Chuanchuan Lin, Yang Xiang, Yangyang Zhang, Zhenxing Yang, Nanxi Chen, Weiwei Zhang, Lanyue Hu, Jianxin Chen, Ya Luo, Xueying Wang, Yanni Xiao, Qing Zhang, Xi Ran, Li Chen, Jigang Dai, Zhongjun Li, Qian Ran
The continuous production of mature blood cell lineages is maintained by hematopoietic stem cells but they are highly susceptible to damage by ionizing radiation (IR) that induces death. Thus, devising therapeutic strategies that can mitigate hematopoietic toxicity caused by IR would benefit acute radiation syndrome (ARS) victims and patients receiving radiotherapy. Herein, we describe the preparation of an injectable hydrogel formulation based on Arg-Gly-Asp-alginate (RGD-Alg) and Laponite using a simple mixing method that ensured a slow and sustained release of interleukin-12 (IL-12) (RGD-Alg/Laponite@IL-12). The local administration of RGD-Alg/Laponite@IL-12 increased survival rates and promoted the hematopoietic recovery of mice who had received sublethal-dose irradiation. Local intra-bone marrow (intra-BM) injection of RGD-Alg/Laponite@IL-12 hydrogel effectively stimulated IL12 receptor-phosphoinositide 3-kinase/protein kinase B (IL-12R-PI3K/AKT) signaling axis, which promoted proliferation and hematopoietic growth factors secretion of BM mesenchymal stem/stromal cells. This signaling axis facilitates the repair of the hematopoietic microenvironment and plays a pivotal role in hematopoietic reconstitution. In conclusion, we describe a biomaterial-sustained release of IL-12 for the treatment of irradiated hematopoietic injury and provide a new therapeutic strategy for hematopoietic ARS.
造血干细胞维持着成熟血细胞系的持续生成,但它们极易受到电离辐射(IR)的损害而导致死亡。因此,制定可减轻电离辐射造成的造血毒性的治疗策略将有益于急性辐射综合征(ARS)患者和接受放疗的病人。在此,我们介绍了一种基于精氨酸-甘氨酰-天冬氨酸(RGD-Alg)和皂石的可注射水凝胶制剂,该制剂采用简单的混合方法,可确保白细胞介素-12(IL-12)的缓慢持续释放(RGD-Alg/Laponite@IL-12)。局部注射RGD-Alg/Laponite@IL-12可提高接受亚致死剂量照射的小鼠的存活率并促进其造血功能的恢复。局部骨髓内注射RGD-Alg/Laponite@IL-12水凝胶能有效刺激IL12受体-磷脂肌醇3激酶/蛋白激酶B(IL-12R-PI3K/AKT)信号轴,促进骨髓间充质干细胞/基质细胞的增殖和造血生长因子的分泌。这一信号轴促进了造血微环境的修复,并在造血重建中发挥了关键作用。总之,我们描述了一种生物材料持续释放 IL-12 治疗辐照造血损伤的方法,为造血 ARS 提供了一种新的治疗策略。
{"title":"Interleukin-12 sustained release system promotes hematopoietic recovery after radiation injury","authors":"Chuanchuan Lin, Yang Xiang, Yangyang Zhang, Zhenxing Yang, Nanxi Chen, Weiwei Zhang, Lanyue Hu, Jianxin Chen, Ya Luo, Xueying Wang, Yanni Xiao, Qing Zhang, Xi Ran, Li Chen, Jigang Dai, Zhongjun Li, Qian Ran","doi":"10.1002/mco2.704","DOIUrl":"https://doi.org/10.1002/mco2.704","url":null,"abstract":"<p>The continuous production of mature blood cell lineages is maintained by hematopoietic stem cells but they are highly susceptible to damage by ionizing radiation (IR) that induces death. Thus, devising therapeutic strategies that can mitigate hematopoietic toxicity caused by IR would benefit acute radiation syndrome (ARS) victims and patients receiving radiotherapy. Herein, we describe the preparation of an injectable hydrogel formulation based on Arg-Gly-Asp-alginate (RGD-Alg) and Laponite using a simple mixing method that ensured a slow and sustained release of interleukin-12 (IL-12) (RGD-Alg/Laponite@IL-12). The local administration of RGD-Alg/Laponite@IL-12 increased survival rates and promoted the hematopoietic recovery of mice who had received sublethal-dose irradiation. Local intra-bone marrow (intra-BM) injection of RGD-Alg/Laponite@IL-12 hydrogel effectively stimulated IL12 receptor-phosphoinositide 3-kinase/protein kinase B (IL-12R-PI3K/AKT) signaling axis, which promoted proliferation and hematopoietic growth factors secretion of BM mesenchymal stem/stromal cells. This signaling axis facilitates the repair of the hematopoietic microenvironment and plays a pivotal role in hematopoietic reconstitution. In conclusion, we describe a biomaterial-sustained release of IL-12 for the treatment of irradiated hematopoietic injury and provide a new therapeutic strategy for hematopoietic ARS.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.704","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174288","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}
Wenbiao Chen, Huixuan Xu, Liliangzi Guo, Fengping Zheng, Jun Yao, Lisheng Wang
The intricate relationship between bile acid (BA) metabolism, M2 macrophage polarization, and hepatitis B virus-hepatocellular carcinoma (HBV-HCC) necessitates a thorough investigation of ACSL4's (acyl-CoA synthetase long-chain family member 4) role. This study combines advanced bioinformatics and experimental methods to elucidate ACSL4's significance in HBV-HCC development. Using bioinformatics, we identified differentially expressed genes in HBV-HCC. STRING and gene set enrichment analysis analyses were employed to pinpoint critical genes and pathways. Immunoinfiltration analysis, along with in vitro and in vivo experiments, assessed M2 macrophage polarization and related factors. ACSL4 emerged as a pivotal gene influencing HBV-HCC. In HBV-HCC liver tissues, ACSL4 exhibited upregulation, along with increased levels of M2 macrophage markers and BA. Silencing ACSL4 led to heightened farnesoid X receptor (FXR) expression, reduced BA levels, and hindered M2 macrophage polarization, thereby improving HBV-HCC conditions. This study underscores ACSL4's significant role in HBV-HCC progression. ACSL4 modulates BA-mediated M2 macrophage polarization and FXR expression, shedding light on potential therapeutic targets and novel insights into HBV-HCC pathogenesis.
