Journal of Advanced Research最新文献

{"title":"KBTBD8/RRP15 as a potential novel therapeutic target associates with lenvatinib-inhibited progression in hepatocellular carcinoma both in vitro and in vivo","authors":"Saili Zhao ,&nbsp;Xuran Wang ,&nbsp;Rui Wu ,&nbsp;Fenglan Wang ,&nbsp;Xiaoxuan Tang ,&nbsp;Junhui Chen ,&nbsp;Runqiu Jiang ,&nbsp;Wei Kang ,&nbsp;Guifang Xu ,&nbsp;Lei Wang ,&nbsp;Zhangding Wang ,&nbsp;Xiaoping Zou ,&nbsp;Bin Zhang","doi":"10.1016/j.jare.2024.12.017","DOIUrl":"10.1016/j.jare.2024.12.017","url":null,"abstract":"<div><h3>Introduction</h3><div>We have previously demonstrated that RRP15 (Ribosomal RNA Processing 15 Homolog) was significantly elevated in hepatocellular carcinoma (HCC) and correlated directly with poor prognosis. RRP15 suppression curtails HCC progression through induction of cellular senescence and apoptosis. However, the impact of RRP15 on the precise therapeutic potential of lenvatinib has remained underexplored.</div></div><div><h3>Objective</h3><div>To investigate the relationship between RRP15 expression and sensitivity of lenvatinib in HCC treatment, and also explore the potential of targeting RRP15 by lenvatinib to inhibit HCC progression.</div></div><div><h3>Methods</h3><div>RRP15 and KBTBD8 (Kelch Repeat and BTB Domain Containing 8) expression was examined using western blot and immunohistochemistry. Cell viability, proliferation, migration and invasion as well as apoptosis were assessed using CCK-8, clonogenic assays, transwell, TUNEL (Terminal Deoxynucleotidyl Transferase mediated dUTP Nick-End Labeling) and Annexin V staining assays. The interaction between RRP15 and KBTBD8 was identified through pull-down and mass spectrometry analysis and further validated by immunofluorescence and co-immunoprecipitation assays. RRP15 ubiquitination and degradation were assessed using cycloheximide treatment, plasmid transfection and co-immunoprecipitation, followed by western blot analysis. Tail vein injection lung metastasis model was performed to determine tumor metastasis <em>in vivo</em>.</div></div><div><h3>Results</h3><div>We reveled a correlation between RRP15 downregulation and enhanced sensitivity to lenvatinib, presenting marked suppression of metastasis and invasiveness. Proteomic analyses and subsequent validation disclosed the pivotal role of the E3 ubiquitin ligase KBTBD8 in mediating the ubiquitination and subsequent degradation of RRP15 protein post-lenvatinib treatment in HCC cells. KBTBD8 inhibition stalled RRP15 ubiquitination and degradation, while its overexpression accelerated these processes. Moreover, RRP15 overexpression fosters HCC cell proliferation and metastasis, a pathological effect mitigated by KBTBD8 overexpression. <em>In vivo</em> experiments further validate the role of lenvatinib in promoting RRP15 degradation via KBTBD8 upregulation.</div></div><div><h3>Conclusions</h3><div>Our study elucidated a previously unidentified mechanism of lenvatinib action and identified the RRP15-KBTBD8 axis as a novel therapeutic target in HCC, offering new avenues for treatment strategies in combating HCC.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 569-583"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809723","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":"Maternal fish oil supplementation enhances nutrient transport in the placenta and milk biosynthesis in the mammary gland via the GPR120 signaling pathway","authors":"Qihui Li ,&nbsp;Qianzi Zhang ,&nbsp;Senlin Su ,&nbsp;Siwang Yang ,&nbsp;Jiayuan Shao ,&nbsp;Wutai Guan ,&nbsp;Shihai Zhang","doi":"10.1016/j.jare.2024.12.029","DOIUrl":"10.1016/j.jare.2024.12.029","url":null,"abstract":"<div><h3>Introduction</h3><div>Maternal fish oil (FO) supplementation during pregnancy has been shown to improve pregnancy outcomes. FO is recognized as dietary source for n-3 polyunsaturated fatty acids (n-3 PUFAs). While early research has focused on the benefits of n-3 PUFAs for fetal neurodevelopment, retinal maturation and neonatal behavior, their roles in the placenta during late pregnancy and in the mammary gland during lactation still remain unknow.</div></div><div><h3>Objectives</h3><div>Here, we aim to clarify the mechanisms by which maternal supplementation with FO during pregnancy and lactation affects placental and mammary gland function.