Journal of advanced research最新文献

{"title":"RNA modification gene WDR4 facilitates tumor progression and immunotherapy resistance in breast cancer.","authors":"Yongzhou Luo, Wenwen Tian, Da Kang, Linyu Wu, Hailin Tang, Sifen Wang, Chao Zhang, Yi Xie, Yue Zhang, Jindong Xie, Xinpei Deng, Hao Zou, Hao Wu, Huan Lin, Weidong Wei","doi":"10.1016/j.jare.2024.06.029","DOIUrl":"10.1016/j.jare.2024.06.029","url":null,"abstract":"<p><strong>Introduction: </strong>Growing interest toward RNA modification in cancer has inspired the exploration of gene sets related to multiple RNA modifications. However, a comprehensive elucidation of the clinical value of various RNA modifications in breast cancer is still lacking.</p><p><strong>Objectives: </strong>This study aimed to provide a strategy based on RNA modification-related genes for predicting therapy response and survival outcomes in breast cancer patients.</p><p><strong>Methods: </strong>Genes related to thirteen RNA modification patterns were integrated for establishing a nine-gene-containing signature-RMscore. Alterations of tumor immune microenvironment and therapy response featured by different RMscore levels were assessed by bulk transcriptome, single-cell transcriptome and genomics analyses. The biological function of key RMscore-related molecules was investigated by cellular experiments in vitro and in vivo, using flow cytometry, immunohistochemistry and immunofluorescence staining.</p><p><strong>Results: </strong>This study has raised an effective therapy strategy for breast cancer patients after a well-rounded investigation of RNA modification-related genes. With a great performance of predicting patient prognosis, high levels of the RMscore proposed in this study represented suppressive immune microenvironment and therapy resistance, including adjuvant chemotherapy and PD-L1 blockade treatment. As the key contributor of the RMscore, inhibition of WDR4 impaired breast cancer progression significantly in vitro and in vivo, as well as participated in regulating cell cycle and mTORC1 signaling pathway via m7G modification.</p><p><strong>Conclusion: </strong>Briefly, this study has developed promising and effective tactics to achieve the prediction of survival probabilities and treatment response in breast cancer patients.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage exosomes mediate palmitic acid-induced metainflammation by transferring miR-3064-5p to target IκBα and activate NF-κB signaling.","authors":"Huiyu Luo, Jiexian Wang, Fengjuan Lin, Yuguo Liu, Xinglong Wu, Gan Li, Chuhong Su, Junbin Chen, Fei Xiong, Jiaqi Mo, Zhongdaixi Zheng, Xiangyi Zheng, Qing Li, Longying Zha","doi":"10.1016/j.jare.2024.06.024","DOIUrl":"10.1016/j.jare.2024.06.024","url":null,"abstract":"<p><strong>Introduction: </strong>High palmitic acid (PA) levels trigger metainflammation, facilitating the onset and progression of chronic metabolic diseases. Recently, exosomes were identified as new inflammation mediators. However, the mechanism by which macrophage exosomes mediate PA-induced inflammation remains unclear.</p><p><strong>Objectives: </strong>To explore how PA induces metainflammation through macrophage exosomes.</p><p><strong>Methods: </strong>Exosomes secreted by RAW264.7 mouse macrophages stimulated with PA (Exos^PA) or not (Exos) were prepared by ultracentrifugation. The differential miRNAs between Exos^PA and Exos were identified by high-throughput sequencing, and their targeted mRNAs and proteins were bioinformatically analyzed and verified by qPCR and western blot. Mouse macrophages and metabolic cells (AML-12 hepatocytes, C2C12 myocytes or 3T3-L1 adipocytes) were treated with Exos^PA or Exos. The verified miRNAs and its targeted molecules related to inflammation were analyzed in recipient cells. Furthers, exosomes were prepared from primary peritoneal macrophages isolated from AIN93G diet-fed (Control PM-Exos) or HPD-fed (PA PM-Exos) mice. Control or PA PM-Exos were then tail vein injected (30 μg) into mice (n = 10), once a week for 2 weeks. The verified miRNA and its targets in blood, blood exosomes, and metabolic tissues were detected. Finally, measured the levels of miRNA, inflammatory factors, and fatty acids in the blood of 20 obese/overweight individuals and 20 healthy individuals.