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Compound heterozygous RYR1-RM mouse model reveals disease pathomechanisms and muscle adaptations to promote postnatal survival 复合杂合子RYR1-RM小鼠模型揭示了疾病的病理机制和促进出生后存活的肌肉适应性。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1096/fj.202401189R
Chen Liang, Sundeep Malik, Miao He, Linda Groom, Sara K. Ture, Thomas N. O'Connor, Craig N. Morrell, Robert T. Dirksen

Pathogenic variants in the type I ryanodine receptor (RYR1) result in a wide range of muscle disorders referred to as RYR1-related myopathies (RYR1-RM). We developed the first RYR1-RM mouse model resulting from co-inheritance of two different RYR1 missense alleles (Ryr1TM/SC-ΔL mice). Ryr1TM/SC-ΔL mice exhibit a severe, early onset myopathy characterized by decreased body/muscle mass, muscle weakness, hypotrophy, reduced RYR1 expression, and unexpectedly, incomplete postnatal lethality with a plateau survival of ~50% at 12 weeks of age. Ryr1TM/SC-ΔL mice display reduced respiratory function, locomotor activity, and in vivo muscle strength. Extensor digitorum longus muscles from Ryr1TM/SC-ΔL mice exhibit decreased cross-sectional area of type IIb and type IIx fibers, as well as a reduction in number of type IIb fibers. Ex vivo functional analyses revealed reduced Ca2+ release and specific force production during electrically-evoked twitch stimulation. In spite of a ~threefold reduction in RYR1 expression in single muscle fibers from Ryr1TM/SC-ΔL mice at 4 weeks and 12 weeks of age, RYR1 Ca2+ leak was not different from that of fibers from control mice at either age. Proteomic analyses revealed alterations in protein synthesis, folding, and degradation pathways in the muscle of 4- and 12-week-old Ryr1TM/SC-ΔL mice, while proteins involved in the extracellular matrix, dystrophin-associated glycoprotein complex, and fatty acid metabolism were upregulated in Ryr1TM/SC-ΔL mice that survive to 12 weeks of age. These findings suggest that adaptations that optimize RYR1 expression/Ca2+ leak balance, sarcolemmal stability, and fatty acid biosynthesis provide Ryr1TM/SC-ΔL mice with an increased survival advantage during postnatal development.

I 型雷诺丁受体(RYR1)的致病变异会导致多种肌肉疾病,这些疾病被称为 RYR1 相关肌病(RYR1-RM)。我们建立了首个由两个不同的 RYR1 错义等位基因共同遗传导致的 RYR1-RM 小鼠模型(Ryr1TM/SC-ΔL 小鼠)。Ryr1TM/SC-ΔL 小鼠表现出严重的早发性肌病,其特征是身体/肌肉质量下降、肌无力、肌营养不良、RYR1 表达减少,而且出乎意料的是,出生后不完全死亡,12 周龄时存活率约为 50%。Ryr1TM/SC-ΔL 小鼠的呼吸功能、运动活性和体内肌力均有所下降。Ryr1TM/SC-ΔL 小鼠的趾长伸肌显示 IIb 型和 IIx 型纤维的横截面积减少,IIb 型纤维的数量也减少。体内外功能分析显示,在电诱发抽动刺激时,Ca2+释放和特定力产生减少。尽管在 4 周龄和 12 周龄时,Ryr1TM/SC-ΔL 小鼠单个肌肉纤维中的 RYR1 表达量减少了约三倍,但在这两个年龄段,RYR1 Ca2+ 泄漏与对照组小鼠的纤维并无不同。蛋白质组分析显示,4周龄和12周龄的Ryr1TM/SC-ΔL小鼠肌肉中的蛋白质合成、折叠和降解途径发生了改变,而在存活至12周龄的Ryr1TM/SC-ΔL小鼠中,细胞外基质、肌营养不良蛋白相关糖蛋白复合物和脂肪酸代谢所涉及的蛋白质均上调。这些研究结果表明,优化 RYR1 表达/Ca2+ 泄漏平衡、肌小球稳定性和脂肪酸生物合成的适应性使 Ryr1TM/SC-ΔL 小鼠在出生后的发育过程中具有更高的存活优势。
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引用次数: 0
Retinal G-protein-coupled receptor deletion exacerbates AMD-like changes via the PINK1–parkin pathway under oxidative stress 视网膜 G 蛋白偶联受体缺失会在氧化应激下通过 PINK1-parkin 通路加剧 AMD 样变。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1096/fj.202401160RR
Yue Guo, Sitong Chen, Wenxue Guan, Ningda Xu, Li Zhu, Wei Du, Zhiming Liu, Henry K. W. Fong, Lvzhen Huang, Mingwei Zhao