</div></div><div><h3>Methods</h3><div>We evaluated the effects of FO on maternal placental nutrient transport, mammary gland milk synthesis and offspring growth. We then explored the molecular mechanisms by which docosahexaenoic acid (DHA) affects the biological function of placental trophoblast cells and mammary epithelial cells through <em>in vitro</em> experiments. Finally, a lipopolysaccharide-challenged experiment was performed to access the potential of maternal FO supplementation in alleviating offspring intestinal inflammation.</div></div><div><h3>Results</h3><div>Maternal supplementation with FO during late pregnancy increased offspring birth weight, associated with enhanced maternal placental vascularization and nutrient transporter abundance. Additionally, maternal FO supplementation during lactation improved milk biosynthesis, increasing the fat, protein, and non-fat solids content in both colostrum and mature milk, thereby promoting offspring growth. The stimulatory effects of DHA on nutrient transportation in placental trophoblast cells and nutrient secretion in mammary gland epithelial cells were mediated by GPR120 signaling pathways. Furthermore, maternal FO supplementation strengthened the placental barrier, reduced placental inflammation, oxidative stress and alleviated lipopolysaccharide-induced intestinal inflammation in offspring.</div></div><div><h3>Conclusion</h3><div>Maternal FO supplementation during late pregnancy and lactation enhances offspring growth by increasing placental nutrient transport and milk biosynthesis, mediated by GPR120. Additionally, maternal FO supplementation reduces the susceptibility of offspring to intestinal inflammation.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 73-89"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849349","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":"Not only the top: Type I topoisomerases function in multiple tissues and organs development in plants","authors":"Hao Zhang ,&nbsp;Lirong Tian ,&nbsp;Yuru Ma ,&nbsp;Jiahui Xu,&nbsp;Tianyu Bai,&nbsp;Qian Wang,&nbsp;Xigang Liu,&nbsp;Lin Guo","doi":"10.1016/j.jare.2024.12.011","DOIUrl":"10.1016/j.jare.2024.12.011","url":null,"abstract":"<div><h3>Background</h3><div>DNA topoisomerases (TOPs) are essential components in a diverse range of biological processes including DNA replication, transcription and genome integrity. Although the functions and mechanisms of TOPs, particularly type I TOP (TOP1s), have been extensively studied in bacteria, yeast and animals, researches on these proteins in plants have only recently commenced.</div></div><div><h3>Aim of Review</h3><div>In this review, the function and mechanism studies of TOP1s in plants and the structural biology of plant TOP1 are presented, providing readers with a comprehensive understanding of the current research status of this essential enzyme.The future research directions for exploring the working mechanism of plant TOP1s are also discussed.</div></div><div><h3>Key Scientific Concepts of Review</h3><div>Over the past decade, it has been discovered TOP1s play a vital role in multiphasic processes of plant development, such as maintaining meristem activity, gametogenesis, flowering time, gravitropic response and so on. Plant TOP1s affects gene transcription by modulating chromatin status, including chromatin accessibility, DNA/RNA structure, and nucleosome positioning. However, the function and mechanism of this vital enzyme is poorly summarized although it has been systematically summarized in other species. This review summarized the research progresses of plant TOP1s according to the diverse functions and working mechanism in different tissues.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 173-190"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793738","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":"Parkin modulates the hepatocellular carcinoma microenvironment by regulating PD-1/PD-L1 signalling","authors":"Guiqin Ye ,&nbsp;Xin Sun ,&nbsp;Jiuzhou Li ,&nbsp;Maomao Pu ,&nbsp;Jianbin Zhang","doi":"10.1016/j.jare.2024.12.045","DOIUrl":"10.1016/j.jare.2024.12.045","url":null,"abstract":"<div><h3>Introduction</h3><div>Parkin-mediated mitophagy is essential for clearing damaged mitochondria, and it inhibits tumour development. The role of mitophagy in modulating tumour immunity is becoming clearer, but the underlying mechanism is still poorly understood.</div></div><div><h3>Objective</h3><div>This study was designed to examine the role of Parkin in the immune microenvironment of liver tumours induced by carbon tetrachloride (CCl₄).