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Dietary Iron Intake Has Long-Term Effects on the Fecal Metabolome and Microbiome. 膳食铁摄入对粪便代谢组和微生物组有长期影响
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-11 DOI: 10.1093/mtomcs/mfae033
Anastasiia Kostenko, Simone Zuffa, Hui Zhi, Kevin Mildau, Manuela Raffatellu, Pieter C Dorrestein, Allegra T Aron

Iron is essential for life, but its imbalances can lead to severe health implications. Iron deficiency is the most common nutrient disorder worldwide, and iron disregulation in early life has been found to cause long-lasting behavioral, cognitive, and neural effects. However, little is known about the effects of dietary iron on gut microbiome function and metabolism. In this study, we sought to investigate the impact of dietary iron on the fecal metabolome and microbiome by using mice fed with three diets with different iron content: an iron deficient, an iron sufficient (standard), and an iron overload diet for seven weeks. Additionally, we sought to understand whether any observed changes would persist past the 7-week period of diet intervention. To assess this, all feeding groups were switched to a standard diet, and this feeding continued for an additional 7 weeks. Analysis of the fecal metabolome revealed that iron overload and deficiency significantly alter levels of peptides, nucleic acids, and lipids, including di- and tri-peptides containing branched-chain amino acids, inosine and guanosine, and several microbial conjugated bile acids. The observed changes in the fecal metabolome persist long after the switch back to a standard diet, with the cecal gut microbiota composition and function of each group distinct after the 7-week standard diet wash-out. Our results highlight the enduring metabolic consequences of nutritional imbalances, mediated by both host and gut microbiome, which persist after returning to original standard diets.

铁是生命所必需的,但铁的失衡会导致严重的健康问题。铁缺乏症是全球最常见的营养失调症,而早期铁失调已被发现会对行为、认知和神经造成长期影响。然而,人们对饮食中的铁对肠道微生物组功能和新陈代谢的影响知之甚少。在这项研究中,我们试图通过用三种含铁量不同的饮食(缺铁饮食、铁充足饮食(标准饮食)和铁超载饮食)喂养小鼠七周,来研究饮食中的铁对粪便代谢组和微生物组的影响。此外,我们还试图了解观察到的任何变化是否会在 7 周的饮食干预后持续存在。为了评估这一点,所有喂食组都换成了标准饮食,并继续喂食 7 周。粪便代谢组分析表明,铁超载和缺铁会显著改变肽、核酸和脂质的水平,包括含有支链氨基酸、肌苷和鸟苷的二肽和三肽,以及几种微生物共轭胆汁酸。观察到的粪便代谢组变化在转回标准膳食后仍长期存在,每组的盲肠肠道微生物群组成和功能在7周的标准膳食冲洗后都截然不同。我们的研究结果突显了营养失衡的持久代谢后果,这种后果由宿主和肠道微生物群介导,在恢复原来的标准饮食后仍会持续。
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引用次数: 0
Elevated thyroid manganese reduces thyroid iodine to induce hypothyroidism in mice, but not rats, lacking SLC30A10 transporter. 在缺乏 SLC30A10 转运体的小鼠(而非大鼠)体内,甲状腺锰升高会减少甲状腺碘,从而诱发甲状腺功能减退症。
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1093/mtomcs/mfae029
Steven Hutchens, Ashvini Melkote, Thomas Jursa, William Shawlot, Leonardo Trasande, Donald R Smith, Somshuvra Mukhopadhyay