{"title":"Role of ACSL4 in modulating farnesoid X receptor expression and M2 macrophage polarization in HBV-induced hepatocellular carcinoma","authors":"Wenbiao Chen, Huixuan Xu, Liliangzi Guo, Fengping Zheng, Jun Yao, Lisheng Wang","doi":"10.1002/mco2.706","DOIUrl":"https://doi.org/10.1002/mco2.706","url":null,"abstract":"<p>The intricate relationship between bile acid (BA) metabolism, M2 macrophage polarization, and hepatitis B virus-hepatocellular carcinoma (HBV-HCC) necessitates a thorough investigation of ACSL4's (acyl-CoA synthetase long-chain family member 4) role. This study combines advanced bioinformatics and experimental methods to elucidate ACSL4's significance in HBV-HCC development. Using bioinformatics, we identified differentially expressed genes in HBV-HCC. STRING and gene set enrichment analysis analyses were employed to pinpoint critical genes and pathways. Immunoinfiltration analysis, along with in vitro and in vivo experiments, assessed M2 macrophage polarization and related factors. ACSL4 emerged as a pivotal gene influencing HBV-HCC. In HBV-HCC liver tissues, ACSL4 exhibited upregulation, along with increased levels of M2 macrophage markers and BA. Silencing ACSL4 led to heightened farnesoid X receptor (FXR) expression, reduced BA levels, and hindered M2 macrophage polarization, thereby improving HBV-HCC conditions. This study underscores ACSL4's significant role in HBV-HCC progression. ACSL4 modulates BA-mediated M2 macrophage polarization and FXR expression, shedding light on potential therapeutic targets and novel insights into HBV-HCC pathogenesis.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.706","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174289","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}
Adenoid cystic carcinoma (ACC) is a malignant tumor primarily originating from the salivary glands, capable of affecting multiple organs. Although ACC typically exhibits slow growth, it is notorious for its propensity for neural invasion, local recurrence, and distant metastasis, making it a particularly challenging cancer to treat. The complexity of ACC's histological and molecular features poses significant challenges to current treatment modalities, which often show limited effectiveness. Recent advancements in single-cell RNA-sequencing (scRNA-seq) have begun to unravel unprecedented insights into the heterogeneity and subpopulation diversity within ACC, revealing distinct cellular phenotypes and origins. This review delves into the intricate pathological and molecular characteristics of ACC, focusing on recent therapeutic advancements. We particularly emphasize the insights gained from scRNA-seq studies that shed light on the cellular landscape of ACC, underscoring its heterogeneity and pathobiology. Moreover, by integrating analyses from public databases, this review proposes novel perspectives for advancing treatment strategies in ACC. This review contributes to the academic understanding of ACC by proposing novel therapeutic approaches informed by cutting-edge molecular insights, paving the way for more effective, personalized therapeutic approaches for this challenging malignancy.
