Cardiovascular disease (CVD) and its complications are a leading cause of death worldwide. Endothelial dysfunction plays a crucial role in the initiation and progression of CVD, serving as a pivotal factor in the pathogenesis of cardiovascular, metabolic, and other related diseases. The regulation of endothelial dysfunction is influenced by various risk factors and intricate signaling pathways, which vary depending on the specific disease context. Despite numerous research efforts aimed at elucidating the mechanisms underlying endothelial dysfunction, the precise molecular pathways involved remain incompletely understood. This review elucidates recent research findings on the pathophysiological mechanisms involved in endothelial dysfunction, including nitric oxide availability, oxidative stress, and inflammation-mediated pathways. We also discuss the impact of endothelial dysfunction on various pathological conditions, including atherosclerosis, heart failure, diabetes, hypertension, chronic kidney disease, and neurodegenerative diseases. Furthermore, we summarize the traditional and novel potential biomarkers of endothelial dysfunction as well as pharmacological and nonpharmacological therapeutic strategies for endothelial protection and treatment for CVD and related complications. Consequently, this review is to improve understanding of emerging biomarkers and therapeutic approaches aimed at reducing the risk of developing CVD and associated complications, as well as mitigating endothelial dysfunction.
{"title":"Endothelial dysfunction: molecular mechanisms and clinical implications","authors":"Xia Wang, Ben He","doi":"10.1002/mco2.651","DOIUrl":"10.1002/mco2.651","url":null,"abstract":"<p>Cardiovascular disease (CVD) and its complications are a leading cause of death worldwide. Endothelial dysfunction plays a crucial role in the initiation and progression of CVD, serving as a pivotal factor in the pathogenesis of cardiovascular, metabolic, and other related diseases. The regulation of endothelial dysfunction is influenced by various risk factors and intricate signaling pathways, which vary depending on the specific disease context. Despite numerous research efforts aimed at elucidating the mechanisms underlying endothelial dysfunction, the precise molecular pathways involved remain incompletely understood. This review elucidates recent research findings on the pathophysiological mechanisms involved in endothelial dysfunction, including nitric oxide availability, oxidative stress, and inflammation-mediated pathways. We also discuss the impact of endothelial dysfunction on various pathological conditions, including atherosclerosis, heart failure, diabetes, hypertension, chronic kidney disease, and neurodegenerative diseases. Furthermore, we summarize the traditional and novel potential biomarkers of endothelial dysfunction as well as pharmacological and nonpharmacological therapeutic strategies for endothelial protection and treatment for CVD and related complications. Consequently, this review is to improve understanding of emerging biomarkers and therapeutic approaches aimed at reducing the risk of developing CVD and associated complications, as well as mitigating endothelial dysfunction.</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/PMC11261813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750146","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}
Mingming You, Nan Chen, Yuanyuan Yang, Lingjun Cheng, Hongzhang He, Yanhua Cai, Yating Liu, Haiyue Liu, Guolin Hong
Previous studies have shown a bidirectional communication between human gut microbiota and the brain, known as the microbiota–gut–brain axis (MGBA). The MGBA influences the host's nervous system development, emotional regulation, and cognitive function through neurotransmitters, immune modulation, and metabolic pathways. Factors like diet, lifestyle, genetics, and environment shape the gut microbiota composition together. Most research have explored how gut microbiota regulates host physiology and its potential in preventing and treating neurological disorders. However, the individual heterogeneity of gut microbiota, strains playing a dominant role in neurological diseases, and the interactions of these microbial metabolites with the central/peripheral nervous systems still need exploration. This review summarizes the potential role of gut microbiota in driving neurodevelopmental disorders (autism spectrum disorder and attention deficit/hyperactivity disorder), neurodegenerative diseases (Alzheimer's and Parkinson's disease), and mood disorders (anxiety and depression) in recent years and discusses the current clinical and preclinical gut microbe-based interventions, including dietary intervention, probiotics, prebiotics, and fecal microbiota transplantation. It also puts forward the current insufficient research on gut microbiota in neurological disorders and provides a framework for further research on neurological disorders.
