Neurochem. Res. [JOURNAL]
Sun
200 papers
Body weight-supported treadmill training enhances motor recovery and ameliorates neuron injury through the MDK/LRP-1 signaling pathway in T10 incomplete spinal cord-injured rats.
Wang Z, Zhu C, Wang Y … +11 more , Zhai C, Cai J, Li X, Fang L, Cao Y, Wu Q, Li X, Cai Y, Wang T, Wu Q, Liu W
Neurochem Res · 2026 Jun · PMID 42257999 · Publisher ↗
Midkine (MDK) could enhance neuron survival through its endocytosis receptor, lipoprotein receptor-related protein-1 (LRP-1). This study was designed to investigate whether body weight-supported treadmill training (BWSTT...
Midkine (MDK) could enhance neuron survival through its endocytosis receptor, lipoprotein receptor-related protein-1 (LRP-1). This study was designed to investigate whether body weight-supported treadmill training (BWSTT) promotes motor function and ameliorates neuronal injury following T10 incomplete contusive spinal cord injury (SCI) through the MDK/LRP-1 signaling pathway. T10 incomplete contusive SCI rats underwent two weeks of BWSTT. LRP-1-siRNA was utilized during the intervention to inhibit the MDK/LRP-1 signaling pathway. The Basso, Beattie, and Bresnahan (BBB) score, three-dimensional gait analysis, Nissl and NeuN staining of the spinal cord, and protein expression of MDK/LRP-1 were evaluated. Downstream activation of PI3K/Akt and BDNF expression was analyzed in vivo and in vitro. Two weeks of BWSTT significantly improved the BBB score after spinal cord injury (SCI) and ameliorated neuronal injury in the lumbar spinal cord. Immunofluorescence co-staining of MDK with NeuN indicates that BWSTT promoted the neuronal localization of MDK. The use of LRP-1-siRNA significantly inhibited the effectiveness of exercise training in enhancing motor function and ameliorating neuronal injury. Additionally, LRP-1-siRNA also hindered the neuronal localization of MDK following exercise training. Furthermore, exercise-induced Akt activation and BDNF upregulation were diminished in vivo by LRP-1-siRNA. In vitro results demonstrated that MDK activates Akt and BDNF, while RAP, an LRP-1 inhibitor, notably inhibited this effect. The neuroprotective effect of exercise training after SCI may be mediated, at least in part, through the MDK/LRP-1 signaling pathway, which promotes Akt activation and BDNF upregulation, contributing to neuronal survival and motor recovery after BWSTT in T10 incomplete spinal cord-injured rats.
Chronic REM Sleep Deprivation Induces Metabolic and Neurotoxic Alterations Associated with Affective and Cognitive Deficit in Male Wistar Rats: Involvement of HPA Axis, Cholinergic, Inflammatory, and Oxidative Stress Pathways.
Baghdad W, El Brouzi MY, Ibouzine-Dine L … +10 more , Abouyaala O, El Arbaoui M, Kessam F, Dimaoui A, Mallouk H, Lamtai M, Satté A, Mesfioui A, El Hessni A, Houssaini YS
Neurochem Res · 2026 Jun · PMID 42257770 · Publisher ↗
Diabetes is a metabolic condition characterized by increased blood glucose levels resulting from defects in insulin secretion, utilization, or both. Sleep deprivation (SD) can alter homeostasis, while the consequences of...
Diabetes is a metabolic condition characterized by increased blood glucose levels resulting from defects in insulin secretion, utilization, or both. Sleep deprivation (SD) can alter homeostasis, while the consequences of diabetes can disrupt sleep homeostasis. These findings support the hypothesis of a bidirectional interaction between sleep homeostasis, metabolic disorders, and neurological or behavioral disorders. The present study aims to investigate the bidirectional interaction between chronic REM-SD and metabolic disorders in rats by combining assessments of affective and cognitive behaviors (anxiety, depression, and memory function), metabolic (glucose homeostasis, glucose tolerance, insulin sensitivity), oxidative, cholinergic, cytotoxic, neuroinflammatory parameters, and histopathological change in hippocampus (HP), hypothalamus (HYP), and prefrontal cortex (PFC) in male Wistar rats. Eighteen male Wistar rats were divided into three groups (CON, WP, and CSD). The REM-SD was carried out for 18 h a day (from 4:00 p.m. to 10:00 a.m.) over a period of five weeks, using the modified multi-platform method (MMPM). Glucose (ipGTT) and insulin tolerance (ipITT), corticosterone and blood hs-CRP levels were evaluated, along with affective behaviors (anxiety- and depression-like) and cognitive functions, including spatial learning, recognition memory, working memory, and long-term memory. We also measured acetylcholinesterase (AchE) activity, neurotoxicity, and oxidative stress markers, as well as histopathological changes in the HP, HYP, and PFC of male Wistar rats. The results demonstrated that chronic REM-SD induced glucose intolerance and insulin resistance, leading to hyperglycemia, which was accompanied by low-grade inflammation and activation of the HPA axis. Regarding behavioral conditions, REM-SD induced anxiety, depression, and learning and memory impairments. Specifically, in relation to the brain region, REM-SD exhibited disruption in cholinergic neurotransmission, oxidative stress balance (increase in NO, MDA, and decrease in CAT and SOD activity), and neurotoxicity (increase in LDH levels). The r-Spearman correlation analysis showed that AchE activity and memory performance were strongly correlated in sleep-deprived rats. In addition, histological examination demonstrates that chronic REM-SD induced structural atrophy, neuronal degeneration, and a marked decrease in neuronal density in the PFC, HYP, and HP, specifically in the CA3 and DG. Briefly, this finding provides novel insight into the bidirectional interplay pathway between SD and metabolic disorders, and between the mechanisms linking sleep health, diabetes, and behavioral disorders. Consequently, our future studies aim to examine the effect of pharmacological treatments and sleep recovery on biochemical and neurobiochemical parameters, cholinergic neurotransmission, and brain architecture.
