IF 10.7

MedComm Pub Date : 2025-02-13 DOI: 10.1002/mco2.70082

Chen Tang, Shengmeng Peng, Yongming Chen, Bisheng Cheng, Shurui Li, Jie Zhou, Yongxin Wu, Lingfeng Li, Haitao Zhong, Zhenghui Guo, Yiming Lai, Hai Huang

{"title":"SHCBP1 is a novel regulator of PLK1 phosphorylation and promotes prostate cancer bone metastasis","authors":"Chen Tang, Shengmeng Peng, Yongming Chen, Bisheng Cheng, Shurui Li, Jie Zhou, Yongxin Wu, Lingfeng Li, Haitao Zhong, Zhenghui Guo, Yiming Lai, Hai Huang","doi":"10.1002/mco2.70082","DOIUrl":"https://doi.org/10.1002/mco2.70082","url":null,"abstract":"Prostate cancer is a common male genitourinary malignancy with bone metastasis posing challenges for prognosis and treatment. This study aimed to investigate the role of SHC protein SH2 structural domain binding protein 1 (SHCBP1) in prostate cancer bone metastasis. Whole transcriptome sequencing of prostate cancer samples was conducted to identify oncogene expression, specifically focusing on SHCBP1. In vivo and in vitro models were used to study SHCBP1's impact on bone metastasis. Through co-immunoprecipitation, mass spectrometry, and Western blot assays, the interaction between SHCBP1 and cell cycle-related proteins was elucidated, along with analysis of downstream protein partners. SHCBP1 was found to enhance prostate cancer cell development, metastasis, and mitosis, with the SHCBP1—polo-like kinase 1 (PLK1)—CDC25C axis playing a key role in promoting tumorigenesis. Therapeutic inhibition of SHCBP1 increased docetaxel sensitivity. Clinical data showed elevated SHCBP1 expression in advanced prostate cancer stages. These findings offer insights into potential therapeutic strategies for prostate cancer bone metastasis and highlight the significance of the SHCBP1-PLK1-CDC25C axis in docetaxel sensitivity.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endothelial monocarboxylate transporter 1 drives atherosclerosis via a lactate/NADH/CtBP-mediated transrepression pathway 内皮单羧酸盐转运体 1 通过乳酸盐/NADH/CtBP 介导的转抑途径驱动动脉粥样硬化

IF 10.7

MedComm Pub Date : 2025-02-13 DOI: 10.1002/mco2.70089

Zou Li, Shuai Guo, Kaixiang Cao, Yuxi Duan, Yuan Zhao, Yuting Zhang, Shihui Yu, Zaixia Bai, Runfa Yu, Yixin Chen, Ziling Li, Shuqi Huang, Mingchuan Song, Cailing Wang, Wenzhong Hou, Jun He, Bin Yang, Yiming Xu

{"title":"Endothelial monocarboxylate transporter 1 drives atherosclerosis via a lactate/NADH/CtBP-mediated transrepression pathway","authors":"Zou Li, Shuai Guo, Kaixiang Cao, Yuxi Duan, Yuan Zhao, Yuting Zhang, Shihui Yu, Zaixia Bai, Runfa Yu, Yixin Chen, Ziling Li, Shuqi Huang, Mingchuan Song, Cailing Wang, Wenzhong Hou, Jun He, Bin Yang, Yiming Xu","doi":"10.1002/mco2.70089","DOIUrl":"https://doi.org/10.1002/mco2.70089","url":null,"abstract":"The accumulation of lactate in tissue microenvironments is associated with atherosclerosis, but its precise role in atherogenesis remains largely unknown. This study demonstrated that lactate accumulation in aortic tissues and blood is correlated with increased monocarboxylate transporter 1 (Mct1) expression in endothelial cells (ECs) within atherosclerotic plaques. Lactate uptake via Mct1 triggers an inflammatory response in ECs. The administration of endothelial-targeting nanoparticles containing siRNA against Mct1 reduces endothelial inflammation and atherogenesis in Apoe−/− mice. Mechanistic studies revealed that the conversion of lactate to pyruvate, along with NADH production and oligomerization of the NADH-sensitive transcriptional corepressor C-terminal binding protein 1 (CtBP1), is necessary for the proinflammatory effects of lactate. Monomeric CtBP1 interacts with the transcriptional repressor forkhead box P1 (FOXP1) to suppress endothelial adhesion molecule expression. However, NADH-induced oligomerization of CtBP1 prevents its binding to FOXP1, significantly reducing FOXP1-mediated transrepression of endothelial adhesion molecules. Moreover, silencing Foxp1 in ECs negates the atheroprotective effect of endothelial Mct1 knockdown in Apoe−/− mice. These findings suggest that lactate/MCT1-induced epigenetic reprogramming represents a potential therapeutic target in atherosclerosis.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gene therapy for genetic diseases: challenges and future directions 遗传疾病的基因治疗：挑战与未来方向

