Advances in experimental medicine and biology最新文献

{"title":"The CRISPR-Cas9 System Is Used to Edit the Autoimmune Regulator Gene in Vitro and in Vivo.","authors":"Pedro P Tanaka, Cíntia J Monteiro, Max J Duarte, Ernna D Oliveira, Ana C Monteleone-Cassiano, Romário S Mascarenhas, Mayara C Vieira Machado, Adriana A Matos, Letícia A Brito, Alina O Oliveira, Thiago M Cunha, Eduardo A Donadi, Geraldo A Passos","doi":"10.1007/978-3-031-77921-3_10","DOIUrl":"10.1007/978-3-031-77921-3_10","url":null,"abstract":"<p><p>Although mutations in the AIRE gene in patients with autoimmune polyendocrine syndrome type 1 (APS-1) syndrome are associated with the onset of this autoimmune disease, much of what is known about its mechanisms has been obtained through studies with Aire mutant Mus musculus mouse model or with Aire mutant medullary thymic epithelial cells (mTEC) cultured in vitro. The in vivo murine model was soon established, and ten mutant strains are currently described. Most Aire mutant mice were obtained through homologous recombination, which generated Aire knockout (KO) animals. Nevertheless, long-term cultures of mTECs from APS-1 patients or Aire mutant mice are difficult to establish. The CRISPR-Cas9 system to edit Aire in a murine mTEC line in vitro and mouse embryo has been successfully used to overcome this. The ribonucleoprotein (RNP) complexes composed of the guide RNA (gRNA), the Cas9 enzyme, and single-stranded oligonucleotides (ssODN) were designed to target Aire exons 6 and 8 separately. The CRISPR-Cas9 makes it possible to produce NHEJ-derived indels or HDR-derived mutations. Efforts are being concentrated on using RNP complex rather than plasmid vectors, as RNP makes recurrent NHEJ-derived mutations among in vitro and in vivo editions. One recurrent mutation was described in the Aire exon 6 (del 3554G) and the other in the exon 8 (del 5676_5677TG), i.e., the exon 6 mutation was kept in an mTEC clone edited in vitro and in vivo in a mouse, and the exon 8 mutation was kept in several mTEC clones in vitro. In contrast, none of the mutations obtained with the nickase system (plasmid expression vector) were recurrent, indicating the participation of the RNP complex in recurring mutation, which offers advantages, as it does not involve recombinant plasmids and does not generate a genetically modified organism but rather a mutant animal or cell.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1471 ","pages":"269-283"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteostasis as a Sentry for Sperm Quality and Male Fertility.","authors":"Peter Sutovsky, Natalie Zelenkova, Pavla Postlerova, Michal Zigo","doi":"10.1007/978-3-031-82990-1_12","DOIUrl":"https://doi.org/10.1007/978-3-031-82990-1_12","url":null,"abstract":"<p><p>In the last two decades, a school of thought emerged that perceives male reproductive health, testicular function, and sperm output as a sentry for general, somatic health. Large-scale epidemiologic studies have already linked the reduced sperm count to increased risk of chronic somatic disease (e.g., cancer, cardiovascular, neurological and bone diseases), yet most of these studies have not taken full advantage of advanced andrological analysis. Altered proteostasis, i.e., the disbalance between protein synthesis and turnover, is a common denominator of many diseases, including but not limited to cancer and neurodegenerative diseases. This chapter introduces the concept of cellular proteostasis as a measure of sperm structural and functional integrity and an endpoint of varied impacts on spermiogenesis and sperm maturation, including heritability, general health, lifestyle, and occupational and environmental reprotoxic exposure. Special consideration is given to small molecule protein modifiers, sperm-binding seminal plasma proteins, zinc-interacting proteins, and redox proteins responsible for the maintenance of protein structure and the protection of spermatozoa from oxidative damage. While the main focus is on human male infertility, serious consideration is given to relevant animal models, and in particular to male food animals with extensive records of fertility from artificial insemination services. Altogether, the proteostatic biomarker discovery and validation studies set the stage for the integration of proteomics of sperm proteostasis with genomic and high throughput phenomic approaches to benefit both human and animal reproductive medicine.