Pub Date : 2024-11-05DOI: 10.1016/j.bbrc.2024.150953
Zhengtian Zhang , Chunhui Zhong , Menghui Guo , Yongyou Yin , Heng Ye , Xiting Lu , Zheng Liu , Guimei Yu
ABCC1/MRP1 in the C branch of Adenosine triphosphate binding cassette (ABC) transporters superfamily, is directly linked to multiple drug resistance in chemotherapy. Here, to further understand the conformational dynamics of ABCC1, we performed single-particle cryo-electron microscopy analysis of purified bovine ABCC1. Two conformational states were found coexisted with nearly equal population. While one state has a wider substrate transporting pathway, akin to the previously reported apo structure, the other is narrower, despite the empty substrate pocket. In addition, multiple lipid-binding interfaces were identified based on the presence of rod-shaped, unmodeled, non-protein densities in the resolved density maps, potentially contributing to the stabilization of TMD0 domain and activity regulation of ABCC1. Further, we found that three asparagine residues in bovine ABCC1 are glycosylated. Together, our study provides fresh insights into the structural features and conformational dynamics of bovine ABCC1, offering a new framework for understanding the function and regulatory mechanisms of ABCC1.
{"title":"Cryo-EM structures of ABCC1 revealing new conformational dynamics in the resting state","authors":"Zhengtian Zhang , Chunhui Zhong , Menghui Guo , Yongyou Yin , Heng Ye , Xiting Lu , Zheng Liu , Guimei Yu","doi":"10.1016/j.bbrc.2024.150953","DOIUrl":"10.1016/j.bbrc.2024.150953","url":null,"abstract":"<div><div>ABCC1/MRP1 in the C branch of Adenosine triphosphate binding cassette (ABC) transporters superfamily, is directly linked to multiple drug resistance in chemotherapy. Here, to further understand the conformational dynamics of ABCC1, we performed single-particle cryo-electron microscopy analysis of purified bovine ABCC1. Two conformational states were found coexisted with nearly equal population. While one state has a wider substrate transporting pathway, akin to the previously reported apo structure, the other is narrower, despite the empty substrate pocket. In addition, multiple lipid-binding interfaces were identified based on the presence of rod-shaped, unmodeled, non-protein densities in the resolved density maps, potentially contributing to the stabilization of TMD0 domain and activity regulation of ABCC1. Further, we found that three asparagine residues in bovine ABCC1 are glycosylated. Together, our study provides fresh insights into the structural features and conformational dynamics of bovine ABCC1, offering a new framework for understanding the function and regulatory mechanisms of ABCC1.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"738 ","pages":"Article 150953"},"PeriodicalIF":2.5,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1016/j.bbrc.2024.150950
Sung Min Choi , Hi Jung Park , Hyun Ji Boo , Kyeong Cheon Jung , Jae Il Lee
Antigen-inexperienced memory-phenotype CD8+ T cells are categorized as innate memory cells in the thymus or virtual memory (VM) CD8+ T cells in peripheral tissues. The key distinction between these cell types is their differing responses to IL-4, but the minimal effect of IL-4 on VM CD8+ T cell expansion in the periphery is not well understood. To address this, we investigated the development of VM CD8+ T cells in the periphery of IL-4 knockout (KO) C57BL/6 mouse. CD8+ splenocytes were isolated from the spleen of wilt-type (WT) and IL-4 KO mice, followed by single-cell RNA sequencing and Seurat analysis on sorted CD8+ cells using the 10x Genomics platform. This study identified various CD8+ T cell subtypes, including naïve, effector, IFN-stimulated, true memory (TM), and VM T cells. VM CD8+ T cells were characterized by high expression of Cd44, Cxcr3, Il2rb, Eomes, Tbx21, Ly6c2, and low expression of Itga4. In IL-4-deficient mouse, macrophages were significantly reduced, while memory T cell populations showed a slight increase compared to WT mouse. Both Itga4+ TM and Itga4- VM CD8+ T cells were more abundant in IL-4 KO mouse. Within the VM T cell group, Ly6a− VM CD8+ T cells were reduced, while Ly6a+ VM CD8+ T cells were increased relative to WT mouse. These Ly6a+ VM CD8+ cells exhibited high expression of genes linked to type I IFN signaling, such as Isg15, Ifit1, and Stat1. Our findings suggest that IFN-influenced Ly6a+ VM CD8+ T cells play a role in maintaining the peripheral VM CD8+ T cell population in the absence of IL-4.
