{"title":"Extracellular Vesicles from Adipose-Derived Mesenchymal Stem Cells Improve Ligament-Bone Integration After Anterior Cruciate Ligament Primary Repair in Rabbit.","authors":"Andre Yanuar, Hasrayati Agustina, Radiana Dhewayani Antarianto, Nucki Nursjamsi Hidajat, Andi Isra Mahyuddin, Ismail Hadisoebroto Dilogo, Nicolaas Cyrillus Budhiparama, Nur Atik","doi":"10.3390/biom15030396","DOIUrl":"10.3390/biom15030396","url":null,"abstract":"<p><strong>Backgrounds: </strong>In this research, we want to find out whether extracellular vesicles (EVs) from adipose-derived mesenchymal stem cells (MSCs) can improve ligament-bone integration after primary Anterior Cruciate Ligament (ACL) repair by performing immunological and biomechanical tests.</p><p><strong>Methods: </strong>All of the rabbits underwent ACL resection at the proximal attachment to the femur bone, and then were divided into four groups. We performed an ELISA examination from the tissue at the bone-ligament interface of iNOS, CD206, MMP-3, and TIMP-1 to evaluate their levels at the inflammatory stage at the end of the first week. Immunoexpression of type I and III collagen and failure load biomechanical tests were performed at the end of the sixth week.</p><p><strong>Result: </strong>The group that underwent ACL repair with EVs augmentation had significantly higher levels of CD206, significantly lower MMP-3 levels, and significantly higher TIMP-1 levels in the first week. The iNOS levels in the group that underwent ACL repair with EVs augmentation were significantly different compared to the control group that did not receive any. The number of type I collagen fibers and the failure load levels in the group that underwent ACL repair with EVs augmentation were significantly higher.</p><p><strong>Conclusions: </strong>EVs from adipose-derived MSCs can improve the outcome of primary ACL repair in rabbits by regulating the inflammatory process during the healing period.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiomoleculesPub Date : 2025-03-10DOI: 10.3390/biom15030394
Arzu Zeynep Karabay, Jaleh Barar, Yalda Hekmatshoar, Yalda Rahbar Saadat
{"title":"Multifaceted Therapeutic Potential of Plant-Derived Exosomes: Immunomodulation, Anticancer, Anti-Aging, Anti-Melanogenesis, Detoxification, and Drug Delivery.","authors":"Arzu Zeynep Karabay, Jaleh Barar, Yalda Hekmatshoar, Yalda Rahbar Saadat","doi":"10.3390/biom15030394","DOIUrl":"10.3390/biom15030394","url":null,"abstract":"<p><p>Most eukaryotic and prokaryotic cells have the potential to secrete a group of structures/membrane-bound organelles, collectively referred to as extracellular vesicles (EVs), which offer several advantages to producer/receiver cells. This review provides an overview of EVs from plant sources with emphasis on their health-promoting potential and possible use as therapeutic agents. This review highlights the essential biological effects of plant-derived extracellular vesicles, including immune modulation, anticancer activities, protection against chemical toxicity and pathogens, as well as anti-aging, anti-melanogenesis, and anti-arthritic effects, along with ongoing clinical studies. Evidence revealed that plant-derived EVs' contents exert their beneficial properties through regulating important signaling pathways by transferring miRNAs and other components. Taken all together, the data proposed that plant-derived EVs can be utilized as nutritional compounds and therapeutic agents, such as drug carriers. However, this emerging research area requires further in vitro/in vivo studies and clinical trials to determine the exact underlying mechanisms of EVs' positive health effects in treating various diseases.