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Transcriptional profiling reveals the role of Candida albicans Rap1 in oxidative stress response. 转录谱分析揭示了白色念珠菌 Rap1 在氧化应激反应中的作用。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-22 DOI: 10.1042/BSR20240689
Wen-Han Wang, Hsuan-Yu Chen, Sheng-Yuan Chen, Chung-Yu Lan

Candida albicans is a member of the human commensal microbiota but can also cause opportunistic infections, including life-threatening invasive candidiasis, particularly in immunocompromised patients. One of the important features of C. albicans commensalism and virulence is its ability to adapt to diverse environmental stress conditions within the host. Rap1 is a DNA-binding protein identified in yeasts, protozoa, and mammalian cells, and it plays multiple functions, including telomere regulation. Intriguingly, our previous study showed that Rap1 is also involved in cell wall integrity, biofilm formation, and virulence in C. albicans. In this work, using RNA-seq analysis and other approaches, the role of C. albicans Rap1 in oxidative stress response was further revealed. The RAP1-deletion mutant exhibited greater resistance to the superoxide generator menadione, a lower level of intracellular reactive oxygen species (ROS) upon menadione treatment, and higher expression levels of superoxide dismutase genes, all in response to oxidative stress. Moreover, the association between Rap1-mediated oxidative stress response and the mitogen-activated protein kinase (MAPK) Hog1, the transcription factor Cap1 and the TOR signaling was also determined. Together, these findings expand our understanding of the complex signaling and transcriptional mechanisms regulating stress responses in C. albicans.

白念珠菌是人类共生微生物群中的一员,但也可引起机会性感染,包括危及生命的侵袭性念珠菌病,尤其是在免疫力低下的患者中。白念珠菌共生和致病的重要特征之一是它能够适应宿主体内不同的环境压力条件。Rap1 是在酵母、原生动物和哺乳动物细胞中发现的一种 DNA 结合蛋白,它具有多种功能,包括端粒调控。有趣的是,我们之前的研究表明,Rap1 还参与了白僵菌细胞壁的完整性、生物膜的形成和毒力的形成。在这项工作中,利用 RNA-seq 分析和其他方法,进一步揭示了白僵菌 Rap1 在氧化应激反应中的作用。RAP1缺失突变体对超氧化物生成物甲萘醌的抵抗力更强,在甲萘醌处理后细胞内活性氧(ROS)水平更低,超氧化物歧化酶基因的表达水平更高,这些都是对氧化应激的反应。此外,还确定了 Rap1 介导的氧化应激反应与丝裂原活化蛋白激酶(MAPK)Hog1、转录因子 Cap1 和 TOR 信号转导之间的关联。这些发现拓展了我们对调控白僵菌应激反应的复杂信号转导和转录机制的理解。
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引用次数: 0
YAP signaling orchestrates the endothelin-1-guided invadopodia formation in high-grade serous ovarian cancer. YAP信号在高级别浆液性卵巢癌中协调内皮素-1引导的内生树突形成。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-04 DOI: 10.1042/BSR20241320
Piera Tocci, Valentina Caprara, Celia Roman, Rosanna Sestito, Laura Rosanò, Anna Bagnato

The high-grade serous ovarian cancer (HG-SOC) is a notoriously challenging disease, characterized by a rapid peritoneal dissemination. HG-SOC cells leverage actin-rich membrane protrusions, known as invadopodia, to degrade the surrounding extracellular matrix (ECM) and invade, initiating the metastatic cascade. In HG-SOC, the endothelin-1 (ET-1)/endothelin A receptor (ETAR)-driven signaling coordinates invadopodia activity, however how this axis integrates pro-oncogenic signaling routes, as YAP-driven one, impacting on the invadopodia-mediated ECM degradation and metastatic progression, deserves a deeper investigation. Herein, we observed that downstream of the ET-1/ET-1R axis, the RhoC and Rac1 GTPases, acting as signaling intermediaries, promote the de-phosphorylation and nuclear accumulation of YAP. Conversely, the treatment with the dual ETA/ETB receptor antagonist, macitentan, inhibits the ET-1-driven YAP activity. Similarly, RhoC silencing, or cell transfection with a dominant inactive form of Rac1, restore the YAP phosphorylated and inhibited state. Mechanistically, the ET-1R/YAP signal alliance coordinates invadopodia maturation into ECM-degrading structures, indicating how such ET-1R-guided protein network represents a route able to enhance the HG-SOC invasive potential. At functional level, we found that the interconnection between the ET-1R/RhoC and YAP signals is required for MMP-2 and MMP-9 proteolytic functions, cell invasion, and cytoskeleton architecture changes, supporting the HG-SOC metastatic strength. In HG-SOC patient-derived xenografts (PDX) macitentan, turning-off the invadopodia regulators RhoC/YAP, halt the metastatic colonization. ET-1R targeting, hindering the YAP activity, weakens the invadopodia machinery, embodying a promising therapeutic avenue to prevent peritoneal dissemination in HG-SOC.

