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Expression, purification and application of a recombinant, membrane permeating version of the light chain of botulinum toxin B. B 型肉毒毒素轻链的重组膜渗透型的表达、纯化和应用。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-31 DOI: 10.1042/BSR20240117
Micaela Vanina Buzzatto, Fabiana Cristina Benegas Guerrero, Pablo Ariel Álvarez, María Paz Zizzias, Luis Mariano Polo, Claudia Nora Tomes

Botulinum neurotoxins (BoNTs) are valuable tools to unveil molecular mechanisms of exocytosis in neuronal and non-neuronal cells due to their peptidase activity on exocytic isoforms of SNARE proteins. They are produced by Clostridia as single-chain polypeptides that are proteolytically cleaved into light, catalytic domains covalently linked via disulfide bonds to heavy, targeting domains. This format of two subunits linked by disulfide bonds is required for the full neurotoxicity of BoNTs. We have generated a recombinant version of BoNT/B that consists of the light chain of the toxin fused to the protein transduction domain of the human immunodeficiency virus-1 (TAT peptide) and a hexahistidine tag. His6-TAT-BoNT/B-LC, expressed in Escherichia coli and purified by affinity chromatography, penetrated membranes and exhibited strong enzymatic activity, as evidenced by cleavage of the SNARE synaptobrevin from rat brain synaptosomes and human sperm cells. Proteolytic attack of synaptobrevin hindered exocytosis triggered by a calcium ionophore in the latter. The novel tool reported herein disrupts the function of a SNARE protein within minutes in cells that may or may not express the receptors for the BoNT/B heavy chain, and without the need for transient transfection or permeabilization.

肉毒杆菌神经毒素(BoNTs)对 SNARE 蛋白的外排异构体具有肽酶活性,是揭示神经元和非神经元细胞外排的分子机制的重要工具。它们是由梭状芽孢杆菌产生的单链多肽,通过蛋白水解作用裂解成轻型催化结构域,并通过二硫键与重型靶向结构域共价连接。这种通过二硫键连接的两个亚基的形式是 BoNTs 充分发挥神经毒性的必要条件。我们生成了一种重组型 BoNT/B,它由融合了人类免疫缺陷病毒-1 蛋白质转导结构域(TAT 肽)的毒素轻链和六组氨酸标签组成。His 6 -TAT-BoNT/B-LC在大肠杆菌中表达,并通过亲和层析法纯化,可穿透膜并表现出很强的酶活性,大鼠脑突触体和人精细胞中的SNARE突触素被裂解就是证明。对突触珠蛋白的蛋白水解作用阻碍了后者由钙离子诱导剂引发的外泌。本文报告的新工具可在几分钟内破坏可能表达或不表达 BoNT/B 重链受体的细胞中 SNARE 蛋白的功能,而且无需瞬时转染或渗透。
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引用次数: 0
Retraction: LncRNA ANRIL affects the sensitivity of ovarian cancer to cisplatin via regulation of let-7a/HMGA2 axis. 撤回:LncRNA ANRIL通过调控let-7a/HMGA2轴影响卵巢癌对顺铂的敏感性
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-31 DOI: 10.1042/BSR-2018-2101_RET
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引用次数: 0
Expression of Concern: Long non-coding RNA TUSC7 suppresses osteosarcoma by targeting miR-211. 表达关注:长非编码 RNA TUSC7 通过靶向 miR-211 抑制骨肉瘤。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-31 DOI: 10.1042/BSR-2019-0291_EOC
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引用次数: 0
Metabolic profiling and combined therapeutic strategies unveil the cytotoxic potential of selenium-chrysin (SeChry) in NSCLC cells. 代谢分析和联合治疗策略揭示了硒-金黄素(SeChry)在 NSCLC 细胞中的细胞毒性潜力。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-31 DOI: 10.1042/BSR20240752
Cindy Mendes, Isabel Lemos, Ana Hipólito, Bruna Abreu, Catarina Freitas-Dias, Filipa Martins, Rita F Pires, Hélio Barros, Vasco D B Bonifácio, Luís G Gonçalves, Jacinta Serpa

