mRNA vaccines are regarded as a highly promising avenue for next-generation cancer therapy. Nevertheless, the intricacy of production, inherent instability, and low expression persistence of linear mRNA significantly restrict their extensive utilization. Circular RNAs (circRNAs) offer a novel solution to these limitations due to their efficient protein expression ability, which can be rapidly generated in vitro without the need for extra modifications. Here, we present a novel neoantigen vaccine based on circRNA that induces a potent anti-tumor immune response by expressing hepatocellular carcinoma-specific tumor neoantigens. By cyclizing linearRNA molecules, we were able to enhance the stability of RNA vaccines and form highly stable circRNA molecules with the capacity for sustained protein expression. We confirmed that neoantigen-encoded circRNA can promote dendritic cell (DC) activation and enhance DC-induced T-cell activation in vitro, thereby enhancing T-cell killing of tumor cells. Encapsulating neoantigen-encoded circRNA within lipid nanoparticles for in vivo expression has enabled the creation of a novel circRNA vaccine platform. This platform demonstrates superior tumor treatment and prevention in various murine tumor models, eliciting a robust T-cell immune response. Our circRNA neoantigen vaccine offers new options and application prospects for neoantigen immunotherapy in solid tumors.
mRNA 疫苗被认为是下一代癌症疗法中极具前景的途径。然而,线性 mRNA 生产的复杂性、固有的不稳定性和低表达持久性极大地限制了其广泛应用。环状核糖核酸(circRNA)具有高效的蛋白质表达能力,无需额外修饰即可在体外快速生成,因此为这些限制提供了一种新的解决方案。在这里,我们展示了一种基于 circRNA 的新型新抗原疫苗,它通过表达肝细胞癌特异性肿瘤新抗原诱导有效的抗肿瘤免疫反应。通过环化线性 RNA 分子,我们提高了 RNA 疫苗的稳定性,并形成了具有持续蛋白质表达能力的高度稳定的 circRNA 分子。我们证实,新抗原编码的 circRNA 可促进树突状细胞(DC)活化,并增强 DC 诱导的体外 T 细胞活化,从而增强 T 细胞对肿瘤细胞的杀伤力。将新抗原编码的 circRNA 封装在脂质纳米颗粒中进行体内表达,从而创建了一种新型 circRNA 疫苗平台。该平台在各种小鼠肿瘤模型中显示出卓越的肿瘤治疗和预防效果,并能激发强大的 T 细胞免疫反应。我们的 circRNA 新抗原疫苗为实体瘤的新抗原免疫疗法提供了新的选择和应用前景。
{"title":"Circular RNA-based neoantigen vaccine for hepatocellular carcinoma immunotherapy","authors":"Fei Wang, Guang Cai, Yingchao Wang, Qiuyu Zhuang, Zhixiong Cai, Yingying Li, Shaodong Gao, Fang Li, Cuilin Zhang, Bixing Zhao, Xiaolong Liu","doi":"10.1002/mco2.667","DOIUrl":"10.1002/mco2.667","url":null,"abstract":"<p>mRNA vaccines are regarded as a highly promising avenue for next-generation cancer therapy. Nevertheless, the intricacy of production, inherent instability, and low expression persistence of linear mRNA significantly restrict their extensive utilization. Circular RNAs (circRNAs) offer a novel solution to these limitations due to their efficient protein expression ability, which can be rapidly generated in vitro without the need for extra modifications. Here, we present a novel neoantigen vaccine based on circRNA that induces a potent anti-tumor immune response by expressing hepatocellular carcinoma-specific tumor neoantigens. By cyclizing linearRNA molecules, we were able to enhance the stability of RNA vaccines and form highly stable circRNA molecules with the capacity for sustained protein expression. We confirmed that neoantigen-encoded circRNA can promote dendritic cell (DC) activation and enhance DC-induced T-cell activation in vitro, thereby enhancing T-cell killing of tumor cells. Encapsulating neoantigen-encoded circRNA within lipid nanoparticles for in vivo expression has enabled the creation of a novel circRNA vaccine platform. This platform demonstrates superior tumor treatment and prevention in various murine tumor models, eliciting a robust T-cell immune response. Our circRNA neoantigen vaccine offers new options and application prospects for neoantigen immunotherapy in solid tumors.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141857501","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}
