Neurochemistry international最新文献

METTL3/IGF2BP2/IκBα axis participates in neuroinflammation in Alzheimer's disease by regulating M1/M2 polarization of microglia.

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-03-17 DOI: 10.1016/j.neuint.2025.105964

Ling Zhu, Congyan Liu, Yang Wang, Xuanang Zhu, Lei Wu, Lvan Chen, Jing Zhou, Fan Wang

Background: Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD.

Method: Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N⁶-methyladenosine (m⁶A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF.

Results: Stimulation with Aβ_1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m⁶A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα.

Conclusion: Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.

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引用次数: 0

Nicotine enhances object recognition memory through activation of the medial prefrontal cortex to the perirhinal cortex pathway

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-03-10 DOI: 10.1016/j.neuint.2025.105963

Hirohito Esaki , Kanta Imai , Keisuke Nishikawa, Naoya Nishitani, Satoshi Deyama, Katsuyuki Kaneda

Nicotine enhances recognition memory across species; however, the underlying neuronal mechanisms remain incompletely understood. Our previous study using a novel object recognition (NOR) test and electrophysiological recordings of mouse brain slices demonstrated that nicotine enhanced object recognition memory by stimulating nicotinic acetylcholine receptors in the medial prefrontal cortex (mPFC). To elucidate this further, we conducted the NOR test combined with pharmacology, chemogenetics, optogenetics, and ex vivo electrophysiology in male C57BL/6J mice. Chemogenetic inhibition of mPFC excitatory neurons suppressed nicotine-induced enhancement of object recognition memory, whereas their activation alone was sufficient to enhance memory. Anatomical studies indicate that the mPFC sends projections to the perirhinal cortex (PRH), a brain region involved in object recognition memory. Therefore, we focused on mPFC-PRH projections. Whole-cell patch-clamp recordings with optogenetic stimulation revealed that PRH pyramidal neurons received monosynaptic and glutamatergic inputs from the mPFC. Chemogenetic suppression of mPFC neurons projecting to the PRH blocked the nicotine-induced enhancement of object recognition memory, whereas activation of these neurons alone was sufficient to enhance memory. To achieve precise temporal control, optogenetic inhibition of the mPFC-PRH pathway during the training session blocked the effects of nicotine, and its activation alone enhanced memory. Furthermore, unilateral intra-mPFC nicotine infusion enhanced object recognition memory, and this effect was suppressed by ipsilateral intra-PRH infusion of an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist. These findings indicate that nicotine enhances object recognition memory by activating glutamatergic projections from the mPFC to PRH.

{"title":"Nicotine enhances object recognition memory through activation of the medial prefrontal cortex to the perirhinal cortex pathway","authors":"Hirohito Esaki , Kanta Imai , Keisuke Nishikawa, Naoya Nishitani, Satoshi Deyama, Katsuyuki Kaneda","doi":"10.1016/j.neuint.2025.105963","DOIUrl":"10.1016/j.neuint.2025.105963","url":null,"abstract":"<div><div>Nicotine enhances recognition memory across species; however, the underlying neuronal mechanisms remain incompletely understood. Our previous study using a novel object recognition (NOR) test and electrophysiological recordings of mouse brain slices demonstrated that nicotine enhanced object recognition memory by stimulating nicotinic acetylcholine receptors in the medial prefrontal cortex (mPFC). To elucidate this further, we conducted the NOR test combined with pharmacology, chemogenetics, optogenetics, and <em>ex vivo</em> electrophysiology in male C57BL/6J mice. Chemogenetic inhibition of mPFC excitatory neurons suppressed nicotine-induced enhancement of object recognition memory, whereas their activation alone was sufficient to enhance memory. Anatomical studies indicate that the mPFC sends projections to the perirhinal cortex (PRH), a brain region involved in object recognition memory. Therefore, we focused on mPFC-PRH projections. Whole-cell patch-clamp recordings with optogenetic stimulation revealed that PRH pyramidal neurons received monosynaptic and glutamatergic inputs from the mPFC. Chemogenetic suppression of mPFC neurons projecting to the PRH blocked the nicotine-induced enhancement of object recognition memory, whereas activation of these neurons alone was sufficient to enhance memory. To achieve precise temporal control, optogenetic inhibition of the mPFC-PRH pathway during the training session blocked the effects of nicotine, and its activation alone enhanced memory. Furthermore, unilateral intra-mPFC nicotine infusion enhanced object recognition memory, and this effect was suppressed by ipsilateral intra-PRH infusion of an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist. These findings indicate that nicotine enhances object recognition memory by activating glutamatergic projections from the mPFC to PRH.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105963"},"PeriodicalIF":4.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biochemical and medical aspects of vitamin B1 research