</p><p><strong>Results: </strong>Exo^PA activate NF-κB signaling and enhance inflammatory enzyme/cytokine production in macrophages and metabolic cells. Exo^PA enrich miR-3064-5p and target to inhibit IκBα as verified by exosome inhibitors and miR-3064-5p mimics and inhibitors. HPD elevates exosomal miR-3064-5p, macrophage exosomal miR-3064-5p, and inflammatory cytokine levels in mice circulation. PA PM-Exos from HPD-fed mice triggered inflammation in the circulation and metabolic tissues/organs of chow diet-fed mice. Overweight/obese individuals exhibit increased levels of circulating palmitoleic acid, exosomal miR-3064-5p, and high-sensitivity C-reactive proteins.</p><p><strong>Conclusions: </strong>Macrophage exosomes transferring miR-3064-5p to target IκBα and activate NF-κB signaling in metabolic cells is a mechanism of PA-induced metainflammation.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of SPI1/VSIG4/THBS1 on glioblastoma progression through modulation of the PI3K/AKT pathway.","authors":"Jie Shen, Lihui Zhou, Ke Ye, Jiangbiao Gong, Fan Wu, Kangnan Mo, Yu Zhu, Chao Chen, Renya Zhan","doi":"10.1016/j.jare.2024.06.023","DOIUrl":"10.1016/j.jare.2024.06.023","url":null,"abstract":"<p><strong>Introduction: </strong>Glioblastoma multiforme (GBM) poses a significant challenge in terms of treatment due to its high malignancy, necessitating the identification of additional molecular targets. VSIG4, an oncogenic gene participates in tumor growth and migration in various cancer types. Nevertheless, the precise process through which VSIG4 facilitates the malignant progression of glioma remains to be elucidated.</p><p><strong>Objectives: </strong>This research aims to explore the function and molecular mechanism involving VSIG4 in the malignant progression of glioma.</p><p><strong>Methods: </strong>The amount of VSIG4 was measured using qPCR, western blotting, and immunohistochemistry. Lentivirus infections were applied for upregulating or downregulating molecules within glioma cells. The incorporation of 5-ethynyl-20-deoxyuridine, Transwell, cell counting kit-8, and clone formation experiments, were applied to assess the biological functions of molecules on glioma cells. Dual luciferase reporter gene, RNA immunoprecipitation, and chromatin immunoprecipitation assays were used to explore the functional relationship among relevant molecules.</p><p><strong>Results: </strong>The upregulation of VSIG4 was observed in GBM tissues, indicating an adverse prognosis. Silencing VSIG4 in glioma cells resulted in a decrease in cell viability, invasion, proliferation, and tumorigenesis, an increase in cell apoptosis, and a stagnation in the cell cycle progression at the G0/G1 phase. Mechanistically, SPI1-mediated upregulation of VSIG4 expression led to binding between VSIG4 and THBS1 protein, ultimately facilitating the malignant progression of glioma cells through the activation of the PI3K/AKT pathway. The inhibited proliferative and invasive capabilities of glioma cells were reversed by overexpressing THBS1 following the knockdown of VSIG4.</p><p><strong>Conclusion: </strong>Our findings provide evidence for the role of VSIG4 as an oncogene and reveal the previously unidentified contribution of the SPI1/VSIG4/THBS1 axis in the malignant progression of glioma. This signaling cascade enhances tumor growth and invasion by modulating the PI3K/AKT pathway. VSIG4 as a potential biomarker may be a viable strategy in the development of tailored molecular therapies for GBM.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host-virus coevolution drives soil microbial function succession along a millennium land reclamation chronosequence.","authors":"Wenbing Li, Yiling Wang, Kankan Zhao, Linya Xu, Tingfeng Shi, Bin Ma, Xiaofei Lv","doi":"10.1016/j.jare.2024.06.022","DOIUrl":"10.1016/j.jare.2024.06.022","url":null,"abstract":"<p><strong>Introduction: </strong>Gene exchange between viruses and hosts plays an important role in driving virus-host coevolution, enabling adaptation of both viruses and hosts to environmental changes. However, the mechanisms and functional significance of virus-host gene exchanges over long-term scales remain largely unexplored.