The Myelin-Derived Peptide NSDP1 Suppresses Neuroinflammation and Attenuates Demyelination in Chronic Cuprizone-Fed Mice via Modulation of cGAS-STING Signaling.
Yang J, Chi Q, Huang M … +3 more , Lu J, Dong X, Li X
Neurochem Res · 2026 Jun · PMID 42234285 · Publisher ↗
Multiple sclerosis (MS) is characterized by demyelination and neuroinflammation. In a cuprizone (CPZ)-induced demyelination mouse model, proteomic analysis revealed the significant downregulation of a myelin basic protei...
Multiple sclerosis (MS) is characterized by demyelination and neuroinflammation. In a cuprizone (CPZ)-induced demyelination mouse model, proteomic analysis revealed the significant downregulation of a myelin basic protein-derived peptide (sequence: DTGILDSIGRFFS), which we have designated as NSDP1 (nervous system-derived peptide 1). In vitro, NSDP1 suppressed LPS-induced microglial activation in BV2 cells, reducing reactive oxygen species (ROS) production, downregulating pro-inflammatory markers (iNOS, TNF-α, IL-1β), and upregulating the expression of anti-inflammatory marker Arg-1. In vivo, NSDP1 administration via intracerebroventricular injection significantly mitigated CPZ-induced weight loss and demyelination in the corpus callosum. NSDP1 attenuated CPZ-induced demyelination, restoring expression of myelin proteins (MAG, MOG), increasing oligodendrocyte precursor cell (OPC) density, improving myelin sheath ultrastructure, and enhancing axonal myelination efficiency. Furthermore, NSDP1 attenuated CPZ-induced reactive gliosis, reducing both microglial activation and astrocytic reactivity in the corpus callosum. RNA sequencing revealed that NSDP1 modulated myelination-related pathways and correlated with improved locomotor recovery. Mechanistically, NSDP1 exerted its anti-inflammatory effects by inhibiting the cGAS-STING signaling pathway, as shown by reduced cGAS and STING expression in LPS-stimulated BV2 cells. The effects of NSDP1 on ROS and pro-inflammatory cytokine release were reversed by the STING activator DMX and mimicked by the STING inhibitor SN-011. Collectively, these findings identify NSDP1 as a downregulated myelin-derived peptide with potent therapeutic potential, which attenuates demyelination and suppresses neuroinflammation in demyelinating diseases by inhibiting the cGAS-STING pathway.
Downregulation of lncRNA SNHG14 Alleviates Neuropathic Pain and Inflammation in CCI Rats by Targeting miR-182-5p/BDNF.
Tang Q, Ma L, Zhao H … +2 more , Liu Y, Zhao Y
Neurochem Res · 2026 Jun · PMID 42228285 · Publisher ↗
Inflammatory processes hold significant importance for the initiation and long-term maintenance of neuropathic pain (NP). This study aimed to investigate the function of long non-coding RNA SNHG14 in NP and the regulator...
Inflammatory processes hold significant importance for the initiation and long-term maintenance of neuropathic pain (NP). This study aimed to investigate the function of long non-coding RNA SNHG14 in NP and the regulatory mechanism underlying its action via the miR-182-5p/ brain-derived neurotrophic factor (BDNF) axis. 80 serum samples were collected from NP patients and 80 from healthy controls, followed by the detection of SNHG14 expression. A chronic constriction injury (CCI) rat model of the sciatic nerve was established, and animals were assigned to experimental groups for behavioral, molecular, and biochemical analyses, including assessment of mechanical and thermal pain thresholds, quantitative reverse transcription polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). RNA immunoprecipitation (RIP), and dual-luciferase assays were used to verify the targeted relationship. In both NP patients and CCI rats, SNHG14 expression was significantly upregulated and showed preliminary diagnostic potential, warranting further validation in larger cohorts. Silencing SNHG14 effectively alleviated pain-related behaviors and concurrently reduced the levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β). Mechanistic investigations revealed that SNHG14 exerted its regulatory effects by directly binding to and negatively modulating miR-182-5p, which in turn targeted and suppressed BDNF expression. Functional rescue experiments indicated that antagomir-miR-182-5p partially reversed the analgesic and anti-inflammatory effects achieved through SNHG14 knockdown. Conversely, BDNF silencing partially counteracted the hyperalgesia and enhanced inflammatory responses induced by antagomir-miR-182-5p. SNHG14 upregulated BDNF expression by sequestering miR-182-5p, thereby enhancing the hyperalgesic response and neuroinflammatory processes in NP and CCI rats.
Prefrontal Cortex Dysregulation of Amino Acid-Glucose Homeostasis Links High-Fat and/or High-Fructose Intake to Cognitive Deficits in Male Mice.
Martínez-Orozco H, Reyes-Castro LA, Lomas-Soria C … +2 more , Solís-Ortíz S, Diaz-Miranda SY
Neurochem Res · 2026 Jun · PMID 42228217 · Full text
Memory processes are susceptible to impairment induced by excessive consumption of hypercaloric diets, particularly those rich in saturated fats and fructose. Such dietary patterns have been linked to disrupted neurotran...