The intake of high dietary fat has been correlated with the progression of age-related macular degeneration (AMD), affecting the function of the retinal pigment epithelium through oxidative stress. A high-fat diet (HFD) can lead to lipid metabolism disorders, excessive production of circulating free fatty acids, and systemic inflammation by aggravating the degree of oxidative stress. Deletion of the retinal G-protein-coupled receptor (RGR-d) has been identified in drusen. In this study, we investigated how the RGR-d exacerbates AMD-like changes under oxidative stress, both in vivo and in vitro. Fundus atrophy became evident, at 12 months old, particularly in the RGR-d + HFD group, and fluorescence angiography revealed narrower retinal vessels and a reduced perfusion area in the peripheral retina. Although rod electroretinography revealed decreasing trends in the a- and b-wave amplitudes in the RGR-d + HFD group at 12 months, the changes were not statistically significant. Mice in the RGR-d + HFD group showed a significantly thinner and more fragile retinal morphology than those in the WT + HFD group, with disordered and discontinuous pigment distribution in the RGR-d + HFD mice. Transmission electron microscopy revealed a thickened Bruch's membrane along the choriocapillaris endothelial cell wall in the RGR-d + HFD mice, and the outer nuclear layer structure appeared disorganized, with reduced nuclear density. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated significantly lower levels of 25(OH)-vitamin D3 metabolites in the RGR-d + HFD group. Under oxidative stress, RGR-d localized to the mitochondria and reduced the levels of the PINK1–parkin pathway. RGR-d mice fed an HFD were used as a new animal model of dry AMD. Under high-fat-induced oxidative stress, RGR-d accumulated in the mitochondria, disrupting normal mitophagy and causing cellular damage, thus exacerbating AMD-like changes both in vivo and in vitro.

高脂肪饮食摄入与老年性黄斑变性(AMD)的进展有关,会通过氧化应激影响视网膜色素上皮细胞的功能。高脂饮食(HFD)会导致脂质代谢紊乱、循环游离脂肪酸产生过多,并通过加重氧化应激程度而引发全身炎症。视网膜 G 蛋白偶联受体(RGR-d)的缺失已在眼底病中被发现。在本研究中,我们研究了在体内和体外氧化应激下,RGR-d如何加剧AMD样变。眼底萎缩在12个月大时变得明显,尤其是在RGR-d + HFD组,荧光血管造影显示视网膜血管变窄,外周视网膜灌注面积减少。尽管杆状视网膜电图显示,RGR-d + HFD 组的 a 波和 b 波振幅在 12 个月大时呈下降趋势,但这些变化在统计学上并不显著。与 WT + HFD 组相比,RGR-d + HFD 组小鼠的视网膜形态明显更薄、更脆弱,RGR-d + HFD 组小鼠的色素分布紊乱且不连续。透射电子显微镜显示,RGR-d + HFD 小鼠沿绒毛膜内皮细胞壁的布鲁氏膜增厚,核外层结构紊乱,核密度降低。京都基因和基因组百科全书》的通路分析表明,RGR-d + HFD 组的 25(OH)-维生素 D3 代谢物水平明显较低。在氧化应激条件下,RGR-d定位于线粒体,并降低了PINK1-parkin通路的水平。RGR-d小鼠被用作干性AMD的新动物模型。在高脂诱导的氧化应激下,RGR-d在线粒体中积累,破坏了正常的有丝分裂,造成细胞损伤,从而加剧了体内和体外的AMD样变。
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引用次数: 0
Motor, mood, and memory impairments persist during remission periods in chronic colitis and are influenced by neuroinflammation and sex 慢性结肠炎患者的运动、情绪和记忆障碍在缓解期持续存在,并受神经炎症和性别的影响。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-26 DOI: 10.1096/fj.202400837R
Gema Sotelo-Parrilla, Alejandro Ruiz-Calero, Pablo García-Miranda, María L. Calonge, María D. Vázquez-Carretero, María J. Peral

