcriptional, post-transcriptional, translational, post-translational, and by protein-protein interactions, with some cell-type- and context-specific mechanisms. Overall, our work highlights the role of xCT and the breadth of axes through which its expression can be modulated.
Retraction Note: Cerebrolysin Attenuates Exacerbation of Neuropathic Pain, Blood-Spinal Cord Barrier Breakdown and Cord Pathology Following Chronic Intoxication of Engineered Ag, Cu or Al (50-60 nm) Nanoparticles.
Sharma HS, Feng L, Chen L … +8 more , Huang H, Tian ZR, Nozari A, Muresanu DF, Lafuente JV, Castellani RJ, Wiklund L, Sharma A
Neurochem Res · 2026 May · PMID 42143192 · Full text
Abstract loading — click title to view on PubMed.
Correction: Targeting Ferroptosis and Necroptosis to Treat Stroke.
Bautista-Perez SM, Silva-Islas CA, Sánchez-Thomas R … +3 more , Figueroa A, Barrera-Oviedo D, Maldonado PD
Neurochem Res · 2026 May · PMID 42142254 · Full text
Abstract loading — click title to view on PubMed.
Compatibility of Acorus tatarinowii Schott and Polygala tenuifolia Willd. alleviate Alzheimer's disease through regulating Nos2-mediated calcium signaling pathway.
Zhou B, Wu X, Wang J … +3 more , Li L, Xu H, Shao W
Neurochem Res · 2026 May · PMID 42101516 · Publisher ↗
Herb pair of Acorus tatarinowii Schott (ATS) and Polygala tenuifolia Willd. (PTW) is a classic drug pair in the treatment of Alzheimer's disease (AD), However, the mechanism by which the drug pair acts on AD is currently...
Herb pair of Acorus tatarinowii Schott (ATS) and Polygala tenuifolia Willd. (PTW) is a classic drug pair in the treatment of Alzheimer's disease (AD), However, the mechanism by which the drug pair acts on AD is currently unknown. To address this, we constructed a PC12 cellular AD model using amyloid-beta peptide (Aβ) (25-35), follow by treating with different concentrations of ATS and PTW alone or their combination (1:1). The cell viability and Aβ-40, Aβ-42 and AQP4 expression were detected. In addition, RNA-sequencing combined with network pharmacology was performed to investigate the action mechanism of ATS and PTW, and the results were validated using in vitro experiments. The results showed that at drug-acting concentrations less than 100 mg/L, both single-agent and combined treatments of ATS and PTW increased the protective effects on PC12 cell, and the herb pair was superior to single-agent. In addition, both single-agent and combined treatments of ATS and PTW (at concentration of 100 mg/L) decreased Aβ-40, Aβ-42 and AQP4 expression compared with AD model. Further RNA-sequencing combined with network pharmacology analysis suggested that the underline action mechanism might be associated with Nos2-mediated calcium signaling pathway regulated. In vitro validation experiments showed that Nos2 overexpression increase the levels of Aβ-40, Aβ-42, AQP4, p-Tau, CaM, and p-CaMKII, which were reversed by the combination treatment of ATS and PTW. In conclusion, this work indicates that ATS and PTW combination might alleviate an Aβ-induced cellular model through regulating Nos2 - mediated calcium signaling pathway.
Ginsenoside Rh2 Protects Against Glutamate-Induced Neurotoxicity in PC12 Cells via Activation of the VEGF-mediated PI3K/Akt/mTOR Signaling Pathway.
Zhang CY, Liu C, Liu LJ … +3 more , Yang JM, Shen LX, Wu ZG
Neurochem Res · 2026 May · PMID 42095927 · Publisher ↗
Ginsenoside Rh2 (GRh2), a major active component of red ginseng, exhibits significant neuroprotective effects against glutamate-induced excitotoxicity in differentiated PC12 cells. This study found that GRh2 concentratio...