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-03-07 DOI: 10.1016/j.neuint.2025.105962

Alexander F. Makarchikov , Pierre Wins , Lucien Bettendorff

Vitamin B₁ is an indispensable food factor for the human and animal body. In animals, vitamin B₁ is found in the form of thiamine and its phosphate esters – thiamine mono-, di- and triphosphate, as well as an adenylated derivative – adenosine thiamine triphosphate. At present, the only vitamin B₁ form with biochemical functions being elucidated is thiamine diphosphate, which serves as a coenzyme for several important enzymes involved in carbohydrate, amino acid, fatty acid and energy metabolism. Here we review the latest developments in the field of vitamin B₁ research in animals. Transport, metabolism and biological role of thiamine and its derivatives are considered as well as the involvement of vitamin B₁-dependent processes in human diseases and its therapeutic issues, a field that has gained momentum with several important recent developments.

引用次数: 0

Repeated administration of esketamine ameliorates mechanical allodynia in mice with chemotherapy-induced peripheral neuropathy: A role of gut microbiota and metabolites

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-03-05 DOI: 10.1016/j.neuint.2025.105961

Wei-wei Luan , Han-wen Gu , Di Qiu , Xin Ding , Pan-miao Liu , Kenji Hashimoto , Jian-jun Yang , Xing-ming Wang

Chemotherapy-induced peripheral neuropathy (CIPN) severely diminishes the quality of life for cancer survivors, yet effective treatments remain scarce. Esketamine, a commonly used anesthetic, has demonstrated neuroprotective effects by restoring gut microbiome dysbiosis. In this study, we investigated the impact of esketamine on nociceptive sensitivity in a mouse model of CIPN and explored the potential involvement of the gut microbiome. In mice treated with oxaliplatin, repeated esketamine doses (in contrast to a single dose) significantly improved the paw withdrawal threshold (PWT). Western blot and qPCR analyses further revealed that repeated esketamine administration markedly reduced microglial activation and neuroinflammation in the dorsal root ganglion (DRG), underscoring its potent anti-inflammatory properties. Moreover, fecal 16S rRNA analysis indicated that esketamine partially restored the abnormal gut microbiota composition (β-diversity). Plasma metabolome analysis showed that repeated esketamine treatment significantly lowered the elevated levels of 6H-indolo[2,3-b]quinoline and restored the reduced levels of (3-exo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octane observed in oxaliplatin-treated mice. In addition, fecal microbiota transplantation from esketamine-treated CIPN mice notably improved both the diminished PWT and DRG neuroinflammation in oxaliplatin-treated mice. Collectively, these findings suggest that repeated esketamine administration may alleviate mechanical allodynia in CIPN mice by modulating neuroinflammation, gut microbiota, and associated metabolites.

