Biochimica et biophysica acta. General subjects最新文献_第7页

Coupling of muscarinic receptors to protein kinase C underlies a feedback regulation of cell responsiveness to acetylcholine 毒蕈碱受体与蛋白激酶C的偶联是细胞对乙酰胆碱反应的反馈调节的基础。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-07-24 DOI: 10.1016/j.bbagen.2025.130844

Ekaterina A. Dymova, Olga A. Rogachevskaja, Vladislav V. Sokolov, Elizaveta Е. Kopylova, Natalia V. Kabanova, Stanislav S. Kolesnikov

Acetylcholine (ACh)-induced Ca²⁺ signaling was analyzed in HEK-293 (WT-HEK) cells and their derivatives, IP3R1-HEK, IP3R2-HEK, and IP3R3-HEK with a single functional IP₃ receptor isoform, IP₃R1, IP₃R2, or IP₃R3, respectively. The initial stimulation of WT-HEK cells triggered a prolonged feedback process that diminished their responsiveness to ACh. Inhibition of protein kinase C (PKC) with Gö 6983 or calphostin C prevented the decline of ACh responsivity, indicating that PKC was involved. Using IP3R1-HEK, IP3R2-HEK, and IP3R3-HEK cells, it was shown that PKC was capable of regulating Ca²⁺ release through each IP₃R isoform. While in control, IP₃ uncaging triggered Ca²⁺ transients in ∼15 % of cells loaded with caged-Ins(145)P3/PM, PKC inhibition enlarged this fraction nearly twofold. These observations suggested that in ACh transduction machinery, PKC targeted primarily IP₃-driven Ca²⁺ release. ADP and 5-HT triggered Ca²⁺ transients in WT-HEK cells and CHO cells expressing endogenous P2Y and recombinant 5HT2C receptors, respectively. The responsiveness of WT-HEK cells to ADP and CHO cells to 5-HT applied serially declined after the initial cell stimulation but PKC inhibition precluded this phenomenon almost completely. The coupling of GPCRs to PKC in living cells, muscarinic and P2Y receptors in WT-HEK cells and 5HT2C receptors in CHO cells, was demonstrated for the first time using real-time fluorescence imaging and sapphireCKAR, a genetically encoded sensor of PKC activity. Altogether, our findings suggest that a PKC-based feedback regulation of agonist-induced Ca²⁺ release might be a common attribute of transduction of various agonists involving GPCRs coupled to the phosphoinositide cascade.

乙酰胆碱（ACh）诱导的Ca2+信号传导在HEK-293 （WT-HEK）细胞及其衍生物IP3R1- hek、IP3R2- hek和IP3R3- hek中分别具有单一功能IP3受体异构体IP3R1、IP3R2或IP3R3。WT-HEK细胞的初始刺激触发了一个延长的反馈过程，降低了它们对乙酰氨基酚的反应性。用Gö 6983或calphostin C抑制蛋白激酶C （PKC）可阻止乙酰胆碱反应性的下降，表明PKC参与其中。使用IP3R1-HEK、IP3R2-HEK和IP3R3-HEK细胞，我们发现PKC能够通过IP3R各亚型调节Ca2+释放。而在对照组中，IP3释放触发了约15% %的携带cage - ins (145)P3/PM的细胞中的Ca2+瞬态，PKC抑制使这一比例增加了近两倍。这些观察结果表明，在ACh转导机制中，PKC主要针对ip3驱动的Ca2+释放。ADP和5-HT分别在表达内源性P2Y和重组5HT2C受体的WT-HEK细胞和CHO细胞中触发Ca2+瞬态。初始细胞刺激后，WT-HEK细胞对ADP和CHO细胞对5-HT的反应性依次下降，但PKC抑制几乎完全阻止了这一现象。利用实时荧光成像技术和PKC活性基因编码传感器sapphirecar，首次证实了gpcr与活细胞中的PKC、WT-HEK细胞中的毒菌碱和P2Y受体以及CHO细胞中的5HT2C受体的偶联。总之，我们的研究结果表明，基于pkc的激动剂诱导的Ca2+释放的反馈调节可能是各种激动剂转导的共同属性，这些激动剂涉及gpcr偶联到磷酸肌苷级联。

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引用次数: 0

MiR-2779-x, a key microRNA that is related to the tumorigenicity of the MDCK cell line MiR-2779-x，一个与MDCK细胞系致瘤性相关的关键microRNA。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-07-18 DOI: 10.1016/j.bbagen.2025.130843