{"title":"The gut microbiota–brain axis in neurological disorders","authors":"Mingming You, Nan Chen, Yuanyuan Yang, Lingjun Cheng, Hongzhang He, Yanhua Cai, Yating Liu, Haiyue Liu, Guolin Hong","doi":"10.1002/mco2.656","DOIUrl":"10.1002/mco2.656","url":null,"abstract":"<p>Previous studies have shown a bidirectional communication between human gut microbiota and the brain, known as the microbiota–gut–brain axis (MGBA). The MGBA influences the host's nervous system development, emotional regulation, and cognitive function through neurotransmitters, immune modulation, and metabolic pathways. Factors like diet, lifestyle, genetics, and environment shape the gut microbiota composition together. Most research have explored how gut microbiota regulates host physiology and its potential in preventing and treating neurological disorders. However, the individual heterogeneity of gut microbiota, strains playing a dominant role in neurological diseases, and the interactions of these microbial metabolites with the central/peripheral nervous systems still need exploration. This review summarizes the potential role of gut microbiota in driving neurodevelopmental disorders (autism spectrum disorder and attention deficit/hyperactivity disorder), neurodegenerative diseases (Alzheimer's and Parkinson's disease), and mood disorders (anxiety and depression) in recent years and discusses the current clinical and preclinical gut microbe-based interventions, including dietary intervention, probiotics, prebiotics, and fecal microbiota transplantation. It also puts forward the current insufficient research on gut microbiota in neurological disorders and provides a framework for further research on neurological disorders.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11260174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141736208","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}
Acquired resistance is a major obstacle to the therapeutic efficacy of osimertinib in lung adenocarcinoma (LUAD), but the underlying mechanisms are still not fully understood. Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in LUAD tumor-microenvironment (TME) and have emerged as a key player in chemoresistance. However, the function of CAFs in osimertinib resistance is still unclear. Here, we showed that CAFs derived from osimertinib-resistant LUAD tissues (CAFOR) produced much more colony-stimulating factor 2 (CSF2) than those isolated from osimertinib-sensitive tissues. CAFOR-derived CSF2 activated the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway and upregulated lnc-CSRNP3 in LUAD cells. Lnc-CSRNP3 then promoted the expression of nearby gene CSRNP3 by recruiting chromodomain helicase DNA binding protein 9 (CHD9) and inhibited the phosphatase activity of the serine/threonine protein phosphatase 1 catalytic subunit α (PP1α), thereby induced osimertinib resistance by enhancing ribosome biogenesis. Collectively, our study reveals a critical role for CAFs in the development of osimertinib resistance and identifies the CSF2 pathway as an attractive target for monitoring osimertinib efficacy and overcoming osimertinib resistance in LUAD.
{"title":"Cancer-associated fibroblast-derived colony-stimulating factor 2 confers acquired osimertinib resistance in lung adenocarcinoma via promoting ribosome biosynthesis","authors":"Yutang Huang, Xiaoqing Wang, Chunjie Wen, Jingchan Wang, Honghao Zhou, Lanxiang Wu","doi":"10.1002/mco2.653","DOIUrl":"https://doi.org/10.1002/mco2.653","url":null,"abstract":"<p>Acquired resistance is a major obstacle to the therapeutic efficacy of osimertinib in lung adenocarcinoma (LUAD), but the underlying mechanisms are still not fully understood. Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in LUAD tumor-microenvironment (TME) and have emerged as a key player in chemoresistance. However, the function of CAFs in osimertinib resistance is still unclear. Here, we showed that CAFs derived from osimertinib-resistant LUAD tissues (CAF<sup>OR</sup>) produced much more colony-stimulating factor 2 (CSF2) than those isolated from osimertinib-sensitive tissues. CAF<sup>OR</sup>-derived CSF2 activated the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway and upregulated lnc-CSRNP3 in LUAD cells. Lnc-CSRNP3 then promoted the expression of nearby gene <i>CSRNP3</i> by recruiting chromodomain helicase DNA binding protein 9 (CHD9) and inhibited the phosphatase activity of the serine/threonine protein phosphatase 1 catalytic subunit α (PP1α), thereby induced osimertinib resistance by enhancing ribosome biogenesis. Collectively, our study reveals a critical role for CAFs in the development of osimertinib resistance and identifies the CSF2 pathway as an attractive target for monitoring osimertinib efficacy and overcoming osimertinib resistance in LUAD.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.653","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732541","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}
Nanomaterials have aroused great interests in drug delivery due to their nanoscale structure, facile modifiability, and multifunctional physicochemical properties. Currently, stimuli-responsive nanomaterials that can respond to endogenous or exogenous stimulus display strong potentials in biomedical applications. In comparison with conventional nanomaterials, stimuli-responsive nanomaterials can improve therapeutic efficiency and reduce the toxicity of drugs toward normal tissues through specific targeting and on-demand drug release at pathological sites. In this review, we summarize the responsive mechanism of a variety of stimulus, including pH, redox, and enzymes within pathological microenvironment, as well as exogenous stimulus such as thermal effect, magnetic field, light, and ultrasound. After that, biomedical applications (e.g., drug delivery, imaging, and theranostics) of stimuli-responsive nanomaterials in a diverse array of common diseases, including cardiovascular diseases, cancer, neurological disorders, inflammation, and bacterial infection, are presented and discussed. Finally, the remaining challenges and outlooks of future research directions for the biomedical applications of stimuli-responsive nanomaterials are also discussed. We hope that this review can provide valuable guidance for developing stimuli-responsive nanomaterials and accelerate their biomedical applications in diseases diagnosis and treatment.