Gene editing is a growing gene engineering technique that allows accurate editing of a broad spectrum of gene-regulated diseases to achieve curative treatment and also has the potential to be used as an adjunct to the conventional treatment of diseases. Gene editing technology, mainly based on clustered regularly interspaced palindromic repeats (CRISPR)–CRISPR-associated protein systems, which is capable of generating genetic modifications in somatic cells, provides a promising new strategy for gene therapy for a wide range of human diseases. Currently, gene editing technology shows great application prospects in a variety of human diseases, not only in therapeutic potential but also in the construction of animal models of human diseases. This paper describes the application of gene editing technology in hematological diseases, solid tumors, immune disorders, ophthalmological diseases, and metabolic diseases; focuses on the therapeutic strategies of gene editing technology in sickle cell disease; provides an overview of the role of gene editing technology in the construction of animal models of human diseases; and discusses the limitations of gene editing technology in the treatment of diseases, which is intended to provide an important reference for the applications of gene editing technology in the human disease.
{"title":"CRISPR technology in human diseases","authors":"Qiang Feng, Qirong Li, Hengzong Zhou, Zhan Wang, Chao Lin, Ziping Jiang, Tianjia Liu, Dongxu Wang","doi":"10.1002/mco2.672","DOIUrl":"10.1002/mco2.672","url":null,"abstract":"<p>Gene editing is a growing gene engineering technique that allows accurate editing of a broad spectrum of gene-regulated diseases to achieve curative treatment and also has the potential to be used as an adjunct to the conventional treatment of diseases. Gene editing technology, mainly based on clustered regularly interspaced palindromic repeats (CRISPR)–CRISPR-associated protein systems, which is capable of generating genetic modifications in somatic cells, provides a promising new strategy for gene therapy for a wide range of human diseases. Currently, gene editing technology shows great application prospects in a variety of human diseases, not only in therapeutic potential but also in the construction of animal models of human diseases. This paper describes the application of gene editing technology in hematological diseases, solid tumors, immune disorders, ophthalmological diseases, and metabolic diseases; focuses on the therapeutic strategies of gene editing technology in sickle cell disease; provides an overview of the role of gene editing technology in the construction of animal models of human diseases; and discusses the limitations of gene editing technology in the treatment of diseases, which is intended to provide an important reference for the applications of gene editing technology in the human disease.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141857502","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}
The JN.1 variant of COVID-19 has emerged as the dominant strain worldwide since the end of 2023. As a subclade of the BA.2.86 variant, JN.1 harbors a unique combination of mutations inherited from the BA.2.86 lineage, notably featuring the novel L455S mutation within its receptor-binding motif. This mutation has been linked to increased transmissibility and enhanced immune evasion capabilities. During the rise of JN.1, evidence of resistance to various monoclonal antibodies and reduced cross-neutralization effects of the XBB.1.5 vaccine have been observed. Although the public health threat posed by the JN.1 variant appears relatively low, concerns persist regarding its evolutionary trajectory under immune pressure. This review provides a comprehensive overview of the evolving JN.1 variant, highlighting the need for continuous monitoring and investigation of new variants that could lead to widespread infection. It assesses the efficacy of current vaccines and therapeutics against emerging variants, particularly focusing on immunocompromised populations. Additionally, this review summarizes potential vaccine advancements and clinical treatments for COVID-19, offering insights to optimize prevention and treatment strategies. This review thoroughly evaluates the JN.1 variant's impact on public health and its implications for future vaccine and therapeutic development, contributing to ongoing efforts to mitigate the risk of virus transmission and disease severity.