IF 10.7

MedComm Pub Date : 2025-02-13 DOI: 10.1002/mco2.70091

Beibei Qie, Jianghua Tuo, Feilong Chen, Haili Ding, Lei Lyu

{"title":"Gene therapy for genetic diseases: challenges and future directions","authors":"Beibei Qie, Jianghua Tuo, Feilong Chen, Haili Ding, Lei Lyu","doi":"10.1002/mco2.70091","DOIUrl":"https://doi.org/10.1002/mco2.70091","url":null,"abstract":"Genetic diseases constitute the majority of rare human diseases, resulting from abnormalities in an individual's genetic composition. Traditional treatments offer limited relief for these challenging conditions. In contrast, the rapid advancement of gene therapy presents significant advantages by directly addressing the underlying causes of genetic diseases, thereby providing the potential for precision treatment and the possibility of curing these disorders. This review aims to delineate the mechanisms and outcomes of current gene therapy approaches in clinical applications across various genetic diseases affecting different body systems. Additionally, genetic muscular disorders will be examined as a case study to investigate innovative strategies of novel therapeutic approaches, including gene replacement, gene suppression, gene supplementation, and gene editing, along with their associated advantages and limitations at both clinical and preclinical levels. Finally, this review emphasizes the existing challenges of gene therapy, such as vector packaging limitations, immunotoxicity, therapy specificity, and the subcellular localization and immunogenicity of therapeutic cargos, while discussing potential optimization directions for future research. Achieving delivery specificity, as well as long-term effectiveness and safety, will be crucial for the future development of gene therapies targeting genetic diseases.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Therapeutic potential of nicotinamide and ABT263 in alcohol-associated liver disease through targeting cellular senescence

IF 10.7

MedComm Pub Date : 2025-02-09 DOI: 10.1002/mco2.70086

Naheemat Modupeola Gold, Qinchao Ding, Yang Yang, Shaoyan Pu, Wenjing Cao, Xinxuan Ge, Pengyun Yang, Michael Ngozi Okeke, Ayesha Nisar, Yongzhang Pan, Qiuni Luo, Xiayan Wang, Han Xu, Rui Tian, Meiting Zi, Xingjie Zhang, Songtao Li, Yonghan He

{"title":"Therapeutic potential of nicotinamide and ABT263 in alcohol-associated liver disease through targeting cellular senescence","authors":"Naheemat Modupeola Gold, Qinchao Ding, Yang Yang, Shaoyan Pu, Wenjing Cao, Xinxuan Ge, Pengyun Yang, Michael Ngozi Okeke, Ayesha Nisar, Yongzhang Pan, Qiuni Luo, Xiayan Wang, Han Xu, Rui Tian, Meiting Zi, Xingjie Zhang, Songtao Li, Yonghan He","doi":"10.1002/mco2.70086","DOIUrl":"https://doi.org/10.1002/mco2.70086","url":null,"abstract":"Alcohol-associated liver disease (ALD) is a major cause of liver-related morbidity and mortality, yet clinically effective therapies for ALD remain lacking. Here, we demonstrate that alcohol intake and its metabolite, acetaldehyde (ACH), induce senescence in the liver and liver cells, respectively. To assess the therapeutic potential of targeting liver senescence in ALD, we treated ALD-affected mice with the senolytic compound ABT263 and the senomorphic NAD+ precursor, nicotinamide (NAM). The results show that ABT263 effectively clears senescent hepatocytes and stellate cells, and reduces liver triglyceride (TG), but increases plasma alanine aminotransferase and TG levels. Conversely, NAM efficiently suppresses senescence and the senescence-associated secretory phenotype (SASP), protecting the liver from alcohol-induced injury in ALD mice. RNA-sequencing analysis revealed that ABT263 treatment downregulated genes involved in adipogenesis while activating the complement pathway. In contrast, NAM upregulated metabolism-related genes, such as Sirt1, and downregulated DNA damage marker genes, including Rec8 and E2f1, in the liver. These findings suggest that cellular senescence plays a critical role in alcohol-induced liver injury. Compared with senescent cell clearance by ABT263, suppressing senescence and SASP by NAM may provide a safer and more effective therapeutic approach for ALD.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Recombinant protein HR212 targeting heptad repeat 2 domain in spike protein S2 subunit elicits broad-spectrum neutralizing antibodies against SARS-CoV-2 and its variants