Ginsenoside Rh2 (GRh2), a major active component of red ginseng, exhibits significant neuroprotective effects against glutamate-induced excitotoxicity in differentiated PC12 cells. This study found that GRh2 concentration-dependently reversed the loss of cell viability caused by glutamate. It effectively attenuated key pathological events, including intracellular calcium overload, reactive oxygen species accumulation, and mitochondrial membrane potential collapse. Furthermore, GRh2 enhanced synaptic plasticity, as evidenced by improved neurite morphology and increased levels of the synaptic markers neurogranin and neuromodulin. Mechanistic investigations revealed that GRh2 upregulated vascular endothelial growth factor (VEGF) expression and subsequently activated the PI3K/Akt/mTOR signaling pathway. This activation led to increased expression of synaptic proteins (PSD-95 and synaptophysin), an elevated Bcl-2/Bax ratio. Critically, the specific VEGF inhibitor SU11248 and PI3K inhibitor LY294002 abolished all the protective effects of GRh2, confirming the indispensable role of the VEGF/PI3K/Akt/mTOR axis. These results indicate that GRh2 alleviates glutamate-induced neurotoxicity by activating the VEGF-mediated PI3K/Akt/mTOR pathway, thereby improving mitochondrial function, inhibiting oxidative stress and apoptosis, and promoting synaptic integrity. This work provides novel molecular insights into the neuroprotective mechanism and potential of GRh2.
Glutathione as a Potential Neuroprotectant Against MDMA-Induced Oxidative Stress, Neuroinflammation, and Apoptosis in the Rat Brain.
Akano OP, Olatinwo G, Hamed MA … +3 more , Oluwole DT, Jegede AJ, Ajayi AF
Neurochem Res · 2026 May · PMID 42090092 · Publisher ↗
3,4-Methylenedioxymethamphetamine (MDMA), widely misused for its euphoric and stimulant properties, induces overt neurotoxicity in rodents and non-human primates and is associated with profound neurochemical and structur...
3,4-Methylenedioxymethamphetamine (MDMA), widely misused for its euphoric and stimulant properties, induces overt neurotoxicity in rodents and non-human primates and is associated with profound neurochemical and structural brain alterations. Its deleterious effects are primarily mediated through oxidative stress, neuroinflammatory responses, and apoptotic pathways. Glutathione, a crucial endogenous antioxidant, has been proposed as a potential neuroprotective agent capable of mitigating MDMA-induced cerebral damage.Sixty adult male Wistar rats were randomly assigned to six experimental groups and administered oral treatments for 56 days: MDMA (5 mg/kg or 15 mg/kg), glutathione (15 mg/kg), or their combinations. After treatment, brain tissues were harvested and evaluated for oxidative stress biomarkers (8-OHdG, MDA, GPx, GSH, GST, SOD), pro-inflammatory cytokines (MPO, NF-κB, TNF-α), ion transport enzymes (Na⁺/K⁺ ATPase, Ca²⁺ ATPase), neurotransmitter levels (dopamine, serotonin, AChE), and the apoptotic marker caspase-3. Histological analysis of the hippocampus was conducted to assess structural integrity. MDMA administration led to significant elevations in MDA and 8-OHdG, reductions in antioxidant enzymes (GPx, GST, GSH, SOD), upregulation of inflammatory mediators (MPO, NF-κB, TNF-α), and disruption of ion homeostasis via altered Na⁺/K⁺ ATPase and Ca²⁺ ATPase activities. Neurotransmitter imbalances were observed, characterized by increased AChE and serotonin levels and decreased dopamine. Caspase-3 activity was markedly elevated, indicating enhanced apoptosis. Co-administration of glutathione at low MDMA doses ameliorated these effects, restoring antioxidant defenses, suppressing inflammation, and preserving hippocampal architecture. However, its protective efficacy was notably diminished at higher MDMA concentrations. Glutathione confers partial neuroprotection against MDMA-induced neurotoxicity, particularly under moderate exposure conditions. Its antioxidative capacity contributes to the restoration of redox equilibrium and cellular integrity. Nonetheless, under high-dose MDMA exposure, the therapeutic potential of glutathione is limited, suggesting the necessity for complementary interventions targeting excitotoxicity and mitochondrial dysfunction.
Hippocampal Lipocalin-2 in T2DM Associated Neurodegeneration: A Therapeutic Perspective.
Panigrahy B, Mukherjee A, Singh S
Neurochem Res · 2026 May · PMID 42082859 · Publisher ↗
The hippocampus is a brain region critically involved in learning and memory and is particularly vulnerable to metabolic and inflammatory stresses. Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), is asso...