{"title":"The rising SARS-CoV-2 JN.1 variant: evolution, infectivity, immune escape, and response strategies","authors":"Yishan Lu, Danyi Ao, Xuemei He, Xiawei Wei","doi":"10.1002/mco2.675","DOIUrl":"10.1002/mco2.675","url":null,"abstract":"<p>The JN.1 variant of COVID-19 has emerged as the dominant strain worldwide since the end of 2023. As a subclade of the BA.2.86 variant, JN.1 harbors a unique combination of mutations inherited from the BA.2.86 lineage, notably featuring the novel L455S mutation within its receptor-binding motif. This mutation has been linked to increased transmissibility and enhanced immune evasion capabilities. During the rise of JN.1, evidence of resistance to various monoclonal antibodies and reduced cross-neutralization effects of the XBB.1.5 vaccine have been observed. Although the public health threat posed by the JN.1 variant appears relatively low, concerns persist regarding its evolutionary trajectory under immune pressure. This review provides a comprehensive overview of the evolving JN.1 variant, highlighting the need for continuous monitoring and investigation of new variants that could lead to widespread infection. It assesses the efficacy of current vaccines and therapeutics against emerging variants, particularly focusing on immunocompromised populations. Additionally, this review summarizes potential vaccine advancements and clinical treatments for COVID-19, offering insights to optimize prevention and treatment strategies. This review thoroughly evaluates the JN.1 variant's impact on public health and its implications for future vaccine and therapeutic development, contributing to ongoing efforts to mitigate the risk of virus transmission and disease severity.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141857503","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}
Jun He, Xianghua Zeng, Chunmei Wang, Enwen Wang, Yongsheng Li
Antibody–drug conjugates (ADCs) consist of monoclonal antibodies that target tumor cells and cytotoxic drugs linked through linkers. By leveraging antibodies’ targeting properties, ADCs deliver cytotoxic drugs into tumor cells via endocytosis after identifying the tumor antigen. This precise method aims to kill tumor cells selectively while minimizing harm to normal cells, offering safe and effective therapeutic benefits. Recent years have seen significant progress in antitumor treatment with ADC development, providing patients with new and potent treatment options. With over 300 ADCs explored for various tumor indications and some already approved for clinical use, challenges such as resistance due to factors like antigen expression, ADC processing, and payload have emerged. This review aims to outline the history of ADC development, their structure, mechanism of action, recent composition advancements, target selection, completed and ongoing clinical trials, resistance mechanisms, and intervention strategies. Additionally, it will delve into the potential of ADCs with novel markers, linkers, payloads, and innovative action mechanisms to enhance cancer treatment options. The evolution of ADCs has also led to the emergence of combination therapy as a new therapeutic approach to improve drug efficacy.
{"title":"Antibody–drug conjugates in cancer therapy: mechanisms and clinical studies","authors":"Jun He, Xianghua Zeng, Chunmei Wang, Enwen Wang, Yongsheng Li","doi":"10.1002/mco2.671","DOIUrl":"10.1002/mco2.671","url":null,"abstract":"<p>Antibody–drug conjugates (ADCs) consist of monoclonal antibodies that target tumor cells and cytotoxic drugs linked through linkers. By leveraging antibodies’ targeting properties, ADCs deliver cytotoxic drugs into tumor cells via endocytosis after identifying the tumor antigen. This precise method aims to kill tumor cells selectively while minimizing harm to normal cells, offering safe and effective therapeutic benefits. Recent years have seen significant progress in antitumor treatment with ADC development, providing patients with new and potent treatment options. With over 300 ADCs explored for various tumor indications and some already approved for clinical use, challenges such as resistance due to factors like antigen expression, ADC processing, and payload have emerged. This review aims to outline the history of ADC development, their structure, mechanism of action, recent composition advancements, target selection, completed and ongoing clinical trials, resistance mechanisms, and intervention strategies. Additionally, it will delve into the potential of ADCs with novel markers, linkers, payloads, and innovative action mechanisms to enhance cancer treatment options. The evolution of ADCs has also led to the emergence of combination therapy as a new therapeutic approach to improve drug efficacy.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11283588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790926","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}
