Biochemistry and Biophysics Reports最新文献_第3页

Dynamic strain and β-catenin mediated suppression of interferon responsive genes in quiescent mesenchymal stromal/stem cells 动态应变和β-catenin介导的静止间充质基质/干细胞干扰素反应基因抑制作用

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports

Pub Date : 2024-10-23 DOI: 10.1016/j.bbrep.2024.101847

Parisa Dashti , Eric A. Lewallen , Gary S. Stein , Bram C.J. van der Eerden , Johannes P.T.M. van Leeuwen , Andre J. van Wijnen

Multipotent bone marrow mesenchymal stromal/stem cells (MSCs) respond to mechanical forces. MSCs perceive static and dynamic forces through focal adhesions, as well as cytoskeletal and intranuclear actin. Dynamic strain stimulates nuclear β-catenin (Ctnnb1) that controls gene expression and suppresses osteogenesis. The sensitivity of MSCs to external mechanical forces may be altered by cessation of proliferation, when MSCs begin to express extracellular matrix (ECM) proteins and generate cell/cell contact. Therefore, we assessed whether and how gene expression of proliferating versus quiescent MSCs responds to mechanical stimuli. We used RNA-seq and RT-qPCR to evaluate transcriptomes at 3 h after dynamic strain (200 cycles × 2 % for 20 min) once daily during a two-day time course in naïve (uninduced) MSCs. Transcriptomes of untreated MSCs show that cells become quiescent at day 2 when proliferation markers are downregulated, and ECM related genes are upregulated. On both day 1 and day 2, dynamic strain stimulates expression of oxidative stress related genes (e.g., Nqo1, Prl2c2, Prl2c3). Strikingly, in quiescent MSCs, we observe that dynamic strain suppresses multiple interferon (IFN) responsive genes (e.g., Irf7, Oasl2 and Isg15). IFN responsive genes are activated in MSCs depleted of β-catenin using siRNAs, indicating that β-catenin normally suppresses these genes. Our data indicate that the functional effects of dynamic strain and β-catenin on IFN responsive genes in MSCs are mechanistically coupled. Because dynamic strain and β-catenin reduce the osteogenic potential of MSCs, our findings suggest that IFN responsive genes are novel biomarkers and potential regulators of mechanical responses at early stages of lineage-commitment in post-proliferative MSCs.

多能骨髓间充质基质/干细胞（间充质干细胞）对机械力做出反应。间充质干细胞通过病灶粘附以及细胞骨架和核内肌动蛋白感知静态和动态力。动态应变会刺激核β-catenin（Ctnnb1），从而控制基因表达并抑制成骨。当间叶干细胞开始表达细胞外基质（ECM）蛋白并产生细胞/细胞接触时，间叶干细胞对外部机械力的敏感性可能会因增殖停止而改变。因此，我们评估了增殖与静止间充质干细胞的基因表达是否以及如何对机械刺激做出反应。我们使用 RNA-seq 和 RT-qPCR 评估了天真（未诱导）间充质干细胞在每天一次的动态应变（200 个周期 × 2 %，20 分钟）后 3 小时的转录组。未经处理的间充质干细胞转录组显示，细胞在第 2 天进入静止期，此时增殖标记下调，而 ECM 相关基因上调。在第 1 天和第 2 天，动态应变都会刺激氧化应激相关基因（如 Nqo1、Prl2c2、Prl2c3）的表达。引人注目的是，在静止间充质干细胞中，我们观察到动态应变抑制了多个干扰素（IFN）反应基因（如 Irf7、Oasl2 和 Isg15）的表达。在使用 siRNA 去除了 β-catenin 的间充质干细胞中，IFN 响应基因被激活，这表明 β-catenin 通常会抑制这些基因。我们的数据表明，动态应变和β-catenin对间叶干细胞中IFN应答基因的功能影响是机理耦合的。由于动态应变和β-catenin降低了间充质干细胞的成骨潜能，我们的研究结果表明，IFN应答基因是新的生物标志物，也是增殖后间充质干细胞在品系承诺早期阶段机械应答的潜在调节因子。

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引用次数: 0

Identification of genes related to fatty acid metabolism in type 2 diabetes mellitus 鉴定与 2 型糖尿病脂肪酸代谢有关的基因

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports

Pub Date : 2024-10-22 DOI: 10.1016/j.bbrep.2024.101849

Ji Yang , Yikun Zhou , Jiarui Zhang , Yongqin Zheng , Jundong He

Aim

Fatty acid metabolism is pivotal for lipid synthesis, cellular signaling, and maintaining cell membrane integrity. However, its diagnostic significance in type 2 diabetes mellitus (T2DM) remains unclear.

