Journal of Advanced Research最新文献

{"title":"Erianin serves as an NFATc1 inhibitor to prevent breast cancer-induced osteoclastogenesis and bone destruction","authors":"Jiehuang Zheng ,&nbsp;Weili He ,&nbsp;Yan Chen ,&nbsp;Lihong Li ,&nbsp;Qinghe Liang ,&nbsp;Wenqi Dai ,&nbsp;Ruopeng Li ,&nbsp;Fengsheng Chen ,&nbsp;Ziye Chen ,&nbsp;Yanhui Tan ,&nbsp;Xiaojuan Li","doi":"10.1016/j.jare.2024.03.021","DOIUrl":"10.1016/j.jare.2024.03.021","url":null,"abstract":"<div><h3>Introduction</h3><div>Breast cancer-related bone metastasis can lead to skeletal-related events (SREs), which decrease patient quality of life. Inhibition of osteoclastogenesis is a key treatment for SREs; however, the availability of clinical drugs remains limited, and all existing ones disrupt physiological bone formation, while exhibiting no effect on patient survival time.</div></div><div><h3>Objectives</h3><div>This study aimed to identify a novel osteoclast inhibitor for the treatment of breast cancer-induced SREs.</div></div><div><h3>Methods</h3><div>The MDA-MB-231 breast cancer cell-induced bone loss model was used to investigate the therapeutic effects of erianin <em>in vivo</em>. Then, we evaluated the inhibitory effects of erianin on osteoclastogenesis and signalling in bone marrow-derived macrophages (BMMs) induced by conditioned medium from MDA-MB-231 breast cancer cells (231 CM) and receptor activator of nuclear factor-κB ligand (RANKL) <em>in vitro</em>. Next, a Cellular Thermal Shift Assay and siRNA-mediate knockdown were performed, to investigate the target of erianin during osteoclast formation. The effects of erianin on human osteoclastogenesis were evaluated using CD14⁺ monocytes obtained from patients with breast cancer.</div></div><div><h3>Results</h3><div>Erianin effectively improved breast cancer cells-induced bone destruction at doses of 2 and 20 mg/kg/day <em>in vivo</em>, while suppressing osteoclastogenesis and the upregulation of SRC-NFATc1, INTEGRIN β3-MMP9 signals induced by 231 CM and RANKL <em>in vitro</em>. Furthermore, erianin interacted with NFATc1 but not SRC, and <em>Nfatc1</em> knockdown eliminated the inhibitory effects of erianin on osteoclastogenesis. Notably, lower expression of <em>NFATc1</em> positively correlated with longer survival in patients with cancer and a high risk of bone metastasis. We further revealed that 62.5–250 nM erianin suppresses NFATc1 and excessive osteoclastogenesis in CD14⁺ monocytes from patients with breast cancer.</div></div><div><h3>Conclusion</h3><div>Erianin acts as an NFATc1 inhibitor that attenuates breast cancer-induced osteoclastogenesis and bone destruction.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 399-411"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140332383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urolithin A inhibits breast cancer progression via activating TFEB-mediated mitophagy in tumor macrophages","authors":"Bowen Zheng ,&nbsp;Yuying Wang ,&nbsp;Baian Zhou ,&nbsp;Fengyuan Qian ,&nbsp;Diya Liu ,&nbsp;Danrong Ye ,&nbsp;Xiqian Zhou ,&nbsp;Lin Fang","doi":"10.1016/j.jare.2024.04.010","DOIUrl":"10.1016/j.jare.2024.04.010","url":null,"abstract":"<div><h3>Introduction</h3><div>Urolithin A (UA) is a naturally occurring compound that is converted from ellagitannin-like precursors in pomegranates and nuts by intestinal flora. Previous studies have found that UA exerts tumor-suppressive effects through antitumor cell proliferation and promotion of memory T-cell expansion, but its role in tumor-associated macrophages remains unknown.</div></div><div><h3>Objectives</h3><div>Our study aims to reveal how UA affects tumor macrophages and tumor cells to inhibit breast cancer progression.</div></div><div><h3>Methods</h3><div>Observe the effect of UA treatment on breast cancer progression though in vivo and in vitro experiments. Western blot and PCR assays were performed to discover that UA affects tumor macrophage autophagy and inflammation. Co-ip and Molecular docking were used to explore specific molecular mechanisms.