International Journal of Molecular Sciences最新文献

{"title":"Enhancing Antimicrobial Peptide Activity through Modifications of Charge, Hydrophobicity, and Structure.","authors":"Przemysław Gagat, Michał Ostrówka, Anna Duda-Madej, Paweł Mackiewicz","doi":"10.3390/ijms251910821","DOIUrl":"https://doi.org/10.3390/ijms251910821","url":null,"abstract":"<p><p>Antimicrobial peptides (AMPs) are emerging as a promising alternative to traditional antibiotics due to their ability to disturb bacterial membranes and/or their intracellular processes, offering a potential solution to the growing problem of antimicrobial resistance. AMP effectiveness is governed by factors such as net charge, hydrophobicity, and the ability to form amphipathic secondary structures. When properly balanced, these characteristics enable AMPs to selectively target bacterial membranes while sparing eukaryotic cells. This review focuses on the roles of positive charge, hydrophobicity, and structure in influencing AMP activity and toxicity, and explores strategies to optimize them for enhanced therapeutic potential. We highlight the delicate balance between these properties and how various modifications, including amino acid substitutions, peptide tagging, or lipid conjugation, can either enhance or impair AMP performance. Notably, an increase in these parameters does not always yield the best results; sometimes, a slight reduction in charge, hydrophobicity, or structural stability improves the overall AMP therapeutic potential. Understanding these complex interactions is key to developing AMPs with greater antimicrobial activity and reduced toxicity, making them viable candidates in the fight against antibiotic-resistant bacteria.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464915","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":"3,8-Disubstituted Pyrazolo[1,5-a]quinazoline as GABA_A Receptor Modulators: Synthesis, Electrophysiological Assays, and Molecular Modelling Studies.","authors":"Letizia Crocetti, Gabriella Guerrini, Fabrizio Melani, Maria Paola Mascia, Maria Paola Giovannoni","doi":"10.3390/ijms251910840","DOIUrl":"https://doi.org/10.3390/ijms251910840","url":null,"abstract":"<p><p>As a continuation of our study in the field of GABA_A receptor modulators, we report the design and synthesis of new pyrazolo[1,5-a]quinazoline (PQ) bearing at the 8-position an oxygen or nitrogen function. All the final compounds and some intermediates, showing the three different forms of the pyrazolo[1,5-a]quinazoline scaffold (5-oxo-4,5-dihydro, -4,5-dihydro, and heteroaromatic form), have been screened with an electrophysiological technique on recombinant GABA_AR (α1β2γ2-GABA_AR), expressed in <i>Xenopus laevis</i> oocytes, by evaluating the variation in produced chlorine current, and permitting us to identify some interesting compounds (<b>6d</b>, <b>8a</b>, <b>8b</b>, and <b>14</b>) on which further functional assays were performed. Molecular modelling studies (docking, minimization of complex ligand-receptor, and MD model) and a statistical analysis by a Hierarchical Cluster Analysis (HCA) have collocated these ligands in the class corresponding to their pharmacological profile. The HCA results are coherent with the model we recently published (Proximity Frequencies), identifying the residues γThr142 and αHis102 as discriminant for the agonist and antagonist profile.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11477267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464777","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":"From Cancer to Immune Organoids: Innovative Preclinical Models to Dissect the Crosstalk between Cancer Cells and the Tumor Microenvironment.","authors":"Francesca Picca, Claudia Giannotta, Jiahao Tao, Lucia Giordanengo, H M Waqas Munir, Virginia Botta, Alessandra Merlini, Andrea Mogavero, Edoardo Garbo, Stefano Poletto, Paolo Bironzo, Gabriella Doronzo, Silvia Novello, Riccardo Taulli, Francesca Bersani","doi":"10.3390/ijms251910823","DOIUrl":"https://doi.org/10.3390/ijms251910823","url":null,"abstract":"<p><p>Genomic-oriented