IF 10.7

MedComm Pub Date : 2025-02-09 DOI: 10.1002/mco2.70088

Ying Lu, An-Qi Li, Fan Shen, Wen-Qiang He, Shu-Heng Yu, Yan-Bo Zhao, Xiao-Li Feng, Ming-Hua Li, Songying Ouyang, Yong-Tang Zheng, Wei Pang

{"title":"Recombinant protein HR212 targeting heptad repeat 2 domain in spike protein S2 subunit elicits broad-spectrum neutralizing antibodies against SARS-CoV-2 and its variants","authors":"Ying Lu, An-Qi Li, Fan Shen, Wen-Qiang He, Shu-Heng Yu, Yan-Bo Zhao, Xiao-Li Feng, Ming-Hua Li, Songying Ouyang, Yong-Tang Zheng, Wei Pang","doi":"10.1002/mco2.70088","DOIUrl":"https://doi.org/10.1002/mco2.70088","url":null,"abstract":"SARS-CoV-2 variants are under continuous emergence carry numerous mutations within S1 subunit in spike protein and have escaped neutralization through many currently used vaccines and antibodies. The development of next-generation vaccines is a continuing and long-term need. In our prior research, the recombinant protein vaccine HR121 targeting the heptad repeat (HR) 1 domain of S2 subunit was constructed, which could evoke highly broad-spectrum neutralizing antibodies in vivo and confer efficient protective effect on several SARS-CoV-2 variants within multiple animal models. Compared with HR1, HR2 domain shows a more conservative degree within SARS-CoV-2 and related coronaviruses. Here, we designed a recombinant protein HR212 consisting of HR2–linker1–HR1–linker2–HR2. HR212 showed a high affinity with HR1 and was functionally analogous to HR2 within fusion intermediate in S2 subunit. Immunizing rabbits using HR212-mediated high nAbs for 28 pseudotyped SARS-CoV-2 variants, like currently circulating variants, such as BA.2.86 and JN.1. Transfer of rabbit anti-HR212 sera or immunization with HR212 offered efficient protective effect on SARS-CoV-2 ancestral strain and Omicron BA.2 variant infections of Syrian golden hamsters. According to our results, HR2 domain of S2 subunit is the novel target that can be used to develop broad-spectrum vaccines to resist SARS-CoV-2 variants.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Circular RNAs in cancer

IF 10.7

MedComm Pub Date : 2025-02-02 DOI: 10.1002/mco2.70079

Yang Guo, Qiang Huang, Yu Heng, Yujuan Zhou, Hui Chen, Chengzhi Xu, Chunping Wu, Lei Tao, Liang Zhou

{"title":"Circular RNAs in cancer","authors":"Yang Guo, Qiang Huang, Yu Heng, Yujuan Zhou, Hui Chen, Chengzhi Xu, Chunping Wu, Lei Tao, Liang Zhou","doi":"10.1002/mco2.70079","DOIUrl":"https://doi.org/10.1002/mco2.70079","url":null,"abstract":"Circular RNA (circRNA), a subtype of noncoding RNA, has emerged as a significant focus in RNA research due to its distinctive covalently closed loop structure. CircRNAs play pivotal roles in diverse physiological and pathological processes, functioning through mechanisms such as miRNAs or proteins sponging, regulation of splicing and gene expression, and serving as translation templates, particularly in the context of various cancers. The hallmarks of cancer comprise functional capabilities acquired during carcinogenesis and tumor progression, providing a conceptual framework that elucidates the nature of the malignant transformation. Although numerous studies have elucidated the role of circRNAs in the hallmarks of cancers, their functions in the development of chemoradiotherapy resistance remain unexplored and the clinical applications of circRNA-based translational therapeutics are still in their infancy. This review provides a comprehensive overview of circRNAs, covering their biogenesis, unique characteristics, functions, and turnover mechanisms. We also summarize the involvement of circRNAs in cancer hallmarks and their clinical relevance as biomarkers and therapeutic targets, especially in thyroid cancer (TC). Considering the potential of circRNAs as biomarkers and the fascination of circRNA-based therapeutics, the “Ying-Yang” dynamic regulations of circRNAs in TC warrant vastly dedicated investigations.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143110430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CD25 downregulation by tumor exosomal microRNA-15a promotes interleukin-17-producing γδ-T-cells-mediated radioresistance in nasopharyngeal carcinoma