Ulcerative colitis is a chronic pathology characterized by relapsing–remitting phases of intestinal inflammation. Additionally, some patients develop neuropsychiatric disorders, such as depression and anxiety, or cognitive deficits. We aimed to investigate whether the development of chronic colitis elicits memory, locomotion, and mood impairments. It further examined whether these impairments are influenced by the relapsing–remitting phases of the colitis or by sex. Here, we used a chronic colitis model in male and female rats, induced with sodium dextran sulfate, mirroring the phases of human ulcerative colitis. Our results revealed that the severity of colitis was slightly higher in males than females. Chronic colitis triggered motor and short-term memory deficits and induced anxiety- and depression-like behaviors that remained throughout the development of the disease. There are also sex differences under control or inflammatory conditions. Therefore, in both situations, females compared to males displayed: (i) slightly lower locomotion, (ii) increased anxiety-like behaviors, (iii) similar depression-like behaviors, and (iv) similar short-term memory deficit. Additionally, under control conditions, the mRNA levels of IL-1β, IL-6, and TNF-α were higher in the female hippocampus. In both sexes, when chronic colitis was established, the neuroinflammation was evidenced by increased mRNA levels of these three cytokines in the hippocampus and in the motor and prefrontal cortices. Interestingly, this neuroinflammation was slightly greater in males. In summary, we show that the development of chronic colitis caused persistent behavioral abnormalities, highlighting sex differences, and that could be a consequence, at least in part, of the increase in IL-1β, IL-6, and TNF-α in the brain.

溃疡性结肠炎是一种以肠道炎症复发-缓解期为特征的慢性病变。此外,一些患者还会出现神经精神障碍,如抑郁、焦虑或认知障碍。我们的目的是研究慢性结肠炎是否会引起记忆、运动和情绪障碍。我们还进一步研究了这些障碍是否会受到结肠炎复发-缓解阶段或性别的影响。在此,我们使用右旋糖酐硫酸钠诱导雌雄大鼠建立慢性结肠炎模型,以反映人类溃疡性结肠炎的不同阶段。结果显示,雄性大鼠结肠炎的严重程度略高于雌性大鼠。慢性结肠炎会引发运动和短期记忆障碍,并诱发焦虑和抑郁样行为,这种行为在疾病发展过程中始终存在。在控制或炎症条件下也存在性别差异。因此,在这两种情况下,与雄性相比,雌性表现出:(i) 稍低的运动能力,(ii) 增加的焦虑样行为,(iii) 相似的抑郁样行为,以及 (iv) 相似的短期记忆缺陷。此外,在对照条件下,雌性海马的 IL-1β、IL-6 和 TNF-α mRNA 水平较高。在男女慢性结肠炎患者中,这三种细胞因子在海马、运动皮层和前额叶皮层中的 mRNA 水平均升高,证明了神经炎症的存在。有趣的是,这种神经炎症在男性中略微严重。总之,我们的研究表明,慢性结肠炎的发展会导致持续的行为异常,突出表现为性别差异,这可能是大脑中IL-1β、IL-6和TNF-α增加的结果,至少部分是这样。
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引用次数: 0
Angiotensin-(1–7) improves intestinal microbiota disturbances and modulates fecal metabolic aberrations in acute pancreatitis 血管紧张素-(1-7)可改善急性胰腺炎患者的肠道微生物群紊乱并调节粪便代谢畸变。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-25 DOI: 10.1096/fj.202401565RR
Ruru Gu, Hongtao Wei, Tianyu Cui, Guoxing Wang, Yingyi Luan, Ruixia Liu, Chenghong Yin

Acute pancreatitis (AP) is a serious health problem that dysregulates intestinal microbiota. Angiotensin (Ang)-(1–7) plays a protective role in the intestinal barrier in AP, but its effect on intestinal microbiota remains clear. To investigate the impact of Ang-(1–7) on AP-induced intestinal microbiota disorder and metabolites. We collected blood and fecal samples from 31 AP patients within 48 h after admission to the hospital, including 11 with mild AP (MAP), 14 with moderately severe AP (MSAP), six with severe AP (SAP). Mice were divided into four groups: control, AP, AP + Ang-(1–7) via tail vein injection, and AP + Ang-(1–7) via oral administration. The samples of mice were collected 12 h after AP. Pancreatic and intestinal histopathology scores were analyzed using the Schmidt and Chiu scores. Fecal microbiota and metabolites analysis was performed via 16S rDNA sequencing and nontargeted metabolomics analysis, respectively. In patients, the abundance of beneficial bacteria (Negativicutes) decreased and pathogenic bacteria (Clostridium bolteae and Ruminococcus gnavus) increased in SAP compared with MAP. Ang-(1–7) levels were associated with changes in the microbiota. There were differences in the intestinal microbiota between control and AP mice. Ang-(1–7) attenuated intestinal microbiota dysbiosis in AP mice, reflecting in the increase in beneficial bacteria (Odoribacter and Butyricimonas) than AP, as well as pancreatic and intestinal injuries. Oral administration of Ang-(1–7) reversing AP-induced decreases in metabolisms: secondary bile acids, emodin, and naringenin. Ang-(1–7) may improve intestinal microbiota dysbiosis and modulate fecal metabolites in AP, thereby reducing the damage of AP.