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Genetic Analysis and Predictive Modeling of COVID-19 Severity in a Hospital-Based Patient Cohort.","authors":"Iraide Alloza-Moral, Ane Aldekoa-Etxabe, Raquel Tulloch-Navarro, Ainhoa Fiat-Arriola, Carmen Mar, Eloisa Urrechaga, Cristina Ponga, Isabel Artiga-Folch, Naiara Garcia-Bediaga, Patricia Aspichueta, Cesar Martin, Aitor Zarandona-Garai, Silvia Pérez-Fernández, Eunate Arana-Arri, Juan-Carlos Triviño, Ane Uranga, Pedro-Pablo España, Koen Vandenbroeck-van-Caeckenbergh","doi":"10.3390/biom15030393","DOIUrl":"10.3390/biom15030393","url":null,"abstract":"<p><p>The COVID-19 pandemic has had a devastating impact, with more than 7 million deaths worldwide. Advanced age and comorbidities partially explain severe cases of the disease, but genetic factors also play a significant role. Genome-wide association studies (GWASs) have been instrumental in identifying loci associated with SARS-CoV-2 infection. Here, we report the results from a >820 K variant GWAS in a COVID-19 patient cohort from the hospitals associated with IIS Biobizkaia. We compared intensive care unit (ICU)-hospitalized patients with non-ICU-hospitalized patients. The GWAS was complemented with an integrated phenotype and genetic modeling analysis using HLA genotypes, a previously identified COVID-19 polygenic risk score (PRS) and clinical data. We identified four variants associated with COVID-19 severity with genome-wide significance (rs58027632 in KIF19; rs736962 in HTRA1; rs77927946 in DMBT1; and rs115020813 in LINC01283). In addition, we designed a multivariate predictive model including HLA, PRS and clinical data which displayed an area under the curve (AUC) value of 0.79. Our results combining human genetic information with clinical data may help to improve risk assessment for the development of a severe outcome of COVID-19.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiomoleculesPub Date : 2025-03-08DOI: 10.3390/biom15030391
Robin Moolan-Vadackumchery, Lan Zhang, Frank Stüber
{"title":"Evaluation of Lipid-Based Transfection in Primary Monocytes Within an Ex Vivo Whole-Blood Model.","authors":"Robin Moolan-Vadackumchery, Lan Zhang, Frank Stüber","doi":"10.3390/biom15030391","DOIUrl":"10.3390/biom15030391","url":null,"abstract":"<p><p>Transfection is a fundamental method in biomedical research to study intracellular molecular mechanisms by manipulating target protein expression. Various methods have been developed to deliver nucleic acids into the cells of interest <i>in vitro</i>, with chemical transfection by cationic lipids being the most widely used for RNA interference (RNAi). However, translating these <i>in vitro</i> results into <i>in vivo</i> remains a significant challenge. In this study, we established an <i>ex vivo</i> transfection model using cationic lipids in human whole blood. Three different lipid-based reagents were evaluated regarding toxicity, transfection efficiency, and immunogenicity across leukocyte populations using spectral flow cytometry. CD14<sup>+</sup> monocytes were identified as the primary population to be transfected by cationic lipids in whole blood. To assess immunogenicity, the monocyte-specific activation markers CD80 and human leukocyte antigen DR isotype (HLA-DR) were analyzed upon transfection. Our results demonstrated that Lipofectamine RNAiMAX outperforms the other two reagents, showing low toxicity and high transfection efficiency in combination with a minimal potential for monocyte activation. Functional knockdown experiments using siRNA targeting <i>CIITA</i> and the microRNA mir-3972 targeting <i>HLA-DRA</i> showed dose-dependent suppression in HLA-DR expression. This study provides the framework for preliminary testing of RNAi in a physiologically relevant <i>ex vivo</i> model, enabling assessment of key endpoints such as toxicity, transfection efficiency, and immune activation potential of gene delivery systems.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11939838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiomoleculesPub Date : 2025-03-08DOI: 10.3390/biom15030388
Irene Mignini, Giulia Piccirilli, Federica Di Vincenzo, Carlo Covello, Marco Pizzoferrato, Giorgio Esposto, Linda Galasso, Raffaele Borriello, Maurizio Gabrielli, Maria Elena Ainora, Antonio Gasbarrini, Maria Assunta Zocco