Memory processes are susceptible to impairment induced by excessive consumption of hypercaloric diets, particularly those rich in saturated fats and fructose. Such dietary patterns have been linked to disrupted neurotransmission in the prefrontal cortex (PFC), where the balance between excitation and inhibition depends on efficient glucose metabolism and the synthesis of neuroactive amino acids. However, the molecular mechanisms underlying these effects remain poorly understood. Here, male C57BL/6 mice were fed for 10 weeks with a control diet, a high-fat diet (HFD), a high-fructose diet (HFrD), or a combined high-fat/high-fructose diet (HFFrD). Their body weight gain and visceral adiposity were primarily driven by saturated fat intake, whereas hyperglycemia was observed across all diets. Also, we assessed metabolic outcomes, recognition memory, and PFC molecular profiles, including neuroactive amino acids (GABA, glutamate, glutamine, aspartate, alanine, glycine, and taurine) and the expression of genes related to glucose metabolism (Slc2a1, Pcx, G6pd, Gck, Pck1, Irs2) and the glutamate/GABA-glutamine cycle (Glul, Glud1, Gad1, Gad2). Behaviorally, HFFrD reduced locomotor activity and caused the most significant impairment in recognition memory. In the PFC, diet composition generated distinct amino acid profiles, revealing vulnerability of the glutamine-glutamate-GABA cycle to hypercaloric intake. Transcriptional responses were diet-specific, with consistent Gad1 upregulation and broader induction of glucose metabolism-related genes. Together, these findings demonstrate diet-dependent metabolic and neurochemical remodeling in the PFC and support a link between excessive fat and/or fructose intake with disrupted glutamine-glutamate homeostasis and memory deficits.
Autophagic Pathway on GABARAP Involved in GABA Receptor Trafficking.
Zhou M, Shi W, Li H … +1 more , Bai J
Neurochem Res · 2026 Jun · PMID 42225974 · Publisher ↗
The formation of lipidated Gamma-Aminobutyric Acid Receptor-Associated Protein (GABARAP), which is a crucial subfamily in the Autophagy-associated protein 8 (Atg8) group, not only requires the intricate collaboration of...
The formation of lipidated Gamma-Aminobutyric Acid Receptor-Associated Protein (GABARAP), which is a crucial subfamily in the Autophagy-associated protein 8 (Atg8) group, not only requires the intricate collaboration of other autophagy-related proteins, but acts to necessarily promote the conduction of autophagy and Gamma-Aminobutyric Acid (GABA) A Receptor (GABAR) trafficking. The molecular pathway on the formation of GABARAP is same as LC3-II, in which GABARAP is activated through Autophagy Activating Kinase 1 (ULK-1), Atg12-Atg5-Atg16L1 and Atg 4, whereas Rapamycin Complex 1 (mTORC1) and AMP-activated protein kinase (AMPK) inhibit Ulk1. The lipidated GABARAP interacts with molecules related to the synapse and regulates GABAR clustering through interactions with postsynaptic scaffolding proteins, such as gephyrin and Ankyrin. GABARAP plays roles in regulating synaptic functions besides autophagy.
Taliglucerase Alfa Reduces Amyloid-β Burden by Restoring Autophagic Pathways in a Neuronal Model of Alzheimer's Disease.
Özkurt Ç, Köse S, Karasu Ç … +2 more , Kortholt A, Kelicen-Uğur P
Neurochem Res · 2026 Jun · PMID 42223785 · Full text
Intraneuronal amyloid-beta (Aβ) accumulation and autophagic dysfunction are key pathological features of Alzheimer's disease (AD). Mutations in GBA1, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are l...
Intraneuronal amyloid-beta (Aβ) accumulation and autophagic dysfunction are key pathological features of Alzheimer's disease (AD). Mutations in GBA1, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are linked to several neurodegenerative disorders, but the role of GCase in AD remains incompletely understood. In this exploratory, proof-of-concept study, we investigated whether taliglucerase alfa (TAL), a recombinant human GCase, may influence intracellular Aβ accumulation by modulating autophagy pathways in a neuronal AD model. Endogenous Aβ accumulation was induced in mouse hippocampal neuronal cells (HT-22) by exposure to low-molecular-weight Aβ oligomer-enriched assemblies (oAβ), followed by treatment with TAL. Soluble Aβ levels and selected components of the autophagy-lysosome pathway, including GCase, cathepsin B, p62/sequestosome-1 (p62/SQSTM1), and mammalian target of rapamycin (mTOR), were evaluated using Western blotting, ELISA, and RT-PCR. In this in vitro model, TAL treatment was associated with a reduction in intracellular monomeric Aβ levels. This observation was accompanied by changes in mTOR signaling and p62 levels, suggestive of modulation of autophagy-related processes. Overall, these results provide preliminary, hypothesis-generating evidence supporting a potential association between lysosomal GCase augmentation and Aβ-related and autophagy-associated processes in AD. Further studies, including expanded experimental validation and in vivo investigations, are required to clarify the underlying mechanisms and translational relevance.
Herkinorin Exerted Neuroprotective Effects After Spinal Cord Injury by Suppression of NF-κB Pathway Activation.
Wang J, Yu J, Han W … +5 more , Ding C, Wang H, Chen S, Huang Y, Lan W
Neurochem Res · 2026 Jun · PMID 42219409 · Full text
The disruption of axonal continuity and neuronal loss at the injury site leads to structural disconnections as well as functional consequences in spinal cord injury. Herkinorin, a structurally unique non-nitrogenous opio...