急性胰腺炎(AP)是一种严重的健康问题,会导致肠道微生物区系失调。血管紧张素(Ang)-(1-7)在急性胰腺炎中对肠道屏障起保护作用,但其对肠道微生物群的影响尚不明确。为了研究血管紧张素(Ang)-(1-7)对 AP 引起的肠道微生物群紊乱和代谢物的影响。我们采集了31名AP患者入院后48小时内的血液和粪便样本,其中包括11名轻度AP患者(MAP)、14名中重度AP患者(MSAP)和6名重度AP患者(SAP)。小鼠分为四组:对照组、AP 组、尾静脉注射 AP + Ang-(1-7) 组和口服 AP + Ang-(1-7) 组。AP 12小时后收集小鼠样本。用 Schmidt 和 Chiu 评分法分析胰腺和肠道组织病理学评分。粪便微生物群和代谢物分析分别通过 16S rDNA 测序和非靶向代谢组学分析进行。与 MAP 相比,SAP 患者体内有益菌(阴性杆菌)的数量减少,而致病菌(梭状芽孢杆菌和反刍球菌)的数量增加。Ang-(1-7)水平与微生物群的变化有关。对照组和 AP 组小鼠的肠道微生物群存在差异。Ang-(1-7) 减轻了 AP 小鼠肠道微生物群的菌群失调,反映在有益菌(Odoribacter 和 Butyricimonas)比 AP 增加,以及胰腺和肠道损伤。口服 Ang-(1-7) 可逆转 AP 诱导的代谢物减少:次生胆汁酸、大黄素和柚皮苷。Ang-(1-7)可改善肠道微生物群失调,调节 AP 粪便代谢物,从而减轻 AP 的损伤。
{"title":"Angiotensin-(1–7) improves intestinal microbiota disturbances and modulates fecal metabolic aberrations in acute pancreatitis","authors":"Ruru Gu,&nbsp;Hongtao Wei,&nbsp;Tianyu Cui,&nbsp;Guoxing Wang,&nbsp;Yingyi Luan,&nbsp;Ruixia Liu,&nbsp;Chenghong Yin","doi":"10.1096/fj.202401565RR","DOIUrl":"10.1096/fj.202401565RR","url":null,"abstract":"<p>Acute pancreatitis (AP) is a serious health problem that dysregulates intestinal microbiota. Angiotensin (Ang)-(1–7) plays a protective role in the intestinal barrier in AP, but its effect on intestinal microbiota remains clear. To investigate the impact of Ang-(1–7) on AP-induced intestinal microbiota disorder and metabolites. We collected blood and fecal samples from 31 AP patients within 48 h after admission to the hospital, including 11 with mild AP (MAP), 14 with moderately severe AP (MSAP), six with severe AP (SAP). Mice were divided into four groups: control, AP, AP + Ang-(1–7) via tail vein injection, and AP + Ang-(1–7) via oral administration. The samples of mice were collected 12 h after AP. Pancreatic and intestinal histopathology scores were analyzed using the Schmidt and Chiu scores. Fecal microbiota and metabolites analysis was performed via 16S rDNA sequencing and nontargeted metabolomics analysis, respectively. In patients, the abundance of beneficial bacteria (<i>Negativicutes</i>) decreased and pathogenic bacteria (<i>Clostridium bolteae and Ruminococcus gnavus</i>) increased in SAP compared with MAP. Ang-(1–7) levels were associated with changes in the microbiota. There were differences in the intestinal microbiota between control and AP mice. Ang-(1–7) attenuated intestinal microbiota dysbiosis in AP mice, reflecting in the increase in beneficial bacteria (<i>Odoribacter and Butyricimonas</i>) than AP, as well as pancreatic and intestinal injuries. Oral administration of Ang-(1–7) reversing AP-induced decreases in metabolisms: secondary bile acids, emodin, and naringenin. Ang-(1–7) may improve intestinal microbiota dysbiosis and modulate fecal metabolites in AP, thereby reducing the damage of AP.</p>","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":"38 20","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
LC3-associated phagocytosis and human diseases: Insights from mechanisms to therapeutic potential LC3相关吞噬作用与人类疾病:从机制到治疗潜力的见解。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-24 DOI: 10.1096/fj.202402126R
Xu Chen, Qi Su, Ruize Gong, Xing Ling, Runxiao Xu, Qijia Feng, Jialiang Ke, Meng Liu, Gulipiyanmu Kahaerjiang, Yuhang Liu, Yanyan Yang, Zhihong Jiang, Hongmei Wu, Yitao Qi

