Life sciences最新文献_第7页

ML-AMPs designed through machine learning show antifungal activity against C. albicans and therapeutic potential on mice model with candidiasis

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123485

Shaojie Zhang , Yiqing Sun , Kedong Yin , Jinhua Zhang , Lingguang Du , Shusong Wang , Dongge Zheng , Ruifang Li

Aims

C. albicans resistant strains have led to increasingly severe treatment challenges. Antimicrobial peptides with low resistance-inducing propensity for pathogens have been developed. A series of antimicrobial peptides de novo designed through machine learning by our research team were named ML-AMPs. In the present research, the antifungal activity of ML-AMPs against C. albicans and its therapeutic potential on Candidiasis mice model were studied.

Main methods

MTT methodology was performed to measure the minimum inhibitory concentrations. Absorbance photometry was utilized to evaluate the erythrocyte toxicity. Optical microscopy was operated to observe C. albicans hyphae. Crystal violet staining was employed to assess biofilm inhibition and reduction. Colony counting was performed to determine the time-kill kinetics. Scanning electron microscopy and fluorescent staining were used to investigate the underlying mechanism of antifungal action. Candidiasis mice model was established to evaluate the in vivo efficacy of ML-AMP2.

Key findings

ML-AMPs exhibited strong anti-Candida activity, with minimum inhibitory concentrations against C. albicans ranging from 3.85 to 12.37 μg/mL. Notably, they exhibited robust fungicidal effects on fluconazole-resistant C. albicans. Moreover, they exhibited fast-killing kinetics, as well as low resistance potential. Additionally, ML-AMPs could effectively inhibit the formation of mycelium and biofilm, and more prominently, their ability to reduce biofilm was higher than that of fluconazole. ML-AMPS increased the permeability of C. albicans cell membrane and induced ROS accumulation. Among ML-AMPs, ML-AMP2 performed the best, which promoted the recovery of Candidiasis mice model.

Significance

ML-AMP2 holds great promise as a candidate molecule for effectively treating drug-resistant C. albicans infections.

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引用次数: 0

Lack of ALCAT1 enhances the protective effects of aerobic exercise on kidney in HFpEF mice

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123500

Lili Zhang , Lili Feng , Yifang Zhao , Yanbin Geng , Renhan Liu , Yixuan Ma , Wenyan Bo , Yue Xi , Zhenjun Tian

Aims

Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent cardiovascular disease, which is often accompanied by kidney dysfunction. Exercise has been recognized as a feasible strategy to improve renal function. The aim of this study was to investigate whether aerobic exercise (AE) could ameliorate HFpEF-induced renal injury by regulating the expression of acyl-coenzyme A: lysocardiolipin acyltransferase-1 (ALCAT1).

Materials and methods

Eight-week-old C57BL/6 and Alcat1 knockout mice were used to establish a HFpEF induced kidney injury model. Mice in the exercise-intervention group were performed a six-week of AE training. Cardiac function and blood pressure were assessed using echocardiography and a non-invasive intelligent blood pressure monitor. Renal morphology and function were detected by HE, Masson, and PAS staining, as well as biochemical assays using commercial kits. Oxidative stress, inflammation, apoptosis, and renal fibrosis-related proteins were detected by Western Blotting.

Key findings

In the HFpEF induced kidney injury model, ALCAT1 protein expression was upregulated, accompanied by cardiac and renal dysfunction. These pathological changes were reversed by AE. In addition, Alcat1 knockout significantly alleviated HFpEF-induced oxidative stress, inflammation, apoptosis, and fibrosis in the kidneys. Furthermore, Alcat1 knockout further enhanced the protective effects of exercise, ameliorating renal injury and improving renal function in HFpEF mice.

Significance

AE significantly improved renal function by alleviating oxidative stress, inflammation, apoptosis, and fibrosis in HFpEF mice. These beneficial effects were further enhanced in the lack of ALCAT1. Thus, ALCAT1 might represent a potential therapeutic target for the treatment of HFpEF-induced kidney injury.