</p><p><strong>Objective: </strong>The present study aimed to gain insights into the role of viruses in virus-host interactions and coevolution by monitoring virome dynamics along a millennium-long land reclamation chronosequence.</p><p><strong>Methods: </strong>We collected 24 soil samples from 8 stages of a millennium-long land reclamation chronosequence, including non-reclamation, and reclamation periods of 10, 50, 100, 300, 500, 700, and 1000 years. We characterized their metagenomes, and identified DNA viruses within these metagenomes.</p><p><strong>Results: </strong>Our findings reveal a significant shift in viral community composition after 50 years of land reclamation, but soil viral diversity reached a stable phase approximately 300 years after the initial reclamation. Analysis of the virus-host network showed a scale-free degree distribution and a reduction in complexity over time, with generalist viruses emerging as key facilitators of horizontal gene transfer.</p><p><strong>Conclusion: </strong>These findings highlight the integral role of viruses, especially generalist types, in mediating gene exchanges between viruses and hosts, thereby influencing the coevolutionary dynamics in soil ecosystems over significant timescales. This study offers novel insights into long-term virus-host interactions, showing how the virome responds to environmental changes, driving shifts in various microbial functions in reclaimed land.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mechanism by which oriented polypropylene packaging alleviates postharvest 'Black Spot' in radish root (Raphanus sativus).","authors":"Zixin Lin, Bihong Feng, Shibei Fang, Xi Pang, Huafeng Liang, Shuzhi Yuan, Xiaodi Xu, Jinhua Zuo, Xiaozhen Yue, Qing Wang","doi":"10.1016/j.jare.2024.06.026","DOIUrl":"10.1016/j.jare.2024.06.026","url":null,"abstract":"<p><strong>Introduction: </strong>The postharvest physiological disorder known as 'black spot' in radish roots (Raphanus sativus) poses a significant challenge to quality maintenance during storage, particularly under summer conditions. The cause of this disorder, however, is poorly understood.</p><p><strong>Objectives: </strong>Characterize the underlying causes of 'black spot' disorder in radish roots and identify strategies to delay its onset.</p><p><strong>Methods: </strong>Radish roots were placed in either polyvinyl chloride (PVC) or oriented polypropylene (OPP) packaging and stored for 4 days at 30 °C. Appearance and physiological parameters were assessed and transcriptomic and metabolomic analyses were conducted to identify the key molecular and biochemical factors contributing to the disorder and strategies for delaying its onset and development.</p><p><strong>Results: </strong>OPP packaging effectively delayed the onset of 'black spot' in radishes, potentially due to changes in phenolic and lipid metabolism. Regarding phenolic metabolism, POD and PPO activity decreased, RsCCR and RsPOD expression was downregulated, genes involved in phenols and flavonoids synthesis were upregulated and their content increased, preventing the oxidative browning of phenols and generally enhancing stress tolerance. Regarding lipid metabolism, the level of alpha-linolenic acid increased, and genes regulating cutin and wax synthesis were upregulated. Notably, high flavonoid and low ROS levels collectively inhibited RsPLA2G expression, which reduced the production of arachidonic acid, pro-inflammatory compounds (LTA₄ and PGG₂), and ROS, alleviating the inflammatory response and oxidative stress in radish epidermal tissues.</p><p><strong>Conclusion: </strong>PVC packaging enhanced the postharvest onset of 'black spot' in radishes, while OPP packaging delayed both its onset and development. Our study provides insights into the response of radishes to different packaging materials during storage, and the causes and host responses that either enhance or delay 'black spot' disorder onset. Further studies will be conducted to confirm the molecular and biochemical processes responsible for the onset and development of 'black spot' in radishes.