</div></div><div><h3>Results</h3><div>We observed that UA treatment could simultaneously inhibit harmful inflammatory factors, especially for InterleuKin-6 (IL-6) and tumor necrosis factor α (TNF-α), in both breast cancer cells and tumor-associated macrophages, thereby improving the tumor microenvironment and delaying tumor progression. Mechanistically, UA induced the key regulator of autophagy, transcription factor EB (TFEB), into the nucleus in a partially mTOR-dependent manner and inhibited the ubiquitination degradation of TFEB, which facilitated the clearance of damaged mitochondria via the mitophagy-lysosomal pathway in macrophages under tumor supernatant stress, and reduced the deleterious inflammatory factors induced by the release of nucleic acid from damaged mitochondria. Molecular docking and experimental studies suggest that UA block the recognition of TFEB by 1433 and induce TFEB nuclear localization. Notably, UA treatment demonstrated inhibitory effects on tumor progression in multiple breast cancer models.</div></div><div><h3>Conclusion</h3><div>Our study elucidated the anti-breast cancer effect of UA from the perspective of tumor-associated macrophages. Specifically, TFEB is a crucial downstream target in macrophages.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 125-138"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140776922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Calcium influx: An essential process by which α-Synuclein regulates morphology of erythrocytes” [J. Adv. Res. 62 (2024) 187–198]","authors":"Ying Yang ,&nbsp;Min Shi ,&nbsp;Xiaodan Liu ,&nbsp;Qiaoyun Zhu ,&nbsp;Zhi Xu ,&nbsp;Genliang Liu ,&nbsp;Tao Feng ,&nbsp;Tessandra Stewart ,&nbsp;Jing Zhang","doi":"10.1016/j.jare.2024.09.018","DOIUrl":"10.1016/j.jare.2024.09.018","url":null,"abstract":"","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 581-583"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factors affecting the intracytoplasmic sperm cell injection outcomes: A meta-analysis of porcine studies","authors":"Muhammad Ameen Jamal, Ali Husnain, Kaixiang Xu, Hong-Jiang Wei","doi":"10.1016/j.jare.2025.02.040","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.040","url":null,"abstract":"<h3>Background</h3>Intracytoplasmic sperm cell injection (ICSI) has the potential to produce gene-edited (GE) pigs for biomedical research, but its success is limited. The factors impeding ICSI in pigs are impractical <em>in-vivo</em> oocyte production, incomplete cytoplasmic maturation of <em>in-vitro</em> matured (IVM) oocytes, inefficient methods for sperm selection and membrane removal, abnormal sperm nucleus decondensation, substandard protocols for oocyte stimulation, suboptimal <em>in-vitro</em> culture (IVC) systems, and high embryonic/fetal losses.<h3>Aim of review</h3>The aim of this review is to investigate the effects of interventions in ICSI on oocyte activation, fertilization, cleavage, blastocyst, blastomere count, and live birth by means of robust statistical <em>meta</em>-analytical methods.<h3>Key scientific concepts of review</h3>A total of 61 studies published between 1905 ∼ 2024 met the inclusion criteria. The results of the <em>meta</em>-analysis suggested that manipulation in the IVM media did not improve oocyte developmental competency to blastocysts but increased the blastomere count, especially with the addition of thiol compounds. Consistently, manipulation with sperm was beneficial only for increasing the cleavage and blastomere count. Exogenous stimulation increased the relative risk (RR) for oocyte activation (10 %), fertilization (33 %), cleavage (18 %), and blastocyst formation (71 %) but did not affect the blastomere count. Chemical stimulation either pre- or post-ICSI was more beneficial than electrical stimulation. Manipulation of the culture increased the RR for oocyte activation (14 %) and fertilization (37 %) but did not benefit cleavage, blastocyst formation, or blastomere count. The subgroup analyses revealed that supplementation with thiol