Lung cancer ranks as the predominant cause of cancer-related mortalities on a global scale. Despite progress in therapeutic interventions, encompassing surgical procedures, radiation, chemotherapy, targeted therapies and immunotherapy, the overall prognosis remains unfavorable. Imbalances in redox equilibrium and disrupted redox signaling, common traits in tumors, play crucial roles in malignant progression and treatment resistance. Cancer cells, often characterized by persistent high levels of reactive oxygen species (ROS) resulting from genetic, metabolic, and microenvironmental alterations, counterbalance this by enhancing their antioxidant capacity. Cysteine availability emerges as a critical factor in chemoresistance, shaping the survival dynamics of non-small cell lung cancer (NSCLC) cells. Selenium-chrysin (SeChry) was disclosed as a modulator of cysteine intracellular availability. This study comprehensively characterizes the metabolism of SeChry and investigates its cytotoxic effects in NSCLC. SeChry treatment induces notable metabolic shifts, particularly in selenocompound metabolism, impacting crucial pathways such as glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism. Additionally, SeChry affects the levels of key metabolites such as acetate, lactate, glucose, and amino acids, contributing to disruptions in redox homeostasis and cellular biosynthesis. The combination of SeChry with other treatments, such as glycolysis inhibition and chemotherapy, results in greater efficacy. Furthermore, by exploiting NSCLC's capacity to consume lactate, the use of lactic acid-conjugated dendrimer nanoparticles for SeChry delivery is investigated, showing specificity to cancer cells expressing monocarboxylate transporters.

在全球范围内,肺癌是造成癌症相关死亡的主要原因。尽管在治疗干预方面取得了进展,包括外科手术、放射治疗、化疗、靶向治疗和免疫治疗,但总体预后仍然不容乐观。氧化还原平衡失衡和氧化还原信号传递紊乱是肿瘤的常见特征,在恶性进展和抗药性方面起着至关重要的作用。由于遗传、代谢和微环境的改变,癌细胞通常具有持续高水平活性氧(ROS)的特征,它们会通过增强自身的抗氧化能力来抵消这种情况。半胱氨酸的可用性成为化疗耐药性的关键因素,影响着非小细胞肺癌(NSCLC)细胞的生存动态。硒-金丝桃素(SeChry)被认为是半胱氨酸细胞内可用性的调节剂。本研究全面描述了 SeChry 的代谢特征,并研究了它对 NSCLC 的细胞毒性作用。SeChry 治疗诱导了显著的代谢转变,尤其是在硒化合物代谢方面,影响了糖酵解、葡萄糖生成、三羧酸(TCA)循环和氨基酸代谢等关键途径。此外,SeChry 还会影响醋酸盐、乳酸盐、葡萄糖和氨基酸等关键代谢物的水平,导致氧化还原平衡和细胞生物合成紊乱。将 SeChry 与糖酵解抑制和化疗等其他治疗方法结合使用,会产生更大的疗效。此外,通过利用 NSCLC 消耗乳酸的能力,研究人员还研究了使用乳酸共轭树枝状聚合物纳米粒子来递送 SeChry,结果显示这种纳米粒子对表达单羧酸盐转运体的癌细胞具有特异性。
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引用次数: 0
Expression of Concern: Erianin induces triple-negative breast cancer cells apoptosis by activating PI3K/Akt pathway. 表达关注:Erianin 可通过激活 PI3K/Akt 通路诱导三阴性乳腺癌细胞凋亡。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-31 DOI: 10.1042/BSR-2021-0093_EOC
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引用次数: 0
Effect of exogenous γ-aminobutyric acid on physiological property, antioxidant activity, and cadmium uptake of quinoa seedlings under cadmium stress. 外源γ-氨基丁酸对镉胁迫下藜麦幼苗生理特性、抗氧化活性和镉吸收的影响
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BSR20240215
Xiao Hua Hao, Ke Xin Liu, Meng Yuan Zhang

