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The different innate immune response to infections in males and females emerges before birth
IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-04 DOI: 10.1016/j.lfs.2025.123521
Valentina Margarita , Valeria Lodde , Paola Rappelli , Laura Doro , Andrea Montella , Pier Luigi Fiori , Ilaria Campesi

Aim

Sex-specific immune responses to intra-amniotic infections remain poorly understood despite their key role in preterm birth.

Methods

We infected male and female amniotic fluid cells (AFCs) with M. hominis to explore the potential impact of sex-specific innate immune responses, evaluating the gene and protein expression levels of IL-1β, IL-6, IL-8, TNF-α, TLR2 and TLR4, the production of nitrites, and the levels of selected miRNAs.

Key findings

The gene expression of IL-1β, IL-6, IL-8, TNF-α, and TLR2 were elevated in infected females AFCs, while only IL-6, IL-8 and TLR4 expression were up-regulated in infected males. Protein levels of IL-6, TNF-α and TLR2 were up-regulated exclusively in infected females. Furthermore, infected female AFCs produced higher levels of nitrites. MiRNA expression revealed an up-regulation of miR-29a-3p in infected females, and miR-223-3p in infected males, with miR-29b-3p showing up-regulation in both sexes upon infection.

Significance

The response to intrauterine infections differs between males and females. Female foetuses may possess a greater capacity to manage the infection and inflammation, underscoring the importance of personalized prenatal care.
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引用次数: 0
Schwann cells secrete IGFBP5 to facilitate the growth of keloids
IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-04 DOI: 10.1016/j.lfs.2025.123534
Kang Wei , Yiran Shi , Min Wang , Lu He , Huanhuan Xu , Haijie Wang , Langjie Chai , Ling Zhou , Yi Zou , Liang Guo
Keloids (KD) are noncancerous fibroproliferative tumors exhibiting cancer-like traits, encompass aggressive unregulated growth, absence of natural regression, and a significantly high rate of recurrence. The precise molecular mechanisms underlying KD pathology remain poorly understood. In this study, we employed single-cell sequencing to examine the characteristics of cells in KD and normal scar (NS) tissue. We evaluated Schwann cells and their secretory protein IGFBP5 function in KD. Then, the recombinant IGFBP5 protein was employed to elucidate the regulatory roles of IGFBP5 in the proliferation, migration, invasion, angiogenesis, and cell cycle of keloids fibroblasts (KF). The rabbit ear scar model was utilized to ascertain the function of IGFBP5 in vivo. We demonstrated that in KD, the proportion of Schwann cells was 4.13 times that of NS. Besides, the IGFBP5 gene exhibited an expression level that was 8.02 times higher in KD Schwann cells compared to those in NS Schwann cells. High IGFBP5 expression was positively associated with the cell proliferation, migration, invasion, angiogenesis, and cell cycle of KF. Additionally, the p53/p21/Cyclin D1 pathway regulated cell cycle and promoted cell proliferation, which was suppressed after rIGFBP5 administration. These findings suggest that Schwann cells infiltrate in KD and secrete IGFBP5 protein to promote KD growth, and targeting IGFBP5 or Schwann cell infiltration could offer novel therapeutic strategies for KD.
{"title":"Schwann cells secrete IGFBP5 to facilitate the growth of keloids","authors":"Kang Wei ,&nbsp;Yiran Shi ,&nbsp;Min Wang ,&nbsp;Lu He ,&nbsp;Huanhuan Xu ,&nbsp;Haijie Wang ,&nbsp;Langjie Chai ,&nbsp;Ling Zhou ,&nbsp;Yi Zou ,&nbsp;Liang Guo","doi":"10.1016/j.lfs.2025.123534","DOIUrl":"10.1016/j.lfs.2025.123534","url":null,"abstract":"<div><div>Keloids (KD) are noncancerous fibroproliferative tumors exhibiting cancer-like traits, encompass aggressive unregulated growth, absence of natural regression, and a significantly high rate of recurrence. The precise molecular mechanisms underlying KD pathology remain poorly understood. In this study, we employed single-cell sequencing to examine the characteristics of cells in KD and normal scar (NS) tissue. We evaluated Schwann cells and their secretory protein IGFBP5 function in KD. Then, the recombinant IGFBP5 protein was employed to elucidate the regulatory roles of IGFBP5 in the proliferation, migration, invasion, angiogenesis, and cell cycle of keloids fibroblasts (KF). The rabbit ear scar model was utilized to ascertain the function of IGFBP5 <em>in vivo.</em> We demonstrated that in KD, the proportion of Schwann cells was 4.13 times that of NS. Besides, the <em>IGFBP5</em> gene exhibited an expression level that was 8.02 times higher in KD Schwann cells compared to those in NS Schwann cells. High IGFBP5 expression was positively associated with the cell proliferation, migration, invasion, angiogenesis, and cell cycle of KF. Additionally, the p53/p21/Cyclin D1 pathway regulated cell cycle and promoted cell proliferation, which was suppressed after rIGFBP5 administration. These findings suggest that Schwann cells infiltrate in KD and secrete IGFBP5 protein to promote KD growth, and targeting IGFBP5 or Schwann cell infiltration could offer novel therapeutic strategies for KD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123534"},"PeriodicalIF":5.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573482","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
Molecular docking- and reporter-based screening identify dicoumarol against ER stress-induced liver injury in mice through inhibiting IRE1α activity
IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-04 DOI: 10.1016/j.lfs.2025.123526
Jifeng Yang , Wei Luo , Yanyu Chen , Yimin Zhou , Jiahai Wang , Lin Mi , Guojun Shi

