Journal of Advanced Research最新文献

{"title":"Advanced machine learning schemes for prediction CO2 flux based experimental approach in underground coal fire areas","authors":"Yongjun Wang, Mingze Guo, Hung Vo Thanh, Hemeng Zhang, Xiaoying Liu, Qian Zheng, Xiaoming Zhang, Mohammad Sh. Daoud, Laith Abualigah","doi":"10.1016/j.jare.2024.10.034","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.034","url":null,"abstract":"<h3>Introduction</h3>Underground coal fires pose significant environmental and health risks due to releasing CO₂ emissions. Predicting surface CO₂ flux accurately in underground coal fire areas is crucial for understanding the distribution of spontaneous combustion zones and developing effective mitigation strategies. In recent years, advanced machine learning techniques have shown promise in various carbon-related studies. This research uses an experimental approach to explore the power of advanced machine learning schemes for predicting CO₂ flux in underground coal fire areas.<h3>Objectives</h3>By leveraging the power of advanced machine learning schemes and experimental approaches, this research aims to provide valuable insights into CO₂ flux prediction in coal fire areas and inform environmental monitoring and management strategies.<h3>Methods</h3>The study involves the collection of an experimental dataset specific to underground coal fire areas, encompassing various parameters related to CO₂ flux and underground coal fire characteristics. Innovative feature engineering techniques are applied to capture the unique characteristics of underground coal fire areas and their impact on CO₂ flux. Different machine learning algorithms, including Natural gradient boosting regression (NGRB), Extreme gradient boosting (XGboost), Light gradient boosting (LGRB), and random forest (RF), are evaluated and compared for their predictive capabilities. The models are trained, optimized, and assessed using appropriate performance metrics.<h3>Results</h3>The NGRB model yields the best predictive performances with <em>R²</em> of 0.967 and MAE of 0.234. The novel contributions of this study include the development of accurate prediction models tailored to underground coal fire areas, shedding light on the underlying factors driving CO₂ flux. The findings have practical implications for delineating the spontaneous combustion zone and mitigating CO₂ emissions from underground coal fires, contributing to global efforts in combating climate change.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"33 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased Rab1a accelerates osteoarthritis by inhibiting autophagy via activation of the mTORC1-S6K pathway","authors":"Ze Chen, Mingze Tang, Zewei Wu, Yongcong Lin, Cuixi Wu, Hong Huang, Jianmao Chen, Zhaohua Zhu, Yongming Liu, Súan Tang, Changhai Ding, Weiyu Han","doi":"10.1016/j.jare.2024.11.009","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.009","url":null,"abstract":"<h3>Introduction</h3>Cartilage degradation is a critical alteration in the progression of osteoarthritis (OA) due to the disorder of chondrocyte metabolic homeostasis. Autophagy plays an important role in maintaining intracellular homeostasis. Recent investigations have increasingly underscored the importance of autophagy in modulating the pathological mechanisms underlying OA. Ras-related protein Rab-1a (Rab1a) has been illustrated to regulate autophagy in many diseases but not in OA.<h3>Objectives</h3>This study aims to elucidate whether Rab1a could regulate the development of OA through modulation of chondrocyte autophagy and apoptosis.<h3>Methods</h3>Proteomic sequencing, Western blotting, and immunohistochemistry were applied to detect the expression level of Rab1a <em>in vitro</em> and <em>in vivo</em>. Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were rigorously identified. The effects of Rab1a and the interaction between Rab1a, mTORC1, autophagy and apoptosis were explored by qPCR, Western blotting, and immunofluorescence. An experimental mouse OA model was also performed to confirm the role of Rab1a in OA pathogenesis <em>in vivo</em>. Histological analysis was employed to demonstrate cartilage damage.