LC3-associated phagocytosis (LAP) is a distinct type of autophagy that involves the sequestration of extracellular material by phagocytes. Beyond the removal of dead cells and cellular debris from eukaryotic cells, LAP is also involved in the removal of a variety of pathogens, including bacteria, fungi, and viruses. These events are integral to multiple physiological and pathological processes, such as host defense, inflammation, and tissue homeostasis. Dysregulation of LAP has been associated with the pathogenesis of several human diseases, including infectious diseases, autoimmune diseases, and neurodegenerative diseases. Thus, understanding the molecular mechanisms underlying LAP and its involvement in human diseases may provide new insights into the development of novel therapeutic strategies for these conditions. In this review, we summarize and highlight the current consensus on the role of LAP and its biological functions in disease progression to propose new therapeutic strategies. Further studies are needed to illustrate the precise role of LAP in human disease and to determine new therapeutic targets for LAP-associated pathologies.

LC3 相关吞噬(LAP)是自噬的一种独特类型,涉及吞噬细胞对细胞外物质的固着。除了清除真核细胞中的死细胞和细胞碎片外,LAP 还参与清除各种病原体,包括细菌、真菌和病毒。这些活动是多种生理和病理过程(如宿主防御、炎症和组织稳态)不可或缺的组成部分。LAP 的失调与多种人类疾病的发病机制有关,包括感染性疾病、自身免疫性疾病和神经退行性疾病。因此,了解 LAP 的分子机制及其在人类疾病中的参与可能会为这些疾病的新型治疗策略的开发提供新的见解。在这篇综述中,我们总结并强调了目前关于 LAP 及其生物功能在疾病进展中的作用的共识,从而提出了新的治疗策略。还需要进一步的研究来说明 LAP 在人类疾病中的确切作用,并确定 LAP 相关病症的新治疗靶点。
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引用次数: 0
Increased neutrophil extracellular traps caused by diet-induced obesity delay fracture healing 饮食引起的肥胖导致中性粒细胞胞外捕获物增加,从而延迟骨折愈合。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-24 DOI: 10.1096/fj.202401523R
Xuan Zhao, Qijun Wang, Wei Wang, Shibao Lu

Obesity, recognized as a risk factor for nonunion, detrimentally impacts bone health, with significant physical and economic repercussions for affected individuals. Nevertheless, the precise pathomechanisms by which obesity impairs fracture healing remain insufficiently understood. Multiple studies have identified neutrophil granulocytes as key players in the systemic immune response, being the predominant immune cells in early fracture hematomas. This study identified a previously unreported critical period for neutrophil infiltration into the callus. In vivo experiments demonstrated that diet-induced obesity (DIO) mice showed earlier neutrophil infiltration, along with increased formation of neutrophil extracellular traps (NETs), compared to control mice during the endochondral phase of fracture repair. Furthermore, Padi4 knockout was found to reduce NET formation and mitigate the fracture healing delays caused by high-fat diets. Mechanistically, in vitro analyses revealed that NETs, by activating NLRP3 inflammasomes, inhibited the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and concurrently promoted M1-like macrophage polarization. These findings establish a connection between NET formation during the endochondral phase and delayed fracture healing, suggesting that targeting NETs could serve as a promising therapeutic approach for addressing obesity-induced delays in fracture recovery.