Elevated manganese (Mn) accumulates in the brain and induces neurotoxicity. SLC30A10 is an Mn efflux transporter that controls body Mn levels. We previously reported that full-body Slc30a10 knockout mice (1) recapitulate the body Mn retention phenotype of humans with loss-of-function SLC30A10 mutations and (2) unexpectedly develop hypothyroidism induced by Mn accumulation in the thyroid, which reduces intra-thyroid thyroxine. Subsequent analyses of National Health and Nutrition Examination Survey data identified an association between serum Mn and subclinical thyroid changes. The emergence of thyroid deficits as a feature of Mn toxicity suggests that changes in thyroid function may be an underappreciated, but critical, modulator of Mn-induced disease. To better understand the relationship between thyroid function and Mn toxicity, here we further defined the mechanism of Mn-induced hypothyroidism using mouse and rat models. Slc30a10 knockout mice exhibited a profound deficit in thyroid iodine levels that occurred contemporaneously with increases in thyroid Mn levels and preceded the onset of overt hypothyroidism. Wild-type Mn-exposed mice also exhibited increased thyroid Mn levels, an inverse correlation between thyroid Mn and iodine levels, and subclinical hypothyroidism. In contrast, thyroid iodine levels were unaltered in newly generated Slc30a10 knockout rats despite an increase in thyroid Mn levels, and the knockout rats were euthyroid. Thus, Mn-induced thyroid dysfunction in genetic or Mn exposure-induced mouse models occurs due to a reduction in thyroid iodine subsequent to an increase in thyroid Mn levels. Moreover, rat and mouse thyroids have differential sensitivities to Mn, which may impact the manifestations of Mn-induced disease in these routinely used animal models.

锰(Mn)升高会在大脑中蓄积并诱发神经中毒。SLC30A10 是一种锰外排转运体,可控制体内的锰含量。我们以前曾报道过全身 Slc30a10 基因敲除小鼠:(1)再现了功能缺失 SLC30A10 基因突变的人类体内锰潴留的表型;(2)出乎意料的是,由于甲状腺中的锰蓄积导致甲状腺内甲状腺素减少,从而诱发甲状腺功能减退症。随后对全国健康与营养调查数据的分析发现,血清锰与亚临床甲状腺变化之间存在关联。甲状腺功能缺陷是锰毒性的一个特征,这表明甲状腺功能的变化可能是锰诱发疾病的一个未被重视但却至关重要的调节因素。为了更好地理解甲状腺功能与锰毒性之间的关系,我们在此利用小鼠和大鼠模型进一步明确了锰诱导甲状腺功能减退的机制。Slc30a10 基因敲除小鼠的甲状腺碘水平严重不足,这种情况与甲状腺锰的增加同时发生,并先于明显的甲状腺功能减退症出现。暴露于锰的野生型小鼠也表现出甲状腺锰水平升高、甲状腺锰和碘水平呈反相关以及亚临床甲状腺机能减退。与此相反,尽管甲状腺锰含量增加,但新产生的 Slc30a10 基因敲除大鼠的甲状腺碘水平没有发生变化,而且基因敲除大鼠是甲状腺功能正常的。因此,在遗传或锰暴露诱导的小鼠模型中,锰诱导的甲状腺功能障碍是由于甲状腺锰增加后甲状腺碘减少所致。此外,大鼠和小鼠甲状腺对锰的敏感性不同,这可能会影响锰诱导的疾病在这些常规使用的动物模型中的表现。
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引用次数: 0
Mitochondrial-targeted cyclometalated Ir(III)-5,7-dibromo/dichloro-2-methyl-8-hydroxyquinoline complexes and their anticancer efficacy evaluation in Hep-G2 cells. 线粒体靶向环金属化 Ir(III)-5,7- 二溴/二氯-2-甲基-8-羟基喹啉配合物及其在 Hep-G2 细胞中的抗癌效果评估。
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1093/mtomcs/mfae032
Ting Meng, Xiongzhi Shi, Hongfen Chen, Zhong Xu, Weirong Qin, Kehua Wei, Xin Yang, Jin Huang, Chuanan Liao

Both 8-hydroxyquinoline compounds and iridium (Ir) complexes have emerged as potential novel agents for tumor therapy. In this study, we synthesized and characterized two new Ir(III) complexes, [Ir(L1)(bppy)2] (Br-Ir) and [Ir(L2)(bppy)2] (Cl-Ir), with 5,7-dibromo-2-methyl-8-hydroxyquinoline (HL-1) or 5,7-dichloro-2-methyl-8-hydroxyquinoline as the primary ligand. Complexes Br-Ir and Cl-Ir successfully inhibited antitumor activity in Hep-G2 cells. In addition, complexes Br-Ir and Cl-Ir were localized in the mitochondrial membrane and caused mitochondrial damage, autophagy, and cellular immunity in Hep-G2 cells. We tested the proteins related to mitochondrial and mitophagy by western blot analysis, which showed that they triggered mitophagy-mediated apoptotic cell death. Remarkably, complex Br-Ir showed high in vivo antitumor activity, and the tumor growth inhibition rate was 63.0% (P < 0.05). In summary, our study on complex Br-Ir revealed promising results in in vitro and in vivo antitumor activity assays.