Aims

Drug-induced liver injury is among the most challenging liver disorders. Endoplasmic reticulum (ER) is responsible for the correct protein folding and secretion, which are highly active in hepatocytes. Failure in maintaining the proper protein folding under pathological condition or external stimuli leads to the unfolded protein response (UPR) to restore ER homeostasis or induce cell death. IRE1α pathway is the most conserved UPR branch with diverse physiological and pathological functions. This study aimed to screen for natural compounds to alleviate hepatic ER stress and liver injury by modulating IRE1α activity.

Materials and methods

ATP-competitive molecules from chemical libraries were recognized by virtual screening for targeting the IRE1α kinase domain. IRE1α activity-based XBP1s-reporter cell lines with flow cytometric analysis were employed to validate candidates from chemical libraries. Then the functions of the top candidate compound on IRE1α signaling were analyzed followed by the treatment with ER stress agonists in vitro. Finally, the candidate compound was used to treat ER stress-induced acute liver injury to evaluate its protective effect in vivo.

Key findings

Dicoumarol (DIC) was discovered as a potential inhibitor of IRE1α activation in HEK293T cells, HepG2 cells and primary hepatocytes. Particularly, DIC ameliorates tunicamycin (Tm)- and carbon tetrachloride (CCl4)-induced acute hepatic ER stress to protect against liver injury.

Significance

This study established a drug screening strategy against IRE1α activation and identified potential new therapeutic effects of DIC in treating liver injury-related diseases.
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引用次数: 0
Sex-specific molecular hallmarks point to increased atherogenesis susceptibility in male senescence-accelerated mice
IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-04 DOI: 10.1016/j.lfs.2025.123529
Ainara González-Moro , Estela Herranz , Miriam Morales Rodríguez de Lope , Ibone Rubio Sanchez-Pajares , Jorge Sánchez-Ramírez , Alan Rivera-Tenorio , Licia Shamoon , Carlos Félix Sánchez-Ferrer , Concepción Peiró , Fernando de la Cuesta

Aims

The senescence-accelerated mouse (SAM) model has been extensively used to study neurological alterations associated with aging. The SAM model has also proved to be useful in the study of vascular aging, but there is still work to be done to better define its utility as a model of atherosclerosis, since contradictory data have been published and sex seems to play a crucial role in potential divergences.

Materials and methods

With this in mind, we aimed to decipher the molecular mechanisms underlying early vascular aging on SAMP8 mice, analyzing the aorta of 10 months-old animals by means of in-depth proteomic analysis, considering sex-specific differences. Validation of the results obtained were performed by western blot in an independent cohort of mice, as well as in human aortic smooth muscle cells (HASMC). Besides, an exhaustive lipoprotein and glycoprotein analysis was performed in blood plasma.

Key findings

Distinct proteomic, lipoprotein and glycoprotein profiles have been found in SAMP8 mice, according to sex. Male SAMP8 mice showed signs of increased atherogenesis susceptibility due to several sex-specific alterations: 1) increased number of VLDLs, as well as in their cholesterol and TG content; 2) upregulation of inflammatory glycoproteins in plasma; and 3) increased features of SASP and vascular calcification: upregulation of exocytic vesicular transport and downregulation of the protein Gas6. On the contrary, female mice showed a much better proteomic and lipoprotein profile.