目的射血分数保留型心力衰竭（HFpEF）是一种日益普遍的心血管疾病，通常伴有肾功能障碍。运动被认为是改善肾功能的可行策略。本研究旨在探讨有氧运动（AE）是否能通过调节酰辅酶A：溶血磷脂酰基转移酶-1（ALCAT1）的表达来改善HFpEF诱导的肾损伤。运动干预组小鼠进行了为期六周的AE训练。使用超声心动图和无创智能血压计评估心脏功能和血压。通过 HE、Masson 和 PAS 染色法检测肾脏形态和功能，并使用商业试剂盒进行生化检测。主要发现在高频肾衰竭诱导的肾损伤模型中，ALCAT1 蛋白表达上调，并伴有心脏和肾脏功能障碍。AE 逆转了这些病理变化。此外，敲除 Alcat1 能显著减轻 HFpEF 诱导的肾脏氧化应激、炎症、细胞凋亡和纤维化。此外，Alcat1 基因敲除进一步增强了运动的保护作用，改善了 HFpEF 小鼠的肾损伤并改善了其肾功能。在缺乏 ALCAT1 的情况下，这些有益作用进一步增强。因此，ALCAT1 可能是治疗 HFpEF 引起的肾损伤的潜在治疗靶点。

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引用次数: 0

A novel zinc ferrite nanoparticle protects against MSU-induced gout arthritis via Nrf2/NF-κB/NLRP3 pathway

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123475

Feng Zhang , Yuehao Gan , Wenteng Xie , Shengyuan Lu , Yang Zha , Yingquan Liang , Junchao Qian , Yajun Duan , Chenzhong Liao , Zhengyan Wu , Shuang Zhang

Aims

Gouty arthritis (GA), a prevalent and intricate form of inflammatory arthritis, affects individuals across all age groups. Existing therapeutic agents for GA are associated with substantial adverse effects. The overarching objective of this study is to identify an efficacious and biocompatible intervention strategy for GA.

Materials and methods

In this investigation, we developed a zinc ferrite nanoparticle (ZFN) characterized by outstanding catalytic activities in anti-inflammatory and antioxidative processes, along with negligible biotoxicity. ZFN features low-content Zn²⁺ doping, which effectively overcomes the issue of low biocompatibility commonly encountered in Zn-based nanoparticles. Both in vitro and in vivo experimental models were utilized to comprehensively evaluate the effects of ZFN.

Key findings

The experimental results demonstrate that ZFN exhibits remarkable efficacy in alleviating inflammation and oxidative stress both in vitro and in vivo. It exerts its therapeutic effect on GA by modulating the NF-κB signaling pathway, suppressing the activation of the NLRP3 inflammasome, and activating the Nrf2 pathway.

Significance

The protective effect of ZFN against GA holds great promise for the clinical translation of biocompatible inorganic nanoplatforms in the treatment of GA. This finding offers a potential alternative to the currently available medications, thereby providing new insights and possibilities for the management of GA.

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引用次数: 0

Idebenone improves mitochondrial respiratory activity and attenuates oxidative damage via the SIRT3-SOD2 pathway in a prion disease cell model

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123481

Zhixin Sun, Pei Wen, Dongming Yang, Jie Li, Zhiping Li, Mengyang Zhao, Dongdong Wang, Fengting Gou, Jingjing Wang, Qing Fan, Yuexin Dai, Yilan Ji, Xueyuan Li, Yingxin Tu, Tianying Ma, Xiaoyu Wang, Deming Zhao, Lifeng Yang

Prion diseases are neurodegenerative diseases that are transmitted between humans and animals, which cause spongiform brain degeneration and neuronal death. Prion diseases are difficult to treat. Mitochondrial damage and oxidative stress occurring early in disease progression. Reducing oxidative stress is a therapeutic strategy for disease. Idebenone (IDE) is an antioxidant that enhances electron transfer in the mitochondrial respiratory chain. To investigate IDE protection mechanisms in prion neuron models, we examined IDE effects on apoptosis, mitochondrial dysfunction, cellular respiratory chain damage, and oxidative stress in N2a cells treated with the prion toxic peptide PrP^106–126. IDE effectively alleviated apoptosis and mitochondrial dysfunction, reduced mitochondrial reactive oxygen species (ROS), attenuated lipid peroxidation, improved glutathione percentages, increased important antioxidant enzyme (superoxide dismutase (SOD) and catalase) activities, and elevated mitochondrial DNA levels. IDE also modulated SOD2 deacetylation and oxidative damage by regulating SIRT3. Overall, IDE exerted significant antioxidant effects in our prion disease cell model and may have therapeutic applications for prion disease.