Jian Tang, Yu Chen, Chunhua Wang, Ying Xia, Tingyu Yu, Mengjun Tang, Kun Meng, Lijuan Yin, Yang Yang, Liang Shen, Hui Xing, Xiaogang Mao
Mesenchymal stem cells (MSCs) are recruited by malignant tumor cells to the tumor microenvironment (TME) and play a crucial role in the initiation and progression of malignant tumors. This role encompasses immune evasion, promotion of angiogenesis, stimulation of cancer cell proliferation, correlation with cancer stem cells, multilineage differentiation within the TME, and development of treatment resistance. Simultaneously, extensive research is exploring the homing effect of MSCs and MSC-derived extracellular vesicles (MSCs-EVs) in tumors, aiming to design them as carriers for antitumor substances. These substances are targeted to deliver antitumor drugs to enhance drug efficacy while reducing drug toxicity. This paper provides a review of the supportive role of MSCs in tumor progression and the associated molecular mechanisms. Additionally, we summarize the latest therapeutic strategies involving engineered MSCs and MSCs-EVs in cancer treatment, including their utilization as carriers for gene therapeutic agents, chemotherapeutics, and oncolytic viruses. We also discuss the distribution and clearance of MSCs and MSCs-EVs upon entry into the body to elucidate the potential of targeted therapies based on MSCs and MSCs-EVs in cancer treatment, along with the challenges they face.
{"title":"The role of mesenchymal stem cells in cancer and prospects for their use in cancer therapeutics","authors":"Jian Tang, Yu Chen, Chunhua Wang, Ying Xia, Tingyu Yu, Mengjun Tang, Kun Meng, Lijuan Yin, Yang Yang, Liang Shen, Hui Xing, Xiaogang Mao","doi":"10.1002/mco2.663","DOIUrl":"10.1002/mco2.663","url":null,"abstract":"<p>Mesenchymal stem cells (MSCs) are recruited by malignant tumor cells to the tumor microenvironment (TME) and play a crucial role in the initiation and progression of malignant tumors. This role encompasses immune evasion, promotion of angiogenesis, stimulation of cancer cell proliferation, correlation with cancer stem cells, multilineage differentiation within the TME, and development of treatment resistance. Simultaneously, extensive research is exploring the homing effect of MSCs and MSC-derived extracellular vesicles (MSCs-EVs) in tumors, aiming to design them as carriers for antitumor substances. These substances are targeted to deliver antitumor drugs to enhance drug efficacy while reducing drug toxicity. This paper provides a review of the supportive role of MSCs in tumor progression and the associated molecular mechanisms. Additionally, we summarize the latest therapeutic strategies involving engineered MSCs and MSCs-EVs in cancer treatment, including their utilization as carriers for gene therapeutic agents, chemotherapeutics, and oncolytic viruses. We also discuss the distribution and clearance of MSCs and MSCs-EVs upon entry into the body to elucidate the potential of targeted therapies based on MSCs and MSCs-EVs in cancer treatment, along with the challenges they face.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11283587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790680","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}
Development of potent and broad-spectrum drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains one of the top priorities, especially in the cases of the emergence of mutant viruses and inability of current vaccines to prevent viral transmission. In this study, we have generated a novel membrane fusion-inhibitory lipopeptide IPB29, which is currently under clinical trials; herein, we report its design strategy and preclinical data. First, we surprisingly found that IPB29 with a rigid linker between the peptide sequence and lipid molecule had greatly improved α-helical structure and antiviral activity. Second, IPB29 potently inhibited a large panel of SARS-CoV-2 variants including the previously and currently circulating viruses, such as Omicron XBB.5.1 and EG.5.1. Third, IPB29 could also cross-neutralize the bat- and pangolin-isolated SARS-CoV-2-related CoVs (RatG13, PCoV-GD, and PCoV-GX) and other human CoVs (SARS-CoV, MERS-CoV, HCoV-NL63, and HCoV-229E). Fourth, IPB29 administrated as an inhalation solution (IPB29-IS) in Syrian hamsters exhibited high therapeutic and preventive efficacies against SARS-CoV-2 Delta or Omicron variant. Fifth, the pharmacokinetic profiles and safety pharmacology of IPB29-IS were extensively characterized, providing data to support its evaluation in humans. In conclusion, our studies have demonstrated a novel design strategy for viral fusion inhibitors and offered an ideal drug candidate against SARS-CoV-2 and other coronaviruses.