高级别浆液性卵巢癌(HG-SOC)是一种臭名昭著的挑战性疾病,其特点是腹膜扩散迅速。HG-SOC细胞利用富含肌动蛋白的膜突起(即侵袭体)来降解周围的细胞外基质(ECM)并进行侵袭,从而启动转移级联反应。在HG-SOC中,内皮素-1(ET-1)/内皮素A受体(ETAR)驱动的信号转导协调着内生型突起的活动,但这一轴心如何与YAP驱动的促致癌信号途径相结合,从而影响内生型突起介导的ECM降解和转移进程,值得深入研究。在此,我们观察到,在 ET-1/ET-1R 轴的下游,RhoC 和 Rac1 GTPases 作为信号中间体,促进了 YAP 的去磷酸化和核积累。相反,ETA/ETB 双受体拮抗剂马西替坦可抑制 ET-1 驱动的 YAP 活性。同样,RhoC 沉默或细胞转染显性无活性形式的 Rac1 可恢复 YAP 的磷酸化和抑制状态。从机理上讲,ET-1R/YAP 信号联盟协调了内吸附体成熟为 ECM 降解结构的过程,表明这种由 ET-1R 引导的蛋白质网络是如何代表了一种能够增强 HG-SOC 侵袭潜力的途径。在功能层面,我们发现 ET-1R/RhoC 和 YAP 信号之间的相互联系是 MMP-2 和 MMP-9 蛋白分解功能、细胞侵袭和细胞骨架结构变化所必需的,从而支持了 HG-SOC 的转移强度。在 HG-SOC 患者衍生异种移植物(PDX)中,马基坦能关闭侵袭性调控因子 RhoC/YAP,阻止转移性定植。以 ET-1R 为靶点,阻碍 YAP 的活性,从而削弱内生癌细胞的内生机制,为防止 HG-SOC 的腹膜扩散提供了一条很有前景的治疗途径。
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引用次数: 0
Causal Effects of Gut Microbiota on Gout and Hyperuricemia: Insights from Genome-Wide Mendelian Randomization, RNA-Sequencing, 16S rRNA Sequencing, and Metabolomes. 肠道微生物群对痛风和高尿酸血症的因果效应:全基因组孟德尔随机化、RNA测序、16S rRNA测序和代谢组的启示。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-04 DOI: 10.1042/BSR20240595
Xia Liu, Zhe Feng, Fenglian Zhang, Bo Wang, Zhijuan Wei, Nanqing Liao, Min Zhang, Jian Liang, Lisheng Wang

Background: This study investigated the causal relationship between gut microbiota (GM), serum metabolome, and host transcriptome in the development of gout and hyperuricemia (HUA) using genome-wide association studies (GWAS) data and HUA mouse model experiments.  Methods: Mendelian randomization (MR) analysis of GWAS summary statistics was performed using an inverse variance weighted (IVW) approach to determine predict the causal role of the gut microbiota on gout. The HUA mouse model was used to characterize changes in the gut microbiome, host metabolome, and host kidney transcriptome by integrating cecal 16S rRNA sequencing, untargeted serum metabolomics, and host mRNA sequencing.