8-羟基喹啉化合物和铱(Ir)配合物已成为治疗肿瘤的潜在新型药物。在这项研究中,我们以 5,7-二溴-2-甲基-8-羟基喹啉(HL-1)或 5,7-二氯-2-甲基-8-羟基喹啉(HL-2)为主要配体,合成了两种新的 Ir(III) 复合物:[Ir(L1)(bppy)2](Br-Ir)和[Ir(L2)(bppy)2](Cl-Ir),并对其进行了表征。络合物 Br-Ir 和 Cl-Ir 成功抑制了 Hep-G2 细胞的抗肿瘤活性。此外,Br-Ir 和 Cl-Ir 复合物定位于线粒体膜,可导致 Hep-G2 细胞线粒体损伤、自噬和细胞免疫。我们通过 Western 印迹分析检测了与线粒体和有丝分裂相关的蛋白质,结果表明它们引发了有丝分裂介导的细胞凋亡。值得注意的是,复合物 Br-Ir 在体内表现出很高的抗肿瘤活性,其肿瘤生长抑制率(IR)为 63.0% (p
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引用次数: 0
Enhanced axon guidance and synaptic markers in rat brains using ferric-tannic nanoparticles. 使用鞣酸铁纳米粒子增强大鼠大脑中的轴突导向和突触标记。
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1093/mtomcs/mfae031
Jantira Sanit, Jannarong Intakhad, Aiyarin Kittilukkana, Arpamas Vachiraarunwong, Rawiwan Wongpoomchai, Chalermchai Pilapong

Ferric-tannic nanoparticles (FTs) are now considered to be new pharmaceuticals appropriate for the prevention of brain aging and related diseases. We have previously shown that FTs could activate axon guidance pathways and cellular clearance functioning in neuronal cell lines. Herein, we further investigated whether FTs could activate the two coordinated neuronal functions of axon guidance and synaptic function in rat brains and neuronal cell lines. A single intravenous injection of a safe dose of FTs has been shown to activate a protein expression of axon attractant Netrin-1 and neurotransmitter receptor GABRA4 in the cerebral cortexes of male Wistar rats. According to RNA-seq with targeted analysis, axon guidance and synapses have been enriched and Ephrin membered genes have been identified as coordinating a network of genes for such processes. In vitro, as expected, FTs are also found to activate axon guidance markers and promote neuronal tubes in neuronal cell lines. At the same time, pre-synaptic markers (synaptophysin), post-synaptic markers (synapsin), and GABRA4 neurotransmitter receptors have been found to be activated by FTs. Interestingly, synaptophysin has been found to localize along the promoted neuronal tubes, suggesting that enhanced axon guidance is associated with the formation and transportation of pre-synaptic vesicles. Preliminarily, repeated injection of FTs into adult rats every 3 days for 10 times could enhance an expression of synaptophysin in the cerebral cortex, as compared to control rats. This work demonstrates that FTs can be used for activating brain function associated with axon guidance and synaptic function.