抗原无经验记忆表型 CD8+ T 细胞可分为胸腺中的先天记忆细胞和外周组织中的虚拟记忆（VM）CD8+ T 细胞。这些细胞类型之间的主要区别在于它们对 IL-4 的不同反应，但 IL-4 对外周 VM CD8+ T 细胞扩增的最小影响尚不十分清楚。为了解决这个问题，我们研究了IL-4基因敲除（KO）C57BL/6小鼠外周VM CD8+ T细胞的发育情况。从Wilt-type（WT）和IL-4 KO小鼠的脾脏中分离出CD8+脾细胞，然后使用10x Genomics平台对分选的CD8+细胞进行单细胞RNA测序和Seurat分析。这项研究确定了各种 CD8+ T 细胞亚型，包括幼稚型、效应型、IFN 刺激型、真正记忆型（TM）和 VM T 细胞。VM CD8+ T细胞的特征是高表达Cd44、Cxcr3、Il2rb、Eomes、Tbx21、Ly6c2，低表达Itga4。与 WT 小鼠相比，IL-4 缺陷小鼠的巨噬细胞明显减少，而记忆 T 细胞群则略有增加。在IL-4 KO小鼠中，Itga4+ TM和Itga4- VM CD8+ T细胞都更多。在VM T细胞组中，与WT小鼠相比，Ly6a- VM CD8+ T细胞减少，而Ly6a + VM CD8+ T细胞增加。这些 Ly6a+ VM CD8+ 细胞表现出与 I 型 IFN 信号转导相关的基因的高表达，如 Isg15、Ifit1 和 Stat1。我们的研究结果表明，在缺乏IL-4的情况下，受IFN影响的Ly6a+ VM CD8+ T细胞在维持外周VM CD8+ T细胞群方面发挥作用。
{"title":"Characterization of CD8+ virtual memory T cells in IL-4 knockout mice using single-cell RNA sequencing","authors":"Sung Min Choi , Hi Jung Park , Hyun Ji Boo , Kyeong Cheon Jung , Jae Il Lee","doi":"10.1016/j.bbrc.2024.150950","DOIUrl":"10.1016/j.bbrc.2024.150950","url":null,"abstract":"<div><div>Antigen-inexperienced memory-phenotype CD8<sup>+</sup> T cells are categorized as innate memory cells in the thymus or virtual memory (VM) CD8<sup>+</sup> T cells in peripheral tissues. The key distinction between these cell types is their differing responses to IL-4, but the minimal effect of IL-4 on VM CD8<sup>+</sup> T cell expansion in the periphery is not well understood. To address this, we investigated the development of VM CD8<sup>+</sup> T cells in the periphery of IL-4 knockout (KO) C57BL/6 mouse. CD8<sup>+</sup> splenocytes were isolated from the spleen of wilt-type (WT) and IL-4 KO mice, followed by single-cell RNA sequencing and Seurat analysis on sorted CD8<sup>+</sup> cells using the 10x Genomics platform. This study identified various CD8<sup>+</sup> T cell subtypes, including naïve, effector, IFN-stimulated, true memory (TM), and VM T cells. VM CD8<sup>+</sup> T cells were characterized by high expression of <em>Cd44</em>, <em>Cxcr3</em>, <em>Il2rb</em>, <em>Eomes</em>, <em>Tbx21</em>, <em>Ly6c2</em>, and low expression of <em>Itga4</em>. In IL-4-deficient mouse, macrophages were significantly reduced, while memory T cell populations showed a slight increase compared to WT mouse. Both <em>Itga4</em><sup>+</sup> TM and <em>Itga4</em><sup>-</sup> VM CD8<sup>+</sup> T cells were more abundant in IL-4 KO mouse. Within the VM T cell group, <em>Ly6a</em><sup>−</sup> VM CD8<sup>+</sup> T cells were reduced, while <em>Ly6a</em> <sup>+</sup> VM CD8<sup>+</sup> T cells were increased relative to WT mouse. These <em>Ly6a</em><sup>+</sup> VM CD8<sup>+</sup> cells exhibited high expression of genes linked to type I IFN signaling, such as <em>Isg15, Ifit1,</em> and <em>Stat1</em>. Our findings suggest that IFN-influenced <em>Ly6a</em> <sup>+</sup> VM CD8<sup>+</sup> T cells play a role in maintaining the peripheral VM CD8<sup>+</sup> T cell population in the absence of IL-4.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"738 ","pages":"Article 150950"},"PeriodicalIF":2.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1016/j.bbrc.2024.150948
Alankar Roy , Ishani Paul , Tanwi Paul, Aritrika Dihidar, Sujay Ray
SARS-CoV-2, responsible for the global COVID-19 pandemic, has undergone significant genetic changes, leading to various variants impacting transmissibility, severity, and vaccine efficacy. The methodology involved evaluating SARS-CoV-2 variants designated by WHO as Variants of Interest (VOIs) and Variants Under Monitoring (VUMs). Several noteworthy mutations including G446S, K417N, T478K, E484A, N501Y, and Y505H exhibit a strong pattern of convergent evolution across all these variants, particularly at antigenic sites within the spike protein. Conformational epitopes mapping and antigenicity shift analyses implicated epitope changes which were compared for therapeutic purposes. VUMs BA.2.86 and XBB.2.3 show significant antigenicity changes and epitope dynamics, correlating with high root mean square deviation values and epitope expansions or contractions. Nonsynonymous mutations are predominant in all variants, suggesting functional changes affecting transmissibility and immune evasion. VOIs XBB.1.5, BA.2.86, and CH.1.1 show high solvent-accessible surface area and radius of gyration, indicating structural expansion and increased epitope availability. In contrast, stable VOI EG.5.1 displays minimal structural changes and moderate epitope expansions. We evaluated two classes of antibodies for their effectiveness in neutralizing SARS-CoV-2 variants. Antibodies CC12.1 and P4A1 from Class I, alongside CV07-250, P5A-2G9, and MW05 from Class II, display strong binding across multiple variants, indicating broad neutralizing capabilities. Specifically, P4A1 shows the highest affinity for EG.5 and EG.5.1, while MW05 exhibits the strongest binding to XBB.1.5, CH.1.1, and XBB.2.3, highlighting their potent neutralization potential. This study aims to elucidate epitope variations in evolving SARS-CoV-2 strains, offering critical insights for developing targeted interventions against current challenges posed by the virus.