oncology has improved tumor classification, treatment options, and patient outcomes. However, genetic heterogeneity, tumor cell plasticity, and the ability of cancer cells to hijack the tumor microenvironment (TME) represent a major roadblock for cancer eradication. Recent biotechnological advances in organotypic cell cultures have revolutionized biomedical research, opening new avenues to explore the use of cancer organoids in functional precision oncology, especially when genomics alone is not a determinant. Here, we outline the potential and the limitations of tumor organoids in preclinical and translational studies with a particular focus on lung cancer pathogenesis, highlighting their relevance in predicting therapy response, evaluating treatment toxicity, and designing novel anticancer strategies. Furthermore, we describe innovative organotypic coculture systems to dissect the crosstalk with the TME and to test the efficacy of different immunotherapy approaches, including adoptive cell therapy. Finally, we discuss the potential clinical relevance of microfluidic mini-organ technology, capable of reproducing tumor vasculature and the dynamics of tumor initiation and progression, as well as immunomodulatory interactions among tumor organoids, cancer-associated fibroblasts (CAFs) and immune cells, paving the way for next-generation immune precision oncology.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464962","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":"Pleiotrophin Activates cMet- and mTORC1-Dependent Protein Synthesis through PTPRZ1-The Role of α_νβ₃ Integrin.","authors":"Eleni Mourkogianni, Katerina Karavasili, Athanasios Xanthopoulos, Michaela-Karina Enake, Lydia Menounou, Evangelia Papadimitriou","doi":"10.3390/ijms251910839","DOIUrl":"https://doi.org/10.3390/ijms251910839","url":null,"abstract":"<p><p>Pleiotrophin (PTN) is a secreted factor that regulates endothelial cell migration through protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) and α_vβ₃ integrin. Genetic deletion of <i>Ptprz1</i> results in enhanced endothelial cell proliferation and migration, due to the decreased expression of β₃ integrin and the subsequent, enhanced cMet phosphorylation. In the present study, we investigated the effect of PTN and PTPRZ1 on activating the mTORC1 kinase and protein synthesis and identified part of the implicated signaling pathway in endothelial cells. PTN or genetic deletion of <i>Ptprz1</i> activates protein synthesis in a mTORC1-dependent manner, as shown by the enhanced phosphorylation of the mTORC1-downstream targets ribosomal protein S6 kinase 1 (SK61) and 4E-binding protein 1 (4EBP1) and the upregulation of HIF-1α. The cMet tyrosine kinase inhibitor crizotinib abolishes the stimulatory effects of PTN or PTPRZ1 deletion on mTORC1 activation and protein synthesis, suggesting that mTORC1 activation is downstream of cMet. The mTORC1 inhibitor rapamycin abolishes the stimulatory effect of PTN or PTPRZ1 deletion on endothelial cell migration, suggesting that mTORC1 is involved in the PTN/PTPRZ1-dependent cell migration. The α_vβ₃ integrin blocking antibody LM609 and the peptide PTN_112-136, both known to bind to α_νβ₃ and inhibit PTN-induced endothelial cell migration, increase cMet phosphorylation and activate mTORC1, suggesting that cMet and mTORC1 activation are required but are not sufficient to stimulate cell migration. Overall, our data highlight novel aspects of the signaling pathway downstream of the PTN/PTPRZ1 axis that regulates endothelial cell functions.