三鞣酸铁纳米粒子(FTs)目前被认为是一种适用于预防大脑衰老和相关疾病的新药物。我们之前已经证明,FTs 可以激活神经元细胞系的轴突导向通路和细胞清除功能。在此,我们进一步研究了 FTs 能否激活大鼠大脑和神经元细胞系中轴突导向和突触功能这两种协调的神经元功能。单次静脉注射安全剂量的 FTs 可激活雄性 Wistar 大鼠大脑皮层中轴突吸引子 Netrin-1 和神经递质受体 GABRA4 的蛋白表达。根据有针对性的 RNA 序列分析,轴突导向和突触已被富集,Ephrin 成员基因已被确定为协调这些过程的基因网络。在体外,正如预期的那样,FTs 还能激活轴突导向标记,促进神经元细胞系中的神经元管。同时,突触前标志物(突触素)、突触后标志物(突触素)和 GABRA4 神经递质受体也被发现被 FTs 激活。有趣的是,突触素被发现沿着促进的神经元管定位,这表明轴突导向的增强与突触前囊泡的形成和运输有关。初步研究表明,与对照组大鼠相比,成年大鼠每3天重复注射10次FTs可增强大脑皮层突触素的表达。这项研究表明,FTs 可用于激活与轴突导向和突触功能相关的大脑功能。
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引用次数: 0
Disruption of Bacterial Biofilms by a Green Synthesized Artemisinin Nano-copper Nanomaterial. 一种绿色合成青蒿素纳米铜材料对细菌生物膜的破坏作用
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-27 DOI: 10.1093/mtomcs/mfae030
Yan Zhang, Xia Hua, Xiaohu Han, Xue Fang, Peng Li, Jingbo Zhai, Lin Xie, Yanming Lv, Yonghao Lai, Chengcheng Meng, Yi Zhang, Shiwei Liu, Zeliang Chen

Bacterial biofilms are associated with antibiotic resistance and account for approximately 80% of all bacterial infections. In this study, we explored novel nanomaterials for combating bacteria and their biofilms. Artemisinin nano-copper (ANC) was synthesised using a green synthesis strategy, and its shape, size, structure, elemental composition, chemical valence, zeta potential, and conductivity were characterised using transmission electron microscopy, X-ray diffractometer, X-ray photoelectron spectroscopy, zeta potential, and dynamic light scattering (DLS). The results showed that ANC was successfully synthesised utilizing a liquid-phase chemical reduction method using chitosan as a modified protectant and l-ascorbic acid as a green reducing agent. The stability of ANC was evaluated using DLS. The results showed that the particle size of the ANC at different concentrations was comparable to that of the original solution after 7 days of storage, and there was no significant change in PDI (P > 0.05). The antibacterial effects of ANC on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were determined by Disk diffusion and broth dilution methods. The results demonstrated that ANC inhibited and killed E. coli and S. aureus. The effect of ANC on bacterial biofilms was investigated using Crystal Violet staining, scanning electron microscopy, laser confocal microscope, and quantitative PCR. The results showed that ANC treatment was able to destroy bacterial biofilms and downregulate biofilm- and virulence-related genes in E. coli (HlyA, gyrA, and F17) and S. aureus (cna, PVL, ClfA, and femB). Green-synthesised ANC possesses excellent anti-biofilm properties and is expected to exhibit antibacterial and anti-biofilm properties.

细菌生物膜与抗生素耐药性有关,约占所有细菌感染的 80%。在这项研究中,我们探索了新型纳米材料,用于对抗细菌及其生物膜。采用绿色合成策略合成了青蒿素纳米铜(ANC),并利用透射电子显微镜、X射线衍射仪、X射线光电子能谱、ZETA电位和动态光散射(DLS)对其形状、尺寸、结构、元素组成、化合价、ZETA电位和电导率进行了表征。结果表明,以壳聚糖为改性保护剂,以抗坏血酸为绿色还原剂,采用液相化学还原法成功合成了 ANC。使用 DLS 评估了 ANC 的稳定性。结果表明,不同浓度的 ANC 在储存 7 天后的粒径与原溶液相当,PDI 没有显著变化(P > 0.05)。采用磁盘扩散法和肉汤稀释法测定了 ANC 对大肠杆菌和金黄色葡萄球菌的抗菌效果。结果表明,ANC 能抑制和杀死大肠杆菌和金黄色葡萄球菌。使用水晶紫染色法、扫描电子显微镜、激光共聚焦显微镜和定量 PCR 研究了 ANC 对细菌生物膜的影响。结果表明,ANC 处理能够破坏细菌生物膜,并下调大肠杆菌(HlyA、gyrA 和 F17)和金黄色葡萄球菌(cna、PVL、ClfA 和 femB)的生物膜和毒力相关基因。绿色合成的 ANC 具有出色的抗生物膜特性,有望表现出抗菌和抗生物膜特性。
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引用次数: 0
Interaction of carbonic anhydrase I released from red blood cells with human plasma in vitro. 红细胞释放的碳酸酐酶 I 与人体血浆在体外的相互作用。
IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-04 DOI: 10.1093/mtomcs/mfae028
Maryam Doroudian, Jürgen Gailer

