Life sciences最新文献_第7页

Vitamin D as a modulator of molecular pathways involved in CVDs: Evidence from preclinical studies 维生素 D 作为心血管疾病分子通路的调节剂：临床前研究的证据。

IF 5.2 2区医学

Life sciences Pub Date : 2024-09-16 DOI: 10.1016/j.lfs.2024.123062

{"title":"Vitamin D as a modulator of molecular pathways involved in CVDs: Evidence from preclinical studies","authors":"","doi":"10.1016/j.lfs.2024.123062","DOIUrl":"10.1016/j.lfs.2024.123062","url":null,"abstract":"<div><div>Vitamin D deficiency (VDD) is a widespread global health issue, affecting nearly a billion individuals worldwide, and mounting evidence links it to an increased risk of cardiovascular diseases like hypertension, atherosclerosis, and heart failure. The discovery of vitamin D receptors and metabolizing enzymes in cardiac and vascular cells, coupled with experimental studies, underscores the complex relationship between vitamin D and cardiovascular health. This review aims to synthesize and critically evaluate the preclinical evidence elucidating the role of vitamin D in cardiovascular health. We examined diverse preclinical in vitro (cardiomyocyte cell line) models and in vivo models, including knockout mice, diet-induced deficiency, and disease-specific animal models (hypertension, hypertrophy and myocardial infarction). These studies reveal that vitamin D modulates vascular tone, and prevents fibrosis and hypertrophy through effects on major signal transduction pathways (NF-kB, Nrf2, PI3K/AKT/mTOR, Calcineurin/NFAT, TGF-β/Smad, AMPK) and influences epigenetic mechanisms governing inflammation, oxidative stress, and pathological remodeling. In vitro studies elucidate vitamin D's capacity to promote cardiomyocyte differentiation and inhibit pathological remodeling. In vivo studies further uncovered detrimental cardiac effects of VDD, while supplementation with vitamin D in cardiovascular disease (CVD) models demonstrated its protective effects by decreasing inflammation, attenuating hypertrophy, reduction in plaque formation, and improving cardiac function. Hence, this comprehensive review emphasizes the critical role of vitamin D in cardiovascular health and its potential as a preventive/therapeutic strategy in CVDs. However, further research is needed to translate these findings into clinical applications as there are discrepancies between preclinical and clinical studies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290427","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

An anti-neoplastic tale of metformin through its transport 二甲双胍通过运输抗肿瘤的故事

IF 5.2 2区医学

Life sciences Pub Date : 2024-09-14 DOI: 10.1016/j.lfs.2024.123060

引用次数: 0

Unconventional p65/p52 NF-κB module regulates key tumor microenvironment-related genes in breast tumor-associated macrophages (TAMs) 非常规 p65/p52 NF-κB 模块调控乳腺肿瘤相关巨噬细胞（TAMs）中与肿瘤微环境有关的关键基因

IF 5.2 2区医学

Life sciences Pub Date : 2024-09-13 DOI: 10.1016/j.lfs.2024.123059

{"title":"Unconventional p65/p52 NF-κB module regulates key tumor microenvironment-related genes in breast tumor-associated macrophages (TAMs)","authors":"","doi":"10.1016/j.lfs.2024.123059","DOIUrl":"10.1016/j.lfs.2024.123059","url":null,"abstract":"<div><p>The complex heterogeneity of tumor microenvironment (TME) of triple-negative breast cancer (TNBC) presents a significant obstacle to cytotoxic immune response and successful treatment, building up one of the most hostile oncological phenotypes. Among the most abundant TME components, tumor-associated macrophages (TAMs) have pivotal pro-tumoral functions, involving discordant roles for the nuclear factor kappa-B (NF-κB) transcription factors and directing to higher levels of pathway complexity.</p><p>In both resting macrophages and TAMs, we recently revealed the existence of the uncharacterized NF-κB p65/p52 dimer. In the present study, we demonstrated its enhanced active nuclear localization in TAMs and validated selected immune target genes as directly regulated by dimer binding on DNA sequences.</p><p>We demonstrated by ChIP-qPCR that p65/p52 enrichment on HSPG2 and CSF-1 regulatory regions is strictly dependent on macrophage polarization and tumor environment.</p><p>Our data provide novel mechanisms of transcriptional regulation in TAMs, orchestrated by the varied and dynamic nature of NF-κB combinations, which needs to be considered when targeting this pathway in cancer therapies.</p><p>Our results offer p65/p52, together with identified regulatory regions on genes impacting macrophage behavior and tumor biology, as novel molecular targets for TNBC, aimed at modulating TAMs functions towards anti-tumoral phenotypes and thus improving cancer treatment outcomes.</p></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0024320524006490/pdfft?md5=af629f02d14f8df4fb95ef99c352ab40&pid=1-s2.0-S0024320524006490-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242187","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