{"title":"Intestinal-Failure-Associated Liver Disease: Beyond Parenteral Nutrition.","authors":"Irene Mignini, Giulia Piccirilli, Federica Di Vincenzo, Carlo Covello, Marco Pizzoferrato, Giorgio Esposto, Linda Galasso, Raffaele Borriello, Maurizio Gabrielli, Maria Elena Ainora, Antonio Gasbarrini, Maria Assunta Zocco","doi":"10.3390/biom15030388","DOIUrl":"10.3390/biom15030388","url":null,"abstract":"<p><p>Short bowel syndrome (SBS), usually resulting from massive small bowel resections or congenital defects, may lead to intestinal failure (IF), requiring intravenous fluids and parenteral nutrition to preserve patients' nutritional status. Approximately 15% to 40% of subjects with SBS and IF develop chronic hepatic damage during their life, a condition referred to as intestinal-failure-associated liver disease (IFALD), which ranges from steatosis to fibrosis or end-stage liver disease. Parenteral nutrition has been largely pointed out as the main pathogenetic factor for IFALD. However, other elements, such as inflammation, bile acid metabolism, bacterial overgrowth and gut dysbiosis also contribute to the development of liver damage and may deserve specific treatment strategies. Indeed, in our review, we aim to explore IFALD pathogenesis beyond parenteral nutrition. By critically analyzing recent literature, we seek to delve with molecular mechanisms and metabolic pathways underlying liver damage in such a complex set of patients.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11939910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiomoleculesPub Date : 2025-03-08DOI: 10.3390/biom15030392
Beatrix M Gyetvai, Csaba Vadasz
{"title":"Pleiotropic Effects of <i>Grm7</i>/<i>GRM7</i> in Shaping Neurodevelopmental Pathways and the Neural Substrate of Complex Behaviors and Disorders.","authors":"Beatrix M Gyetvai, Csaba Vadasz","doi":"10.3390/biom15030392","DOIUrl":"10.3390/biom15030392","url":null,"abstract":"<p><p>Natural gene variants of metabotropic glutamate receptor subtype 7 (<i>Grm7</i>), coding for mGluR7, affect individuals' alcohol-drinking preference. Psychopharmacological investigations have suggested that mGluR7 is also involved in responses to cocaine, morphine, and nicotine exposures. We review the pleiotropic effects of <i>Grm7</i> and the principle of recombinant quantitative trait locus introgression (RQI), which led to the discovery of the first mammalian quantitative gene accounting for alcohol-drinking preference. <i>Grm7</i>/<i>GRM7</i> can play important roles in mammalian ontogenesis, brain development, and predisposition to addiction. It is also involved in other behavioral phenotypes, including emotion, stress, motivated cognition, defensive behavior, and pain-related symptoms. This review identified pleiotropy and the modulation of neurobehavioral processes by variations in the gene <i>Grm7</i>/<i>GRM7</i>. Patterns of pleiotropic genes can form oligogenic architectures whosecombined additive and interaction effects can significantly predispose individuals to the expressions of disorders. Identifying and characterizing pleiotropic genes are necessary for understanding the expressions of complex traits. This requires tasks, such as discovering and identifying novel genetic elements of the genetic architecture, which are unsuitable for AI but require classical experimental genetics.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiomoleculesPub Date : 2025-03-08DOI: 10.3390/biom15030390
Daniela Pavlíková, Veronika Zemanová, Milan Pavlík, Marie Lhotská, Jan Kubeš, Milan Novák, Petre I Dobrev, Václav Motyka
{"title":"Phytohormone and Amino Acid Changes in Cherry Radish as Metabolic Adaptive Response to Arsenic Single and Multi-Contamination.","authors":"Daniela Pavlíková, Veronika Zemanová, Milan Pavlík, Marie Lhotská, Jan Kubeš, Milan Novák, Petre I Dobrev, Václav Motyka","doi":"10.3390/biom15030390","DOIUrl":"10.3390/biom15030390","url":null,"abstract":"<p><p>This study investigated the metabolic adaptive responses to As contamination and As co-contamination with cadmium, lead, and zinc in the leaves and tubers of cherry radish (<i>Raphanus sativus</i> var. <i>sativus</i> Pers.). The response was assessed by measuring malondialdehyde levels, total phenolic content (TPC), total anthocyanin pigment (TAC), growth and stress phytohormone concentration, and free amino acid