Red blood cells (RBCs) constitute ∼50% of the bloodstream and represent an important target for environmental pollutants and bacterial/viral infections, which can result in their rupture. In addition, diseases such as sickle cell anaemia and paroxysmal nocturnal haemoglobinuria can also result in the rupture of RBCs, which can be potentially life-threatening. With regard to the release of cytosolic metalloproteins from RBCs into the blood-organ system, the biochemical fate of haemoglobin is rather well understood, while comparatively little is known about another highly abundant Zn-metalloprotein, carbonic anhydrase (CA I). To gain insight into the interaction of CA I with human blood plasma constituents, we have employed a metallomics tool comprised of size-exclusion chromatography (SEC) coupled online with an inductively coupled plasma atomic emission spectrometer (ICP-AES), which allows to simultaneously observe all Cu, Fe, and Zn-metalloproteins. After the addition of CA I to human blood plasma incubated at 37°C, the SEC-ICP-AES analysis using phosphate buffered saline (pH 7.4) after 5 min, 1 h, and 2 h revealed that CA I eluted after all endogenous Zn-metalloproteins in the 30 kDa range. Matrix-assisted laser desorption-time of flight mass spectrometry analysis of the collected Zn-peak confirmed that CA I eluted from the column intact. Our in vitro results suggest that CA I released from RBCs to plasma remains free and may be actively involved in health-relevant adverse processes that unfold at the bloodstream-endothelial interface, including atherosclerosis and vision loss.

红细胞(RBC)占血液的 50%,是环境污染物和细菌/病毒感染的重要目标,可导致红细胞破裂。此外,镰状细胞性贫血和阵发性夜间血红蛋白尿等疾病也会导致红细胞破裂,从而可能危及生命。关于细胞膜金属蛋白从红细胞释放到血液器官系统的问题,人们对血红蛋白的生化命运已经有了相当深入的了解,而对另一种含量极高的锌金属蛋白--碳酸酐酶(CA I)却知之甚少。为了深入了解 CA I 与人体血浆成分的相互作用,我们采用了一种金属组学工具,该工具由尺寸排阻色谱(SEC)与电感耦合等离子体原子发射光谱仪(ICP-AES)联机组成,可同时观察所有铜、铁和锌金属蛋白。在 37°C 培养的人体血浆中加入 CA I 后,使用磷酸盐缓冲盐水(pH 值为 7.4)在 5 分钟、1 小时和 2 小时后进行 SEC-ICP-AES 分析,结果显示 CA I 在 30 kDa 范围内的所有内源性锌金属蛋白之后洗脱。对收集到的 Zn 峰进行的基质辅助激光解吸-飞行时间质谱分析证实,CA I 完整地从色谱柱中洗脱出来。我们的体外研究结果表明,从红细胞释放到血浆中的 CA I 仍然是游离的,并可能积极参与在血液-内皮界面展开的与健康相关的不良过程,包括动脉粥样硬化和视力下降。
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引用次数: 0
Novel binuclear copper(II) complexes with sulfanylpyrazole ligands: synthesis, crystal structure, fungicidal, cytostatic, and cytotoxic activity. 具有硫酰吡唑配体的新型双核铜(II)配合物:合成、晶体结构、杀菌、细胞抑制和细胞毒性活性。
IF 3.4 3区 生物学 Q1 Medicine Pub Date : 2024-06-04 DOI: 10.1093/mtomcs/mfae024
Vnira R Akhmetova, Nail S Akhmadiev, Aidar T Gubaidullin, Aida I Samigullina, Andrey B Glazyrin, Rais A Sadykov, Diana V Ishmetova, Yulia V Vakhitova