{"title":"Exploring B-cell epitope conservation and antigenicity shift in current COVID-19 variants: Analyzing spike-antibody interactions for therapeutic uses","authors":"Alankar Roy , Ishani Paul , Tanwi Paul, Aritrika Dihidar, Sujay Ray","doi":"10.1016/j.bbrc.2024.150948","DOIUrl":"10.1016/j.bbrc.2024.150948","url":null,"abstract":"<div><div>SARS-CoV-2, responsible for the global COVID-19 pandemic, has undergone significant genetic changes, leading to various variants impacting transmissibility, severity, and vaccine efficacy. The methodology involved evaluating SARS-CoV-2 variants designated by WHO as Variants of Interest (VOIs) and Variants Under Monitoring (VUMs). Several noteworthy mutations including G446S, K417N, T478K, E484A, N501Y, and Y505H exhibit a strong pattern of convergent evolution across all these variants, particularly at antigenic sites within the spike protein. Conformational epitopes mapping and antigenicity shift analyses implicated epitope changes which were compared for therapeutic purposes. VUMs BA.2.86 and XBB.2.3 show significant antigenicity changes and epitope dynamics, correlating with high root mean square deviation values and epitope expansions or contractions. Nonsynonymous mutations are predominant in all variants, suggesting functional changes affecting transmissibility and immune evasion. VOIs XBB.1.5, BA.2.86, and CH.1.1 show high solvent-accessible surface area and radius of gyration, indicating structural expansion and increased epitope availability. In contrast, stable VOI EG.5.1 displays minimal structural changes and moderate epitope expansions. We evaluated two classes of antibodies for their effectiveness in neutralizing SARS-CoV-2 variants. Antibodies CC12.1 and P4A1 from Class I, alongside CV07-250, P5A-2G9, and MW05 from Class II, display strong binding across multiple variants, indicating broad neutralizing capabilities. Specifically, P4A1 shows the highest affinity for EG.5 and EG.5.1, while MW05 exhibits the strongest binding to XBB.1.5, CH.1.1, and XBB.2.3, highlighting their potent neutralization potential. This study aims to elucidate epitope variations in evolving SARS-CoV-2 strains, offering critical insights for developing targeted interventions against current challenges posed by the virus.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"739 ","pages":"Article 150948"},"PeriodicalIF":2.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1016/j.bbrc.2024.150951
Pengfei Wu , Wen Zhang , Xitong Zuo , Shengran Liu , Tianrong Jin , Jialin Jia , Bangwei Luo , Guansong Wang , Zhiren Zhang
The main function of erythropoietin (EPO) is to promote hematopoiesis and improve anemia. In addition, EPO also has many non-hematopoietic effects such as anti-inflammation, anti-apoptosis and anti-oxidation. To achieve the protective effects, large doses of EPO are required, so the probability of side effects increases. Previous studies have revealed that EPO can improve pulmonary fibrosis in mice, but it has not been clarified whether the hematopoiesis of EPO contributes to amelioration of pulmonary fibrosis and whether EPO improves overall mortality. Our results show that EPO decreases hydroxyproline content, α-sma and col-1 protein levels in mice with bleomycin-induced pulmonary fibrosis. However, compared with the control group, the weight loss and mortality rate of the EPO group were not improved, while the number of red blood cells (RBCs), hemoglobin (Hb), red cell width distribution-coefficient of variation (RDW-CV) and hematocrit (HCT) were significantly higher. Furthermore, we observed massive thrombosis in the lung of EPO treated lung fibrosis mice but not in control mice. Therefore, our results show that in the condition of lung fibrosis, the hematopoietic activity of exogenous EPO is not conducive to its tissue protective effect.