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11477150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465179","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":"The Association of <i>IFNL4</i> Gene Polymorphisms with Hepatitis B Virus (HBV) Infection in the Northern Region of Pará, Brazil.","authors":"Álesson Adam Fonseca Andrade, Carolina Cabral Angelim, Letícia Dias Martins, Amanda Roberta Vieira Sacramento, Renata Santos de Sousa, Raissa Lima Correa, Simone Regina Souza da Silva Conde, Antonio Carlos Rosário Vallinoto, Rosimar Neris Martins Feitosa, Greice de Lemos Cardoso Costa","doi":"10.3390/ijms251910836","DOIUrl":"https://doi.org/10.3390/ijms251910836","url":null,"abstract":"<p><p>It is heavily suggested that one <i>IFNL4</i> gene polymorphism, rs12979860 (T/C), exerts influence on the outcome of HBV infection, with the rs12979860-T allele being classified as a risk predictor, and the rs12979860-C allele being classified as a protective one. This study investigated whether the rs12979860 <i>IFNL4</i> gene polymorphism presented any association with the clinical severity for HBV carriers in an admixed population in Northern Brazil. A total of 69 samples were investigated from infected people from the city of Belém-Pará. The rs12979860-T allele was positively associated with HBV infection, suggesting a higher risk of chronicity. This research's importance is that the polymorphism influence was investigated in a population of HBV carriers with a heterogeneous genetic profile, formed through the extensive admixture of different ethnic groups, including Europeans, Africans, and Natives with indigenous heritage. This analysis is particularly important since highly mixed populations do not always follow the same association patterns previously established by studies using populations classified as more genetically homogeneous, due to a different formation process.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142485961","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":"Cleavage of DNA Substrate Containing Nucleotide Mismatch in the Complementary Region to sgRNA by Cas9 Endonuclease: Thermodynamic and Structural Features.","authors":"Svetlana V Baranova, Polina V Zhdanova, Anastasia D Koveshnikova, Pavel E Pestryakov, Ivan P Vokhtantsev, Alexander A Chernonosov, Vladimir V Koval","doi":"10.3390/ijms251910862","DOIUrl":"https://doi.org/10.3390/ijms251910862","url":null,"abstract":"<p><p>The non-ideal accuracy and insufficient selectivity of CRISPR/Cas9 systems is a serious problem for their use as a genome editing tool. It is important to select the target sequence correctly so that the CRISPR/Cas9 system does not cut similar sequences. This requires an understanding of how and why mismatches in the target sequence can affect the efficiency of the Cas9/sgRNA complex. In this work, we studied the catalytic activity of the Cas9 enzyme to cleave DNA substrates containing nucleotide mismatch at different positions relative to the PAM in the \"seed\" sequence. We show that mismatches in the complementarity of the sgRNA/DNA duplex at different positions relative to the protospacer adjacent motif (PAM) sequence tend to decrease the cleavage efficiency and increase the half-maximal reaction time. However, for two mismatches at positions 11 and 20 relative to the PAM, an increase in cleavage efficiency was observed, both with and without an increase in half-reaction time. Thermodynamic parameters were obtained from molecular dynamics results, which showed that mismatches at positions 8, 11, and 20 relative to the PAM thermodynamically stabilize the formed complex, and a mismatch at position 2 of the PAM fragment exerts the greatest stabilization compared to the original DNA sequence. The weak correlation of the thermodynamic binding parameters of the components of the Cas9/sgRNA:dsDNA complex with the cleavage data of DNA substrates containing mismatches indicates that the efficiency of Cas9 operation is mainly affected by the conformational changes in Cas9 and the mutual arrangement of sgRNA and substrates.