New binuclear copper(II) [Cu(II)] tetraligand complexes (six examples) with sulfanylpyrazole ligands were synthesized. Electron spin resonance (ESR) studies have shown that in solution the complexes are transformed to the mononuclear one. Fungicidal properties against Candida albicans were found for the Cu complexes with benzyl and phenyl substituents. An in vitro evaluation of the cytotoxic properties of Cu chelates against HEK293, Jurkat, MCF-7, and THP-1 cells identified the Cu complex with the cyclohexylsulfanyl substituent in the pyrazole core as the lead compound, whereas the Cu complex without a sulfur atom in the pyrazole ligand had virtually no cytotoxic or fungicidal activity. The lead Cu(II) complex was more active than cisplatin. Effect of the S-containing Cu complex on apoptosis and cell cycle distribution has been investigated as well.

我们合成了带有硫酰吡唑配体的新双核铜(II)四配体络合物(六个实例)。EPR 研究表明,这些配合物在溶液中会转变为单核配合物。研究发现,具有苄基和苯基取代基的铜配合物对白色念珠菌有杀菌作用。通过体外评估铜螯合物对 Hek293、Jurkat、MCF-7 和 THP-1 细胞的细胞毒性特性,发现吡唑核心中含有环己基硫代物的铜络合物是主要化合物,而吡唑配体中没有硫原子的铜络合物几乎没有细胞毒性或杀真菌活性。铅 Cu(II) 复合物的活性高于顺铂。此外,还研究了含 S 的铜络合物对细胞凋亡和细胞周期分布的影响。
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引用次数: 0
Dietary and homeostatic controls of Zn isotopes in rats: a controlled feeding experiment and modeling approach. 大鼠体内锌同位素的膳食和体内平衡控制:控制进食实验和建模方法。
IF 3.4 3区 生物学 Q1 Medicine Pub Date : 2024-06-04 DOI: 10.1093/mtomcs/mfae026
Nicolas Bourgon, Théo Tacail, Klervia Jaouen, Jennifer N Leichliter, Jeremy McCormack, Daniela E Winkler, Marcus Clauss, Thomas Tütken

The stable isotope composition of zinc (δ66Zn), which is an essential trace metal for many biological processes in vertebrates, is increasingly used in ecological, archeological, and paleontological studies to assess diet and trophic level discrimination among vertebrates. However, the limited understanding of dietary controls and isotopic fractionation processes on Zn isotope variability in animal tissues and biofluids limits precise dietary reconstructions. The current study systematically investigates the dietary effects on Zn isotope composition in consumers using a combined controlled feeding experiment and box-modeling approach. For this purpose, 21 rats were fed one of seven distinct animal- and plant-based diets and a total of 148 samples including soft and hard tissue, biofluid, and excreta samples of these individuals were measured for δ66Zn. Relatively constant Zn isotope fractionation is observed across the different dietary groups for each tissue type, implying that diet is the main factor controlling consumer tissue δ66Zn values, independent of diet composition. Furthermore, a systematic δ66Zn diet-enamel fractionation is reported for the first time, enabling diet reconstruction based on δ66Zn values from tooth enamel. In addition, we investigated the dynamics of Zn isotope variability in the body using a box-modeling approach, providing a model of Zn isotope homeostasis and inferring residence times, while also further supporting the hypothesis that δ66Zn values of vertebrate tissues are primarily determined by that of the diet. Altogether this provides a solid foundation for refined (paleo)dietary reconstruction using Zn isotopes of vertebrate tissues.