</div></div><div><h3>Methods</h3><div>Single-cell RNA sequencing analysis, Western blot, immunofluorescence and co-immunoprecipitation were used to verify the mechanism of Parkin affecting the tumour microenvironment by altering the expression of PD-1.</div></div><div><h3>Results</h3><div>Our data revealed that <em>Park2^-/-</em> mice showed severe liver damage and increased malignancy. Single-cell RNA sequencing analysis of T lymphocytes in liver tumours showed that the number of cytotoxic CD8⁺ T cells (Gzmb/Ifng/Fasl) was significantly decreased and the number of exhausted CD8⁺ T cells (Pdcd1/Lag3/Tigit/Havcr2/Ctla4) was significantly increased in <em>Park2^-/-</em> mice, indicating the immune suppressive microenvironment. Single-cell RNA sequencing analysis of myeloid-derived cells also displayed the increase of M2-like macrophages in <em>Park2^-/-</em> mice. Through quantitative proteomic analysis, it was found that the differential protein expression between the two groups mainly localized in the plasma membrane and extracellular, including PD-1, MHC-Ⅰ molecules etc., and was mainly associated with PD-1 and antigen presentation pathways. It could impair the antitumour immune response with Parkin deficiency. Parkin deficiency leads to the decrease of hepatic mitophagy levels and the formation of an immune suppressive microenvironment, which promotes the tumourigenesis of liver cancer.</div></div><div><h3>Conclusion</h3><div>As an E3 ubiquitin ligase, Parkin induces the ubiquitination and degradation of PD-1 in liver cancer and could influence antitumour immunity through the PD-1/PD-L1 signalling pathway. Thus, remodeling the tumour microenvironment through the reintroduction of Parkin or enhancement of mitophagy could activate the anti-tumour immune response and improve the immunotherapy efficacy, which may be a promising strategy for the treatment of HCC.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 731-744"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912032","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":"D-Mannose-Mediated metabolic pathways sustain the molecular signatures of sperm function and fertilization","authors":"Wenlong Zhao ,&nbsp;Nihao Gu ,&nbsp;Xueyuan Liu ,&nbsp;Ningxin Qing ,&nbsp;Jianzhong Sheng ,&nbsp;Xianhua Lin ,&nbsp;Hefeng Huang","doi":"10.1016/j.jare.2024.12.035","DOIUrl":"10.1016/j.jare.2024.12.035","url":null,"abstract":"<div><h3>Introduction</h3><div>Mammalian sperm within a single ejaculate exhibit significant heterogeneity, with only a subset possessing the molecular characteristics required for successful fertilization. Identifying the defining traits of these high-fertility sperm remains an open question.</div></div><div><h3>Objectives</h3><div>To elucidate the molecular markers and mechanisms underlying the fertilization potential of sperm in both mice and humans, with a focus on the role of D-mannose.</div></div><div><h3>Methods</h3><div>Sperm morphology and functionality were analyzed using flow cytometry, biochemical assays, and immunofluorescence. Multi-omics analyses, including proteomics, metabolomics, and lipidomics, were conducted to identify distinct molecular signatures. Pharmacological interventions were employed to validate the role of key pathways, particularly Akt/mTOR signaling.</div></div><div><h3>Results</h3><div>Sperm with longer flagella demonstrated enhanced motility, mitochondrial activity, and fertilization potential in both mice and humans. Multi-omics analyses revealed distinct molecular profiles in high-fertility sperm, characterized by specific proteins, lipids, and metabolites. Notably, D-mannose supplementation enhanced sperm motility and fertilization capacity, even in asthenozoospermic sperm, by activating the Akt/mTOR pathway. This effect was not replicated by D-glucose or ATP supplementation. Mechanistically, D-mannose bypassed glycolytic rate-limiting steps, increasing ATP production and promoting mitochondrial and acrosomal integrity.</div></div><div><h3>Conclusion</h3><div>This study identifies key molecular signatures of fertilization-competent sperm and highlights D-mannose as a novel modulator of sperm quality and function. These findings provide valuable insights into sperm biology and propose innovative therapeutic strategies for treating male infertility and optimizing assisted reproduction technologies.