{"title":"Biomedical applications of stimuli-responsive nanomaterials","authors":"Xiaojie Chen, Di Wu, Zhong Chen","doi":"10.1002/mco2.643","DOIUrl":"https://doi.org/10.1002/mco2.643","url":null,"abstract":"<p>Nanomaterials have aroused great interests in drug delivery due to their nanoscale structure, facile modifiability, and multifunctional physicochemical properties. Currently, stimuli-responsive nanomaterials that can respond to endogenous or exogenous stimulus display strong potentials in biomedical applications. In comparison with conventional nanomaterials, stimuli-responsive nanomaterials can improve therapeutic efficiency and reduce the toxicity of drugs toward normal tissues through specific targeting and on-demand drug release at pathological sites. In this review, we summarize the responsive mechanism of a variety of stimulus, including pH, redox, and enzymes within pathological microenvironment, as well as exogenous stimulus such as thermal effect, magnetic field, light, and ultrasound. After that, biomedical applications (e.g., drug delivery, imaging, and theranostics) of stimuli-responsive nanomaterials in a diverse array of common diseases, including cardiovascular diseases, cancer, neurological disorders, inflammation, and bacterial infection, are presented and discussed. Finally, the remaining challenges and outlooks of future research directions for the biomedical applications of stimuli-responsive nanomaterials are also discussed. We hope that this review can provide valuable guidance for developing stimuli-responsive nanomaterials and accelerate their biomedical applications in diseases diagnosis and treatment.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.643","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732540","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}
Peng Liang, Minhua Peng, Jinsheng Tao, Bo Wang, Jinwang Wei, Lixuan Lin, Bo Cheng, Shan Xiong, Jianfu Li, Caichen Li, Ziwen Yu, Chunyan Li, Jun Wang, Hui Li, Zhiwei Chen, Jian-Bing Fan, Wenhua Liang, Jianxing He
To tackle misdiagnosis in lung cancer screening with low-dose computed tomography (LDCT), we aimed to compile a genome atlas for differentiating benign, preinvasive, and invasive lung nodules and characterize their molecular pathogenesis. We collected 432 lung nodule tissue samples from Chinese patients, spanning benign, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA). We performed comprehensive sequencing, examining somatic variants, gene expressions, and methylation levels. Our findings uncovered EGFR and TP53 mutations as key drivers in - early lung cancer development, with EGFR mutation frequency increasing with disease progression. Both EGFR mutations and EGF/EGFR hypo-methylation activated the EGFR pathway, fueling cancer growth. Transcriptome analysis identified four lung nodule subtypes (G1-4) with distinct molecular features and immune cell infiltrations: EGFR-driven G1, EGFR/TP53 co-mutation G2, inflamed G3, stem-like G4. Estrogen/androgen response was associated with the EGFR pathway, proposing a new therapy combining tyrosine kinase inhibitors with antiestrogens. Preinvasive nodules exhibited stem cell pathway enrichment, potentially hindering invasion. Epigenetic regulation of various genes was essential for lung cancer initiation and development. This study provides insights into the molecular mechanism of neoplastic progression and identifies potential diagnostic biomarkers and therapeutic targets for lung cancer.