肥胖被认为是骨折不愈合的风险因素之一,会对骨骼健康产生不利影响,对患者的身体和经济造成重大影响。然而,人们对肥胖影响骨折愈合的确切病理机制仍缺乏足够了解。多项研究发现,中性粒细胞是全身免疫反应的关键参与者,是早期骨折血肿中的主要免疫细胞。本研究发现了中性粒细胞渗入胼胝体的一个以前未报道过的关键时期。体内实验表明,与对照组小鼠相比,饮食诱导肥胖(DIO)小鼠在骨折修复的软骨内阶段表现出更早的中性粒细胞浸润,同时中性粒细胞胞外捕获物(NET)的形成也有所增加。此外,还发现 Padi4 基因敲除可减少 NET 的形成,并缓解高脂饮食导致的骨折愈合延迟。从机理上讲,体外分析表明,NET通过激活NLRP3炎症小体,抑制了骨髓间充质干细胞(BMSCs)的成骨分化,同时促进了M1样巨噬细胞的极化。这些发现证实了软骨内层阶段NET的形成与骨折愈合延迟之间的联系,表明针对NET的治疗可作为解决肥胖引起的骨折恢复延迟的一种有前途的治疗方法。
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引用次数: 0
Dissecting the role of transcription factor AP2-M in Babesia asexual replication 剖析转录因子 AP2-M 在巴贝西亚无性繁殖中的作用。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-23 DOI: 10.1096/fj.202400127RRR
Jinming Wang, Yijun Chai, Jifei Yang, Yuxin Ye, Jianxun Luo, Hong Yin, Guiquan Guan

Babesia spp. are obligate intracellular parasites that invade host cells to complete their asexual development and transmission. Here, we identified a transcription factor AP2-M (BXIN_0799) in Babesia sp. Xinjiang (Bxj), a member of the Apicomplexan AP2 family, which regulates gene expression related to red blood cell (RBC) invasion and cell cycle progression. Our genome-wide analysis of (Cut-Tag) data shows that AP2-M specifically recognized DNA motifs in the promoters of target genes. AP2-M target genes included other AP2 gene family members and epigenetic markers, which could modulate gene expression involved in RBC invasion, merozoite morphology, and cell cycle phases, as indicated by RNA sequencing, proteomics, and single-cell RNA sequencing (scRNA-seq) data from an ap2-m gene disrupted strain (AP2-M (−)). We conclude that AP2-M appeared to contribute to the process of red blood cell invasion, maintain merozoite morphology, and cell cycle progression through GS and MS phases.

巴贝西亚原虫(Babesia spp.)是侵入宿主细胞完成无性发育和传播的细胞内寄生虫。在这里,我们在新疆巴贝西亚原虫(Bxj)中发现了一种转录因子 AP2-M (BXIN_0799),它是吸虫 AP2 家族的成员,可调控与红细胞(RBC)侵袭和细胞周期进展相关的基因表达。我们对(Cut-Tag)数据进行的全基因组分析表明,AP2-M 能特异性识别目标基因启动子中的 DNA 主题。AP2-M 基因的靶基因包括其他 AP2 基因家族成员和表观遗传标记物,它们可以调节涉及 RBC 侵袭、裂头蚴形态和细胞周期阶段的基因表达,这一点已通过 AP2-M 基因破坏株(AP2-M (-))的 RNA 测序、蛋白质组学和单细胞 RNA 测序(scRNA-seq)数据得到证实。我们得出的结论是,AP2-M 似乎有助于红细胞入侵过程、维持裂殖体形态以及通过 GS 和 MS 阶段的细胞周期进展。
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引用次数: 0
Glaucoma-inducing retinal ganglion cell degeneration alters diurnal rhythm of key molecular components of the central clock and locomotor activity in mice 青光眼诱导的视网膜神经节细胞变性改变了小鼠中枢时钟关键分子成分的昼夜节律和运动活动。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-23 DOI: 10.1096/fj.202401105R
Pietra Souza Barsanele, Leonardo Vinícius Monteiro de Assis, Juliano Jefferson da Silva, Eliz Maria de Oliveira Furtado, Paola Fernandes, José Cipolla-Neto, Maristela Oliveira Poletini, Maria Nathália Moraes

Glaucoma is a chronic optic neuropathy characterized by the progressive degeneration of retinal ganglion cells (RGC). These cells play a crucial role in transmitting visual and non-visual information to brain regions, including the suprachiasmatic nucleus (SCN), responsible for synchronizing biological rhythms. To understand how glaucoma affects circadian rhythm synchronization, we investigated potential changes in the molecular clock machinery in the SCN. We found that the progressive increase in intraocular pressure (IOP) negatively correlated with spontaneous locomotor activity (SLA). Transcriptome analysis revealed significant alterations in the SCN of glaucomatous mice, including downregulation of genes associated with circadian rhythms. In fact, we showed a loss of diurnal oscillation in the expression of vasoactive intestinal peptide (Vip), its receptor (Vipr2), and period 1 (Per1) in the SCN of glaucomatous mice. These findings were supported by the 7-h phase shift in the peak expression of arginine vasopressin (Avp) in the SCN of mice with glaucoma. Despite maintaining a 24-h period under both light/dark (LD) and constant dark (DD) conditions, glaucomatous mice exhibited altered SLA rhythms, characterized by decreased amplitude. Taken altogether, our findings provide evidence of how glaucoma affects the regulation of the central circadian clock and its consequence on the regulation of circadian rhythms.