{"title":"Adenoid cystic carcinoma: insights from molecular characterization and therapeutic advances","authors":"Yunxuan Jia, Yupeng Liu, Haitang Yang, Feng Yao","doi":"10.1002/mco2.734","DOIUrl":"https://doi.org/10.1002/mco2.734","url":null,"abstract":"<p>Adenoid cystic carcinoma (ACC) is a malignant tumor primarily originating from the salivary glands, capable of affecting multiple organs. Although ACC typically exhibits slow growth, it is notorious for its propensity for neural invasion, local recurrence, and distant metastasis, making it a particularly challenging cancer to treat. The complexity of ACC's histological and molecular features poses significant challenges to current treatment modalities, which often show limited effectiveness. Recent advancements in single-cell RNA-sequencing (scRNA-seq) have begun to unravel unprecedented insights into the heterogeneity and subpopulation diversity within ACC, revealing distinct cellular phenotypes and origins. This review delves into the intricate pathological and molecular characteristics of ACC, focusing on recent therapeutic advancements. We particularly emphasize the insights gained from scRNA-seq studies that shed light on the cellular landscape of ACC, underscoring its heterogeneity and pathobiology. Moreover, by integrating analyses from public databases, this review proposes novel perspectives for advancing treatment strategies in ACC. This review contributes to the academic understanding of ACC by proposing novel therapeutic approaches informed by cutting-edge molecular insights, paving the way for more effective, personalized therapeutic approaches for this challenging malignancy.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.734","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170199","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}
Di He, Xinyi He, Dongchao Shen, Liyang Liu, Xunzhe Yang, Meng Hao, Yi Wang, Yi Li, Qing Liu, Mingsheng Liu, Jiucun Wang, Xue Zhang, Liying Cui
Despite being one of the most prevalent RNA modifications, the role of N6-methyladenosine (m6A) in amyotrophic lateral sclerosis (ALS) remains ambiguous. In this investigation, we explore the contribution of genetic defects of m6A-related genes to ALS pathogenesis. We scrutinized the mutation landscape of m6A genes through a comprehensive analysis of whole-exome sequencing cohorts, encompassing 508 ALS patients and 1660 population-matched controls. Our findings reveal a noteworthy enrichment of RNA binding motif protein X-linked (RBMX) variants among ALS patients, with a significant correlation between pathogenic m6A variants and adverse clinical outcomes. Furthermore, Rbmx knockdown in NSC-34 cells overexpressing mutant TDP43Q331K results in cell death mediated by an augmented p53 response. Similarly, RBMX knockdown in ALS motor neurons derived from induced pluripotent stem cells (iPSCs) manifests morphological defects and activation of the p53 pathway. Transcriptional analysis using publicly available single-cell sequencing data from the primary motor cortex indicates that RBMX-regulated genes selectively influence excitatory neurons and exhibit enrichment in ALS-implicated pathways. Through integrated analyses, our study underscores the emerging roles played by RBMX in ALS, suggesting a potential nexus between the disease and dysregulated m6A-mediated mRNA metabolism.
尽管N6-甲基腺苷(m6A)是最常见的RNA修饰之一,但它在肌萎缩性脊髓侧索硬化症(ALS)中的作用仍不明确。在这项研究中,我们探讨了 m6A 相关基因的遗传缺陷对 ALS 发病机制的贡献。我们通过对 508 例 ALS 患者和 1660 例人群匹配对照的全外显子组测序队列进行全面分析,仔细研究了 m6A 基因的突变情况。我们的研究结果表明,在 ALS 患者中,RNA 结合基调蛋白 X-连锁(RBMX)变异显著增高,致病性 m6A 变异与不良临床结果之间存在显著相关性。此外,在过表达突变型 TDP43Q331K 的 NSC-34 细胞中敲除 Rbmx 会导致细胞因 p53 反应增强而死亡。同样,在由诱导多能干细胞(iPSCs)衍生的 ALS 运动神经元中敲除 RBMX 会导致形态学缺陷和 p53 通路的激活。利用公开的初级运动皮层单细胞测序数据进行的转录分析表明,RBMX调控的基因选择性地影响兴奋性神经元,并在ALS相关通路中表现出富集。通过综合分析,我们的研究强调了 RBMX 在 ALS 中扮演的新角色,表明这种疾病与 m6A 介导的 mRNA 代谢失调之间存在潜在联系。
{"title":"Loss-of-function variants in RNA binding motif protein X-linked induce neuronal defects contributing to amyotrophic lateral sclerosis pathogenesis","authors":"Di He, Xinyi He, Dongchao Shen, Liyang Liu, Xunzhe Yang, Meng Hao, Yi Wang, Yi Li, Qing Liu, Mingsheng Liu, Jiucun Wang, Xue Zhang, Liying Cui","doi":"10.1002/mco2.712","DOIUrl":"https://doi.org/10.1002/mco2.712","url":null,"abstract":"<p>Despite being one of the most prevalent RNA modifications, the role of N6-methyladenosine (m6A) in amyotrophic lateral sclerosis (ALS) remains ambiguous. In this investigation, we explore the contribution of genetic defects of m6A-related genes to ALS pathogenesis. We scrutinized the mutation landscape of m6A genes through a comprehensive analysis of whole-exome sequencing cohorts, encompassing 508 ALS patients and 1660 population-matched controls. Our findings reveal a noteworthy enrichment of RNA binding motif protein X-linked (<i>RBMX</i>) variants among ALS patients, with a significant correlation between pathogenic m6A variants and adverse clinical outcomes. Furthermore, <i>Rbmx</i> knockdown in NSC-34 cells overexpressing mutant TDP43<sup>Q331K</sup> results in cell death mediated by an augmented p53 response. Similarly, <i>RBMX</i> knockdown in ALS motor neurons derived from induced pluripotent stem cells (iPSCs) manifests morphological defects and activation of the p53 pathway. Transcriptional analysis using publicly available single-cell sequencing data from the primary motor cortex indicates that RBMX-regulated genes selectively influence excitatory neurons and exhibit enrichment in ALS-implicated pathways. Through integrated analyses, our study underscores the emerging roles played by <i>RBMX</i> in ALS, suggesting a potential nexus between the disease and dysregulated m6A-mediated mRNA metabolism.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.712","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142169853","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}
Yanqi Dai, Merve Gultekinoglu, Cem Bayram, Hettiyahandi Binodh De Silva, Mohan Edirisinghe