{"title":"Development of a genome atlas for discriminating benign, preinvasive, and invasive lung nodules","authors":"Peng Liang, Minhua Peng, Jinsheng Tao, Bo Wang, Jinwang Wei, Lixuan Lin, Bo Cheng, Shan Xiong, Jianfu Li, Caichen Li, Ziwen Yu, Chunyan Li, Jun Wang, Hui Li, Zhiwei Chen, Jian-Bing Fan, Wenhua Liang, Jianxing He","doi":"10.1002/mco2.644","DOIUrl":"https://doi.org/10.1002/mco2.644","url":null,"abstract":"<p>To tackle misdiagnosis in lung cancer screening with low-dose computed tomography (LDCT), we aimed to compile a genome atlas for differentiating benign, preinvasive, and invasive lung nodules and characterize their molecular pathogenesis. We collected 432 lung nodule tissue samples from Chinese patients, spanning benign, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA). We performed comprehensive sequencing, examining somatic variants, gene expressions, and methylation levels. Our findings uncovered EGFR and TP53 mutations as key drivers in - early lung cancer development, with EGFR mutation frequency increasing with disease progression. Both EGFR mutations and EGF/EGFR hypo-methylation activated the EGFR pathway, fueling cancer growth. Transcriptome analysis identified four lung nodule subtypes (G1-4) with distinct molecular features and immune cell infiltrations: EGFR-driven G1, EGFR/TP53 co-mutation G2, inflamed G3, stem-like G4. Estrogen/androgen response was associated with the EGFR pathway, proposing a new therapy combining tyrosine kinase inhibitors with antiestrogens. Preinvasive nodules exhibited stem cell pathway enrichment, potentially hindering invasion. Epigenetic regulation of various genes was essential for lung cancer initiation and development. This study provides insights into the molecular mechanism of neoplastic progression and identifies potential diagnostic biomarkers and therapeutic targets for lung cancer.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.644","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730250","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}
Xuan Liu, Ming Zhou, Mujing Fang, Ying Xie, Peiwen Chen, Rirong Chen, Kun Wu, Jianghui Ye, Che Liu, Huachen Zhu, Tong Cheng, Lunzhi Yuan, Hui Zhao, Yi Guan, Ningshao Xia
The poor prognosis observed in elderly individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a serious clinical burden and the underlying mechanism is unclear, which necessities detailed investigation of disease characteristics and research for efficient countermeasures. To simulate lethal coronavirus disease 2019 (COVID-19) in senescent human patients, 80-week-old male hamsters are intranasally inoculated with different doses of SARS-CoV-2 Omicron BA.5 variant. Exposure to a low dose of the Omicron BA.5 variant results in early activation of the innate immune response, followed by rapid viral clearance and minimal lung damage. However, a high dose of BA.5 results in impaired interferon signaling, cytokine storm, uncontrolled viral replication, and severe lung injury. To decrease viral load and reverse the deterioration of COVID-19, a new bio-mimic decoy called CoVR-MV is used as a preventive or therapeutic agent. Administration of CoVR-MV as a preventive or therapeutic intervention in the early stages of infection can effectively suppress viral load, regulate the immune response, and rescue animals from death and critical illness. These findings underscore the risk associated with SARS-CoV-2 Omicron BA.5 exposure in senescent hamsters and highlight the importance of early intervention to prevent disease progression.