Materials and methods

Three datasets and fatty acid metabolism-related genes were retrieved. Differential expression analysis, WGCNA, machine learning algorithms, diagnostic analysis, and validation were employed to identify key feature genes. Functional analysis, ceRNA network construction, immune microenvironment assessment, and drug prediction were conducted to explore the underlying molecular mechanisms.

Results

Six feature genes were identified with strong diagnostic performance and were involved in processes such as ribosome function and fatty acid metabolism. Immune cells, including dendritic cells, eosinophils, and neutrophils, may play a role in the progression of T2DM. ceRNA and drug-target network analysis revealed potential interactions, such as RP11-miR-29a-YTHDF3 and BPA-MSANTD1. The expression patterns of the feature genes, except for YTHDF3, were consistently upregulated in T2DM, aligning with trends observed in the training set.

Conclusion

This study investigated the potential molecular mechanisms of six fatty acid metabolism-related genes in T2DM, offering valuable insights that may guide future research and therapeutic development.

目的脂肪酸代谢对脂质合成、细胞信号传导和维持细胞膜完整性至关重要。材料与方法检索了三个数据集和脂肪酸代谢相关基因。采用差异表达分析、WGCNA、机器学习算法、诊断分析和验证来确定关键特征基因。结果发现了六个具有较强诊断能力的特征基因，它们参与了核糖体功能和脂肪酸代谢等过程。ceRNA和药物靶点网络分析发现了潜在的相互作用，如RP11-miR-29a-YTHDF3和BPA-MSANTD1。除 YTHDF3 外，其他特征基因的表达模式在 T2DM 中持续上调，与训练集中观察到的趋势一致。

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引用次数: 0

An in-silico approach to target multiple proteins involved in anti-microbial resistance using natural compounds produced by wild mushrooms 利用野生蘑菇产生的天然化合物靶向涉及抗微生物抗药性的多种蛋白质的硅内方法

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports

Pub Date : 2024-10-21 DOI: 10.1016/j.bbrep.2024.101854

Gagandeep Singh , Md Alamgir Hossain , Dhurgham Al-Fahad , Vandana Gupta , Smriti Tandon , Hemant Soni , Cheemalapati Venkata Narasimhaji , Mariusz Jaremko , Abdul-Hamid Emwas , Md Jamir Anwar , Faizul Azam

Bacterial resistance to antibiotics and the number of patients infected by multi-drug-resistant bacteria have increased significantly over the past decade. This study follows a computational approach to identify potential antibacterial compounds from wild mushrooms. Twenty-six known compounds produced by wild mushrooms were docked to assess their affinity with drug targets of antibiotics such as penicillin-binding protein-1a (PBP1a), DNA gyrase, and isoleucyl-tRNA synthetase (ILERS). Docking scores were further validated by multiple receptor conformer (MRC)-based docking studies. Based on the MRC-based docking results, eight molecules were shortlisted for ADMET analysis. Molecular dynamics (MD) simulations were further performed to evaluate the conformational stability of the ligand-protein complexes. Binding energies were computed by the gmx_MMPBSA method. The data were obtained in terms of root-mean square deviation, and root-mean square fluctuation justified the stability of Austrocortilutein A, Austrocortirubin, and Confluentin in complex with several proteins under physiological conditions. Among these, Austrocortilutein A displayed better binding affinity with PBP1a and ILERS when compared with their respective reference ligands. This study is preliminary and aims to help drive the search for compounds that have the capacity to overcome the anti-microbial resistance of prevalent bacteria, using natural compounds produced by wild mushrooms. Further experimental validation is required to justify the clinical use of the studied compounds.