Significance

The results obtained suggest that male SAMP8 mice will be more susceptible to develop atherosclerosis under a HFD than female mice.
{"title":"Sex-specific molecular hallmarks point to increased atherogenesis susceptibility in male senescence-accelerated mice","authors":"Ainara González-Moro ,&nbsp;Estela Herranz ,&nbsp;Miriam Morales Rodríguez de Lope ,&nbsp;Ibone Rubio Sanchez-Pajares ,&nbsp;Jorge Sánchez-Ramírez ,&nbsp;Alan Rivera-Tenorio ,&nbsp;Licia Shamoon ,&nbsp;Carlos Félix Sánchez-Ferrer ,&nbsp;Concepción Peiró ,&nbsp;Fernando de la Cuesta","doi":"10.1016/j.lfs.2025.123529","DOIUrl":"10.1016/j.lfs.2025.123529","url":null,"abstract":"<div><h3>Aims</h3><div>The senescence-accelerated mouse (SAM) model has been extensively used to study neurological alterations associated with aging. The SAM model has also proved to be useful in the study of vascular aging, but there is still work to be done to better define its utility as a model of atherosclerosis, since contradictory data have been published and sex seems to play a crucial role in potential divergences.</div></div><div><h3>Materials and methods</h3><div>With this in mind, we aimed to decipher the molecular mechanisms underlying early vascular aging on SAMP8 mice, analyzing the aorta of 10 months-old animals by means of in-depth proteomic analysis, considering sex-specific differences. Validation of the results obtained were performed by western blot in an independent cohort of mice, as well as in human aortic smooth muscle cells (HASMC). Besides, an exhaustive lipoprotein and glycoprotein analysis was performed in blood plasma.</div></div><div><h3>Key findings</h3><div>Distinct proteomic, lipoprotein and glycoprotein profiles have been found in SAMP8 mice, according to sex. Male SAMP8 mice showed signs of increased atherogenesis susceptibility due to several sex-specific alterations: 1) increased number of VLDLs, as well as in their cholesterol and TG content; 2) upregulation of inflammatory glycoproteins in plasma; and 3) increased features of SASP and vascular calcification: upregulation of exocytic vesicular transport and downregulation of the protein Gas6. On the contrary, female mice showed a much better proteomic and lipoprotein profile.</div></div><div><h3>Significance</h3><div>The results obtained suggest that male SAMP8 mice will be more susceptible to develop atherosclerosis under a HFD than female mice.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123529"},"PeriodicalIF":5.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552152","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
Advancements in the study of short-chain fatty acids and their therapeutic effects on atherosclerosis
IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-04 DOI: 10.1016/j.lfs.2025.123528
Yongsen Wang , Wei Dou , Xin Qian , Hao Chen , Yi Zhang , Liu Yang , Ya Wu , Xiongfei Xu
Atherosclerosis (AS) remains a leading cause of cardiovascular disease and mortality globally. This chronic condition is characterized by inflammation, lipid accumulation, and the deposition of cellular components within arterial walls. Emerging evidence has highlighted the multifaceted therapeutic potential of short-chain fatty acids (SCFAs) in mitigating AS progression. SCFAs have demonstrated anti-inflammatory properties and the ability to regulate immune responses, metabolic pathways, vascular integrity, and intestinal barrier function in animal models of AS. Consequently, SCFAs have garnered significant attention as a promising approach for the prevention and treatment of AS. However, further clinical trials and studies are necessary to fully elucidate the underlying mechanisms and effects of SCFAs. Additionally, different types of SCFAs may exert distinct impacts, necessitating more in-depth investigation into their specific roles and mechanisms. This review provides an overview of the diverse cellular mechanisms contributing to AS formation, as well as a discussion of the significance of SCFAs in AS pathogenesis and their multifaceted therapeutic potential. Nonetheless, additional research is warranted to comprehensively understand and harness the potential of various SCFAs in the context of AS.