P2Y12-targeted modulation of microglial phenotypes: A novel therapeutic strategy for enhanced axonal regeneration post-spinal cord injury P2Y12 靶向调节小胶质细胞表型：增强脊髓损伤后轴突再生的新型治疗策略

IF 5.2 2区医学

Life sciences Pub Date : 2024-09-12 DOI: 10.1016/j.lfs.2024.123057

{"title":"P2Y12-targeted modulation of microglial phenotypes: A novel therapeutic strategy for enhanced axonal regeneration post-spinal cord injury","authors":"","doi":"10.1016/j.lfs.2024.123057","DOIUrl":"10.1016/j.lfs.2024.123057","url":null,"abstract":"<div><h3>Aims</h3><p>Microglia activation after spinal cord injury (SCI) is a double-edged sword, modulation of the activated microglia populations toward pro-regenerative phenotypes highlights the potential therapeutic implications. P2Y12, a microglia-specific marker, remains underexplored in its capacity to polarize microglial activation populations in SCI repair. We aimed to explore the effects of modulating P2Y12 on microglia function after spinal cord injury, and further on axonal regeneration and motor recovery after spinal cord injury.</p></div><div><h3>Materials and methods</h3><p>The study employed both in vitro and in vivo models, using BV2 cells and a mouse model of SCI, respectively. Ticagrelor, a P2Y12 antagonist, was administered via a collagen scaffold to ensure stable and sustained release. Transcriptome sequencing analysis, immunofluorescence staining, and Basso Mouse Scale (BMS) scores were used to assess microglial activation, axonal regeneration, and functional recovery.</p></div><div><h3>Key findings</h3><p>Herein, we observed P2Y12<sup>+</sup> microglia localized predominantly at the lesion periphery within 3 days post injury (dpi), manifesting a pro-inflammatory phenotype, but not anti-inflammatory phenotype. In vitro investigations revealed that P2Y12 inhibition of the activated microglia curtailed pro-inflammatory differentiation while augmenting anti-inflammatory differentiation.</p></div><div><h3>Significance</h3><p>Leveraging this insight, we engineered a collagen scaffold-based delivery system for sustained release of the P2Y12 antagonist, ticagrelor, at the injury site in a mouse complete SCI model. Notably, P2Y12 suppression markedly enhanced axonal regeneration within the injured site and ameliorated lower limb motor functions in SCI mice. Collectively, our findings illuminate P2Y12-targeted microglial modulation as a promising therapeutic approach for SCI.</p></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230433","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

Nrf2 pathways in neuroprotection: Alleviating mitochondrial dysfunction and cognitive impairment in aging 神经保护中的 Nrf2 通路：缓解衰老过程中的线粒体功能障碍和认知障碍

IF 5.2 2区医学

Life sciences Pub Date : 2024-09-12 DOI: 10.1016/j.lfs.2024.123056

{"title":"Nrf2 pathways in neuroprotection: Alleviating mitochondrial dysfunction and cognitive impairment in aging","authors":"","doi":"10.1016/j.lfs.2024.123056","DOIUrl":"10.1016/j.lfs.2024.123056","url":null,"abstract":"<div><p>Mitochondrial dysfunction and cognitive impairment are widespread phenomena among the elderly, being crucial factors that contribute to neurodegenerative diseases. Nuclear factor erythroid 2–related factor 2 (Nrf2) is an important regulator of cellular defense systems, including that against oxidative stress. As such, increased Nrf2 activity may serve as a strategy to avert mitochondrial dysfunction and cognitive decline. Scientific data on Nrf2-mediated neuroprotection was collected from PubMed, Google Scholar, and Science Direct, specifically addressing mitochondrial dysfunction and cognitive impairment in older people. Search terms included “Nrf2”, “mitochondrial dysfunction,” “cognitive impairment,” and “neuroprotection.” Studies focusing on in vitro and in vivo models and clinical investigations were included to review Nrf2's therapeutic potential comprehensively. The relative studies have demonstrated that increased Nrf2 activity could improve mitochondrial performance, decrease oxidative pressure, and mitigate cognitive impairment. To a large extent, this is achieved through the modulation of critical cellular signalling pathways such as the Keap1/Nrf2 pathway, mitochondrial biogenesis, and neuroinflammatory responses. The present review summarizes the recent progress in comprehending the molecular mechanisms regarding the neuroprotective benefits mediated by Nrf2 through its substantial role against mitochondrial dysfunction and cognitive impairment. This review also emphasizes Nrf2-target pathways and their contribution to cognitive function improvement and rescue from mitochondria-related abnormalities as treatment strategies for neurodegenerative diseases that often affect elderly individuals.</p></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274132","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 potential therapeutic effect of human umbilical cord mesenchymal stem cell-derived exosomes in bronchopulmonary dysplasia 人脐带间充质干细胞衍生的外泌体对支气管肺发育不良的潜在治疗作用