在过去十年中，细菌对抗生素的耐药性和感染多重耐药菌的患者人数大幅增加。本研究采用计算方法从野生蘑菇中找出潜在的抗菌化合物。研究人员对野生蘑菇产生的 26 种已知化合物进行了对接，以评估它们与青霉素结合蛋白-1a (PBP1a)、DNA 回旋酶和异亮氨酰-tRNA 合成酶 (ILERS) 等抗生素药物靶标的亲和力。基于多重受体构象（MRC）的对接研究进一步验证了对接得分。根据基于 MRC 的对接结果，筛选出 8 个分子进行 ADMET 分析。为评估配体-蛋白质复合物的构象稳定性，进一步进行了分子动力学（MD）模拟。结合能由 gmx_MMPBSA 方法计算得出。得到的均方根偏差和均方根波动数据证明了奥曲肽肽 A、奥曲肽和 Confluentin 在生理条件下与几种蛋白质复合物的稳定性。其中，奥曲肽 A 与 PBP1a 和 ILERS 的结合亲和力优于各自的参考配体。这项研究是初步性的，目的是利用野生蘑菇产生的天然化合物，帮助寻找有能力克服流行细菌抗微生物耐药性的化合物。要证明所研究化合物的临床用途，还需要进一步的实验验证。

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引用次数: 0

A diet high in glucose and deficient in dietary fibre causes fat accumulation in the liver without weight gain 高葡萄糖和缺乏膳食纤维的饮食会导致脂肪在肝脏堆积，但体重不会增加

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports

Pub Date : 2024-10-19 DOI: 10.1016/j.bbrep.2024.101848

Sonoko Karino , Haruki Usuda , Shoma Kanda , Takayuki Okamoto , Tomomi Niibayashi , Takahisa Yano , Kohji Naora , Koichiro Wada

This study investigated whether a standard calorie diet that is high in glucose and deficient in dietary fibre (described as HGD [high glucose diet]) induces hepatic fat accumulation in mice. We evaluated hepatic steatosis at 7 days and 14 days after the commencement of the HGD. Hepatic triglycerides and areas of oil droplets increased in the HGD group both at day 7 and day 14, whereas weight gain, weight of epididymal fat, and plasma levels of triglycerides were unaffected by HGD consumption. A microarray analysis of the livers revealed that the expression of lipogenesis-related genes was the most affected by HGD consumption. Furthermore, HGD consumption induced the expression of hepatic proteins of fatty acid synthetase, acetyl-CoA carboxylase alpha, and stearoyl-CoA desaturase 1, which are known to be involved in the synthesis of triglyceride. These results indicate that HGD consumption causes fat accumulation in the liver, with an increase in enzymes that are involved in de novo lipogenesis without an accompanying weight or obesity phenotype. Our new findings suggest that HGD consumption could serve as a breeding ground for liver steatosis.

本研究调查了高葡萄糖和缺乏膳食纤维的标准热量饮食（称为 HGD [高葡萄糖饮食]）是否会诱发小鼠肝脏脂肪堆积。我们在 HGD 开始后的 7 天和 14 天对肝脏脂肪变性进行了评估。HGD组小鼠肝脏甘油三酯和油滴面积在第7天和第14天均有所增加，而体重增加、附睾脂肪重量和血浆甘油三酯水平则不受HGD影响。对肝脏进行的芯片分析表明，摄入 HGD 对脂肪生成相关基因的表达影响最大。此外，摄入 HGD 会诱导肝脏中脂肪酸合成酶、乙酰-CoA 羧化酶 alpha 和硬脂酰-CoA 去饱和酶 1 蛋白的表达，而已知这些蛋白参与了甘油三酯的合成。这些结果表明，摄入 HGD 会导致脂肪在肝脏中蓄积，参与新脂肪生成的酶会增加，但不会伴随体重或肥胖表型。我们的新发现表明，摄入 HGD 可能成为肝脏脂肪变性的温床。

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引用次数: 0

Correlation of SNHG7 and BGL3 expression in patients with de novo acute myeloid leukemia; novel insights into lncRNA effect in PI3K signaling context in AML pathogenesis 新发急性髓性白血病患者中 SNHG7 和 BGL3 表达的相关性；关于 lncRNA 在急性髓性白血病发病机制中 PI3K 信号转导背景下的作用的新见解

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports

Pub Date : 2024-10-18 DOI: 10.1016/j.bbrep.2024.101850

Saeed Hassani , Parsa Rostami , Meshkat Pourtavakol , Amirhossein Karamashtiani , Mohammad Sayyadi

Background

Acute myeloid leukemia (AML) has been identified as a top priority for discovering a reliable biomarker for treatment improvement and patient outcome prediction due to the heterogeneous nature of AML and the obstacle to find an appropriate treatment strategy for this malignancy. Considering the involvement of long noncoding RNA (lncRNA) SNHG7 and BGL3 found in various cancers, the exact expression pattern of these lncRNAs and their clinical implications in acute myeloid leukemia (AML) continue to be elusive. In order to demonstrate a possible mechanism underlying AML pathogenesis, our goal was to examine BGL3 and SNHG7 lncRNA expressions in PI3K pathway.

