Journal of Advanced Research最新文献

{"title":"Metabolic responses of sea anemone and jellyfish to temperature and UV bleaching: Insights into stress adaptation using LCMS-based metabolomics, molecular networking and chemometrics","authors":"Mohamed A. Farag, Doaa B. Saied, Sherif M. Afifi, Andreas Kunzmann, Ludger A. Wessjohann, Hildegard Westphal, Holger Kühnhold, Marleen Stuhr","doi":"10.1016/j.jare.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.007","url":null,"abstract":"<h3>Introduction</h3>Climate change poses various threats to marine life, particularly in shallow tropical waters. Objective: The impact of increased temperature and ultraviolet (UV) exposure on two photosymbiotic Cnidarians, a common bubble-tip anemone and an upside-down jellyfish, was investigated.<h3>Methods</h3>To illustrate the response of aquatic organisms, the metabolomes of unstressed <em>Entacmaea quadricolor</em> and <em>Cassiopea andromeda</em> were compared for detailed metabolite profiling. UHPLC-MS coupled with chemometrics and GNPS molecular networking was employed for sample classification and identification of markers unique to stress responses in each organism.<h3>Results</h3>Several compounds with bioactive functions, including peptides and terpenoids, were reported for the first time in both organisms, viz. cyclic tetraglutamate, campestriene, and ceramide aminoethyl phosphonate (CEAP d18:2/16:0). Both anemone and jellyfish were subjected to either elevated UV-B light intensity up to 6.6 KJ m⁻² or increased temperatures (28 °C, 30 °C, 32 °C, and 34 °C) over 4 days. Phospholipids, steroids, and ceramides emerged as chief markers of both types of stress, as revealed by the multivariate data analysis. Lysophosphatidylcholine (LPC 16:0), LPC (18:0/0:0), and echinoclasterol sulfate appeared as markers in both UV and thermal stress models of the anemone, whereas methyl/propyl cholestane-<em>hexa</em>-ol were discriminatory in the UV stress model only. In the case of jellyfish, nonpolar glycosyl ceramide GlcCer (d14:1/28:6) served as a marker for UV stress, whereas polar peptides were elevated in the thermal stress model. Interestingly, both models of jellyfish share a phospholipid, lysophosphatidylethanolamine (LPE 20:4), as a distinctive marker for stress, reported to be associated indirectly with the activity of innate immune response within other photosymbiotic Cnidaria such as corals and appears to be a fundamental stress response in marine organisms.<h3>Conclusion</h3>This study presents several bioinformatic tools for the first time in two cnidarian organisms to provide not only a broader coverage of their metabolome but also broader insights into cnidarian bleaching in response to different stressors, i.e., heat and UV light, by comparing their effects in anemone versus jellyfish.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"32 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436429","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":"Single-cell transcriptomic profiling uncovers cellular complexity and microenvironment in gastric tumorigenesis associated with Helicobacter pylori","authors":"Nianshuang Li, Sihai Chen, Xinbo Xu, Huan Wang, Pan Zheng, Xiao Fei, Huajing Ke, Yuting Lei, Yanan Zhou, Xiaoyu Yang, Yaobin Ouyang, Chuan Xie, Cong He, Yi Hu, Yi Cao, Zhengrong Li, Yong Xie, Zhongming Ge, Xu Shu, Nonghua Lu, Yin Zhu","doi":"10.1016/j.jare.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.012","url":null,"abstract":"<h3>Introduction</h3><em>Helicobacter pylori</em> (<em>H. pylori</em>) infection is the main risk for gastric cancer (GC). However, the cellular heterogeneity and underlying molecular mechanisms in <em>H. pylori</em>-driven gastric tumorigenesis are poorly understood.<h3>Objective</h3>Here, we generated a single-cell atlas of gastric tumorigenesis comprising 18 specimens of gastritis, gastric intestinal metaplasia (IM) and GC with or without <em>H. pylori</em> infection.<h3>Methods</h3>Single-cell RNA sequencing (scRNA-seq) was performed. Immunofluorescence, immunohistochemistry and qRT-PCR analysis were applied in a second human gastric tissues cohort for validation. Bioinformatics analyses of public TCGA and GEO datasets were applied.