Increasing cadmium (Cd) pollution has negative effects on quinoa growth and production. Gamma-aminobutyric acid (GABA) confers plants with stress resistance to heavy metals; however, the mechanism remains unclear. We explored the effects of exogenous GABA on the physiological characteristics, antioxidant capacity, and Cd accumulation of quinoa seedlings under Cd stress using hydroponic experiments. Partial least-squares regression was used to identify key physical and chemical indices of seedlings affecting Cd accumulation. Compared with those of the CK group, exposure to 10 and 25 µmol·L-1 Cd significantly reduced the photosynthetic pigment contents, photosynthesis, and biomass accumulation of quinoa seedlings; resulted in shorter and thicker roots; decreased the length of the lateral roots; decreased the activities of superoxide dismutase (SOD) and peroxide (POD); and increased H2O2 and malondialdehyde (MDA) contents. Exogenous GABA reduced the Cd content in the stem/leaves and roots of quinoa seedlings under Cd stress by 13.22-21.63% and 7.92-28.32%, decreased Cd accumulation by 5.37-6.71% and 1.91-4.09%, decreased the H2O2 content by 38.21-47.46% and 45.81-55.73%, and decreased the MDA content by 37.65-48.12% and 29.87-32.51%, respectively. GABA addition increased the SOD and POD activities in the roots by 2.78-5.61% and 13.81-18.33%, respectively, under Cd stress. Thus, exogenous GABA can reduce the content and accumulation of Cd in quinoa seedlings by improving the photosynthetic characteristics and antioxidant enzyme activity and reducing the degree of lipid peroxidation in the cell membrane to alleviate the toxic effect of Cd stress on seedling growth.

镉(Cd)污染的增加对藜麦的生长和产量产生了负面影响。γ-氨基丁酸(GABA)可赋予植物对重金属的抗逆性,但其机制尚不清楚。我们利用水培实验探讨了外源 GABA 对藜麦幼苗在镉胁迫下的生理特性、抗氧化能力和镉积累的影响。实验采用偏最小二乘回归法确定了影响镉积累的主要理化指标。与 CK 组相比,暴露于 10 µmol-L-1 和 25 µmol-L-1 Cd 会显著降低藜麦幼苗的光合色素含量、光合作用和生物量积累;导致根系变短变粗;侧根长度减少;超氧化物歧化酶(SOD)和过氧化物酶(POD)活性降低;H2O2 和丙二醛(MDA)含量增加。外源 GABA 可使镉胁迫下藜麦幼苗茎/叶和根中的镉含量分别减少 13.22-21.63% 和 7.92-28.32%,镉积累分别减少 5.37-6.71% 和 1.91-4.09%,H2O2 含量分别减少 38.21-47.46% 和 45.81-55.73%,MDA 含量分别减少 37.65-48.12% 和 29.87-32.51%。在镉胁迫下,添加 GABA 可使根中的 SOD 和 POD 活性分别提高 2.78-5.61% 和 13.81-18.33%。因此,外源 GABA 可通过改善藜麦幼苗的光合特性和抗氧化酶活性,降低细胞膜脂质过氧化程度,从而减少镉在幼苗中的含量和积累,减轻镉胁迫对幼苗生长的毒害作用。
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引用次数: 0
Expression of Concern: Madecassoside protects retinal pigment epithelial cells against hydrogen peroxide induced oxidative stress and apoptosis through the activation of Nrf2/HO-1 pathway. 表达关注:麦迪卡索苷通过激活 Nrf2/HO-1 通路,保护视网膜色素上皮细胞免受过氧化氢诱导的氧化应激和细胞凋亡。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BSR-2019-4347_EOC
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引用次数: 0
Bioactivity, hemocompatibility, and inflammatory response of calcium incorporated sulfonated polyether ether ketone on mouse-derived bone marrow cells. 钙结合磺化聚醚醚酮对小鼠骨髓细胞的生物活性、血液相容性和炎症反应
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BSR20232162
Shanmuga Sundar Saravanabhavan, Prabhu Narayanaswamy Venkatesan, Narendranath Jonna, Kamalakannan Vasantha Palaniappan, Zsolt Sarang, Balasubramanian Natesan, Consolato M Sergi

Natural and synthetic polymeric materials, particularly soft and hard tissue replacements, are paramount in medicine. We prepared calcium-incorporated sulfonated polyether-ether ketone (SPEEK) polymer membranes for bone applications. The bioactivity was higher after 21 days of immersion in simulated body fluid (SBF) due to calcium concentration in the membrane. We present a new biomaterial healing system composed of calcium and sulfonated polyether ether ketone (Ca-SPEEK) that can function as a successful biomaterial without causing inflammation when tested on bone marrow cells. The Ca-SPEEK exhibited 13 ± 0.5% clot with low fibrin mesh formation compared to 21 ± 0.5% in SPEEK. In addition, the Ca-SPEEK showed higher protein adsorption than SPEEK membranes. As an inflammatory response, IL-1 and TNF-α in the case of Ca-SPEEK were lower than those for SPEEK. We found an early regulation of IL-10 in the case of Ca-SPEEK at 6 h, which may be attributed to the down-regulation of the inflammatory markers IL-1 and TNF-α. These results evidence the innovative bioactivity of Ca-SPEEK with low inflammatory response, opening venues for bone applications.