 Results: Our analysis demonstrated causal effects of seven gut microbiota taxa on gout, including genera of Ruminococcus, Odoribacter, and Bacteroides. Thirty-eight, immune cell traits were associated with gout. Dysbiosis of Dubosiella, Lactobacillus,Bacteroides, Alloprevotella, and Lachnospiraceae_NK4A136_group genera were associated with changes in the serum metabolites and kidney transcriptome of the HUA model mice. The changes in the gut microbiome of the HUA model mice correlated significantly with alterations in the levels of serum metabolites such as taurodeoxycholic acid, phenylacetylglycine, vanylglycol, methyl hexadecanoic acid, carnosol, 6-aminopenicillanic acid, sphinganine, p-hydroxyphenylacetic acid, pyridoxamine, and de-o-methylsterigmatocystin, and expression of kidney genes such as CNDP2, SELENOP, TTR, CAR3, SLC12A3, SCD1, PIGR, CD74, MFSD4B5, and NAPSA.

 Conclusion: Our study demonstrated a causal relationship between GM, immune cells, and gout. HUA development involved alterations in the vitamin B6 metabolism because of gut microbiota dysbiosis that resulted in altered pyridoxamine and pyridoxal levels, dysregulated sphingolipid metabolism, and excessive inflammation.

.

研究背景本研究利用全基因组关联研究(GWAS)数据和HUA小鼠模型实验,研究了痛风和高尿酸血症(HUA)发病过程中肠道微生物群(GM)、血清代谢组和宿主转录组之间的因果关系:采用反方差加权法(IVW)对全基因组关联研究(GWAS)摘要统计进行孟德尔随机化(MR)分析,以确定预测肠道微生物群对痛风的因果作用。通过整合盲肠 16S rRNA 测序、非靶向血清代谢组学和宿主 mRNA 测序,利用 HUA 小鼠模型描述了肠道微生物组、宿主代谢组和宿主肾脏转录组的变化:我们的分析表明,七个肠道微生物群分类群对痛风有因果影响,其中包括反刍球菌属、Odoribacter 和 Bacteroides。38种免疫细胞特征与痛风有关。Dubosiella、Lactobacillus、Bacteroides、Alloprevotella和Lachnospiraceae_NK4A136_group等菌属的菌群失调与HUA模型小鼠血清代谢物和肾脏转录组的变化有关。6-氨基青霉烷酸、鞘氨醇、对羟基苯乙酸、吡哆胺和去甲基异麦角胱氨酸等肾脏代谢产物,以及 CNDP2、SELENOP、TTR、CAR3、SLC12A3、SCD1、PIGR、CD74、MFSD4B5 和 NAPSA 等肾脏基因的表达。 结论:我们的研究证明了 GM、免疫细胞和痛风之间的因果关系。由于肠道微生物群失调导致吡哆胺和吡哆醛水平改变、鞘脂代谢失调和过度炎症,HUA 的发生涉及维生素 B6 代谢的改变。
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引用次数: 0
Expression of Concern: LncRNA MIR155HG contributes to smoke-related chronic obstructive pulmonary disease by targeting miR-128-5p/BRD4 axis. 表达关注:LncRNA MIR155HG通过靶向miR-128-5p/BRD4轴导致与烟雾相关的慢性阻塞性肺病。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BSR-2019-2567_EOC
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引用次数: 0
Expression of Concern: Apc gene suppresses intracranial aneurysm formation and rupture through inhibiting the NF-κB signaling pathway mediated inflammatory response. 表达关注:Apc 基因通过抑制 NF-κB 信号通路介导的炎症反应,抑制颅内动脉瘤的形成和破裂。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BSR-2018-1909_EOC
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引用次数: 0
C4 grasses employ distinct strategies to acclimate rubisco activase to heat stress. C4 禾本科植物采用不同策略使 Rubisco 激活酶适应热胁迫
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BSR20240353
Sarah C Stainbrook, Lindsey N Aubuchon, Amanda Chen, Emily Johnson, Audrey Si, Laila Walton, Angela J Ahrendt, Daniela Strenkert, Joseph M Jez

