Frontiers in bioscience (Landmark edition)最新文献

{"title":"Elucidating Mechanisms Underlying Fibrocyte-Mediated Myelofibrosis Induction in Myelodysplastic Syndromes.","authors":"Takaaki Maekawa, Nobuyuki Mukai, Yurika Yanaki, Emi Kemmoku, Takuto Shonai, Kota Kawasaki, Takehiro Sone, Kohei Takada, Hiraku Ogata, Keita Saito, Noriaki Tachi, Toshikuni Kawamura, Shoichiro Kato, Yukiko Osawa, Shinichi Kobayashi","doi":"10.31083/FBL54751","DOIUrl":"https://doi.org/10.31083/FBL54751","url":null,"abstract":"<p><strong>Background: </strong>The mechanism underlying myelofibrosis, which is associated with poor prognosis in myelodysplastic syndromes (MDS), remains unclear.</p><p><strong>Methods: </strong>We investigated the mechanisms underlying myelofibrosis using peripheral blood mononuclear cells (PBMCs) from healthy donors, MDS92 cell culture supernatants and <i>Polg</i>^A/+ and <i>Polg</i>^A/A mice treated with high-dose romiplostim as an MDS model. We used the LEGENDplex™ immunoassay to analyze cytokine levels in MDS92 culture supernatants and serum samples from 12 patients with MDS or acute myeloid leukemia with myelodysplasia-related cytogenetic abnormalities.</p><p><strong>Results: </strong>The MDS92 cell culture supernatants inhibited monocyte differentiation into fibrocytes and contained significantly lower levels of CXCL1 (C-X-C motif chemokine ligand 1), IL-6 (Interleukin-6), and CCL22 (C-C motif chemokine ligand 22) than PBMC culture supernatants from healthy donors. Among serum samples from patients with MDS, IL-18 level was positively correlated with myelofibrosis grade and splenomegaly. In <i>Polg</i>^A/A mice, the F4/80^high CD11b^low/int cell fraction of the spleen was significantly increased following romiplostim administration, compared with <i>Polg</i>^A/+ mice; however, worsening of splenomegaly was not observed. Furthermore, reticulin fibers were observed mainly in the subcortical region in all <i>Polg</i>^A/+ mice but were rare in the <i>Polg</i>^A/A mice.</p><p><strong>Conclusions: </strong>These findings suggest an association between altered cytokine signaling fibrocyte differentiation, and myelofibrosis in MDS. Further studies are required to clarify how cytokine levels and cellular responsiveness contribute to fibrocyte-mediated myelofibrosis.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"54751"},"PeriodicalIF":3.1,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082977","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":"FOS-Like Antigen 1 Regulates Proliferating Cell Nuclear Antigen Expression and Pancreatic Cancer Cell Proliferation and Migration.","authors":"Xueyan Zhang, Yu An, Jipin Li, Yali Chen, Tingyu Zeng, Shuping Wang","doi":"10.31083/FBL52523","DOIUrl":"https://doi.org/10.31083/FBL52523","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic cancer ranks among the leading causes of cancer-related death worldwide, and novel therapeutic strategies are urgently needed for advanced or metastatic disease states. Notably, targeted therapy remains a particularly promising approach. The transcription factor FOS-like antigen 1 (<i>FOSL1</i>) is overexpressed in refractory pancreatic cancers and drives tumor progression, correlating with unfavorable clinical outcomes. Thus, this study aimed to investigate the molecular mechanisms through which FOSL1 and proliferating cell nuclear antigen (PCNA) promote pancreatic cancer progression by regulating DNA repair, invasion, and migration.</p><p><strong>Methods: </strong>We evaluated the role of <i>FOSL1</i> in pancreatic cancer cell proliferation, DNA repair, stemness, invasion, and migration, and identified downstream targets and pathways through transcriptomic analysis. Mechanistically, we validated the FOSL1-PCNA interaction, FOSL1 binding to the <i>PCNA</i> promoter, and the role of FOSL1 in regulating PCNAubiquitination. Finally, we assessed whether FOSL1 functions through PCNA and explored the effects of combined FOSL1 knockdown and PCNA inhibition.