<h3>Results</h3>Single-cell RNA profile highlights cellular heterogeneity and alterations in tissue ecology throughout the progression of gastric carcinoma. Various cell lineages exhibited unique cancer-associated expression profiles, such as tumor-like epithelial cell subset (EPC), inflammatory cancer-associated fibroblasts (iCAFs) and Tumor-associated macrophage (TAM). Notably, we revealed that the specific epithelial subset enterocytes from the precancerous lesion GIM, exhibited elevated expression of genes related to lipid metabolism, and HNF4G was predicted as its specific transcription factor. Furthermore, we identified differentially expressed genes in <em>H. pylori</em>-positive and negative epithelial cells, fibroblasts and myeloid cells were identified. Futhermore, <em>H. pylori</em>-positive specimens exhibited enriched cell–cell communication, characterized by significantly active TNF, SPP1, and THY1 signaling networks.<h3>Conclusions</h3>Our study provides a comprehensive landscape of the gastric carcinogenesis ecosystem and novel insights into the molecular mechanisms of different cell types in <em>H. pylori</em>-induced GC.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"66 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439586","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":"Applications of single-cell analysis in immunotherapy for lung cancer: Current progress, new challenges and expectations","authors":"Nan Xiao, Hongyang Liu, Chenxing Zhang, Huanxiang Chen, Yang Li, Ying Yang, Hongchun Liu, Junhu Wan","doi":"10.1016/j.jare.2024.10.008","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.008","url":null,"abstract":"<h3>Background</h3>Lung cancer is a prevalent form of cancer worldwide, presenting a substantial risk to human well-being. Lung cancer is classified into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The advancement of tumor immunotherapy, specifically immune checkpoint inhibitors and adaptive T-cell therapy, has encountered substantial obstacles due to the rapid progression of SCLC and the metastasis, recurrence, and drug resistance of NSCLC. These challenges are believed to stem from the tumor heterogeneity of lung cancer within the tumor microenvironment.<h3>Aim of review</h3>This review aims to comprehensively explore recent strides in single-cell analysis, a robust sequencing technology, concerning its application in the realm of tumor immunotherapy for lung cancer. It has been effectively integrated with transcriptomics, epigenomics, genomics, and proteomics for various applications. Specifically, these techniques have proven valuable in mapping the transcriptional activity of tumor-infiltrating lymphocytes in patients with NSCLC, identifying circulating tumor cells, and elucidating the heterogeneity of the tumor microenvironment.<h3>Key scientific concepts of review</h3>The review emphasizes the paramount significance of single-cell analysis in mapping the immune cells within NSCLC patients, unveiling circulating tumor cells, and elucidating the tumor microenvironment heterogeneity. Notably, these advancements highlight the potential of single-cell analysis to revolutionize lung cancer immunotherapy by characterizing immune cell fates, improving therapeutic strategies, and identifying promising targets or prognostic biomarkers. Its potential to unravel the complexities within the tumor microenvironment and enhance treatment strategies marks a significant step towards more effective therapies and improved patient outcomes.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"51 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142415836","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":"Food inflammation index reveals the key inflammatory components in foods and heterogeneity within food groups: How do we choose food?","authors":"Zhangtie Wang, Changzheng Yuan, Yansong Zhang, Nesma S. Abdelaty, Cheng Chen, Jianfu Shen, Liangxiao Zhang, Baiyi Lu, Ruihai Liu, Peiwu Li","doi":"10.1016/j.jare.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.010","url":null,"abstract":"<h3>Introduction</h3>Food is a critical factor of chronic inflammation. Few studies tried to quantize inflammatory effects of food. Moreover, the discrepancies in inflammatory effects among foods within the same food group are frequently ignored.<h3>Objectives</h3>This study aimed to compare inflammatory effects of food based on Food Composition Tables via a Food Inflammation Index (FII). We aimed to reveal heterogeneity within food groups in dietary guidelines and identify the key components.<h3>Methods</h3>The FII was adapted from Dietary Inflammation Index (DII) with a weighted algorithm, validated by NHANES.<!-- --> <!