{"title":"Repeated administration of esketamine ameliorates mechanical allodynia in mice with chemotherapy-induced peripheral neuropathy: A role of gut microbiota and metabolites","authors":"Wei-wei Luan , Han-wen Gu , Di Qiu , Xin Ding , Pan-miao Liu , Kenji Hashimoto , Jian-jun Yang , Xing-ming Wang","doi":"10.1016/j.neuint.2025.105961","DOIUrl":"10.1016/j.neuint.2025.105961","url":null,"abstract":"<div><div>Chemotherapy-induced peripheral neuropathy (CIPN) severely diminishes the quality of life for cancer survivors, yet effective treatments remain scarce. Esketamine, a commonly used anesthetic, has demonstrated neuroprotective effects by restoring gut microbiome dysbiosis. In this study, we investigated the impact of esketamine on nociceptive sensitivity in a mouse model of CIPN and explored the potential involvement of the gut microbiome. In mice treated with oxaliplatin, repeated esketamine doses (in contrast to a single dose) significantly improved the paw withdrawal threshold (PWT). Western blot and qPCR analyses further revealed that repeated esketamine administration markedly reduced microglial activation and neuroinflammation in the dorsal root ganglion (DRG), underscoring its potent anti-inflammatory properties. Moreover, fecal 16S rRNA analysis indicated that esketamine partially restored the abnormal gut microbiota composition (β-diversity). Plasma metabolome analysis showed that repeated esketamine treatment significantly lowered the elevated levels of 6H-indolo[2,3-b]quinoline and restored the reduced levels of (3-exo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octane observed in oxaliplatin-treated mice. In addition, fecal microbiota transplantation from esketamine-treated CIPN mice notably improved both the diminished PWT and DRG neuroinflammation in oxaliplatin-treated mice. Collectively, these findings suggest that repeated esketamine administration may alleviate mechanical allodynia in CIPN mice by modulating neuroinflammation, gut microbiota, and associated metabolites.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105961"},"PeriodicalIF":4.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Age-related memory decline is accelerated by pinealectomy in young adult and middle-aged rats via BDNF / ERK / CREB signalling

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-03-04 DOI: 10.1016/j.neuint.2025.105960

Jana Tchekalarova , Dimitrinka Atanasova , Desislava Krushovlieva , Darina Barbutska , Milena Atanasova , Pavel Rashev , Zlatina Nenchovska , Milena Mourdjeva , Yvetta Koeva

Memory decline is considered a normal part of aging, while the relationship between melatonin deficiency and cognitive function is complex and not fully understood. The present study investigated the role of melatonin deficiency at different ages on working and short-term recognition and spatial memory in rats. An age-related decline in memory function was tested using the Y-maze, the object recognition test, and the radial arm maze. The brain-derived neurotrophic factor (BDNF), TrkB receptor, the extracellular signal-regulated kinase (ERK)1/2 and pERK1/2 expression in the hippocampus was assessed by immunohistochemistry. The pCREB/CREB ratio in the frontal cortex (FC) and hippocampus was evaluated by ELISA. Young adult and middle-aged rats with pinealectomy had memory impairment whereas old melatonin-deficient rats were unaffected. Aging was associated with reduced expression of BDNF and its receptor throughout the hippocampus and reduced ratio of pCREB/CREB in the FC and hippocampus, whereas pinealectomy exacerbated this process in 3- and 14-month-old rats. The region-specific reduced expression of the ERK1/2 and pERK1/2 was observed in young adult rats with pinealectomy. However, in middle-aged rats, the expression of these signaling molecules was either downregulated or upregulated in different regions of the hippocampus. Our study provides insights into the molecular pathways involved in age-related memory changes associated with melatonin deficiency, highlighting the importance of the BDNF/ERK1/2/CREB pathway in the hippocampus and suggesting a critical period for intervention.

