Life sciences最新文献_第2页

Hypoxanthine ameliorates diet-induced insulin resistance by improving hepatic lipid metabolism and gluconeogenesis via AMPK/mTOR/PPARα pathway 次黄嘌呤通过AMPK/mTOR/PPARα途径改善肝脏脂质代谢和葡萄糖生成，从而改善饮食引起的胰岛素抵抗。

IF 5.2 2区医学

Life sciences Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123096

{"title":"Hypoxanthine ameliorates diet-induced insulin resistance by improving hepatic lipid metabolism and gluconeogenesis via AMPK/mTOR/PPARα pathway","authors":"","doi":"10.1016/j.lfs.2024.123096","DOIUrl":"10.1016/j.lfs.2024.123096","url":null,"abstract":"<div><h3>Aim</h3><div>Insulin resistance (IR) is a pivotal metabolic disorder associated with type 2 diabetes and metabolic syndrome. This study investigated the potential of hypoxanthine (Hx), a purine metabolite and uric acid precursor, in ameliorating IR and regulating hepatic glucose and lipid metabolism.</div></div><div><h3>Methods</h3><div>We utilized both in vitro IR-HepG2 cells and in vivo diet-induced IR mice to investigate the impact of Hx. The HepG2 cells were treated with Hx to evaluate its effects on glucose production and lipid deposition. Activity-based protein profiling (ABPP) was applied to identify Hx-target proteins and the underlying pathways. In vivo studies involved administration of Hx to IR mice, followed by assessments of IR-associated indices, with explores on the potential regulating mechanisms on hepatic glucose and lipid metabolism.</div></div><div><h3>Key findings</h3><div>Hx intervention significantly reduced glucose production and lipid deposition in a dose-dependent manner without affecting cell viability in IR-HepG2 cells. ABPP identified key Hx-target proteins engaged in fatty acid and pyruvate metabolism. In vivo, Hx treatment reduced IR severities, as evidenced by decreased HOMA-IR, fasting blood glucose, and serum lipid profiles. Histological assessments confirmed reduced liver lipid deposition. Mechanistic insights revealed that Hx suppresses hepatic gluconeogenesis and fatty acid synthesis, and promotes fatty acid oxidation via the AMPK/mTOR/PPARα pathway.</div></div><div><h3>Significance</h3><div>This study delineates a novel role of Hx in regulating hepatic metabolism, offering a potential therapeutic strategy for IR and associated metabolic disorders. The findings provide a foundation for further investigation into the role of purine metabolites in metabolic regulation and their clinical implications.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of the FOXO1–ROCK1 axis mitigates cardiomyocyte injury under chronic hypoxia in Tetralogy of Fallot by maintaining mitochondrial quality control 通过维持线粒体质量控制，抑制 FOXO1-ROCK1 轴可减轻法洛氏四联症慢性缺氧对心肌细胞的损伤。

IF 5.2 2区医学

Life sciences Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123084

{"title":"Inhibition of the FOXO1–ROCK1 axis mitigates cardiomyocyte injury under chronic hypoxia in Tetralogy of Fallot by maintaining mitochondrial quality control","authors":"","doi":"10.1016/j.lfs.2024.123084","DOIUrl":"10.1016/j.lfs.2024.123084","url":null,"abstract":"<div><h3>Introduction</h3><div>Persistent chronic myocardial hypoxia causes disturbances in mitochondrial quality control (MQC), ultimately leading to increased cardiomyocyte injury in patients with Tetralogy of Fallot (TOF). The present study aimed to identify the key effector molecules of cardiomyocyte injury under chronic hypoxia in TOF.</div></div><div><h3>Methods</h3><div>Clinical data from TOF patients were collected and whole transcriptome sequencing was performed on myocardial samples. Chronic hypoxia models were established in cardiac-specific knockout mice and cardiomyocytes, and a series of molecular experiments were used to determine the specific mechanisms involved.</div></div><div><h3>Results</h3><div>Clinical cohort data and whole-transcriptome sequencing analysis of myocardial samples from TOF patients revealed that forkhead box O1 (FOXO1) plays an important role in chronic hypoxic cardiomyocyte injury. In a model of chronic hypoxia established in FOXO1 cardiac-specific knockout mice and FOXO1 gene-deficient cardiomyocytes, the AMPK signaling pathway regulates the expression of FOXO1, which in turn disrupts MQC by regulating the transcriptional activation of Rho-associated protein kinase 1 (ROCK1), and increasing the production of mitochondrial ROS, thereby exacerbating damage to cardiomyocytes. Excessive reactive oxygen species (ROS) production during MQC dysfunction further activates Cox7a2L to increase the assembly of the respiratory chain supercomplex. In addition, we found that miR-27b-3p partially binds to the 3′ untranslated region of FOXO1 to exert a protective effect.</div></div><div><h3>Conclusions</h3><div>Maintenance of MQC under chronic hypoxia is achieved through a series of injury-protection mechanisms, suggesting that FOXO1 inhibition may be crucial for future mitigation of chronic hypoxic cardiomyocyte injury in TOF.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TFF3 and PVRL2 co-targeting identified by multi-omics approach as an effective cancer immunosuppression strategy 通过多组学方法发现 TFF3 和 PVRL2 共同靶向是一种有效的癌症免疫抑制策略。