{"title":"Development of potent pan-coronavirus fusion inhibitors with a new design strategy","authors":"Yuanmei Zhu, Zhongcai Gao, Xiaoli Feng, Lin Cheng, Nian Liu, Chao Liu, Shaowei Han, Qiaojiang Yang, Qingcui Zou, Huihui Chong, Zheng Zhang, Minghua Li, Gengshen Song, Yuxian He","doi":"10.1002/mco2.666","DOIUrl":"10.1002/mco2.666","url":null,"abstract":"<p>Development of potent and broad-spectrum drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains one of the top priorities, especially in the cases of the emergence of mutant viruses and inability of current vaccines to prevent viral transmission. In this study, we have generated a novel membrane fusion-inhibitory lipopeptide IPB29, which is currently under clinical trials; herein, we report its design strategy and preclinical data. First, we surprisingly found that IPB29 with a rigid linker between the peptide sequence and lipid molecule had greatly improved α-helical structure and antiviral activity. Second, IPB29 potently inhibited a large panel of SARS-CoV-2 variants including the previously and currently circulating viruses, such as Omicron XBB.5.1 and EG.5.1. Third, IPB29 could also cross-neutralize the bat- and pangolin-isolated SARS-CoV-2-related CoVs (RatG13, PCoV-GD, and PCoV-GX) and other human CoVs (SARS-CoV, MERS-CoV, HCoV-NL63, and HCoV-229E). Fourth, IPB29 administrated as an inhalation solution (IPB29-IS) in Syrian hamsters exhibited high therapeutic and preventive efficacies against SARS-CoV-2 Delta or Omicron variant. Fifth, the pharmacokinetic profiles and safety pharmacology of IPB29-IS were extensively characterized, providing data to support its evaluation in humans. In conclusion, our studies have demonstrated a novel design strategy for viral fusion inhibitors and offered an ideal drug candidate against SARS-CoV-2 and other coronaviruses.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11283584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790679","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}
As a highly dynamic tissue, bone is continuously rebuilt throughout life. Both bone formation by osteoblasts and bone resorption by osteoclasts constitute bone reconstruction homeostasis. The equilibrium of bone homeostasis is governed by many complicated signaling pathways that weave together to form an intricate network. These pathways coordinate the meticulous processes of bone formation and resorption, ensuring the structural integrity and dynamic vitality of the skeletal system. Dysregulation of the bone homeostatic regulatory signaling network contributes to the development and progression of many skeletal diseases. Significantly, imbalanced bone homeostasis further disrupts the signaling network and triggers a cascade reaction that exacerbates disease progression and engenders a deleterious cycle. Here, we summarize the influence of signaling pathways on bone homeostasis, elucidating the interplay and crosstalk among them. Additionally, we review the mechanisms underpinning bone homeostatic imbalances across diverse disease landscapes, highlighting current and prospective therapeutic targets and clinical drugs. We hope that this review will contribute to a holistic understanding of the signaling pathways and molecular mechanisms sustaining bone homeostasis, which are promising to contribute to further research on bone homeostasis and shed light on the development of targeted drugs.