{"title":"Advancements in the study of short-chain fatty acids and their therapeutic effects on atherosclerosis","authors":"Yongsen Wang ,&nbsp;Wei Dou ,&nbsp;Xin Qian ,&nbsp;Hao Chen ,&nbsp;Yi Zhang ,&nbsp;Liu Yang ,&nbsp;Ya Wu ,&nbsp;Xiongfei Xu","doi":"10.1016/j.lfs.2025.123528","DOIUrl":"10.1016/j.lfs.2025.123528","url":null,"abstract":"<div><div>Atherosclerosis (AS) remains a leading cause of cardiovascular disease and mortality globally. This chronic condition is characterized by inflammation, lipid accumulation, and the deposition of cellular components within arterial walls. Emerging evidence has highlighted the multifaceted therapeutic potential of short-chain fatty acids (SCFAs) in mitigating AS progression. SCFAs have demonstrated anti-inflammatory properties and the ability to regulate immune responses, metabolic pathways, vascular integrity, and intestinal barrier function in animal models of AS. Consequently, SCFAs have garnered significant attention as a promising approach for the prevention and treatment of AS. However, further clinical trials and studies are necessary to fully elucidate the underlying mechanisms and effects of SCFAs. Additionally, different types of SCFAs may exert distinct impacts, necessitating more in-depth investigation into their specific roles and mechanisms. This review provides an overview of the diverse cellular mechanisms contributing to AS formation, as well as a discussion of the significance of SCFAs in AS pathogenesis and their multifaceted therapeutic potential. Nonetheless, additional research is warranted to comprehensively understand and harness the potential of various SCFAs in the context of AS.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123528"},"PeriodicalIF":5.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552153","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
Muscarinic receptors at the auditory thalamocortical circuits and relevance to hearing
IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-03 DOI: 10.1016/j.lfs.2025.123522
Shivani Sharma , Avinash Wadkar , Srinivasa Prasad Kommajosyula
The auditory thalamus and cortex are the critical structures in the auditory hierarchy, owing to their crucial role in plasticity, auditory object formation, speech understanding, and spatiotemporal integration. Acetylcholine, a key neuromodulator, alters the abovementioned processes by orchestrating its effects with other neurotransmitters and its high-affinity receptor, the muscarinic receptor. This manuscript extensively covers the localization and function of different muscarinic receptors in the auditory thalamocortical system. Gaps in research of muscarinic localization and function are identified in hearing function. Also, a scarcity of studies examining muscarinic structure and function with tinnitus and hearing loss (age-related/noise-induced) is presented. Central changes in neurotransmitter receptors and auditory coding occur due to maladaptive plasticity in hearing loss and tinnitus and alter auditory object formation and spatiotemporal discrimination behaviors. Addressing these gaps are key to developing therapeutic strategies for hearing loss and tinnitus, apart from rectifying cochlear insult that led to hearing loss/tinnitus. Focusing on the muscarinic receptors is important owing to their abundance and demonstrated functional role in the auditory thalamocortical circuits and cortical development in mutant mice. In conclusion, this review emphasizes the need to answer questions on the localization and function of muscarinic receptors.
{"title":"Muscarinic receptors at the auditory thalamocortical circuits and relevance to hearing","authors":"Shivani Sharma ,&nbsp;Avinash Wadkar ,&nbsp;Srinivasa Prasad Kommajosyula","doi":"10.1016/j.lfs.2025.123522","DOIUrl":"10.1016/j.lfs.2025.123522","url":null,"abstract":"<div><div>The auditory thalamus and cortex are the critical structures in the auditory hierarchy, owing to their crucial role in plasticity, auditory object formation, speech understanding, and spatiotemporal integration. Acetylcholine, a key neuromodulator, alters the abovementioned processes by orchestrating its effects with other neurotransmitters and its high-affinity receptor, the muscarinic receptor. This manuscript extensively covers the localization and function of different muscarinic receptors in the auditory thalamocortical system. Gaps in research of muscarinic localization and function are identified in hearing function. Also, a scarcity of studies examining muscarinic structure and function with tinnitus and hearing loss (age-related/noise-induced) is presented. Central changes in neurotransmitter receptors and auditory coding occur due to maladaptive plasticity in hearing loss and tinnitus and alter auditory object formation and spatiotemporal discrimination behaviors. Addressing these gaps are key to developing therapeutic strategies for hearing loss and tinnitus, apart from rectifying cochlear insult that led to hearing loss/tinnitus. Focusing on the muscarinic receptors is important owing to their abundance and demonstrated functional role in the auditory thalamocortical circuits and cortical development in mutant mice. In conclusion, this review emphasizes the need to answer questions on the localization and function of muscarinic receptors.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123522"},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562196","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
KMT2D: A key emerging epigenetic regulator in head and neck diseases and tumors
IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-03 DOI: 10.1016/j.lfs.2025.123523