Di Yang , Lingwei Huang , Jiachen Shi , Zhenbin Liu , Jiamin Wang , Zhongren Ma , Ayimuguli Abudureyimu , Zilin Qiao , Jianguo Chen

The tumorigenicity of MDCK cell line is a major concern with respect to its safety for vaccine production, the effect of miRNAs on the tumorigenicity of MDCK cells is poorly understood. In this study, we performed miRNA-Seq on two MDCK cell lines with tumorigenic potential and their derived monoclonal cell lines that lack tumorigenicity. Through bioinformatics analysis, we identified differentially expressed miRNAs and conducted GO and KEGG pathway analyses of their target genes. Our results indicated that miR-2779-x and its target genes exhibited the most significant characteristics associated with tumorigenesis. Injection of live cells overexpressing miR-2779-x into nude mice resulted in a markedly reduced tumorigenesis rate (1/10). Overexpression of miR-2779-x significantly decreased the proliferation and migration capabilities of MDCK cells while enhancing their invasive potential. To identify and localize miR-2779-x target genes, we employed bioinformatics prediction, RT-qPCR, immunofluorescence assays (IFA), fluorescence in situ hybridization (FISH), and dual-luciferase reporter assays. We found that miR-2779-x negatively regulates the expression of PI3KR1 and Caspase 9 at both the gene and protein levels. Additionally, miR-2779-x co-localizes with PI3KR1 in the cytoplasm and directly targets the 3’UTR of PI3KR1. Overexpression of PI3KR1 in miR-2779-x-overexpressing cells restored cellular functions, leading to increased proliferation and migration but decreased invasion. Moreover, miR-2779-x modulates MDCK cell growth and tumorigenesis by influencing the expression and phosphorylation levels of proteins involved in the PI3K/AKT and apoptosis signaling pathways. We proposed the key pathways of miRNA involvement in MDCK cell tumorigenicity and initially revealed the function of miR-2779-x in MDCK cell tumorigenicity.

MDCK细胞系的致瘤性是其疫苗生产安全性的主要问题，mirna对MDCK细胞致瘤性的影响尚不清楚。在这项研究中，我们对两个具有致瘤潜力的MDCK细胞系及其衍生的缺乏致瘤性的单克隆细胞系进行了miRNA-Seq分析。通过生物信息学分析，我们鉴定了差异表达的mirna，并对其靶基因进行了GO和KEGG通路分析。我们的研究结果表明，miR-2779-x及其靶基因表现出与肿瘤发生相关的最显著特征。将过表达miR-2779-x的活细胞注射到裸鼠体内，可显著降低肿瘤发生率（1/10）。过表达miR-2779-x可显著降低MDCK细胞的增殖和迁移能力，同时增强其侵袭潜能。为了鉴定和定位miR-2779-x靶基因，我们采用了生物信息学预测、RT-qPCR、免疫荧光测定（IFA）、荧光原位杂交（FISH）和双荧光素酶报告基因测定。我们发现miR-2779-x在基因和蛋白水平上负调控PI3KR1和Caspase 9的表达。此外，miR-2779-x在细胞质中与PI3KR1共定位，直接靶向PI3KR1的3'UTR。在mir -2779-x过表达的细胞中，PI3KR1过表达可以恢复细胞功能，导致增殖和迁移增加，但侵袭减少。此外，miR-2779-x通过影响PI3K/AKT和凋亡信号通路相关蛋白的表达和磷酸化水平来调节MDCK细胞的生长和肿瘤发生。我们提出了miRNA参与MDCK细胞致瘤性的关键途径，并初步揭示了miR-2779-x在MDCK细胞致瘤性中的作用。

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引用次数: 0

Phase separation via protein-protein and protein-RNA networks coordinates ribosome assembly in the nucleolus 相分离通过蛋白质-蛋白质和蛋白质- rna网络协调核糖体在核仁中的组装

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-07-16 DOI: 10.1016/j.bbagen.2025.130835