Methods

This case-control cross-sectional study were conducted on RNA extracted from blood samples of 30 patients diagnosed with AML (Ayatollah-Khansari hospital, Arak, Iran) and 30 (age and gender matched) healthy controls. The expression levels of SNHG7 and BGL3 lncRNAs and their target genes Akt and PTEN, were measured using qRT-PCR. Subsequently, by means of statistical analysis, we determined the plausible correlation between the expressions of the aforementioned genes and lncRNA respectively.

Results

In AML samples, a considerable increase in the expression levels of SNHG7 lncRNA and Akr gene was accompanied by a marked reduction in the expression levels of BGL3 lncRNA and PTEN gene. Nevertheless, No significant relationship between the expression level of the indicated genes/lncRNAs and age and sex was found. The remarkable correlation between the expression of genes/lncRNAs and the blast percentage in patients was the notable point in the result of this study.

Conclusions

As the most straightforward interpretation of our results, we propose that perhaps the association between SNHG7 and BGL3 built through the interaction between Akt and PTEN may play a crucial role in the AML pathogenesis and any element of this axis could be a potential novel target for further profound treatment strategies. Nonetheless, in the context of Hematological Malignancies, particularly AML, more detailed studies are needed in this area to elucidate the precise role played by this interesting testis-specific pathway.

背景由于急性髓性白血病（AML）的异质性，以及为这种恶性肿瘤寻找合适治疗策略的障碍，发现一种可靠的生物标志物以改善治疗和预测患者预后已被确定为当务之急。考虑到长非编码RNA（lncRNA）SNHG7和BGL3在各种癌症中的参与，这些lncRNA的确切表达模式及其在急性髓性白血病（AML）中的临床意义仍然难以捉摸。为了证明急性髓性白血病发病的可能机制，我们的目标是检测 BGL3 和 SNHG7 lncRNA 在 PI3K 通路中的表达。采用 qRT-PCR 技术测定了 SNHG7 和 BGL3 lncRNA 及其靶基因 Akt 和 PTEN 的表达水平。结果在 AML 样本中，SNHG7 lncRNA 和 Akr 基因的表达水平显著升高，而 BGL3 lncRNA 和 PTEN 基因的表达水平明显降低。不过，上述基因/lncRNA的表达水平与年龄和性别之间并无明显关系。结论作为对研究结果最直观的解释，我们认为 SNHG7 和 BGL3 通过 Akt 和 PTEN 之间的相互作用而建立的关联可能在急性髓细胞性白血病的发病机制中起着至关重要的作用，而这一轴心的任何元素都可能成为进一步深入治疗策略的潜在新靶点。然而，对于血液恶性肿瘤，尤其是急性髓细胞性白血病，还需要在这一领域进行更详细的研究，以阐明这一有趣的睾丸特异性通路所发挥的确切作用。