<p>Dear Editor,</p><p>Alginate (Alg) is of particular interest as a natural biomaterial due to its unique gelling properties and water absorption capacity. Despite these advantages, the transformation of Alg into commercially value-added products still faces many challenges.<span><sup>1</sup></span> Our recent study investigates an advanced spinning technology for the facile and large-scale production of small-structure Alg antibacterial natural patches incorporated with Ceylon cinnamon.</p><p>In this work, nozzle-pressurized spinning (NPS)<span><sup>2</sup></span> functioned as a jet generation apparatus (Figure S1) spinning Na-Alg jets into a Ca<sup>2+</sup>-riched coagulation bath. Ca<sup>2+</sup> combined with Alg chains in the cross-linked “egg-box” model to form Alg fibers. Na-Alg solutions were generally significantly viscous even at a relatively low concentration (< 5 wt%), exhibiting a pronounced solid-like behavior. The high pressure applied in NPS effectively mitigates these viscous effects, facilitating Na-Alg jet formation. Additionally, given the significant production efficiency of NPS, this strategy stands out as a promising approach for the scaling up of Alg fiber production, compared with prevailing methods like electrospinning and wet spinning.</p><p>Figure 1A illustrates a marked alteration in the morphology of the obtained Alg products correlating with changes in Na-Alg/H<sub>2</sub>O solution concentration in NPS. As the concentration increased, the Alg morphology evolved from a thin film to a ribbon-like structure, ultimately obtaining a filamentous form at the concentration of 3.0 wt%. The rapid increase of solution viscosity with its increasing concentration is a remarkable feature of Na-Alg/H<sub>2</sub>O solution, accompanied by a significant reduction in its fluidity.<span><sup>3</sup></span> Thereby, the morphology of the resulting Alg products varied. Meeting the critical rheological properties is the key to producing Alg fibers with well-defined filamentous structures (Figure 1A). Weighing the synergistic effect of solution properties and system parameters, we successfully produced Alg fibers with an average diameter of 10 µm using 3.2 wt% Na-Alg/H<sub>2</sub>O solution.</p><p>Following the established correlation between Alg products and solution properties/processing parameters, Ceylon cinnamon (grounded cinnamon, GC; supplied by HDDES Extracts [PVT] Ltd) was incorporated into Alg fibers using NPS to generate Alg-GC fibrous patches, with weight ratios of GC of 1%, 2%, and 4% (Alg-GC1, Alg-GC2, and, Alg-GC4). The potential of the resulting Alg-GC fibrous patches as a biomaterial candidate was evaluated in terms of in-vitro cell viability and antibacterial properties.</p><p>Indirect cytotoxicity tests of pure Alg fibers and Alg-GC patches were performed by WST-1 assay according to ISO10993-5 standard for medical devices.<span><sup>4</sup></span> The results proved that Alg is a biocompatible biomaterial and fibro
{"title":"Antibacterial properties of natural cinnamon-alginate fibrous patches produced by modified nozzle-pressurized spinning","authors":"Yanqi Dai, Merve Gultekinoglu, Cem Bayram, Hettiyahandi Binodh De Silva, Mohan Edirisinghe","doi":"10.1002/mco2.731","DOIUrl":"https://doi.org/10.1002/mco2.731","url":null,"abstract":"<p>Dear Editor,</p><p>Alginate (Alg) is of particular interest as a natural biomaterial due to its unique gelling properties and water absorption capacity. Despite these advantages, the transformation of Alg into commercially value-added products still faces many challenges.<span><sup>1</sup></span> Our recent study investigates an advanced spinning technology for the facile and large-scale production of small-structure Alg antibacterial natural patches incorporated with Ceylon cinnamon.</p><p>In this work, nozzle-pressurized spinning (NPS)<span><sup>2</sup></span> functioned as a jet generation apparatus (Figure S1) spinning Na-Alg jets into a Ca<sup>2+</sup>-riched coagulation bath. Ca<sup>2+</sup> combined with Alg chains in the cross-linked “egg-box” model to form Alg fibers. Na-Alg solutions were generally significantly viscous even at a relatively low concentration (< 5 wt%), exhibiting a pronounced solid-like behavior. The high pressure applied in NPS effectively mitigates these viscous effects, facilitating Na-Alg jet formation. Additionally, given the significant production efficiency of NPS, this strategy stands out as a promising approach for the scaling up of Alg fiber production, compared with prevailing methods like electrospinning and wet spinning.</p><p>Figure 1A illustrates a marked alteration in the morphology of the obtained Alg products correlating with changes in Na-Alg/H<sub>2</sub>O solution concentration in NPS. As the concentration increased, the Alg morphology evolved from a thin film to a ribbon-like structure, ultimately obtaining a filamentous form at the concentration of 3.0 wt%. The rapid increase of solution viscosity with its increasing concentration is a remarkable feature of Na-Alg/H<sub>2</sub>O solution, accompanied by a significant reduction in its fluidity.<span><sup>3</sup></span> Thereby, the morphology of the resulting Alg products varied. Meeting the critical rheological properties is the key to producing Alg fibers with well-defined filamentous structures (Figure 1A). Weighing the synergistic effect of solution properties and system parameters, we successfully produced Alg fibers with an average diameter of 10 µm using 3.2 wt% Na-Alg/H<sub>2</sub>O solution.</p><p>Following the established correlation between Alg products and solution properties/processing parameters, Ceylon cinnamon (grounded cinnamon, GC; supplied by HDDES Extracts [PVT] Ltd) was incorporated into Alg fibers using NPS to generate Alg-GC fibrous patches, with weight ratios of GC of 1%, 2%, and 4% (Alg-GC1, Alg-GC2, and, Alg-GC4). The potential of the resulting Alg-GC fibrous patches as a biomaterial candidate was evaluated in terms of in-vitro cell viability and antibacterial properties.</p><p>Indirect cytotoxicity tests of pure Alg fibers and Alg-GC patches were performed by WST-1 assay according to ISO10993-5 standard for medical devices.<span><sup>4</sup></span> The results proved that Alg is a biocompatible biomaterial and fibro","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.731","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142169854","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}