The disruption of axonal continuity and neuronal loss at the injury site leads to structural disconnections as well as functional consequences in spinal cord injury. Herkinorin, a structurally unique non-nitrogenous opioid receptor agonist, demonstrates significant neuroprotective efficacy in models of ischemic brain injury and epilepsy. In this report, we aimed to explore the role and underlying mechanism of Herkinorin in axon regeneration and functional recovery in SCI. Oxygen-glucose deprivation and restoration (OGD/R) condition was used in cell line rat pheochromocytoma cells (PC12) and primary cortical neurons to mimic SCI context in vitro. and apoptosis of the cells were detected. A rat SCI model was conducted by Allen's impactor. Cells were treated with Herkinorin under OGD/R condition. Footprint analysis and BBB scale was to evaluate locomotor function. Western blot and immunofluorescence staining of proteins Map2, GAP43 and Ace-tubulin to assess microtubule stabilization and Bax, Bad, Bcl2 as well as cleaved caspase3 to detect apoptosis. The TNFα was employed to determine the expression profiles of NF-κB. Herkinorin alleviated OGD/R-induced neuronal apoptosis and axonal damage in PC12 cells and primary neurons by enhancing microtubule stability and inhibiting NF-κB, effects abolished by TNFα. Crucially, in a rat SCI model, Herkinorin improved locomotor function (BBB scores, gait) and mitigated spinal cord neuronal loss and microtubule disassembly. Herkinorin confers neuroprotection and pro-regenerative effects against neuronal injury both in vitro and in vivo, mechanistically linked to microtubule stabilization and NF-κB pathway suppression, positioning it as a promising candidate for SCI therapy.
Interference with HMGB1 Inhibits Neuronal Ferroptosis Following Spinal Cord Injury through Targeting ACSL4.
Wu Z, Zhong Q, Li T … +7 more , Yuan H, Zeng T, Zhang J, Feng K, Ye X, Jiang Q, Huang Q
Neurochem Res · 2026 May · PMID 42207425 · Publisher ↗
This study aimed to investigate the regulatory role of High-mobility group box 1 (HMGB1) in neuronal ferroptosis following spinal cord injury (SCI) and its underlying mechanisms. Iron ion deposition, malondialdehyde (MDA...
This study aimed to investigate the regulatory role of High-mobility group box 1 (HMGB1) in neuronal ferroptosis following spinal cord injury (SCI) and its underlying mechanisms. Iron ion deposition, malondialdehyde (MDA) and glutathione (GSH) levels, as well as the expressions of HMGB1, acyl-CoA synthetase long-chain family member 4 (ACSL4), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) in spinal cord tissue of SCI rats were measured at 24 h, 72 h and 1 week post-injury. Then, an in vitro neuronal ferroptosis model was established and neuronal cells were transfected with lentiviral vectors for HMGB1 interference or ACSL4 overexpression. Iron ion levels, MDA content, GSH activity, and the expressions of HMGB1, ACSL4, SLC7A11 and GPX4 were measured. And the interaction between HMGB1 and ACSL4 was assessed. Finally, SCI rats were administered the HMGB1 inhibitor glycyrrhizic acid (GA) and the effects GA on the iron ion deposition, MDA and SOD levels, as well as the expressions of HMGB1, ACSL4, SLC7A11 and GPX4 in spinal cord tissues were evaluated. SCI induced time-dependent iron deposition, increased MDA, HMGB1, and ACSL4, and decreased GSH, GPX4, and SLC7A11. The administration of GA in SCI rats significantly reduces iron ion deposition, decreases the levels of MDA, HMGB1 and ACSL4, and increases the levels of GSH, GPX4, and SLC7A11. Furthermore, cellular-level results demonstrated that interfering with HMGB1 attenuated ferroptosis in rat spinal cord neurons by suppressing ACSL4. Targeted suppression of ACSL4 expression through interference with HMGB1 inhibits neuronal ferroptosis in SCI rats.
Intermittent Fasting Attenuates Cognitive Decline in D-Galactose-Induced Aging Rats in Association with β-Hydroxybutyrate and PI3K/AKT/GSK-3β Signaling.
Lin X, Huang L, Ling X … +5 more , Lu J, Lin L, Ding L, Lin X, Chen T
Neurochem Res · 2026 May · PMID 42207407 · Publisher ↗
Age-related cognitive decline is a major public health concern, with few effective interventions available. Intermittent fasting (IF) has emerged as a promising metabolic intervention, potentially enhancing neuroprotecti...
Age-related cognitive decline is a major public health concern, with few effective interventions available. Intermittent fasting (IF) has emerged as a promising metabolic intervention, potentially enhancing neuroprotection through increased β-hydroxybutyrate (BHB) production. This study aimed to test the hypothesis that IF attenuates cognitive decline in D-galactose (D-gal)-induced aging rats, at least partly in association with BHB elevation and modulation of PI3K/AKT/GSK-3β signaling. Forty-six male Sprague-Dawley rats (2 months old) were assigned to five groups: Control, D-gal-induced aging (D-gal), D-gal + IF, D-gal + IF + LY294002 (a PI3K inhibitor), and D-gal + IF + Solvent. IF was administered for 6 weeks in conjunction with D-gal treatment. Recognition memory and spatial learning/memory were assessed using the novel object recognition and Morris water maze tests, respectively; the open field test was used to evaluate locomotor activity and anxiety-like behavior. Biochemical assays (ELISA, Western blot), histological staining, and RNA-seq transcriptomic analysis were performed. IF improved recognition memory and spatial learning/memory, preserved hippocampal neuronal morphology, increased the proportion of morphologically normal CA1 neurons, elevated serum BHB levels, reduced neuroinflammation and tau phosphorylation, and restored brain-derived neurotrophic factor (BDNF) expression. These improvements were attenuated by LY294002 intervention, supporting the involvement of the PI3K/AKT/GSK-3β pathway. Transcriptomic analysis revealed suppression of senescence-related genes and modulation of neuroprotective pathways. IF attenuated cognitive decline in D-gal-induced aging rats in association with increased BHB levels and modulation of the PI3K/AKT/GSK-3β pathway. These findings suggest that IF may represent a promising non-pharmacological intervention for age-related cognitive dysfunction, although causal roles of ketone metabolism require further validation.
