Sub-cellular biochemistry最新文献

{"title":"Energy-Dependent Urea Transports in Mammals and their Functional Consequences.","authors":"Lise Bankir, Gilles Crambert","doi":"10.1007/978-981-96-6898-4_10","DOIUrl":"https://doi.org/10.1007/978-981-96-6898-4_10","url":null,"abstract":"<p><p>In lower organisms (bacteria, fungi, yeast), some species that express the enzyme urease take up urea from the surrounding medium as a source of nitrogen, by energy-dependent urea transporters. In contrast, in mammals, urea is an endproduct of nitrogen metabolism, and the energy-dependent urea transports are associated with either the need to excrete nitrogen efficiently, in the case of excess nitrogen intake, or the need to conserve nitrogen and re-use it, in the case of low nitrogen supply.Three different energy-dependent urea transports have been characterized functionally in the mammalian kidney. One responsible for urea secretion in the straight segment of the proximal tubule (proximal straight tubule, PST), another for urea reabsorption in the upper third of the inner medullary collecting duct (IMCD), and one in the very late portion of the IMCD. But intriguingly, up to now, none of the membrane transporters responsible for these transports has been characterized molecularly.This review describes these urea transports functionally and proposes a candidate transporter responsible for urea secretion in the PST. Based on the study of knockout mice, SLC6A18 has been characterized as a glycine transporter, but several previous observations suggest that it may also serve another function. SLC6A18 is very likely a urea/glycine, sodium-dependent antiport. These observations are described in detail.Energy-dependent urea transport is suspected to also take place in two other organs that express facilitated urea transporters; in the testis, urea secretion could initiate a flux of fluid in seminiferous tubules to ensure sperm transport into the lumen; in the bladder, urea secretion could reclaim urea that is at permanent risk of dissipation, due to the large urea concentration difference between urine and blood and the high expression of the facilitated transporter UT-B on the basal membrane of the urothelium.The energy-dependent secretion of urea in the PST has a number of consequences. (1) It allows a better efficiency of urea excretion and thus may prevent some toxicity of urea. (2) It provides a much better understanding of the urine concentrating mechanism. (3) It explains how urea may influence glomerular filtration rate, indirectly.</p>","PeriodicalId":21991,"journal":{"name":"Sub-cellular biochemistry","volume":"118 ","pages":"193-228"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein Structures of Urea Transporters.","authors":"Mengyao Xiong, Shenming Huang, Jinpeng Sun, Baoxue Yang","doi":"10.1007/978-981-96-6898-4_2","DOIUrl":"https://doi.org/10.1007/978-981-96-6898-4_2","url":null,"abstract":"<p><p>Urea transporters (UTs) facilitate the rapid transport of urea from the extracellular space to the intracellular space through a selective transport mechanism driven by urea concentration gradients. Advances in Cryo-electron microscopy and X-ray crystallography have enabled us to solve the homotrimer structures of UT-A and UT-B, which share a common feature comprising two homologous domains surrounding a continuous transmembrane pore, indicating that UTs transport urea via a channel-like mechanism. By analyzing the structures of ligand-protein complexes, results from molecular dynamics simulations, and functional data on urea analogues and small molecule permeation inhibitors, we can gain a deeper understanding of the conservation and specificity of the urea channel architecture, and clearly recognize how urea is transported by UTs and the mechanisms of small molecule inhibition. This will provide an important structural basis for drug design and development.