{"title":"Regulation of bone homeostasis: signaling pathways and therapeutic targets","authors":"Zebin Wu, Wenming Li, Kunlong Jiang, Zhixiang Lin, Chen Qian, Mingzhou Wu, Yu Xia, Ning Li, Hongtao Zhang, Haixiang Xiao, Jiaxiang Bai, Dechun Geng","doi":"10.1002/mco2.657","DOIUrl":"10.1002/mco2.657","url":null,"abstract":"<p>As a highly dynamic tissue, bone is continuously rebuilt throughout life. Both bone formation by osteoblasts and bone resorption by osteoclasts constitute bone reconstruction homeostasis. The equilibrium of bone homeostasis is governed by many complicated signaling pathways that weave together to form an intricate network. These pathways coordinate the meticulous processes of bone formation and resorption, ensuring the structural integrity and dynamic vitality of the skeletal system. Dysregulation of the bone homeostatic regulatory signaling network contributes to the development and progression of many skeletal diseases. Significantly, imbalanced bone homeostasis further disrupts the signaling network and triggers a cascade reaction that exacerbates disease progression and engenders a deleterious cycle. Here, we summarize the influence of signaling pathways on bone homeostasis, elucidating the interplay and crosstalk among them. Additionally, we review the mechanisms underpinning bone homeostatic imbalances across diverse disease landscapes, highlighting current and prospective therapeutic targets and clinical drugs. We hope that this review will contribute to a holistic understanding of the signaling pathways and molecular mechanisms sustaining bone homeostasis, which are promising to contribute to further research on bone homeostasis and shed light on the development of targeted drugs.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11266958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763998","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}
Xiaofei Shen, Hongling Yang, Yang Yang, Xianjun Zhu, Qingxiang Sun
Metabolic disorders, including obesity, dyslipidemia, diabetes, nonalcoholic fatty liver disease, and metabolic syndrome, are characterized by insulin resistance, abnormalities in circulating cholesterol and lipid profiles, and hypertension. The most common pathophysiologies of metabolic disorders are glucose/lipid metabolism dysregulation, insulin resistance, inflammatory response, and oxidative stress. Although several agents have been approved for the treatment of metabolic disorders, there is still a strong demand for more efficacious drugs with less side effects. Natural products have been critical sources of drug research and discovery for decades. However, the usefulness of bioactive natural products is often limited by incomplete understanding of their direct cellular targets. In this review, we highlight the current understanding of the established and emerging molecular mechanisms of metabolic disorders. We further summarize the therapeutic effects and underlying mechanisms of natural products on metabolic disorders, with highlights on their direct cellular targets, which are mainly implicated in the regulation of glucose/lipid metabolism, insulin resistance, metabolic inflammation, and oxidative stress. Finally, this review also covers the clinical studies of natural products in metabolic disorders. These progresses are expected to facilitate the application of these natural products and their derivatives in the development of novel drugs against metabolic disorders.
{"title":"The cellular and molecular targets of natural products against metabolic disorders: a translational approach to reach the bedside","authors":"Xiaofei Shen, Hongling Yang, Yang Yang, Xianjun Zhu, Qingxiang Sun","doi":"10.1002/mco2.664","DOIUrl":"10.1002/mco2.664","url":null,"abstract":"<p>Metabolic disorders, including obesity, dyslipidemia, diabetes, nonalcoholic fatty liver disease, and metabolic syndrome, are characterized by insulin resistance, abnormalities in circulating cholesterol and lipid profiles, and hypertension. The most common pathophysiologies of metabolic disorders are glucose/lipid metabolism dysregulation, insulin resistance, inflammatory response, and oxidative stress. Although several agents have been approved for the treatment of metabolic disorders, there is still a strong demand for