青光眼是一种慢性视神经病变,其特点是视网膜神经节细胞(RGC)逐渐退化。这些细胞在向大脑区域(包括负责同步生物节律的视上核(SCN))传递视觉和非视觉信息方面发挥着至关重要的作用。为了了解青光眼是如何影响昼夜节律同步的,我们研究了SCN中分子钟机制的潜在变化。我们发现,眼压(IOP)的逐渐升高与自发性运动活动(SLA)呈负相关。转录组分析显示,青光眼小鼠的SCN发生了显著变化,包括与昼夜节律相关的基因下调。事实上,我们发现在青光眼小鼠的SCN中,血管活性肠肽(Vip)、其受体(Vipr2)和周期1(Per1)的表达失去了昼夜振荡。青光眼小鼠SCN中精氨酸加压素(Avp)的峰值表达发生了7小时的相移,这也支持了上述发现。尽管在光照/黑暗(LD)和恒定黑暗(DD)条件下维持了24小时,但青光眼小鼠的SLA节律发生了改变,其特点是振幅降低。综上所述,我们的研究结果为青光眼如何影响中枢昼夜节律钟的调节及其对昼夜节律调节的影响提供了证据。
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引用次数: 0
Paricalcitol ameliorates diabetic nephropathy by promoting EETs and M2 macrophage polarization and inhibiting inflammation by regulating VDR/CYP2J2 axis 帕立骨化醇通过调节 VDR/CYP2J2 轴促进 EETs 和 M2 巨噬细胞极化并抑制炎症,从而改善糖尿病肾病。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-23 DOI: 10.1096/fj.202401489R
Shiqi Tang, Jun Tan, Shikun Yang, Aimei Li, Jishi Liu, Wei Zhang, Hao Zhang, Yan Liu

Previous studies have shown that paricalcitol (PA) has a protective effect on the kidneys. However, the exact molecular mechanism by which PA affects diabetic nephropathy (DN) progression remains uncertain. PBMCs of patients with DN were isolated, and CYP2J2 and VDR levels were detected by qPCR. Pearson correlation analysis was utilized to detect the relationship between uACR and CYP2J2 and VDR and between CYP2J2 and VDR. The protective effects of PA on DN have been examined by TUNEL, HE staining, ELISA, and Flow cytometry assays in STZ-induced mice. Moreover, THP-1 cells were stimulated with HG/LPS for in vitro studies. ELISA, qPCR, western blot, and Flow cytometry assays were utilized to assess the effects of PA on DN progression by regulating CYP2J2. The interaction between CYP2J2 and VDR was analyzed by CHIP-qPCR and luciferase experiments. CYP2J2 and VDR levels were downregulated and uACR level was upregulated in DN patients. CYP2J2 and VDR were positively correlated in PBMCs. Both CYP2J2 and VDR are inversely correlated with uACR. Moreover, after PA treatment, 11, 12-EET levels increased, inflammatory factor levels decreased, and M2 macrophage polarization was promoted in STZ-induced mice and HG/LPS-triggered THP-1 cells. Depletion of CYP2J2 and VDR decreased 11, 12-EET level, enhanced inflammatory factor levels, and inhibited M2 macrophage polarization, which were reversed by CYP2J2 overexpression in HG/LPS-treated cells. Furthermore, VDR bound to the CYP2J2 promoter and promoted CYP2J2 transcriptional expression. The present work pointed out a new use for PA to inhibit DN progression by increasing EET level, inhibiting inflammatory response, and inducing M2 macrophage polarization via regulating the VDR/CYP2J2 axis.