{"title":"Correlation of SNHG7 and BGL3 expression in patients with de novo acute myeloid leukemia; novel insights into lncRNA effect in PI3K signaling context in AML pathogenesis","authors":"Saeed Hassani , Parsa Rostami , Meshkat Pourtavakol , Amirhossein Karamashtiani , Mohammad Sayyadi","doi":"10.1016/j.bbrep.2024.101850","DOIUrl":"10.1016/j.bbrep.2024.101850","url":null,"abstract":"<div><h3>Background</h3><div>Acute myeloid leukemia (AML) has been identified as a top priority for discovering a reliable biomarker for treatment improvement and patient outcome prediction due to the heterogeneous nature of AML and the obstacle to find an appropriate treatment strategy for this malignancy. Considering the involvement of long noncoding RNA (lncRNA) SNHG7 and BGL3 found in various cancers, the exact expression pattern of these lncRNAs and their clinical implications in acute myeloid leukemia (AML) continue to be elusive. In order to demonstrate a possible mechanism underlying AML pathogenesis, our goal was to examine BGL3 and SNHG7 lncRNA expressions in PI3K pathway.</div></div><div><h3>Methods</h3><div>This case-control cross-sectional study were conducted on RNA extracted from blood samples of 30 patients diagnosed with AML (Ayatollah-Khansari hospital, Arak, Iran) and 30 (age and gender matched) healthy controls. The expression levels of SNHG7 and BGL3 lncRNAs and their target genes Akt and PTEN, were measured using qRT-PCR. Subsequently, by means of statistical analysis, we determined the plausible correlation between the expressions of the aforementioned genes and lncRNA respectively.</div></div><div><h3>Results</h3><div>In AML samples, a considerable increase in the expression levels of SNHG7 lncRNA and Akr gene was accompanied by a marked reduction in the expression levels of BGL3 lncRNA and PTEN gene. Nevertheless, No significant relationship between the expression level of the indicated genes/lncRNAs and age and sex was found. The remarkable correlation between the expression of genes/lncRNAs and the blast percentage in patients was the notable point in the result of this study.</div></div><div><h3>Conclusions</h3><div>As the most straightforward interpretation of our results, we propose that perhaps the association between SNHG7 and BGL3 built through the interaction between Akt and PTEN may play a crucial role in the AML pathogenesis and any element of this axis could be a potential novel target for further profound treatment strategies. Nonetheless, in the context of Hematological Malignancies, particularly AML, more detailed studies are needed in this area to elucidate the precise role played by this interesting testis-specific pathway.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"40 ","pages":"Article 101850"},"PeriodicalIF":2.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparison of two-dimensional and three-dimensional culture systems and their responses to chemotherapy in cells representing disease progression of high-grade serous ovarian cancer 比较二维和三维培养系统及其对代表高级别浆液性卵巢癌疾病进展的细胞化疗的反应

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports

Pub Date : 2024-10-17 DOI: 10.1016/j.bbrep.2024.101838

Naya El Mokbel , Alicia A. Goyeneche , Rewati Prakash , Benjamin N. Forgie , Farah H. Abdalbari , Xing Zeng , Basile Tessier-Cloutier , Shuk On Annie Leung , Carlos M. Telleria

High-grade serous cancer is the most common type of ovarian cancer and is usually diagnosed at advanced stages with high mortality due to recurrence and eventual resistance to standard platinum therapy. The aim of this study was to compare two-dimensional (2D) versus tridimensional (3D) cell culture as a preclinical model of response to carboplatin, paclitaxel and niraparib using PEO1, PEO4 and PEO6 cell lines, which were generated from the same patient along disease progression. Morphologically, cells formed flat adherent layers versus spheroidal structures with different compaction patterns in 2D and 3D respectively. In 2D, apoptosis was rare whereas in 3D cells formed a multilayered structure with an outer layer of live proliferating cells and an inner core of apoptotic cells. Furthermore, a differential capacity to produce ATP was observed among the cell lines in 3D but not in 2D. While response to carboplatin, paclitaxel and niraparib in both settings followed a similar trend, a lower sensitivity was observed in 3D with respect to 2D. Overall, 3D cell culture is likely more reflective of the in vivo cellular tumor behavior and more suitable of therapeutic evaluation given its added complexity absent in 2D.

高级别浆液性癌是最常见的卵巢癌类型，通常诊断为晚期，由于复发和最终对标准铂类疗法产生耐药性，死亡率很高。本研究的目的是比较二维（2D）和三维（3D）细胞培养作为临床前模型对卡铂、紫杉醇和尼拉帕利的反应，使用的细胞系为 PEO1、PEO4 和 PEO6，这些细胞系由同一患者在疾病进展过程中产生。从形态上看，细胞在二维和三维中分别形成了具有不同压实模式的扁平粘附层和球形结构。二维细胞很少发生凋亡，而三维细胞则形成多层结构，外层为活体增殖细胞，内核为凋亡细胞。此外，在三维细胞系中观察到细胞产生 ATP 的能力不同，而在二维细胞系中则没有。虽然在两种情况下对卡铂、紫杉醇和尼拉帕利的反应趋势相似，但在三维中观察到的敏感性低于二维。总之，三维细胞培养可能更能反映体内细胞的肿瘤行为，也更适合进行治疗评估，因为它增加了二维细胞培养所没有的复杂性。

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引用次数: 0

Effect of (R)-(−)-Linalool on endothelial damage: Sex differences (R)-(-)-芳樟醇对内皮损伤的影响：性别差异