</p><p><strong>Results: </strong><i>FOSL1</i> depletion altered cell proliferation, steady-state DNA damage, stemness-associated markers, invasion, and migration. <i>PCNA</i> overexpression partially rescued the reduction in colony formation caused by <i>FOSL1</i> knockdown. Mechanistically, FOSL1 binds the <i>PCNA</i> promoter, and FOSL1 knockdown reduced <i>PCNA</i> mRNA expression. Moreover, chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) showed that FOSL1 occupies the <i>PCNA</i> promoter region. Conversely, PCNA knockdown suppressed pancreatic cancer cell proliferation and impaired the expression of genes involved in DNA repair, stemness, and epithelial-mesenchymal transition (EMT)-mediated invasion and migration.</p><p><strong>Conclusion: </strong>Our findings indicate that FOSL1 promotes pancreatic cancer progression, at least in part by upregulating PCNA expression. We hypothesize that combined inhibition of FOSL1 and PCNA may represent a therapeutic strategy for advanced pancreatic cancer.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"52523"},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083007","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":"Mechanism of the NAMPT-SIRT2-Lactate Axis in Senescence of Human Nucleus Pulposus Cells.","authors":"Wensheng Zhang, Ling Mo, Haiwei Guo, Xibing Zhang, Hanwu Tang, Wenchao Li, Caijun Liu","doi":"10.31083/FBL51724","DOIUrl":"https://doi.org/10.31083/FBL51724","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Intervertebral disc degeneration (IDD) is a primary cause of low back pain, closely associated with the senescence of nucleus pulposus cells (NPCs). Energy metabolism disorders and lactate accumulation are observed in degenerated intervertebral discs. However, the molecular mechanism through which lactate accumulation induces IDD and its upstream regulatory factors remain unclear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Clinical degenerated intervertebral disc tissues were collected. Lactate content was measured using the water-soluble tetrazolium salt-8 (WST-8) method, and the expression of nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin 2 (SIRT2) was analyzed by western blotting. NPCs were cultured &lt;i&gt;in vitro&lt;/i&gt; and treated with lactate. Lactate levels, protein lactylation, p38 mitogen-activated protein kinase (p38-MAPK) pathway activity, and cellular senescence were assessed using lactate assay kits, western blotting, and senescence-associated β-galactosidase staining, respectively. Furthermore, small interfering RNA (siRNA) and overexpression plasmids were used to regulate NAMPT expression, combined with SIRT2 activators or inhibitors, to explore the role of the NAMPT/SIRT2 axis in regulating lactate metabolism and cellular senescence.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Lactate was detected in all four degenerated intervertebral disc tissue samples examined, with variable levels among individuals. NAMPT and SIRT2 protein expression showed similar expression patterns across these samples, suggesting a potential relationship that warrants further investigation in larger cohorts. &lt;i&gt;In vitro&lt;/i&gt; experiments confirmed that lactate treatment significantly elevated global protein lactylation levels, activated the p38-MAPK pathway, and induced cellular senescence in NPCs. Knockdown of NAMPT expression reduced lactate and NAD&lt;sup&gt;+&lt;/sup&gt; levels. Notably, treatment with a SIRT2 activator partially restored the decrease in lactate content but had no significant effect on nicotinamide adenine dinucleotide (NAD&lt;sup&gt;+&lt;/sup&gt;) levels. Overexpression of NAMPT led to lactate accumulation and cellular senescence, both of which could be antagonized by either a lactate inhibitor or a SIRT2 inhibitor.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;&lt;i&gt;In vitro&lt;/i&gt; experiments indicate that NAMPT appears to modulate lactate metabolism in a SIRT2-dependent manner, which subsequently activates the p38-MAPK signaling pathway and contributes to nucleus pulposus cell senescence. These findings suggest a functional NAMPT/SIRT2/lactate/p38-MAPK signaling axis that may play a role in intervertebral disc degeneration. However, the clinical relevance of these observations requires validation in larger patient cohorts with appropriate normal controls. Although further &lt;i&gt;in vivo&lt;/i&gt; validation and mechanistic details (e.g., direct regulation of SIRT2 activity) are required, this axis may represent a potential therapeutic target for intervening in IDD.