<h3>Results</h3>Rab1a expression was significantly upregulated in inflamed chondrocytes and knee OA cartilage. Inhibition of Rab1a partially attenuated the degradation of the extracellular matrix and cell apoptosis both <em>in vitro</em> and <em>in vivo</em>, whereas overexpression of Rab1a intensified cartilage matrix degradation and cellular apoptosis. Additionally, elevated Rab1a levels were observed to suppress autophagy and activate the mTORC1-S6K signaling pathway, thereby aggravating OA pathogenesis.<h3>Conclusion</h3>The augmentation of Rab1a expression impairs autophagy and promotes apoptosis through the activation of the mTORC1-S6K signaling pathway, further exacerbating OA pathogenesis. This finding suggests that Rab1a serves as a promising and innovative therapeutic target for the prevention and treatment of OA.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"144 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Akt-FoxO signaling drives co-adaptation to insecticide and host plant stresses in an herbivorous insect","authors":"Huihui Zhang, Haoli Gao, Xumin Lin, Baojun Yang, Jingting Wang, Xiaowei Yuan, Zhen Zhang, Tianshun He, Zewen Liu","doi":"10.1016/j.jare.2024.11.006","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.006","url":null,"abstract":"<h3>Introduction</h3>Ongoing interactions between host and herbivorous insect trigger a co-evolutionary arms race. Genetic diversity within insects facilitates their adaptation to phytochemicals and their derivatives, including plant-derived insecticides. Cytochrome P450s play important roles in metabolizing phytochemicals and insecticides, due to their diversity and almost perfect evolution.<h3>Objectives</h3>This study aims to uncover a common molecular mechanism in herbivorous insects by investigating the role of kinase-transcription factor regulation of P450s in conferring tolerance to both insecticides and phytochemicals.<h3>Methods</h3>RNA interference, transcriptome sequencing, insecticide, and phytochemical bioassays were conducted to validate the functions of Akt, FoxO, and candidate P450s. Dual-luciferase activity assays were employed to identify the regulation of P450s by the Akt-FoxO signaling pathway. Recombinant P450 enzymes were utilized to investigate the metabolism of insecticides and phytochemicals.<h3>Results</h3>We identified an Akt-FoxO signaling cascade, a representative of kinase-transcription factor pathways. This cascade mediates the expression of eight P450 enzymes involved in the metabolism of insecticides and phytochemicals in <em>Nilaparvata lugens</em>. These P450s are from different families and with different substrate selectivity, enabling them to respectively metabolize insecticides and phytochemicals with structure diversity. Nevertheless, the eight P450 genes were up-regulated by FoxO, which was inhibited in a higher cascade by Akt through phosphorylation. The discovery of the Akt-FoxO signaling pathway regulating a series of P450 genes elucidates the finely tuned regulatory mechanism in insects for adapting to phytochemicals and insecticides.<h3>Conclusion</h3>These finding sheds light on the physiological balance maintained by these regulatory processes. The work provides the experimental evidence of co-adaptation to the stresses imposed by host plant and insecticide within the model of the kinase-TF involving various P450s. This model provides a comprehensive view of how pests adapt to multiple environmental stresses.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"8 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A molecular perspective on the role of FERONIA in root growth, nutrient uptake, stress sensing and microbiome assembly","authors":"Sajad Ali, Anshika Tyagi, Suvin Park, Rajeev K. Varshney, Hanhong Bae","doi":"10.1016/j.jare.2024.11.002","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.002","url":null,"abstract":"<h3>Background</h3>Roots perform multifaceted functions in plants including the movement of nutrients and water, sensing stressors, shaping microbiome, and providing structural support. How roots perceive and respond above traits at the molecular level remains largely unknown. Although crop development has greatly advanced, most current efforts have concentrated on above-ground traits leaving significant knowledge gaps in root biology. Also, studying root system architecture (RSA) is more difficult due to its intricacy and the difficulties