IF 10.7

MedComm Pub Date : 2025-02-02 DOI: 10.1002/mco2.70078

Xiwei Wang, Zheng Xiang, Yanmei Zhang, Chloe Ran Tu, Chunyu Huang, Yuet Chung, Wenyue Zhang, Manni Wang, Yinping Liu, Wenwei Tu

{"title":"CD25 downregulation by tumor exosomal microRNA-15a promotes interleukin-17-producing γδ-T-cells-mediated radioresistance in nasopharyngeal carcinoma","authors":"Xiwei Wang, Zheng Xiang, Yanmei Zhang, Chloe Ran Tu, Chunyu Huang, Yuet Chung, Wenyue Zhang, Manni Wang, Yinping Liu, Wenwei Tu","doi":"10.1002/mco2.70078","DOIUrl":"https://doi.org/10.1002/mco2.70078","url":null,"abstract":"Interleukin (IL)-17-producing γδ-T cells (γδT-17) are a major source of IL-17 within the tumor microenvironment and have been shown to influence tumor development and therapy outcomes in various cancers. However, the role and presence of γδT-17 cells in nasopharyngeal carcinoma (NPC) remain poorly understood. It is also unclear how these cells might affect radiotherapy, the primary treatment for NPC patients. In this study, we discovered that NPC tumor tissues were rich in γδT-17 cells. Exosomes released from NPC cells (NPC-Exos) could direct γδ-T cells to differentiate into γδT-17 cells. These NPC-Exos-induced γδT-17 cells were found to enhance radioresistance in NPC, both in vitro and in vivo. Blocking IL-17 secreted by NPC-Exos-induced γδT-17 cells restored NPC cell sensitivity to radiation and elevated radiation-induced cell death. Mechanistic studies revealed that NPC-Exos not only increased the release of IL-17-promoting cytokines IL-1β, IL-6, and IL-23 from dendritic cells, but also suppressed CD25/IL-2 signaling in γδ-T cells, facilitating γδT-17 differentiation. The suppression of CD25/IL-2 signaling was driven by microRNA-15a (miR-15a) carried by NPC exosomes. Furthermore, miR-15a inhibitors were able to prevent γδT-17 induction by NPC-Exos. Our findings reveal a novel immunoregulatory role of NPC-Exos and offer potential strategies to combat NPC radioresistance.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143110433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antimicrobial peptide DP7 alleviates dextran sulfate sodium (DSS)-induced colitis via modifying gut microbiota and regulating intestinal barrier function

IF 10.7

MedComm Pub Date : 2025-01-30 DOI: 10.1002/mco2.70085

Binyan Zhao, Hongyou Zhou, Ke Lin, Jie Xu, Bailing Zhou, Daoyuan Xie, Jing Ma, Lei Yang, Chunyan Su, Li Yang

{"title":"Antimicrobial peptide DP7 alleviates dextran sulfate sodium (DSS)-induced colitis via modifying gut microbiota and regulating intestinal barrier function","authors":"Binyan Zhao, Hongyou Zhou, Ke Lin, Jie Xu, Bailing Zhou, Daoyuan Xie, Jing Ma, Lei Yang, Chunyan Su, Li Yang","doi":"10.1002/mco2.70085","DOIUrl":"10.1002/mco2.70085","url":null,"abstract":"Inflammatory bowel diseases (IBDs), such as Crohn's disease (CD) and ulcerative colitis (UC), represent a growing global health concern. Restoring the balance of the gut microbiota, a crucial factor in intestinal health, offers potential for treating IBD. DP7, a novel antimicrobial peptide with potent antibacterial activity, was investigated for its anti-inflammatory effects in a dextran sulfate sodium (DSS)-induced UC mouse model. DP7 significantly ameliorated key disease parameters, including disease activity index, weight loss, and shortened colon length, while preserving colonic epithelial integrity and reducing inflammatory infiltration. Further analysis revealed potential targets of DP7, highlighting the significant role of Muribaculaceae bacteria during inflammatory states. To further explore the role of the gut microbiota in DP7's efficacy, fecal microbiota transplantation (FMT) was performed using feces from DP7-treated mice. FMT successfully ameliorated colitis in recipient mice, providing further evidence for the crucial role of the gut microbiome in IBD treatment and DP7's ability to modulate the gut microbiota for therapeutic benefit. Moreover, our findings suggest that DP7's modulation of the immune system is intricately linked to the complex microbial environment. Our findings demonstrate that DP7 effectively mitigates inflammation, attenuates barrier dysfunction, and shapes the gut microbiota, suggesting its potential as a therapeutic agent for UC.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Outer membrane vesicle contributes to the Pseudomonas aeruginosa resistance to antimicrobial peptides in the acidic airway of bronchiectasis patients

