Molecular Medicine最新文献

{"title":"N-formylmethionine-leucyl-phenylalanine protects against irradiation-induced damage to hematopoiesis and intestines","authors":"Zhihua Li, Yatong Wu, Jicong Du, Wen Qian, Sinian Wang, Fengsheng Li, Suhe Dong, Shunchang Jiao","doi":"10.1186/s10020-024-00918-4","DOIUrl":"https://doi.org/10.1186/s10020-024-00918-4","url":null,"abstract":"Ionizing radiation (IR), including radiotherapy, can exert lasting harm on living organisms. While liposaccharide (LPS) offers resistance to radiation damage, it also induces toxic responses. Thankfully, an LPS analogue called N-formylmethionine-leucyl-phenylalanine (fMLP) holds the potential to mitigate this toxicity, offering hope for radiation protection. Survival of C57BL/6 mice exposed to IR after administration with fMLP/LPS/WR-2721 or saline was recorded. Cell viability and apoptosis assay of bone marrow (BMC), spleen and small intestinal epithelial (HIECs) cells were tested by Cell Counting Kit-8 (CCK-8) and flow cytometry assay. Tissue damage was evaluated by Hematoxilin and Eosin (H&E), Ki-67, and TUNEL staining. RNA sequencing was performed to reveal potential mechanisms of fMLP-mediated radiation protection. Flow cytometry and western blot were performed to verify the radiation protection mechanism of fMLP on the cell cycle. The survival rates of C57BL/6 mice exposed to ionizing radiation after administering fMLP increased. fMLP demonstrated low toxicity in vitro and in vivo, maintaining cell viability and mitigating radiation-induced apoptosis. Moreover, it protected against tissue damage in the hematopoietic and intestinal system. RNA sequencing shed light on fMLP’s potential mechanism, suggesting its role in modulating innate immunity and cell cycling. This was evidenced by its ability to reverse radiation-induced G2/M phase arrests in HIECs. fMLP serves as a promising radioprotective agent, preserving cells and radiosensitive tissues from IR. Through its influence on the cell cycle, particularly reversing radiation-induced arrest in G2/M phases, fMLP offers protection against IR’s detrimental effects.","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227725","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}

{"title":"ZCCHC8 p.P410A disrupts nucleocytoplasmic localization, promoting idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease","authors":"Chen-Yu Wang, Si-Hua Chang, Cheng-Feng Hu, Yi-Qiao Hu, Hong Luo, Lv Liu, Liang-Liang Fan","doi":"10.1186/s10020-024-00913-9","DOIUrl":"https://doi.org/10.1186/s10020-024-00913-9","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a special kind of chronic interstitial lung disease with insidious onset. Previous studies have revealed that mutations in ZCCHC8 may lead to IPF. The aim of this study is to explore the ZCCHC8 mutations in Chinese IPF patients. Here, we enrolled 124 patients with interstitial lung disease from 2017 to 2023 in our hospital. Whole exome sequencing and Sanger sequencing were employed to explore the genetic lesions of these patients. Among these 124 patients, a novel mutation (NM_017612: c.1228 C > G/p.P410A) of Zinc Finger CCHC-Type Containing 8 (ZCCHC8)was identified in a family with IPF and chronic obstructive lung disease. As a component of the nuclear exosome-targeting complex that regulates the turnover of human telomerase RNA, ZCCHC8 mutations have been reported may lead to IPF in European population and American population. Functional study confirmed that the novel mutation can disrupt the nucleocytoplasmic localization of ZCCHC8, which further decreased the expression of DKC1 and RTEL1, and finally reduced the length of telomere and led to IPF and related disorders. We may first report the ZCCHC8 mutation in Asian population with IPF. Our study broadens the mutation, phenotype, and population spectrum of ZCCHC8 deficiency.","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226788","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}