IF 5.2 2区医学

Life sciences Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123113

{"title":"TFF3 and PVRL2 co-targeting identified by multi-omics approach as an effective cancer immunosuppression strategy","authors":"","doi":"10.1016/j.lfs.2024.123113","DOIUrl":"10.1016/j.lfs.2024.123113","url":null,"abstract":"<div><h3>Background</h3><div>The immunosuppressive tumour microenvironment (TME) plays a critical role in cancer progression and relapse by significantly influencing cancer pathogenesis through autocrine and paracrine signalling. Trefoil factor 3 (TFF3), a secreted protein, has been implicated in modulating the TME to promote cancer advancement. Herein, we investigated the potential association between TFF3 and key immunosuppressive TME components to distinguish a co-targetable oncotherapeutic strategy.</div></div><div><h3>Methods</h3><div>The TFF3-PVRL2 association were identified and investigated by integrating multiple bioinformatic-tools. The virtual compound screening for PVRL2 inhibitors was done with EasyVS. The TFF3-PVRL2 protein-level correlation was validated by immunoblotting, and the effectiveness of co-inhibiting TFF3 and PVRL2 was assessed using siRNA and AMPC (a TFF3 inhibitor).</div></div><div><h3>Results</h3><div>Analysis of the TISIDB database revealed a positive correlation between <em>TFF3</em> and <em>PVRL2</em> mRNA levels across multiple cancer types. This correlation was confirmed at the protein level through immunoblot analysis. Further evaluation using TCGA pan-cancer datasets demonstrated that TFF3 and PVRL2 interact to establish an immunosuppressive TME, promoting cancer progression in BRCA, LUAD, PAAD, PRAD, and STAD. Enrichment analyses of positively correlated genes, PPI network hub proteins, and ceRNA networks involving TFF3 and PVRL2, conducted using LinkedOmics, STRING, and Cytoscape, provided insights into their potential co-functions in cancer. A cell-based assay was performed to evaluate the combined therapeutic efficacy of targeting both, TFF3 and PVRL2 and virtual screening identified potential drugs for inhibiting PVRL2.</div></div><div><h3>Conclusion</h3><div>PVRL2 has emerged as a promising immunoinhibitory target with significant associations with TFF3 and represents a key co-targetable molecule for effective oncotherapeutic strategies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advancing thyroid disease research: The role and potential of zebrafish model 推进甲状腺疾病研究：斑马鱼模型的作用和潜力

IF 5.2 2区医学

Life sciences Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123099

引用次数: 0

Unveiling the roles of LEMD proteins in cellular processes 揭示 LEMD 蛋白在细胞过程中的作用。

IF 5.2 2区医学

Life sciences Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123116

引用次数: 0

Exosomes from human bone marrow MSCs alleviate PD-1/PD-L1 inhibitor-induced myocardial injury in melanoma mice by regulating macrophage polarization and pyroptosis 来自人骨髓间充质干细胞的外泌体通过调节巨噬细胞的极化和热解作用减轻了PD-1/PD-L1抑制剂诱发的黑色素瘤小鼠心肌损伤。

IF 5.2 2区医学

Life sciences Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123108

{"title":"Exosomes from human bone marrow MSCs alleviate PD-1/PD-L1 inhibitor-induced myocardial injury in melanoma mice by regulating macrophage polarization and pyroptosis","authors":"","doi":"10.1016/j.lfs.2024.123108","DOIUrl":"10.1016/j.lfs.2024.123108","url":null,"abstract":"<div><div>Myocarditis, which can be triggered by immune checkpoint inhibitor (ICI) treatment, represents a critical and severe adverse effect observed in cancer therapy. Thus, elucidating the underlying mechanism and developing effective strategies to mitigate its harmful impact is of utmost importance. The objective of this study is to investigate the potential role and regulatory mechanism of exosomes derived from human bone marrow mesenchymal stem cells (hBMSC-Exos) in providing protection against myocardial injury induced by ICIs. We observed that the administration of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor BMS-1 in tumor-bearing mice led to evident cardiac dysfunction and myocardial injury, which were closely associated with M1 macrophage polarization and cardiac pyroptosis. Remarkably, these adverse effects were significantly alleviated through tail-vein injection of hBMSC-Exos. Moreover, either BMS-1 or hBMSC-Exos alone demonstrated the ability to reduce tumor size, while the combination of hBMSC-Exos with BMS-1 treatment not only effectively improved the probability of tumor inhibition but also alleviated cardiac anomalies induced by BMS-1.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Formononetin alleviates no reflow after myocardial ischemia-reperfusion via modulation of gut microbiota to inhibit inflammation 福莫西汀通过调节肠道微生物群来抑制炎症，从而缓解心肌缺血再灌注后的无回流现象。