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1469 ","pages":"273-303"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain-Body Communication in Glucose Metabolism.","authors":"Astrid A S van Irsen, Andries Kalsbeek, Susanne E la Fleur","doi":"10.1007/978-3-031-89525-8_3","DOIUrl":"https://doi.org/10.1007/978-3-031-89525-8_3","url":null,"abstract":"<p><p>Glucose is an essential fuel for the brain, and its concentration must be maintained within strict boundaries for optimal fitness. Maintaining glucose homeostasis involves a balance between glucose uptake and output, as well as the management of daily rhythms in glucose concentrations. This chapter explores the roles of various brain regions in glucose homeostasis and their connections through the sympathetic and parasympathetic nervous systems to peripheral organs such as the pancreas and liver. Key hypothalamic nuclei, including the arcuate nucleus and the ventromedial hypothalamus, are well established in their roles in glucose regulation. Additionally, cortico-limbic areas, such as the nucleus accumbens and amygdala, contribute to the modulation of glucose metabolism. These brain regions communicate with the pancreas and liver via autonomic pathways, influencing insulin secretion, hepatic glucose production, and overall metabolic balance. By examining the neural circuits and mechanisms involved, this chapter aims to provide a comprehensive understanding of how brain-body interactions maintain glucose homeostasis and their implications for metabolic health.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1477 ","pages":"63-81"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genes as Genome Stabilizers in Pluripotent Stem Cells.","authors":"Asmita Karmakar, Allan Blessing Harison Raj Augustine, Rajkumar P Thummer","doi":"10.1007/5584_2025_853","DOIUrl":"10.1007/5584_2025_853","url":null,"abstract":"<p><p>Pluripotent stem cells, comprising embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are characterized by their self-renewal capacity and the ability to differentiate into cells of all three germ layers of an adult animal. Out of the two, iPSCs are generated through the reprogramming of somatic cells by inducing a pluripotency-specific transcriptional program. This process requires a resetting of the somatic cell genome to a pluripotent cell-specific genome, resulting in cellular stress at genomic, epigenetic, and transcriptional levels. Notably, in contrast to the predominant compact and inactive organization of chromatin in somatic cells, the chromatin in ESCs and iPSCs is open. Furthermore, maintaining a pluripotent state needs a plethora of changes in the genetic landscape of the cells. Here, we attempt to elucidate how certain genes safeguard genomic stability in ESCs and iPSCs, aiding in the complex cellular mechanisms that regulate self-renewal, pluripotency, and somatic reprogramming.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":" ","pages":"21-47"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antifungal Innate Immunity.","authors":"Sarah Sze Wah Wong, Sarah Dellière, Mathieu Lepas, Vishukumar Aimanianda","doi":"10.1007/978-3-031-85340-1_9","DOIUrl":"https://doi.org/10.1007/978-3-031-85340-1_9","url":null,"abstract":"<p><p>Despite being common inhabitants of human barrier surfaces (skin, oral cavity, gut, lungs, vagina), diseases caused by fungi are rare owing to their surveillance by and sentinel function of human innate immune system. Whereas a compromised or suppressed immunity facilitates the establishment of fungal infections, the consequence of which ranges from superficial infections affecting life quality to life-threatening invasive fungal diseases. Over the last few decades, the number of people at risk for invasive fungal infections has increased due to immunosuppressive medical interventions. Also, there is an alarming increase in incidence of antifungal drug resistance, which demands alternative antifungal strategies. In vivo experimental studies have indicated that immunotherapies could be promising to combat fungal pathogens. Nevertheless, development of an effective clinical immunotherapy requires in-depth knowledge on pathobiology of fungi and the consequent host responses. Here is an overview of the defense mechanisms exerted by the human innate immune system against fungal pathogens, counteracting virulence mechanisms associated with these fungal pathogens and the innate immune system-based antifungal therapeutic strategies developed so far.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1476 ","pages":"225-250"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Complement System.","authors":"Margot Revel, Alessandra Zarantonello, Lubka T Roumenina","doi":"10.1007/978-3-031-85340-1_7","DOIUrl":"https://doi.org/10.1007/978-3-031-85340-1_7","url":null,"abstract":"<p><p>The complement system is an ancient component of innate immunity, playing a crucial part in the defense against pathogens and maintaining homeostasis. Complement assures the opsonization of pathogens, facilitating phagocytosis. It generates potent mediators of inflammation recruiting and activating immune and stromal cells at the site of infection. Finally, it contributes to the direct killing of gram-negative bacteria by membrane perforation. The relevance of the complement system as an innate immune defense is evident from the increased susceptibility to infections in individuals with a deficiency of its components. As with every defensive mechanism, complement can turn against the host when dysregulated, causing severe organ damage. Therefore, understanding complement function is critical to understand human and animal homeostasis and defense against infection.