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports

Pub Date : 2024-10-15 DOI: 10.1016/j.bbrep.2024.101846

Laura Doro , Alessandra T. Peana , Rossana Migheli , Giampiero Capobianco , Massimo Criscione , Andrea Montella , Ilaria Campesi

Oxidative stress and inflammation are responsible for endothelial damage displaying many sex differences. Lipopolysaccharide (LPS) is a pathogenic stimulus that can trigger inflammation, contributing to endothelial dysfunction. Given the scientific evidence on the effectiveness of herbal extracts in managing endothelial dysfunction, we considered the (R)-(−)-Linalool (LIN), an aromatic monoterpene alcohol, as a bioactive phytochemical compound that could prevent and improve endothelial injury. In this study, we evaluated the effect of the LIN on LPS-induced damage in female and male human umbilical vein endothelial cells (FHUVECs and MHUVECs), measuring cell viability, cytokines release (IL-6 and TNF-α), malondialdehyde (MDA), and nitrites.

LPS significantly reduced viability both in MHUVECs and FHUVECs. Moreover, LPS increased the IL-6, TNF-α, and MDA level only in FHUVECs if compared to basal value; despite that, LPS reduced nitrites only in MHUVECs. LIN alone did not affect the parameters measured except for an increase in nitrites in FHUVECs. Nevertheless, LIN reduced damage and restored endothelium viability reduced by LPS without a clear sex difference. Under LPS, LIN inhibited IL-6 release and reduced MDA levels only in FHUVECs.

The present data confirm the existence of sex differences in the behavior of HUVECs under LPS conditions. The administration of LIN seems to have a more evident effect on FHUVECs after damage induced by LPS. These LIN effects are important to conduct further well-designed studies on the sex-specific use of this compound on vascular endothelial injury.

氧化应激和炎症是造成内皮损伤的原因，并显示出许多性别差异。脂多糖（LPS）是一种致病性刺激物，可引发炎症，导致内皮功能障碍。鉴于有科学证据表明草药提取物可有效控制内皮功能障碍，我们认为芳香单萜醇 (R)-(-)- 芳樟醇 (LIN) 是一种生物活性植物化学物质，可预防和改善内皮损伤。在这项研究中，我们评估了 LIN 对 LPS 诱导的雌性和雄性人脐静脉内皮细胞（FHUVECs 和 MHUVECs）损伤的影响，测量了细胞活力、细胞因子释放量（IL-6 和 TNF-α）、丙二醛（MDA）和亚硝酸盐。此外，与基础值相比，LPS仅增加了FHUVECs的IL-6、TNF-α和MDA水平；尽管如此，LPS仅降低了MHUVECs的亚硝酸盐水平。除了亚硝酸盐在 FHUVECs 中增加外，LIN 本身对测量的参数没有影响。尽管如此，LIN 减少了 LPS 对内皮细胞的损伤，恢复了内皮细胞的活力，而且没有明显的性别差异。在 LPS 条件下，LIN 仅在 FHUVECs 中抑制 IL-6 的释放并降低 MDA 水平。在 LPS 诱导的损伤后，给予 LIN 似乎对 FHUVECs 有更明显的作用。LIN 的这些作用对于进一步精心设计该化合物对血管内皮损伤的性别特异性研究非常重要。

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引用次数: 0

Identification of cell wall binding domains and repeats in Streptococcus pneumoniae phage endolysins: A molecular and diversity analysis 鉴定肺炎链球菌噬菌体内溶菌素的细胞壁结合域和重复序列：分子和多样性分析

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports

Pub Date : 2024-10-14 DOI: 10.1016/j.bbrep.2024.101844

Tahsin Khan , Shakhinur Islam Mondal , Araf Mahmud , Daniyal Karim , Lorraine A. Draper , Colin Hill , Abul Kalam Azad , Arzuba Akter