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引用次数: 0

Targeting JAML promotes normalization of tumour blood vessels to antagonize tumour progression via FAK/SRC and VEGF/VEGFR2 signalling pathways

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123474

Yanan Liu , Yawen Zheng , Xinchao Zhao , Zhilin Dong , Mingyan Zhang , Yuying Fang , Yufeng Wang , Zewen Wang , Ning Liu , Peng Yan , Yuan Ma , Fei Yang , Yan Zheng , Wencheng Zhang , Jianmin Yang , Meili Sun

Background

Angiogenesis is a crucial process in tumour growth and metastasis. Junctional adhesion molecule-like protein (JAML) plays an important role in cancer proliferation; however, its expression and role in tumour angiogenesis remains unexplored.

Methods

We collected colorectal cancer from Jinan Central Hospital, using immunofluorescence staining to confirm the expression of JAML in vascular endothelial cells of cancer and adjacent tissue. Then we used the endothelial-specific knockout of JAML mice and human umbilical vein endothelial cells (HUVECs) to clarify the role of JAML in vivo and in vitro.

Result

Our findings indicated a significant upregulation of JAML in vascular endothelial cells of colorectal cancer tissues compared to adjacent tissues. Endothelial-specific knockout of JAML effectively inhibited tumour growth through normalization of tumour blood vessels in multiple mice tumour models. The deletion of JAML in endothelial cells facilitated tumour vascular normalization, which was evident from increased pericyte coverage, vessel perfusion and T lymphocytes infiltration, decreased hypoxia, vessel density and leakage in tumour tissues. Further analysis showed that the phosphorylation of FAK/SRC/AKT/ERK pathway and VEGFR2 were suppressed in JAML^endo−/− mice with tumour.

Conclusion

This study concluded that JAML is specifically highly expressed in the vascular endothelial cells of tumour, promoting tumour progression by angiogenesis through the activation of the FAK/SRC/ERK/AKT pathway and VEGF/VEGFR2 pathway. JAML might be a new target for antiangiogenesis and provide valuable insights into the development of novel therapeutic approaches for cancer patients.

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引用次数: 0

6-Cyanodopamine as an endogenous modulator of heart chronotropism and inotropism

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123504

José Britto-Júnior , Antonio Tiago Lima , Denis Lima Oliveira , Fernanda V. Mariano , Valéria Barbosa de Souza , André Almeida Schenka , Larryn W. Peterson , Maria Skovbjerg Slot , Rebecca Fjord , Tobias Wang , Edson Antunes , Gilberto De Nucci

Rat isolated atria and ventricles release endothelium-derived 6-nitrodopamine, which induces potent positive chronotropic and inotropic responses. 6-Cyanodopamine is released from rabbit isolated atria and ventricles; however, it is not known whether this novel catecholamine has any action on the isolated heart. Therefore, it was investigated whether rat isolated ventricles release 6-cyanodopamine and its action on the rat isolated heart.

Basal release of 6-cyanodopamine was assessed by LC-MS/MS method. Tyrosine hydroxylase expression was measured by both immunohistochemistry and fluorescence in situ hybridization (FISH). Chronotropic and inotropic effects were evaluated in isolated atria and Langendorff's preparation, respectively.

