Life sciences最新文献

{"title":"Preservation solution protects isolated hair micrografts by inhibiting apoptosis of hair bulb","authors":"Junfei Huang ,&nbsp;Yi Zhou ,&nbsp;Haoyuan Li ,&nbsp;Lijuan Du ,&nbsp;Yangpeng Chen ,&nbsp;Zhiqi Hu ,&nbsp;Yong Miao","doi":"10.1016/j.lfs.2024.123292","DOIUrl":"10.1016/j.lfs.2024.123292","url":null,"abstract":"<div><h3>Aims</h3><div>To investigate the effectiveness of histidine-tryptophan-ketoglutarate (HTK) solution compared to Ringer's (RS) solution for preserving isolated hair follicles (HFs), focusing on structural integrity, cell viability, apoptosis prevention, and identifying the mechanisms of cell death during the preservation period.</div></div><div><h3>Materials and methods</h3><div>Isolated human HFs were preserved in HTK or RS solution for periods ranging from 2 to 12 h. Morphological changes were assessed using H&amp;E staining and transmission electron microscopy (TEM). Cell viability, proliferation, and apoptosis were evaluated through Ki-67/TUNEL staining, live/dead cell staining, and immunofluorescence. Quantitative real-time PCR and Western blot analysis were conducted to examine apoptosis-related gene expression, and qPCR array analyses were performed to determine the pathways involved in HF apoptosis.</div></div><div><h3>Key findings</h3><div>HTK solution preserved the structure of HFs more effectively than RS, maintaining collagen organization, preventing intercellular edema, and sustaining cell membrane integrity. HFs preserved in HTK solution exhibited significantly higher viability and proliferation rates, with a reduced rate of apoptosis compared to RS. Gene expression profiling indicated that HTK group inhibited the activation of the TNF signaling pathway and mitochondrial dysfunction, which were associated with apoptosis in RS-preserved HFs.</div></div><div><h3>Significance</h3><div>This study demonstrates that HTK solution is more effective than RS solution for HF preservation, particularly in extended storage settings required for large-scale hair transplantation. By inhibiting apoptosis pathways and preserving cellular integrity, HTK solution may enhance the success and outcomes of hair transplant procedures, providing insights into optimizing micrograft preservation and reducing ischemia-hypoxia injury in isolated HFs.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"361 ","pages":"Article 123292"},"PeriodicalIF":5.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792128","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":"The CB1 antagonist Rimonabant improves muscle regeneration and remodels the inflammatory and endocannabinoid profile upon injury in male mice","authors":"Sebastiaan Dalle ,&nbsp;Moniek Schouten ,&nbsp;Kaat Vanderbeke ,&nbsp;Evy Van Parys ,&nbsp;Monique Ramaekers ,&nbsp;Martine Thomis ,&nbsp;Domiziana Costamagna ,&nbsp;Katrien Koppo","doi":"10.1016/j.lfs.2024.123296","DOIUrl":"10.1016/j.lfs.2024.123296","url":null,"abstract":"<div><div>Skeletal muscle regeneration upon injury requires timely activation of inflammatory, myogenic, fibrotic, apoptotic and anabolic systems. Optimization of these features might improve the recovery process. Whereas recent data indicate that the endocannabinoid system, and more particularly cannabinoid receptor 1 (CB1) antagonism, is involved in the regulation of inflammatory, myogenic, fibrotic, apoptotic and anabolic pathways, it was never studied whether CB1 antagonism can improve muscle regeneration. The present study investigated the effect of the CB1 antagonist Rimonabant (10 mg/kg/d) on functional (5 days post-cardiotoxin injury; 5DPI) and molecular muscle responses (3DPI and 7DPI) in mice. Rimonabant prevented cardiotoxin-induced muscle strength loss 5DPI, increased myofiber growth (7DPI) and improved the muscle molecular profile 3DPI and 7DPI. In general, inflammation (e.g. p-p65NF-κB, CD80) and apoptosis (e.g. cleaved caspase-3, cleaved PARP) were downregulated by Rimonabant, whereas it upregulated the expression of Pax7 but other myogenic factors remained unaffected by rimonabant. In addition, Rimonabant restored the injury-induced (inflammatory) lipid profile to a large extent, including oxygenated fatty acids, unsaturated fatty acids and endocannabinoids such as 2-arachidonoyl glycerol and palmitoylethanolamide. Altogether, these data show that the endocannabinoid system might be a novel therapeutic target to improve muscle regeneration, which is relevant for age- and disease-related muscle degeneration.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"361 ","pages":"Article 123296"},"PeriodicalIF":5.