{"title":"Age-related memory decline is accelerated by pinealectomy in young adult and middle-aged rats via BDNF / ERK / CREB signalling","authors":"Jana Tchekalarova , Dimitrinka Atanasova , Desislava Krushovlieva , Darina Barbutska , Milena Atanasova , Pavel Rashev , Zlatina Nenchovska , Milena Mourdjeva , Yvetta Koeva","doi":"10.1016/j.neuint.2025.105960","DOIUrl":"10.1016/j.neuint.2025.105960","url":null,"abstract":"<div><div>Memory decline is considered a normal part of aging, while the relationship between melatonin deficiency and cognitive function is complex and not fully understood. The present study investigated the role of melatonin deficiency at different ages on working and short-term recognition and spatial memory in rats. An age-related decline in memory function was tested using the Y-maze, the object recognition test, and the radial arm maze. The brain-derived neurotrophic factor (BDNF), TrkB receptor, the extracellular signal-regulated kinase (ERK)1/2 and pERK1/2 expression in the hippocampus was assessed by immunohistochemistry. The pCREB/CREB ratio in the frontal cortex (FC) and hippocampus was evaluated by ELISA. Young adult and middle-aged rats with pinealectomy had memory impairment whereas old melatonin-deficient rats were unaffected. Aging was associated with reduced expression of BDNF and its receptor throughout the hippocampus and reduced ratio of pCREB/CREB in the FC and hippocampus, whereas pinealectomy exacerbated this process in 3- and 14-month-old rats. The region-specific reduced expression of the ERK1/2 and pERK1/2 was observed in young adult rats with pinealectomy. However, in middle-aged rats, the expression of these signaling molecules was either downregulated or upregulated in different regions of the hippocampus. Our study provides insights into the molecular pathways involved in age-related memory changes associated with melatonin deficiency, highlighting the importance of the BDNF/ERK1/2/CREB pathway in the hippocampus and suggesting a critical period for intervention.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105960"},"PeriodicalIF":4.4,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Research progress on the mechanisms of microglial extracellular vesicles affecting the prognosis of ischemic stroke 小胶质细胞胞外小泡影响缺血性脑卒中预后机制的研究进展。

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-25 DOI: 10.1016/j.neuint.2025.105949

Yang An , Gang Su , Wei Chen , Jinyang Song , Miao Chai , Longni Zhu , Zhenchang Zhang

Ischemic stroke is the major type of stroke and one of the main causes of morbidity, mortality, and long-term disability worldwide. Microglia play a complex and crucial role in stroke. They are the primary immune cells in the brain and can rapidly respond to the pathological changes caused by stroke. They promote neuroprotection and repair after ischemic stroke through various mechanisms, such as activation and polarization, dynamic interactions with other cells (neurons, astrocytes, oligodendrocytes, vascular endothelial cells, etc.), and phagocytosis to clear dead cell debris. Among the multiple pathways through which microglia exert their neuroprotective effects, the secretion of extracellular vesicles is one of the most important. The focus of this review is to analyze the latest progress in research on ischemic stroke related to microglia-derived extracellular vesicles, discuss their mechanisms of action, and provide new strategies for improving stroke prognosis. To obtain relevant articles, we conducted a comprehensive search in Pubmed and Web of Science, with keywords related to ischemic stroke and microglia-derived extracellular vesicles or exosomes. A total of 59 articles were included in the review. Existing studies have shown that after a stroke occurs, microglia release extracellular vesicles containing proteins, nucleic acids, metabolites, etc. These vesicles target corresponding receptor cells and can slow down the development of stroke and improve stroke outcomes through various means, such as reducing neuronal apoptosis, inhibiting neuronal autophagy, suppressing neuronal ferroptosis, preventing neuronal pyroptosis, alleviating inflammatory responses, reducing glial scar formation, promoting myelin regeneration and repair, and facilitating blood-brain barrier repair.