Priyanka Dogra , Richard W. Kriwacki

The nucleolus, the largest membraneless organelle in the nucleus, functions as the site for ribosome biogenesis. While long known for its complex and dynamic structure, our mechanistic understanding of nucleolar organization has advanced dramatically in the past 15 years. The process of phase separation (PS) facilitates the compartmentalization of ribosomal components with assembly factors in the nucleolus, underlying complex ribosome biogenesis processes. Multicomponent PS creates multiple nucleolar sub-compartments that function from inside out as a ribosome assembly line. In this review, we discuss the molecular basis of nucleolar organization, including how different types of protein-protein and protein-RNA interactions create the multilayered architecture that enables ribosome biogenesis. Key proteins including nucleolin, fibrillarin, and nucleophosmin mediate nucleolar compartmentalization through their unique structural features and multivalent interactions. The processes of ribosomal RNA (rRNA) transcription, modification and splicing, and folding are spatially and temporally segregated within different regions of the nucleolus. rRNA matures and changes form along this processing continuum, continually altering its interactions with proteins, creating multiple separate liquid phases that establish sub-compartments. We highlight how both folded domains and intrinsically disordered regions (IDRs) in nucleolar proteins contribute to multivalent interactions underlying PS and nucleolar compartmentalization. We also discuss how perturbation of nucleolar PS alters nucleolar structure, dynamics, and function and contributes to a range of pathological conditions.

核仁是细胞核中最大的无膜细胞器，是核糖体生物发生的场所。虽然核仁的复杂和动态结构早已为人所知，但在过去的15年中，我们对核仁组织的机制理解有了显着的进展。相分离（PS）过程促进了核糖体成分与核核中组装因子的区隔化，是复杂的核糖体生物发生过程的基础。多组分PS产生多个核仁亚室，从内到外作为核糖体装配线发挥作用。在这篇综述中，我们讨论了核仁组织的分子基础，包括不同类型的蛋白质-蛋白质和蛋白质- rna相互作用如何创建使核糖体生物发生的多层结构。核仁蛋白、纤维蛋白和核磷蛋白等关键蛋白通过其独特的结构特征和多价相互作用介导核仁区隔化。核糖体RNA （rRNA）的转录、修饰、剪接和折叠过程在空间和时间上分离于核仁的不同区域。rRNA沿着这一加工连续体成熟并改变形态，不断改变其与蛋白质的相互作用，形成多个独立的液相，建立子区室。我们强调了核仁蛋白中的折叠结构域和内在无序区域（IDRs）如何促进PS和核仁区隔化背后的多价相互作用。我们还讨论了核仁PS的扰动如何改变核仁结构，动力学和功能，并有助于一系列病理条件。

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引用次数: 0

Pharmacological role of MLN4924 in cisplatin-induced acute kidney injury MLN4924在顺铂致急性肾损伤中的药理作用

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-07-13 DOI: 10.1016/j.bbagen.2025.130842

Feng Chen , Ayinigaer Yusufu , Gang Li , Xueyun Gao , Danqin Lu , Xiaoyan Wu , Lihua Ni

Background

Cisplatin-induced acute kidney injury (Cis-AKI) is a major complication that limits the clinical use of cisplatin, largely due to its cytotoxic effects on renal tubular epithelial cells. Recent studies have shown that MLN4924, a NEDD8-activating enzyme inhibitor, can modulate key cellular processes such as apoptosis, autophagy, and DNA damage repair. However, its precise role and regulatory mechanisms in the context of Cis-AKI remain largely undefined.

Purpose

This study aimed to elucidate the renoprotective mechanisms of MLN4924 in Cis-AKI.

Materials and methods

A cisplatin-induced nephrotoxicity mouse model and a human renal tubular epithelial (HK−2) damage cellular model were established. Kidney injury was evaluated by histopathology and RNA-sequencing. To explore whether MLN4924 alleviates Cis-AKI via modulation of the p53 and MAPK pathways, we analyzed pathway-specific regulatory changes in response to MLN4924 treatment.

Results

Compared to the group exposed to cisplatin, MLN4924 mitigated the pathological alterations and reduced the expression of molecules associated with renal injury. RNA-sequencing analysis indicated that the p53 and MAPK signaling pathways were inhibited by MLN4924 treatment compared to the cisplatin-exposed group. Moreover, silencing p53 or p38 exacerbates the renal protection conferred by MLN4924 in cisplatin-treated HK-2 cells, while their activation abolishes this effect. Mechanically, p38 activity promoted p53-dependent nephrotoxicity by increasing p53 expression.

Conclusions

MLN4924 exhibits a protective effect against Cis-AKI, as evidenced by inhibition of p53 and MAPK signaling pathways. These results suggest that MLN4924 holds potential as an adjuvant therapeutic agent in the treatment of kidney diseases associated with chemotherapy.