{"title":"The hematopoietic activity of EPO is unfavorable to the treatment of bleomycin-induced pulmonary fibrosis in mice","authors":"Pengfei Wu , Wen Zhang , Xitong Zuo , Shengran Liu , Tianrong Jin , Jialin Jia , Bangwei Luo , Guansong Wang , Zhiren Zhang","doi":"10.1016/j.bbrc.2024.150951","DOIUrl":"10.1016/j.bbrc.2024.150951","url":null,"abstract":"<div><div>The main function of erythropoietin (EPO) is to promote hematopoiesis and improve anemia. In addition, EPO also has many non-hematopoietic effects such as anti-inflammation, anti-apoptosis and anti-oxidation. To achieve the protective effects, large doses of EPO are required, so the probability of side effects increases. Previous studies have revealed that EPO can improve pulmonary fibrosis in mice, but it has not been clarified whether the hematopoiesis of EPO contributes to amelioration of pulmonary fibrosis and whether EPO improves overall mortality. Our results show that EPO decreases hydroxyproline content, α-sma and col-1 protein levels in mice with bleomycin-induced pulmonary fibrosis. However, compared with the control group, the weight loss and mortality rate of the EPO group were not improved, while the number of red blood cells (RBCs), hemoglobin (Hb), red cell width distribution-coefficient of variation (RDW-CV) and hematocrit (HCT) were significantly higher. Furthermore, we observed massive thrombosis in the lung of EPO treated lung fibrosis mice but not in control mice. Therefore, our results show that in the condition of lung fibrosis, the hematopoietic activity of exogenous EPO is not conducive to its tissue protective effect.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"739 ","pages":"Article 150951"},"PeriodicalIF":2.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1016/j.bbrc.2024.150954
Ziqiang Chu , Ye Zheng , Qi Shen , Keli Yang , Hui Wang , Kui Ma , Yaying Hao , Junli Chen , Haihong Li , Xiaobing Fu , Cuiping Zhang
Neutrophil plays an important role in the early stage of wound healing. Excessive neutrophil extracellular traps (NETs) which are produced by neutrophil have been proved as a significant unfavorable factor for wound healing by impairing the function of human skin fibroblasts. However, the effect of NETs with low concentrations on fibroblasts remains unclear. The interaction between CCDC25 and ILK in fibroblast were found to be activated by NET-DNA with low concentrations. Additionally, phosphorylation of PI3K and AKT was increased in NET-stimulated fibroblasts but was inhibited by CCDC25 knockout or ILK knockdown. NETs-induces proliferation and migration ability of fibroblast were also reduced by application of CCDC25 sgRNAs or ILK shRNAs. This study demonstrates that low concentrations of NETs, upon biding with CCDC25, activates the ILK/PI3K/AKT signaling pathway in skin fibroblasts, leading to increased cell proliferation and migration activity.