of observing them during plant life cycle. However, with the aid of high throughput phenotyping and genotyping tools many developmental and stress-mediated regulation of RSA has emerged in both model and crop plants leading to new insights in root biology. Our current understanding of upstream signaling events (cell wall, apoplast) in roots and how they are interconnected with downstream signaling cascades has largely been constrained by the fact that most research in plant systems concentrates on cytosolic signal transduction pathways while ignoring the early perception by cells’ exterior parts. In this regard, we discussed the role of FERONIA (FER) a cell wall receptor-like kinase (RLK) which acts as a sensor and a bridge between apoplast and cytosolic signaling pathways in root biology.<h3>Aim of the review</h3>The goal of this study is to provide valuable insights into present understanding and future research perspectives on how FER regulates distinct root responses related to growth and adaptation.<h3>Key scientific concepts of review</h3>In plants, FER is a unique RLK because it can act as a multitasking sensor regulate diverse growth, and adaptive traits. In this review, we mainly highlighted its role in root biology like how it modulates distinct root responses such as root development, sensing abiotic stressors, mechanical stimuli, nutrient transport, and shaping microbiome. Further, we provided an update on how FER controls root traits by involving RALF peptides, calcium, ROS and hormones. We also highlight number of outstanding questions in FER mediated root responses that warrant future investigation. We believe that FER can provide novels insights for the development of future climate resilient and high yielding crops based on the modified root system.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"242 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-genome analysis reveals genomic variations during enoki mushroom domestication, with emphasis on genetic signatures of cap color and stipe length","authors":"Fei Liu, Xin-Bing Ma, Bei Han, Bo Wang, Jian-Ping Xu, Bin Cao, Zhi-Lin Ling, Mao-Qiang He, Xin-Yu Zhu, Rui-Lin Zhao","doi":"10.1016/j.jare.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.005","url":null,"abstract":"<h3>Introduction</h3>The domestication of edible mushrooms, including Flammulina filiformis, offers valuable insights into the genetic changes driven by artificial selection. Understanding these changes is crucial for uncovering the mechanisms behind genome evolution in domesticated mushrooms.<h3>Objectives</h3>This study aims to investigate the population structure, genetic diversity, and domestication-related genomic changes in <em>F. filiformis</em>. By comparing the genome sequences of 199 wild and cultivated strains, we aim to elucidate the impact of domestication on F. filiformis.<h3>Methods</h3>We performed de novo genome assembly and gene-based pan-genome analysis on the 199 strains, which included both wild and cultivated strains. We also conducted genome-wide association studies (GWAS) using presence-absence variation (PAV) and SNP data, combined with RNA sequencing, to identify genes associated with domestication traits, such as cap color and stalk length. Gene functional confirmation was achieved through genetic transformation experiments.<h3>Results</h3>Our analysis grouped the strains into four distinct populations, which correlated with varying intensities of artificial selection. The three cultivated populations exhibited smaller genome sizes, fewer genes, lower genetic variation, reduced gene expression diversity, and lower heterozygosity compared to the wild population. The analysis revealed the loss of genes related to the beta-lactam antibiotic catabolic process and specific MAPK pathway genes during domestication, rendering domesticated strains more susceptible to diseases. Four genes closely associated with cap color and stipe length were identified, but genetic transformation experiments confirmed the functional relevance of only two (<em>FfB</em> and <em>FfD</em>) identified through PAV-based GWAS.