compounds was indeed beneficial. Our network <em>meta</em>-analysis also supported the findings of classical <em>meta</em>-analyses showing that cysteine, cysteamine, epidermal growth factor, amino acid supplementation in maturation and culture media, and Triton treatment of sperm improved blastocyst formation. The overall success rate of live births from total embryos transferred after ICSI was not greater than 2 %. Although, manipulations that were beneficial for ICSI outcomes were identified in this <em>meta</em>-analysis, however, areas where more robust data are needed to reach a conclusive decision are highlighted.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"54 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526373","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":"Sweet regulation – The emerging immunoregulatory roles of hexoses","authors":"Junjie Xu ,&nbsp;Yuening Zhao ,&nbsp;Randall Tyler Mertens ,&nbsp;Yimin Ding ,&nbsp;Peng Xiao","doi":"10.1016/j.jare.2024.04.014","DOIUrl":"10.1016/j.jare.2024.04.014","url":null,"abstract":"<div><h3>Background</h3><div>It is widely acknowledged that dietary habits have profound impacts on human health and diseases. As the most important sweeteners and energy sources in human diets, hexoses take part in a broad range of physiopathological processes. In recent years, emerging evidence has uncovered the crucial roles of hexoses, such as glucose, fructose, mannose, and galactose, in controlling the differentiation or function of immune cells.</div></div><div><h3>Aim of Review</h3><div>Herein, we reviewed the latest research progresses in the hexose-mediated modulation of immune responses, provided in-depth analyses of the underlying mechanisms, and discussed the unresolved issues in this field.</div></div><div><h3>Key Scientific Concepts of Review</h3><div>Owing to their immunoregulatory effects, hexoses affect the onset and progression of various types of immune disorders, including inflammatory diseases, autoimmune diseases, and tumor immune evasion. Thus, targeting hexose metabolism is becoming a promising strategy for reversing immune abnormalities in diseases.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 361-379"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140604283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Punicalagin attenuates hyperuricemia via restoring hyperuricemia-induced renal and intestinal dysfunctions","authors":"Qing-qing Han ,&nbsp;Qi-dong Ren ,&nbsp;Xu Guo ,&nbsp;Mohamed A. Farag ,&nbsp;Yu-hong Zhang ,&nbsp;Meng-qi Zhang ,&nbsp;Ying-ying Chen ,&nbsp;Shu-tao Sun ,&nbsp;Jin-yue Sun ,&nbsp;Ning-yang Li ,&nbsp;Chao Liu","doi":"10.1016/j.jare.2024.03.029","DOIUrl":"10.1016/j.jare.2024.03.029","url":null,"abstract":"<div><h3>Introduction</h3><div>It is estimated that 90% of hyperuricemia cases are attributed to the inability to excrete uric acid (UA). The two main organs in charge of excreting UA are the kidney (70%) and intestine (30%). Previous studies have reported that punicalagin (PU) could protect against kidney and intestinal damages, which makes it a potential candidate for alleviating hyperuricemia. However, the effects and deeper action mechanisms of PU for managing hyperuricemia are still unknown.</div></div><div><h3>Objective</h3><div>To investigate the effect and action mechanisms of PU for ameliorating hyperuricemia.</div></div><div><h3>Methods</h3><div>The effects and action mechanisms of PU on hyperuricemia were assessed using a hyperuricemia mice model. Phenotypic parameters, metabolomics analysis, and 16S rRNA sequencing were applied to explore the effect and fundamental action mechanisms inside the kidney and intestine of PU for improving hyperuricemia.