以往的研究表明,帕立骨化醇(PA)对肾脏有保护作用。然而,PA 影响糖尿病肾病(DN)进展的确切分子机制仍不确定。我们分离了 DN 患者的 PBMCs,并通过 qPCR 检测了 CYP2J2 和 VDR 的水平。利用皮尔逊相关分析检测 uACR 与 CYP2J2 和 VDR 之间以及 CYP2J2 与 VDR 之间的关系。在 STZ 诱导的小鼠中,通过 TUNEL、HE 染色、ELISA 和流式细胞术检测了 PA 对 DN 的保护作用。此外,还用 HG/LPS 刺激 THP-1 细胞进行体外研究。利用 ELISA、qPCR、Western 印迹和流式细胞术检测评估了 PA 通过调节 CYP2J2 对 DN 进展的影响。CHIP-qPCR和荧光素酶实验分析了CYP2J2和VDR之间的相互作用。在 DN 患者中,CYP2J2 和 VDR 水平下调,uACR 水平上调。在 PBMCs 中,CYP2J2 和 VDR 呈正相关。CYP2J2 和 VDR 与 uACR 呈反向相关。此外,经 PA 处理后,STZ 诱导的小鼠和 HG/LPS 触发的 THP-1 细胞中 11, 12-EET 水平升高,炎症因子水平降低,M2 巨噬细胞极化得到促进。消耗 CYP2J2 和 VDR 可降低 11、12-EET 水平,提高炎症因子水平,抑制 M2 巨噬细胞极化。此外,VDR 与 CYP2J2 启动子结合,促进了 CYP2J2 的转录表达。本研究指出了 PA 通过调节 VDR/CYP2J2 轴增加 EET 水平、抑制炎症反应和诱导 M2 巨噬细胞极化来抑制 DN 进展的新用途。
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引用次数: 0
FTO in oral diseases: Functions, mechanisms, and therapeutic potential 口腔疾病中的 FTO:功能、机制和治疗潜力。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-22 DOI: 10.1096/fj.202401406RR
Biao Li, Leilei Wang, Mingyuan Du, Hong He

Fat mass and obesity-associated protein (FTO) is the first identified N6-methyladenosine (m6A) demethylase widely distributed in various tissues in adults and children. It plays an essential role in diverse mRNA-associated processes including transcriptional stability, selective splicing, mRNA translocation, and also protein translation. Recently, emerging studies have shown that FTO is involved in the genesis and development of oral diseases. However, the correlation between FTO and oral diseases and its specific regulatory mechanism still needs further study. In this review, we will summarize the discovery, distribution, gene expression, protein structure, biological functions, inhibitors, and quantifying methods of FTO, as well as its regulatory role and mechanism in oral diseases. Notably, FTO genetic variants are strongly associated with periodontal diseases (PDs), temporomandibular joint osteoarthritis (TMJOA), and obstructive sleep apnea (OSA). Besides, the latest studies that describe the relationship between FTO and PDs, head and neck squamous cell carcinoma (HNSCCs), TMJOA, and OSA will be discussed. We elaborate on the regulatory roles of FTO in PDs, HNSCCs, and TMJOA, which are modulated through cell proliferation, cell migration, apoptosis, bone metabolism, and immune response. The review will enrich our understanding of RNA epigenetic modifications in oral diseases and present a solid theoretical foundation for FTO to serve as a novel diagnosis and prognostic biomarker for oral diseases.

脂肪量与肥胖相关蛋白(FTO)是第一个被发现的 N6-甲基腺苷(m6A)去甲基化酶,广泛分布于成人和儿童的各种组织中。它在多种 mRNA 相关过程中发挥着重要作用,包括转录稳定性、选择性剪接、mRNA 转位以及蛋白质翻译。最近,新的研究表明,FTO 与口腔疾病的发生和发展有关。然而,FTO 与口腔疾病的相关性及其具体调控机制仍有待进一步研究。在这篇综述中,我们将总结 FTO 的发现、分布、基因表达、蛋白结构、生物学功能、抑制剂和量化方法,以及它在口腔疾病中的调控作用和机制。值得注意的是,FTO 基因变异与牙周疾病(PDs)、颞下颌关节骨关节炎(TMJOA)和阻塞性睡眠呼吸暂停(OSA)密切相关。此外,我们还将讨论描述 FTO 与牙周病、头颈部鳞状细胞癌(HNSCC)、颞下颌关节骨关节炎(TMJOA)和阻塞性睡眠呼吸暂停(OSA)之间关系的最新研究。我们将详细阐述 FTO 在前列腺癌、HNSCCs 和 TMJOA 中的调控作用,这些作用通过细胞增殖、细胞迁移、细胞凋亡、骨代谢和免疫反应进行调节。这篇综述将丰富我们对口腔疾病中 RNA 表观遗传修饰的理解,并为 FTO 成为口腔疾病的新型诊断和预后生物标记物奠定坚实的理论基础。
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引用次数: 0
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