IF 10.7

MedComm Pub Date : 2025-01-30 DOI: 10.1002/mco2.70084

Yingzhou Xie, Yi-Han Shi, Le-Le Wang, Cheng-Wei Li, Min Wu, Jin-Fu Xu

{"title":"Outer membrane vesicle contributes to the Pseudomonas aeruginosa resistance to antimicrobial peptides in the acidic airway of bronchiectasis patients","authors":"Yingzhou Xie, Yi-Han Shi, Le-Le Wang, Cheng-Wei Li, Min Wu, Jin-Fu Xu","doi":"10.1002/mco2.70084","DOIUrl":"10.1002/mco2.70084","url":null,"abstract":"Pseudomonas aeruginosa is the predominant pathogen causing chronic infection in the airway of patients with bronchiectasis (BE), a chronic respiratory disease with high prevalence worldwide. Environmental factors are vital for bacterial successful colonization. Here, with sputa and bronchoalveolar lavage fluids, we determined that the concentration of airway antimicrobial peptide LL-37 and lactate was elevated in BE patients, especially in those infected with P. aeruginosa. The in vitro antibacterial assay revealed the bactericidal activity of LL-37 against the clinical P. aeruginosa isolates, which were dampened in the acidic condition. P. aeruginosa production of outer membrane vesicles (OMVs) enhanced in the lactate-adjusted acidic condition. Transcriptomic analysis suggested that OMVs induce the hyperproduction of the chemical compound 2-heptyl-4-quinolone (HHQ) in the bacterial population, which was verified by high-performance liquid chromatography. The positively charged HHQ interfered with the binding of LL-37 to bacterial cell membrane, potentiating the P. aeruginosa resistance to LL-37. To our knowledge, this is a new resistance mechanism of P. aeruginosa against antimicrobial peptides and may provide theoretical support for the development of new antibacterial therapies.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Salt-inducible kinase 2 confers radioresistance in colorectal cancer by facilitating homologous recombination repair

IF 10.7

MedComm Pub Date : 2025-01-28 DOI: 10.1002/mco2.70083

Yuan Meng, Shuo Li, Da-Shan Lu, Xue Chen, Lu Li, You-fa Duan, Gao-yuan Wang, Wenlin Huang, Ran-yi Liu

{"title":"Salt-inducible kinase 2 confers radioresistance in colorectal cancer by facilitating homologous recombination repair","authors":"Yuan Meng, Shuo Li, Da-Shan Lu, Xue Chen, Lu Li, You-fa Duan, Gao-yuan Wang, Wenlin Huang, Ran-yi Liu","doi":"10.1002/mco2.70083","DOIUrl":"10.1002/mco2.70083","url":null,"abstract":"Resistance to radiotherapy remains a critical barrier in treating colorectal cancer (CRC), particularly in cases of locally advanced rectal cancer (LARC). To identify key kinases involved in CRC radioresistance, we employed a kinase-targeted CRISPR-Cas9 library screen. This approach aimed to identify potential kinase inhibitors as radiosensitizers. Our screening identified salt-inducible kinase 2 (SIK2) as a critical factor in CRC radioresistance. Increased SIK2 expression correlated with reduced tumor regression and poorer outcomes in LARC patients undergoing neoadjuvant chemoradiotherapy. The depletion of SIK2 significantly enhanced radiation-induced apoptosis and tumor regression. Mechanistically, SIK2 interacts with valosin-containing protein (VCP), promoting its hyperphosphorylation. This modification improves VCP's capacity to extract K48-linked ubiquitin-conjugated proteins from chromatin, thus aiding the recruitment of RPA and RAD51 to DNA damage sites. This mechanism strengthens homologous recombination–mediated DNA repair, which contributes to radioresistance. Importantly, ARN-3236, a SIK2 inhibitor, markedly sensitized CRC cells to radiation both in vivo and in vitro, providing a potential strategy to overcome radioresistance. In summary, our findings reveal a novel mechanism by which SIK2 contributes to the radioresistance of CRC, proposing SIK2 as a potential therapeutic target with its inhibitor significantly enhancing CRC radiotherapy efficacy.","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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