-- -->The Food Inflammation Scores of Individuals (FISI) of various dietary patterns were analyzed and compared. FII scores were converted to percentages for intuitive grading using the United States Department of Agriculture Food Composition Table (USDA-FCT), and China-FCT was also used for validation.<!-- --> <!-- -->The FII scores of various food groups based on USDA-FCT and dietary guidelines were counted and compared to reveal the heterogeneity within food groups.<h3>Results</h3>FII proves effective in delineating food inflammatory effects. It reveals substantial inflammatory risk even with adherence to the Mediterranean diet, highlighting the need to address intra-group heterogeneity. Within USDA-FCT, nuts and select vegetable oils (rich in flavonoids and n-3 polyunsaturated fatty acids) are notable anti-inflammatory foods, contrasting with pro-inflammatory meats high in saturated fats. According to the current dietary nutrition guidelines, the inflammatory effects of food groups vary greatly. Further subdivision of food groups can weaken the problem of heterogeneity within food groups, thereby providing more accurate dietary recommendations.<h3>Conclusion</h3>Quantifying the inflammatory effects of whole foods is important for general consumers to realize their own dietary inflammatory exposure risk. The FII reveals the heterogeneity within food groups and can be a reference for dietary recommendations. This public tool could be beneficial for consumer choice, dietary guideline revision, science research for healthier eating.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"57 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142415810","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":"Effect of mitochondrial translocator protein TSPO on LPS-induced cardiac dysfunction","authors":"Xingyue Li, Xiao Chen, Feng-yuan Yang, Tingting Shu, Lintao Jiang, Bo He, Ming Tang, Xingbing Li, Dandong Fang, Pedro A. Jose, Yu Han, Yongjian Yang, Chunyu Zeng","doi":"10.1016/j.jare.2024.10.004","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.004","url":null,"abstract":"<h3>Introduction</h3>Sepsis-induced cardiac dysfunction is one of the most serious complications of sepsis. The mitochondrial translocator protein (TSPO), a mitochondrial outer membrane protein, is widely used as a diagnostic marker of inflammation-related diseases and can also lead to the release of inflammatory components. However, whether TSPO has a therapeutic effect on sepsis-induced cardiac dysfunction is unclear.<h3>Objectives</h3>The aim of this study is to investigate the involvement of TSPO in the pathogenesis of sepsis-induced cardiac dysfunction and elucidate its underlying mechanism, as well as develop therapeutic strategies targeting TSPO for the prevention and treatment of sepsis-induced cardiac dysfunction.<h3>Methods</h3>The sepsis-induced cardiac dysfunction model was established by intraperitoneal injection of lipopolysaccharide (LPS)in C57BL/6 mice (LPS-induced cardiac dysfunction, LICD). TSPO knockout mice were constructed,and the effects of TSPO was detected by survival rate, echocardiography, HE staining, mitochondrial electron microscopy, TUNEL staining. TSPO-binding proteins were identified by co-immunoprecipitation and mass spectrometry. The mechanisms underlying between TSPO and voltage-dependent anion channel (VDAC) was studied through western blot and immunofluorescence. Proteolysis-Targeting Chimeras (PROTAC) technology was used to construct TSPO-PROTAC molecules that can degrade TSPO.<h3>Results</h3>Our present study found that LPS increased cardiac TSPO expression. Knockout of TSPO in C57BL/6 mice with LICD attenuated the cardiac pathology, mitochondrial dysfunction, and apoptosis of cardiomyocytes and significantly improved cardiac function and survival rate. Co-immunoprecipitation and mass spectrometry identified VDAC as a TSPO binding protein.Down-regulation of TSPO reduced PKA-mediated VDAC phosphorylation and VDAC oligomerization, ameliorated mitochondrial function, and reduced cardiomyocyte apoptosis. The study has clinical translational potential, because administration of TSPO-PROTAC to degrade TSPO improved cardiac function in mice with LICD.<h3>Conclusion</h3>This study elucidated the effect of TSPO in LICD, providing a new therapeutic strategy to down-regulate TSPO by administration of TSPO-PROTAC for the prevention and treatment of LICD.