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792129","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":"Trimethylamine N-oxide in cardiovascular disease: Pathophysiology and the potential role of statins","authors":"Fakhar Latif ,&nbsp;Ayesha Mubbashir ,&nbsp;Muhammad Sohaib Khan ,&nbsp;Zain Shaikh ,&nbsp;Aaima Memon ,&nbsp;Jenelle Alvares ,&nbsp;Ayesha Azhar ,&nbsp;Hritvik Jain ,&nbsp;Raheel Ahmed ,&nbsp;Sai Gautham Kanagala","doi":"10.1016/j.lfs.2024.123304","DOIUrl":"10.1016/j.lfs.2024.123304","url":null,"abstract":"<div><div>Cardiovascular diseases are one of the leading causes of mortality and morbidity worldwide, with the total number of cases increasing to 523 million in 2019. Despite the advent of new drugs, cardiovascular mortality has increased at an alarming rate of 53.7 % from 12.1 million deaths in 1990. Recently, the role of gut microbiome metabolites, such as Trimethylamine N-Oxide (TMAO), in the pathogenesis of cardiovascular disease (CVD) has attracted significant attention. The gut microbiome is critical in various physiological processes including metabolism, immune function, and inflammation. Elevated TMAO levels are associated with atherosclerosis, heart failure, arrhythmia, and atrial fibrillation. TMAO accelerates atherosclerosis by promoting vascular inflammation and reducing reverse cholesterol transport, which leads to lipid accumulation and vessel narrowing. Previous research has indicated that a Mediterranean diet rich in fiber and phytochemicals can reduce TMAO levels by limiting precursors and fostering beneficial gut microbiota. Prebiotics and probiotics also decrease TMAO, while drugs such as meldonium, aspirin, and antibiotics have shown promise. However, recent studies have demonstrated major potential for the use of statins in reducing TMAO levels. Statin therapy can significantly reduce TMAO levels independent of their cholesterol-lowering effects. This reduction may involve direct interactions with the gut microbiome, changes in cholesterol metabolism, and changes in bile acid composition. This review aims to comprehensively evaluate the therapeutic potential of statins in reducing TMAO levels to improve CV outcomes.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"361 ","pages":"Article 123304"},"PeriodicalIF":5.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822317","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":"Poststroke hyperglycemia dysregulates cap-dependent translation in neural cells","authors":"Pargol Tayefeh Ghahremani ,&nbsp;Soha BaniArdalan ,&nbsp;Parsa Alehossein ,&nbsp;Arshi Parveen ,&nbsp;Masoumeh Jorjani ,&nbsp;Candice M. Brown ,&nbsp;Werner J. Geldenhuys ,&nbsp;Jason D. Huber ,&nbsp;Tauheed Ishrat ,&nbsp;Sanaz Nasoohi","doi":"10.1016/j.lfs.2024.123336","DOIUrl":"10.1016/j.lfs.2024.123336","url":null,"abstract":"<div><h3>Aims</h3><div>Post stroke hyperglycemia has been shown to deter functional recovery. Earlier findings have indicated the cap-dependent translation regulator 4E-BP1 is detrimentally upregulated in hyperglycemic conditions. The present study aims to test the hypothesis that hyperglycemic ischemic reperfusion injury (I/R) affects normal protein translation poststroke.</div></div><div><h3>Methods</h3><div>Rat primary cortical neurons (PCNs) were exposed to oxygen glucose deprivation (OGD) followed by increasing glucose concentration (0, 5, 10, 25 mM) at reoxygenation. In vivo, adult rats were subjected to two hours transient distal middle cerebral artery occlusion (t-dMCAO) and hyperglycemic reperfusion.</div></div><div><h3>Key findings</h3><div>In PCN cultures, high glucose levels impaired normal neurite growth at 24 h I/R where it drastically depressed S6 ribosomal protein phosphorylation at serine 235/236 residues in 40S ribosomal subunit. This concurred with substantial hypoxia inducible factor-1α (HIF-1α) destabilization and sustained vascular endothelial growth factor (VEGF). Our immunoblotting findings indicated HIF-1α stabilization and AMPK activation rely on glucose availability. Incremental glucose concentrations above the physiological levels, induced a shift towards 4E-BP1, eIF-4E hypo-phosphorylated forms leading to reduced eIF-4E availability and efficacy, as the key to recruit the 40S ribosomal subunit to the 5′ end of mRNA. In vivo, immunostaining of t-dMCAO rat brains showed remarkable decrease in phosphorylated 4E-BP1 and particularly s6 ribosomal protein in the marginal cortical tissue of hyperglycemic compared to normoglycemic animals.