IF 5.2 2区医学

Life sciences Pub Date : 2024-09-12 DOI: 10.1016/j.lfs.2024.123047

{"title":"The potential therapeutic effect of human umbilical cord mesenchymal stem cell-derived exosomes in bronchopulmonary dysplasia","authors":"","doi":"10.1016/j.lfs.2024.123047","DOIUrl":"10.1016/j.lfs.2024.123047","url":null,"abstract":"<div><p>Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants, with its incidence rising due to improved survival rates of these infants. BPD results from a combination of prenatal and postnatal factors, such as mechanical ventilation, oxygen toxicity, and infections, all of which significantly impact the prognosis and growth of affected infants. Current treatment options for BPD are largely supportive and do not address the underlying pathology. Exosomes are cell-derived bilayer-enclosed membrane structures enclosing proteins, lipids, RNAs, growth factors, cytokines and metabolites. They have become recognized as crucial regulators of intercellular communication in various physiological and pathological processes. Previous studies have revealed the therapeutic potential of human umbilical cord mesenchymal stem cells-derived exosomes (HUCMSCs-Exos) in promoting tissue repair and regeneration. Therefore, HUCMSCs-Exos maybe a promising and effective therapeutic modality for BPD. In this review, we firstly provide a comprehensive overview of BPD, including its etiology and the mechanisms of lung injury. Then we detail the isolation, characterization, and contents of HUCMSCs-Exos, and discuss their potential mechanisms of HUCMSCs-Exos in BPD treatment. Additionally, we summarize current clinical trials and discuss the challenges in translating these findings from bench to bedside. This review aims to lay the groundwork for future clinical applications of HUCMSCs-Exos in treating BPD.</p></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242172","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

Sex-dependent differential increase of specialized pro-resolving mediators in extracellular vesicles secreted by human primary conjunctival goblet cells during allergic inflammation 过敏性炎症期间人原代结膜上皮细胞分泌的细胞外小泡中特化的促溶解介质的增加与性别有关

IF 5.2 2区医学

Life sciences Pub Date : 2024-09-12 DOI: 10.1016/j.lfs.2024.123058

{"title":"Sex-dependent differential increase of specialized pro-resolving mediators in extracellular vesicles secreted by human primary conjunctival goblet cells during allergic inflammation","authors":"","doi":"10.1016/j.lfs.2024.123058","DOIUrl":"10.1016/j.lfs.2024.123058","url":null,"abstract":"<div><h3>Aims</h3><p>Conjunctival epithelium lines the inside of the eyelids and covers the sclera, thus providing stability to the eye surface. Goblet cells in conjunctival epithelium (CjGCs) are well known for their mucin-secretion function, which wet and protect the ocular surface, but other aspects are still not well understood. To expand our understanding beyond their mucin-secreting function, we investigated CjGC-secreted extracellular vesicles (EVs) and lipid mediators therein.</p></div><div><h3>Materials and methods</h3><p>Using histamine-mediated allergic inflammation in human primary CjGCs (HCjGCs) as a disease model, we quantified using ELISA a proinflammatory mediator PGE2 and two specialized pro-resolving mediators (SPMs) LXA4 and RvD1 in EVs secreted during allergic inflammation.</p></div><div><h3>Key findings</h3><p>At 18 h post histamine stimulation, the amount of LXA4 and RvD1 in EVs was notably higher compared to those in unstimulated. Interestingly, this increase was only observed in female EVs but not in males. The mean fold increase of LXA4 and RvD1 in female EVs was 3.9 and 3.4, respectively, but it was only 0.9 and 1.0 in male EVs. Supplying docosahexaenoic acid (DHA, the source of RvD1 and other SPMs) to the culture medium during the allergic inflammation resulted in even higher mean fold increase of 5.3 and 6.9 for LXA4 and RvD1 in female EVs, respectively, but it was only 0.5 and 0.8 in male EVs.</p></div><div><h3>Significance</h3><p>We conclude that HCjGCs show a clear sex difference in allergic response. Our results may also provide a new insight into the male predisposition to severe forms of allergic conjunctivitis and potential improvement in disease care in the clinic.</p></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230434","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

Deletion of the foxO1 gene reduces hypoxia tolerance in zebrafish embryos by influencing erythropoiesis 缺失 foxO1 基因会影响红细胞生成，从而降低斑马鱼胚胎对缺氧的耐受性。