中性粒细胞在伤口愈合的早期阶段发挥着重要作用。由中性粒细胞产生的过多的中性粒细胞胞外捕获物（NETs）已被证实会损害人体皮肤成纤维细胞的功能，是影响伤口愈合的一个重要不利因素。然而，低浓度的NETs对成纤维细胞的影响仍不清楚。研究发现，低浓度的NET-DNA可激活成纤维细胞中CCDC25和ILK之间的相互作用。此外，在NET刺激的成纤维细胞中，PI3K和AKT的磷酸化增加，但CCDC25敲除或ILK敲除可抑制PI3K和AKT的磷酸化。应用 CCDC25 sgRNAs 或 ILK shRNAs 也会降低 NET 诱导的成纤维细胞增殖和迁移能力。这项研究表明，低浓度的NET与CCDC25结合后，会激活皮肤成纤维细胞中的ILK/PI3K/AKT信号通路，导致细胞增殖和迁移活性增强。
{"title":"Neutrophil extracellular traps with low concentrations induce proliferation and migration of human fibroblasts via activating CCDC25/ILK/PI3K/AKT pathway","authors":"Ziqiang Chu , Ye Zheng , Qi Shen , Keli Yang , Hui Wang , Kui Ma , Yaying Hao , Junli Chen , Haihong Li , Xiaobing Fu , Cuiping Zhang","doi":"10.1016/j.bbrc.2024.150954","DOIUrl":"10.1016/j.bbrc.2024.150954","url":null,"abstract":"<div><div>Neutrophil plays an important role in the early stage of wound healing. Excessive neutrophil extracellular traps (NETs) which are produced by neutrophil have been proved as a significant unfavorable factor for wound healing by impairing the function of human skin fibroblasts. However, the effect of NETs with low concentrations on fibroblasts remains unclear. The interaction between CCDC25 and ILK in fibroblast were found to be activated by NET-DNA with low concentrations. Additionally, phosphorylation of PI3K and AKT was increased in NET-stimulated fibroblasts but was inhibited by CCDC25 knockout or ILK knockdown. NETs-induces proliferation and migration ability of fibroblast were also reduced by application of CCDC25 sgRNAs or ILK shRNAs. This study demonstrates that low concentrations of NETs, upon biding with CCDC25, activates the ILK/PI3K/AKT signaling pathway in skin fibroblasts, leading to increased cell proliferation and migration activity.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"738 ","pages":"Article 150954"},"PeriodicalIF":2.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The emergence of new influenza virus strains presents a continuous challenge for global public health. mRNA technology offers a promising platform for rapidly developing therapeutics, particularly monoclonal antibodies, that can protect against viral infections. In this study, we engineered mRNA constructs encoding two types of antibodies: secreted antibodies specific to the hemagglutinin of the influenza A virus, based on previously characterized Fi6 antibodies, and intracellular Fab fragments targeting the nucleoprotein of the influenza B virus, derived from the 2/3 antibodies. The administration of mRNA constructs in vitro resulted in the successful synthesis of functional antibodies, which exhibited antiviral activity against influenza viruses. This study confirms the feasibility of using mRNA technology to develop therapeutic antibodies against influenza virus infections. The findings pave the way for future clinical applications of mRNA-based therapeutics, enhancing preparedness for emerging viral threats.
{"title":"mRNA encoding antibodies against hemagglutinin and nucleoprotein prevents influenza virus infection in vitro","authors":"Y.A. Zabrodskaya , N.V. Gavrilova , E.A. Elpaeva , A.A. Lozhkov , V.V. Vysochinskaya , O.A. Dobrovolskaya , O.V. Dovbysh , E.L. Zimmerman , P.N. Dav , A.V. Brodskaia , E.I. Sakhenberg , A.A. Shaldzhyan , A.A. Demaev , M.A. Maslov , A.V. Vasin","doi":"10.1016/j.bbrc.2024.150945","DOIUrl":"10.1016/j.bbrc.2024.150945","url":null,"abstract":"<div><div>The emergence of new influenza virus strains presents a continuous challenge for global public health. mRNA technology offers a promising platform for rapidly developing therapeutics, particularly monoclonal antibodies, that can protect against viral infections. In this study, we engineered mRNA constructs encoding two types of antibodies: secreted antibodies specific to the hemagglutinin of the influenza A virus, based on previously characterized Fi6 antibodies, and intracellular Fab fragments targeting the nucleoprotein of the influenza B virus, derived from the 2/3 antibodies. The administration of mRNA constructs <em>in vitro</em> resulted in the successful synthesis of functional antibodies, which exhibited antiviral activity against influenza viruses. This study confirms the feasibility of using mRNA technology to develop therapeutic antibodies against influenza virus infections. The findings pave the way for future clinical applications of mRNA-based therapeutics, enhancing preparedness for emerging viral threats.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"738 ","pages":"Article 150945"},"PeriodicalIF":2.5,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-02DOI: 10.1016/j.bbrc.2024.150943
Jyotika Rajawat , Monisha Banerjee
Cervical cancer affects more than half a million women and treatment options for advanced disease and recurrence is limited. Poly (ADP-ribose) polymerase1 (PARP1) is a critical nuclear protein regulating several components and functions of cellular machinery, including cancer. PARP1 expression and activity plays a crucial dynamics in the tumor microenvironment. PARP inhibitors are being considered as a viable option for treating BRCA deficient ovarian and breast cancer patients. However, the role of PARP1 in cervical cancer tumorigenesis is less known. The aim of the present review is to provide a comprehensive insight about the role of PARP1 in cervical cancer pathogenesis in context to PARP1 expression as a molecular marker for identifying cancer and in predicting treatment response and prognosis. PARP1 expression is found to be elevated in cervical cancer tissues in comparison to that in the normal surrounding tissues. The cellular proteins linked with PARP1 have been described along with the association of SNPs in PARP1 gene with cervical cancer. Promising results of PARP inhibitors with immunotherapy and clinical trials with cisplatin have also been discussed. This review provides an up-to-date description of PARP1 expression, its role in cervical cancer pathogenesis and reported clinical trials of PARP inhibitors in adjuvant therapy.