Krüppel-like factors (KLFs) are a family of basic transcription factors with three conserved Cys2/His2 zinc finger domains located in their C-terminal regions. It is acknowledged that KLFs exert complicated effects on cell proliferation, differentiation, survival, and responses to stimuli. Dysregulation of KLFs is associated with a range of diseases including cardiovascular disorders, metabolic diseases, autoimmune conditions, cancer, and neurodegenerative diseases. Their multidimensional roles in modulating critical pathways underscore the significance in both physiological and pathological contexts. Recent research also emphasizes their crucial involvement and complex interplay in the skeletal system. Despite the substantial progress in understanding KLFs and their roles in various cellular processes, several research gaps remain. Here, we elucidated the multifaceted capabilities of KLFs on body health and diseases via various compliable signaling pathways. The associations between KLFs and cellular energy metabolism and epigenetic modification during bone reconstruction have also been summarized. This review helps us better understand the coupling effects and their pivotal functions in multiple systems and detailed mechanisms of bone remodeling and develop potential therapeutic strategies for the clinical treatment of pathological diseases by targeting the KLF family.
{"title":"Krüppel-like factors family in health and disease","authors":"Tingwen Xiang, Chuan Yang, Zihan Deng, Dong Sun, Fei Luo, Yueqi Chen","doi":"10.1002/mco2.723","DOIUrl":"https://doi.org/10.1002/mco2.723","url":null,"abstract":"<p>Krüppel-like factors (KLFs) are a family of basic transcription factors with three conserved Cys2/His2 zinc finger domains located in their C-terminal regions. It is acknowledged that KLFs exert complicated effects on cell proliferation, differentiation, survival, and responses to stimuli. Dysregulation of KLFs is associated with a range of diseases including cardiovascular disorders, metabolic diseases, autoimmune conditions, cancer, and neurodegenerative diseases. Their multidimensional roles in modulating critical pathways underscore the significance in both physiological and pathological contexts. Recent research also emphasizes their crucial involvement and complex interplay in the skeletal system. Despite the substantial progress in understanding KLFs and their roles in various cellular processes, several research gaps remain. Here, we elucidated the multifaceted capabilities of KLFs on body health and diseases via various compliable signaling pathways. The associations between KLFs and cellular energy metabolism and epigenetic modification during bone reconstruction have also been summarized. This review helps us better understand the coupling effects and their pivotal functions in multiple systems and detailed mechanisms of bone remodeling and develop potential therapeutic strategies for the clinical treatment of pathological diseases by targeting the KLF family.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.723","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142169852","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}
Weicheng Qiu, Jinguo Meng, Zhipeng Su, Wei Xie, Gaojie Song
<p>Dear Editor,</p><p>Specific immunological challenges can stimulate T helper 2 (Th2) cells and trigger immune response by secreting cytokines such as interleukin-4 (IL-4), IL-5, and IL-13, and dysregulation of these cytokines are closely related to the pathogenesis of diseases such as atopic dermatitis and allergic asthma.<span><sup>1</sup></span> At the molecular level, these cytokines function by binding to different cytokine receptors, thus triggering various inflammatory responses. IL-4 can either bind individually via a heterodimeric receptor composed of IL-4Rα(CD124) and γc (CD132) to trigger a type I inflammatory response or signal through a shared type II inflammatory response with IL-13 to bind another heterodimeric receptor composed of IL-4Rα and IL-13α1. Both types of receptor complexes can activate the phosphorylation of the signal transducer and activator of the transcription (STAT6) pathway via Janus kinase. In addition, IL-5 functions via the IL-5 receptor, which is also a heterodimer consisting of a specific α subunit for binding (IL-5Rα) and a shared β subunit for signal transduction (colony-stimulating factor 2 receptor beta, CSF2RB). Currently, several monoclonal antibody drugs are approved for marketing worldwide for asthma indications, but these are mainly single-target blockers related to IL-4, IL-5, and IL-13 signaling pathways,<span><sup>1</sup></span> and most of these medicines have individual limitations. According to investigations of Th2 cell-related signaling pathways and the outcomes of some clinical trials,<span><sup>2</sup></span> blocking different steps within the type II inflammatory pathway may produce better efficacy as this approach is expected to produce synergistic effects.</p><p>Here, we attempted to develop a bispecific antibody targeting both IL-4Rα and IL-5 within the type II inflammatory pathway. To obtain the VHHs, we immunized alpaca with individual proteins of IL-4Rα or IL-5 (Figure 1A). Taking IL-4Rα for example, total RNA was extracted from lymphocytes to construct a VHH library. 