<h3>Conclusion</h3>This study uncovered significant genomic variations between cultivated and wild Flammulina filiformis populations, including the loss of pathogen resistance genes during domestication. We also identified key genes linked to cap color and stipe length, demonstrating for the first time the important role of PAV variation in mushroom domestication. These insights provide a foundation for future mushroom breeding and evolutionary research.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"91 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioinspired injectable hydrogels for bone regeneration","authors":"Xuan Tang, Fengjin Zhou, Sicheng Wang, Guangchao Wang, Long Bai, Jiacan Su","doi":"10.1016/j.jare.2024.10.032","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.032","url":null,"abstract":"The effective regeneration of bone/cartilage defects remains a significant clinical challenge, causing irreversible damage to millions annually.<!-- --> <!-- -->Conventional therapies such as autologous or artificial bone grafting often yield unsatisfactory outcomes, emphasizing the urgent need for innovative treatment methods. Biomaterial-based strategies, including hydrogels and active scaffolds, have shown potential in promoting bone/cartilage regeneration. Among them, injectable hydrogels have garnered substantial attention in recent years on account of their minimal invasiveness, shape adaptation, and controlled spatiotemporal release. This review systematically discusses the synthesis of injectable hydrogels, bioinspired approaches-covering microenvironment, structural, compositional, and bioactive component-inspired strategies-and their applications in various bone/cartilage disease models, highlighting bone/cartilage regeneration from an innovative perspective of bioinspired design. Taken together, bioinspired injectable hydrogels offer promising and feasible solutions for promoting bone/cartilage regeneration, ultimately laying the foundations for clinical applications. Furthermore, insights into further prospective directions for AI in injectable hydrogels screening and organoid construction are provided.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"24 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kaempferol alleviates myocardial ischemia injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway","authors":"Zejun Yue, Yirong Zhang, Wei Zhang, Nanbo Zheng, Jiazeng Wen, Lingxuan Ren, XiaoYu Rong, Liang Bai, Rong Wang, Sihai Zhao, Enqi Liu, Weirong Wang","doi":"10.1016/j.jare.2024.10.037","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.037","url":null,"abstract":"<h3>Introduction</h3>Kaempferol (KAE) is a flavonoid found in various plants. Recent studies showed that high dietary intake of KAE was associated with a lower risk of myocardial infarction; however, the cardioprotective mechanism of KAE remains unknown.<h3>Objectives</h3>To determine the effect of KAE on cardiac injury in isoproterenol (ISO)-induced rats and cobalt chloride (CoCl₂)-treated cardiomyocytes<em>,</em> and the underlying mechanisms.<h3>Methods</h3>Male rats were pretreated with different doses of KAE for 14 days, and then injected with ISO to induce myocardial ischemia injury. We also established a model of myocardial cell injury using rat H9c2 cardiomyocytes stimulated with CoCl₂.<h3>Results</h3>We found that KAE pretreatment significantly alleviated myocardial injury and improved cardiac function in ISO-injected rats. In addition, KAE reduced oxidative stress in rats with myocardial ischemia by decreasing malondialdehyde concentration and increasing superoxide dismutase activity, and protection of the myocardial mitochondrial structure. KAE also attenuated CoCl₂-induced injury<!-- --> <!-- -->of H9c2 cardiomyocytes via suppression of<!-- --> <!-- -->oxidative stress. With regard to the mechanism, we found that KAE down-regulated HDAC3 expression and up-regulated Nrf2 expression in ISO-induced rats and CoCl₂-stimulated cardiomyocytes. Incubation of cardiomyocytes with HDAC3-selective inhibitor RGFP966 augmented the protective effect of KAE and reduced oxidative stress. By contrast, HDAC3 overexpression by adenovirus attenuated the effect of KAE on oxidative stress compared with KAE treatment group. HDAC3 also regulated Nrf2 expression in the cardiomyocytes with RGFP966 or an adenovirus overexpressing HDAC3; but Nrf2 inhibition reduced the effect of KAE on ROS generation in CoCl₂-induced cardiomyocytes. Immunoprecipitation assay showed that HDAC3 interacted with Nrf2 in cardiomyocytes. Further studies found that KAE increased the acetylation level of Nrf2, while HDAC3 overexpression decreased the acetylation of Nrf2 compared with KAE treatment group.