WGCNA-Based Identification of HSPB1 Reveals a HOXA5/METTL1-m7G Regulatory Axis that Promotes Malignant Progression and Suppresses Ferroptosis in Glioblastoma.
Li H, Chen Y, Zhu Y … +2 more , Ke S, Wu D
Neurochem Res · 2026 May · PMID 42201601 · Publisher ↗
Glioblastoma (GBM) is the most aggressive primary brain tumor with a dismal prognosis. Ferroptosis is implicated in GBM pathogenesis. Heat shock protein B1 (HSPB1) is associated with tumor progression, yet its precise fu...
Glioblastoma (GBM) is the most aggressive primary brain tumor with a dismal prognosis. Ferroptosis is implicated in GBM pathogenesis. Heat shock protein B1 (HSPB1) is associated with tumor progression, yet its precise function and regulatory mechanism in GBM ferroptosis remain elusive. Differentially expressed genes were identified from the GSE151352 dataset. WGCNA was employed to identify GBM-associated modules, which were then intersected with genes from the FerrDb V2 database. HSPB1 expression and prognostic value were validated using TCGA and GEPIA databases, and clinical specimens. Functional assays (EdU, TUNEL, and Transwell) and ferroptosis indicators (lipid ROS, Fe, GSH) were assessed following HSPB1 modulation. Bioinformatics tools predicted METTL1-mediated m7G modification of HSPB1, and results were validated by RIP, dual-luciferase reporter assay, and mRNA stability assays. Transcriptional regulation of HSPB1 by HOXA5 was predicted and confirmed. A subcutaneous xenograft model was used to evaluate the METTL1-HSPB1 axis in vivo. Analysis revealed 2985 DEGs. WGCNA identified a GBM-correlated "red" module; intersection with ferroptosis genes pinpointed HSPB1. HSPB1 was significantly overexpressed in GBM, correlating with poor patient survival. HSPB1 knockdown suppressed GBM cell proliferation, migration, invasion, and induced ferroptosis. Mechanistically, METTL1 mediated m7G modification to HSPB1 mRNA to enhance its stability. Concurrently, HOXA5 bound to the HSPB1 promoter to activate its transcription. Silencing either METTL1 or HOXA5 downregulated HSPB1, inhibiting GBM malignant phenotypes. In vivo, the METTL1-HSPB1 axis promoted tumor growth. METTL1 stabilizes HSPB1 mRNA through m7G methylation, and HOXA5 transcriptionally activates HSPB1 expression. This regulation promotes GBM malignant progression.
Ethylmalonic and Methylsuccinic Acids Disrupt Bioenergetics and Induce Mitochondrial Permeability Transition Through Thiol Redox Modulation in Rat Striatum: Potential Mechanisms Involved in Ethylmalonic Encephalopathy.
Marcuzzo MB, Zemniaçak ÂB, da Rosa JS … +11 more , Verdi BSS, Benati MPDV, de Andrade Silveira J, do Nascimento JG, de Almeida Moreira H, Dias-Oliveira M, Souza DO, Amaral AU, Zanatta G, Wajner M, Leipnitz G
Neurochem Res · 2026 May · PMID 42201462 · Full text
Ethylmalonic (EMA) and methylsuccinic (MSA) acids concentrations are elevated in tissues and body fluids of patients with ethylmalonic encephalopathy (EE), a mitochondrial disorder associated with basal ganglia abnormali...
Ethylmalonic (EMA) and methylsuccinic (MSA) acids concentrations are elevated in tissues and body fluids of patients with ethylmalonic encephalopathy (EE), a mitochondrial disorder associated with basal ganglia abnormalities. To clarify the pathophysiology of this disorder, we evaluated the effects of EMA and MSA on bioenergetics, redox homeostasis and mitochondrial permeability transition (MPT) in rat striatum. We verified that EMA and MSA reduced state 3 and uncoupled respiration and inhibited the activities of α-ketoglutarate dehydrogenase and complex IV of the electron transport chain. Both organic acids also decreased mitochondrial membrane potential and Ca retention capacity, which were normalized by cyclosporine A and ADP, indicating induction of MPT pore opening. These effects were further mitigated by N-ethylmaleimide and dithiothreitol, suggesting that thiol groups of the MPT pore were oxidized by EMA and MSA. Moreover, EMA and MSA mildly decreased reduced glutathione concentrations, reinforcing that thiol group are oxidized by these organic acids. Therefore, it is presumed that EMA- and MSA-induced bioenergetic impairment associated with MPT pore opening is involved in the pathophysiology of basal ganglia injury observed in EE.
From the Scientific Underground to the Height of Recognition: The 40th Anniversary of Rita Levi-Montalcini's Nobel Prize and the Promising Horizon in Psychiatry.