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 251-269"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888402","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":"Adiponectin deficiency prevents chronic colitis-associated colonic fibrosis via inhibiting CXCL13 production","authors":"Haitao Xiao ,&nbsp;Tianhang Xing ,&nbsp;Miao Qiu ,&nbsp;Guangtao Zhang ,&nbsp;Gongli Yang ,&nbsp;Wenke Chen ,&nbsp;Die Hu ,&nbsp;Deao Xue ,&nbsp;Jiao Peng ,&nbsp;Bin Du","doi":"10.1016/j.jare.2024.12.032","DOIUrl":"10.1016/j.jare.2024.12.032","url":null,"abstract":"<div><h3>Introduction</h3><div>Colonic fibrosis is a long-term complication of inflammatory bowel disease (IBD), often leading to functional impairment, intestinal obstruction, and surgery. Adiponectin (APN) is an adipokine derived from adipocytes that plays a pleiotropic role in fibrosis regulation, depending on tissue and cell type specific or disease context, but its role in colonic fibrosis remains unclear.</div></div><div><h3>Objective</h3><div>To explore the role and involved mechanism of APN in chronic colitis-associated colonic fibrosis.</div></div><div><h3>Methods</h3><div>Studies were performed in GEO database, colonic tissues of UC patients, dextran sulfate sodium (DSS)-induced colonic fibrosis in male wild-type (WT) and APN^-/- mice, mouse L929 and human CCD-18Co fibroblasts treated with recombinant CXCL13 protein, and colonic fibrosis in WT mice infected with shRNA of CXCL13.</div></div><div><h3>Results</h3><div>APN was highly expressed in the colonic tissues of UC patients and positively correlated with the colonoscopy score and colonic fibrosis markers COL1A1 and COL3A1. APN deficiency significantly improved chronic colitis-induced colonic fibrosis in mice with down-regulating collagenase accumulation and expressions of TGF-β, α-SMA, COL1A1, COL3A1, and MMP-9 in colonic tissues. Transcriptomics showed that APN deficiency mainly affected cytokine-cytokine receptor interactions, especially CXCL13 signaling. Follow-up studies showed that APN deficiency significantly decreased the number of colonic F4/80⁺CD206⁺CXCL13⁺ macrophages by weakening Akt phosphorylation. Additional experiments confirmed that CXCL13 notably increased the expressions of α-SMA and COL1A1 in mouse and human fibroblasts by activating p-Akt, p-p38, p-ERK, and p-JNK. Moreover, inhibiting CXCL13 with shRNA significantly ameliorated colonic fibrosis in mice with DSS-induced chronic colitis. Immunohistochemistry analysis revealed high expression of CXCL13 in the colon tissues of patients with UC, showing a positive correlation with APN, COL1A1, and COL3A1.</div></div><div><h3>Conclusion</h3><div>APN contributes to the progression of colonic fibrosis and can exacerbate this condition by regulating the secretion of CXCL13 in the colon, offering potential new perspectives on the pathophysiology of colonic fibrosis.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 639-653"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884686","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":"CD34+CLDN5+ tumor associated senescent endothelial cells through IGF2-IGF2R signaling increased cholangiocellular phenotype in hepatocellular carcinoma","authors":"Xin-yu Zhu ,&nbsp;Wen-ting Liu ,&nbsp;Xiao-juan Hou ,&nbsp;Chen Zong ,&nbsp;Wei Yu ,&nbsp;Zhe-min Shen ,&nbsp;Shu-ping Qu ,&nbsp;Min Tao ,&nbsp;Meng-meng Xue ,&nbsp;Dao-yu Zhou ,&nbsp;Hao-ran Bai ,&nbsp;Lu Gao ,&nbsp;Jing-hua Jiang ,&nbsp;Qiu-dong Zhao ,&nbsp;Li-xin Wei ,&nbsp;Xue Yang ,&nbsp;Zhi-peng Han ,&nbsp;Li Zhang","doi":"10.1016/j.jare.2024.12.008","DOIUrl":"10.1016/j.jare.2024.12.008","url":null,"abstract":"<div><h3>Introduction</h3><div>The heterogeneity of hepatocellular carcinoma (HCC) is linked to tumor malignancy and poor prognosis. Nevertheless, the precise mechanisms underlying the development of the cholangiocellular phenotype (CCA) within HCC remain unclear. Emerging studies support that the cross-talk among the host cells within tumor microenvironment (TME) sustains the cancer cell plasticity.</div></div><div><h3>Objectives</h3><div>This study sought to identify the specific cell types involved in the formation of CCA and to elucidate their functional roles in the progression of HCC.