Kexin Wang , Fang Zhan , Xiaochen Yang , Mengyu Jiao , Peiyan Wang , Hui Zhang , Wei Shang , Jing Deng , Lin Wang
Histone modifications are critical determinants of chromatin accessibility and gene expression, both of which are intrinsically linked to human development and disease. Lysine methyltransferase 2D (KMT2D), a prominent member of the H3K4 methyltransferase family, is ubiquitously expressed across human tissues. Recent studies have found that it can regulate gene expression and signal pathway opening and closing in more than one way, playing an important role in cell proliferation and cell cycle homeostasis. Although previous studies have identified KMT2D as a potentially pivotal factor in the development and pathology of head and neck tissues, the regulatory networks associated with KMT2D in various complex head and neck diseases remain incompletely elucidated. This review seeks to consolidate recent findings on KMT2D's involvement in head and neck diseases, thereby laying the groundwork for future research into its mechanistic role in disease progression. A deeper understanding of KMT2D's functions and regulatory mechanisms is essential for advancing our comprehension of histone modifications and for the development of diagnostic tools and targeted therapeutic strategies for head and neck diseases.
{"title":"KMT2D: A key emerging epigenetic regulator in head and neck diseases and tumors","authors":"Kexin Wang ,&nbsp;Fang Zhan ,&nbsp;Xiaochen Yang ,&nbsp;Mengyu Jiao ,&nbsp;Peiyan Wang ,&nbsp;Hui Zhang ,&nbsp;Wei Shang ,&nbsp;Jing Deng ,&nbsp;Lin Wang","doi":"10.1016/j.lfs.2025.123523","DOIUrl":"10.1016/j.lfs.2025.123523","url":null,"abstract":"<div><div>Histone modifications are critical determinants of chromatin accessibility and gene expression, both of which are intrinsically linked to human development and disease. Lysine methyltransferase 2D (KMT2D), a prominent member of the H3K4 methyltransferase family, is ubiquitously expressed across human tissues. Recent studies have found that it can regulate gene expression and signal pathway opening and closing in more than one way, playing an important role in cell proliferation and cell cycle homeostasis. Although previous studies have identified KMT2D as a potentially pivotal factor in the development and pathology of head and neck tissues, the regulatory networks associated with KMT2D in various complex head and neck diseases remain incompletely elucidated. This review seeks to consolidate recent findings on KMT2D's involvement in head and neck diseases, thereby laying the groundwork for future research into its mechanistic role in disease progression. A deeper understanding of KMT2D's functions and regulatory mechanisms is essential for advancing our comprehension of histone modifications and for the development of diagnostic tools and targeted therapeutic strategies for head and neck diseases.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"369 ","pages":"Article 123523"},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566589","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
SNORD9 promotes ovarian cancer tumorigenesis via METTL3/IGF2BP2-mediated NFYA m6A modification and is a potential target for antisense oligonucleotide therapy
IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-03 DOI: 10.1016/j.lfs.2025.123527
Shuo Chen , Jing-Tao Wen , Song Zhang , Jie-Lin Wang , Jing Yuan , Hai-Juan Bao , Xi Chen , Yang Zhao
C/D box small nucleolar noncoding RNAs (snoRNAs) are known to bind and induce 2’-O-ribose methylation of RNAs, participate in cancer tumorigenesis and development. However, their involvement in regulating m6A modification remains unreported. Analysis of the TCGA database revealed that SNORD9 was an unfavorable prognostic factor for ovarian cancer. Besides, SNORD9 was elevated in ovarian cancer. The overexpression of SNORD9 induced ovarian cancer cell proliferation and migration in vitro and induce tumorigenicity in vivo, increased the m6A modification level by binding to m6A-methyltransferase METTL3 to affect NFYA m6A modification; besides, m6A-reader IGF2BP2 was 2’-O-methylated by SNORD9, thereby affect NFYA mRNA stability, upregulate NFYA and its downstream proteins CCND1, CDK4 and VEGFA, promote ovarian cancer tumorigenesis. ASO-mediated silencing of SNORD9 suppressed tumorigenicity both in vitro and in vivo, and effectively inhibited the growth of patient-derived organoids of ovarian cancer (OC-PDO). In conclusions, we demonstrated for the first time that SNORD9 induces NFYA m6A methylation by binding to m6A methylase METTL3; modifying IGF2BP2 mRNA by 2’-O-methylation and improve NFYA mRNA stability, thus promote the tumorigenesis of ovarian cancer. Targeting ASO to SNORD9 may have efficacy in the treatment of ovarian cancer.
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引用次数: 0
The interplay between COVID-19 and heart disease: Unravelling a complex connection COVID-19 与心脏病之间的相互作用:解开复杂的联系
IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-03 DOI: 10.1016/j.lfs.2025.123524
G.D. Duerr , M. Hamiko , J. Beer , J. Nattermann , M. Schafhaus , S.A.E. Held , J.C. Schewe , M. Wittmann , C. Kurts , S. Zimmer , M. Velten , A. Heine
The intersection of coronavirus (COVID-19) and heart disease has emerged as a critical nexus in the landscape of global health. Individuals with heart disease face elevated risks when infected with Severe Acute Respiratory-Syndrome Coronavirus-type-2 (SARS-CoV-2) leading to COVID-19. The virus can directly affect the heart, resulting in myocarditis, arrhythmias, and heart failure, even in individuals without prior medical cardiac history. Therefore, tools identifying patients with cardiac infestation and predicting disease severity are of utmost importance. This study's unbiased stratification of clinical and immunological parameters of 134 SARS-CoV-2 positive patients revealed clusters of course-severity within the established WHO ordinal severity-scale leading to its summary (SWOSS) into three categories, A-C. PE and SWOSS-C were significantly associated with reduced survival of COVID-19 patients. The previously introduced CD8/Treg/monocyte-ratio which hints at a dysfunctional antiviral immunity associated with poor prognosis could be verified in this larger study population. However, the number of circulating CD14 + HLA-DR+ monocytes represented the most significant predictor for myocardial damage indicated by PE. We used all available data for an unbiased examination of associations and predictions by machine learning algorithms: Predictive markers for PE can be obtained in clinic and may serve as prognostic features. Among numerous parameters, C-reactive protein (CRP) was the most important in determining the presence of PE and SWOSS-category. Prediction of survival was most relevantly influenced by SWOSS-category underlining the benefit of this condensed classification for clinical practice. All AI-revealed prognostic features serve as promising starting-point to gain further understanding of the interplay between COVID-19 and heart disease.
{"title":"The interplay between COVID-19 and heart disease: Unravelling a complex connection","authors":"G.D. Duerr ,&nbsp;M. Hamiko ,&nbsp;J. Beer ,&nbsp;J. Nattermann ,&nbsp;M. Schafhaus ,&nbsp;S.A.E. Held ,&nbsp;J.C. Schewe ,&nbsp;M. Wittmann ,&nbsp;C. Kurts ,&nbsp;S. Zimmer ,&nbsp;M. Velten ,&nbsp;A. Heine","doi":"10.1016/j.lfs.2025.123524","DOIUrl":"10.1016/j.lfs.2025.123524","url":null,"abstract":"<div><div>The intersection of coronavirus (COVID-19) and heart disease has emerged as a critical nexus in the landscape of global health. Individuals with heart disease face elevated risks when infected with Severe Acute Respiratory-Syndrome Coronavirus-type-2 (SARS-CoV-2) leading to COVID-19. The virus can directly affect the heart, resulting in myocarditis, arrhythmias, and heart failure, even in individuals without prior medical cardiac history. Therefore, tools identifying patients with cardiac infestation and predicting disease severity are of utmost importance. This study's unbiased stratification of clinical and immunological parameters of 134 SARS-CoV-2 positive patients revealed clusters of course-severity within the established WHO ordinal severity-scale leading to its summary (SWOSS) into three categories, A-C. PE and SWOSS-C were significantly associated with reduced survival of COVID-19 patients. The previously introduced CD8/Treg/monocyte-ratio which hints at a dysfunctional antiviral immunity associated with poor prognosis could be verified in this larger study population. However, the number of circulating CD14 + HLA-DR+ monocytes represented the most significant predictor for myocardial damage indicated by PE. We used all available data for an unbiased examination of associations and predictions by machine learning algorithms: Predictive markers for PE can be obtained in clinic and may serve as prognostic features. Among numerous parameters, C-reactive protein (CRP) was the most important in determining the presence of PE and SWOSS-category. Prediction of survival was most relevantly influenced by SWOSS-category underlining the benefit of this condensed classification for clinical practice. All AI-revealed prognostic features serve as promising starting-point to gain further understanding of the interplay between COVID-19 and heart disease.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"370 ","pages":"Article 123524"},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567032","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
Repurposing fenticonazole nitrate to restore colistin susceptibility in multidrug-resistant bacteria.
IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2025-03-02 DOI: 10.1016/j.lfs.2025.123511
Yueyue Ji, Chenchen Wang, Hongjiang Lai, Xiaodan Li, Zhaoran Zhang, Xiangru Wang, Huanchun Chen, Chen Tan