Rat isolated ventricles presented basal release of 6-cyanodopamine, which was unaffected by pre-treatment with the voltage-gated sodium channel blocker tetrodotoxin. Immunohistochemistry and FISH assays identified tyrosine hydroxylase expression in both endothelium and cardiomyocytes. 6-Cyanodopamine at 10 and 100 pM significantly increased the atrial rate, which was maintained even at 30 min after washing the preparation. In the Langendorff's preparation, 1-min infusion of 6-cyanodopamine (10 and 100 pM) significantly increased heart frequency, left ventricular developed pressure (LVDP), and maximal rate of rise of the left ventricular pressure (dP/dt_max). Bolus injection of noradrenaline at 1 pmol had no effect on any of these parameters; however, in the presence of 6-cyanodopamine (0.01 pM), noradrenaline (1 pmol) significantly increased heart frequency, LVDP, and dP/dt(max).

The results indicate that 6-cyanodopamine is a potent endogenous catecholamine mediating both chronotropism and inotropism in the rat isolated heart. 6-Cyanodopamine may have potential therapeutic effect in heart failure and may be useful as a biomarker of cardio-renal diseases.

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引用次数: 0

The antifibrotic potential of transglutaminase 2 inhibition beyond TGFβ1 release in human kidney tissue and isolated cell cultures

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123503

Judit Prat-Duran , Camilla Merrild , Nina Juste , Estéfano Pinilla , Ulf Simonsen , Rikke Nørregaard , Niels Henrik Buus

Aims

The open conformation of the enzyme transglutaminase 2 (TG2) contributes to kidney fibrosis through transamidase activity by cross-linking extracellular matrix fibres and releasing transforming growth factor β1 (TGFβ1), a key driver of fibrogenesis. We investigated the antifibrotic potential of TG2 inhibition downstream of TGFβ1 using two TG2 inhibitors, LDN27219 and Z-DON, which modulate TG2 into the closed and open state, respectively.

Materials and methods

The TG2 inhibitors were studied in human precision-cut kidney slices (PCKS) and in cell cultures of primary renal cell types: endothelial and epithelial cells, and fibroblasts. PCKS and cell cultures were stimulated with TGFβ1 (10 ng/ml) for 48 h with or without LDN27219 (10 μmol/l) or Z-DON (40 μmol/l). We evaluated mRNA and protein expression of TG2 and fibrosis markers (fibronectin, α-smooth muscle actin and collagens), and TG2 transamidase activity.

Key findings

In PCKS, TG2 was unaffected by TGFβ1, but mRNA levels of fibrosis markers increased with the stimulation and decreased in most LDN27219-treated PCKS compared to the control. No changes in protein expression of fibrosis markers were achieved with TGFβ1. In endothelial and epithelial cells, but not fibroblasts, fibronectin expression was increased with TG2 inhibition. Conversely, collagen 3α1 decreased by TG2 inhibition, further amplified by the closed conformation.

Significance

The antifibrotic effects of TG2 inhibition extend beyond the release of TGFβ1, specifically in the closed conformation, although this varies among cell types. Our results indicate that the closed conformation of TG2 has an active antifibrotic potential in humans, in addition to blocking transamidase activity.

目的转谷氨酰胺酶2（TG2）的开放构象通过转酰胺酶活性交联细胞外基质纤维并释放转化生长因子β1（TGFβ1），从而促进肾脏纤维化。我们使用两种 TG2 抑制剂 LDN27219 和 Z-DON，研究了 TG2 抑制 TGFβ1 下游的抗纤维化潜力，这两种抑制剂可分别调节 TG2 进入闭合和开放状态。用 TGFβ1（10 ng/ml）刺激 PCKS 和细胞培养物 48 小时，同时加入或不加入 LDN27219（10 μmol/l）或 Z-DON（40 μmol/l）。我们评估了 TG2 和纤维化标志物（纤连蛋白、α-平滑肌肌动蛋白和胶原）的 mRNA 和蛋白表达以及 TG2 转酰胺酶活性。主要发现在 PCKS 中，TG2 不受 TGFβ1 的影响，但纤维化标志物的 mRNA 水平随刺激而增加，与对照组相比，大多数经 LDN27219 处理的 PCKS 的 mRNA 水平降低。TGFβ1 未改变纤维化标志物的蛋白表达。在内皮细胞和上皮细胞中，但不包括成纤维细胞，纤维粘连蛋白的表达随着 TG2 的抑制而增加。意义TG2抑制的抗纤维化作用超出了TGFβ1的释放，特别是在封闭构象中，尽管这在不同类型的细胞中有所不同。我们的研究结果表明，在人体中，TG2 的封闭构象除了能阻断转酰胺酶的活性外，还具有积极的抗纤维化潜力。