content. The characteristic As accumulation of single contamination resulted in a decrease in tuber growth. However, in the case of co-contamination, As uptake was influenced by the presence of other potentially toxic elements (PTEs), mainly zinc, with no significant effect on growth. Both contaminated treatments exhibited significant differences in metabolite levels among the organs, along with notable changes in their contents. Increases in malondialdehyde, TPC, and TAC indicated induced oxidative stress and an antioxidant response that was more pronounced by As co-contamination. Also, the results for phytohormones, which showed both increases and decreases, along with selected free amino acids (which showed increases), demonstrated a more significant influence of As co-contamination. Based on these findings, it can be concluded that the response of cherry radish to contaminated treatments exhibited significant differences in the studied parameters, along with variability in the results, reflecting the extent of the effects of PTEs that induce oxidative stress.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Effects of Brimonidine, Latanoprost, and Omidenepag on Tunicamycin-Induced Endoplasmic Reticulum Stress and Fibrosis in Human Trabecular Meshwork Cells.","authors":"Mengxuan Liu, Megumi Honjo, Reiko Yamagishi, Makoto Aihara","doi":"10.3390/biom15030389","DOIUrl":"10.3390/biom15030389","url":null,"abstract":"<p><p>This study evaluated the effects of α2-adrenergic agonist, prostaglandin F2α analog, and EP2 receptor agonist on tunicamycin-induced endoplasmic reticulum (ER) stress and fibrosis in human trabecular meshwork (TM) cells. Human TM cells were treated with tunicamycin for 24 h, followed by cotreatment with brimonidine (BRI), latanoprost (LAT), or omidenepag (OMD). Immunocytochemistry was used to assess expressions of collagen type I alpha 1 chain (COL1A1), fibronectin, F-actin, and alpha-smooth muscle actin (α-SMA). Western blotting was performed to evaluate levels of C/EBP homologous protein (CHOP), 78-kDa glucose-regulated protein (GRP78), and splicing X-box binding protein-1 (sXBP-1). Real-time qPCR was used to examine the mRNA expressions of COL1A1, connective tissue growth factor (CTGF), fibronectin, α-SMA, CHOP, GRP78, and sXBP-1. Expressions of COL1A1, CTGF, F-actin, fibronectin, α-SMA, CHOP, GRP78, and sXBP-1 significantly increased after tunicamycin treatment. BRI cotreatment significantly downregulated the mRNA and protein expressions of GRP78, and LAT or OMD cotreatment significantly reduced the CHOP and sXBP-1 expressions compared to the tunicamycin-treated group. BRI, LAT, or OMD cotreatment significantly attenuated cellular cytoskeletal changes and the increase of fibrosis markers such as COL1A1, CTGF, fibronectin, and α-SMA. In addition, COL1A1 mRNA expression was significantly lowered with LAT or OMD cotreatment compared to the BRI-cotreated group. Cotreatment with α2-adrenergic agonist, prostaglandin F2α analog, or EP2 receptor agonist alleviates tunicamycin-induced ER stress in human TM cells.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiomoleculesPub Date : 2025-03-07DOI: 10.3390/biom15030386
Elda Alba, Yolanda García-Mesa, Ramón Cobo, Patricia Cuendias, José Martín-Cruces, Iván Suazo, Graciela Martínez-Barbero, José A Vega, Olivia García-Suárez, Teresa Cobo
{"title":"Immunohistochemical Detection of PIEZO Ion Channels in the Human Carotid Sinus and Carotid Body.","authors":"Elda Alba, Yolanda García-Mesa, Ramón Cobo, Patricia Cuendias, José Martín-Cruces, Iván Suazo, Graciela Martínez-Barbero, José A Vega, Olivia García-Suárez, Teresa Cobo","doi":"10.3390/biom15030386","DOIUrl":"10.3390/biom15030386","url":null,"abstract":"<p><p>The carotid sinus and the carotid body are major peripheral chemo- and baro(mechano)receptors that sense changes in arterial wall pressure and in oxygen, carbon dioxide, and pH in arterial blood. Recently, it was demonstrated that the PIEZO1 and PIEZO2 mechanoreceptor/mechanotransducers are responsible for the baroreflex in the murine aortic arch (aortic sinus). Furthermore, some experimental evidence