</p>","PeriodicalId":21991,"journal":{"name":"Sub-cellular biochemistry","volume":"118 ","pages":"19-43"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urea Transport Mediated by Membrane Proteins of Non-urea-Transporters.","authors":"Minghui Wang, Weidong Wang, Chunling Li","doi":"10.1007/978-981-96-6898-4_9","DOIUrl":"https://doi.org/10.1007/978-981-96-6898-4_9","url":null,"abstract":"<p><p>Urea is generated by the urea cycle enzymes, which are mainly in the liver but are also ubiquitously expressed at low levels in other tissues of mammals. Urea is then eliminated through fluids, especially urine. Urea also serves as a readily available nitrogen source for the growth of many organisms, including plants and bacteria. Urea transporters are recognized as the primary membrane proteins responsible for urea transport in organisms. However, an increasing body of studies has identified additional membrane proteins in animals, plants, and microbes that exhibit urea transport capabilities or potential. The contribution of these membrane proteins to the maintenance of physiological homeostasis and their interactions with urea transporters remains to be fully elucidated. In this chapter, transport, characteristics, regulation, as well as cellular localization of non-urea-transporter membrane proteins facilitating urea transport, are reviewed to highlight their roles in physiology and pathophysiology. Specifically, the mammalian aquaporins AQP3, AQP6, AQP7, AQP8, AQP9, AQP10, and a sodium-glucose transporter (SGLT1) in the kidney are permeable to urea. In plants, tonoplast intrinsic proteins (TIPs), a member of aquaporin family, and the DUR3 orthologue, potentially play roles in low- and high-affinity urea transport, respectively. Two urea transporters pH-independent (Yut) and pH-dependent transporters (ureI) in bacteria are known to play roles in disease conditions.</p>","PeriodicalId":21991,"journal":{"name":"Sub-cellular biochemistry","volume":"118 ","pages":"167-191"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urea Transporters and Their Gene Mutations in Diseases.","authors":"Boyue Huang, Hongkai Wang, Jiaoyu Hou, Jianhua Ran","doi":"10.1007/978-981-96-6898-4_7","DOIUrl":"https://doi.org/10.1007/978-981-96-6898-4_7","url":null,"abstract":"<p><p>Urea transporters (UTs) UT-As (encoded by Slc14A2) and UT-B (encoded by Slc14A1), are important members of the solute carrier family. They are a group of membrane channel proteins that are selectively permeable to urea. Slc14A1 is considered the key gene determining the Kidd blood group system, and its variants can lead to the loss of Jk antigens, resulting in transfusion-related complications. Additionally, studies have shown that Slc14A1 is closely associated with cancer development and progression, with its expression level and promoter methylation status potentially serving as biomarkers for cancer progression and prognosis. Recent research suggests that UT-B functional deficiency may cause neurodegenerative diseases by accumulating urea in the brain, thereby affecting neuronal function and viability. Mutations of Slc14A2 are linked to hypertension and metabolic syndrome, due to its essential role in maintaining urea homeostasis. This chapter aims to introduce the clinical significance of UT-B and UT-A and highlight their potential roles as diagnostic and therapeutic targets.</p>","PeriodicalId":21991,"journal":{"name":"Sub-cellular biochemistry","volume":"118 ","pages":"127-140"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetics in Neurodegenerative Diseases.","authors":"Brigitte van Zundert, Martin Montecino","doi":"10.1007/978-3-031-75980-2_3","DOIUrl":"10.1007/978-3-031-75980-2_3","url":null,"abstract":"<p><p>Healthy brain functioning requires a continuous fine-tuning of gene expression, involving changes in the epigenetic landscape and 3D chromatin organization. Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are three multifactorial neurodegenerative diseases (NDDs) that are partially explained by genetics (gene mutations and genetic risk factors) and influenced by non-genetic factors (i.e., aging, lifestyle, and environmental conditions). Examining comprehensive studies of global and locus-specific (epi)genomic and transcriptomic alterations in human and mouse brain samples at the cell-type resolution has uncovered important phenomena associated with AD. First, DNA methylation and histone marks at promoters contribute to transcriptional dysregulation of genes that are directly implicated in AD pathogenesis (i.e., APP), neuroplasticity and cognition (i.e., PSD95), and microglial activation (i.e., TREM2). Second, the presence of AD genetic risk variants in cell-type-specific distal enhancers (i.e., BIN1 in microglia) alters transcription, presumably by disrupting associated enhancer-promoter interactions and chromatin looping. Third, epigenomic erosion is associated with widespread transcriptional disruption and cell identity loss. And fourth, aging, high cholesterol, air pollution, and pesticides have emerged as potential drivers of AD by inducing locus-specific and global epigenetic modifications that impact key AD-related pathways. Epigenetic studies in ALS/FTD also provide evidence that genetic and non-genetic factors alter gene expression profiles in neurons and astrocytes through aberrant epigenetic mechanisms. We additionally overview the recent development of potential new therapeutic strategies involving (epi)genetic editing and the use of small chromatin-modifying molecules (epidrugs).