Junkes L, Nardi AE, Clementi E
Neurochem Res · 2026 May · PMID 42185713 · Full text
Forty years ago, in 1986, Rita Levi-Montalcini was awarded the Nobel Prize in Physiology or Medicine for the discovery of Nerve Growth Factor, a fundamental finding that inaugurated the field of trophic signaling in the...
Forty years ago, in 1986, Rita Levi-Montalcini was awarded the Nobel Prize in Physiology or Medicine for the discovery of Nerve Growth Factor, a fundamental finding that inaugurated the field of trophic signaling in the nervous system. Her research, conducted with credibility and consistency under the precarious conditions of an Italy enduring the Second World War, and later refined in the United States, rigorously demonstrated that neuronal growth and survival are regulated by specific chemical signals, not merely by intrinsic processes. Using biological assays involving sarcoma and chicken embryos, Levi-Montalcini identified a protein substance that promoted exuberant nerve fiber growth from sensory and sympathetic ganglia. The subsequent purification and biochemical characterization of Nerve Growth Factor by biochemist Stanley Cohen - with whom she shared the Nobel Prize - confirmed its protein nature. This discovery scientifically proved the existence of signaling molecules that guide nervous system development, including critical processes such as neuronal differentiation, axonal growth, and apoptosis, programmed cell death. The concept that target-cells secrete trophic factors for maintenance and survival became fundamental in neuroembryology. The impact of Levi-Montalcini's work transcended developmental neurobiology. The Nerve Growth Factor model paved the way for the discovery of a family of neurotrophins, elucidating mechanisms of neural plasticity, regeneration, and brain aging, with profound implications for the understanding of mental illnesses, neurodegenerative diseases, and cancer. For establishing, with experimental precision, a universal principle of cellular communication in the nervous system, Rita Levi-Montalcini - a scientist who expanded scientific frontiers - was honored with numerous awards, alongside the Nobel Prize, consolidating her position as an influential female figure in 20th-century neuroscience.
Overexpression of WNT3a in the Hippocampus Can Partly Alleviate Deficits in Animal Models of Alzheimer's Disease.
Gerasimov KA, Ignasheva YE, Dobryakova YV … +4 more , Korotkova TA, Koryagina AA, Markevich VA, Bolshakov AP
Neurochem Res · 2026 May · PMID 42185674 · Publisher ↗
Dysregulation of the WNT signaling pathway is implicated in the synaptic dysfunction underlying Alzheimer's disease (AD). This study investigates whether enhancing WNT signaling through hippocampal overexpression of the...
Dysregulation of the WNT signaling pathway is implicated in the synaptic dysfunction underlying Alzheimer's disease (AD). This study investigates whether enhancing WNT signaling through hippocampal overexpression of the WNT3a ligand can mitigate functional deficits in two distinct animal models of AD pathology. We used a rat model of cholinergic deficit, induced by intraseptal 192IgG-saporin injections, and a transgenic 5XFAD mouse model of amyloidosis. Adeno-associated viruses were used to overexpress WNT3a in the hippocampal CA1 region. We assessed cognitive and sensorimotor behavior, synaptic plasticity (long-term potentiation, LTP) in vivo (rats) and in vitro (mice), and analyzed key proteins of the WNT signaling pathway. In rats with cholinergic deficit, WNT3a overexpression ameliorated sensorimotor coordination deficits and restored the initial phase of hippocampal LTP in vivo, without preventing the loss of cholinergic neurons or the decrease in acetylcholinesterase activity. In 5XFAD mice, which exhibited impaired LTP in vitro, WNT3a overexpression significantly enhanced the early phase of potentiation. This functional rescue was associated with a recovery of elevated phospho-β-catenin levels in the 5XFAD hippocampus. WNT3a did not affect behavior in the 5XFAD model and its benefits were independent of changes in cholinergic markers in both models. Our findings demonstrate that targeted WNT3a overexpression in the hippocampus can partially alleviate synaptic and functional deficits in AD models by directly modulating synaptic plasticity, primarily through the restoration of the Wnt/β-catenin pathway. This positions WNT3a gene therapy as a promising strategy for counteracting synaptic failure in Alzheimer's disease.
Lipid Nanoparticle-Delivered Circ_0017866 Alleviates Cerebral Ischemia-Reperfusion Injury by Suppressing Endothelial-Mesenchymal Transition via the miR-124-3p/CLDND1 Axis.
Wang Y, Cai Y, Zhang X … +4 more , Wang D, Xin B, Cai X, Sun J
Neurochem Res · 2026 May · PMID 42176037 · Publisher ↗
Ischemic stroke poses a severe threat to human health, and cerebral ischemia-reperfusion injury (CIRI) following recanalization remains a critical challenge for patient prognosis. This study investigated the role and mec...