</div></div><div><h3>Results</h3><div>PU administration significantly decreased elevated serum uric acid (SUA) levels in hyperuricemia mice, and effectively alleviated the kidney and intestinal damage caused by hyperuricemia. In the kidney, PU down-regulated the expression of UA resorption protein URAT1 and GLUT9, while up-regulating the expression of UA excretion protein ABCG2 and OAT1 as mediated <em>via</em> the activation of MAKP/NF-κB in hyperuricemia mice. Additionally, PU attenuated renal glycometabolism disorder, which contributed to improving kidney dysfunction and inflammation. Similarly, PU increased UA excretion protein expression <em>via</em> inhibiting MAKP/NF-κB activation in the intestine of hyperuricemia mice. Furthermore, PU restored gut microbiota dysbiosis in hyperuricemia mice.</div></div><div><h3>Conclusion</h3><div>This research revealed the ameliorating impacts of PU on hyperuricemia by restoring kidney and intestine damage in hyperuricemia mice, and to be considered for the development of nutraceuticals used as UA-lowering agent.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 449-461"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140640594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The circadian rhythm: A new target of natural products that can protect against diseases of the metabolic system, cardiovascular system, and nervous system","authors":"Meiling Xin ,&nbsp;Fangjie Bi ,&nbsp;Chao Wang ,&nbsp;Yuhong Huang ,&nbsp;Yujia Xu ,&nbsp;Shufei Liang ,&nbsp;Tianqi Cai ,&nbsp;Xiaoxue Xu ,&nbsp;Ling Dong ,&nbsp;Tianxing Li ,&nbsp;Xueke Wang ,&nbsp;Yini Fang ,&nbsp;Zhengbao Xu ,&nbsp;Meng Wang ,&nbsp;Xinhua Song ,&nbsp;Yanfei Zheng ,&nbsp;Wenlong Sun ,&nbsp;Lingru Li","doi":"10.1016/j.jare.2024.04.005","DOIUrl":"10.1016/j.jare.2024.04.005","url":null,"abstract":"<div><h3>Background</h3><div>The treatment of metabolic system, cardiovascular system, and nervous system diseases remains to be explored. In the internal environment of organisms, the metabolism of substances such as carbohydrates, lipids and proteins (including biohormones and enzymes) exhibit a certain circadian rhythm to maintain the energy supply and material cycle needed for the normal activities of organisms. As a key factor for the health of organisms, the circadian rhythm can be disrupted by pathological conditions, and this disruption accelerates the progression of diseases and results in a vicious cycle. The current treatments targeting the circadian rhythm for the treatment of metabolic system, cardiovascular system, and nervous system diseases have certain limitations, and the identification of safer and more effective circadian rhythm regulators is needed.</div></div><div><h3>Aim of the review</h3><div>To systematically assess the possibility of using the biological clock as a natural product target for disease intervention, this work reviews a range of evidence on the potential effectiveness of natural products targeting the circadian rhythm to protect against diseases of the metabolic system, cardiovascular system, and nervous system. This manuscript focuses on how natural products restore normal function by affecting the amplitude of the expression of circadian factors, sleep/wake cycles and the structure of the gut microbiota.</div></div><div><h3>Key scientific concepts of the review</h3><div>This work proposes that the circadian rhythm, which is regulated by the amplitude of the expression of circadian rhythm-related factors and the sleep/wake cycle, is crucial for diseases of the metabolic system, cardiovascular system and nervous system and is a new target for slowing the progression of diseases through the use of natural products. This manuscript provides a reference for the molecular modeling of natural products that target the circadian rhythm and provides a new perspective for the time-targeted action of drugs.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 495-514"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140640661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient chemo-immunotherapy leveraging minimalist electrostatic complex nanoparticle as “in situ” vaccine integrated tumor ICD and immunoagonist","authors":"Yunfei Han ,&nbsp;Mingxia Jiang ,&nbsp;Yanju Sun ,&nbsp;Wenqiang Chen ,&nbsp;Yanli Zhao ,&nbsp;Xiuwen Guan ,&nbsp;Weifen Zhang","doi":"10.1016/j.jare.2024.03.010","DOIUrl":"10.1016/j.jare.2024.03.010","url":null,"abstract":"<div><h3>Introduction</h3><div>Immunotherapy has unprecedentedly opened up a series of neoteric tactics for cancer treatment. As a burgeoning approach, chemo-immunotherapy has innovatively expanded the accomplishments of conventional chemotherapeutic agents for cancer governing.