</p>","PeriodicalId":21991,"journal":{"name":"Sub-cellular biochemistry","volume":"108 ","pages":"73-109"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Promise of Epigenetic Editing for Treating Brain Disorders.","authors":"Luis A González Molina, Amalia M Dolga, Marianne G Rots, Federica Sarno","doi":"10.1007/978-3-031-75980-2_4","DOIUrl":"10.1007/978-3-031-75980-2_4","url":null,"abstract":"<p><p>Brain disorders, especially neurodegenerative diseases, affect millions of people worldwide. There is no causal treatment available; therefore, there is an unmet clinical need for finding therapeutic options for these diseases. Epigenetic research has resulted in identification of various genomic loci with differential disease-specific epigenetic modifications, mainly DNA methylation. These biomarkers, although not yet translated into clinically approved options, offer therapeutic targets as epigenetic modifications are reversible. Indeed, clinical trials are designed to inhibit epigenetic writers, erasers, or readers using epigenetic drugs to interfere with epigenetic dysregulation in brain disorders. However, since such drugs elicit genome-wide effects and potentially cause toxicity, the recent developments in the field of epigenetic editing are gaining widespread attention. In this review, we provide examples of epigenetic biomarkers and epi-drugs, while describing efforts in the field of epigenetic editing, to eventually make a difference for the currently incurable brain disorders.</p>","PeriodicalId":21991,"journal":{"name":"Sub-cellular biochemistry","volume":"108 ","pages":"111-190"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue Distribution, Expression and Regulation of Urea Transporters.","authors":"Nannan Li, Janet D Klein, Jeff M Sands, Baoxue Yang","doi":"10.1007/978-981-96-6898-4_3","DOIUrl":"https://doi.org/10.1007/978-981-96-6898-4_3","url":null,"abstract":"<p><p>UT-A and UT-B families of urea transporters consist of multiple isoforms with the majority of the isoforms located in the kidney. UT-B (Slc14A1) in kidney is primarily located in the descending vasa recta. The UT-A (Slc14A2) urea transporter family comprises six distinct isoforms, three of which are predominantly found in the kidney. Specifically, UT-A1 and UT-A3 are located in the inner medullary collecting duct (IMCD), while UT-A2 is situated in the thin descending limb. These transporters play a crucial role in the renal concentration of urine. The regulation of renal urea transporter activity involves acute modifications through phosphorylation and subsequent translocation to the plasma membrane. In response to stimulation by vasopressin or hypertonicity, UT-A1 and UT-A3 accumulate in the IMCD plasma membrane. Chronic regulation of IMCD urea transporters involves hormonal modulation of protein expression levels, such as adrenal steroids, low-protein diets, electrolyte abnormalities, aging or other pathologic conditions. This chapter provides a brief overview of the tissue distribution, expression of the urea transporter isoforms, locations in the kidney, and regulation of urea transporters.