109 unique binders for IL4Rα were identified after library screening. After validating binding and blocking capacity, we selected two binders (dAb1 and dAb2) for further engineering and humanization. These two nanobodies exhibited similar EC<sub>50</sub> (single digit nanomolar) when associated with IL-4Rα in either VHH or Fc-fused form, with dAb1 performing slightly better when blocking the IL-4<b>–</b>IL-4Rα interaction (Figure S1A–D). We further found that dAb1 shows an IC<sub>50</sub> of ∼0.15 nM in either IL-4 or IL-13-induced TF-1 cell proliferation assay (Figure 1B), which is comparable with the efficacy of dupilumab (Figure S1E,F). Subsequently, dAb1 was selected and recombined with the best VHH against IL-5 (which was generated and selected using a similar process) to produce a bispecific antibody.</p><p>Interestingly, we found the IL4Rα-binding nanobody dAb1 binds only to human IL-4Rα but has no cross-reactiv
{"title":"Structural insight into interleukin-4Rα and interleukin-5 inhibition by nanobodies from a bispecific antibody","authors":"Weicheng Qiu, Jinguo Meng, Zhipeng Su, Wei Xie, Gaojie Song","doi":"10.1002/mco2.700","DOIUrl":"https://doi.org/10.1002/mco2.700","url":null,"abstract":"<p>Dear Editor,</p><p>Specific immunological challenges can stimulate T helper 2 (Th2) cells and trigger immune response by secreting cytokines such as interleukin-4 (IL-4), IL-5, and IL-13, and dysregulation of these cytokines are closely related to the pathogenesis of diseases such as atopic dermatitis and allergic asthma.<span><sup>1</sup></span> At the molecular level, these cytokines function by binding to different cytokine receptors, thus triggering various inflammatory responses. IL-4 can either bind individually via a heterodimeric receptor composed of IL-4Rα(CD124) and γc (CD132) to trigger a type I inflammatory response or signal through a shared type II inflammatory response with IL-13 to bind another heterodimeric receptor composed of IL-4Rα and IL-13α1. Both types of receptor complexes can activate the phosphorylation of the signal transducer and activator of the transcription (STAT6) pathway via Janus kinase. In addition, IL-5 functions via the IL-5 receptor, which is also a heterodimer consisting of a specific α subunit for binding (IL-5Rα) and a shared β subunit for signal transduction (colony-stimulating factor 2 receptor beta, CSF2RB). Currently, several monoclonal antibody drugs are approved for marketing worldwide for asthma indications, but these are mainly single-target blockers related to IL-4, IL-5, and IL-13 signaling pathways,<span><sup>1</sup></span> and most of these medicines have individual limitations. According to investigations of Th2 cell-related signaling pathways and the outcomes of some clinical trials,<span><sup>2</sup></span> blocking different steps within the type II inflammatory pathway may produce better efficacy as this approach is expected to produce synergistic effects.</p><p>Here, we attempted to develop a bispecific antibody targeting both IL-4Rα and IL-5 within the type II inflammatory pathway. To obtain the VHHs, we immunized alpaca with individual proteins of IL-4Rα or IL-5 (Figure 1A). Taking IL-4Rα for example, total RNA was extracted from lymphocytes to construct a VHH library. 109 unique binders for IL4Rα were identified after library screening. After validating binding and blocking capacity, we selected two binders (dAb1 and dAb2) for further engineering and humanization. These two nanobodies exhibited similar EC<sub>50</sub> (single digit nanomolar) when associated with IL-4Rα in either VHH or Fc-fused form, with dAb1 performing slightly better when blocking the IL-4<b>–</b>IL-4Rα interaction (Figure S1A–D). We further found that dAb1 shows an IC<sub>50</sub> of ∼0.15 nM in either IL-4 or IL-13-induced TF-1 cell proliferation assay (Figure 1B), which is comparable with the efficacy of dupilumab (Figure S1E,F). Subsequently, dAb1 was selected and recombined with the best VHH against IL-5 (which was generated and selected using a similar process) to produce a bispecific antibody.</p><p>Interestingly, we found the IL4Rα-binding nanobody dAb1 binds only to human IL-4Rα but has no cross-reactiv","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.700","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158574","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}
Wenle He, Wenhui Huang, Lu Zhang, Xuewei Wu, Shuixing Zhang, Bin Zhang
Genomics allows the tracing of origin and evolution of cancer at molecular scale and underpin modern cancer diagnosis and treatment systems. Yet, molecular biomarker-guided clinical decision-making encounters major challenges in the realm of individualized medicine, consisting of the invasiveness of procedures and the sampling errors due to high tumor heterogeneity. By contrast, medical imaging enables noninvasive and global characterization of tumors at a low cost. In recent years, radiomics has overcomes the limitations of human visual evaluation by high-throughput quantitative analysis, enabling the comprehensive utilization of the vast amount of information underlying radiological images. The cross-scale integration of radiomics and genomics (hereafter radiogenomics) has the enormous potential to enhance cancer decoding and act as a catalyst for digital precision medicine. Herein, we provide a comprehensive overview of the current framework and potential clinical applications of radiogenomics in patient care. We also highlight recent research advances to illustrate how radiogenomics can address common clinical problems in solid tumors such as breast cancer, lung cancer, and glioma. Finally, we analyze existing literature to outline challenges and propose solutions, while also identifying future research pathways. We believe that the perspectives shared in this survey will provide a valuable guide for researchers in the realm of radiogenomics aiming to advance precision oncology.