</div></div><div><h3>Objectives</h3><div>An efficacious chemo-immunotherapy leveraging minimalist electrostatic complex nanoparticle (NP) integrated tumor immunogenic cell death (ICD) and immunoagonist was developed as a watertight “<em>in situ</em>” vaccine for cancer therapy through convenient intratumoral administration with minimized systemic toxicity.</div></div><div><h3>Methods</h3><div>Chemical-modified pH-sensitive <em>cis</em>-aconityl-doxorubicin (CAD) and immunoadjuvant unmethylated cytosine-phosphate-guanine (CpG) were co-packaged by polycationic polyethylenimine (PEI) though electrostatic-interaction to construct PEI/CpG/CAD NP. By intratumoral injection, this positively charged NP could be detained at tumor site and endocytosed by tumor cells effortlessly. Then, doxorubicin was released through <em>cis</em>-aconityl cleavage induced by endosomal-acidity and further triggered tumor ICD, the moribund tumor cells could release damage-associated molecular patterns (DAMPs) to recruit dendritic cells (DCs). Meanwhile, the entire tumor debris derived into diversified antigens and cooperated with immunostimulatory CpG to excite DC maturation and activated comprehensive antitumor immunity.</div></div><div><h3>Results</h3><div>Prominent tumor suppression was achieved in aggressive mouse melanoma tumor model, which verified the feasibility and effectiveness of this minimalist CAD/CpG-codelivered NP.</div></div><div><h3>Conclusion</h3><div>This study has provided a convenient and promising paradigm for potent cancer chemo-immunotherapy.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 169-179"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircHIPK3 targets DRP1 to mediate hydrogen peroxide-induced necroptosis of vascular smooth muscle cells and atherosclerotic vulnerable plaque formation","authors":"Xiaolu Li ,&nbsp;Yanyan Yang ,&nbsp;Zhibin Wang ,&nbsp;Xiaotong Lin ,&nbsp;Xiuxiu Fu ,&nbsp;Xiangqin He ,&nbsp;Meixin Liu ,&nbsp;Jian-Xun Wang ,&nbsp;Tao Yu ,&nbsp;Pin Sun","doi":"10.1016/j.jare.2024.04.011","DOIUrl":"10.1016/j.jare.2024.04.011","url":null,"abstract":"<div><h3>Introduction</h3><div>Necroptosis triggered by H₂O₂ is hypothesized to be a critical factor in the rupture of atherosclerotic plaques, which may precipitate acute cardiovascular events. Nevertheless, the specific regulatory molecules of this development remain unclear. We aims to elucidate a mechanism from the perspective of circular RNA.</div></div><div><h3>Objectives</h3><div>There are few studies on circRNA in VSMCs necroptosis. The objective of our research is to shed light on the intricate roles that circHIPK3 plays in the process of necroptosis in VSMCs and the development of atherosclerotic plaques that are prone to rupture. Our study elucidates the specific molecular mechanisms by which circHIPK3 regulates necroptosis and atherosclerotic vulnerable plaque formation through targeted proteins. Identifying this mechanism at the cellular level offers a molecular framework for understanding plaque progression and stability regulation, as well as a potential biomarker for the prognosis of susceptible atherosclerotic plaques.</div></div><div><h3>Methods</h3><div>We collected clinical vascular tissue for HE staining and Masson staining to determine the presence and stability of plaques. Then, NCBI database was used to screen out circRNA with elevated expression level in plaque tissue, and the up-regulated circRNA, circHIPK3, was verified by qRT-PCR and FISH. Further, we synthesized circHIPK3′s small interference sequence and overexpressed plasmid in vitro, and verified its regulation effect on necroptosis of VSMCs under physiological and pathological conditions by WB, qRT-PCR and PI staining. Through RNA pull down, mass spectrometry and RNA immunoprecipitation, DRP1 was identified as circHIPK3 binding protein and was positively regulated by circHIPK3. Meanwhile, on the basis of silencing of DRP1, the regulation of circHIPK3 on necroptosis is verified to be mediated by DRP1. Finally, we validated the regulation of circHIPK3 on vulnerable plaque formation in ApoE^-/- mice.