more efficacious drugs with less side effects. Natural products have been critical sources of drug research and discovery for decades. However, the usefulness of bioactive natural products is often limited by incomplete understanding of their direct cellular targets. In this review, we highlight the current understanding of the established and emerging molecular mechanisms of metabolic disorders. We further summarize the therapeutic effects and underlying mechanisms of natural products on metabolic disorders, with highlights on their direct cellular targets, which are mainly implicated in the regulation of glucose/lipid metabolism, insulin resistance, metabolic inflammation, and oxidative stress. Finally, this review also covers the clinical studies of natural products in metabolic disorders. These progresses are expected to facilitate the application of these natural products and their derivatives in the development of novel drugs against metabolic disorders.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11266934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763655","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}
Colorectal cancer (CRC) is one of the most common malignancies worldwide. In the clinical realm, platinum-based drugs hold an important role in the chemotherapy of CRC. Nonetheless, a multitude of patients, due to tumor protein 53 (TP53) gene mutations, experience the emergence of drug resistance. This phenomenon gravely impairs the effectiveness of therapy and long-term prognosis. Gallium, a metallic element akin to iron, has been reported that has the potential to be used to develop new metal anticancer drugs. In this study, we screened and established the gallium complex K6 as a potent antitumor agent in both in vitro and in vivo. K6 exhibited superior efficacy in impeding the growth, proliferation, and viability of CRC cells carrying TP53 mutations compared to oxaliplatin. Mechanistically, K6 escalated reactive oxygen species levels and led deoxyribonucleic acid (DNA) damage. Furthermore, K6 effectively suppressed the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/glycogen synthase kinase 3 beta (GSK3β) pathway, leading to the degradation of its downstream effectors myelocytomatosis (c-Myc) and Krueppel-like factor 5 (KLF5). Conversely, K6 diminished the protein expression of WW domain-containing protein 1 (WWP1) while activating phosphatase and tensin homolog (PTEN) through c-Myc degradation. This dual action further demonstrated the potential of K6 as a promising therapeutic compound for TP53-mutated CRC.
{"title":"Gallium complex K6 inhibits colorectal cancer by increasing ROS levels to induce DNA damage and enhance phosphatase and tensin homolog activity","authors":"Wei Li, Chuanyu Yang, Zhuo Cheng, Yuanyuan Wu, Sihan Zhou, Xiaowei Qi, Yi Zhang, Jinhui Hu, Mingjin Xie, Ceshi Chen","doi":"10.1002/mco2.665","DOIUrl":"10.1002/mco2.665","url":null,"abstract":"<p>Colorectal cancer (CRC) is one of the most common malignancies worldwide. In the clinical realm, platinum-based drugs hold an important role in the chemotherapy of CRC. Nonetheless, a multitude of patients, due to tumor protein 53 (<i>TP53</i>) gene mutations, experience the emergence of drug resistance. This phenomenon gravely impairs the effectiveness of therapy and long-term prognosis. Gallium, a metallic element akin to iron, has been reported that has the potential to be used to develop new metal anticancer drugs. In this study, we screened and established the gallium complex K6 as a potent antitumor agent in both in vitro and in vivo. K6 exhibited superior efficacy in impeding the growth, proliferation, and viability of CRC cells carrying <i>TP53</i> mutations compared to oxaliplatin. Mechanistically, K6 escalated reactive oxygen species levels and led deoxyribonucleic acid (DNA) damage. Furthermore, K6 effectively suppressed the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/glycogen synthase kinase 3 beta (GSK3β) pathway, leading to the degradation of its downstream effectors myelocytomatosis (c-Myc) and Krueppel-like factor 5 (KLF5). Conversely, K6 diminished the protein expression of WW domain-containing protein 1 (WWP1) while activating phosphatase and tensin homolog (PTEN) through c-Myc degradation. This dual action further demonstrated the potential of K6 as a promising therapeutic compound for <i>TP53</i>-mutated CRC.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11266899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763654","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}