顺铂诱导的急性肾损伤（Cis-AKI）是限制顺铂临床应用的主要并发症，主要是由于其对肾小管上皮细胞的细胞毒性作用。最近的研究表明，nedd8激活酶抑制剂MLN4924可以调节细胞凋亡、自噬和DNA损伤修复等关键细胞过程。然而，其在Cis-AKI中的确切作用和调控机制在很大程度上仍未明确。目的探讨MLN4924在Cis-AKI中的肾保护机制。材料和方法建立顺铂所致肾毒性小鼠模型和人肾小管上皮（HK−2）损伤细胞模型。通过组织病理学和rna测序评估肾损伤。为了探讨MLN4924是否通过调节p53和MAPK通路来缓解Cis-AKI，我们分析了MLN4924治疗后通路特异性的调控变化。结果与顺铂暴露组相比，MLN4924减轻了肾损伤的病理改变，降低了肾损伤相关分子的表达。rna测序分析表明，与顺铂暴露组相比，MLN4924治疗抑制了p53和MAPK信号通路。此外，在顺铂治疗的HK-2细胞中，沉默p53或p38会加重MLN4924赋予的肾脏保护作用，而它们的激活则会消除这种作用。机械上，p38活性通过增加p53表达促进了p53依赖性肾毒性。结论smln4924通过抑制p53和MAPK信号通路，对Cis-AKI具有保护作用。这些结果表明，MLN4924有潜力作为化疗相关肾脏疾病的辅助治疗剂。

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引用次数: 0

Gamma radiation assisted green synthesis of spirulina-reduced graphene oxide and its anti-inflammatory effect against renal injury induced by gamma irradiation via IRE1α -TRAF2 pathway γ辐射辅助螺旋藻还原氧化石墨烯的绿色合成及其通过IRE1α -TRAF2途径抗γ辐射肾损伤的作用

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-07-13 DOI: 10.1016/j.bbagen.2025.130840

M.M. Atta , Marwa A. Mohamed , Aliaa Mazhar , Fatma Y. Abdou , E.O. Taha , Mahmoud E. Habieb

Background

Combining gamma rays with natural antioxidants leads to the formation of reduced graphene oxide (RGO) biocomposites from graphene oxide (GO) in a way that is both incredibly safe and environmentally friendly, unlocking new possibilities for medical use.

Methods

In the present study, spirulina-reduced graphene oxide nanocomposites (SRGOs) were fabricated by gamma rays as a one-step and straightforward technique.The loading and reduction of graphene oxide in the presence of different spirulina ratios (25, 50, 100, and 200 wt%) under gamma irradiation were verified by diverse characterization apparatuses, including XRD, FTIR, HRTEM, and XPS. Moreover, in vivo studies are conducted to investigate the anti-inflammatory properties of the selected SRGO nanocomposite in preventing kidney injury caused by gamma irradiation.

Results

SRGO amended the renal levels of interleukin-6 (IL-6), IL-8, Inositol requirement enzyme 1α (IRE1α), and TNF receptor-associated factor 2 (TRAF2), the protein expression of NF-κB p65, and the levels of GSH, MDA, serum urea, and creatinine. In the context of oxidative stress and inflammatory biomarkers, the histopathological study results of kidney tissue concurred with those of the molecular biochemical examinations.

Conclusion

The findings endorsed SRGO biocomposite as a promising antioxidant, radioprotector, and anti-inflammatory agent in mitigating kidney damage caused by γ-radiation via significant inhibition of the IRE1α-TRAF2 signaling pathway.

将伽马射线与天然抗氧化剂相结合，可以从氧化石墨烯（GO）中形成还原氧化石墨烯（RGO）生物复合材料，这种方式既安全又环保，为医疗用途开辟了新的可能性。方法采用伽马射线法一步制备螺旋藻还原氧化石墨烯纳米复合材料（SRGOs）。通过XRD、FTIR、HRTEM和XPS等多种表征仪器，验证了不同螺旋藻比例（25、50、100和200 wt%）下氧化石墨烯在γ射线照射下的负载和还原。此外，还进行了体内研究，以研究所选择的SRGO纳米复合材料在预防γ辐射引起的肾损伤方面的抗炎特性。结果ssrgo可改变大鼠肾组织白细胞介素-6 （IL-6）、IL-8、肌醇需要酶1α (IRE1α)、TNF受体相关因子2 （TRAF2）水平、NF-κB p65蛋白表达及GSH、MDA、血清尿素、肌酐水平。在氧化应激和炎症生物标志物的背景下，肾组织的组织病理学研究结果与分子生化检查结果一致。结论SRGO生物复合材料可通过显著抑制IRE1α-TRAF2信号通路减轻γ-辐射引起的肾脏损伤，是一种有前景的抗氧化剂、放射保护剂和抗炎剂。