</div></div><div><h3>Significance</h3><div>These findings suggest a remarkable association between hyperglycemic I/R injury with dysregulated cap-dependent translation poststroke. Further loss/gain of function experiment may elucidate the potential therapeutic targets in regulation of HIF-1α/translation in hyperglycemic I/R injury.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"361 ","pages":"Article 123336"},"PeriodicalIF":5.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886035","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":"Modulating intestinal viruses: A potential avenue for improving metabolic diseases with unresolved challenges","authors":"Xiaoxiao Cheng ,&nbsp;Jie Yang ,&nbsp;Zhijie Wang ,&nbsp;Kefan Zhou ,&nbsp;Xuejiao An ,&nbsp;Zhenjiang Zech Xu ,&nbsp;Hui Lu","doi":"10.1016/j.lfs.2024.123309","DOIUrl":"10.1016/j.lfs.2024.123309","url":null,"abstract":"<div><div>The gut microbiome affects the occurrence and development of metabolic diseases, with a significant amount of research focused on intestinal bacteria. As an important part of the gut microbiome, gut viruses were studied recently, particularly through fecal virome transplantation (FVT), revealing manipulating the gut virus could reverse overweight and glucose intolerance in mice. And human cohort studies found gut virome changed significantly in patients with metabolic disease. By summarizing those studies, we compared the research and analytical methods, as well as the similarities and differences in their results, and analyzed the reasons for these discrepancies. FVT provided potential value to improve metabolic diseases, but the mechanisms involved and the effect of FVT on humans should be investigated further. The potential methods of regulating intestinal virome composition and the possible mechanisms of intestinal virome changes affecting metabolic diseases were also discussed.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"361 ","pages":"Article 123309"},"PeriodicalIF":5.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824307","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":"The ameliorating effect of intermittent fasting on intestinal glucagon-like peptide 1 in rats fed a high-fat diet via the Farnesoid X receptor and the Melanocortin-4 receptor","authors":"Salma M. Eraky ,&nbsp;Nehal M. Ramadan ,&nbsp;Huda M. Atif ,&nbsp;Amr M. Mahmoud ,&nbsp;Nada F. Abo El-Magd","doi":"10.1016/j.lfs.2024.123327","DOIUrl":"10.1016/j.lfs.2024.123327","url":null,"abstract":"<div><div>Obesity and its associated intestinal inflammatory responses represent a significant global challenge. (IF) is a dietary intervention demonstrating various health benefits, including weight loss, enhanced metabolic health, and increased longevity. However, its effect on the intestinal inflammation induced by high-fat diet (HFD) is still not fully comprehended. Thirty-four male Sprague-Dawley rats were randomized into three groups: Control (fed standard chow diet for 24 weeks); the HFD group (fed HFD for 24 weeks); and the HFD + IF group (fed HFD for 12 weeks, followed by an alternate day regimen of fasting and HFD for 12 weeks). The results revealed that IF significantly reduced body weight, food intake, and blood glucose levels compared to the HFD group. Furthermore, rats undergoing the intermittent fasting regimen exhibited a significant reduction in resting time, along with increased durations of grooming and exploration when compared to those on HFD. IF significantly reduced HFD-induced intestinal oxidative stress by lowering malondialdehyde levels and substantially increasing intestinal total antioxidant capacity, consistent with histopathological findings of gastric and intestinal tissues. The investigation of the underlying mechanisms revealed that IF significantly increased the intestinal expression of Farnesoid X receptor (FXR), glucagon-like peptide 1 (GLP-1), and melanocortin-4 receptors (MC4R), with a significant decrease in gastrointestinal peroxisome proliferator-activated receptor-γ (PPAR-γ) compared to the HFD group. The findings indicate that IF can mitigate HFD-induced intestinal inflammation via the FXR/GLP-1/MC4R/ PPAR-γ pathway. This highlights the need for further research to elucidate these mechanisms.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"361 ","pages":"Article 123327"},"PeriodicalIF":5.