</div></div><div><h3>Methods</h3><div><strong>S</strong>ingle-cell RNA sequencing was employed to identify the specific cell types involved in the formation of CCA. Both in vitro and vivo analyses were used to identify the tumor-associated senescent ECs and investigate the function in TME. The diethylnitrosamine-induced model was utilized to investigate the interaction between senescent ECs and MSCs, aiming to elucidate their synergistic contributions to the progression of CCA.</div></div><div><h3>Results</h3><div>Using single-cell RNA sequencing, we identified a distinct senescent-associated subset of endothelial cells (ECs), namely CD34⁺CLDN5⁺ ECs, which mainly enriched in tumor tissue. Further, the senescent ECs were observed to secrete IGF2, which recruited mesenchymal stem cells (MSCs) into the TME through IGF2R/MAPK signaling. In primary liver cancer model, MSCs exhibited a strong tumor-promoting effect, increasing the CCA and tumor malignancy after HCC formation. Interestingly, knockdown of IGF2R expression in MSCs inhibited the increase of CCA caused by MSCs in HCC. Meanwhile, it was revealed that MSCs released multiple inflammatory and trophic-related cytokines to enhance the cancer stem cell-like characteristics in HCC cells. Finally, we demonstrated that CEBPβ up-regulated IGF2 expression in tumor senescent ECs by combining with <em>Igf2</em>-promtor-sequence.</div></div><div><h3>Conclusions</h3><div>Together, our findings illustrated that tumor associated senescent ECs in HCC recruited the MSCs into TME, enhancing cancer stem cell (CSC)-like features of HCC cells and contributing to the CCA formation.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 511-528"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816332","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":"Predictive value of remnant cholesterol inflammatory index for stroke risk: Evidence from the China health and Retirement Longitudinal study","authors":"Jiaying Chen ,&nbsp;Qiheng Wu ,&nbsp;Haotian Liu ,&nbsp;Weike Hu ,&nbsp;JiaJia Zhu ,&nbsp;Zhong Ji ,&nbsp;Jia Yin","doi":"10.1016/j.jare.2024.12.015","DOIUrl":"10.1016/j.jare.2024.12.015","url":null,"abstract":"<div><h3>Introduction</h3><div>Remnant cholesterol (RC) and high-sensitivity C-reactive protein (hs-CRP) are established stroke risk factors, but their joint impact remains unclear.</div></div><div><h3>Objectives</h3><div>This study aimed to evaluate the predictive value of the remnant cholesterol inflammatory index (RCII), a novel index integrating RC and hs-CRP, in assessing stroke risk.</div></div><div><h3>Methods</h3><div>We analyzed 9,898 participants aged 45 years or older, with no history of stroke at baseline, from the China Health and Retirement Longitudinal Study (CHARLS). RCII was calculated using the formula: RCII = RC (mg/dL) × hs-CRP(mg/L)/10. A subset of 5,704 participants was studied to investigate the relationship between cumulative RCII exposure and stroke incidence. The associations of both baseline and cumulative RCII with stroke risk were assessed using Cox proportional hazards regression model.</div></div><div><h3>Results</h3><div>During a median 7-year follow-up, 560 participants (5.7 %) experienced an incident stroke. Stroke incidence escalated with increasing RCII quartiles, from 3.5 % (Q1) to 7.6 % (Q4). In multivariable-adjusted analyses, each standard deviation increase in RCII was significantly associated with a 10.6 % increased risk of stroke (HR = 1.106, 95 % CI: 1.048–1.167). ROC analysis revealed that RCII had the highest AUC at 0.581, higher than RC (0.566) and hs-CRP (0.560), though the difference with RC was not statistically significant (P = 0.166). Mediation analysis indicated a reciprocal mediation between RC and hs-CRP on stroke risk. In a 3-year subset analysis, 288 participants suffered a stroke. Participants with cumulative RCII levels exceeding 36.14 had a significantly increased risk of incident stroke (HR = 1.462, 95 % CI: 1.102–1.939). Subgroup analyses showed a significant positive association between elevated RCII levels and stroke risk in males, but not in females.</div></div><div><h3>Conclusions</h3><div>Elevated levels of RCII, both at baseline and cumulative, are significantly associated with an increased risk of stroke. Early intervention in patients with high RCII may further help reduce stroke risk.