{"title":"Decisive reversal of lethal coronavirus disease 2019 in senescent hamster by synchronic antiviral and immunoregulatory intervention","authors":"Xuan Liu, Ming Zhou, Mujing Fang, Ying Xie, Peiwen Chen, Rirong Chen, Kun Wu, Jianghui Ye, Che Liu, Huachen Zhu, Tong Cheng, Lunzhi Yuan, Hui Zhao, Yi Guan, Ningshao Xia","doi":"10.1002/mco2.642","DOIUrl":"https://doi.org/10.1002/mco2.642","url":null,"abstract":"<p>The poor prognosis observed in elderly individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a serious clinical burden and the underlying mechanism is unclear, which necessities detailed investigation of disease characteristics and research for efficient countermeasures. To simulate lethal coronavirus disease 2019 (COVID-19) in senescent human patients, 80-week-old male hamsters are intranasally inoculated with different doses of SARS-CoV-2 Omicron BA.5 variant. Exposure to a low dose of the Omicron BA.5 variant results in early activation of the innate immune response, followed by rapid viral clearance and minimal lung damage. However, a high dose of BA.5 results in impaired interferon signaling, cytokine storm, uncontrolled viral replication, and severe lung injury. To decrease viral load and reverse the deterioration of COVID-19, a new bio-mimic decoy called CoVR-MV is used as a preventive or therapeutic agent. Administration of CoVR-MV as a preventive or therapeutic intervention in the early stages of infection can effectively suppress viral load, regulate the immune response, and rescue animals from death and critical illness. These findings underscore the risk associated with SARS-CoV-2 Omicron BA.5 exposure in senescent hamsters and highlight the importance of early intervention to prevent disease progression.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.642","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730249","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}
SAG (Sensitive to Apoptosis), also known as RBX2 (RING-box protein-2), is the RING subunit of Cullin-RING ligase-1 (CRL-1) and CRL-5, required for their ligase activities. Our recent studies found that in KrasG12D-induced mouse tumor models, Sag played an oncogenic or tumor-suppressive role in an organ-dependent manner.1-5 Specifically, Sag deletion significantly inhibited lung tumorigenesis by causing the accumulation of a variety of tumor suppressor proteins, including NOXA, p21/p27, DEPTOR, and IκBα.2 In the pancreas, Sag deletion converted mPanINs to neoplastic cystic lesions by causing Shoc2 accumulation,3 whereas Sag transgenic expression promoted mPanIN1 formation as the early event, and impairs pancreatic functions as the late event by causing accumulation of Deptor and Nrf2.5 However, in the skin, Sag deletion driven by a leaky expression of Pdx1-Cre promoted skin tumorigenesis through blocking autophagy and senescence by causing accumulation of Erbin to inactivate the Ras–Raf pathway, and of Nrf2 to scavenge the reactive oxygen species.4 Our earlier study also found that in a 7,12-dimethylbenz[a]anthracene/phorbol ester 12-O-tetradecanoylphorbol 13-acetate (DMBA/TPA)-induced skin carcinogenesis model, transgenic SAG expression inhibits the early-stage tumor progression by promoting c-Jun degradation to inhibit AP-1, and accelerates the late-stage tumor growth by promoting IκBα degradation to activate NF-κB and inhibit apoptosis.1 Whether and how Sag deletion affects skin carcinogenesis induced by DMBA/TPA is previously unknown.
In this study, we generated a K5-Cre;Sagfl/fl (designated as Sag−/−) mouse model in FVB/N background, in which Sag is conditionally deleted in the skin, driven by K5-Cre, along with the control mice with genotype of Sagfl/fl (designated as Sag+/+). Mice at the age of 7−8 weeks were used for the DMBA/TPA two-stage carcinogenesis protocol. Specifically, a single dose of DMBA (100 nmol) was topically applied to the shaved backs of mice, and TPA (5 nmol) was, 2 weeks after initiation, administrated twice weekly to the dorsal skin for 20 weeks. While Sag+/+ control mice developed a very limited number of skin tumors only in two out of seven mice, Sag−/- mice developed a much greater number of tumors in 4 out of 5 mice (Figure 1A, top and middle panels, and Figure S1A), indicating that Sag deletion promoted the development of skin tumors in this two-stage chemical carcinogenesis model.