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882405","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":"A novel chemical chaperone ameliorates osteoblast homeostasis and extracellular matrix in osteogenesis imperfecta","authors":"Nadia Garibaldi ,&nbsp;Roberta Besio ,&nbsp;Valentina Pirota ,&nbsp;Benedetta Albini ,&nbsp;Giorgio Colombo ,&nbsp;Pietro Galinetto ,&nbsp;Filippo Doria ,&nbsp;Alessandra Carriero ,&nbsp;Antonella Forlino","doi":"10.1016/j.lfs.2024.123320","DOIUrl":"10.1016/j.lfs.2024.123320","url":null,"abstract":"<div><h3>Aims</h3><div>Osteogenesis imperfecta (OI) is a collagen I-related heritable family of skeletal diseases associated to extreme bone fragility and deformity. Its classical forms are caused by dominant mutations in <em>COL1A1</em> and <em>COL1A2</em>, which encode for the protein α chains, and are characterized by impairment in collagen I structure, folding, and secretion. Mutant collagen I assembles in an altered extracellular matrix affecting mineralization and bone properties and partially accumulating inside the cells, leading to impaired trafficking and cellular stress. Recently, the chemical chaperone 4-phenylbutyrate (4-PBA) has been proposed as an innovative drug for OI based on its ability to restore intracellular homeostasis, stimulate secretion, and ameliorate collagen-producing cell functions, positively affecting bone properties. However, the limited half-life of the molecule represents a serious hurdle for its use.</div></div><div><h3>Materials and methods</h3><div>To efficiently target cellular stress as OI treatment, two new compounds were designed by molecular modelling based on the 4-PBA structure to increase its stability and its ability to implement protein secretion. The short butyryl fatty acid chain of 4-PBA was substituted with a nitro functional group or with a glycine, respectively. The latter, N-benzyl glycine (N-BG), showed the best docking score, less toxicity, and higher stability than 4-PBA.</div></div><div><h3>Key findings</h3><div>N-BG improved extracellular matrix quality and mineral content together with ameliorating OI cells' homeostasis by increasing ER-associated degradation pathway, reducing apoptosis, and stimulating protein secretion, thus facilitating intracellular clearance from accumulated misfolded proteins.</div></div><div><h3>Significance</h3><div>In conclusion, N-BG represents a novel potential available compound to target altered homeostasis in OI with the aim to ameliorate the disease phenotype.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"361 ","pages":"Article 123320"},"PeriodicalIF":5.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872357","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":"Altered GnRH neuron-glia networks close to interface of polycystic ovary syndrome: Molecular mechanism and clinical perspectives","authors":"Ruoxi Dai ,&nbsp;Yan Sun","doi":"10.1016/j.lfs.2024.123318","DOIUrl":"10.1016/j.lfs.2024.123318","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) has been noticed as a neuroendocrine syndrome manifested by reproductive hormone dysregulation involving increased luteinizing hormone (LH) pulse frequency and an increased LH to follicle-stimulating hormone ratio, yet theory is just beginning to be established. Neuroglia located in the arcuate nucleus and median eminence (ARC-ME) that are close to gonadotropin-releasing hormone (GnRH) axon terminals, comprise the blood-brain barrier and fenestrated vessels implying their putative roles in the modulation of the abnormal GnRH pulse in PCOS. This review outlines the disturbances of neuron-glia networks that underlie hypothetically the deregulation of GnRH-LH release and impaired sex hormone negative feedback in PCOS. We then discuss chronic and low-grade inflammatory status together with gut dysbiosis and how the detriments may intrude the hypothalamus by virtue of violating interfaces between the brain and periphery, which might contribute to the etiology of the impaired neural circuits in the ARC-ME to induce PCOS.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"361 ","pages":"Article 123318"},"PeriodicalIF":5.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886029","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":"Evaluating the efficacy of intra-articular polydioxanone (PDO) injections as a novel viscosupplement in osteoarthritis treatment","authors":"Linh Thi Thuy Le ,&nbsp;Pham Ngoc Chien ,&nbsp;Thuy-Tien Thi Trinh ,&nbsp;Ji-Won Seo ,&nbsp;Nguyen Ngan Giang ,&nbsp;Pham Thi Nga ,&nbsp;Xin Rui Zhang ,&nbsp;Yong Xun Jin ,&nbsp;Sun-Young Nam ,&nbsp;Chan-Yeong Heo","doi":"10.1016/j.lfs.2024.123303","DOIUrl":"10.1016/j.lfs.2024.123303","url":null,"abstract":"<div><h3>Aims</h3><div>Osteoarthritis (OA) is a chronic joint disorder marked by cartilage breakdown, bone alterations, and inflammation, leading to significant pain and disability. Current therapeutic strategies, ranging from lifestyle interventions to pharmacological and surgical treatments, offer limited efficacy and are often accompanied by side effects. This study investigates the potential of Polydioxanone (PDO), a biocompatible synthetic polymer, as a novel intra-articular (IA) viscosupplement in OA.