Life sciences最新文献_第2页

2-Mercaptoethanol enhances the yield of exosomes showing therapeutic potency in alleviating spinal cord injury mice

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-07 DOI: 10.1016/j.lfs.2025.123451

Yang Wang , Hanxiao Yi , Keqi Huang , Yi Zeng , Ping Miao , Yating Zhang , Nan Hu

Background

Limited passage numbers of mesenchymal stem cells (MSCs) present challenges in producing sufficient exosomes for spinal cord injury (SCI) treatment.

Objectives

This study investigates whether β-mercaptoethanol (BME) preconditioning of MSCs can increase exosome yield for SCI therapy.

Methods

Exosomal content was analyzed using silver staining and SYBR Gold staining. Cell viability was assessed via CCK-8 and EdU assays. IL-1β, IL-6, TNF-α, and MCP-1 levels were measured by enzyme-linked immunosorbent assay (ELISA). Neuronal differentiation influenced by astrocytes was evaluated through neurite outgrowth and migration assays. Neuronal survival and motor function recovery in SCI mice were assessed using TUNEL staining, the Basso Mouse Scale (BMS), muscle strength tests, and motor evoked potential (MEP) measurements.

Results

BME treatment significantly increased exosome quantity, including proteins and microRNAs, without drastic changes in exosomal content spectrum. Exosomes from BME-treated MSCs more effectively suppressed IL-1β, IL-6, TNF-α, and MCP-1 secretion by astrocytes, reducing neuronal inflammation. Yap1 activation reduced the exosomes' inhibitory effects on inflammatory cytokines. Mice treated with exosomes from BME-treated MSCs showed better outcomes: lower GFAP and C3 expression, reduced inflammation, increased NF-H levels, higher BMS scores, and greater MEP peaks. Exosome treatment also reduced bladder volume, residual urine, and the time to regain spontaneous urination after uroschesis.

Conclusion

BME preconditioning enhances exosome yield from hUC-MSCs, offering improved therapeutic potential for SCI.

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引用次数: 0

Lycopene inhibits doxorubicin-induced heart failure by inhibiting ferroptosis through the Nrf2 signaling pathway

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-07 DOI: 10.1016/j.lfs.2025.123452

Rong Huang , Chao Zhou , Tianxiang Wang , Yuanli Chen , Zhouling Xie , Lingling Wei , Yajun Duan , Chenzhong Liao , Chuanrui Ma , Xiaoxiao Yang

Aims

Lycopene (LYC) is a dietary nutrient that plays a protective role in various cardiovascular diseases. Doxorubicin (DOX)-induced cardiotoxicity is an important cause of poor prognosis in many cancer patients treated with anthracyclines. This study aims to investigate the protective effects of LYC against DOX-induced heart failure (HF) and specific underlying mechanisms.

Materials and methods

DOX was used to establish HF model in cardiomyocytes and C57BL/6J mice to assess the protection of LYC against DOX-induced HF on inflammation, oxidative stress, and ferroptosis.

Key findings

LYC ameliorated DOX-induced deterioration of cardiac function. Mechanistically, LYC reduced collagen content and fibrosis by inhibiting the expression of matrix metalloproteinase 2 (MMP-2) and MMP-9. Additionally, LYC inhibited reactive oxygen species (ROS) production by upregulating antioxidant enzymes expression. LYC enhanced B-cell lymphoma 2 (Bcl-2), but reduced apoptosis positive cells by reducing tumor protein 53 (p53), Bcl-2 associated X protein (Bax), and cleaved-Caspase 3 (c-Casp3) levels. Besides, LYC reduced inflammatory cytokine levels through activating peroxisome proliferator activated receptor gamma (PPARγ). Moreover, LYC ameliorated DOX-induced ferroptosis both in vivo and in vitro. Furthermore, we showed that LYC inhibited DOX-induced ferroptosis via binding to nuclear factor-erythroid 2-related factor 2 (Nrf2) to enhance its expression.

Significance

LYC improved DOX-induced cardiac dysfunction by reducing oxidative stress and inflammation, which was contributed by the reduction of ferroptosis. At molecular levels, LYC ameliorated DOX-induced ferroptosis through activating the Nrf2 signaling pathway. These findings indicate the potential of LYC as a therapeutic option for HF treatment.

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引用次数: 0

Carnosinase inhibition enhances reactive species scavenging in high fat diet

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-07 DOI: 10.1016/j.lfs.2025.123448

Charlie Jr. Lavilla , Merell P. Billacura , Suniya. Khatun , Daniel P. Cotton , Vivian.K. Lee , Sreya. Bhattacharya , Paul W. Caton , Craig Sale , John D. Wallis , A. Christopher Garner , Mark D. Turner

Aims

Life expectancy is typically reduced by 2–4 years in people with a body mass index (BMI) of 30–35 kg/m² and by 8–10 years in people with a BMI of 40–50 kg/m². Obesity is also associated with onset, or exacerbation of, multiple chronic diseases. Mechanistically, this, in part, involves formation of advanced glycation and lipidation end-products that directly bond with proteins, lipids, or DNA, thereby perturbing typical cellular function. Here we seek to prevent these damaging adduction events through inhibition of carnosinase enzymes that rapidly degrade the physiological reactive species scavenger, carnosine, in the body.

Main methods

Herein we performed in silico computational modelling of a compound library of ∼53,000 molecules to identify carnosine-like molecules with intrinsic resistance to carnosinase turnover.

Key findings

We show that leading candidate molecules reduced reactive species in C2C12 myotubes, and that mice fed N-methyl-[6-(2-furyl)pyrid-3-yl]methylamine alongside a high fat diet had significantly decreased amounts of damaging plasma 4-hydroxynonenal and 3-nitrotyrosine reactive species. Oral administration of N-methyl-[6-(2-furyl)pyrid-3-yl]methylamine to high fat-fed mice also resulted in a modest ∼10 % reduction in weight gain when compared to mice fed only high fat diet.

Significance

Our findings suggest that inhibition of carnosinase enzymes can increase the life-span, and thereby enhance the efficacy, of endogenous carnosine in vivo, thereby offering potential therapeutic benefits against obesity and other cardiometabolic diseases characterised by metabolic stress.

{"title":"Carnosinase inhibition enhances reactive species scavenging in high fat diet","authors":"Charlie Jr. Lavilla , Merell P. Billacura , Suniya. Khatun , Daniel P. Cotton , Vivian.K. Lee , Sreya. Bhattacharya , Paul W. Caton , Craig Sale , John D. Wallis , A. Christopher Garner , Mark D. Turner","doi":"10.1016/j.lfs.2025.123448","DOIUrl":"10.1016/j.lfs.2025.123448","url":null,"abstract":"<div><h3>Aims</h3><div>Life expectancy is typically reduced by 2–4 years in people with a body mass index (BMI) of 30–35 kg/m<sup>2</sup> and by 8–10 years in people with a BMI of 40–50 kg/m<sup>2</sup>. Obesity is also associated with onset, or exacerbation of, multiple chronic diseases. Mechanistically, this, in part, involves formation of advanced glycation and lipidation end-products that directly bond with proteins, lipids, or DNA, thereby perturbing typical cellular function. Here we seek to prevent these damaging adduction events through inhibition of carnosinase enzymes that rapidly degrade the physiological reactive species scavenger, carnosine, in the body.</div></div><div><h3>Main methods</h3><div>Herein we performed in silico computational modelling of a compound library of ∼53,000 molecules to identify carnosine-like molecules with intrinsic resistance to carnosinase turnover.</div></div><div><h3>Key findings</h3><div>We show that leading candidate molecules reduced reactive species in C2C12 myotubes, and that mice fed <em>N</em>-methyl-[6-(2-furyl)pyrid-3-yl]methylamine alongside a high fat diet had significantly decreased amounts of damaging plasma 4-hydroxynonenal and 3-nitrotyrosine reactive species. Oral administration of <em>N</em>-methyl-[6-(2-furyl)pyrid-3-yl]methylamine to high fat-fed mice also resulted in a modest ∼10 % reduction in weight gain when compared to mice fed only high fat diet.</div></div><div><h3>Significance</h3><div>Our findings suggest that inhibition of carnosinase enzymes can increase the life-span, and thereby enhance the efficacy, of endogenous carnosine in vivo, thereby offering potential therapeutic benefits against obesity and other cardiometabolic diseases characterised by metabolic stress.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123448"},"PeriodicalIF":5.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349640","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

Carboxyaminotriazole: A bone savior in collagen-induced arthritis—Halting osteoclastogenesis via interleukin-1β downregulation

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-06 DOI: 10.1016/j.lfs.2025.123440

Mei Yang , Shan Lu , Juan Li , Lei Zhu

Aims

Rheumatoid arthritis (RA), a prevalent autoimmune disease, features inflammation and bone erosion, correlating with osteoclast hyperactivation and enhanced responsiveness to inflammatory factors. Reducing osteoclast formation and inflammatory mediator expression might avert bone erosion in RA. Carboxyaminotriazole (CAI) holds potential for treating autoinflammatory disorders and impeding cancer-related bone metastases. Yet, its bone-protective role and mechanism remain elusive. This study targets to explore the impacts and underlying mechanisms of CAI in preventing bone erosion in RA.

Materials and methods

A collagen-induced arthritis (CIA) rat model was utilized to evaluate the anti-RA potential of CAI. CCK-8, TRAP staining, TRAP activity assay, pit formation assay, RT-qPCR, Western blotting, immunofluorescence, and ELISA, were conducted to assess the effects and potential mechanisms of CAI in the management of RA.

Key findings

CAI not only reduces inflammatory symptoms, but it also offers superior bone protection compared to methotrexate (MTX) and works synergistically with MTX, the preferred anchoring agent for the treatment of RA. In vitro studies show that CAI inhibits osteoclast differentiation and function, as well as the expression of specific genes, by inhibiting NF-κB/MAPK pathways and reducing IL-1β levels. The deletion of Il-1 and the application of IL-1β inhibitors suggest that CAI retards osteoclastogenesis through the downregulation of IL-1β.

Significance

CAI may have therapeutic value in treating RA-related bone erosion, likely due to its inhibition of overactive osteoclasts by suppressing the NF-κB/MAPK pathways and the subsequent expression of IL-1β.

{"title":"Carboxyaminotriazole: A bone savior in collagen-induced arthritis—Halting osteoclastogenesis via interleukin-1β downregulation","authors":"Mei Yang , Shan Lu , Juan Li , Lei Zhu","doi":"10.1016/j.lfs.2025.123440","DOIUrl":"10.1016/j.lfs.2025.123440","url":null,"abstract":"<div><h3>Aims</h3><div>Rheumatoid arthritis (RA), a prevalent autoimmune disease, features inflammation and bone erosion, correlating with osteoclast hyperactivation and enhanced responsiveness to inflammatory factors. Reducing osteoclast formation and inflammatory mediator expression might avert bone erosion in RA. Carboxyaminotriazole (CAI) holds potential for treating autoinflammatory disorders and impeding cancer-related bone metastases. Yet, its bone-protective role and mechanism remain elusive. This study targets to explore the impacts and underlying mechanisms of CAI in preventing bone erosion in RA.</div></div><div><h3>Materials and methods</h3><div>A collagen-induced arthritis (CIA) rat model was utilized to evaluate the anti-RA potential of CAI. CCK-8, TRAP staining, TRAP activity assay, pit formation assay, RT-qPCR, Western blotting, immunofluorescence, and ELISA, were conducted to assess the effects and potential mechanisms of CAI in the management of RA.</div></div><div><h3>Key findings</h3><div>CAI not only reduces inflammatory symptoms, but it also offers superior bone protection compared to methotrexate (MTX) and works synergistically with MTX, the preferred anchoring agent for the treatment of RA. <em>In vitro</em> studies show that CAI inhibits osteoclast differentiation and function, as well as the expression of specific genes, by inhibiting NF-κB/MAPK pathways and reducing IL-1β levels. The deletion of <em>Il-1</em> and the application of IL-1β inhibitors suggest that CAI retards osteoclastogenesis through the downregulation of IL-1β.</div></div><div><h3>Significance</h3><div>CAI may have therapeutic value in treating RA-related bone erosion, likely due to its inhibition of overactive osteoclasts by suppressing the NF-κB/MAPK pathways and the subsequent expression of IL-1β.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123440"},"PeriodicalIF":5.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143348643","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

The effect of proteasome in heart transplantation: From mechanisms to therapeutic potential

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-06 DOI: 10.1016/j.lfs.2025.123446

Ye Zhou , Yu Chen , Mengyao Xu , Ying Zhang , Xiaoning Wan , Yudong Xia , Hongjie Wang , Hesong Zeng

Heart transplantation is a critical treatment for end-stage heart failure. However, its clinical efficacy is hindered by some challenges, such as ischemia-reperfusion injury (IRI) and post-transplant rejection. These complications significantly contribute to graft dysfunction and compromise patient survival. Emerging evidence underscores the involvement of proteasome in the pathophysiology of both IRI and post-transplant rejection. Proteasome inhibition has demonstrated potential in attenuating IRI by limiting oxidative damage and apoptosis while also mitigating rejection through the regulation of adaptive and innate immune responses. Recent advances in the development of proteasome inhibitors, particularly in optimizing specificity and minimizing adverse effects, have further strengthened their prospects for clinical application. This review focuses on the roles of the proteasome and its inhibitors in heart transplantation, with an emphasis on their mechanisms and therapeutic applications in managing IRI and rejection.

引用次数: 0

Decreased energy production and Ca2+ homeostasis imbalance induce myocardial hypertrophy in PDHA1-deficient human pluripotent stem cell derived cardiomyocytes 能量生成减少和 Ca2+ 平衡失调诱导 PDHA1 缺失的人多能干细胞衍生心肌细胞心肌肥厚

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-06 DOI: 10.1016/j.lfs.2025.123439

Jihong Sun , Chongpei Hua , Jianchao Zhang , Ningyu Ding , Yangyang Liu , Mengduan Liu , Hailong Tao , Jianzeng Dong , Xiaoyan Zhao , Xiaowei Li

Aims

The PDHA1 gene, responsible for regulating the conversion of the glycolytic product pyruvate to acetyl CoA, is significantly reduced in cardiomyocytes of patients with hypertrophic cardiomyopathy. Cardiac-specific PDHA1-deficient mice demonstrate cardiac hypertrophy and heart failure. However, the mechanisms underlying the pathogenesis of PDHA1 deficiency remain unclear.

Main methods

PDHA1 gene in human induced pluripotent stem cell line (iPSC) was knockout (KO) using CRISPR-Cas9 technology and differentiated it into cardiomyocytes (CMs) in vitro. Contractile force was quantified by video analysis, Ca²⁺ handling was assessed with Ca²⁺ transient analysis and mitochondrial function was detected using flow cytometry.

Key findings

The PDHA1 KO iPSC-CMs displayed myocardial hypertrophy phenotypes by day 40 post-differentiation, characterized by enlarged cell size, increased contractility, abnormal calcium handling, and progressed to mimic heart failure phenotypes by day 50, including reduced contractility, lower calcium release and increased ROS generation. RNA-seq analysis revealed dysregulated expression of pathways related to cardiac hypertrophy and the calcium signaling pathway in KO iPSC-CMs. Furthermore, KO iPSC-CMs exhibited decreased energy production before the manifestation of myocardial hypertrophic phenotype at day 30, exacerbating intracellular lactate accumulation, leading to increased sodium‑hydrogen and sodium‑calcium exchange, ultimately resulting in elevated diastolic calcium concentration. Augmenting energy production with l-carnitine restored diastolic Ca²⁺ and prevented the development of myocardial hypertrophy in KO iPSC-CMs.

Significance

Elevated diastolic Ca²⁺ resulting from reduced energy production and lactate accumulation can trigger overactivation of the calcium signaling pathway, diastolic dysfunction, mitochondrial damage, which constitutes the core pathogenic mechanism of myocardial hypertrophy in KO iPSC-CMs.

{"title":"Decreased energy production and Ca2+ homeostasis imbalance induce myocardial hypertrophy in PDHA1-deficient human pluripotent stem cell derived cardiomyocytes","authors":"Jihong Sun , Chongpei Hua , Jianchao Zhang , Ningyu Ding , Yangyang Liu , Mengduan Liu , Hailong Tao , Jianzeng Dong , Xiaoyan Zhao , Xiaowei Li","doi":"10.1016/j.lfs.2025.123439","DOIUrl":"10.1016/j.lfs.2025.123439","url":null,"abstract":"<div><h3>Aims</h3><div>The <em>PDHA1</em> gene, responsible for regulating the conversion of the glycolytic product pyruvate to acetyl CoA, is significantly reduced in cardiomyocytes of patients with hypertrophic cardiomyopathy. Cardiac-specific PDHA1-deficient mice demonstrate cardiac hypertrophy and heart failure. However, the mechanisms underlying the pathogenesis of PDHA1 deficiency remain unclear.</div></div><div><h3>Main methods</h3><div>PDHA1 gene in human induced pluripotent stem cell line (iPSC) was knockout (KO) using CRISPR-Cas9 technology and differentiated it into cardiomyocytes (CMs) in vitro. Contractile force was quantified by video analysis, Ca<sup>2+</sup> handling was assessed with Ca<sup>2+</sup> transient analysis and mitochondrial function was detected using flow cytometry.</div></div><div><h3>Key findings</h3><div>The <em>PDHA1</em> KO iPSC-CMs displayed myocardial hypertrophy phenotypes by day 40 post-differentiation, characterized by enlarged cell size, increased contractility, abnormal calcium handling, and progressed to mimic heart failure phenotypes by day 50, including reduced contractility, lower calcium release and increased ROS generation. RNA-seq analysis revealed dysregulated expression of pathways related to cardiac hypertrophy and the calcium signaling pathway in KO iPSC-CMs. Furthermore, KO iPSC-CMs exhibited decreased energy production before the manifestation of myocardial hypertrophic phenotype at day 30, exacerbating intracellular lactate accumulation, leading to increased sodium‑hydrogen and sodium‑calcium exchange, ultimately resulting in elevated diastolic calcium concentration. Augmenting energy production with <span>l</span>-carnitine restored diastolic Ca<sup>2+</sup> and prevented the development of myocardial hypertrophy in KO iPSC-CMs.</div></div><div><h3>Significance</h3><div>Elevated diastolic Ca<sup>2+</sup> resulting from reduced energy production and lactate accumulation can trigger overactivation of the calcium signaling pathway, diastolic dysfunction, mitochondrial damage, which constitutes the core pathogenic mechanism of myocardial hypertrophy in KO iPSC-CMs.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123439"},"PeriodicalIF":5.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143369731","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

Small for gestational age children at risk: Identifying placenta-brain axis genes as biomarkers for early prediction of neurodevelopmental delay

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-06 DOI: 10.1016/j.lfs.2025.123450

Jingjing Cheng , Heyue Jin , Yimin Zhang , Jiawen Ren , Kun Huang , Juan Tong , Hong Gan , Jia Lv , Qu'nan Wang , Fangbiao Tao , Yumin Zhu

Aims

Small for gestational age (SGA) is a prevalent issue in global public health. The relationship between SGA and neurodevelopmental delay remains a topic of debate and the exploration of potential biomarkers is crucial. The identification of placental-brain axis genes offers novel perspectives for anticipating neurodevelopmental delay.

Main methods

First, we utilized multiple logistic regression to assess Ages and Stages Questionnaire of China (ASQ-C) scores in children at 6 months, 18 months, and 48 months of age. Next, we analyzed the placental transcriptome data from SGA and appropriate for gestational age (AGA) children in the Ma'anshan Birth Cohort (MABC) and validated it through Real-time quantitative PCR (RT-qPCR). Finally, we combined the experimental data with clinical data to establish a predictive model.

Key findings

SGA children were found to have a higher risk of neurodevelopmental delay at 6 months and 18 months of age. Further experimental validation found that decreased RPS27A gene expression was associated with developmental delay in solving-problem and personal-social domain at 6 months of age in SGA children.

Significance

Our study focused on the neurodevelopmental results of children from three time points, analyzed the mechanism of neurodevelopmental delay in SGA from the perspective of placenta-brain axis, and conducted experimental verification of the selected biomarkers. Therefore, our study has certain novelty and persuasive, providing new insights for early detection of neurodevelopmental delay in children with SGA.

{"title":"Small for gestational age children at risk: Identifying placenta-brain axis genes as biomarkers for early prediction of neurodevelopmental delay","authors":"Jingjing Cheng , Heyue Jin , Yimin Zhang , Jiawen Ren , Kun Huang , Juan Tong , Hong Gan , Jia Lv , Qu'nan Wang , Fangbiao Tao , Yumin Zhu","doi":"10.1016/j.lfs.2025.123450","DOIUrl":"10.1016/j.lfs.2025.123450","url":null,"abstract":"<div><h3>Aims</h3><div>Small for gestational age (SGA) is a prevalent issue in global public health. The relationship between SGA and neurodevelopmental delay remains a topic of debate and the exploration of potential biomarkers is crucial. The identification of placental-brain axis genes offers novel perspectives for anticipating neurodevelopmental delay.</div></div><div><h3>Main methods</h3><div>First, we utilized multiple logistic regression to assess Ages and Stages Questionnaire of China (ASQ-C) scores in children at 6 months, 18 months, and 48 months of age. Next, we analyzed the placental transcriptome data from SGA and appropriate for gestational age (AGA) children in the Ma'anshan Birth Cohort (MABC) and validated it through Real-time quantitative PCR (RT-qPCR). Finally, we combined the experimental data with clinical data to establish a predictive model.</div></div><div><h3>Key findings</h3><div>SGA children were found to have a higher risk of neurodevelopmental delay at 6 months and 18 months of age. Further experimental validation found that decreased <em>RPS27A</em> gene expression was associated with developmental delay in solving-problem and personal-social domain at 6 months of age in SGA children.</div></div><div><h3>Significance</h3><div>Our study focused on the neurodevelopmental results of children from three time points, analyzed the mechanism of neurodevelopmental delay in SGA from the perspective of placenta-brain axis, and conducted experimental verification of the selected biomarkers. Therefore, our study has certain novelty and persuasive, providing new insights for early detection of neurodevelopmental delay in children with SGA.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"365 ","pages":"Article 123450"},"PeriodicalIF":5.2,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374374","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

MiR-222-3p loaded stem cell nanovesicles repair myocardial ischemia damage via inhibiting mitochondrial oxidative stress

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-06 DOI: 10.1016/j.lfs.2025.123447

Mei Liu , Le Wang , Zhao Liu , Dongyue Liu , Tianshuo Li , Lini Ding , Shasha Zeng , Zi Wang , Jiaqiu Wang , Fan Zhang , Jun Zhang , Limin Zhang , Meng Li , Gang Liu , Xianyun Wang , Mingqi Zheng

Aims

Mitochondrial oxidative stress (MOS) is a key contributor to poor cardiac function and a major driver of myocardial ischemia-reperfusion injury (MIRI). Our previous research demonstrated that stem cell-derived nanovesicles (NVs) enhanced cardiac function following ischemia-reperfusion (I/R) injury, although the underlying mechanisms remain unclear. We constructed and characterized miR-222-3p-loaded NVs.

Materials and methods

An in vitro hypoxia-reoxygenation (H/R) model was established using H9C2 cardiomyocytes. Mitochondrial oxidative respiratory function was assessed using Seahorse XF technology, while mitochondrial reactive oxygen species (mtROS) levels were quantified via flow cytometry. Additional assessments included mitochondrial permeability transition pore (mPTP) status, mitochondrial membrane potential, and mitochondrial DNA (mtDNA) integrity. An in vivo H/R model was developed using C57BL/6 mice. The therapeutic effects of NVs on MOS reduction and cardiac function improvement were evaluated through Masson's staining, immunofluorescence, echocardiography, transmission electron microscopy (TEM), and positron emission tomography/computed tomography (PET/CT).

Key findings

RNA immunoprecipitation (RIP) confirmed that miR-222-3p directly targets cyp1a1. Overexpression of miR-222-3p or knockdown of cyp1a1 significantly improved mitochondrial activity in cardiomyocytes and conferred protection against I/R injury. Conversely, overexpression of cyp1a1 abrogated the protective effects of miR-222-3p. In vivo, NV treatment enhanced cardiac function, reduced MOS, and improved mitochondrial respiratory capacity in MIRI model mice. NV treatment, via miR-222-3p-mediated suppression of cyp1a1, mitigates MOS, enhances mitochondrial respiratory function, and improves cardiac outcomes in MIRI models.

Significance

These findings provide a foundational basis for the clinical translation of NV-based therapies.

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引用次数: 0

The effect of modulation Piezo2 by IGF-1 on tactile hypersensitivity in BTBR model mice

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-05 DOI: 10.1016/j.lfs.2025.123449

Jinhe Zhai , Haiying Hao , Zihan Xu , Akemi Tomoda , Xinyi Zhang , Xinxin Wang , Yutong Liu , Xuan Cao , Dongxin Li , Yuying Zhang , Xueke Yao , Lili Fan , Jia Wang

Aims

Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder. Individuals with ASD exhibit a higher incidence of tactile hypersensitivity. However, the underlying mechanisms remain unclear. The dorsal root ganglion (DRG) plays a crucial role in influencing tactile processing. This study aims to integrate RNA sequencing (RNA-seq) and molecular biology experiments to identify key molecules involved in tactile hypersensitivity in ASD, further investigate related mechanisms, and develop effective intervention strategy.

Main methods

Using BTBR as the ASD model mouse and wild-type C57BL/6J as the control mouse, the differences in tactile sensitivity between them was compared. DRG were collected for RNA-seq analysis. Immunofluorescence and Enzyme-linked immunosorbent assay (ELISA) techniques were employed to validate the identified key molecules. And combined western blot to investigate the associated regulatory pathways.

Key findings

BTBR mice exhibit tactile hypersensitivity, which are associated with the upregulation of IGF-1 in the DRG. IGF-1 regulates the expression of Piezo2 ion channels. Inhibition of the IGF-1/Piezo2 pathway can significantly alleviate tactile hypersensitivity and social deficits in BTBR mice. Additionally, gentle touch intervention has been shown to reduce the overexpression of IGF-1/Piezo2 in the DRG, thereby ameliorating ASD symptoms.

Significance

The upregulation of the IGF-1/Piezo2 pathway in DRG may serve as a potential mechanism for tactile hypersensitivity observed in BTBR mice. Restoring the normalization of the IGF-1/Piezo2 is crucial for alleviating tactile hypersensitivity and synergistically rescues social deficits. Gentle touch intervention has the potential to ameliorate these behaviors through regulating IGF-1/Piezo2, positioning it as a promising strategy for ASD.

{"title":"The effect of modulation Piezo2 by IGF-1 on tactile hypersensitivity in BTBR model mice","authors":"Jinhe Zhai , Haiying Hao , Zihan Xu , Akemi Tomoda , Xinyi Zhang , Xinxin Wang , Yutong Liu , Xuan Cao , Dongxin Li , Yuying Zhang , Xueke Yao , Lili Fan , Jia Wang","doi":"10.1016/j.lfs.2025.123449","DOIUrl":"10.1016/j.lfs.2025.123449","url":null,"abstract":"<div><h3>Aims</h3><div>Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder. Individuals with ASD exhibit a higher incidence of tactile hypersensitivity. However, the underlying mechanisms remain unclear. The dorsal root ganglion (DRG) plays a crucial role in influencing tactile processing. This study aims to integrate RNA sequencing (RNA-seq) and molecular biology experiments to identify key molecules involved in tactile hypersensitivity in ASD, further investigate related mechanisms, and develop effective intervention strategy.</div></div><div><h3>Main methods</h3><div>Using BTBR as the ASD model mouse and wild-type C57BL/6J as the control mouse, the differences in tactile sensitivity between them was compared. DRG were collected for RNA-seq analysis. Immunofluorescence and Enzyme-linked immunosorbent assay (ELISA) techniques were employed to validate the identified key molecules. And combined western blot to investigate the associated regulatory pathways.</div></div><div><h3>Key findings</h3><div>BTBR mice exhibit tactile hypersensitivity, which are associated with the upregulation of IGF-1 in the DRG. IGF-1 regulates the expression of Piezo2 ion channels. Inhibition of the IGF-1/Piezo2 pathway can significantly alleviate tactile hypersensitivity and social deficits in BTBR mice. Additionally, gentle touch intervention has been shown to reduce the overexpression of IGF-1/Piezo2 in the DRG, thereby ameliorating ASD symptoms.</div></div><div><h3>Significance</h3><div>The upregulation of the IGF-1/Piezo2 pathway in DRG may serve as a potential mechanism for tactile hypersensitivity observed in BTBR mice. Restoring the normalization of the IGF-1/Piezo2 is crucial for alleviating tactile hypersensitivity and synergistically rescues social deficits. Gentle touch intervention has the potential to ameliorate these behaviors through regulating IGF-1/Piezo2, positioning it as a promising strategy for ASD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"364 ","pages":"Article 123449"},"PeriodicalIF":5.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143339842","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

Identification of biomarkers associated with macrophage polarization in diabetic cardiomyopathy based on bioinformatics and machine learning approaches

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-04 DOI: 10.1016/j.lfs.2025.123443

Yi Liu , Juan Zhang , Quancheng Han , Yan Li , Yitao Xue , Xiujuan Liu

Background

Numerous studies have investigated the role of macrophages in the pathogenesis of diabetic cardiomyopathy (DCM); however, the underlying mechanisms remain unclear.

Methods

The DCM dataset (GSE62203) was downloaded from the GEO database. DEGs and WGCNA key module genes were identified. Macrophage polarization-associated genes were obtained from the GeneCards database. GO and KEGG functional enrichment were constructed. Two machine learning techniques, LASSO logistic regression and random forest, were further used to identify hub genes. The diagnostic efficiency was evaluated using ROC curves. Single-gene GSEA investigated the biological functions. Then, the relationship between hub genes and macrophage pathways was explored. Predicted Transcription factor (TF), miRNA, and lncRNA. Single cell sequencing analysis was performed. Finally, experimental validation of the hub genes using the DCM rat model.

Results

Three hub genes (PGK1, LDHA, EDN1) were identified through machine learning approaches. All three hub genes were found to be associated with the HIF-1 signaling pathway. Functional enrichment analysis revealed that the HIF-1 signaling pathway and Glycolysis/Gluconeogenesis are potentially linked to DCM-induced macrophage polarization. The mRNA and protein expression levels of the hub genes were consistent with the bioinformatics analysis. Furthermore, mRNA expression of the hub genes showed a positive correlation with CD80 and CD86.

Conclusion

PGK1, LDHA, and EDN1 represent potential biomarkers for M1 macrophage polarization in DCM. These genes may facilitate M1 macrophage polarization in DCM. Targeting macrophage polarization could represent a novel therapeutic strategy for DCM.

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引用次数: 0