锌(δ66Zn)是脊椎动物许多生物过程中不可或缺的微量金属,其稳定同位素组成越来越多地用于生态学、考古学和古生物学研究,以评估脊椎动物的膳食和营养级区分。然而,对动物组织和生物流体中锌同位素变异的膳食控制和同位素分馏过程的了解有限,限制了精确的膳食重建。本研究采用控制喂养实验和箱式建模相结合的方法,系统地研究了膳食对消费者体内锌同位素组成的影响。为此,研究人员给 21 只大鼠喂食了七种不同的动物性和植物性膳食中的一种,并对这些大鼠的软组织、硬组织、生物流体和排泄物等共计 148 个样本进行了 δ66Zn 测量。在不同的食物组别中,每种组织类型的锌同位素分馏相对稳定,这意味着食物是控制消费者组织δ66Zn值的主要因素,而与食物组成无关。此外,我们首次报道了系统的δ66Zn膳食-牙釉质分馏,从而能够根据牙釉质中的δ66Zn值重建膳食。此外,我们还利用盒式建模方法研究了体内锌同位素变异的动态变化,提供了一个锌同位素平衡模型,并推断了停留时间,同时也进一步支持了脊椎动物组织的δ66Zn值主要由饮食决定的假说。总之,这为利用脊椎动物组织的锌同位素进行精细的(古)膳食重建奠定了坚实的基础。
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引用次数: 0
Association of barium deficiency with Type 2 diabetes mellitus incident risk was mediated by mitochondrial DNA copy number (mtDNA-CN): A follow-up study. 线粒体DNA拷贝数(mtDNA-CN)介导钡缺乏症与2型糖尿病发病风险的关系:随访研究。
IF 3.4 3区 生物学 Q1 Medicine Pub Date : 2024-05-21 DOI: 10.1093/mtomcs/mfae027
Yiqin Zhang, Jing Ye, Lina Zhou, Xianfa Xuan, Liping Xu, Xia Cao, Tianyu Lv, Jianhua Yan, Siyu Zhang, Yuxin Wang, Qingyu Huang, Meiping Tian

Accumulating evidence indicates that plasma metals levels may associate with Type 2 diabetes mellitus (T2DM) incident risk. Mitochondrial function such as mitochondrial DNA copy number (mtDNA-CN) might be linked metal exposure and physiological metabolism. Mediation analysis was conducted to determine the mediating roles of mtDNA-CN in the associations of plasma metals with diabetes risk. In the present study, we investigated associations between plasma metals levels, mtDNA-CN and T2DM incident in elderly population with 6-year follow-up (2 times) study. Ten plasma metals (i.e. manganese (Mg), aluminium (Al), calcium (Ca), ferrum (Fe), barium (Ba), arsenic (As), copper (Cu), selenium (Se), titanium (Ti) and cesium (Sr) were measured by using inductively coupled plasma mass spectrometry (ICP-MS). Mitochondrial DNA copy number was measured by real-time PCR. Multivariable linear regression and logistic regression models were carried out to estimate the relationship between plasma metal concentrations, mtDNA-CN and T2DM incident risk in the current work. Plasma Ba deficiency and mtDNA-CN decline associated with T2DM incident risk during aging process. Meanwhile plasma Ba found to be positively associated with mtDNA-CN. Mitochondrial function mtDNA-CN demonstrated mediating effects in association between plasma Ba deficiency and T2DM incident risk, and 49.8% of the association was mediated by mtDNA-CN. These findings extend the knowledge of T2DM incident risk factors and highlight the point that mtDNA-CN may be linked metals element and T2DM incident risk.