Ischemic stroke poses a severe threat to human health, and cerebral ischemia-reperfusion injury (CIRI) following recanalization remains a critical challenge for patient prognosis. This study investigated the role and mechanism of the circ_0017866/miR-124-3p/claudin domain containing 1 (CLDND1) axis in CIRI-induced endothelial-mesenchymal transition (EndMT) and evaluated the therapeutic potential of lipid nanoparticle (LNP)-encapsulated circ_0017866. Both oxygen-glucose deprivation/reperfusion cell and middle cerebral artery occlusion/reperfusion mouse models were established. Molecular interactions and gene/protein expression were validated using dual-luciferase reporter assays, quanti-tative real-time PCR, western blot, and immunofluorescence. In vitro, endothelial cell viability and function were assessed through CCK-8, Transwell migration, and tube formation assays. In vivo, LNP-mediated delivery of circ_0017866 was employed, and neurological deficits and cerebral infarct volume were evaluated using modified neu-rological severity scores and 2,3,5-triphenyltetrazolium chloride staining. Both in vivo and in vitro studies demonstrated that after ischemia-reperfusion, the expression of circ_0017866 and CLDND1 was downregulated, while miR-124-3p expression was upregulated. The dual-luciferase assay confirmed that miR-124-3p directly targets both circ_0017866 and CLDND1. In the OGD/R model, either circ_0017866 overexpression or miR-124-3p inhibition upregulated the expression of CLDND1 and occludin, downregulated α-smooth muscle actin (α-SMA) and Snail, and improved endothelial function. In the MCAO/R model, LNP-circ_0017866 treatment significantly improved neurological deficits, reduced infarct volume, and decreased the abnormal expression of EndMT-related markers. Circ_0017866 alleviates CIRI-induced EndMT by functioning as a molecular sponge for miR-124-3p to indirectly regulate CLDND1 expression. LNP-delivered circ_0017866 effectively mitigates neurological deficits and reduces cerebral infarct volume, providing a promising therapeutic strategy for ischemic stroke.
Clinical Significance and Mechanistic Role of circLPAR3/miR-634 in Ischemic Stroke.
Chen J, Yang J, Wu Q … +3 more , Chen L, Wang H, Wu J
Neurochem Res · 2026 May · PMID 42171873 · Publisher ↗
Individuals with hypertension carry a high risk of stroke, which endangers human health. The study systematically elucidated the dynamic expression, functional effects, and molecular mechanisms of the circular RNA LPAR3...
Individuals with hypertension carry a high risk of stroke, which endangers human health. The study systematically elucidated the dynamic expression, functional effects, and molecular mechanisms of the circular RNA LPAR3 in ischemic stroke (IS). 300 essential-hypertension (EH) patients were enrolled, comprising 165 cases diagnosed with IS. mRNA abundance was quantified via RT-qPCR. C57BL/6 mice treated with MACO and Neuro-2a cells receiving oxygen-glucose deprivation/reoxygenation (OGD/R) were applied for functional experiments. Neurological deficits and infarct volume of mice were evaluated. Besides, key cellular behaviors encompassing proliferative capacity, apoptotic rate, and inflammatory response were monitored. The putative binding event was interrogated through luciferase reporter and RIP coupled to qPCR assays. A diminished level of circLPAR3 was evidenced in the plasma of IS patients, which can distinguish IS cases from EH and remains an independent predictor of patients' poor prognosis. In vivo, overexpression of circLPAR3 alleviated MACO-mediated neurological deficit and cerebral infarction. In vitro, OGD/R triggered the surge in cell apoptosis and pro-inflammatory cytokine release, but it was attenuated by circLPAR3 upregulation. Mechanistically, the neuro-rescue driven by circLPAR3 was offset by miR-634, whose plasma expression was negatively correlated with circLPAR3. KLB expression was significantly downregulated in cellular models and co-regulated by circLPAR3 and miR-634. circLPAR3/miR-634 modulates the pathological progression of IS by directly regulating neuronal apoptosis and orchestrating inflammatory responses, and KLB may serve as a key downstream target mediating the biological functions.
TDP-43 Acetylation at the Neuroimmune Interface: A Hypothesis-Driven Framework for Peripheral Inflammatory Stratotypes in ALS.
Condorelli GA, Iozzia A, Bonifacio D … +1 more , Pelin A
Neurochem Res · 2026 May · PMID 42171861 · Publisher ↗
Transactive Response Deoxyribonucleic Acid-Binding Protein-43 (TDP-43) acetylation may couple motor-neuron degeneration to systemic immune orchestration in Amyotrophic Lateral Sclerosis (ALS). Upon nuclear clearance and...
Transactive Response Deoxyribonucleic Acid-Binding Protein-43 (TDP-43) acetylation may couple motor-neuron degeneration to systemic immune orchestration in Amyotrophic Lateral Sclerosis (ALS). Upon nuclear clearance and mislocalisation, TDP-43 enters the periphery; acetylation shapes its conformation, trafficking and immunogenicity. This narrative review synthesises single-cell transcriptomics, proteomic immunoprofiling and clinical inflammatory phenotyping to examine whether site-specific acetylated TDP-43 species may be associated with peripheral inflammatory signatures relevant to ALS immunopathology. By integrating separate datasets on acetylated TDP-43, monocyte phenotypes and cytokine modules, we propose two provisional endotypes characterised by monocyte reprogramming, cytokine modules and Blood-Brain Barrier (BBB) dysfunction-each representing clinically actionable pathways. Framed as a provisional neuroimmune interface, the acetylation state is considered here as a plausible molecular correlate and potential therapeutic entry point: a measurable clue to inform pharmacological targeting and, potentially, a modifiable target via p300CREB-Binding Protein (CBP)-Histone Deacetylase (HDAC) axes or sirtuin activity. Recasting TDP-43 from neuropathological hallmark to immunoactive sentinel supports a shift from descriptive nosology to stratified immunotherapy, in which treatment allocation is informed by acetylation-defined peripheral signatures.
Alkaloids from Dendrobium Nobile Lindl Improves Mitochondrial Function by Enhancing the Activity of v-ATPase in APP/PS1 Mice.
Li Q, Yang Y, Guo B … +4 more , Liu X, Luo G, Wu Y, Nie J
Neurochem Res · 2026 May · PMID 42171843 · Publisher ↗
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal loss and cognitive deficiency. Mitochondrial dysfunction and lysosomal abnormalities are critical during AD pathogenesis. The vesicular A...