{"title":"Poly(ADP-ribose) polymerase1 (PARP1) and PARP inhibitors: New frontiers in cervical cancer","authors":"Jyotika Rajawat , Monisha Banerjee","doi":"10.1016/j.bbrc.2024.150943","DOIUrl":"10.1016/j.bbrc.2024.150943","url":null,"abstract":"<div><div>Cervical cancer affects more than half a million women and treatment options for advanced disease and recurrence is limited. Poly (ADP-ribose) polymerase1 (PARP1) is a critical nuclear protein regulating several components and functions of cellular machinery, including cancer. PARP1 expression and activity plays a crucial dynamics in the tumor microenvironment. PARP inhibitors are being considered as a viable option for treating BRCA deficient ovarian and breast cancer patients. However, the role of PARP1 in cervical cancer tumorigenesis is less known. The aim of the present review is to provide a comprehensive insight about the role of PARP1 in cervical cancer pathogenesis in context to PARP1 expression as a molecular marker for identifying cancer and in predicting treatment response and prognosis. PARP1 expression is found to be elevated in cervical cancer tissues in comparison to that in the normal surrounding tissues. The cellular proteins linked with PARP1 have been described along with the association of SNPs in PARP1 gene with cervical cancer. Promising results of PARP inhibitors with immunotherapy and clinical trials with cisplatin have also been discussed. This review provides an up-to-date description of PARP1 expression, its role in cervical cancer pathogenesis and reported clinical trials of PARP inhibitors in adjuvant therapy.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"738 ","pages":"Article 150943"},"PeriodicalIF":2.5,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-02DOI: 10.1016/j.bbrc.2024.150942
Chuandong Jiang , Yangyang Li , Ran Wang , Xiao Sun , Yan Zhang , Qiang Zhang
Genome editing technologies hold significant potential for targeted mutagenesis in crop development, aligning with evolving agricultural needs. Point mutations, or single nucleotide polymorphisms (SNPs), define key agronomic traits in various crop species and play a pivotal role. The implementation of single nucleotide variations through genome editing-based base editing offers substantial promise in expediting crop improvement by inducing advantageous trait variations. Among many genome editing techniques, base editing stands out as an advanced next-generation technology, evolved from the CRISPR/Cas9 system.Base editing, a recent advancement in genome editing, enables precise DNA modification without the risks associated with double-strand breaks. Base editors, designed as precise genome editing tools, enable the direct and irreversible conversion of specific target bases. Base editors consist of catalytically active CRISPR-Cas9 domains, including Cas9 variants, fused with domains like cytidine deaminase, adenine deaminase, or reverse transcriptase. These fusion proteins enable the introduction of specific point mutations in target genomic regions. Currently developed are cytidine base editors (CBEs), mutating C to T; adenine base editors (ABEs), changing A to G; and prime editors (PEs), enabling arbitrary base conversions, precise insertions, and deletions. In this review, the research, development, and progress of various base editing systems, along with their potential applications in crop improvement, were intended to be summarized. The limitations of this technology will also be discussed. Finally, an outlook on the future of base editors will be provided.