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引用次数: 0

Mechanism of alkaloid-based inhibition of aldose reductase: Computational perspectives and experimental validations 基于生物碱的醛糖还原酶抑制机制：计算视角和实验验证

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-07-09 DOI: 10.1016/j.bbagen.2025.130841

Emadeldin M. Kamel , Saleh Maodaa , Sarah I. Othman , Adil Abalkhail , Faris F. Aba Alkhayl , Al Mokhtar Lamsabhi

Excessive aldose reductase activity drives the polyol-pathway damage that underlies diabetic cataract, neuropathy and nephropathy, yet few safe, potent AR inhibitors have reached the clinic. Here we integrated virtual screening, atomistic simulation and enzymology to evaluate six natural alkaloids—calycanthine, rutaecarpine, glaucine, sparteine, berbamine and tetrandrine—as prospective AR antagonists. A 2500-compound AutoDock Vina screen singled out these scaffolds for high predicted affinity (≤ − 7.0 kcal mol⁻¹), chemotype diversity and favorable in silico developability. Docking located all ligands within the catalytic cleft; 200-ns MD trajectories plus free-energy landscapes revealed that rutaecarpine and the bis-benzylisoquinolines tetrandrine and berbamine clamp the anion-binding and specificity pockets simultaneously, collapsing conformational space into a single deep basin. MM/PBSA analysis ranked tetrandrine highest (ΔG_total = −35.8 ± 2.5 kcal mol⁻¹) followed by rutaecarpine (−23.0 ± 1.3 kcal mol⁻¹) and berbamine (−19.4 ± 2.7 kcal mol⁻¹); per-residue decomposition highlighted Phe122, Trp219 and Leu300 as recurring hot-spots. In vitro, the same hierarchy emerged: tetrandrine inhibited recombinant human AR with an IC₅₀ of 1.56 ± 0.23 μM, outperforming quercetin (2.37 ± 0.27 μM), while rutaecarpine and berbamine yielded IC₅₀ values of 4.84 ± 0.81 and 7.35 ± 0.78 μM, respectively. Lineweaver–Burk and Michaelis–Menten plots demonstrated non-competitive inhibition, aligning with the MD-inferred pocket-clamping mechanism. ADMET profiling identified rutaecarpine as the most balanced lead (Lipinski-compliant, moderate hERG/CYP risk), whereas tetrandrine's hERG liability and low solubility call for scaffold refinement. This study validates bis-benzylisoquinoline and indolo-quinazolinone frameworks as privileged AR inhibitory chemotypes and showcases an end-to-end computational–experimental pipeline that rapidly converts ethnopharmacological molecules into mechanistically characterized leads for managing diabetic complications.

过度的醛糖还原酶活性导致多元醇通路损伤，而多元醇通路损伤是糖尿病性白内障、神经病变和肾病的基础，但很少有安全、有效的AR抑制剂进入临床。在这里，我们综合了虚拟筛选、原子模拟和酶学来评估六种天然生物碱——花青素、芦果卡松、青氨酸、sparteine、小檗碱和粉防己碱——作为潜在的AR拮抗剂。2500个化合物的AutoDock Vina筛选筛选出这些支架具有高预测亲和力（≤- 7.0 kcal mol - 1），化学型多样性和良好的硅显影性。对接定位所有配体在催化裂孔内；200-ns MD轨迹和自由能景观显示，rutaecarpine和双苄基异喹啉粉防己碱和小檗碱同时夹住阴离子结合和特异性口袋，将构象空间塌陷成一个单一的深盆地。MM/PBSA分析显示粉防己碱最高（ΔGtotal =−35.8±2.5 kcal mol−1），其次是胡卡松碱（−23.0±1.3 kcal mol−1）和小檗胺（−19.4±2.7 kcal mol−1）；残基分解突出显示Phe122、Trp219和Leu300是反复出现的热点。在体外，出现了相同的层次结构：粉防己碱抑制重组人AR的IC₅₀值为1.56±0.23 μM，优于槲皮素（2.37±0.27 μM），而芦卡松和小檗胺的IC₅₀值分别为4.84±0.81和7.35±0.78 μM。Lineweaver-Burk和Michaelis-Menten图显示非竞争性抑制，与md推断的口袋夹紧机制一致。ADMET分析确定rutaecarpine是最平衡的铅（Lipinski-compliant，中度hERG/CYP风险），而粉防己碱的hERG敏感性和低溶解度需要支架改进。本研究验证了双苄基异喹啉和吲哚-喹唑啉酮框架是优越的AR抑制化学型，并展示了端到端计算实验管道，可快速将民族药理学分子转化为机制特征的先导物，用于管理糖尿病并发症。