越来越多的证据表明,血浆金属水平可能与 2 型糖尿病(T2DM)的发病风险有关。线粒体 DNA 拷贝数(mtDNA-CN)等线粒体功能可能与金属暴露和生理代谢有关。为了确定 mtDNA-CN 在血浆金属与糖尿病风险的关联中的中介作用,我们进行了中介分析。在本研究中,我们对老年人群进行了为期6年(2次)的随访研究,调查了血浆金属水平、mtDNA-CN与T2DM发病之间的关系。研究采用电感耦合等离子体质谱法(ICP-MS)测量了 10 种血浆金属(即锰(Mg)、铝(Al)、钙(Ca)、铁(Fe)、钡(Ba)、砷(As)、铜(Cu)、硒(Se)、钛(Ti)和铯(Sr))。线粒体 DNA 的拷贝数是通过实时 PCR 测定的。本研究采用多变量线性回归和逻辑回归模型来估计血浆金属浓度、mtDNA-CN 和 T2DM 发病风险之间的关系。结果表明,血浆钡缺乏和mtDNA-CN下降与衰老过程中T2DM发病风险有关。同时发现血浆钡与 mtDNA-CN 呈正相关。线粒体功能 mtDNA-CN 在血浆 Ba 缺乏与 T2DM 发病风险的关联中显示出中介效应,49.8% 的关联由 mtDNA-CN 中介。这些发现扩展了人们对 T2DM 发病风险因素的认识,并强调了 mtDNA-CN 可能与金属元素和 T2DM 发病风险有关。
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引用次数: 0
Stage-specific exposure of Caenorhabditis elegans to cadmium identifies unique transcriptomic response cascades and an uncharacterized cadmium responsive transcript. 草履虫暴露于镉的特异性阶段确定了独特的转录组反应级联和一种未表征的镉反应转录本。
IF 3.4 3区 生物学 Q1 Medicine Pub Date : 2024-05-02 DOI: 10.1093/mtomcs/mfae016
Norah Almutairi, Naema Khan, Alexandra Harrison-Smith, Volker M Arlt, Stephen R Stürzenbaum

Age/stage sensitivity is considered a significant factor in toxicity assessments. Previous studies investigated cadmium (Cd) toxicosis in Caenorhabditis elegans, and a plethora of metal-responsive genes/proteins have been identified and characterized in fine detail; however, most of these studies neglected age sensitivity and stage-specific response to toxicants at the molecular level. This present study compared the transcriptome response between C. elegans L3 vs L4 larvae exposed to 20 µM Cd to explore the transcriptional hallmarks of stage sensitivity. The results showed that the transcriptome of the L3 stage, despite being exposed to Cd for a shorter period, was more affected than the L4 stage, as demonstrated by differences in transcriptional changes and magnitude of induction. Additionally, T08G5.1, a hitherto uncharacterized gene located upstream of metallothionein (mtl-2), was transcriptionally hyperresponsive to Cd exposure. Deletion of one or both metallothioneins (mtl-1 and/or mtl-2) increased T08G5.1 expression, suggesting that its expression is linked to the loss of metallothionein. The generation of an extrachromosomal transgene (PT08G5.1:: GFP) revealed that T08G5.1 is constitutively expressed in the head neurons and induced in gut cells upon Cd exposure, not unlike mtl-1 and mtl-2. The low abundance of cysteine residues in T08G5.1 suggests, however, that it may not be involved directly in Cd sequestration to limit its toxicity like metallothionein, but might be associated with a parallel pathway, possibly an oxidative stress response.

年龄/阶段敏感性被认为是毒性评估的一个重要因素。以往的研究调查了秀丽隐杆线虫(Caenorhabditis elegans)的镉(Cd)中毒症,发现了大量金属反应基因/蛋白,并对其进行了详细表征;然而,这些研究大多忽视了分子水平上的年龄敏感性和特定阶段对毒物的反应。本研究比较了暴露于 20 µM Cd 的 elegans L3 与 L4 幼虫的转录组反应,以探索阶段敏感性的转录特征。结果表明,尽管 L3 阶段暴露于镉的时间较短,但其转录组受到的影响比 L4 阶段更大,这体现在转录变化和诱导程度的差异上。此外,位于金属硫蛋白(mtl-2)上游的一个迄今尚未定性的基因 T08G5.1 对镉暴露具有高转录反应性。缺失一种或两种金属硫蛋白(mtl-1 和/或 mtl-2)会增加 T08G5.1 的表达,这表明其表达与金属硫蛋白的缺失有关。染色体外转基因(PT08G5.1::GFP)的产生表明,T08G5.1 在头部神经元中组成型表达,并在镉暴露时在肠道细胞中诱导表达,这一点与 mtl-1 和 mtl-2 不同。然而,T08G5.1 中半胱氨酸残基的低丰度表明,它可能不像金属硫蛋白那样直接参与镉的螯合以限制其毒性,而可能与一个平行途径有关,可能是氧化应激反应。
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