suggests that the carotid body could participate in mechanosensing. In this study, we used immunohistochemistry and immunofluorescence in conjunction with laser confocal microscopy to study the distribution of PIEZO1 and PIEZO2 in the human carotid sinus and carotid body as well as in the petrosal ganglion of the glossopharyngeal nerve and the superior cervical sympathetic ganglion. PIEZO1 and PIEZO2 were detected in different morphotypes of sensory nerve formations in the walls of the carotid sinus and carotid artery walls. In the carotid body, PIEZO1 was present in a small population of type I glomus cells and absent in nerves, whereas PIEZO2 was present in both clusters of type I glomus cells and nerves. The most prominent expression of PIEZO1 and PIEZO2 in the carotid body was found in type II glomus cells. On the other hand, in the petrosal ganglion, around 25% of neurons were PIEZO1-positive, and around 85% were PIEZO2-positive; regarding the superior cervical sympathetic ganglion, around 71% and 86% displayed PIEZO1 and PIEZO2, respectively. The results of this study suggest that PIEZO1 and PIEZO2 could be involved in the detection and/or mechanotransduction of the human carotid sinus, whereas the role of the carotid body is more doubtful since PIEZO1 and PIEZO2 were only detected in some nerves and PIEZO2 was present in a small population of type I glomus cells, with PIEZO1 being absent in these cells. However, since immunoreactivity for PIEZO2 was detected in type II glomus cells, researchers should investigate whether these cells play a role in the detection of mechanical stimuli and/or participate in mechanotransduction.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BiomoleculesPub Date : 2025-03-07DOI: 10.3390/biom15030387
Gorka Larrinaga, Jon Danel Solano-Iturri, Inés Arrieta-Aguirre, Asier Valdivia, David Lecumberri, Ane Miren Iturregui, Charles H Lawrie, María Armesto, Juan F Dorado, Caroline E Nunes-Xavier, Rafael Pulido, José I López, Javier C Angulo
{"title":"Prognostic and Therapeutic Implications of Alamandine Receptor MrgD Expression in Clear Cell Renal Cell Carcinoma with Development of Metastatic Disease.","authors":"Gorka Larrinaga, Jon Danel Solano-Iturri, Inés Arrieta-Aguirre, Asier Valdivia, David Lecumberri, Ane Miren Iturregui, Charles H Lawrie, María Armesto, Juan F Dorado, Caroline E Nunes-Xavier, Rafael Pulido, José I López, Javier C Angulo","doi":"10.3390/biom15030387","DOIUrl":"10.3390/biom15030387","url":null,"abstract":"<p><p>Despite advances in the management of advanced clear cell renal cell carcinoma (ccRCC), robust biomarkers for prognosis and therapeutic response prediction remain elusive. Dysregulation of the intrarenal renin-angiotensin system (RAS) has been implicated in renal carcinogenesis but little explored, particularly regarding biomarker discovery and therapeutic innovation. Consequently, this study investigates the immunohistochemical expression and clinical relevance of the Mas-related G-protein-coupled receptor D (MrgD) in patients with ccRCC who developed metastatic disease (mccRCC). A cohort of 132 patients treated between 2008 and 2018 with nephrectomy and tyrosine kinase inhibitor (TKI)-based sequential therapy was analyzed. Treatment response was assessed using both the MASS and RECIST scoring systems. High MrgD expression in primary tumors was significantly associated with larger size, advanced stage, higher histological grade, and worse overall survival. Among 81 patients with metachronous metastases, high MrgD expression independently predicted shorter disease-free survival. High MrgD staining intensity correlated with poorer TKI responses in first-line therapy but improved outcomes with second-line mTORC1 inhibitors. These findings suggest that MrgD may be a useful biomarker of RAS linked to tumor aggressiveness in ccRCC. MrgD holds potential for identifying high-risk patients and guiding treatment selection in advanced disease. Further research is needed to unlock its clinical potential.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11939982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}