{"title":"Advanced glycation end products and reactive oxygen species: uncovering the potential role of ferroptosis in diabetic complications","authors":"Yanchi Chen, Zihan Meng, Yong Li, Shibo Liu, Pei Hu, En Luo","doi":"10.1186/s10020-024-00905-9","DOIUrl":"https://doi.org/10.1186/s10020-024-00905-9","url":null,"abstract":"Advanced glycation end products (AGEs) are a diverse range of compounds that are formed when free amino groups of proteins, lipids, and nucleic acids are carbonylated by reactive carbonyl species or glycosylated by reducing sugars. Hyperglycemia in patients with diabetes can cause an overabundance of AGEs. Excess AGEs are generally acknowledged as major contributing factors to the development of diabetic complications because of their ability to break down the extracellular matrix directly and initiate intracellular signaling pathways by binding to the receptor for advanced glycation end products (RAGE). Inflammation and oxidative stress are the two most well-defined pathophysiological states induced by the AGE–RAGE interaction. In addition to oxidative stress, AGEs can also inhibit antioxidative systems and disturb iron homeostasis, all of which may induce ferroptosis. Ferroptosis is a newly identified contributor to diabetic complications. This review outlines the formation of AGEs in individuals with diabetes, explores the oxidative damage resulting from downstream reactions of the AGE-RAGE axis, and proposes a novel connection between AGEs and the ferroptosis pathway. This study introduces the concept of a vicious cycle involving AGEs, oxidative stress, and ferroptosis in the development of diabetic complications.","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226791","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}

{"title":"Protective effect of ghrelin in oxidative stress-induced age-related macular degeneration in vitro and in vivo","authors":"Jie Bai, Yanqing Wang, Yanze Li, Yan Liu, Shan Wang","doi":"10.1186/s10020-024-00920-w","DOIUrl":"https://doi.org/10.1186/s10020-024-00920-w","url":null,"abstract":"Oxidative damage to human retinal pigment epithelial (RPE) cells is the main cause of age-related macular degeneration (AMD), in our previous work, we showed that ghrelin has an antioxidative effect on human lens epithelium (HLE) cells, however, the studies of using ghrelin in treating the degenerative diseases of the retina have rarely been reported. In this article, we assessed the effect of ghrelin on preventing oxidative stress induced by hydrogen peroxide (H2O2) in ARPE-19 cells and its mechanism. We observed that pretreatment with ghrelin protected ARPE-19 cells from H2O2-induced cell oxidative injuries and apoptosis responses. Furthermore, an oxidative stress-induced mouse model of AMD was established via injection of sodium iodate (NaIO3) to tail veins, and treatment with ghrelin preserved retinal function, and protected photoreceptors. The first to report ghrelin’ protective effect on H2O2-induced RPE cells. Treatment with ghrelin inhibits NaIO3-induced retinal cell apoptosis in vivo. Combined with in vitro and in vivo experiments, the results are comprehensive and reliable.","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226790","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}

{"title":"NAT10-mediated ac4C acetylation of TFRC promotes sepsis-induced pulmonary injury through regulating ferroptosis","authors":"Pengcheng Xing, Minjie Zhou, Jian Sun, Donglian Wang, Weipeng Huang, Peng An","doi":"10.1186/s10020-024-00912-w","DOIUrl":"https://doi.org/10.1186/s10020-024-00912-w","url":null,"abstract":"Sepsis-induced pulmonary injury (SPI) is a common complication of sepsis with a high rate of mortality. N4-acetylcytidine (ac4C) is mediated by the ac4C “writer”, N-acetyltransferase (NAT)10, to regulate the stabilization of mRNA. This study aimed to investigate the role of NAT10 in SPI and the underlying mechanism. Twenty-three acute respiratory distress syndrome (ARDS) patients and 27 non-ARDS volunteers were recruited. A sepsis rat model was established. Reverse transcription-quantitative polymerase chain reaction was used to detect the expression of NAT10 and transferrin receptor (TFRC). Cell viability was detected by cell counting kit-8. The levels of Fe2+, glutathione, and malondialdehyde were assessed by commercial kits. Lipid reactive oxygen species production was measured by flow cytometric analysis. Western blot was used to detect ferroptosis-related protein levels. Haematoxylin & eosin staining was performed to observe the pulmonary pathological symptoms. The results showed that NAT10 was increased in ARDS patients and lipopolysaccharide-treated human lung microvascular endothelial cell line-5a (HULEC-5a) cells. NAT10 inhibition increased cell viability and decreased ferroptosis in HULEC-5a cells. TFRC was a downstream regulatory target of NAT10-mediated ac4C acetylation. Overexpression of TFRC decreased cell viability and promoted ferroptosis. In in vivo study, NAT10 inhibition alleviated SPI. NAT10-mediated ac4C acetylation of TFRC aggravated SPI through promoting ferroptosis. ","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226792","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}