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142397697","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":"Activity-based protein profiling guided new target identification of quinazoline derivatives for expediting bactericide discovery: Activity-based protein profiling derived new target discovery of antibacterial quinazolines","authors":"Jiao Meng, Ling Zhang, Xinxin Tuo, Yue Ding, Kunlun Chen, Mei Li, Biao Chen, Qingsu Long, Zhenchao Wang, Guiping Ouyang, Xiang Zhou, Song Yang","doi":"10.1016/j.jare.2024.10.002","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.002","url":null,"abstract":"<h3>Introduction</h3>The looming antibiotic-resistance problem has imposed an enormous crisis on global public health and agricultural development. Even worse, the evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens have made the resurgence of diseases that were once easily treatable deadly again. The development of antibiotics with novel mechanisms of action is urgently required.<h3>Objectives</h3>Inspired by charming activity-based protein profiling (ABPP) technology and increasing attention to quinazolines in the development of antibacterial agents, this study engineered a series of new quinazoline derivatives, assessed their antibacterial profiles, and first identified the possible target.<h3>Methods</h3>The target identification and their possible binding sites were verified by ABPP technology, molecular docking, and molecular dynamic simulations. The fatty acid synthesis process was analyzed by gas chromatography, propidium iodide staining, and scanning electron microscopy. The physicochemical properties and fungicide-likeness were evaluated using the Fungicide Physicochemical-properties Analysis Database.<h3>Results</h3>Compound 7a, an acrylamide-functionalized quinazoline derivative, exhibited excellent antibacterial potency against <em>Xanthomonas oryzae</em> pv. <em>oryzae</em> with an EC₅₀ value of 13.20 µM. More importantly, ABPP technology showed that β-ketoacyl-ACP-synthase Ⅱ (FabF) was the first identified quinazolines’ potential target. Compound 7a could selectively bind to the Cys151 residue of FabF through covalent interaction, suppress fatty acid biosynthesis, and damage the cell membrane integrity, thereby killing the bacteria. The pot experiment results showed that compound 7a demonstrated protective and curative values of 49.55 % and 47.46 %, surpassing controls bismerthiazol and thiodiazole copper. Finally, compound 7a exhibited low toxicity towards non-target organisms. These unprecedented performances contributed to excavating new quinazoline-based bactericidal agents.<h3>Conclusion</h3>Our research highlights the superiority of ABPP technology, for the first time, identifies the target of engineered quinazolines in pathogenic bacteria, and their potential target fished by ABPP tools holds great promise for the development of quinazoline-based and/or FabF-targeted bactericides.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"207 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142397696","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":"Elevated muramyl dipeptide by sialic acid-facilitated postantibiotic pathobiont expansion contributes to gut dysbiosis-induced mastitis in mice","authors":"Min Qiu, Cong Ye, Lijuan Bao, Keyi Wu, Yihong Zhao, Xiaotong Zhao, Ruibo Tang, Ruping Shang, Shan Shang, Chongshan Yuan, Xiaoyu Hu, Naisheng Zhang, Yunhe Fu, Jun Wang, Caijun Zhao","doi":"10.1016/j.jare.2024.09.023","DOIUrl":"https://doi.org/10.1016/j.jare.2024.09.023","url":null,"abstract":"<h3>Introduction</h3>In responses to antibiotics exposure, gut dysbiosis is a risk factor not only for pathogen infection but also for facilitating pathobiont expansion, resulting in increased inflammatory responses in the gut and distant organs. However, how this process is regulated has not been fully elucidated.<h3>Objectives</h3>In this study, we investigated the role of sialic acid, a host-derived carbohydrate, in the pathogenesis of gut dysbiosis-derived inflammation in distant organs.<h3>Methods</h3>Ampicillin (Amp)-induced gut dysbiotic mice were treated with N-glycolylneuraminic acid (Neu5Gc) and N-acetylneuraminic acid (Neu5Ac) for three weeks to assess the role of sialic acids in mastitis. The underlying mechanism by which sialic acids regulate mastitis was explored using 16S rRNA sequencing, transcriptomics and employed multiple molecular approaches.