Rising temperatures due to the current climate crisis will soon have devastating impacts on crop performance and resilience. In particular, CO2 assimilation is dramatically limited at high temperatures. CO2 assimilation is accomplished by rubisco, which is inhibited by the binding of inhibitory sugar phosphates to its active site. Plants therefore utilize the essential chaperone rubisco activase (RCA) to remove these inhibitors and enable continued CO2 fixation. However, RCA does not function at moderately high temperatures (42°C), resulting in impaired rubisco activity and reduced CO2 assimilation. We set out to understand temperature-dependent RCA regulation in four different C4 plants, with a focus on the crop plants maize (two cultivars) and sorghum, as well as the model grass Setaria viridis (setaria) using gas exchange measurements, which confirm that CO2 assimilation is limited by carboxylation in these organisms at high temperatures (42°C). All three species express distinct complements of RCA isoforms and each species alters the isoform and proteoform abundances in response to heat; however, the changes are species-specific. We also examine whether the heat-mediated inactivation of RCA is due to biochemical regulation rather than simple thermal denaturation. We reveal that biochemical regulation affects RCA function differently in different C4 species, and differences are apparent even between different cultivars of the same species. Our results suggest that each grass evolved different strategies to maintain RCA function during stress and we conclude that a successful engineering approach aimed at improving carbon capture in C4 grasses will need to accommodate these individual regulatory mechanisms.

当前的气候危机导致气温不断升高,这将很快对作物的生长性能和抗逆性产生破坏性影响。特别是,二氧化碳的同化作用在高温下会受到极大限制。二氧化碳同化作用是由 Rubisco 完成的,而 Rubisco 的活性位点会受到抑制性糖磷酸盐的抑制。因此,植物利用重要的合子 Rubisco 激活酶(RCA)来清除这些抑制剂,使二氧化碳的固定得以继续。然而,RCA 在中度高温(42 摄氏度)下不起作用,导致 Rubisco 活性受损,二氧化碳同化能力降低。我们开始利用气体交换测量来了解四种不同 C4 植物的温度依赖性 RCA 调节,重点是作物玉米(两个栽培品种)和高粱,以及模式草 Setaria viridis(莎草),测量结果证实这些生物在高温(42oC)下的二氧化碳同化受到羧化的限制。所有三个物种都表达不同的 RCA 同工酶,并且每个物种都会改变同工酶和蛋白酶的丰度以应对高温;然而,这些变化是物种特异性的。我们还研究了热介导的 RCA 失活是否是由于生化调节而非简单的热变性。我们发现,在不同的 C4 植物中,生化调节对 RCA 功能的影响不同,甚至在同一物种的不同栽培品种之间也存在明显差异。我们的研究结果表明,每种禾本科植物都进化出了不同的策略,以在胁迫期间维持 RCA 的功能。我们的结论是,旨在改善 C4 禾本科植物碳捕获的成功工程方法需要适应这些不同的调节机制。
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引用次数: 0
Interaction with IP6K1 supports pyrophosphorylation of substrate proteins by the inositol pyrophosphate 5-InsP7. 与 IP6K1 相互作用,支持肌醇焦磷酸 5-InsP7 对底物蛋白质进行焦磷酸化。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BSR20240792
Aisha Hamid, Jayashree S Ladke, Akruti Shah, Shubhra Ganguli, Monisita Pal, Arpita Singh, Rashna Bhandari

Inositol pyrophosphates (PP-InsPs) are a sub-family of water soluble inositol phosphates that possess one or more diphosphate groups. PP-InsPs can transfer their β-phosphate group to a phosphorylated Ser residue to generate pyrophosphorylated Ser. This unique post-translational modification occurs on Ser residues that lie in acidic stretches within an intrinsically disordered protein sequence. Serine pyrophosphorylation is dependent on the presence of Mg2+ ions, but does not require an enzyme for catalysis. The mechanisms by which cells regulate PP-InsP-mediated pyrophosphorylation are still unknown. We performed mass spectrometry to identify interactors of IP6K1, an enzyme responsible for the synthesis of the PP-InsP 5-InsP7. Interestingly, IP6K1 interacted with several proteins that are known to undergo 5-InsP7-mediated pyrophosphorylation, including the nucleolar proteins NOLC1, TCOF and UBF1, and AP3B1, the β subunit of the AP3 adaptor protein complex. The IP6K1 interactome also included CK2, a protein kinase that phosphorylates Ser residues prior to pyrophosphorylation. We observe the formation of a protein complex between IP6K1, AP3B1, and the catalytic α-subunit of CK2, and show that disrupting IP6K1 binding to AP3B1 lowers its in vivo pyrophosphorylation. We propose that assembly of a substrate-CK2-IP6K complex would allow for coordinated pre-phosphorylation and pyrophosphorylation of the target serine residue, and provide a mechanism to regulate this enzyme-independent modification.