{"title":"Key subdomains of mesencephalic astrocyte-derived neurotrophic factor attenuate myocardial ischemia/reperfusion injury by JAK1/STAT1/NF-κB signaling pathway.","authors":"Haibin Dong, Wenjuan Jia, Chunxiao Wang, Da Teng, Bowen Xu, Xiaoning Ding, Jun Yang, Lin Zhong, Lei Gong","doi":"10.1186/s10020-024-00916-6","DOIUrl":"10.1186/s10020-024-00916-6","url":null,"abstract":"<p><strong>Background: </strong>Myocardial ischemia/reperfusion (I/R) injury is a common pathological process in clinical practice. Developing effective therapeutic strategies to reduce or prevent this injury is crucial. The article aimed to investigate the role and mechanism of mesencephalic astrocyte-derived neurotrophic factor (MANF) and its key subdomains in modulating myocardial I/R-induced cardiomyocyte apoptosis.</p><p><strong>Methods: </strong>MANF stable knockout cell line and MANF mutant overexpression plasmids were constructed. The effects of MANF and mutants on apoptosis and endoplasmic reticulum (ER) stress related proteins were evaluated in hypoxia/reoxygenation-induced HL-1 cardiomyocytes by western blot, immunofluorescence, Tunel and flow cytometry. Echocardiography, ELISA, TTC and Masson were used to observe the effects of recombinant MANF protein (rMANF) on cardiac function in myocardial I/R mice.</p><p><strong>Results: </strong>This study observed increased expression of MANF in both myocardial infarction patients and I/R mice. MANF overexpression in cardiomyocytes decreased ER stress-induced apoptosis, while MANF knockout exacerbated it. rMANF improved cardiac function in I/R mice by reducing injury and inflammation. This study specifically demonstrates that mutations in the α-helix of MANF were more effective in reducing ER stress and cardiomyocyte apoptosis. Mechanistically, MANF and the α-helix mutant attenuated I/R injury by inhibiting the JAK1/STAT1/NF-κB signaling pathway in addition to reducing ER stress-induced apoptosis.</p><p><strong>Conclusion: </strong>These findings highlight MANF and its subdomains as critical regulators of myocardial I/R injury, offering promising therapeutic targets with significant clinical implications for I/R-related diseases.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145984","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}

{"title":"Role of the GalNAc-galectin pathway in the healing of premature rupture of membranes.","authors":"Jia-Le Chen, Lou Liu, Xin-Rui Peng, Yan Wang, Xiang Xiang, Yu Chen, De-Xiang Xu, Dao-Zhen Chen","doi":"10.1186/s10020-024-00908-6","DOIUrl":"10.1186/s10020-024-00908-6","url":null,"abstract":"<p><strong>Background: </strong>Premature rupture of the membranes (PROM) is a key cause of preterm birth and represents a major cause of neonatal mortality and morbidity. Natural products N-acetyl-d-galactosamine (GalNAc), which are basic building blocks of important polysaccharides in biological cells or tissues, such as chitin, glycoproteins, and glycolipids, may improve possible effects of wound healing.</p><p><strong>Methods: </strong>An in vitro inflammation and oxidative stress model was constructed using tumor necrosis-α (TNF-α) and lipopolysaccharide (LPS) action on WISH cells. Human amniotic epithelial cells (hAECs) were primarily cultured by digestion to construct a wound model. The effects of GalNAc on anti-inflammatory and anti-oxidative stress, migration and proliferation, epithelial-mesenchymal transition (EMT), glycosaminoglycan (GAG)/hyaluronic acid (HA) production, and protein kinase B (Akt) pathway in hAECs and WISH cells were analyzed using the DCFH-DA fluorescent probe, ELISA, CCK-8, scratch, transwell migration, and western blot to determine the mechanism by which GalNAc promotes amniotic wound healing.</p><p><strong>Results: </strong>GalNAc decreased IL-6 expression in TNF-α-stimulated WISH cells and ROS expression in LPS-stimulated WISH cells (P < 0.05). GalNAc promoted the expression of Gal-1 and Gal-3 with anti-inflammatory and anti-oxidative stress effects. GalNAc promoted the migration of hAECs (50% vs. 80%) and WISH cells through the Akt signaling pathway, EMT reached the point of promoting fetal membrane healing, and GalNAc did not affect the activity of hAECs and WISH cells (P > 0.05). GalNAc upregulated the expression of sGAG in WISH cells (P < 0.05) but did not affect HA levels (P > 0.05).</p><p><strong>Conclusions: </strong>GalNAc might be a potential target for the prevention and treatment of PROM through the galectin pathway, including (i) inflammation; (ii) epithelial-mesenchymal transition; (iii) proliferation and migration; and (iv) regression, remodeling, and healing.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11375961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133248","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}