</div></div><div><h3>Results</h3><div>We investigated that circHIPK3 was highly expressed in vulnerable plaques, and the increase in expression level promoted H₂O₂ induced necroptosis of VSMCs. CircHIPK3 targeted the protein DRP1, leading to an elevation in mitochondrial division rate, resulting in increased reactive oxygen species and impaired mitochondrial function, ultimately leading to necroptosis of VSMCs and vulnerable plaque formation.</div></div><div><h3>Conclusion</h3><div>CircHIPK3 interact with DRP1 involve in H₂O₂ induced Mitochondrial damage and necroptosis of VSMCs, and Silencing circHIPK3 in vivo can reduce atherosclerotic vulnerable plaque formation. Our research findings may have applications in providing diagnostic biomarkers for vulnerable plaques.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 329-341"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140604247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FGF21 ameliorates septic liver injury by restraining proinflammatory macrophages activation through the autophagy/HIF-1α axis","authors":"Junjie Zhu ,&nbsp;Zhouxiang Jin ,&nbsp;Jie Wang ,&nbsp;Zhaohang Wu ,&nbsp;Tianpeng Xu ,&nbsp;Gaozan Tong ,&nbsp;Enzhao Shen ,&nbsp;Junfu Fan ,&nbsp;Chunhui Jiang ,&nbsp;Jiaqi Wang ,&nbsp;Xiaokun Li ,&nbsp;Weitao Cong ,&nbsp;Li Lin","doi":"10.1016/j.jare.2024.04.004","DOIUrl":"10.1016/j.jare.2024.04.004","url":null,"abstract":"<div><h3>Introduction</h3><div>Sepsis, a systemic immune syndrome caused by severe trauma or infection, poses a substantial threat to the health of patients worldwide. The progression of sepsis is heavily influenced by septic liver injury, which is triggered by infection and cytokine storms, and has a significant impact on the tolerance and prognosis of septic patients. The objective of our study is to elucidate the biological role and molecular mechanism of fibroblast growth factor 21 (FGF21) in the process of sepsis.</div></div><div><h3>Objectives</h3><div>This study was undertaken in an attempt to elucidate the function and molecular mechanism of FGF21 in therapy of sepsis.</div></div><div><h3>Methods</h3><div>Serum concentrations of FGF21 were measured in sepsis patients and septic mice. Liver injury was compared between mice FGF21 knockout (KO) mice and wildtype (WT) mice. To assess the therapeutic potential, recombinant human FGF21 was administered to septic mice. Furthermore, the molecular mechanism of FGF21 was investigated in mice with myeloid-cell specific HIF-1α overexpression mice (LyzM-Cre^DIO-HIF-1α) and myeloid-cell specific <em>Atg7</em> knockout mice (<em>Atg7</em>^△mye).</div></div><div><h3>Results</h3><div>Serum level of FGF21 was significantly increased in sepsis patients and septic mice. Through the use of recombinant human FGF21 (rhFGF21) and FGF21 KO mice, we found that FGF21 mitigated septic liver injury by inhibiting the initiation and propagation of inflammation. Treatment with rhFGF21 effectively suppressed the activation of proinflammatory macrophages by promoting macroautophagy/autophagy degradation of hypoxia-inducible factor-1α (HIF-1α). Importantly, the therapeutic effect of rhFGF21 against septic liver injury was nullified in LyzM-Cre^DIO-HIF-1α mice and <em>Atg7</em>^△mye mice.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that FGF21 considerably suppresses inflammation upon septic liver injury through the autophagy/ HIF-1α axis.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"69 ","pages":"Pages 477-494"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140604292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}