肌醇焦磷酸盐(PP-InsPs)是水溶性肌醇磷酸盐的一个亚家族,具有一个或多个二磷酸基团。PP-InsPs 可将其β-磷酸基转移到磷酸化的丝氨酸残基上,生成焦磷酸化丝氨酸。 这种独特的翻译后修饰发生在位于内在无序蛋白质序列中酸性绵延的丝氨酸残基上。丝氨酸焦磷酸化依赖于 Mg2+ 离子的存在,但不需要酶来催化。细胞调控 PP-InsP 介导的焦磷酸化的机制尚不清楚。我们用质谱法鉴定了 IP6K1(一种负责合成 PP-InsP 5-InsP7 的酶)的相互作用体。有趣的是,IP6K1 与几个已知会发生 5-InsP7 介导的焦磷酸化的蛋白质发生了相互作用,包括核仁蛋白 NOLC1、TCOF 和 UBF1 以及 AP3 适应蛋白复合物的 β 亚基 AP3B1。IP6K1 的相互作用组还包括 CK2,这是一种蛋白激酶,可在焦磷酸化之前使 Ser 残基磷酸化。我们观察到 IP6K1、AP3B1 和 CK2 的催化 α 亚基之间形成了一个蛋白复合物,并表明破坏 IP6K1 与 AP3B1 的结合会降低其体内焦磷酸化。我们提出,底物-CK2-IP6K 复合物的组装将使目标丝氨酸残基的预磷酸化和焦磷酸化得以协调进行,并提供了一种调节这种不依赖于酶的修饰的机制。
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引用次数: 0
Deficiency of GPR10 and NPFFR2 receptors leads to sex-specific prediabetic syndrome and late-onset obesity in mice. GPR10 和 NPFFR2 受体的缺失会导致小鼠出现性别特异性糖尿病前期综合征和晚发性肥胖症。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BSR20241103
Alena Morgan, Nivasini Shekhar, Veronika Strnadová, Zdenko Pirník, Eliška Haasová, Jan Kopecký, Andrea Pačesová, Blanka Železná, Jaroslav Kuneš, Kristina Bardová, Lenka Maletínská

GPR10 and neuropeptide FF receptor 2 (NPFFR2) play important role in the regulation of food intake and energy homeostasis. Understanding the interaction between these receptors and their specific ligands, such as prolactin-releasing peptide, is essential for developing stable peptide analogs with potential for treating obesity. By breeding and characterizing double knockout (dKO) mice fed standard or high-fat diet (HFD), we provide insights into the metabolic regulation associated with the GPR10 and NPFFR2 deficiency. Both WT and dKO mice were subjected to behavioral tests and an oral glucose tolerance test. Moreover, dual-energy X-ray absorptiometry (DEXA) followed by indirect calorimetry were performed to characterize dKO mice. dKO mice of both sexes, when exposed to an HFD, showed reduced glucose tolerance, hyperinsulinemia, and insulin resistance compared with controls. Moreover, they displayed increased liver weight with worsened hepatic steatosis. Mice displayed significantly increased body weight, which was more pronounced in dKO males and caused by higher caloric intake on a standard diet, while dKO females displayed obesity characterized by increased white adipose tissue and enhanced hepatic lipid accumulation on an HFD. Moreover, dKO females exhibited anxiety-like behavior in the open field test. dKO mice on a standard diet had a lower respiratory quotient, with no significant changes in energy expenditure. These results provide insights into alterations associated with disrupted GPR10 and NPFFR2 signaling, contributing to the development of potential anti-obesity treatment.