<h3>Conclusion</h3>Our data show that KAE ameliorates cardiac injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway in cardiomyocytes.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"242 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPM2-mediated feed-forward loop promotes chondrocyte damage in osteoarthritis via calcium-cGAS-STING-NF-κB pathway","authors":"Kai Sun, Xiong Zhang, Liangcai Hou, Fan Lu, Haigang Liu, Zehang Zheng, Zhou Guo, Jingting Xu, Zhaoxuan Ruan, Yanjun Hou, Junchen He, Fengjing Guo, Kaixiang Yang","doi":"10.1016/j.jare.2024.11.007","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.007","url":null,"abstract":"<h3>Introductions</h3>Osteoarthritis (OA) is a significant contributor to disability in the elderly population. However, current therapeutic options are limited. The transient receptor potential melastatin 2 (TRPM2) is involved in a range of disease processes, yet its role in OA remains unclear.<h3>Objectives</h3>To investigate the role of TRPM2 in OA.<h3>Methods</h3>Cartilage samples were collected from patients with osteoarthritis (OA) and mice with OA to examine TRPM2 expression levels. To investigate the effects of TRPM2 modulation on the destabilization of the medial meniscus (DMM) induced knee OA in mice, we utilized TRPM2 knockout mice and employed adenovirus-mediated overexpression of TRPM2. Furthermore, siRNA-mediated TRPM2 knockdown or plasmid-mediated TRPM2 overexpression was conducted to explore the role of TRPM2 in IL-1β-induced chondrocytes. The regulatory mechanism of IL-1β on TRPM2 expression was screened by signaling pathway inhibitors, and the transcription factors and binding sites of TRPM2 were predicted using the database. The binding of RELA (NF-κB-p65) to the Trpm2 promoter was verified by chip-PCR and ChIP-qPCR. The therapeutic potential of Ca²⁺ chelation with BAPTA-AM for the treatment of osteoarthritis (OA) was investigated.<h3>Results</h3>An increased expression of TRPM2 was observed in the cartilage of OA patients and OA mice. Furthermore, mice deficient in Trpm2 exhibited a protective effect against DMM-induced OA progression. In contrast, TRPM2 overexpression resulted in exacerbation of DMM-induced OA and the<!-- --> <!-- -->promotion of an OA-like phenotype of chondrocytes. TRPM2 was upregulated by IL-1β in an NF-κB-p65-dependent manner. Subsequently, the TRPM2-Ca²⁺-mtDNA-cGAS-STING-NF-κB axis in the progression of OA was validated. Furthermore, inhibition of the TRPM2-Ca²⁺ axis with BAPTA-AM effectively attenuated established OA.<h3>Conclusions</h3>Our data collectively revealed a pathological feedback loop involving TRPM2, Ca²⁺, mtDNA, cGAS, STING, and NF-κB in OA chondrocytes. This suggests that disrupting this loop could be a viable therapeutic approach for OA<strong>.</strong>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"87 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142579874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetrahydrocurcumin targets TRIP13 inhibiting the interaction of TRIP13/USP7/c-FLIP to mediate c-FLIP ubiquitination in triple-negative breast cancer","authors":"Yu-jie Sun, Qiang Zhang, Shi-jie Cao, Xiao-hu Sun, Ji-chao Zhang, Bing-yang Zhang, Ze-bin Shang, Chong-yan Zhao, Zhi-yong Cao, Qiu-ju Zhang, Xiu-mei Gao, Feng Qiu, Ning Kang","doi":"10.1016/j.jare.2024.11.004","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.004","url":null,"abstract":"<h3>Introduction</h3>Triple-negative breast cancer (TNBC) has a high mortality rate and limited treatment options. Tetrahydrocurcumin (THC), a major metabolite of curcumin, has potential antitumor activities. However, the antitumor effects and mechanism of THC in TNBC remain elusive.<h3>Objectives</h3>To investigate the mechanism of THC in combating TNBC by targeting TRIP13 to disrupt the interaction of the TRIP13/USP7/c-FLIP complex and mediate c-FLIP ubiquitination both in vitro and in vivo.