{"title":"Research progress on the mechanisms of microglial extracellular vesicles affecting the prognosis of ischemic stroke","authors":"Yang An , Gang Su , Wei Chen , Jinyang Song , Miao Chai , Longni Zhu , Zhenchang Zhang","doi":"10.1016/j.neuint.2025.105949","DOIUrl":"10.1016/j.neuint.2025.105949","url":null,"abstract":"<div><div>Ischemic stroke is the major type of stroke and one of the main causes of morbidity, mortality, and long-term disability worldwide. Microglia play a complex and crucial role in stroke. They are the primary immune cells in the brain and can rapidly respond to the pathological changes caused by stroke. They promote neuroprotection and repair after ischemic stroke through various mechanisms, such as activation and polarization, dynamic interactions with other cells (neurons, astrocytes, oligodendrocytes, vascular endothelial cells, etc.), and phagocytosis to clear dead cell debris. Among the multiple pathways through which microglia exert their neuroprotective effects, the secretion of extracellular vesicles is one of the most important. The focus of this review is to analyze the latest progress in research on ischemic stroke related to microglia-derived extracellular vesicles, discuss their mechanisms of action, and provide new strategies for improving stroke prognosis. To obtain relevant articles, we conducted a comprehensive search in Pubmed and Web of Science, with keywords related to ischemic stroke and microglia-derived extracellular vesicles or exosomes. A total of 59 articles were included in the review. Existing studies have shown that after a stroke occurs, microglia release extracellular vesicles containing proteins, nucleic acids, metabolites, etc. These vesicles target corresponding receptor cells and can slow down the development of stroke and improve stroke outcomes through various means, such as reducing neuronal apoptosis, inhibiting neuronal autophagy, suppressing neuronal ferroptosis, preventing neuronal pyroptosis, alleviating inflammatory responses, reducing glial scar formation, promoting myelin regeneration and repair, and facilitating blood-brain barrier repair.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105949"},"PeriodicalIF":4.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DOT1L in neural development and neurological and psychotic disorders

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-22 DOI: 10.1016/j.neuint.2025.105955

Feiyan Shen , Linghui Zeng , Yanpan Gao

Disruptor of Telomeric Silencing 1-Like (DOT1L) is the sole methyltransferase in mammals responsible for catalyzing the mono-, di-, and trimethylation of histone H3 at lysine 79 (H3K79), a modification crucial for various cellular processes, including gene transcription, cell cycle regulation, DNA repair, and development. Recent studies have increasingly linked DOT1L to the nervous system, where it plays a vital role in neurodevelopment and neuronal function. It has been shown to regulate the proliferation and differentiation of neural progenitor cells, promote neuronal maturation, and influence synaptic function, all of which are essential for proper neural circuit formation and brain function. Moreover, dysregulation of DOT1L has been associated with several neurological disorders, highlighting its potential role in disease pathology. Abnormal expression or activity of DOT1L has been implicated in cognitive deficits and neurodegenerative diseases, underscoring the enzyme's significance in both the development and maintenance of the nervous system. This review synthesizes recent findings on DOT1L's role in the nervous system, emphasizing its importance in neurodevelopment and exploring its potential as a therapeutic target for treating neurological disorders.

{"title":"DOT1L in neural development and neurological and psychotic disorders","authors":"Feiyan Shen , Linghui Zeng , Yanpan Gao","doi":"10.1016/j.neuint.2025.105955","DOIUrl":"10.1016/j.neuint.2025.105955","url":null,"abstract":"<div><div>Disruptor of Telomeric Silencing 1-Like (DOT1L) is the sole methyltransferase in mammals responsible for catalyzing the mono-, di-, and trimethylation of histone H3 at lysine 79 (H3K79), a modification crucial for various cellular processes, including gene transcription, cell cycle regulation, DNA repair, and development. Recent studies have increasingly linked DOT1L to the nervous system, where it plays a vital role in neurodevelopment and neuronal function. It has been shown to regulate the proliferation and differentiation of neural progenitor cells, promote neuronal maturation, and influence synaptic function, all of which are essential for proper neural circuit formation and brain function. Moreover, dysregulation of DOT1L has been associated with several neurological disorders, highlighting its potential role in disease pathology. Abnormal expression or activity of DOT1L has been implicated in cognitive deficits and neurodegenerative diseases, underscoring the enzyme's significance in both the development and maintenance of the nervous system. This review synthesizes recent findings on DOT1L's role in the nervous system, emphasizing its importance in neurodevelopment and exploring its potential as a therapeutic target for treating neurological disorders.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"185 ","pages":"Article 105955"},"PeriodicalIF":4.4,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Kaempferol promotes angiogenesis through HIF-1α/VEGF-A/Notch1 pathway in ischemic stroke rats