{"title":"Radiogenomics: bridging the gap between imaging and genomics for precision oncology","authors":"Wenle He, Wenhui Huang, Lu Zhang, Xuewei Wu, Shuixing Zhang, Bin Zhang","doi":"10.1002/mco2.722","DOIUrl":"https://doi.org/10.1002/mco2.722","url":null,"abstract":"<p>Genomics allows the tracing of origin and evolution of cancer at molecular scale and underpin modern cancer diagnosis and treatment systems. Yet, molecular biomarker-guided clinical decision-making encounters major challenges in the realm of individualized medicine, consisting of the invasiveness of procedures and the sampling errors due to high tumor heterogeneity. By contrast, medical imaging enables noninvasive and global characterization of tumors at a low cost. In recent years, radiomics has overcomes the limitations of human visual evaluation by high-throughput quantitative analysis, enabling the comprehensive utilization of the vast amount of information underlying radiological images. The cross-scale integration of radiomics and genomics (hereafter radiogenomics) has the enormous potential to enhance cancer decoding and act as a catalyst for digital precision medicine. Herein, we provide a comprehensive overview of the current framework and potential clinical applications of radiogenomics in patient care. We also highlight recent research advances to illustrate how radiogenomics can address common clinical problems in solid tumors such as breast cancer, lung cancer, and glioma. Finally, we analyze existing literature to outline challenges and propose solutions, while also identifying future research pathways. We believe that the perspectives shared in this survey will provide a valuable guide for researchers in the realm of radiogenomics aiming to advance precision oncology.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.722","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158576","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}
Qingjia Sun, Rui Gao, Yingxin Lin, Xianchao Zhou, Tao Wang, Jian He
Hepatocellular carcinoma (HCC) is a typical highly heterogeneous solid tumor with high morbidity and mortality worldwide, especially in China; however, the immune microenvironment of HCC has not been clarified so far. Here, we employed single-cell RNA sequencing (scRNA-seq) on diethylnitrosamine (DEN)-induced mouse HCC model to dissect the immune cell dynamics during tumorigenesis. Our findings reveal distinct immune profiles in both precancerous and cancerous lesions, indicating early tumor-associated immunological alterations. Notably, specific T and B cell subpopulations are preferentially enriched in the HCC tumor microenvironment (TME). Furthermore, we identified a subpopulation of naïve B cells with high CD83 expression, correlating with improved prognosis in human HCC. These signature genes were validated in The Cancer Genome Atlas HCC RNA-seq dataset. Moreover, cell interaction analysis revealed that subpopulations of B cells in both mouse and human samples are activated and may potentially contribute to oncogenic processes. In summary, our study provides insights into the dynamic immune microenvironment and cellular networks in HCC pathogenesis, with a specific emphasis on naïve B cells. These findings emphasize the significance of targeting TME in HCC patients to prevent HCC pathological progression, which may give a new perspective on the therapeutics for HCC.