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引用次数: 0

Neu1 sialidase regulates heterospecific social interaction in zebrafish via D1 dopamine receptor Neu1唾液酸酶通过D1多巴胺受体调节斑马鱼的异种社会交往。

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-07-04 DOI: 10.1016/j.bbagen.2025.130839

Sumomo Tsuji , Asami Ikeda , Yurina Kubo , Toshiki Hyodo , Mika Ishii , Masaharu Komatsu , Kazuhiro Shiozaki

Neu1 sialidase catalyzes the removal of sialic acids from oligosaccharides and glycoproteins in lysosomes and plasma membranes. Recently, the association between Neu1 and psychiatric disorders, such as manic depression and schizophrenia, has attracted attention. neu1^−/− zebrafish (Neu1-KO) exhibit low anxiety, low aggressiveness, and increased social interaction with unfamiliar conspecific and heterospecific groups; however, the underlying mechanisms of action remain unclear. This study investigated alterations in monoamine levels in the Neu1-KO zebrafish brain and their significance in the unique behavioral response toward heterospecifics. The dopamine (DA) and serotonin (5-HT) levels were significantly elevated in the brains of Neu1-KO zebrafish compared with those of wild-type (WT) zebrafish, accompanied by a decrease in noradrenaline (NE). Immunohistochemical (IHC) analysis revealed increased numbers of DA and 5-HT neurons in the Neu1-KO zebrafish brain. Behavioral analysis revealed that treatment with a D1 receptor antagonist significantly suppressed heterospecific interactions in Neu1-KO zebrafish, whereas treatment with D2 and 5-HT receptor antagonists did not. IHC showed that polysialic acid (PSA), a known regulator of DA neuronal function, was predominantly distributed in the hypothalamus of zebrafish, with markedly enhanced signals in Neu1-KO zebrafish. These findings elucidate the role of Neu1 sialidase in regulating social interaction behaviors via DA neurons, potentially as a mechanism for mitigating risks in social environments.

Neu1唾液酸酶催化从溶酶体和质膜中的低聚糖和糖蛋白中去除唾液酸。最近，Neu1与精神疾病（如躁狂抑郁症和精神分裂症）之间的联系引起了人们的关注。neu1-/-斑马鱼（neu1- ko）表现出低焦虑、低攻击性，与不熟悉的同种和异种群体的社会互动增加；然而，其潜在的作用机制尚不清楚。本研究研究了Neu1-KO斑马鱼大脑中单胺水平的变化及其在对异种鱼的独特行为反应中的意义。与野生型（WT）斑马鱼相比，Neu1-KO斑马鱼脑内多巴胺（DA）和血清素（5-HT）水平显著升高，同时去甲肾上腺素（NE）降低。免疫组织化学（IHC）分析显示，Neu1-KO斑马鱼大脑中DA和5-HT神经元数量增加。行为学分析显示，D1受体拮抗剂显著抑制了Neu1-KO斑马鱼的异源相互作用，而D2和5-HT受体拮抗剂则没有作用。免疫组化结果显示，聚唾液酸（PSA）是一种已知的DA神经元功能调节剂，主要分布在斑马鱼的下丘脑，在Neu1-KO斑马鱼中信号明显增强。这些发现阐明了Neu1唾液酸酶在通过DA神经调节社会互动行为中的作用，可能作为一种减轻社会环境风险的机制。

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引用次数: 0

EP300-mediated H3K18la regulation of METTL3 promotes macrophage ferroptosis and atherosclerosis through the m6A modification of SLC7A11 ep300介导的H3K18la调控METTL3通过m6A修饰SLC7A11促进巨噬细胞铁凋亡和动脉粥样硬化。

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-06-28 DOI: 10.1016/j.bbagen.2025.130838

Jingquan Chen , Zongrong Liu , Zhujun Yue , Qiang Tan , Hongshun Yin , Haifei Wang , Zhilong Chen , Yanbing Zhu , Jianghua Zheng