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WTAP/YTHDF1-mediated m⁶A modification amplifies IFN-γ-induced immunosuppressive properties of human MSCs.","authors":"Quan Chen, Luoquan Ao, Qing Zhao, Lu Tang, Yanli Xiong, Yuchuan Yuan, Xiaofeng Wu, Wei Xing, Zhan Li, Wei Guo, Huaping Liang, Song Guo Zheng, Qizhou Lian, Di Lu, Weijun Wan, Xiang Xu","doi":"10.1016/j.jare.2024.06.019","DOIUrl":"10.1016/j.jare.2024.06.019","url":null,"abstract":"<p><strong>Introduction: </strong>The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the \"license\" of several pro-inflammatory factors to express immunosuppressive molecular profiles, which determines the therapeutic efficacy of MSCs in immune-mediated inflammatory diseases. Of those, interferon-γ (IFN-γ) is a key inducer for the expression of immunosuppressive molecular profiles; however, the mechanism underlying this effect is unknown.</p><p><strong>Objectives: </strong>To elucidate the regulation mechanism and biological functions of N⁶-methyladenosine (m⁶A) modification in the immunosuppressive functions by the IFN-γ-licensing MSCs.</p><p><strong>Methods: </strong>Epitranscriptomic microarray analysis and MeRIP-qPCR assay were performed to identify the regulatory effect of WTAP in the IFN-γ-licensing MSCs. RIP-qPCR, western blot, qRT-PCR and RNA stability assays were used to determine the regulation of WTAP/m⁶A/YTHDF1 signaling axis in the expression of immunosuppressive molecules. Further, functional capacity of T cells was tested using flow cytometry, and both DSS-induced colitis mice and CIA mice were constructed to clarify the effect of WTAP and YTHDF1 in MSC-mediated immunosuppression.</p><p><strong>Results: </strong>We identified that IFN-γ increased the m⁶A methylation levels of immunosuppressive molecules, while WTAP deficiency abolished the IFN-γ-induced promotion of m⁶A modification. IFN-γ activated ERK signaling, which induced WTAP phosphorylation. Additionally, the stabilization of WTAP post-transcriptionally increased the mRNA expression of immunosuppressive molecules (IDO1, PD-L1, ICAM1, and VCAM1) in an m⁶A-YTHDF1-dependent manner; this effect further impacted the immunosuppressive capacity of IFN-γ licensing MSCs on activated T cells. Notably, WTAP/YTHDF1 overexpression enhanced the therapeutic efficacy of IFN-γ licensing MSCs and restructures the ecology of inflammation in both colitis and arthritis models.</p><p><strong>Conclusion: </strong>Our results showed that m⁶A modification of IDO1, PD-L1, ICAM1, and VCAM1 mRNA mediated by WTAP-YTHDF1 is involved in the regulation of IFN-γ licensing MSCs immunosuppressive abilities, and shed a light to enhance the clinical therapeutic potential of IFN-γ-licensing MSCs.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing a multi-modular assembled prime editing (mPE) system improved precise multi-base insertion efficiency in dicots.","authors":"Pengjun Lu, Erwei Zuo, Jianbin Yan","doi":"10.1016/j.jare.2024.06.021","DOIUrl":"10.1016/j.jare.2024.06.021","url":null,"abstract":"<p><strong>Introduction: </strong>The Prime Editing (PE) system is a precise and versatile genome editing tool with great potential in plant breeding and plant synthetic biology. However, low PE efficiency severely restricts its application, especially in dicots. PE can introduce small tags to trace target protein or cis-element to regulate gene transcription which is an expertise superior to other gene editing tools. Owing to low efficiency, PE adaption in stably transformed Arabidopsis is lacking.</p><p><strong>Objectives: </strong>This study aimed to investigate the issue of low PE efficiency in dicots and develop systematic solutions to improve it. Currently, PE in dicots is undetectable and inconsistent, and this study seeks to address it. Split PE into several parts showed better performance in some target sites in mammal cells. We plan to discover the optimal split PE combination in dicot.</p><p><strong>Methods: </strong>We conducted large-scale transformation experiments in dicot model plants Arabidopsis thaliana (At) and Nicotiana benthamiana (Nb) by Agrobacterium-mediated transformation with deep amplicon sequencing (0.2-0.5 million clean total reads).