<h3>Methods</h3>Apoptosis was measured by TUNEL and flow cytometry. Click chemistry-based target fishing, CETSA, DARTS, and SPR were used to identify direct target of THC. Protein interactions was examined using co-immunoprecipitation. The role of USP7 in THC-mediated c-FLIP ubiquitination was evaluated by in vitro deubiquitination assay. Human breast cancer clinical samples were employed to assess the expression of c-FLIP, TRIP13, and USP7. The impact of THC on USP7/TRIP13/c-FLIP was analyzed using co-immunoprecipitation, confocal microscopy, molecular docking and dynamics simulations.<h3>Results</h3>THC effectively inhibits TNBC cell proliferation and tumor growth in vitro and in vivo without significant toxicity. Mechanistically, THC induces extrinsic apoptosis in TNBC primarily by promoting degradation of c-FLIP, a key negative regulator in the apoptotic pathway. Furthermore, utilizing click chemistry-based target fishing, we identified TRIP13, a component of the highly conserved AAA ATPase family, as a direct target of THC in combating TNBC. Interestingly, contrary to previous drug-target studies, the knockdown of TRIP13 further amplified the antitumor effects of THC. After in-depth investigation, it was revealed that TRIP13 forms a trimeric complex with USP7 and c-FLIP in TNBC cells. THC specifically targets TRIP13 to disrupt the interaction of TRIP13/USP7/c-FLIP, leading to the ubiquitination of c-FLIP, ultimately inducing extrinsic apoptosis.<h3>Conclusions</h3>These findings offer new insights into the novel molecular mechanisms of anti-TNBC effects of THC and present a promising targeted therapeutic strategy for TNBC.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"27 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trichosanthin elicits antitumor activity via MICU3 mediated mitochondria calcium influx","authors":"Yunbin Zhang, Xuping Ding, Qian Zhang, Cong Zeng, Hongzhuan Chen, Liming Lu","doi":"10.1016/j.jare.2024.11.001","DOIUrl":"https://doi.org/10.1016/j.jare.2024.11.001","url":null,"abstract":"<h3>Introduction</h3>Trichosanthin (TK) is a glycoprotein extracted from the Chinese medicinal herb Trichosanthes kirilowi, which has anti-virus and anti-tumor activity. However, the target and detailed mechanism of TK remains elusive.<h3>Objectives</h3>We aimed to identify novel antitumor targets of TK in lung adenocarcinoma and study its anti-tumor mechanism.<h3>Methods</h3>We utilized a Lewis lung carcinoma mouse model to evaluate the inhibition of TK on tumor growth. CCK8 assay was utilized to calculate IC₅₀ of trichosanthin on A549 and H1299. In-vitro cellular assays and in-vivo xenograft mice studies were used to investigate MICU3 overexpression and TK treatment on tumor growth. Fluo-4 dye and JC-1 staining was used to measure the mitochondrial calcium levels and membrane potential. H&amp;E and immunohistochemistry staining were applied the asses the effect of TK on tumor and microenvironment. RNA sequencing was applied to analyze transcriptome changes in TK-treated and MICU3-overexpressed tumor cells. The influence of trichosanthin on DNMT3B expression and MICU3 methylation were detected by qPCR and Western blotting. Transcriptional activity of the MICU3 gene was measured by ChIP-PCR and luciferase assays.<h3>Results</h3>Trichosanthin ihibited the tumor growth in vivo, resulting cancer cell growth inhibition and cell death, with almost no effect on normal cells. IC₅₀ of trichosanthin in A549 and H1299 cells were 62.8 μg/ml and 39.7 μg/ml, respectively. Mitochondrial Calcium Uptake Family complex MICU3 was shown to associated with favorable prognosis and was upregulated upon trichosanthin treatment, along with reduces tumor cell growth and migration, and increased cell death both in vitro and in vivo. Increased mitochondrial calcium level was observed in MICU3 overexpression cells. Pathway analysis of RNA-seq data revealed that cytokine and receptor pathways were enriched in MICU3-overexpressing cells. Trichosanthin decreased DNMT3B expression and altered MICU3 methylation while increased FOSL2 expression and reduced methylation that correlated with increased transcription of the MICU3 gene.<h3>Conclusion</h3>Trichosanthin elicits antitumor activity in lung adenocarcinoma via repressing DNMT3B and increasing FOSL2, which in turn induces MICU3-mediated mitochondrial calcium influx and tumor cell death.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"67 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}