基因组编辑技术在作物开发的定向诱变方面具有巨大潜力，符合不断发展的农业需求。点突变或单核苷酸多态性（SNP）决定了各种作物的关键农艺性状，并发挥着举足轻重的作用。通过以基因组编辑为基础的碱基编辑实现单核苷酸变异，为通过诱导优势性状变异加快作物改良带来了巨大希望。在众多基因组编辑技术中，碱基编辑技术脱颖而出，成为从 CRISPR/Cas9 系统演化而来的先进的新一代技术。碱基编辑是基因组编辑领域的最新进展，它可以实现精确的 DNA 修饰，而不会有双链断裂带来的风险。碱基编辑器被设计为精确的基因组编辑工具，可直接对特定目标碱基进行不可逆的转换。碱基编辑器由具有催化活性的CRISPR-Cas9结构域（包括Cas9变体）与胞苷脱氨酶、腺嘌呤脱氨酶或反转录酶等结构域融合而成。这些融合蛋白可以在目标基因组区域引入特定的点突变。目前开发的有可将 C 突变为 T 的胞苷碱基编辑器（CBEs）、将 A 变为 G 的腺嘌呤碱基编辑器（ABEs）和可实现任意碱基转换、精确插入和删除的质粒编辑器（PEs）。本综述旨在总结各种碱基编辑系统的研究、开发和进展及其在作物改良中的潜在应用。此外，还将讨论这项技术的局限性。最后，还将对碱基编辑器的未来进行展望。
{"title":"Development and optimization of base editors and its application in crops","authors":"Chuandong Jiang , Yangyang Li , Ran Wang , Xiao Sun , Yan Zhang , Qiang Zhang","doi":"10.1016/j.bbrc.2024.150942","DOIUrl":"10.1016/j.bbrc.2024.150942","url":null,"abstract":"<div><div>Genome editing technologies hold significant potential for targeted mutagenesis in crop development, aligning with evolving agricultural needs. Point mutations, or single nucleotide polymorphisms (SNPs), define key agronomic traits in various crop species and play a pivotal role. The implementation of single nucleotide variations through genome editing-based base editing offers substantial promise in expediting crop improvement by inducing advantageous trait variations. Among many genome editing techniques, base editing stands out as an advanced next-generation technology, evolved from the CRISPR/Cas9 system.Base editing, a recent advancement in genome editing, enables precise DNA modification without the risks associated with double-strand breaks. Base editors, designed as precise genome editing tools, enable the direct and irreversible conversion of specific target bases. Base editors consist of catalytically active CRISPR-Cas9 domains, including Cas9 variants, fused with domains like cytidine deaminase, adenine deaminase, or reverse transcriptase. These fusion proteins enable the introduction of specific point mutations in target genomic regions. Currently developed are cytidine base editors (CBEs), mutating C to T; adenine base editors (ABEs), changing A to G; and prime editors (PEs), enabling arbitrary base conversions, precise insertions, and deletions. In this review, the research, development, and progress of various base editing systems, along with their potential applications in crop improvement, were intended to be summarized. The limitations of this technology will also be discussed. Finally, an outlook on the future of base editors will be provided.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"739 ","pages":"Article 150942"},"PeriodicalIF":2.5,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liver fibrosis, an abnormal accumulation of collagen fibers in the liver, is caused due to several chronic liver diseases including viral hepatitis, alcoholic steatohepatitis, and metabolic dysfunction-associated steatohepatitis. Among the various symptoms of chronic hepatitis, liver fibrosis is the most crucial factor in determining patient prognosis. Extensive liver fibrosis leads to cirrhosis and liver cancer and shortens the lifespans of patients. However, no drug is currently approved for the treatment of liver fibrosis. Therefore, the identification of molecular mechanisms and druggable targets of liver fibrosis is urgently needed. Interleukin-11 is a member of the interleukin-6 family of inflammatory cytokines that is involved in multiple processes of inflammation and tissue repair. Recent reports also suggest the pro-fibrogenic function of interleukin-11 in various organs. In this study, we examined the fibrogenic potential of interleukin-11 in the liver using a choline-deficient, amino acid-defined high-fat diet, a mouse model of metabolic dysfunction-associated steatohepatitis that rapidly develops liver fibrosis. Although interleukin-11 was specifically upregulated in the liver in this pathological model, the loss of interleukin-11 signaling played minor roles in liver injury, inflammation, fibrosis, and signal transduction pathways. Our results indicate that the pro-fibrogenic function of interleukin-11 may vary among organs and disease etiologies.