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142485854","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":"A Rare Case of <i>TP63</i>-Associated Lymphopenia Revealed by Newborn Screening Using TREC.","authors":"Andrey Marakhonov, Elena Serebryakova, Anna Mukhina, Anastasia Vechkasova, Nikolai Prokhorov, Irina Efimova, Natalia Balinova, Anastasia Lobenskaya, Tatyana Vasilyeva, Victoria Zabnenkova, Oxana Ryzhkova, Yulia Rodina, Dmitry Pershin, Nadezhda Soloveva, Anna Fomenko, Djamila Saydaeva, Aset Ibisheva, Taisiya Irbaieva, Alexander Koroteev, Rena Zinchenko, Sergey Voronin, Anna Shcherbina, Sergey Kutsev","doi":"10.3390/ijms251910844","DOIUrl":"https://doi.org/10.3390/ijms251910844","url":null,"abstract":"<p><p>The expanded newborn screening (NBS) program in the Russian Federation was initiated in 2023, among which severe combined immunodeficiency (SCID) is screened using TREC/KREC assays. Here, we report a rare case of a <i>TP63</i>-associated disease identified through this NBS program. Dried blood spots from newborns were initially screened for TREC/KREC levels, and those with values below the cut-off underwent confirmatory testing and further genetic analysis, including whole-exome sequencing (WES). A male newborn was identified with significantly reduced TREC values, indicative of T cell lymphopenia. Genetic analysis revealed a heterozygous NM_003722.5:c.1027C>T variant in <i>TP63</i>, leading to the p.(Arg343Trp) substitution within the DNA binding domain. This mutation has been previously associated with Ectrodactyly-Ectodermal Dysplasia-Cleft lip/palate syndrome (EEC) syndrome and shown to reduce the transactivation activity of TP63 in a dominant-negative manner. This case represents one of the few instances of immune system involvement in a patient with a <i>TP63</i> mutation, highlighting the need for further investigation into the immunological aspects of <i>TP63</i>-associated disorders. Our findings suggest that comprehensive immunological evaluation should be considered for patients with <i>TP63</i> mutations to better understand and manage potential immune dysfunctions.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464794","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":"B-Cell Maturation Antigen (BCMA) as a Biomarker and Potential Treatment Target in Systemic Lupus Erythematosus.","authors":"Jonas Martin, Qingyu Cheng, Sarah A Laurent, Franziska S Thaler, Anne Elisabeth Beenken, Edgar Meinl, Gerhard Krönke, Falk Hiepe, Tobias Alexander","doi":"10.3390/ijms251910845","DOIUrl":"https://doi.org/10.3390/ijms251910845","url":null,"abstract":"<p><p>The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HCs) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as a clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI and contributed to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as a biomarker for disease activity.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464753","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":"Compound Heterozygous <i>RYR1</i> Variants in a Patient with Severe Congenital Myopathy: Case Report and Comparison with Additional Cases of Recessive <i>RYR1</i>-Related Myopathy.","authors":"Sören Janßen, Leoni S Erbe, Moritz Kneifel, Matthias Vorgerd, Kristina Döring, Krzysztof P Lubieniecki, Joanna M Lubieniecka, Wanda M Gerding, Nicolas Casadei, Anne-Katrin Güttsches, Christoph Heyer, Thomas Lücke, Hoa Huu Phuc Nguyen, Cornelia Köhler, Sabine Hoffjan","doi":"10.3390/ijms251910867","DOIUrl":"https://doi.org/10.3390/ijms251910867","url":null,"abstract":"<p><p>Pathogenic variants in the ryanodine receptor 1 (<i>RYR1</i>) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype-phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes. We present a 6-year-old patient with severe congenital myopathy, carrying a heterozygous pathogenic <i>RYR1</i> variant inherited from the healthy mother. Through whole genome sequencing we identified a second, deep intronic <i>RYR1</i> variant that has recently been described in another patient with severe congenital myopathy and shown to affect splicing. Segregation analyses confirmed the variants to be compound heterozygous. We compared our patient's phenotype to that of the patient from the literature as well as five additional patients with compound heterozygous <i>RYR1</i> variants from our center. The main overlapping features comprised congenital onset, predominant muscular hypotonia, and normal creatine kinase (CK) levels, while overall clinical expression varied substantially. Interestingly, both patients carrying the new intronic splice variant showed a very severe disease course. More widespread use of genome sequencing will open the way for better genotype-phenotype correlations.