IF 5.2 2区医学

Life sciences Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123110

{"title":"Formononetin alleviates no reflow after myocardial ischemia-reperfusion via modulation of gut microbiota to inhibit inflammation","authors":"","doi":"10.1016/j.lfs.2024.123110","DOIUrl":"10.1016/j.lfs.2024.123110","url":null,"abstract":"<div><div>Gut microflora plays an important role in relieving myocardial no-reflow (NR), formononetin (FMN) has potential effects on NR, however, the relationship between this effect and gut microflora remains unclear. This study aimed to evaluate the role of FMN in alleviating NR by regulating gut microflora. We used a myocardial NR rat model to confirm the effect and mechanism of action of FMN in alleviating NR. The rats were randomly divided into sham operation group (Sham), NR group, FMN group and sodium nitroprusside (SNP) group. Thioflavin S staining, Hematoxylin Eosin (HE), myocardial enzyme activity, ultrasonic cardiogram and RT-PCR detection showed that FMN could effectively reduce inflammatory cell infiltration, NR and ischemic area, improve cardiac structure and function and reduce <em>TNF-α</em> and <em>NF-κB</em> gene expression in NR rats. The results of 16S rRNA high-throughput sequencing showed that FMN could increase the abundance of anti-inflammatory bacteria such as Ligilactobacillus, Coprococcus, Blautia and Muribaculaceae and decrease the abundance of pro-inflammatory bacteria such as Treponema in Spirochaetota and Campylobacterota. The correlation between the differential bacteria in the gut microflora(anti-inflammatory bacteria and pro-inflammatory bacteria) and <em>TNF-α</em> and <em>NF-κB</em>, showed that they had a strong correlation. Therefore, the anti-NR mechanism of FMN may be related to increasing the abundance of anti-inflammatory bacteria and reducing the abundance of pro-inflammatory bacteria to inhibit inflammation. This study provides innovative mechanistic insights into the relationship between gut microbiota and myocardial protection, suggesting potential strategy for future treatment of NR.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Innovative mechanisms of micro- and nanoplastic-induced brain injury: Emphasis on the microbiota-gut-brain axis 微塑料和纳米塑料诱发脑损伤的创新机制：强调微生物群-肠-脑轴。

IF 5.2 2区医学

Life sciences Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123107

{"title":"Innovative mechanisms of micro- and nanoplastic-induced brain injury: Emphasis on the microbiota-gut-brain axis","authors":"","doi":"10.1016/j.lfs.2024.123107","DOIUrl":"10.1016/j.lfs.2024.123107","url":null,"abstract":"<div><div>Micro- and nanoplastics (MNPs), emerging environmental pollutants, infiltrate marine, terrestrial, and freshwater systems via diverse pathways, culminating in their accumulation in the human body through food chain transmission, posing potential health risks. Researches have demonstrated that MNPs disrupt gut microbiota equilibrium and compromise intestinal barrier integrity, as well as traverse the blood-brain barrier, leading to brain damage. Moreover, the complex interaction between the gut and the nervous system, facilitated by the “gut-brain axis,” indicates an additional pathway for MNPs-induced brain damage. This has intensified scientific interest in the intercommunication between MNPs and the gut-brain axis. While existing studies have documented microbial imbalances and metabolic disruptions subsequent to MNPs exposure, the precise mechanisms by which the microbiota-gut-brain axis contributes to MNPs-induced central nervous system damage remain unclear. This review synthesizes current knowledge on the microbiota-gut-brain axis, elucidating the pathogenesis of MNPs-induced gut microbiota dysbiosis and its consequent brain injury. It emphasizes the complex interrelation between MNPs and the microbiota-gut-brain axis, advocating for the gut microbiota as a novel therapeutic target to alleviate MNP-induced brain harm.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring the characteristics and antecedents of clinically significant long COVID: A longitudinal cohort study 探索具有临床意义的长期 COVID 的特征和前因后果：一项纵向队列研究。