Aims: To explore the synergistic effect of the combination of FN and colistin on Escherichia coli and further elucidate the mechanism of this effect.

Main methods: Antimicrobial efficacy of the combination of fenticonazole nitrate and colistin against Escherichia coli in vitro using MIC assays, checkerboard assays, growth curves, and time-kill curves. Crystalline violet staining for detection of biofilm. Mechanisms analysis using fluorescence detection, SEM. Analysis of fenticonazole nitrate and MCR-1 interaction using molecular docking and ITC. Finally, the efficacy of combination therapy for MCR-1-positive Escherichia coli was assessed in vivo.

Key findings: Fenticonazole nitrate significantly enhanced the ability of colistin to combat mcr-1-positive E. coli 42 in vitro. The combination could effectively inhibit biofilm formation and eradicate established biofilms. Fenticonazole nitrate and colistin could increase the outer membrane permeability of E. coli 42, disrupting the membrane potential and impairing PMF synthesis, which in turn led to a reduction in ATP levels and cell death. Further, we found that the outer membrane barrier of Gram-negative bacteria and the innate resistance mechanism mediated by efflux pumps can impair the antimicrobial activity of fenticonazole nitrate. Finally, the combination demonstrated strong synergistic effects in a mouse model of infection with mcr-1-positive E. coli 42. Compared to the colistin only group, the survival rate increased by 40 %.

Conclusion: Fenticonazole nitrate is a promising antibiotic adjuvant against infections caused by MCR-1-positive multidrug-resistant pathogens.

{"title":"Repurposing fenticonazole nitrate to restore colistin susceptibility in multidrug-resistant bacteria.","authors":"Yueyue Ji, Chenchen Wang, Hongjiang Lai, Xiaodan Li, Zhaoran Zhang, Xiangru Wang, Huanchun Chen, Chen Tan","doi":"10.1016/j.lfs.2025.123511","DOIUrl":"https://doi.org/10.1016/j.lfs.2025.123511","url":null,"abstract":"<p><strong>Aims: </strong>To explore the synergistic effect of the combination of FN and colistin on Escherichia coli and further elucidate the mechanism of this effect.</p><p><strong>Main methods: </strong>Antimicrobial efficacy of the combination of fenticonazole nitrate and colistin against Escherichia coli in vitro using MIC assays, checkerboard assays, growth curves, and time-kill curves. Crystalline violet staining for detection of biofilm. Mechanisms analysis using fluorescence detection, SEM. Analysis of fenticonazole nitrate and MCR-1 interaction using molecular docking and ITC. Finally, the efficacy of combination therapy for MCR-1-positive Escherichia coli was assessed in vivo.</p><p><strong>Key findings: </strong>Fenticonazole nitrate significantly enhanced the ability of colistin to combat mcr-1-positive E. coli 42 in vitro. The combination could effectively inhibit biofilm formation and eradicate established biofilms. Fenticonazole nitrate and colistin could increase the outer membrane permeability of E. coli 42, disrupting the membrane potential and impairing PMF synthesis, which in turn led to a reduction in ATP levels and cell death. Further, we found that the outer membrane barrier of Gram-negative bacteria and the innate resistance mechanism mediated by efflux pumps can impair the antimicrobial activity of fenticonazole nitrate. Finally, the combination demonstrated strong synergistic effects in a mouse model of infection with mcr-1-positive E. coli 42. Compared to the colistin only group, the survival rate increased by 40 %.</p><p><strong>Conclusion: </strong>Fenticonazole nitrate is a promising antibiotic adjuvant against infections caused by MCR-1-positive multidrug-resistant pathogens.</p>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":" ","pages":"123511"},"PeriodicalIF":5.2,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557183","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
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