天然和合成聚合材料,尤其是软组织和硬组织替代材料,在医学中占有重要地位。我们制备了用于骨骼应用的钙掺杂磺化聚醚醚酮(SPEEK)聚合物膜。 在模拟体液(SBF)中浸泡 21 天后,由于膜中的钙浓度,其生物活性更高。 我们提出了一种由钙和磺化聚醚醚酮(Ca-SPEEK)组成的新型生物材料愈合系统,在对骨髓细胞进行测试时,该系统可作为一种成功的生物材料发挥作用,且不会引起炎症。与 SPEEK 的 21±0.5% 相比,Ca-SPEEK 的凝块率为 13±0.5%,纤维蛋白网的形成率较低。此外,与 SPEEK 膜相比,Ca-SPEEK 的蛋白质吸附率更高。在炎症反应方面,Ca-SPEEK 膜的 IL-1 和 TNF-α 低于 SPEEK 膜。我们发现,钙-SPEEK 膜在 6 小时内对 IL-10 有早期调节作用,这可能是由于下调了炎症标志物 IL-1 和 TNF-。这些结果证明了低炎症反应的 Ca-SPEEK 具有创新的生物活性,为骨应用开辟了道路。
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引用次数: 0
Spatiotemporal regulation of the hepatocyte growth factor receptor MET activity by sorting nexins 1/2 in HCT116 colorectal cancer cells. HCT116 大肠癌细胞中肝细胞生长因子受体 MET 活性受分拣 nexins 1/2 的时空调控。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BSR20240182
Laiyen Garcia Delgado, Amélie Derome, Samantha Longpré, Marilyne Giroux-Dansereau, Ghenwa Basbous, Christine Lavoie, Caroline Saucier, Jean-Bernard Denault

Cumulative research findings support the idea that endocytic trafficking is crucial in regulating receptor signaling and associated diseases. Specifically, strong evidence points to the involvement of sorting nexins (SNXs), particularly SNX1 and SNX2, in the signaling and trafficking of the receptor tyrosine kinase (RTK) MET in colorectal cancer (CRC). Activation of hepatocyte growth factor (HGF) receptor MET is a key driver of CRC progression. In the present study, we utilized human HCT116 CRC cells with SNX1 and SNX2 genes knocked out to demonstrate that their absence leads to a delay in MET entering early endosomes. This delay results in increased phosphorylation of both MET and AKT upon HGF stimulation, while ERK1/2 (extracellular signal-regulated kinases 1 and 2) phosphorylation remains unaffected. Despite these changes, HGF-induced cell proliferation, scattering, and migration remain similar between the parental and the SNX1/2 knockout cells. However, in the absence of SNX1 and SNX2, these cells exhibit increased resistance to TRAIL-induced apoptosis. This research underscores the intricate relationship between intracellular trafficking, receptor signaling, and cellular responses and demonstrates for the first time that the modulation of MET trafficking by SNX1 and SNX2 is critical for receptor signaling that may exacerbate the disease.