Streptococcus pneumoniae (pneumococcus) is a multidrug-resistant pathogen associated with pneumonia, otitis media, meningitis and other severe complications that are currently a global threat to human health. The World Health Organization listed Pneumococcus as the fourth of twelve globally prioritized pathogens. Identifying alternatives to antibiotic therapies is urgently needed to combat Pneumococcus. Bacteriophage-derived endolysins can be used as alternative therapeutics due to their bacterial cell wall hydrolyzing capability. In this study, S. pneumoniae phage genomes were screened to create a database of endolysins for molecular modelling and diversity analysis of these lytic proteins. A total of 89 lytic proteins were curated from 81 phage genomes and categorized into eight groups corresponding to their different enzymatically active (EAD) domains and cell wall binding (CBDs) domains. We then constructed three-dimensional structures that provided insights into these endolysins. Group I, II, III, V, and VI endolysins showed conserved catalytic and ion-binding residues similar to existing endolysins available in the Protein Data Bank. While performing structural and sequence analysis with template lysin, an additional cell wall binding repeat was observed in Group II lysin, which was not previously known. Molecular docking performed with choline confirmed the existence of this additional repeat. Group III endolysins showed 99.16 % similarity to LysME-EF1, a lysin derived from Enterococcus faecalis. Furthermore, the comparative computational analysis revealed the existence of CBDs in Group III lysin. This study provides the first insight into the molecular and diversity analysis of S. pneumoniae phage endolysins that could be valuable for developing novel lysin-based therapeutics.

肺炎链球菌（肺炎球菌）是一种具有多重耐药性的病原体，与肺炎、中耳炎、脑膜炎和其他严重并发症有关，是目前威胁人类健康的全球性疾病。世界卫生组织将肺炎球菌列为十二种全球优先病原体中的第四种。目前迫切需要找到抗生素疗法的替代品来抗击肺炎球菌。噬菌体衍生的内溶素具有水解细菌细胞壁的能力，可用作替代疗法。在这项研究中，对肺炎双球菌噬菌体基因组进行了筛选，以建立一个内溶菌素数据库，用于这些溶菌蛋白的分子建模和多样性分析。我们从 81 个噬菌体基因组中筛选出 89 种溶菌酶蛋白，并根据其不同的酶活性（EAD）结构域和细胞壁结合（CBDs）结构域将其分为八组。然后，我们构建了三维结构，以便深入了解这些内溶菌素。第一组、第二组、第三组、第五组和第六组内溶酶原显示出保守的催化和离子结合残基，与蛋白质数据库中现有的内溶酶原相似。在对模板溶菌素进行结构和序列分析时，在第二组溶菌素中发现了一个额外的细胞壁结合重复序列，这在以前是不为人知的。与胆碱进行的分子对接证实了这一额外重复的存在。第 III 组溶菌素与粪肠球菌的溶菌素 LysME-EF1 的相似度为 99.16%。此外，比较计算分析表明，第 III 组溶菌酶中存在 CBD。这项研究首次揭示了肺炎双球菌噬菌体内溶菌素的分子和多样性分析，对开发基于溶菌素的新型疗法很有价值。

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引用次数: 0

MYH7, c.2011C>T, is responsible for congenital scoliosis in a Chinese family MYH7，c.2011C>T，是一个中国家族先天性脊柱侧弯症的病因

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports

Pub Date : 2024-10-13 DOI: 10.1016/j.bbrep.2024.101845

Ping Wei , Fulong Xu , Caixia Xian , Yanhan Liu , Yibo Xu , Ting Zhang , Weizhe Shi , Sihong Huang , Xiang Zhou , Mingwei Zhu , Hongwen Xu

Neuromuscular scoliosis can be caused by muscular or nervous system dysfunction resulting from genetic variants. Variation in MYH7 may cause hypertrophic or dilated cardiomyopathy, skeletal myopathies, or a combination of both; however, scoliosis has rarely been reported. We analyzed a Chinese pedigree with two members suffering from scoliosis. Whole-exome sequencing identified a variant (NM_000257.4:c.2011C > T) of MYH7 that cosegregated with the scoliosis phenotype. The variant resulted in a change in the evolutionarily conserved amino acid residue 671 from arginine to cystine (p.R671C), which was predicted to disrupt the structure and function of the motor domain of the slow/β-cardiac myosin heavy chain encoded by MYH7. To date, 913 MYH7 variants were associated with cardiomyopathy and/or skeletal myopathies according to the Human Gene Mutation Database. However, only 15 cases of scoliosis have been reported. In our case, the c.2011C > T variant caused scoliosis with 100 % penetrance and hypertrophic cardiomyopathy with partial penetrance.