Lijun Chen, Yuqi Huang, Ning Zhang, Jingjing Qu, Yangxin Fang, Jiamin Fu, Yin Yuan, Qi Zhang, Hang Li, Zuoshi Wen, Li Yuan, Lu Chen, Zhenyu Xu, Yifei Li, Huadong Yan, Hiromi Izawa, Lanjuan Li, Charlie Xiang
Liver fibrosis can cause hepatitis B virus (HBV)-associated hepatocellular carcinoma. Menstrual blood-derived mesenchymal stem cells (MenSCs) can ameliorate liver fibrosis through paracrine. Single-cell RNA sequencing (scRNA-seq) may be used to explore the roadmap of activated hepatic stellate cell (aHSC) inactivation to target liver fibrosis. This study established HBV transgenic (HBV-Tg) mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis and demonstrated that MenSCs migrated to the injured liver to improve serological indices and reduce fibrotic accumulation. RNA-bulk analysis revealed that MenSCs mediated extracellular matrix accumulation and cell adhesion. Liver parenchymal cells and nonparenchymal cells were identified by scRNA-seq in the control, CCl4, and MenSC groups, revealing the heterogeneity of fibroblasts/HSCs. A CellChat analysis revealed that diminished intercellular adhesion molecule (ICAM) signaling is vital for MenSC therapy. Specifically, Icam1 in aHSCs acted on Itgal/Itgb2 and Itgam/Itgb2 in neutrophils, causing decreased adhesion. The expression of Itgal, Itgam, and Itgb2 was higher in CCl4 group than in the control group and decreased after MenSC therapy in neutrophil clusters. The Lcn2, Pglyrp1, Wfdc21, and Mmp8 had high expression and may be potential targets in neutrophils. This study highlights interacting cells, corresponding molecules, and underlying targets for MenSCs in treating HBV-associated liver fibrosis.
{"title":"Single-cell RNA sequencing reveals reduced intercellular adhesion molecule crosstalk between activated hepatic stellate cells and neutrophils alleviating liver fibrosis in hepatitis B virus transgenic mice post menstrual blood-derived mesenchymal stem cell transplantation","authors":"Lijun Chen, Yuqi Huang, Ning Zhang, Jingjing Qu, Yangxin Fang, Jiamin Fu, Yin Yuan, Qi Zhang, Hang Li, Zuoshi Wen, Li Yuan, Lu Chen, Zhenyu Xu, Yifei Li, Huadong Yan, Hiromi Izawa, Lanjuan Li, Charlie Xiang","doi":"10.1002/mco2.654","DOIUrl":"10.1002/mco2.654","url":null,"abstract":"<p>Liver fibrosis can cause hepatitis B virus (HBV)-associated hepatocellular carcinoma. Menstrual blood-derived mesenchymal stem cells (MenSCs) can ameliorate liver fibrosis through paracrine. Single-cell RNA sequencing (scRNA-seq) may be used to explore the roadmap of activated hepatic stellate cell (aHSC) inactivation to target liver fibrosis. This study established HBV transgenic (HBV-Tg) mouse model of carbon tetrachloride (CCl<sub>4</sub>)-induced liver fibrosis and demonstrated that MenSCs migrated to the injured liver to improve serological indices and reduce fibrotic accumulation. RNA-bulk analysis revealed that MenSCs mediated extracellular matrix accumulation and cell adhesion. Liver parenchymal cells and nonparenchymal cells were identified by scRNA-seq in the control, CCl<sub>4</sub>, and MenSC groups, revealing the heterogeneity of fibroblasts/HSCs. A CellChat analysis revealed that diminished intercellular adhesion molecule (ICAM) signaling is vital for MenSC therapy. Specifically, <i>Icam1</i> in aHSCs acted on <i>Itgal</i>/<i>Itgb2</i> and <i>Itgam</i>/<i>Itgb2</i> in neutrophils, causing decreased adhesion. The expression of <i>Itgal</i>, <i>Itgam</i>, and <i>Itgb2</i> was higher in CCl<sub>4</sub> group than in the control group and decreased after MenSC therapy in neutrophil clusters. The <i>Lcn2</i>, <i>Pglyrp1</i>, <i>Wfdc21</i>, and <i>Mmp8</i> had high expression and may be potential targets in neutrophils. This study highlights interacting cells, corresponding molecules, and underlying targets for MenSCs in treating HBV-associated liver fibrosis.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11261812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750080","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}