</p><p><strong>Results: </strong>The editing efficiency decreased upon using a fused reverse transcriptase (RT) or an extended pegRNA separately and further decreased dramatically when these were used together. With the help of the pol II strategy to express PE gRNA (pegRNA), we named the most effective split PE combination as a multi-modular assembled prime editing system (mPE). mPE exhibited improved precise editing efficiency on most gene sites with various editing types, ranging from 1.3-fold to 1288.5-fold and achieved PE on some sites that could not be edited by original PE2. Especially, mPE showed superiority for multi-base insertion with an average improvement of 197.9-fold.</p><p><strong>Conclusion: </strong>The original PE architecture strongly inhibited the cleavage activity of Cas9. Split PE improved PE efficiency extensively and was in favor of introducing small insertions in dicot plants, indicating that different PE variants might have their own expertise.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic profiling of gastrointestinal tracts in dairy cattle during lactation reveals molecular adaptations for milk synthesis.","authors":"Yahui Gao, George E Liu, Li Ma, Lingzhao Fang, Cong-Jun Li, Ransom L Baldwin","doi":"10.1016/j.jare.2024.06.020","DOIUrl":"10.1016/j.jare.2024.06.020","url":null,"abstract":"<p><p>During lactation, dairy cattle's digestive tract requires significant adaptations to meet the increased nutrient demands for milk production. As we attempt to improve milk-related traits through selective pressure, it is crucial to understand the biological functions of the epithelia of the rumen, small intestine, and colonic tissues in response to changes in physiological state driven by changes in nutrient demands for milk synthesis. In this study, we obtained a total of 108 transcriptome profiles from three tissues (epithelia of the colon, duodenum, and rumen) of five Holstein cows, spanning eight time points from the early, mid, late lactation periods to the dry period. On average 97.06% of reads were successfully mapped to the reference genome assembly ARS-UCD1.2. We analyzed 27,607 gene expression patterns at multiple periods, enabling direct comparisons within and among tissues during different lactation stages, including early and peak lactation. We identified 1645, 813, and 2187 stage-specific genes in the colon, duodenum, and rumen, respectively, which were enriched for common or specific biological functions among different tissues. Time series analysis categorized the expressed genes within each tissue into four clusters. Furthermore, when the three tissues were analyzed collectively, 36 clusters of similarly expressed genes were identified. By integrating other comprehensive approaches such as gene co-expression analyses, functional enrichment, and cell type deconvolution, we gained profound insights into cattle lactation, revealing tissue-specific characteristics of the gastrointestinal tract and shedding light on the intricate molecular adaptations involved in nutrient absorption, immune regulation, and cellular processes for milk synthesis during lactation.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141461421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis.","authors":"Ran You, Yanwei Li, Yuteng Jiang, Dandan Hu, Menglei Gu, Wei Zhou, Shengnan Zhang, Mi Bai, Yunwen Yang, Yue Zhang, Songming Huang, Zhanjun Jia, Aihua Zhang","doi":"10.1016/j.jare.2024.06.015","DOIUrl":"10.1016/j.jare.2024.06.015","url":null,"abstract":"<p><strong>Introduction: </strong>Acute kidney injury (AKI) is associated with high morbidity and mortality rates. The molecular mechanisms underlying AKI are currently being extensively investigated. WWP2 is an E3 ligase that regulates cell proliferation and differentiation. Whether WWP2 plays a regulatory role in AKI remains to be elucidated.</p><p><strong>Objectives: </strong>We aimed to investigate the implication of WWP2 in AKI and its underlying mechanism in the present study.