The hippocampus is a brain region critically involved in learning and memory and is particularly vulnerable to metabolic and inflammatory stresses. Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), is associated with cognitive decline and structural alterations in the hippocampus, a condition commonly referred to as diabetic encephalopathy (DE). Lipocalin-2 (LCN-2), an acute-phase glycoprotein involved in iron homeostasis and innate immunity, has emerged as an important mediator of neuroinflammation and glial reactivity in the central nervous system. Although LCN-2 has been implicated in several neurodegenerative disorders, its region-specific role in hippocampal dysfunction during T2DM remains incompletely understood. Unlike prior reviews that address DE broadly, the present review synthesizes current experimental and clinical evidence linking hippocampal LCN-2 to neuroinflammation, synaptic dysfunction, and cognitive impairment in T2DM, with particular emphasis on astrocyte-microglia crosstalk. We further discuss the potential therapeutic strategy of selectively modulating LCN-2 signaling as an alternative to broad anti-inflammatory approaches, along with its potential advantages and limitations.
Lamotrigine Improves Spatial Learning and Attenuates AD-Related Pathology in APP/PS1 Mice, with Possible Involvement of the cAMP/PKA/CREB Pathway.
Zheng X, Chen P, Li D … +3 more , Li W, Liao J, Zhang M
Neurochem Res · 2026 May · PMID 42082835 · Publisher ↗
Alzheimer's disease (AD) is characterized by impaired spatial learning functions, amyloid-β accumulation, tau hyperphosphorylation, and neuroinflammation. Antiepileptic drugs such as lamotrigine have shown promise in imp...
Alzheimer's disease (AD) is characterized by impaired spatial learning functions, amyloid-β accumulation, tau hyperphosphorylation, and neuroinflammation. Antiepileptic drugs such as lamotrigine have shown promise in improving brain functions in AD, but the underlying mechanisms remain unclear. This study aimed to evaluate the therapeutic effects of lamotrigine in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and elucidate the underlying molecular mechanisms using integrated transcriptomic and metabolomic analyses. APP/PS1 mice were treated with lamotrigine from 3 months of age, and spatial learning performance was assessed using the Morris water maze test. Histological and molecular changes were evaluated through hematoxylin and eosin staining, Western blotting, ELISA, and immunohistochemistry. High-throughput RNA sequencing and untargeted metabolomics were performed to explore differentially expressed genes, metabolites, and enriched signaling pathways. Western blot validation and pharmacological inhibition were used to verify pathway involvement. Lamotrigine treatment significantly improved spatial learning performance, ameliorated neuronal degeneration, and decreased Aβ1 levels and tau phosphorylation in the brains of APP/PS1 mice. Inflammatory markers and glial activation were also markedly suppressed. Multi-omics analysis revealed alterations in key pathways related to synaptic plasticity, lipid metabolism, and autophagy. Notably, both omics data and protein validation highlighted the cAMP/PKA/CREB pathway as a potentially relevant pathway. Co-administration of the PKA inhibitor H89 abolished lamotrigine-induced upregulation of p-CREB and BDNF, supporting the involvement of this pathway. Lamotrigine improves spatial learning and attenuates AD-related pathology in APP/PS1 mice, possibly through modulation of the cAMP/PKA/CREB signaling pathway, highlighting its potential as a candidate for further investigation.
Interleukin-17A as a Potential Mediator in Inflammatory Mechanisms of Insomnia.
Xerfan EMS, Andersen ML, Facina AS … +2 more , Tufik S, Tomimori J
Neurochem Res · 2026 May · PMID 42082723 · Publisher ↗
The interaction between immune cytokines and sleep can be bidirectional, and the circadian rhythm balance has a crucial role to the immune and inflammatory regulation. Insomnia is a prevalent sleep disorder, in which occ...
The interaction between immune cytokines and sleep can be bidirectional, and the circadian rhythm balance has a crucial role to the immune and inflammatory regulation. Insomnia is a prevalent sleep disorder, in which occur modifications in immune expression, including the cytokines pattern. Some somnogenic cytokines, such as interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) have been classically recognized for their direct association with sleep behavior and circadian alignment. More recent evidence has increasingly implicated the role of IL-17A in sleep disturbances and neuroinflammation. However, its specific relationship with insomnia disorder remains underexplored. This cytokine is considered as a relevant immune component in the pathways involved in inflammatory and autoimmune issues. Previous and rare studies on the behavior of IL-17A in insomnia related with comorbid disease suggested that increased IL-17A serum levels may be linked to poor sleep quality. We suggest that further experimental and clinical studies examining the role of IL-17A should shed more light in its relationship with insomnia; and on the immunological and neuroinflammatory associations with this sleep disorder.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe