Life sciences最新文献_第9页

Effects of high levels of androgens on oocyte maturation and potential regulatory role of retinoic acid

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-11 DOI: 10.1016/j.lfs.2025.123463

Yongfeng Zhou , Qi Zhang , Ran Ding, Xinyuan Fan, Qi Li, Ziyi Li

Aims

Polycystic ovary syndrome (PCOS) is a prevalent condition among women, characterized by hyperandrogenism. This study aims to investigate the underlying mechanisms by which testosterone impact oocyte maturation and potential methods for addressing this condition.

Materials and methods

Testosterone propionate (TP) was incorporated into the oocyte maturation medium to simulate the typical hyperandrogenic environment associated with PCOS, facilitating an investigation the effect of hyperandrogen on oocyte maturation in vitro. The gene expression profiles of porcine cumulus-oocyte complexes (COCs) during in vitro maturation (IVM) following TP treatment were analyzed using RNA-seq.

Key findings

TP downregulated two genes, TNFAIP6 and EREG, associated with follicular development process. Additionally, GSEA analysis indicated that TP upregulated the retinol metabolism gene set. Both TP and retinoic acid (RA) were added to the oocyte maturation medium. Subsequently, we evaluated the molecular characteristics of COCs in various treatment groups and assessed the blastocyst formation rate following parthenogenetic activation of COCs. The results indicated that RA effectively reversed TP-induced meiotic repression by downregulating the elevated expression level of WEE2 in TP-treated oocytes. However, RA exhibited distinct effects on TP-induced alterations in gene expression, including EREG and TNFAIP6, at different stages.

Significance

RA could mitigate the adverse effects of hyperandrogenism on oocytes during maturation. Moreover, RA and testosterone exert a dual regulatory effect on extracellular matrix remodeling in cumulus cells. These findings suggest the potential therapeutic application of RA in androgen-induced PCOS.

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引用次数: 0

Peptide-driven strategies against lung cancer

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-07 DOI: 10.1016/j.lfs.2025.123453

Vijayshree S. Karankar, Saurabh Awasthi, Nidhi Srivastava

Lung cancer remains one of the most significant global health challenges, accounting for 18 % of all cancer-related deaths. While risk factors such as heavy metal exposure and cigarette smoking are well-known contributors, the limitations of conventional treatments including severe side effects and drug resistance highlight the urgent need for more targeted and safer therapeutic options. In this context, peptides have emerged as a novel, precise, and effective class of therapies for lung cancer treatment. They have shown promise in limiting lung cancer progression by targeting key molecular pathways involved in tumour growth. Anti-non-small cell lung cancer peptides that specifically target proteins such as EGFR, TP53, BRAF, MET, ROS1, and ALK have demonstrated potential in improving lung cancer outcomes. Additionally, anti-inflammatory and apoptosis-inducing peptides offer further therapeutic benefits. This review provides a comprehensive overview of the peptides currently in use or under investigation for the treatment of lung cancer, highlighting their mechanisms of action and therapeutic potential. As research continues to advance, peptides are poised to become a promising new therapeutic option in the fight against lung cancer.

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引用次数: 0

DLGAP5 upregulates E2F1 to promote prostate adenocarcinoma neuroendocrine differentiation

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-07 DOI: 10.1016/j.lfs.2025.123442

Linghui Liang , Zhiyi Shen , Kaiyu Zhang , Chenglong Zhang , Lai Dong , Rongjie Shi , Lixin Hua , Ruizhe Zhao , Ninghan Feng

Aims

DLGAP5 plays a significant role in promoting cancer progression across various cancers. However, the specific role of DLGAP5 in neuroendocrine differentiation (NED) of prostate cancer (PCa) remains elusive. Our objective is to explore the mechanism by which DLGAP5 mediates NED in PCa.

Materials and methods

Utilizing diverse public databases, we conducted bioinformatics analysis to examine DLGAP5 expression in PCa. We confirmed aberrant DLGAP5 expression in various PCa cell lines through Western blotting. Functional assays both in vivo and in vitro have validated the oncogenic role of DLGAP5 in PCa. Furthermore, we sought to identify downstream key genes to elucidate the mechanisms underlying DLGAP5-mediated NED in PCa. We also identified a small molecule drug, AAPK-25, which specifically targets DLGAP5.

Key findings

DLGAP5 was highly expressed in NEPC. The suppression of AR signaling promoted DLGAP5 transcription. DLGAP5 endowed PCa cells with a robust ability to proliferate and migrate. E2F1 was an important downstream target of DLGAP5. DLGAP5 mediated the NED of PCa through E2F1. AAPK-25, as an inhibitor of DLGAP5, inhibited PRAD proliferation by repressing the DLGAP5/E2F1 axis both in vitro and in vivo.

Significance

We identified the AR/DLGAP5/E2F1 signaling pathway as a pivotal mechanism that facilitates the transition of PCa towards a neuroendocrine phenotype. This pathway may represent a promising therapeutic target for NEPC patients.

{"title":"DLGAP5 upregulates E2F1 to promote prostate adenocarcinoma neuroendocrine differentiation","authors":"Linghui Liang , Zhiyi Shen , Kaiyu Zhang , Chenglong Zhang , Lai Dong , Rongjie Shi , Lixin Hua , Ruizhe Zhao , Ninghan Feng","doi":"10.1016/j.lfs.2025.123442","DOIUrl":"10.1016/j.lfs.2025.123442","url":null,"abstract":"<div><h3>Aims</h3><div>DLGAP5 plays a significant role in promoting cancer progression across various cancers. However, the specific role of DLGAP5 in neuroendocrine differentiation (NED) of prostate cancer (PCa) remains elusive. Our objective is to explore the mechanism by which DLGAP5 mediates NED in PCa.</div></div><div><h3>Materials and methods</h3><div>Utilizing diverse public databases, we conducted bioinformatics analysis to examine DLGAP5 expression in PCa. We confirmed aberrant DLGAP5 expression in various PCa cell lines through Western blotting. Functional assays both in vivo and in vitro have validated the oncogenic role of DLGAP5 in PCa. Furthermore, we sought to identify downstream key genes to elucidate the mechanisms underlying DLGAP5-mediated NED in PCa. We also identified a small molecule drug, AAPK-25, which specifically targets DLGAP5.</div></div><div><h3>Key findings</h3><div>DLGAP5 was highly expressed in NEPC. The suppression of AR signaling promoted DLGAP5 transcription. DLGAP5 endowed PCa cells with a robust ability to proliferate and migrate. E2F1 was an important downstream target of DLGAP5. DLGAP5 mediated the NED of PCa through E2F1. AAPK-25, as an inhibitor of DLGAP5, inhibited PRAD proliferation by repressing the DLGAP5/E2F1 axis both in vitro and in vivo.</div></div><div><h3>Significance</h3><div>We identified the AR/DLGAP5/E2F1 signaling pathway as a pivotal mechanism that facilitates the transition of PCa towards a neuroendocrine phenotype. This pathway may represent a promising therapeutic target for NEPC patients.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"365 ","pages":"Article 123442"},"PeriodicalIF":5.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382746","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

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.

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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.

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引用次数: 0