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11477233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464863","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":"Role of Na⁺-K⁺ ATPase Alterations in the Development of Heart Failure.","authors":"Naranjan S Dhalla, Vijayan Elimban, Adriana Duris Adameova","doi":"10.3390/ijms251910807","DOIUrl":"https://doi.org/10.3390/ijms251910807","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Na&lt;sup&gt;+&lt;/sup&gt;-K&lt;sup&gt;+&lt;/sup&gt; ATPase is an integral component of cardiac sarcolemma and consists of three major subunits, namely the α-subunit with three isoforms (α&lt;sub&gt;1&lt;/sub&gt;, α&lt;sub&gt;2&lt;/sub&gt;, and α&lt;sub&gt;3&lt;/sub&gt;), β-subunit with two isoforms (β&lt;sub&gt;1&lt;/sub&gt; and β&lt;sub&gt;2&lt;/sub&gt;) and γ-subunit (phospholemman). This enzyme has been demonstrated to transport three Na and two K ions to generate a trans-membrane gradient, maintain cation homeostasis in cardiomyocytes and participate in regulating contractile force development. Na&lt;sup&gt;+&lt;/sup&gt;-K&lt;sup&gt;+&lt;/sup&gt; ATPase serves as a receptor for both exogenous and endogenous cardiotonic glycosides and steroids, and a signal transducer for modifying myocardial metabolism as well as cellular survival and death. In addition, Na&lt;sup&gt;+&lt;/sup&gt;-K&lt;sup&gt;+&lt;/sup&gt; ATPase is regulated by different hormones through the phosphorylation/dephosphorylation of phospholemman, which is tightly bound to this enzyme. The activity of Na&lt;sup&gt;+&lt;/sup&gt;-K&lt;sup&gt;+&lt;/sup&gt; ATPase has been reported to be increased, unaltered and depressed in failing hearts depending upon the type and stage of heart failure as well as the association/disassociation of phospholemman and binding with endogenous cardiotonic steroids, namely endogenous ouabain and marinobufagenin. Increased Na&lt;sup&gt;+&lt;/sup&gt;-K&lt;sup&gt;+&lt;/sup&gt; ATPase activity in association with a depressed level of intracellular Na&lt;sup&gt;+&lt;/sup&gt; in failing hearts is considered to decrease intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; and serve as an adaptive mechanism for maintaining cardiac function. The slight to moderate depression of Na&lt;sup&gt;+&lt;/sup&gt;-K&lt;sup&gt;+&lt;/sup&gt; ATPase by cardiac glycosides in association with an increased level of Na&lt;sup&gt;+&lt;/sup&gt; in cardiomyocytes is known to produce beneficial effects in failing hearts. On the other hand, markedly reduced Na&lt;sup&gt;+&lt;/sup&gt;-K&lt;sup&gt;+&lt;/sup&gt; ATPase activity associated with an increased level of intracellular Na&lt;sup&gt;+&lt;/sup&gt; in failing hearts has been demonstrated to result in an intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; overload, the occurrence of cardiac arrhythmias and depression in cardiac function during the development of heart failure. Furthermore, the status of Na&lt;sup&gt;+&lt;/sup&gt;-K&lt;sup&gt;+&lt;/sup&gt; ATPase activity in heart failure is determined by changes in isoform subunits of the enzyme, the development of oxidative stress, intracellular Ca&lt;sup&gt;2+&lt;/sup&gt;-overload, protease activation, the activity of inflammatory cytokines and sarcolemmal lipid composition. Evidence has been presented to show that marked alterations in myocardial cations cannot be explained exclusively on the basis of sarcolemma alterations, as other Ca&lt;sup&gt;2+&lt;/sup&gt; channels, cation transporters and exchangers may be involved in this event. A marked reduction in Na&lt;sup&gt;+&lt;/sup&gt;-K&lt;sup&gt;+&lt;/sup&gt; ATPase activity due to a shift in its isoform subunits in association with intracellular Ca&lt;sup&gt;2+&lt;/sup&gt;-overload, cardiac energy depletion, increased membrane permeability, Ca&lt;sup&gt;2+&lt;/sup&gt;-handling abnormalities and damage to myocardial u","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465141","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}