IF 5.2 2区医学

Life sciences Pub Date : 2024-09-11 DOI: 10.1016/j.lfs.2024.123048

{"title":"Deletion of the foxO1 gene reduces hypoxia tolerance in zebrafish embryos by influencing erythropoiesis","authors":"","doi":"10.1016/j.lfs.2024.123048","DOIUrl":"10.1016/j.lfs.2024.123048","url":null,"abstract":"<div><div>FoxO1 (Forkhead box O1) belongs to the evolutionarily conserved FoxO subfamily and is involved in diverse physiologic processes, including apoptosis, cell cycle, DNA damage repair, oxidative stress and cell differentiation. FoxO1 plays an important role in regulating the hypoxia microenvironment such as cancers, but its role in hypoxia adaptation remains unclear in animals. To understand the function of <em>foxO1</em> in hypoxia response, we constructed <em>foxO1a</em> and <em>foxO1b</em> mutant zebrafish using CRISPR/Cas9 technology. It was found that <em>foxO1a</em> and <em>foxO1b</em> destruction affected the hematopoietic system in the early zebrafish embryos. Specifically, FoxO1a and FoxO1b were found to affect the transcriptional activity of <em>runx1</em>, a marker gene for hematopoietic stem cells (HSCs). Moreover, <em>foxO1a</em> and <em>foxO1b</em> had complementary features in hypoxia response, and <em>foxO1a</em> or/and <em>foxO1b</em> destruction resulted in tolerance of zebrafish becoming weakened in hypoxia due to insufficient hemoglobin supply. Additionally, the transcriptional activity of these two genes was demonstrated to be regulated by Hif1α. In conclusion, <em>foxO1a</em> and <em>foxO1b</em> respond to Hif1α-mediated hypoxia response by participating in zebrafish erythropoiesis. These results will provide a theoretical basis for further exploring the function of FoxO1 in hematopoiesis and hypoxia response.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290421","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

Vitamin B1 and calcitriol enhance glibenclamide suppression of diabetic nephropathy: Role of HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories 维生素 B1 和钙三醇能增强格列本脲对糖尿病肾病的抑制作用HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA轨迹的作用

IF 5.2 2区医学

Life sciences Pub Date : 2024-09-08 DOI: 10.1016/j.lfs.2024.123046

{"title":"Vitamin B1 and calcitriol enhance glibenclamide suppression of diabetic nephropathy: Role of HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories","authors":"","doi":"10.1016/j.lfs.2024.123046","DOIUrl":"10.1016/j.lfs.2024.123046","url":null,"abstract":"<div><p>Glibenclamide is one of the most prescribed insulin secretagogues in diabetes due to its low cost, but its efficacy on suppressing diabetic complications is limited. Here, we examine whether addition of either vitamin B1 or calcitriol to glibenclamide could produce more suppression of diabetic nephropathy. Type 2 diabetes was induced by high fructose (10 % in drinking water), high salt (3 % in diet), and high fat diet (25 % in diet) for 3 weeks, followed by single dose of STZ (40 mg/kg, i.p.). Diabetic rats were treated with either glibenclamide (0.6 mg/kg), vitamin B1 (70 mg/kg), glibenclamide/vitamin B1, calcitriol (0.1 μg/kg), or glibenclamide/calcitriol. Addition of either vitamin B1 or calcitriol to glibenclamide therapy enabled more suppression of diabetic nephropathy development as evidenced by more preserved creatinine clearance and less renal damage scores. Combination therapy resulted in mild enhancement in the effect of glibenclamide on glucose tolerance without affecting the area under the curve. Combination therapy was associated with more suppression of inflammatory cascades as evidenced by reducing the expression of high mobility group box-1 (HMGB1), toll-like receptor-4 (TLR4), nuclear factor-kappa B (NF-κB), and tumor necrosis factor-α (TNF-α). In addition, combination therapy enhanced the antioxidant mechanisms as evidenced by increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione content and reducing malondialdehyde and nitric oxide levels. Furthermore, combination therapy provided more suppression of fibrotic pathways as appear from reducing collagen deposition and the expression of α- smooth muscle actin (α-SMA). In conclusion, addition of vitamin B1 or calcitriol to glibenclamide therapy can enhance the therapeutic efficiency of glibenclamide in suppressing diabetic nephropathy progression to the same extend, the protective effect is mediated through modulating HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories.</p></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171667","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

Research progress of traditional Chinese medicine in the treatment of ischemic stroke by regulating mitochondrial dysfunction 中药调节线粒体功能障碍治疗缺血性中风的研究进展

IF 5.2 2区医学

Life sciences Pub Date : 2024-09-07 DOI: 10.1016/j.lfs.2024.123045

引用次数: 0