To pursue the underlying mechanism, we hypothesized that Sag deletion would cause the accumulation of the oncogenic proteins to promote carcinogenesis. We then focused on yes-associated prot
总之,我们的研究符合以下工作模型:在DMBA-TPA诱导的皮肤癌变和TPA诱导的皮肤增殖过程中,Sag与Cul-5偶联,促进致癌蛋白(如Yap和c-Jun)的泛素化和降解,从而抑制肿瘤的进展。删除 Sag 后,这种抑制生长的作用被削弱,导致增殖和肿瘤进展加速。因此,Sag 似乎是皮肤中的肿瘤抑制因子。J.X.和Y.S.分析数据。Y.S.构思、指导项目并撰写手稿。本项目得到了国家重点研发计划(2021YFA1101000,Y.S.)和国家自然科学基金(U22A20317 和 92253203,Y.S.)的资助。所有程序均经密歇根大学动物使用和护理委员会批准(PRO00008986)。动物护理符合美国国家研究委员会《实验动物护理和使用指南》中规定的原则和程序。
{"title":"Sag deletion promotes DMBA/TPA-induced skin carcinogenesis via YAP accumulation","authors":"Yi Sun, Jie Xu, Dongping Wei, Hua Li","doi":"10.1002/mco2.648","DOIUrl":"10.1002/mco2.648","url":null,"abstract":"<p>Dear Editor,</p><p>SAG (Sensitive to Apoptosis), also known as RBX2 (RING-box protein-2), is the RING subunit of Cullin-RING ligase-1 (CRL-1) and CRL-5, required for their ligase activities. Our recent studies found that in <i>Kras<sup>G12D</sup></i>-induced mouse tumor models, Sag played an oncogenic or tumor-suppressive role in an organ-dependent manner.<span><sup>1-5</sup></span> Specifically, <i>Sag</i> deletion significantly inhibited lung tumorigenesis by causing the accumulation of a variety of tumor suppressor proteins, including NOXA, p21/p27, DEPTOR, and IκBα.<span><sup>2</sup></span> In the pancreas, <i>Sag</i> deletion converted mPanINs to neoplastic cystic lesions by causing Shoc2 accumulation,<span><sup>3</sup></span> whereas Sag transgenic expression promoted mPanIN1 formation as the early event, and impairs pancreatic functions as the late event by causing accumulation of Deptor and Nrf2.<span><sup>5</sup></span> However, in the skin, <i>Sag</i> deletion driven by a leaky expression of Pdx1-Cre promoted skin tumorigenesis through blocking autophagy and senescence by causing accumulation of Erbin to inactivate the Ras–Raf pathway, and of Nrf2 to scavenge the reactive oxygen species.<span><sup>4</sup></span> Our earlier study also found that in a 7,12-dimethylbenz[a]anthracene/phorbol ester 12-O-tetradecanoylphorbol 13-acetate (DMBA/TPA)-induced skin carcinogenesis model, transgenic SAG expression inhibits the early-stage tumor progression by promoting c-Jun degradation to inhibit AP-1, and accelerates the late-stage tumor growth by promoting IκBα degradation to activate NF-κB and inhibit apoptosis.<span><sup>1</sup></span> Whether and how <i>Sag</i> deletion affects skin carcinogenesis induced by DMBA/TPA is previously unknown.</p><p>In this study, we generated a <i>K5-Cre;Sag<sup>fl/fl</sup></i> (designated as <i>Sag<sup>−/−</sup></i>) mouse model in FVB/N background, in which <i>Sag</i> is conditionally deleted in the skin, driven by K5-Cre, along with the control mice with genotype of <i>Sag<sup>fl/fl</sup></i> (designated as <i>Sag<sup>+/+</sup></i>). Mice at the age of 7−8 weeks were used for the DMBA/TPA two-stage carcinogenesis protocol. Specifically, a single dose of DMBA (100 nmol) was topically applied to the shaved backs of mice, and TPA (5 nmol) was, 2 weeks after initiation, administrated twice weekly to the dorsal skin for 20 weeks. While <i>Sag<sup>+/+</sup></i> control mice developed a very limited number of skin tumors only in two out of seven mice, <i>Sag<sup>−/-</sup></i> mice developed a much greater number of tumors in 4 out of 5 mice (Figure 1A, top and middle panels, and Figure S1A), indicating that <i>Sag</i> deletion promoted the development of skin tumors in this two-stage chemical carcinogenesis model.</p><p>To pursue the underlying mechanism, we hypothesized that <i>Sag</i> deletion would cause the accumulation of the oncogenic proteins to promote carcinogenesis. We then focused on yes-associated prot","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11253290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636317","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}
Overweight and obesity affect almost 2 billion adults worldwide, and food restriction (FR) is commonly used to reduce body fat. Whether refeeding (Re) after FR at different ages and to different degrees leads to overweight and its possible mechanisms are uncertain. In this study, adult and young mice were both restricted to 15% and 40% of their casual food intake, and then were fed 60% high-fat chow (FR15%–Re, FR40%–Re), whereas the control groups(CON) consumed high-fat or normal food throughout, respectively. The results of the study suggest that mild FR-heavy feeding may lead to more significant abnormal fat accumulation, liver damage, and increased recruitment of intestinal inflammatory factors and immune cells in mice of different ages and involves multiple types of alterations in the gut microbiota. Further fecal transplantation experiments as well as serum and liver enzyme-linked immunosorbent assay experiments preliminarily suggest that the link between lipid metabolism and inflammatory responses and the gut microbiota may be related to the regulation of the gut and live by Lipopolysaccharides(LPS) and Peroxisome Proliferator-Activated Receptor-Alpha(PPAR-α). In addition, our study may also serve as a reference for studying obesity prevention and treatment programs at different ages.