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-21 DOI: 10.1016/j.neuint.2025.105953

Sen Zhang , Chengdi Liu , Wan Li , Yizhi Zhang , Yihui Yang , Hong Yang , Ziyuan Zhao , Fang Xu , Wanxin Cao , Xiaoxue Li , Jinhua Wang , Linglei Kong , Guanhua Du

Stroke is a severe disease characterized by the obstruction of blood vessels in the central nervous system. An essential therapeutic strategy for ischemic stroke is strengthening angiogenesis, which effectively promotes the long-term recovery of neurological function. Therefore, it is critical to explore and develop new drugs that promote angiogenesis after ischemic stroke. Kaempferol has been employed to treat ischemic diseases; However, its proangiogenic effects in ischemic stroke remain unclear. In the study, we explored the long-term therapeutic effects and mechanisms of kaempferol on ischemic stroke in vivo and in vitro. A rat model of autologous thrombus stroke and oxygen–glucose deprivation (OGD)-induced human brain microvascular endothelial cells (HBMECs) model was established to assess the effects of kaempferol in vivo (50 mg/kg/d, ig, 14 d) and in vitro (0.1, 0.3, 1 μmol L⁻¹). The results showed that long-term administration of kaempferol ameliorated neurological deficits and infarct volume in ischemic stroke rats. In addition, kaempferol relieved vascular embolization; enhanced microvascular endothelial cell survival, proliferation, migration, and lumen formation; increased the density of microvessels in the peri-infarct cortex; and promoted neovascular structure remodeling by increasing the coverage of astrocyte end-feet and expression of tight–junction proteins (TJPs). Further analysis revealed that the HIF-1α/VEGF-A/Notch1 signaling pathway was activated by kaempferol, and that inhibition of Notch1 blocked kaempferol-induced angiogenesis. Taken together, our results indicate that kaempferol exerts neuroprotective effects by stimulating endogenous angiogenesis and neovascular structural remodeling via the HIF-1α/VEGF-A/Notch1 signaling pathway, suggesting the therapeutic potential of kaempferol in ischemic stroke.

中风是一种以中枢神经系统血管阻塞为特征的严重疾病。缺血性脑卒中的重要治疗策略是加强血管生成，从而有效促进神经功能的长期恢复。因此，探索和开发促进缺血性中风后血管生成的新药至关重要。山奈酚已被用于治疗缺血性疾病，但其在缺血性脑卒中中的促血管生成作用尚不明确。本研究探讨了山奈酚在体内和体外对缺血性中风的长期治疗作用和机制。我们建立了自体血栓脑卒中大鼠模型和氧-葡萄糖剥夺（OGD）诱导的人脑微血管内皮细胞（HBMECs）模型，以评估山奈酚在体内（50 mg/kg/d, ig, 14 d）和体外（0.1, 0.3, 1 μmol-L-1）的作用。结果表明，长期服用山奈酚可改善缺血性脑卒中大鼠的神经功能缺损和梗死体积。此外，山奈酚还能缓解血管栓塞；增强微血管内皮细胞的存活、增殖、迁移和管腔形成；增加梗死周围皮层的微血管密度；通过增加星形胶质细胞端足的覆盖率和紧密连接蛋白（TJPs）的表达，促进新生血管结构的重塑。进一步的分析表明，山奈酚激活了 HIF-1α/VEGF-A/Notch1 信号通路，而抑制 Notch1 则阻断了山奈酚诱导的血管生成。综上所述，我们的研究结果表明，山奈酚通过HIF-1α/VEGF-A/Notch1信号通路刺激内源性血管生成和新生血管结构重塑，从而发挥神经保护作用，提示山奈酚对缺血性脑卒中具有治疗潜力。