</p>","PeriodicalId":21991,"journal":{"name":"Sub-cellular biochemistry","volume":"118 ","pages":"45-62"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Remodeling the Epigenome Through Meditation: Effects on Brain, Body, and Well-being.","authors":"Sabrina Venditti","doi":"10.1007/978-3-031-75980-2_7","DOIUrl":"10.1007/978-3-031-75980-2_7","url":null,"abstract":"<p><p>Epigenetic mechanisms are key processes that constantly reshape genome activity carrying out physiological responses to environmental stimuli. Such mechanisms regulate gene activity without modifying the DNA sequence, providing real-time adaptation to changing environmental conditions. Both favorable and unfavorable lifestyles have been shown to influence body and brain by means of epigenetics, leaving marks on the genome that can either be rapidly reversed or persist in time and even be transmitted trans-generationally. Among virtuous habits, meditation seemingly represents a valuable way of activating inner resources to cope with adverse experiences. While unhealthy habits, stress, and traumatic early-life events may favor the onset of diseases linked to inflammation, neuroinflammation, and neuroendocrine dysregulation, the practice of mindfulness-based techniques was associated with the alleviation of many of the above symptoms, underlying the importance of lifestyles for health and well-being. Meditation influences brain and body systemwide, eliciting structural/morphological changes as well as modulating the levels of circulating factors and the expression of genes linked to the HPA axis and the immune and neuroimmune systems. The current chapter intends to give an overview of pioneering research showing how meditation can promote health through epigenetics, by reshaping the profiles of the three main epigenetic markers, namely DNA methylation, histone modifications, and non-coding RNAs.</p>","PeriodicalId":21991,"journal":{"name":"Sub-cellular biochemistry","volume":"108 ","pages":"231-260"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genes and Evolution of Urea Transporters.","authors":"Yi Ying, Bo Kan, Baoxue Yang, Jeff M Sands","doi":"10.1007/978-981-96-6898-4_1","DOIUrl":"https://doi.org/10.1007/978-981-96-6898-4_1","url":null,"abstract":"<p><p>Urea transporters (UTs) are a group of membrane channel proteins that specifically facilitate the permeation of urea, from bacteria to mammals, playing an essential role in urea reabsorption and water conservation. In mammals, there are two subfamilies of UT: the UT-A group originally isolated from the kidney inner medulla, and UT-B originally isolated from erythrocytes. The human UT-B gene (Slc14a1) arises from a single locus located on chromosome 18q12.1-q21.1, which is close to the UT-A gene (Slc14a2). The human Slc14a1 gene includes 11 exons, with the coding region extending from exon 4 to exon 11, and is approximately 30 kb in length. The rat Slc14a2 gene is very large, containing 24 exons, approximately 300 kb in length, and encodes 6 different isoforms. The Slc14a2 gene has two promoter elements: promoter I, located upstream of exon 1, drives the transcription of UT-A1, UT-A1b, UT-A3, UT-A3b, and UT-A4; promoter II, located within intron 12, drives the transcription of UT-A2 and UT-A2b. This chapter will summarize the evolution and genetic characteristics of UTs.</p>","PeriodicalId":21991,"journal":{"name":"Sub-cellular biochemistry","volume":"118 ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transport Characteristics of Urea Transporters.","authors":"Zhizhen Huang, Baoxue Yang","doi":"10.1007/978-981-96-6898-4_5","DOIUrl":"https://doi.org/10.1007/978-981-96-6898-4_5","url":null,"abstract":"<p><p>Rapid urea permeation mediated by urea transporters (UTs) is crucial for maintaining normal physiological processes in organisms. UTs not only facilitate urea transport but also water transport, further underscoring their role in maintaining fluid balance. Advances in structural biology have led to the elucidation of high-resolution three-dimensional structures of various UTs, offering critical insights into the molecular mechanisms underlying their efficiency in transporting urea and water. UT-B displays high permeability to urea analogs, which can competitively inhibit urea permeation by obstructing the channel. However, whether UT-A is capable of transporting urea analogs remains contentious. Additionally, further investigation is required to determine if UTs can facilitate ammonia transport. Urea permeability (P_urea) in erythrocytes differs between different mammals. Carnivores exhibit high P_urea. In contrast, herbivores show much lower P_urea. Erythrocyte P_urea in omnivores was intermediate. Rodents and lagomorphs have P_urea intermediate between carnivores and omnivores. This chapter provides information about the transporter characteristics of UTs.</p>","PeriodicalId":21991,"journal":{"name":"Sub-cellular biochemistry","volume":"118 ","pages":"87-104"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}