Macrophages, as the primary immune cell population in atherosclerosis (AS), exhibit complex pathogenic mechanisms that are not fully elucidated. This study aims to explore the interplay between histone lactylation and methyltransferase-like protein 3 (METTL3)-mediated m6A modification and their potential mechanisms in AS. We demonstrate that METTL3 is highly expressed in macrophages in both in vivo and in vitro models of atherosclerosis, and myeloid cell-specific deletion of METTL3 attenuates the progression of atherosclerosis. Furthermore, the accumulation of lactate levels in macrophages promotes METTL3 expression through EP300-mediated histone H3 lysine 18 lactylation (H3K18la) binding to the METTL3 promoter site. We found that METTL3-mediated m6A modifications are enriched in solute carrier family 7 member 11 (SLC7A11) and accelerate its mRNA degradation in a YTH domain family member 2 (YTHDF2)-dependent manner, thereby promoting ferroptosis in macrophages. Additionally, lactate stimulation downregulates SLC7A11 through the METTL3/YTHDF2 pathway, further promoting ferroptosis. Overall, during AS, lipid peroxidation induces an increase in lactate levels within macrophages, which enhances METTL3 expression through EP300-mediated H3K18la. This further accelerates the degradation of SLC7A11 mRNA via the YTHDF2-dependent m6A modification pathway, inducing ferroptosis in macrophages. This discovery provides new insights into the mechanisms of macrophage function in AS and offers a theoretical basis for the development of therapies for AS.

巨噬细胞作为动脉粥样硬化（as）的主要免疫细胞群，表现出复杂的致病机制，目前尚未完全阐明。本研究旨在探讨组蛋白乳酸化与甲基转移酶样蛋白3 （METTL3）介导的m6A修饰之间的相互作用及其在AS中的潜在机制。我们证明，在体内和体外动脉粥样硬化模型中，METTL3在巨噬细胞中高表达，髓细胞特异性缺失METTL3可以减缓动脉粥样硬化的进展。此外，巨噬细胞中乳酸水平的积累通过ep300介导的组蛋白H3赖氨酸18乳酸化（H3K18la）结合METTL3启动子位点促进METTL3的表达。我们发现mettl3介导的m6A修饰富集于溶质载体家族7成员11 （SLC7A11）中，并以依赖于YTH结构域家族成员2 （YTHDF2）的方式加速其mRNA降解，从而促进巨噬细胞铁凋亡。此外，乳酸刺激通过METTL3/YTHDF2途径下调SLC7A11，进一步促进铁下垂。总体而言，AS期间，脂质过氧化诱导巨噬细胞内乳酸水平升高，从而通过ep300介导的H3K18la增强METTL3表达。这进一步通过ythdf2依赖的m6A修饰途径加速SLC7A11 mRNA的降解，诱导巨噬细胞铁凋亡。这一发现为巨噬细胞在AS中的功能机制提供了新的见解，并为AS治疗的发展提供了理论基础。

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引用次数: 0

Drought stress induces variation in DNA methylation pattern in a genotype-dependent manner in chickpea 干旱胁迫诱导鹰嘴豆DNA甲基化模式以基因型依赖的方式发生变化。

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-06-21 DOI: 10.1016/j.bbagen.2025.130836

Khushboo Gupta, Rohini Garg

When plants are exposed to harsh environmental conditions, such as extreme temperatures or drought, certain genes are turned on or off. This process can be controlled by a chemical modification to their DNA called methylation. Here, we examined the impact of DNA methylation during drought stress on two chickpea genotypes, ICC 1882 (drought sensitive, DS) and ICC 4958 (drought tolerant, DT) chickpea genotypes via whole-genome bisulfite sequencing. A higher degree of hypomethylation in the DT genotype and more hypermethylation in the DS genotype were observed. A positive correlation was observed between CG methylation with genes and CHH methylation with TEs. Functional annotation of differentially methylated regions associated with differentially expressed genes revealed distinct pathways enriched in DS, such as enrichment of genes involved in root development, telomere maintenance, ion transport, and regulation of gene expression, while pathways like apoptosis, silencing by miRNAs, programmed cell death and carotenoid metabolic processes were enriched in DT genotype. Further, small RNA distribution and non-CWA context methylation density in TEs suggested the role of the RdDM pathway in mediating CHH hypermethylation in transposable elements. Overall, we observed distinct genes are differentially expressed and differentially methylated under drought stress in sensitive and tolerant genotypes.