{"title":"Fetal origin of bronchopulmonary dysplasia: contribution of intrauterine inflammation.","authors":"Haoting Yu, Danni Li, Xinyi Zhao, Jianhua Fu","doi":"10.1186/s10020-024-00909-5","DOIUrl":"10.1186/s10020-024-00909-5","url":null,"abstract":"<p><p>Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in infants and the most frequent adverse outcome of premature birth, despite major efforts to minimize injury. It is thought to result from aberrant repair response triggered by either prenatal or recurrent postnatal injury to the lungs during development. Intrauterine inflammation is an important risk factor for prenatal lung injury, which is also increasingly linked to BPD. However, the specific mechanisms remain unclear. This review summarizes clinical and animal research linking intrauterine inflammation to BPD. We assess how intrauterine inflammation affects lung alveolarization and vascular development. In addition, we discuss prenatal therapeutic strategies targeting intrauterine inflammation to prevent or treat BPD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126166","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}

{"title":"Insights into RNA N6-methyladenosine and programmed cell death in atherosclerosis.","authors":"Haijiao Long, Yulu Yu, Jie Ouyang, Hongwei Lu, Guojun Zhao","doi":"10.1186/s10020-024-00901-z","DOIUrl":"10.1186/s10020-024-00901-z","url":null,"abstract":"<p><p>N6-methyladenosine (m⁶A) modification stands out among various RNA modifications as the predominant form within eukaryotic cells, influencing numerous cellular processes implicated in disease development. m⁶A modification has gained increasing attention in the development of atherosclerosis and has become a research hotspot in recent years. Programmed cell death (PCD), encompassing apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, plays a pivotal role in atherosclerosis pathogenesis. In this review, we delve into the intricate interplay between m⁶A modification and diverse PCD pathways, shedding light on their complex association during the onset and progression of atherosclerosis. Clarifying the relationship between m⁶A and PCD in atherosclerosis is of great significance to provide novel strategies for cardiovascular disease treatment.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126167","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}

{"title":"Molecular mechanism and potential role of mitophagy in acute pancreatitis.","authors":"Lili Zhu, Yunfei Xu, Jian Lei","doi":"10.1186/s10020-024-00903-x","DOIUrl":"10.1186/s10020-024-00903-x","url":null,"abstract":"<p><p>Acute pancreatitis (AP) is a multifaceted inflammatory disorder stemming from the aberrant activation of trypsin within the pancreas. Despite the contribution of various factors to the pathogenesis of AP, such as trypsin activation, dysregulated increases in cytosolic Ca²⁺ levels, inflammatory cascade activation, and mitochondrial dysfunction, the precise molecular mechanisms underlying the disease are still not fully understood. Mitophagy, a cellular process that preserves mitochondrial homeostasis under stress, has emerged as a pivotal player in the context of AP. Research suggests that augmenting mitophagy can mitigate pancreatic injury by clearing away malfunctioning mitochondria. Elucidating the role of mitophagy in AP may pave the way for novel therapeutic strategies. This review article aims to synthesize the current research findings on mitophagy in AP and underscore its significance in the clinical management of the disorder.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126168","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}