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引用次数: 0

Heightened sensitivity to adverse effects of metformin in mtDNA mutant patient cells

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123486

Sanna Ryytty , Katriina Nurminen , Petri Mäkinen , Anu Suomalainen , Riikka H. Hämäläinen

Aims

Metformin (Met) is a widely used, cost-effective, and relatively safe drug, primarily prescribed for diabetes, that also exhibits beneficial effects in other conditions, such as in cardiovascular diseases, neurological disorders, and cancer. Despite its common use, the safety of Met in patients with primary mitochondrial disease remains uncertain, as both Met and mitochondrial dysfunction increase the risk of lactic acidosis. Here we have examined the effects of Met in patient cells with m.3243A>G mitochondrial DNA mutation.

Materials and methods

We utilized induced pluripotent stem cells (iPSCs) derived from two m.3243A>G patients, alongside cardiomyocytes differentiated from these iPSCs (iPSC-CMs). The cells were exposed to 10, 100, and 1000 μM Met for 24 h, and the effects on cellular metabolism and mitochondrial function were evaluated.

Key findings

While low concentrations, relative to common therapeutic plasma levels, increased mitochondrial respiration, higher concentrations decreased respiration in both patient and control cells. Furthermore, cells with high level of the m.3243A>G mutation were more sensitive to Met than control cells. Additionally, we observed a clear patient-specific response to Met in cardiomyocytes.

Significance

The findings emphasize the critical importance of selecting appropriate Met concentrations in cellular experiments and demonstrate the variability in Met's effects between individuals. Moreover, the results highlight the need for caution when considering Met use in patients with primary mitochondrial disorders.

{"title":"Heightened sensitivity to adverse effects of metformin in mtDNA mutant patient cells","authors":"Sanna Ryytty , Katriina Nurminen , Petri Mäkinen , Anu Suomalainen , Riikka H. Hämäläinen","doi":"10.1016/j.lfs.2025.123486","DOIUrl":"10.1016/j.lfs.2025.123486","url":null,"abstract":"<div><h3>Aims</h3><div>Metformin (Met) is a widely used, cost-effective, and relatively safe drug, primarily prescribed for diabetes, that also exhibits beneficial effects in other conditions, such as in cardiovascular diseases, neurological disorders, and cancer. Despite its common use, the safety of Met in patients with primary mitochondrial disease remains uncertain, as both Met and mitochondrial dysfunction increase the risk of lactic acidosis. Here we have examined the effects of Met in patient cells with m.3243A>G mitochondrial DNA mutation.</div></div><div><h3>Materials and methods</h3><div>We utilized induced pluripotent stem cells (iPSCs) derived from two m.3243A>G patients, alongside cardiomyocytes differentiated from these iPSCs (iPSC-CMs). The cells were exposed to 10, 100, and 1000 μM Met for 24 h, and the effects on cellular metabolism and mitochondrial function were evaluated.</div></div><div><h3>Key findings</h3><div>While low concentrations, relative to common therapeutic plasma levels, increased mitochondrial respiration, higher concentrations decreased respiration in both patient and control cells. Furthermore, cells with high level of the m.3243A>G mutation were more sensitive to Met than control cells. Additionally, we observed a clear patient-specific response to Met in cardiomyocytes.</div></div><div><h3>Significance</h3><div>The findings emphasize the critical importance of selecting appropriate Met concentrations in cellular experiments and demonstrate the variability in Met's effects between individuals. Moreover, the results highlight the need for caution when considering Met use in patients with primary mitochondrial disorders.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"366 ","pages":"Article 123486"},"PeriodicalIF":5.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143446088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Adrenocorticotropic hormone and its receptor as a novel testicular system involves in the development of spermatogenesis 肾上腺皮质激素及其受体是参与精子发生过程的新型睾丸系统。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123480

Ali AbuMadighem , Eitan Rubin , Eden Arazi , Eitan Lunenfeld , Mahmoud Huleihel

Aims

To identify functional membrane-associate-specific SSC markers and examine the development of these cells under in vitro conditions.