肝细胞癌(HCC)是一种典型的高度异质性实体瘤,在世界范围内尤其在中国发病率和死亡率都很高;然而,迄今为止,HCC的免疫微环境尚未被阐明。在此,我们采用单细胞RNA测序技术(scRNA-seq)对二乙基亚硝胺(DEN)诱导的小鼠HCC模型进行了研究,以揭示肿瘤发生过程中免疫细胞的动态变化。我们的发现揭示了癌前病变和癌变病变中不同的免疫特征,表明早期肿瘤相关的免疫学改变。值得注意的是,特定的 T 和 B 细胞亚群在 HCC 肿瘤微环境(TME)中优先富集。此外,我们还发现了高 CD83 表达的幼稚 B 细胞亚群,这与人类 HCC 预后的改善相关。这些特征基因在癌症基因组图谱 HCC RNA-seq 数据集中得到了验证。此外,细胞相互作用分析表明,小鼠和人类样本中的B细胞亚群都被激活了,并有可能导致致癌过程。总之,我们的研究深入揭示了 HCC 发病过程中的动态免疫微环境和细胞网络,并特别强调了幼稚 B 细胞。这些发现强调了靶向 HCC 患者的 TME 对预防 HCC 病理进展的重要意义,从而为 HCC 的治疗提供了新的视角。
{"title":"Leveraging single-cell RNA-seq for uncovering naïve B cells associated with better prognosis of hepatocellular carcinoma","authors":"Qingjia Sun, Rui Gao, Yingxin Lin, Xianchao Zhou, Tao Wang, Jian He","doi":"10.1002/mco2.563","DOIUrl":"https://doi.org/10.1002/mco2.563","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is a typical highly heterogeneous solid tumor with high morbidity and mortality worldwide, especially in China; however, the immune microenvironment of HCC has not been clarified so far. Here, we employed single-cell RNA sequencing (scRNA-seq) on diethylnitrosamine (DEN)-induced mouse HCC model to dissect the immune cell dynamics during tumorigenesis. Our findings reveal distinct immune profiles in both precancerous and cancerous lesions, indicating early tumor-associated immunological alterations. Notably, specific T and B cell subpopulations are preferentially enriched in the HCC tumor microenvironment (TME). Furthermore, we identified a subpopulation of naïve B cells with high CD83 expression, correlating with improved prognosis in human HCC. These signature genes were validated in The Cancer Genome Atlas HCC RNA-seq dataset. Moreover, cell interaction analysis revealed that subpopulations of B cells in both mouse and human samples are activated and may potentially contribute to oncogenic processes. In summary, our study provides insights into the dynamic immune microenvironment and cellular networks in HCC pathogenesis, with a specific emphasis on naïve B cells. These findings emphasize the significance of targeting TME in HCC patients to prevent HCC pathological progression, which may give a new perspective on the therapeutics for HCC.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.563","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158575","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}
N6-methyladenosine (m6A) is the most abundant modification of RNA in eukaryotic cells. Previous studies have shown that m6A is pivotal in diverse diseases especially cancer. m6A corelates with the initiation, progression, resistance, invasion, and metastasis of cancer. However, despite these insights, a comprehensive understanding of its specific roles and mechanisms within the complex landscape of cancer is still elusive. This review begins by outlining the key regulatory proteins of m6A modification and their posttranslational modifications (PTMs), as well as the role in chromatin accessibility and transcriptional activity within cancer cells. Additionally, it highlights that m6A modifications impact cancer progression by modulating programmed cell death mechanisms and affecting the tumor microenvironment through various cancer-associated immune cells. Furthermore, the review discusses how microorganisms can induce enduring epigenetic changes and oncogenic effect in microorganism-associated cancers by altering m6A modifications. Last, it delves into the role of m6A modification in cancer immunotherapy, encompassing RNA therapy, immune checkpoint blockade, cytokine therapy, adoptive cell transfer therapy, and direct targeting of m6A regulators. Overall, this review clarifies the multifaceted role of m6A modification in cancer and explores targeted therapies aimed at manipulating m6A modification, aiming to advance cancer research and improve patient outcomes.
{"title":"Role of N6-methyladenosine RNA modification in cancer","authors":"Yi Qu, Nannan Gao, Shengwei Zhang, Limin Gao, Bing He, Chao Wang, Chunli Gong, Qiuyue Shi, Zhibin Li, Shiming Yang, Yufeng Xiao","doi":"10.1002/mco2.715","DOIUrl":"https://doi.org/10.1002/mco2.715","url":null,"abstract":"<p>N6-methyladenosine (m6A) is the most abundant modification of RNA in eukaryotic cells. Previous studies have shown that m6A is pivotal in diverse diseases especially cancer. m6A corelates with the initiation, progression, resistance, invasion, and metastasis of cancer. However, despite these insights, a comprehensive understanding of its specific roles and mechanisms within the complex landscape of cancer is still elusive. This review begins by outlining the key regulatory proteins of m6A modification and their posttranslational modifications (PTMs), as well as the role in chromatin accessibility and transcriptional activity within cancer cells. Additionally, it highlights that m6A modifications impact cancer progression by modulating programmed cell death mechanisms and affecting the tumor microenvironment through various cancer-associated immune cells. Furthermore, the review discusses how microorganisms can induce enduring epigenetic changes and oncogenic effect in microorganism-associated cancers by altering m6A modifications. Last, it delves into the role of m6A modification in cancer immunotherapy, encompassing RNA therapy, immune checkpoint blockade, cytokine therapy, adoptive cell transfer therapy, and direct targeting of m6A regulators. Overall, this review clarifies the multifaceted role of m6A modification in cancer and explores targeted therapies aimed at manipulating m6A modification, aiming to advance cancer research and improve patient outcomes.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.715","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158577","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}