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal loss and cognitive deficiency. Mitochondrial dysfunction and lysosomal abnormalities are critical during AD pathogenesis. The vesicular ATPase (v-ATPase) is a core regulator of lysosomal function, and its dysfunction impairs iron-sulfur protein synthesis and mitochondrial function. In this study, 4-month-old amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice were treated with alkaloids from Dendrobium nobile Lindl (DNLA) at 20 and 40 mg/kg/day via oral gavage for 5 months (n = 10 per group). The Y-maze test showed that DNLA alleviated cognitive dysfunction in APP/PS1 mice. HE, Nissl, and β-galactosidase staining indicated that DNLA mitigated brain damage. DNLA also increased the protein levels of v-ATPase subunits ATP6V1A and ATP6V0a1 in the cortex, promoted mitochondrial iron uptake and utilization, enhanced mitochondrial function, and reduced neuronal damage. Dendrobine (DDB) accounted for 84.6% in DNLA used for animal experiments, and purified DDB (99.7%) was applied for in vitro assays. In PC12 cells, DDB restored ATP6V1A expression, enhanced v-ATPase activity, delayed cellular senescence, improved iron utilization, and elevated mitochondrial membrane potential and ATP levels in ATP6V1A-knockdown cells. These findings suggest that DNLA may attenuate learning and memory impairment in APP/PS1 mice. The mechanism may be related to enhanced v-ATPase activity, promoted mitochondrial iron uptake and utilization, and improved mitochondrial function.
Fecal Microbiota Transplantation from Exercise-Preconditioned Mice Attenuates Post-stroke Cognitive Impairment by Preserving Gut and Blood-Brain Barrier Integrity.
Yu Y, Tian M, Sun S … +6 more , Wang H, Qin M, Gao Y, Jia X, Gao Q, Jiang F
Neurochem Res · 2026 May · PMID 42171840 · Publisher ↗
Exercise preconditioning reduces post-stroke cognitive impairment (PSCI), but the contribution of the gut microbiota (GM) to barrier protection remains unclear. We examined whether exercise-preconditioned GM contributes...
Exercise preconditioning reduces post-stroke cognitive impairment (PSCI), but the contribution of the gut microbiota (GM) to barrier protection remains unclear. We examined whether exercise-preconditioned GM contributes to PSCI improvement and preservation of gut and blood-brain barrier (BBB) integrity. Mice were preconditioned with 4 weeks of voluntary wheel running prior to stroke induction. We assessed cognitive function, GM composition, fecal short-chain fatty acid (SCFA) levels, inflammation, and gut-blood-brain barrier (BBB) integrity. Then, we used fecal microbiota transplantation (FMT) to evaluate how GM contributes to the benefits of voluntary exercise. Our results showed that exercise remodeled the GM composition and elevated SCFAs levels. Also, exercise suppressed systemic, colonic, and neuroinflammation, enhanced the barrier-related protein (Occludin, Claudin-5, and ZO-1) levels, maintained barrier integrity, and alleviated cognitive dysfunction after ischemic stroke. FMT from exercised mice partially reproduced the cognitive and anti-inflammatory benefits. SCFA levels were associated with reduced inflammatory markers and increased expression of barrier-related proteins. The findings suggest that exercise preconditioning is associated with coordinated preservation of gut and BBB integrity and improved cognition after stroke. Moreover, FMT from exercised mice conferred partial protection against PSCI.
β-Asarone, Tenuifolin, and YuanZhi Decoction Restore Cognitive Function and Modulate GRIN2B-Associated Autophagy in Alzheimer's Disease.
Tang H, Peng F, Shi Q … +5 more , Dai X, Hou F, Dong H, Zhang L, Shuai Z
Neurochem Res · 2026 May · PMID 42171824 · Publisher ↗
Alzheimer's disease (AD) is characterized by neurodegeneration, autophagy dysregulation, and mitochondrial stress. β-asarone and tenuifolin have shown neuroprotective effects, but their mechanisms remain unclear. YuanZhi...
Alzheimer's disease (AD) is characterized by neurodegeneration, autophagy dysregulation, and mitochondrial stress. β-asarone and tenuifolin have shown neuroprotective effects, but their mechanisms remain unclear. YuanZhi decoction, a traditional formula containing Polygala tenuifolia, is used for cognitive impairment, yet its active constituents are not fully understood. A D-galactose-induced AD mouse model (150 mg/kg/day, s.c., 42 days) was established to evaluate β-asarone, tenuifolin, their combination, and YuanZhi decoction. Behavioral tests (MWM and NOR), Nissl staining, IHC, network pharmacology, molecular docking (including the GRIN2B inhibitor ifenprodil as positive control), Western blotting, biochemical assays, and RT-qPCR were performed. All treatments improved cognitive function, attenuated hippocampal neuronal loss and tau pathology, and restored metabolic parameters (ATP, ROS, DT, SOD2). Network pharmacology identified GRIN2B as a key hub target. Molecular docking revealed that β-asarone and senegenin (the active metabolite of tenuifolin) bind to the same allosteric pocket as ifenprodil on GRIN2B, sharing highly consistent interaction residues. GRIN2B upregulation in AD mice was accompanied by autophagic dysfunction (increased LC3B/LC3A ratio and PINK1, reduced p62) and mitochondrial stress. These abnormalities were significantly reversed by all treatments, with the combination and YuanZhi decoction showing greater efficacy. β-asarone, tenuifolin, their combination, and YuanZhi decoction alleviate GRIN2B-linked autophagic imbalance and mitochondrial stress in AD-like mice, supporting their therapeutic potential.
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