IF 5.2 2区医学

Life sciences Pub Date : 2024-10-04 DOI: 10.1016/j.lfs.2024.123114

{"title":"Exploring the characteristics and antecedents of clinically significant long COVID: A longitudinal cohort study","authors":"","doi":"10.1016/j.lfs.2024.123114","DOIUrl":"10.1016/j.lfs.2024.123114","url":null,"abstract":"<div><h3>Background</h3><div>A significant number of coronavirus disease 2019 (COVID-19) survivors are experiencing long COVID, with symptoms lasting beyond three months. While diverse long COVID symptoms are established, there are gaps in understanding its long-term trends, intensity, and risk factors, requiring further investigation.</div></div><div><h3>Aims</h3><div>This study aimed to investigate the long COVID characteristics and associated factors by following COVID-19 survivors for one year post-infection and comparing them with healthy counterparts.</div></div><div><h3>Main methods</h3><div>In this longitudinal, correlational study, COVID-19 survivors diagnosed between November 2021 and February 2023 were monitored every three months for a year. Participants aged ≥18 years who had reported a positive COVID-19 test were recruited via social media and healthcare provider referrals.</div></div><div><h3>Key findings</h3><div>Out of 182 survivors who initially agreed to participate, 176 completed the study. The mean age was 47.56 years (SD = 16.2), and 51.1 % were female. There was a clinically significant decline in cognitive function and health-related quality of life over time, with symptoms like shortness of breath, reduced physical fitness, and increased health concerns. Those with severe acute COVID-19 symptoms experienced greater cognitive and physical declines and more shortness of breath a year later. Lower financial status was linked to poorer health-related quality of life and increased health concerns.</div></div><div><h3>Significance</h3><div>A year post-infection, COVID-19's impact on cognitive function and health-related quality of life remains significant, affecting individuals and communities. Survivors with severe initial symptoms and economic disadvantages need more attention. Future research should identify additional predictors of severe long COVID.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AP-2α decreases TMZ resistance of recurrent GBM by downregulating MGMT expression and improving DNA damage AP-2α 通过下调 MGMT 表达和改善 DNA 损伤，降低复发性 GBM 对 TMZ 的耐药性。

IF 5.2 2区医学

Life sciences Pub Date : 2024-10-04 DOI: 10.1016/j.lfs.2024.123111

{"title":"AP-2α decreases TMZ resistance of recurrent GBM by downregulating MGMT expression and improving DNA damage","authors":"","doi":"10.1016/j.lfs.2024.123111","DOIUrl":"10.1016/j.lfs.2024.123111","url":null,"abstract":"<div><h3>Aims</h3><div>The incidence of recurrent gliomas is high, exerting low survival rates and poor prognoses. Transcription factor AP-2α has been reported to regulate the progression of primary glioblastoma (GBM). However, the function of AP-2α in recurrent gliomas is largely unclear.</div></div><div><h3>Methods</h3><div>The expression of AP-2α and O6-methylguanine DNA-methyltransferase (MGMT) was detected in recurrent glioma tissues and cell lines by Western blots, the regulation mechanisms between AP-2α/MGMT promoter and RA/AP-2α promoter were studied by luciferase reporter assays, EMSA, and chIP assays. The effects of AP-2α and TMZ/RA treatment on cell viability <em>in vitro</em> and <em>in vivo</em> were investigated by MTT assays, γH<sub>2</sub>AX staining, comet assays and intracranial injection.</div></div><div><h3>Key findings</h3><div>AP-2α expression negatively correlates with the expression of MGMT in glioma samples. AP-2α could directly bind with the promoter of the MGMT gene, suppresses transcriptional levels of MGMT and downregulate MGMT expression in TMZ-resistant U87MG-R and T98G cells, but TMZ treatment decreases AP-2α expression and increases MGMT expression. The extended TMZ treatment and increased TMZ concentrations reversed these effects. Moreover, AP-2α overexpression combines with TMZ to decrease cell viability, concurrently with improved DNA damage marker γH<sub>2</sub>AX. Furthermore, retinoic acid (RA) activates RAR/RXR heterodimers, which bind to RA-responsive elements (RAREs) of the AP-2α promoter, and activates AP-2α expression in recurrent glioma cells. Finally, in intracranial relapsed glioma mouse model, both RA and TMZ could retard tumor development and prolong the mouse survival.</div></div><div><h3>Significance</h3><div>AP-2α activation by gene overexpression or RA treatment reveals the suppressive effects on glioma relapse, providing a novel therapeutic strategy against malignant refractory gliomas.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0