{"title":"Different depths of food restriction and high-fat diet refeeding in mice impact host obesity and metabolic phenotypes with correlative changes in the gut microbiota","authors":"Jiaqi Xu, Huangru Xu, Feiyan Yang, Yawen Xie, Fangfang Cai, Siyu Mao, Min Lu, Hongqin Zhuang, Zi-Chun Hua","doi":"10.1002/mco2.641","DOIUrl":"10.1002/mco2.641","url":null,"abstract":"<p>Overweight and obesity affect almost 2 billion adults worldwide, and food restriction (FR) is commonly used to reduce body fat. Whether refeeding (Re) after FR at different ages and to different degrees leads to overweight and its possible mechanisms are uncertain. In this study, adult and young mice were both restricted to 15% and 40% of their casual food intake, and then were fed 60% high-fat chow (FR15%–Re, FR40%–Re), whereas the control groups(CON) consumed high-fat or normal food throughout, respectively. The results of the study suggest that mild FR-heavy feeding may lead to more significant abnormal fat accumulation, liver damage, and increased recruitment of intestinal inflammatory factors and immune cells in mice of different ages and involves multiple types of alterations in the gut microbiota. Further fecal transplantation experiments as well as serum and liver enzyme-linked immunosorbent assay experiments preliminarily suggest that the link between lipid metabolism and inflammatory responses and the gut microbiota may be related to the regulation of the gut and live by Lipopolysaccharides(LPS) and Peroxisome Proliferator-Activated Receptor-Alpha(PPAR-α). In addition, our study may also serve as a reference for studying obesity prevention and treatment programs at different ages.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11253304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636316","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}
Neutrophil extracellular traps (NETs), which consist of chromatin DNA studded with granule proteins, are released by neutrophils in response to both infectious and sterile inflammation. Beyond the canonical role in defense against pathogens, the extrusion of NETs also contributes to the initiation, metastasis, and therapeutic response of malignant diseases. Recently, NETs have been implicated in the development and therapeutic responses of various types of tumors. Although extensive work regarding inflammation in tumors has been reported, a comprehensive summary of how these web-like extracellular structures initiate and propagate tumor progression under the specific microenvironment is lacking. In this review, we demonstrate the initiators and related signaling pathways that trigger NETs formation in cancers. Additionally, this review will outline the current molecular mechanisms and regulatory networks of NETs during dormant cancer cells awakening, circulating tumor cells (CTCs) extravasation, and metastatic recurrence of cancer. This is followed by a perspective on the current and potential clinical potential of NETs as therapeutic targets in the treatment of both local and metastatic disease, including the improvement of the efficacy of existing therapies.
中性粒细胞胞外捕获物(NET)由染色质 DNA 和颗粒蛋白质组成,在感染性和无菌性炎症时由中性粒细胞释放。除了在防御病原体方面的典型作用外,NETs 的挤出还有助于恶性疾病的发生、转移和治疗反应。最近,NETs 与各类肿瘤的发展和治疗反应有关。虽然有关肿瘤炎症的大量工作已经报道,但还缺乏对这些网状细胞外结构如何在特定微环境下启动和传播肿瘤进展的全面总结。在本综述中,我们将展示引发癌症中 NET 形成的启动因子和相关信号通路。此外,本综述还将概述目前在休眠癌细胞苏醒、循环肿瘤细胞(CTC)外渗和癌症转移复发过程中 NETs 的分子机制和调控网络。随后,还将透视 NETs 作为治疗靶点在治疗局部和转移性疾病方面的当前和潜在临床潜力,包括改善现有疗法的疗效。
{"title":"Neutrophil extracellular traps in cancer","authors":"Yuxi Ma, Jielin Wei, Wenshan He, Jinghua Ren","doi":"10.1002/mco2.647","DOIUrl":"https://doi.org/10.1002/mco2.647","url":null,"abstract":"<p>Neutrophil extracellular traps (NETs), which consist of chromatin DNA studded with granule proteins, are released by neutrophils in response to both infectious and sterile inflammation. Beyond the canonical role in defense against pathogens, the extrusion of NETs also contributes to the initiation, metastasis, and therapeutic response of malignant diseases. Recently, NETs have been implicated in the development and therapeutic responses of various types of tumors. Although extensive work regarding inflammation in tumors has been reported, a comprehensive summary of how these web-like extracellular structures initiate and propagate tumor progression under the specific microenvironment is lacking. In this review, we demonstrate the initiators and related signaling pathways that trigger NETs formation in cancers. Additionally, this review will outline the current molecular mechanisms and regulatory networks of NETs during dormant cancer cells awakening, circulating tumor cells (CTCs) extravasation, and metastatic recurrence of cancer. This is followed by a perspective on the current and potential clinical potential of NETs as therapeutic targets in the treatment of both local and metastatic disease, including the improvement of the efficacy of existing therapies.