当植物暴露在恶劣的环境条件下，比如极端温度或干旱，某些基因就会开启或关闭。这个过程可以通过一种叫做甲基化的化学修饰来控制。通过亚硫酸盐全基因组测序，研究了干旱胁迫下DNA甲基化对两种鹰嘴豆基因型ICC 1882（干旱敏感型，DS）和ICC 4958（干旱耐旱型，DT）的影响。DT基因型的低甲基化程度较高，DS基因型的高甲基化程度较高。CG甲基化与基因呈正相关，CHH甲基化与TEs呈正相关。对与差异表达基因相关的差异甲基化区域的功能注释显示，DS中富集了不同的途径，如参与根发育、端粒维持、离子运输和基因表达调控的基因，而DT基因型中富集了凋亡、mirna沉默、细胞程序性死亡和类胡萝卜素代谢过程等途径。此外，te中较小的RNA分布和非cwa上下文甲基化密度表明RdDM途径在介导转座元件CHH超甲基化中的作用。总的来说，我们观察到在干旱胁迫下，敏感型和耐受性基因型中不同基因的差异表达和差异甲基化。

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引用次数: 0

Nitric oxide in plant stress: Rewilding and restoring signaling for enhancing plant growth and development 植物胁迫中的一氧化氮：重新野生和恢复促进植物生长和发育的信号

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. General subjects

Pub Date : 2025-06-20 DOI: 10.1016/j.bbagen.2025.130837

Sumreen Amin Shah , Awdhesh Kumar Mishra , Abdul Rehaman , Sumit G. Gandhi , Arif Tasleem Jan

Plants, represented as a complex system, are continuously exposed to environmental conditions that affect their growth and development, and sometimes their survival. Being sessile, they complete their life cycle under the influence of varied environmental constraints (biotic and abiotic), that adversely affect the produce's quality and productivity. Plants have evolved several defense strategies orchestrated through phytohormones that play a pivotal role in conferring resistance to stress. Nitric oxide (NO), an endogenously produced gaseous hormone, has emerged as a saviour in plant's response to different stresses. It plays an active role in the growth and development of plants, from seed dormancy and germination to growth, differentiation, flowering, fruiting, and ripening, besides affecting key metabolic processes such as photosynthesis. Endogenous production of NO and its interaction with phytohormones across different signaling cascades helps in alleviating the cellular damage caused by free radicals during drought, salinity, and other stresses. It contributes to stress resilience by inducing the synthesis of stress hormones such as ethylene (ET), which help plants to withstand adverse environmental constraints by minimizing the damage caused by different stresses. Exogenous application of NO exerts protective effects against different stresses by breaking seed dormancy and modulating germination, enhancing acquisition of mineral nutrients, photosynthetic functioning, production of antioxidant enzymes capable of neutralizing free radicals, and maintaining membrane integrity. These multifaceted roles of NO underscore its significance in plant stress tolerance. The present study offers valuable insights into NO production methods, involvement in growth and development, and a mechanistic view of its role in alleviating different stresses. In the current scenario, continued research into NO signaling mechanisms and cross-talk with other pathways seems essential for harnessing its potential in developing crops with enhanced resilience to environmental challenges.

植物作为一个复杂的系统，不断地暴露在影响其生长发育，有时甚至影响其生存的环境条件下。它们是不稳定的，在各种环境约束（生物和非生物）的影响下完成其生命周期，这对农产品的质量和生产力产生不利影响。植物已经进化出几种防御策略，这些策略是通过植物激素来协调的，这些激素在赋予植物抵抗压力的能力中起着关键作用。一氧化氮（NO）是一种内源性气体激素，在植物对不同胁迫的反应中起着救星的作用。它在植物的生长发育过程中起着积极的作用，从种子休眠、萌发到生长、分化、开花、结果、成熟，并影响光合作用等关键代谢过程。内源性NO的产生及其通过不同的信号级联与植物激素的相互作用有助于减轻自由基在干旱、盐度和其他胁迫下造成的细胞损伤。它通过诱导乙烯（ET）等应激激素的合成，帮助植物抵御不利的环境约束，最大限度地减少不同胁迫造成的损害，从而有助于抗逆性。外源施用NO通过打破种子休眠和调节萌发、增强矿质营养物质的获取、促进光合作用、产生能够中和自由基的抗氧化酶和维持膜完整性等方式对不同胁迫产生保护作用。一氧化氮在植物抗逆性中的重要作用。本研究对NO的产生方法、参与生长和发育以及其在缓解不同应激中的作用提供了有价值的见解。在目前的情况下，对NO信号机制的持续研究以及与其他途径的相互作用似乎对于利用其潜力开发具有增强环境适应能力的作物至关重要。

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引用次数: 0