Materials and methods

Cells were enzymatically isolated from seminiferous tubules (STs) of immature mice. Spermatogonial cells (Thy1, alpha-6-integrin, and C-KIT) were sorted by FACS. RNA was extracted from these cells for RNAseq analysis. The effect of adrenocorticotropic hormone (ACTH) – the ligand of MC2R- on the development of mouse spermatogonial cells was performed in vitro using a methylcellulose culture system (MCS). Immunofluorescence staining was used to localize MC2R-positive cells in the testes of immature and adult humans and mice and testes of busulfan-treated immature mice.

Key findings

Our RNAseq analysis revealed a high expression of melanocortin receptor 2 (MC2R) in Thy1-positive sorted cells. MC2R-positive cells were localized in the periphery of the STs of humans (prepubertal and adults) and mice at immature and adult ages (normal and busulfan-treated mice). MC2R was doubled stained with PLZF and CDH1 (SSC markers). ACTH was localized in mouse testicular germ cells (pre-meiotic, meiotic, and post-meiotic cells) and somatic cells (Sertoli, Leydig, and peritubular cells). The addition of ACTH to isolated cells from mouse STs in MCS significantly increased the development of pre-meiotic and meiotic/post-meiotic cells in vitro.

Significance

We were able to identify, for the first time, a novel membrane-associated and functional SSC marker (MC2R) with relation to ACTH. This marker can be used in future male fertility preservation strategies. Furthermore, we explored a novel testicular system (ACTH system) that regulates the development of spermatogenesis.

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引用次数: 0

IKKβ inhibits cognitive memory and adult hippocampal neurogenesis by modulating the β-catenin pathway IKKβ通过调节β-catenin通路抑制认知记忆和成人海马神经发生

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-19 DOI: 10.1016/j.lfs.2025.123490

Kyung-Joo Seong , Bo-Ram Mun , Shintae Kim , Won-Seok Choi , Sung Joong Lee , Ji-Yeon Jung , Won-Jae Kim

Aim

The IKKβ signaling pathway regulates NF-κB, influencing inflammation and cell survival in the brain. Radial glia cells are crucial for hippocampal neurogenesis and cognition. However, the role and mechanisms of IKKβ in modulating radial glia behavior and its impact on memory and neurogenesis remain unclear. Further studies are needed to understand how alterations in this pathway affect hippocampal function.

Main methods

The role of IKKβ in memory and hippocampal neurogenesis was examined using GFAP-CreERT2/IKKβ^flox/flox mice with IKKβ knockdown in radial glia cells. IKKβ expression, NSC proliferation, and differentiation were assessed by immunohistochemistry. NF-κB and β-catenin interactions were evaluated by immunoprecipitation. Cultured adult hippocampal NSCs, with IKKβ or β-catenin shRNA transfection, were analyzed by flow cytometry and western blot to examine stem cell characteristics, NF-κB signaling, cell cycle, and β-catenin pathways.

Key findings

Our results showed IKKβ cKD increased exploratory activity in the open-field and hyperactivity in the Y-maze, as well as enhanced spatial memory in the object location and Morris water maze tests. It also promoted adult hippocampal NSC proliferation by upregulating positive and inhibiting negative cell cycle regulators. Neuronal differentiation was enhanced, affecting β-catenin signaling and NeuroD1 expression. Additionally, IKKβ cKD promoted NSC survival, as shown by decreased cleaved caspase-3 and reduced Bax and cytochrome c in the hippocampus.

Significance

These findings suggest that in hippocampal NSCs, IKKβ inhibits locomotion, cognitive function, and adult hippocampal neurogenesis by suppressing the β-catenin signaling, highlighting its key role in decreasing hippocampal neurogenesis and cognitive function through NF-κB signaling in adult NSCs.

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引用次数: 0