{"title":"Interleukin-11 signaling plays limited roles for liver fibrosis in a mouse model of metabolic dysfunction-associated steatohepatitis","authors":"Yuichi Tsuchiya , Takashi Nishina , Sachiko Komazawa-Sakon , Takao Seki , Tetuo Mikami , Hiroyasu Nakano","doi":"10.1016/j.bbrc.2024.150938","DOIUrl":"10.1016/j.bbrc.2024.150938","url":null,"abstract":"<div><div>Liver fibrosis, an abnormal accumulation of collagen fibers in the liver, is caused due to several chronic liver diseases including viral hepatitis, alcoholic steatohepatitis, and metabolic dysfunction-associated steatohepatitis. Among the various symptoms of chronic hepatitis, liver fibrosis is the most crucial factor in determining patient prognosis. Extensive liver fibrosis leads to cirrhosis and liver cancer and shortens the lifespans of patients. However, no drug is currently approved for the treatment of liver fibrosis. Therefore, the identification of molecular mechanisms and druggable targets of liver fibrosis is urgently needed. Interleukin-11 is a member of the interleukin-6 family of inflammatory cytokines that is involved in multiple processes of inflammation and tissue repair. Recent reports also suggest the pro-fibrogenic function of interleukin-11 in various organs. In this study, we examined the fibrogenic potential of interleukin-11 in the liver using a choline-deficient, amino acid-defined high-fat diet, a mouse model of metabolic dysfunction-associated steatohepatitis that rapidly develops liver fibrosis. Although interleukin-11 was specifically upregulated in the liver in this pathological model, the loss of interleukin-11 signaling played minor roles in liver injury, inflammation, fibrosis, and signal transduction pathways. Our results indicate that the pro-fibrogenic function of interleukin-11 may vary among organs and disease etiologies.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"739 ","pages":"Article 150938"},"PeriodicalIF":2.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.bbrc.2024.150935
Panayiota Markou , Constantine Garagounis , Dionysia A. Fasoula , Ioannis M. Ioannides , Michalis Omirou , Kalliope K. Papadopoulou
Oxidosqualene cyclases (OSCs) are important regulatory enzymes involved in cyclization reactions of 2, 3-oxidosqualene to form triterpenes and sterols. This study presents the identification and characterization of three OSC genes, a β – amyrin synthase (VuβAS), a lupeol synthase (VuLUS) and a cycloartenol synthase (VuCAS) in Vigna unguiculata, an edible leguminous plant with high nutritional and nutraceutical value. Phylogenetic analysis showed that the VuβAS, VuLUS and VuCAS were clustered within the clades of previously characterized β – amyrin synthases, lupeol synthases and cycloartenol synthases. Heterologous expression in Saccharomyces cerevisiae and Gas Chromatography – Mass Spectrometry (GC – MS) analysis in different plant stages confirmed their specific functions. VuβAS showed higher expression in roots from early germinating seedlings to older plants (4-day to 28-day), while VuLUS expression levels were higher in the roots of older plants only (14-day to 28-day). VuCAS expression was increased in all the tissues of 4-day seedlings, with a peak in stem and leaves and a lower accumulation in radicles. These findings revealed the presence and function of OSC genes in V. unguiculata, and future research could lead to the discovery of promising biologically active compounds.
{"title":"Identification, functional characterization and expression profiling of three triterpene synthases from the legume plant Vigna unguiculata","authors":"Panayiota Markou , Constantine Garagounis , Dionysia A. Fasoula , Ioannis M. Ioannides , Michalis Omirou , Kalliope K. Papadopoulou","doi":"10.1016/j.bbrc.2024.150935","DOIUrl":"10.1016/j.bbrc.2024.150935","url":null,"abstract":"<div><div>Oxidosqualene cyclases (OSCs) are important regulatory enzymes involved in cyclization reactions of 2, 3-oxidosqualene to form triterpenes and sterols. This study presents the identification and characterization of three OSC genes, a β – amyrin synthase (<em>Vu</em>βAS), a lupeol synthase (<em>Vu</em>LUS) and a cycloartenol synthase (<em>Vu</em>CAS) in <em>Vigna unguiculata,</em> an edible leguminous plant with high nutritional and nutraceutical value. Phylogenetic analysis showed that the <em>Vu</em>βAS, <em>Vu</em>LUS and <em>Vu</em>CAS were clustered within the clades of previously characterized β – amyrin synthases, lupeol synthases and cycloartenol synthases. Heterologous expression in <em>Saccharomyces cerevisiae</em> and Gas Chromatography – Mass Spectrometry (GC – MS) analysis in different plant stages confirmed their specific functions. <em>Vu</em>βAS showed higher expression in roots from early germinating seedlings to older plants (4-day to 28-day), while <em>Vu</em>LUS expression levels were higher in the roots of older plants only (14-day to 28-day). <em>Vu</em>CAS expression was increased in all the tissues of 4-day seedlings, with a peak in stem and leaves and a lower accumulation in radicles. These findings revealed the presence and function of OSC genes in <em>V. unguiculata</em>, and future research could lead to the discovery of promising biologically active compounds.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"738 ","pages":"Article 150935"},"PeriodicalIF":2.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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