<h3>Results</h3>Administration of Neu5Ac and Neu5Gc exacerbated gut dysbiosis-induced mastitis and systemic inflammation. The gut dysbiosis caused by Amp was also aggravated by sialic acid. Notably, increased <em>Enterococcus</em> expansion, which was positively correlated with inflammatory markers, was observed in both Neu5Ac- and Neu5Gc-treated gut dysbiotic mice. Treatment of mice with <em>Enterococcus cecorum</em> (<em>E. cecorum</em>) aggravated gut dysbiosis-induced mastitis. Mechanically, sialic acid-facilitated <em>E. cecorum</em> expansion promoted muramyl dipeptide (MDP) release, which induced inflammatory responses by activating the NOD2-RIP2-NF-κB axis.<h3>Conclusions</h3>Collectively, our data reveal a role of sialic acid-facilitated postantibiotic pathobiont expansion in gut dysbiosis-associated inflammation, highlighting a potential strategy for disease prevention by regulating the MDP-NOD2-RIP2 axis.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"12 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377739","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":"Columbianadin ameliorates rheumatoid arthritis by attenuating synoviocyte hyperplasia through targeted vimentin to inhibit the VAV2/Rac-1 signaling pathway","authors":"Yuli Han, Changqing Liu, Shujing Chen, Huihui Sun, Zhaoyu Jia, Jiaxin Shi, Lirong Wang, Kunze Du, Yanxu Chang","doi":"10.1016/j.jare.2024.09.030","DOIUrl":"https://doi.org/10.1016/j.jare.2024.09.030","url":null,"abstract":"<h3>Introduction</h3>Rheumatoid arthritis (RA) is an autoimmune disease pathologically characterized by synovial inflammation. The abnormal activation of synoviocytes seems to accompany the progression of RA. The role and exact molecular mechanism in RA of columbianadin (CBN) which is a natural coumarin is still unclear.<h3>Objectives</h3>The present research aimed to investigate the effect of vimentin on the abnormal growth characteristics of RA synoviocytes and the targeted regulatory role of CBN.<h3>Methods</h3>Cell migration and invasion were detected using the wound healing and transwell method. Mechanistically, the direct molecular targets of CBN were screened and identified by activity-based protein profiling. The expression of relevant proteins and mRNA in cells and mouse synovium was detected by western blotting and qRT-PCR. Changes in the degree of paw swelling and body weight of mice were recorded. H&amp;E staining, toluidine blue staining, and micro-CT were used to visualize the degree of pathological damage in the ankle joints of mice. Small interfering RNA and plasmid overexpression of vimentin were used to observe their effects on MH7A cell proliferation, migration, apoptosis, and downstream molecular signaling.<h3>Results</h3>The TNF-α-induced proliferation and migration of MH7A cells could be significantly repressed by CBN (25,50 μM), and the expression of apoptosis and autophagy-associated proteins could be modulated. Furthermore, CBN could directly bind to vimentin and inhibit its expression and function in synoviocytes, thereby ameliorating foot and paw swelling and joint damage in CIA mice. Silencing and overexpression of vimentin might be involved in developing RA synovial hyperplasia and invasive cartilage by activating VAV2 phosphorylation-mediated expression of Rac-1, which affects abnormal growth characteristics, such as synoviocyte invasion and migration.<h3>Conclusion</h3>CBN-targeted vimentin restrains the overactivation of RA synoviocytes thereby delaying the pathological process in CIA mice, which provides valuable targets and insights for understanding the pathological mechanisms of RA synovial hyperplasia.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"192 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374612","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":"Serum metabolite biomarkers for the early diagnosis and monitoring of age-related macular degeneration","authors":"Shengjie Li, Yichao Qiu, Yingzhu Li, Jianing Wu, Ning Yin, Jun Ren, Mingxi Shao, Jian Yu, Yunxiao Song, Xinghuai Sun, Shunxiang Gao, Wenjun Cao","doi":"10.1016/j.jare.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.jare.2024.10.001","url":null,"abstract":"<h3>Introduction</h3>Age-related macular degeneration (AMD) is a leading cause of irreversible blindness worldwide, with significant challenges for early diagnosis and treatment.<h3>Objectives</h3>To identify new biomarkers that are important for the early diagnosis and monitoring of the severity/progression of AMD.