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.647","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141624512","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}
Minimal hepatic encephalopathy (MHE) has a substantial impact on the clinical outcomes and quality of life (QOL) of patients with cirrhosis. However, timely diagnosis and intervention are challenging due to sophisticated diagnostic methods. In this study, 673 healthy controls and 905 patients with cirrhosis were screened, and 660 healthy controls and 757 patients with cirrhosis, divided into the test (292 patients) and validation (465 patients) cohort, were analyzed after screening. A diagnostic model of the Stroop test (Stroop-CN) was constructed by multivariate linear regression based on the results of healthy controls. The prevalence of MHE and the comparison results with psychometric hepatic encephalopathy score through the Stroop-CN model were stable in the test and validation cohorts. Moreover, the prevalence of MHE remained significantly higher in patients with worse disease conditions marked as high Child–Pugh grades and the Model for End-stage Liver Disease and Sodium (MELD-Na) scores in the test and validation cohort. The EuroQol 5-D questionnaire revealed that patients with MHE had a worse QOL than those without MHE both in the test and validation cohort. In conclusion, an easy and practical Stroop-CN model for MHE diagnosis based on the EncephalApp is established. It is found that a considerable number of Chinese patients with cirrhosis experience MHE, which significantly impacts their QOL.
{"title":"Detection of minimal hepatic encephalopathy in patients with cirrhosis based on the Stroop-CN model (NCRCID-CHESS 2106): a prospective multicenter study","authors":"Xiaoyan Li, Shanghao Liu, Ying Guo, Hongmei Zu, Huiling Xiang, Shaoqi Yang, Xiaoning Zhang, Fanping Meng, Yangzhen Bianba, Jie Li, Fei Liu, Chuang Lei, Jiaojian Lv, Qiao-hua Yang, Wei Fu, Wei Ye, Jiafang Chen, Yanjing Gao, Caiyun Wu, Ningning Wang, Qi Zheng, Fang Wang, Jiali Yu, Jing Wang, Xiaoting Yang, Xiangmei Wang, Yayuan Liu, Xuelan Zhao, Chenxi Wu, Wei Gou, Jasmohan S. Bajaj, Fu-Sheng Wang, Junliang Fu, Xiaolong Qi","doi":"10.1002/mco2.627","DOIUrl":"https://doi.org/10.1002/mco2.627","url":null,"abstract":"<p>Minimal hepatic encephalopathy (MHE) has a substantial impact on the clinical outcomes and quality of life (QOL) of patients with cirrhosis. However, timely diagnosis and intervention are challenging due to sophisticated diagnostic methods. In this study, 673 healthy controls and 905 patients with cirrhosis were screened, and 660 healthy controls and 757 patients with cirrhosis, divided into the test (292 patients) and validation (465 patients) cohort, were analyzed after screening. A diagnostic model of the Stroop test (Stroop-CN) was constructed by multivariate linear regression based on the results of healthy controls. The prevalence of MHE and the comparison results with psychometric hepatic encephalopathy score through the Stroop-CN model were stable in the test and validation cohorts. Moreover, the prevalence of MHE remained significantly higher in patients with worse disease conditions marked as high Child–Pugh grades and the Model for End-stage Liver Disease and Sodium (MELD-Na) scores in the test and validation cohort. The EuroQol 5-D questionnaire revealed that patients with MHE had a worse QOL than those without MHE both in the test and validation cohort. In conclusion, an easy and practical Stroop-CN model for MHE diagnosis based on the EncephalApp is established. It is found that a considerable number of Chinese patients with cirrhosis experience MHE, which significantly impacts their QOL.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.627","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141624514","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}