GPR10和神经肽FF受体2(NPFFR2)在调节食物摄入和能量平衡方面发挥着重要作用。了解这些受体与其特定配体(如催乳素释放肽)之间的相互作用,对于开发具有治疗肥胖症潜力的稳定肽类似物至关重要。通过培育和鉴定以标准或高脂饮食(HFD)喂养的双基因敲除(dKO)小鼠,我们深入了解了与 GPR10 和 NPFFR2 缺乏有关的代谢调节。我们对 WT 和 dKO 小鼠进行了行为测试和口服葡萄糖耐量测试。与对照组相比,雌雄dKO小鼠在摄入高氟日粮后表现出糖耐量降低、高胰岛素血症和胰岛素抵抗。此外,它们的肝脏重量增加,肝脏脂肪变性恶化。dKO雄性小鼠的体重明显增加,这是因为它们在标准饮食中摄入了更多的热量,而dKO雌性小鼠则表现出肥胖,其特征是白色脂肪组织增加,肝脏脂质积累增加。此外,dKO雌性小鼠在空场试验中表现出类似焦虑的行为。dKO小鼠在标准饮食中的呼吸商较低,能量消耗没有显著变化。这些结果让我们了解了与GPR10和NPFFR2信号传导紊乱有关的改变,有助于开发潜在的抗肥胖治疗方法。
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引用次数: 0
Protective effect of (E)-(2,4-dihydroxy)-α-aminocinnamic acid, a hydroxy cinnamic acid derivative, in an ulcerative colitis model induced by TNBS. (E)-(2,4-二羟基)-a-氨基肉桂酸(一种羟基肉桂酸衍生物)对 TNBS 诱导的溃疡性结肠炎模型的保护作用。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BSR20240797
Astrid Mayleth Rivera Antonio, Itzia Irene Padilla Martínez, Yazmín Karina Márquez-Flores, Alan Hipólito Juárez Solano, Mónica A Torres Ramos, Martha Cecilia Rosales Hernández

Ulcerative colitis (UC) is a multifactorial disease that causes long-lasting inflammation and ulcers in the digestive tract. UC is the most common form of inflammatory bowel disease (IBD). The current treatment for mild-to-moderate UC involves the use of 5-aminosalicylates (5-ASA), but much of this compound is unabsorbed and metabolized by N-acetylation. Several efforts have since been made to evaluate new molecules from synthetic or natural sources. Recently, it was reported that (E)-(5-chloro-2-hydroxy)-α-aminocinnamic acid (2c) and (E)-(2,4-dihydroxy)-α-aminocinnamic acid (2f) are as good or better myeloperoxidase (MPO) inhibitors and antioxidants than 5-ASA. Then, the present study aimed to evaluate the protective effects of 2c and 2f on a rat model of UC induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The results showed that TNBS caused the induction of colonic ulcers, as well as a significant increase in MPO activity and malondialdehyde (MDA) and a decrease in glutathione (GSH) content. The administration of 2f, 2c and 5-ASA, decreased the ulcers presence, inhibited MPO peroxidation activity and MPO presence (as determined by immunofluorescence), and increased GSH and reduced MDA content. However, 2f was better than 2c and 5-ASA, then, the principal mechanism by which 2f presented a protective effect in a UC model induced by TNBS in rats is by inhibiting MPO activity and due to its antioxidant activity.