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 543-552"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816383","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":"Loss of glomerular aldolase B in diabetic nephropathy promotes renal fibrosis via activating Akt/GSK/β-catenin axis","authors":"Minghui Liu ,&nbsp;Wenwen Yang ,&nbsp;Shuang Qu ,&nbsp;Tingting Zhao ,&nbsp;Song Jiang ,&nbsp;Suming Peng ,&nbsp;Mingchao Zhang ,&nbsp;Ji Xuan ,&nbsp;Zhihong Liu ,&nbsp;Ke Zen","doi":"10.1016/j.jare.2024.12.027","DOIUrl":"10.1016/j.jare.2024.12.027","url":null,"abstract":"<div><h3>Objective</h3><div>Diabetic nephropathy (DN), characterized by a complex and multifaceted pathogenesis, stands as the foremost catalyst behind end-stage renal disease (ESRD). This study aims to analyze the level and non-metabolic role of glomerular aldolase B (ALDOB) in DN progression.</div></div><div><h3>Methods</h3><div>Glomerular proteomics and transcriptome are analyzed from 50 DN patients and 25 controls, respectively. Human kidney biopsy, cultured podocytes and mouse models are employed to study ALDOB levels and function.</div></div><div><h3>Results</h3><div>ALDOB is strongly downregulated in DN-affected glomeruli, as well as in human and murine podocytes exposed to inflammatory cytokines. ALDOB reduction increases podocyte injury, while adenovirus-mediated ALDOB overexpression leads to substantial alleviation of renal injuries in a diabetic mouse model. Mechanistically, ALDOB reduction triggers the Akt/GSK/β-catenin signaling cascade within podocytes.</div></div><div><h3>Conclusion</h3><div>Our findings reveal a novel non-metabolic role of glomerular ALDOB in protecting against podocyte injury and renal fibrosis.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 207-218"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884688","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":"Lonicera caerulea genome reveals molecular mechanisms of freezing tolerance and anthocyanin biosynthesis","authors":"Jing Wang ,&nbsp;Xiaotong Wang ,&nbsp;Yuwei Ma ,&nbsp;Ranran Gao ,&nbsp;Yongmiao Wang ,&nbsp;Zhoujie An ,&nbsp;Ya Tian ,&nbsp;Huihua Wan ,&nbsp;Dianwen Wei ,&nbsp;Feng Wang ,&nbsp;Baojiang Zheng ,&nbsp;Baozhong Duan ,&nbsp;Li Xiang ,&nbsp;Gangqiang Dong ,&nbsp;Wei Sun ,&nbsp;Zhichao Xu","doi":"10.1016/j.jare.2024.12.038","DOIUrl":"10.1016/j.jare.2024.12.038","url":null,"abstract":"<div><h3>Introduction</h3><div><em>Lonicera caerulea</em> L. (blue honeysuckle) is a noteworthy fleshy-fruited tree and a prominent medicinal plant, which possesses notable characteristics such as exceptional resilience to winter conditions and early maturation, and the richest source of functional anthocyanins, particularly cyanidin-3-glucoside. The molecular mechanisms responsible for its freezing tolerance and anthocyanin biosynthesis remain largely unknown.</div></div><div><h3>Objectives</h3><div>Here, a chromosome-scale genome of <em>L. caerulea</em> was presented, aiming to examine the genetic foundations that underlie these characteristics of blue honeysuckle.</div></div><div><h3>Methods</h3><div>The PacBio HiFi reads and Hi-C data were used to construct high-quality genome of blue honeysuckle. Comparative genomic and transcriptomic analyses were conducted to elucidate the molecular mechanisms of freezing tolerance and anthocyanin biosynthesis.</div></div><div><h3>Results</h3><div>Comparative genomics analysis between <em>L. caerulea</em> and <em>L. japonica</em> revealed that the dynamic changes of duplicated genes contributed to their phytochemical reconstruction and environmental adaptation. Moreover, the ABA and ICE-CBF-COR signaling pathways were closely correlated to the freezing tolerance of <em>L. caerulea</em>. Genome-wide identification and biochemical function indicated that three anthocyanin 3′,5′-<em>O</em>-methyltransferases (<em>LcOMT2</em>, <em>LcOMT14</em>, and <em>LcOMT20</em>) and two 3′-<em>O</em>-glycosyltransferases (<em>LcUGT78X1</em> and <em>LcUGT95P1</em>) were responsible for anthocyanin biosynthesis. In addition, <em>LcUGT78X1</em> was regarded as the potent glycosyltransferase for the accumulation of cyanidin-3-glucoside in <em>L. caerulea</em>.</div></div><div><h3>Conclusion</h3><div>This research elucidates the crucial roles of the ABA and ICE-CBF-COR signaling pathways in enhancing freezing tolerance, while also identifying highly efficient anthocyanin biosynthetic enzymes in <em>L. caerulea</em>. These findings advance the understanding of environmental adaptation and phytochemical production in <em>Lonicera</em> species.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 293-305"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886712","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}