</div></div><div><h3>Materials and methods</h3><div>A validated rabbit model of OA was employed to compare the therapeutic effects of IA injections of PDO against established viscosupplements like hyaluronic acid (HA) and Conjuran (CJR). Sixty rabbits with collagenase-induced OA were randomized into four groups, receiving respective treatments over 12 weeks. The effect of PDO was analyzed by histopathological examination, immunofluorescence staining (IF), immunoblotting, quantitative real-time polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA).</div></div><div><h3>Key findings</h3><div>The histopathological examination revealed substantial improvements in the PDO group's cartilage structure and matrix composition. qRT-PCR, IF staining, and Western Blot showed significant downregulation of matrix metalloproteinases (MMPs) and upregulation of type II collagen (COL II) and aggrecan (ACAN). ELISA results corroborated decreased inflammatory mediators- interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in the PDO-treatment group.</div></div><div><h3>Significance</h3><div>Preliminary results indicate that PDO may enhance cartilage regeneration and reduce inflammation, suggesting it is a viable and superior treatment option for OA. These findings merit further investigation to translate into clinical applications.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"361 ","pages":"Article 123303"},"PeriodicalIF":5.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813668","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":"Neuronal nitric oxide synthase activation by tadalafil protects neurological impairments in a zebrafish larva model of hyperammonemia","authors":"Poonam Dhiman,&nbsp;Rajneesh Kumar,&nbsp;Damanpreet Singh","doi":"10.1016/j.lfs.2024.123325","DOIUrl":"10.1016/j.lfs.2024.123325","url":null,"abstract":"<div><h3>Aims</h3><div>Hyperammonaemia (HA) is a metabolic disorder characterized by increased ammonia levels in the blood and is associated with severe neurological impairments. Some previous findings have shown the involvement of the nitric oxide pathway in HA-induced neurological impairments. The current study explored the impact of tadalafil on neurological impairments induced by HA in a zebrafish larval model due to its reported indirect interactions with the nitric oxide pathway.</div></div><div><h3>Material and methods</h3><div>HA was induced in zebrafish larvae by ammonium acetate exposure from 2 to 9 days post fertilization (<em>dpf</em>). Locomotor and cognitive functions were analysed following the treatment. The levels of gamma-aminobutyric acid (GABA), glutamate, and dopamine were measured in the larval head. The expression of genes associated with apoptosis (<em>baxa</em> and <em>bcl2a</em>), selected neurotransmitter receptors and <em>bdnf</em> was analysed. The protein levels of CREB and nNOS were also quantified.</div></div><div><h3>Key findings</h3><div>Tadalafil incubation reversed the HA-associated locomotor and cognitive impairments in larvae. The treatment modulated GABA, dopamine, and glutamate levels. An upregulation in the expression of <em>grin1a</em>, <em>gria2b</em>, <em>drd1b</em>, <em>drd2b</em>, <em>bdnf</em>, and <em>bcl2a</em>, and downregulation of <em>gabrz</em>, <em>gabrd</em>, <em>gabrg2</em> and <em>baxa</em> was observed following tadalafil treatment. The protein expression showed increased nNOS, p-CREB(Ser¹³³), and decreased p-nNOS(Ser⁸⁴⁷) levels in the larvae incubated with tadalafil.</div></div><div><h3>Significance</h3><div>The study concluded that tadalafil mitigates HA-induced neurological impairments by activating neuronal nitric oxide synthase. The study highlighted the possible application of tadalafil in the symptomatic management of neurological impairments in HA provided its efficacy and safety are further ensured in higher mammals.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"361 ","pages":"Article 123325"},"PeriodicalIF":5.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877488","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}