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1476 ","pages":"147-198"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The C-Type Lectin Receptors.","authors":"Kasturi Ganguly, Taruna Madan","doi":"10.1007/978-3-031-85340-1_5","DOIUrl":"https://doi.org/10.1007/978-3-031-85340-1_5","url":null,"abstract":"<p><p>C-type lectins (CTLs) form a broad and diverse protein superfamily with the ability to identify a wide array of ligands with their characteristic C-type lectin-like domains (CTLDs), thus governing a broad spectrum of physiological functions. CTLD-containing proteins (CTLDcps) are now classified into 17 groups based on their phylogeny and overall domain organization. While much research has centered on the role of C-type lectins in innate and adaptive antimicrobial immune responses, their significance extends further. They are increasingly acknowledged for their significant involvement in cancer biology. It has been evident that the CLR signaling can wield dual effects akin to a double-edged sword across various microbial or oncogenic scenarios. Consequently, the therapeutic potential of both agonists and antagonists targeting CLR signaling is now surfacing as innovative strategies. The growing body of evidence highlighting the indispensable role of C-type lectin receptors (CTLR) in numerous biological processes underscores the necessity for a deeper comprehension of their functional capabilities in both immune defense and disease contexts.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1476 ","pages":"107-119"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnosis and Treatment of HFE^C282Y-Linked Hemochromatosis.","authors":"Paul C Adams","doi":"10.1007/978-3-031-92033-2_9","DOIUrl":"https://doi.org/10.1007/978-3-031-92033-2_9","url":null,"abstract":"<p><p>Genetic variants for hemochromatosis have been identified in human fossils that are over 4000 years old in Northern Ireland. Iron overload can lead to life-threatening complications, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. In this review, the emphasis is on developments in the diagnosis and treatment of C282Y-linked hemochromatosis. There is a need for earlier diagnosis leading to earlier treatment to prevent morbidity and mortality.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1480 ","pages":"119-130"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary Iron Absorption: Biochemical and Nutritional Aspects.","authors":"David M Frazer, Gregory J Anderson, James F Collins","doi":"10.1007/978-3-031-92033-2_6","DOIUrl":"https://doi.org/10.1007/978-3-031-92033-2_6","url":null,"abstract":"<p><p>Iron is an essential nutrient for most organisms; however, it can also be toxic when present in excess. For this reason, life has evolved complex pathways to tightly control the amount of iron contained within body tissues. Unlike most other nutrients, mammals do not have a regulated excretory mechanism for iron and, therefore, must regulate body iron levels at the point of dietary iron absorption in the proximal small intestine. In this chapter, we will describe the molecules and pathways involved in this important process, including our current understanding of the mechanisms of both heme and non-heme iron absorption. The regulation of this process will also be discussed, with particular emphasis on local and systemic factors that affect how much iron is absorbed from the diet. We also highlight areas where our knowledge is incomplete and where more research is required to fully understand the molecular mechanisms responsible for this essential process.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1480 ","pages":"75-87"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepcidin and Tissue-Specific Iron Regulatory Networks.","authors":"Samira Lakhal-Littleton, Carole Peyssonnaux","doi":"10.1007/978-3-031-92033-2_7","DOIUrl":"https://doi.org/10.1007/978-3-031-92033-2_7","url":null,"abstract":"<p><p>Hepcidin is primarily secreted by the liver and functions as an endocrine hormone. However, a growing number of studies show that hepcidin can also be produced locally by other cells and organs, where it acts in an autocrine/paracrine manner to mediate important iron-dependent pathways. These pathways can operate under normal homeostatic conditions or become relevant in pathophysiological conditions (inflammation, infection, cancer, liver disease, myocardial infarction, etc.). This chapter will delve into the local roles of hepcidin, highlighting its unconventional functions in barrier maintenance, host defense, growth, tissue housekeeping, and injury repair.</p>","PeriodicalId":7270,"journal":{"name":"Advances in experimental medicine and biology","volume":"1480 ","pages":"89-102"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}