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引用次数: 0

Dysregulation of immune system markers, gut microbiota and short-chain fatty acid production following prenatal alcohol exposure: A developmental perspective

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-21 DOI: 10.1016/j.neuint.2025.105952

Victoria R. Vella , Garrett Ainsworth-Cruickshank , Carolina Luft , Kingston E. Wong , Laura W. Parfrey , A. Wayne Vogl , Parker J. Holman , Tamara S. Bodnar , Charlis Raineki

Prenatal alcohol exposure (PAE) can severely impact fetal development, including alterations to the developing immune system. Immune perturbations, in tandem with gut dysbiosis, have been linked to brain and behavioral dysfunction, but this relationship is poorly understood in the context of PAE. This study takes an ontogenetic approach to evaluate PAE-induced alterations to brain and serum cytokine levels and both the composition and metabolic output of the gut microbiota. Using a well-established rat model of PAE, cytokine levels in the serum, prefrontal cortex, amygdala, and hypothalamus as well as gut microbiota composition and short-chain fatty acid (SCFA) levels were assessed at three postnatal (P) timepoints: P8 (infancy), P22 (weaning), and P38 (adolescence). Male PAE rats had increased cytokine levels in the amygdala and hypothalamus, but not prefrontal cortex, at P8. This altered neuroimmune function was not seen in the PAE females. The effect of PAE on central cytokine levels was reduced at P22/38, the same age at which PAE-induced alterations in serum cytokine levels emerge in both sexes. PAE reduced bacterial diversity in both sexes at P8, but only in females at P38, where a PAE-induced unique community composition emerged. Both sexes had alterations to specific bacterial taxa (e.g., Firmicutes), some of which are important in producing the SCFA butyric acid, which was decreased in PAE animals at P22. These results demonstrate that PAE leads to sex- and age-specific alterations in immune function, gut microbiota and SCFA production, highlighting the need to consider both age and sex in future work.

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引用次数: 0

Astrocyte-neuron metabolic crosstalk in ischaemic stroke

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2025-02-21 DOI: 10.1016/j.neuint.2025.105954

Zi-Lin Ren , Xin Lan , Jia-Lin Cheng , Yu-Xiao Zheng , Cong-Ai Chen , Ying Liu , Yan-Hui He , Jin-Hua Han , Qing-Guo Wang , Fa-Feng Cheng , Chang-Xiang Li , Xue-Qian Wang

Ischemic stroke (IS) is caused by temporary or permanent obstruction of the brain's blood supply. The disruption in glucose and oxygen delivery that results from the drop in blood flow impairs energy metabolism. A significant pathological feature of IS impaired energy metabolism. Astrocytes, as the most prevalent glial cells in the brain, sit in between neurons and the microvasculature. By taking advantage of their special anatomical location, they play a crucial part in regulating cerebral blood flow (CBF) and metabolism. Astrocytes can withstand hypoxic and ischemic conditions better than neurons do. Additionally, astrocytes are essential for maintaining the metabolism and function of neurons. Therefore, the "neurocentric" perspective on neuroenergetics is gradually giving way to a more comprehensive perspective that takes into account metabolic interaction between astrocytes and neurons. Since neurons in the core region of the infarct are unable to undergo oxidative metabolism, the focus of attention in this review is on neurons in the peri-infarct region. We'll go over the metabolic crosstalk of astrocytes and neurons during the acute phase of IS using three different types of metabolites: lactate, fatty acids (FAs), and amino acids, as well as the mitochondria. After IS, astrocytes in the peri-infarct zone can produce lactate, ketone bodies (KBs), glutamine (Gln), and l-serine, shuttling these metabolites, along with mitochondria, to neurons. This process helps maintain the energy requirements of neurons, preserves their redox state, and regulates neurotransmitter receptor activity.

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引用次数: 0