溃疡性结肠炎(UC)是一种多因素疾病,会引起消化道长期炎症和溃疡。溃疡性结肠炎是最常见的炎症性肠病(IBD)。目前治疗轻度至中度 UC 的方法是使用 5-氨基水杨酸盐(5-ASA),但这种化合物大部分未被吸收,而是通过 N-乙酰化代谢。此后,人们开始努力评估来自合成或天然来源的新分子。最近有报道称,(E)-(5-氯-2-羟基)-α-氨基肉桂酸(2c)和(E)-(2,4-二羟基)-a-氨基肉桂酸(2f)是与 5-ASA 一样好或更好的髓过氧化物酶(MPO)抑制剂和抗氧化剂。因此,本研究旨在评估 2c 和 2f 对 2,4,6-三硝基苯磺酸(TNBS)诱导的 UC 大鼠模型的保护作用。结果表明,TNBS 会诱导大鼠出现结肠溃疡,并导致 MPO 活性和丙二醛(MDA)显著升高,谷胱甘肽(GSH)含量下降。服用 2f、2c 和 5-ASA 可减少溃疡的出现,抑制 MPO 过氧化活性和 MPO 的存在(通过免疫荧光测定),增加 GSH 并降低 MDA 含量。因此,在 TNBS 诱导的大鼠 UC 模型中,2f 发挥保护作用的主要机制是通过抑制 MPO 活性及其抗氧化活性。
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引用次数: 0
Effect of the polyphenol flavonoids fisetin and quercetin on the adipogenic differentiation of human mesenchymal stromal cells. 多酚黄酮类化合物鱼腥草素和槲皮素对人间质基质细胞脂肪分化的影响
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BSR20240623
Chanchao Lorthongpanich, Thanapon Charoenwongpaiboon, Praphasri Septham, Chuti Laowtammathron, Pimonwan Srisook, Pakpoom Kheolamai, Sirikul Manochantr, Surapol Issaragrisil

Fisetin and quercetin, polyphenol flavonoids, have been shown to have a wide range of beneficial pharmacological effects including anti-inflammatory, antioxidative, and anti-cancer. Our previous work shows that fisetin also affects the specification of the adipogenic-osteogenic lineage of human mesenchymal stem cells (hMSCs) by modulating the Hippo-YAP signaling pathway. Although quercetin has a structure similar to that of fisetin, its effects on the functional properties of hMSCs have not yet been investigated. The objective of the present study is to determine the effects of quercetin on the various properties of hMSCs, including proliferation, migration, and differentiation capacity toward adipogenic and osteogenic lineages. The results show that while fisetin increases hMSC adipogenic differentiation, quercetin inhibited adipogenic differentiation of hMSCs. The inhibition is mediated, at least in part, by the activation of hippo signaling and up-regulation of miR-27b, which inhibits the expression of genes involved in all critical steps of lipid droplet biogenesis, resulting in a decrease in the number of lipid droplets in hMSCs. It is possible that the lack of hydroxylation of the 5 position on the A ring of quercetin could be responsible for its different effect on the adipogenic-osteogenic lineage specification of hMSCs compared with fisetin. Molecular docking and molecular dynamics simulation suggested that fisetin and quercetin possibly bind to serine / threonine protein kinases 4 (STK4/MST1), which is an upstream kinase responsible for LATS phosphorylation. Taken together, our results demonstrate more insight into the mechanism underlying the role of flavonoid fisetin and quercetin in the regulation of adipogenesis.

鱼腥草素和槲皮素是多酚黄酮类化合物,已被证明具有抗炎、抗氧化和抗癌等多种有益的药理作用。我们之前的研究表明,鱼腥草素还能通过调节 Hippo-YAP 信号通路影响人类间充质干细胞(hMSCs)的成脂-成骨谱系。虽然槲皮素的结构与鱼腥草素相似,但其对 hMSCs 功能特性的影响尚未得到研究。本研究的目的是确定槲皮素对 hMSCs 各种特性的影响,包括增殖、迁移以及向脂肪生成系和成骨系分化的能力。结果表明,虽然鱼藤黄素能增加 hMSCs 的成脂分化,但槲皮素却能抑制 hMSCs 的成脂分化。这种抑制作用至少部分是通过激活 hippo 信号传导和上调 miR-27b 来实现的,miR-27b 可抑制参与脂滴生物生成所有关键步骤的基因的表达,从而导致 hMSCs 中脂滴数量的减少。与鱼腥草素相比,槲皮素的 A 环上的 5 位缺乏羟基化可能是其对 hMSCs 的成脂-成骨细胞系分化产生不同影响的原因。分子对接和分子动力学模拟表明,鱼腥草素和槲皮素可能与丝氨酸/苏氨酸蛋白激酶4(STK4/MST1)结合,而STK4/MST1是导致LATS磷酸化的上游激酶。综上所述,我们的研究结果进一步揭示了黄酮类化合物鱼腥草素和槲皮素在调控脂肪生成过程中的作用机制。
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