神经肌肉脊柱侧弯可由基因变异导致的肌肉或神经系统功能障碍引起。MYH7的变异可能导致肥厚型或扩张型心肌病、骨骼肌病或两者的合并症；然而，脊柱侧弯却很少见报道。我们分析了一个有两名脊柱侧弯患者的中国血统。全基因组测序发现了一个与脊柱侧凸表型共整合的MYH7变异体（NM_000257.4:c.2011C >T）。该变异导致进化保守的氨基酸残基 671 从精氨酸变为胱氨酸（p.R671C），据预测，这将破坏 MYH7 编码的慢/β-心肌肌球蛋白重链运动结构域的结构和功能。迄今为止，根据人类基因突变数据库（Human Gene Mutation Database），913 个 MYH7 变异与心肌病和/或骨骼肌病相关。然而，仅有15例脊柱侧弯的报道。在我们的病例中，c.2011C >T变异导致100%渗透性脊柱侧弯和部分渗透性肥厚型心肌病。

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引用次数: 0

Impact of T-2 toxin on intestinal inflammation and transcriptional regulation of inflammatory response in mouse macrophages T-2 毒素对肠道炎症和小鼠巨噬细胞炎症反应转录调控的影响

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports

Pub Date : 2024-10-13 DOI: 10.1016/j.bbrep.2024.101840

Xinghui Yang , Xiaoli Xu , Qiuhong Zhong , Haifeng Cui , Junfeng Xu , Wei Wei

T-2 toxin, a fungal secondary metabolite produced by toxigenic Fusarium species, poses a significant threat to grain food and feed due to its potential to cause intestinal inflammation in livestock and poultry. Macrophages play a crucial role as integral components of the body's immune system during intestinal inflammation. This study aimed to elucidate the mechanism behind the inflammatory response triggered by T-2 toxin in macrophages. Compared to the control group, gavage administration of T-2 toxin (0.33, 1, and 4 mg kg⁻¹) led to a decrease in body weight and feed intake, along with histopathological alterations in the colon of mice. In addition, T-2 toxin induced the upregulation of macrophage-derived cytokines like IL-1β, IL-6, and TNF-α, as well as a rise in the population of F4/80⁺ macrophages in the colon. T-2 toxin also led to the upregulation of IL-1β, IL-6, and TNF-α in mouse bone marrow-derived macrophages (BMDMs). Furthermore, the transcriptomic analysis of BMDMs exposed to T-2 toxin (10 nM) identified the "TNF signaling pathway," "Lipid and atherosclerosis," "Epstein-Barr virus infection," "MAPK signaling pathway," and the "NF-kappa B signaling pathway" as the top five significantly enriched pathways. Subsequently, twelve inflammation-related genes were randomly chosen for validation through quantitative reverse transcription PCR (RT-qPCR), with the results corroborating those from the transcriptomic analysis. The comprehensive analysis of transcriptome data highlights the activation of several signaling pathways associated with the inflammatory response following T-2 toxin-induced BMDMs, offering potential therapeutic targets for the prevention and treatment of T-2 toxin-induced intestinal inflammation.

T-2 毒素是一种由致毒镰刀菌产生的真菌次级代谢产物，由于可能导致家畜和家禽肠道发炎，因此对谷物食品和饲料构成了重大威胁。巨噬细胞作为人体免疫系统的组成部分，在肠道炎症中发挥着至关重要的作用。本研究旨在阐明 T-2 毒素引发巨噬细胞炎症反应的机制。与对照组相比，灌胃 T-2 毒素（0.33、1 和 4 毫克/千克-1）会导致小鼠体重和采食量下降，并引起结肠组织病理学改变。此外，T-2 毒素还诱导巨噬细胞衍生的细胞因子（如 IL-1β、IL-6 和 TNF-α）上调，以及结肠中 F4/80+ 巨噬细胞数量的增加。T-2 毒素还导致小鼠骨髓源巨噬细胞（BMDMs）中的 IL-1β、IL-6 和 TNF-α 上调。此外，对暴露于T-2毒素（10 nM）的BMDMs进行的转录组分析发现，"TNF信号通路"、"脂质和动脉粥样硬化"、"Epstein-Barr病毒感染"、"MAPK信号通路 "和 "NF-kappa B信号通路 "是前五条显著富集的通路。随后，通过定量反转录 PCR（RT-qPCR）随机选择了 12 个炎症相关基因进行验证，结果与转录组分析的结果相吻合。对转录组数据的综合分析凸显了与 T-2 毒素诱导的 BMDMs 炎症反应相关的几种信号通路的激活，为预防和治疗 T-2 毒素诱导的肠道炎症提供了潜在的治疗靶点。

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引用次数: 0