累积的研究结果支持这样一种观点,即内细胞转运在调节受体信号传导和相关疾病中至关重要。具体而言,有确凿证据表明,分选内含蛋白(SNXs),尤其是 SNX1 和 SNX2,参与了结直肠癌(CRC)中受体酪氨酸激酶(RTK)MET 的信号转导和转运。肝细胞生长因子(HGF)受体 MET 的激活是导致 CRC 进展的关键因素。在这项研究中,我们利用敲除了 SNX1 和 SNX2 基因的人 HCT116 CRC 细胞证明,缺少这两个基因会导致 MET 进入早期内体的时间延迟。这种延迟导致 MET 和 AKT 在 HGF 刺激下磷酸化增加,而 ERK1/2(细胞外信号调节激酶 1 和 2)磷酸化不受影响。尽管发生了这些变化,亲代细胞和 SNX1/2 基因敲除细胞在 HGF 诱导的细胞增殖、分散和迁移方面仍然相似。然而,在缺乏 SNX1 和 SNX2 的情况下,这些细胞对 TRAIL 诱导的细胞凋亡表现出更强的抵抗力。这项研究强调了细胞内转运、受体信号转导和细胞反应之间错综复杂的关系,并首次证明了 SNX1 和 SNX2 对 MET 转运的调控对于可能加剧疾病的受体信号转导至关重要。
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引用次数: 0
UCHL1-dependent control of hypoxia-inducible factor transcriptional activity during liver fibrosis. 肝纤维化过程中 UCHL1 对低氧诱导因子转录活性的依赖性控制
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BSR20232147
Amy Collins, Rebecca Scott, Caroline L Wilson, Giuseppe Abbate, Gabrielle B Ecclestone, Adam G Albanese, Demi Biddles, Steven White, Jeremy French, John Moir, Wasfi Alrawashdeh, Colin Wilson, Sanjay Pandanaboyana, John S Hammond, Rohan Thakkar, Fiona Oakley, Jelena Mann, Derek A Mann, Niall S Kenneth

Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in most types of chronic liver disease. At the cellular level, liver fibrosis is associated with the activation of hepatic stellate cells (HSCs) which transdifferentiate into a myofibroblast-like phenotype that is contractile, proliferative and profibrogenic. HSC transdifferentiation induces genome-wide changes in gene expression that enable the cell to adopt its profibrogenic functions. We have previously identified that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is highly induced following HSC activation; however, the cellular targets of its deubiquitinating activity are poorly defined. Here, we describe a role for UCHL1 in regulating the levels and activity of hypoxia-inducible factor 1 (HIF1), an oxygen-sensitive transcription factor, during HSC activation and liver fibrosis. HIF1 is elevated during HSC activation and promotes the expression of profibrotic mediator HIF target genes. Increased HIF1α expression correlated with induction of UCHL1 mRNA and protein with HSC activation. Genetic deletion or chemical inhibition of UCHL1 impaired HIF activity through reduction of HIF1α levels. Furthermore, our mechanistic studies have shown that UCHL1 elevates HIF activity through specific cleavage of degradative ubiquitin chains, elevates levels of pro-fibrotic gene expression and increases proliferation rates. As we also show that UCHL1 inhibition blunts fibrogenesis in a pre-clinical 3D human liver slice model of fibrosis, these results demonstrate how small molecule inhibitors of DUBs can exert therapeutic effects through modulation of HIF transcription factors in liver disease. Furthermore, inhibition of HIF activity using UCHL1 inhibitors may represent a therapeutic opportunity with other HIF-related pathologies.

肝纤维化是大多数慢性肝病中出现的细胞外基质蛋白的过度积累。 在细胞水平上,肝纤维化与肝星状细胞(HSCs)的活化有关,这些细胞转分化为肌成纤维细胞样表型,具有收缩、增殖和嗜碱性。 造血干细胞的转分化会诱导全基因组的基因表达发生变化,从而使细胞具有嗜碱性功能。 在这里,我们描述了 UCHL1 在造血干细胞活化和肝纤维化过程中调节缺氧诱导因子 1(HIF1)(一种对氧敏感的转录因子)的水平和活性的作用。 HIF1 在造血干细胞活化过程中会升高,并促进坏死介质 HIF 靶基因的表达。HIF1α 表达的增加与 HSC 激活时 UCHL1 mRNA 和蛋白质的诱导相关。基因缺失或化学抑制 UCHL1 会降低 HIF1α 的水平,从而削弱 HIF 的活性。此外,我们的机理研究表明,UCHL1 通过特异性裂解降解泛素链提高 HIF 活性,提高促纤维化基因的表达水平并增加增殖率。我们还发现,在临床前三维人体肝纤维化切片模型中,抑制 UCHL1 可减轻纤维化的发生,这些结果证明了小分子 DUB 抑制剂如何通过调节肝病中的 HIF 转录因子发挥治疗作用。 此外,使用 UCHL1 抑制剂抑制 HIF 活性可能是治疗其他 HIF 相关病症的一个机会。
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引用次数: 0
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