</p><p><strong>Methods: </strong>We utilized renal tissues from patients with AKI and established AKI models in global or tubule-specific knockout (cKO) mice strains to study WWP2's implication in AKI. We also systemically analyzed ubiquitylation omics and proteomics to decipher the underlying mechanism.</p><p><strong>Results: </strong>In the present study, we found that WWP2 expression significantly increased in the tubules of kidneys with AKI. Global or tubule-specific knockout of WWP2 significantly aggravated renal dysfunction and tubular injury in AKI kidneys, whereas WWP2 overexpression significantly protected tubular epithelial cells against cisplatin. WWP2 deficiency profoundly affected autophagy in AKI kidneys. Further analysis with ubiquitylation omics, quantitative proteomics and experimental validation suggested that WWP2 mediated poly-ubiquitylation of CDC20, a negative regulator of autophagy. CDC20 was significantly decreased in AKI kidneys, and selective inhibiting CDC20 with apcin profoundly alleviated renal dysfunction and tubular injury in the cisplatin model with or without WWP2 cKO, indicating that CDC20 may serve as a downstream target of WWP2 in AKI. Inhibiting autophagy with 3-methyladenine blocked apcin's protection against cisplatin-induced renal tubular cell injury. Activating autophagy by rapamycin significantly protected against cisplatin-induced AKI in WWP2 cKO mice, whereas inhibiting autophagy by 3-methyladenine further aggravated apoptosis in cisplatin-exposed WWP2 KO cells.</p><p><strong>Conclusion: </strong>Taken together, our data indicated that the WWP2/CDC20/autophagy may be an essential intrinsic protective mechanism against AKI. Further activating WWP2 or inhibiting CDC20 may be novel therapeutic strategies for AKI.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141444000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the STAT3/IL-36G signaling pathway can be a promising approach to treat rosacea.","authors":"Xin Meng, Yun Zhong, Xuyuan Kuang, Yiya Zhang, Li Yang, Yisheng Cai, Fan Wang, Fanping He, Hongfu Xie, Ben Wang, Ji Li","doi":"10.1016/j.jare.2024.06.013","DOIUrl":"10.1016/j.jare.2024.06.013","url":null,"abstract":"<p><strong>Background: </strong>Rosacea is an inflammatory skin disorder characterized by the release of inflammatory mediators from keratinocytes, which are thought to play a crucial role in its pathogenesis. Despite an incidence of approximately 5.5%, rosacea is associated with a poor quality of life. However, as the pathogenesis of rosacea remains enigmatic, treatment options are limited.</p><p><strong>Objectives: </strong>To investigate the pathogenesis of rosacea and explore new therapeutic strategies.</p><p><strong>Methods: </strong>Transcriptome data from rosacea patients combined with immunohistochemical staining were used to investigate the activation of STAT3 in rosacea. The role of STAT3 activation in rosacea was subsequently explored by inhibiting STAT3 activation both in vivo and in vitro. The key molecules downstream of STAT3 activation were identified through data analysis and experiments. Dual-luciferase assay and ChIP-qPCR analysis were used to validate the direct binding of STAT3 to the IL-36G promoter. DARTS, in combination with experimental screening, was employed to identify effective drugs targeting STAT3 for rosacea treatment.</p><p><strong>Results: </strong>STAT3 signaling was hyperactivated in rosacea and served as a promoter of the keratinocyte-driven inflammatory response. Mechanistically, activated STAT3 directly bind to the IL-36G promoter region to amplify downstream inflammatory signals by promoting IL-36G transcription, and treatment with a neutralizing antibody (α-IL36γ) could mitigate rosacea-like inflammation. Notably, a natural plant extract (pogostone), which can interact with STAT3 directly to inhibit its activation and affect the STAT3/IL36G signaling pathway, was screened as a promising topical medication for rosacea treatment.</p><p><strong>Conclusions: </strong>Our study revealed a pivotal role for STAT3/IL36G signaling in the development of rosacea, suggesting that targeting this pathway might be a potential strategy for rosacea treatment.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141443987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}