<h3>Methods</h3>We investigated the diagnostic and monitoring potential of blood metabolites in a cohort of 547 individuals (167 healthy controls, 240 individuals with other eye diseases as eye disease controls, and 140 individuals with AMD) from 2 centers over three phases: discovery phase 1, discovery phase 2, and an external validation phase. The samples were analyzed via a mass spectrometry-based, widely targeted metabolomic workflow. In discovery phases 1 and 2, we built a machine learning algorithm to predict the probability of AMD. In the external validation phase, we further confirmed the performance of the biomarker panel identified by the algorithm. We subsequently evaluated the performance of the identified biomarker panel in monitoring the progression and severity of AMD.<h3>Results</h3>We developed a clinically specific three-metabolite panel (hypoxanthine, 2-furoylglycine, and 1-hexadecyl-2-azelaoyl-<em>sn</em>-glycero-3-phosphocholine) via five machine learning models. The random forest model effectively discriminated patients with AMD from patents in the other two groups and showed acceptable calibration (area under the curve (AUC) = 1.0; accuracy = 1.0) in both discovery phases 1 and 2. An independent validation phase confirmed the diagnostic model’s efficacy (AUC = 0.962; accuracy = 0.88). The three-biomarker panel model demonstrated an AUC of 1.0 in differentiating the severity of AMD via RF machine learning, which was consistent across both the discovery and external validation phases. Additionally, the biomarker concentrations remained stable under repeated freeze–thaw cycles (P &gt; 0.05).<h3>Conclusions</h3>This study reveals distinct metabolite variations in the serum of AMD patients, paving the way for the development of the first routine laboratory test for AMD.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"21 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374624","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":"Hippocampal dipeptidyl peptidase 9 bidirectionally regulates memory associated with synaptic plasticity","authors":"Ya-Bo Zhao, Shi-Zhe Wang, Wen-Ting Guo, Le Wang, Xun Tang, Jin-Nan Li, Lin Xu, Qi-Xin Zhou","doi":"10.1016/j.jare.2024.09.031","DOIUrl":"https://doi.org/10.1016/j.jare.2024.09.031","url":null,"abstract":"<h3>Introduction</h3>Subtypes of the dipeptidyl peptidase (DPP) family, such as DPP4, are reportedly associated with memory impairment. DPP9 is widely distributed in cells throughout the body, including the brain. However, whether DPP9 regulates memory has not yet been elucidated.<h3>Objectives</h3>This study aimed to elucidate the role of DPP9 in memory, as well as the underlying molecular mechanism.<h3>Methods</h3>We performed immunofluorescence on mouse brains to explore the distribution of DPP9 in different brain regions and used AAV vectors to construct knockdown and overexpression models. The effects of changing DPP9 expression on memory were demonstrated through behavioral experiments. Finally, we used electrophysiology, proteomics and affinity purification mass spectrometry (AP-MS) to study the molecular mechanism by which DPP9 affects memory.<h3>Results</h3>Here, we report that DPP9, which is found almost exclusively in neurons, is expressed and has enzyme activity in many brain regions, especially in the hippocampus. Hippocampal DPP9 expression increases after fear memory formation. Fear memory was impaired by DPP9 knockdown and enhanced by DPP9 protein overexpression in the hippocampus. According to subsequent hippocampal proteomics, multiple pathways, including the peptidase pathway, which can be bidirectionally regulated by DPP9. DPP9 directly interacts with its enzymatic substrate neuropeptide Y (NPY) in neurons. Hippocampal long-term potentiation (LTP) is also bidirectionally regulated by DPP9. Moreover, inhibiting DPP enzyme activity impaired both LTP and memory. In addition, AP-MS revealed that DPP9-interacting proteins are involved in the functions of dendritic spines and axons. By combining AP-MS and proteomics, DPP9 was shown to play a role in regulating actin functions.<h3>Conclusion</h3>Taken together, our findings reveal that DPP9 affects the CNS not only through enzymatic activity but also through protein–protein interactions. This study provides new insights into the molecular mechanisms of memory and DPP family functions.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"12 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374611","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}