&lt;/","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"51724"},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083126","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":"Telomeric Replication Stress Promotes ALT-Associated Hallmarks in ATRX- and p53-Deficient Cells.","authors":"Roberta Amato, Emanuela Micheli, Chiara Focaccetti, Roberto Bei, Piergiorgio La Rosa, Antonella Sgura, Francesco Berardinelli","doi":"10.31083/FBL52954","DOIUrl":"https://doi.org/10.31083/FBL52954","url":null,"abstract":"<p><strong>Background: </strong>Most human tumors maintain telomeres through telomerase activation; however, a subset relies on the telomerase-independent mechanism known as Alternative Lengthening of Telomeres (ALT). ALT-positive tumors are frequently characterized by inactivating alterations in ATRX (Alpha Thalassemia/Mental Retardation Syndrome X-linked) and p53 and by distinct molecular and cellular features. Although chronic telomeric replication stress has been proposed as a trigger for ALT, several aspects of this process remain poorly understood. Recent evidence suggests that ATRX depletion promotes the persistence of DNA secondary structures, including G-quadruplexes (G4), which can impair replication fork progression, leading to fork stalling and DNA damage.</p><p><strong>Methods: </strong>To investigate whether ATRX and p53 deficiency sensitize telomerase-positive cells to develop ALT-associated molecular features in response to telomeric replication stress, we analyzed telomeric DNA damage, telomere sister chromatid exchange (T-SCE), Telomeric Repeat-containing RNA (TERRA) expression, and C-circle formation in HCT116 cells proficient or deficient for ATRX and p53. ATRX was depleted using both transient (siRNA-mediated knockdown) and stable (shRNA-expressing clones) approaches, allowing us to distinguish the early cellular response from the features arising upon persistent ATRX loss. To further assess the contribution of telomeric replication stress, cells were treated with the G4-stabilizing ligand RHPS4.</p><p><strong>Results: </strong>Our data show that G4 stabilization, in the context of ATRX and/or p53 deficiency, promotes the appearance of multiple ALT-associated hallmarks, including telomeric DNA damage, increased T-SCE, and elevated TERRA expression. Moreover, the combined loss of ATRX and p53 permits cell-cycle progression despite the presence of RHPS4-induced telomeric replication stress and telomeric DNA damage.</p><p><strong>Conclusions: </strong>These findings clarify how ATRX and p53 loss, even in telomerase-positive cells, are permissive conditions for the emergence of ALT-associated hallmarks under telomeric replication stress and highlight the G2/M checkpoint as a critical barrier limiting the propagation of cells displaying these features.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"52954"},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082941","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":"Multi-Omics Analysis and Experimental Validation Uncover Neddylation-Associated Biomarkers and Cellular Landscape in Lung Adenocarcinoma.","authors":"Xiaogang Peng, Guangming Xiang, Gengyun Sun","doi":"10.31083/FBL52485","DOIUrl":"https://doi.org/10.31083/FBL52485","url":null,"abstract":"<p><strong>Background: </strong>Accumulating evidence suggests that neddylation contributes to tumor initiation and progression. Nonetheless, its biological functions and regulatory mechanisms in lung adenocarcinoma (LUAD) remain poorly understood.</p><p><strong>Methods: </strong>Bioinformatics analyses integrated single-cell RNA sequencing (scRNA-seq) datasets from the Gene Expression Omnibus (GEO) with bulk RNA-seq data from The Cancer Genome Atlas (TCGA). The Seurat package was used for scRNA-seq processing, including cell clustering, annotation, cell-cell interaction analysis, and pseudotime trajectory inference. The survival and pROC packages were used for Kaplan-Meier (KM) survival and receiver operating characteristic (ROC) analyses, respectively. Tissue microarray (TMA) and immunohistochemistry (IHC) analyses were performed to validate biomarker expression. Functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, wound healing, and Transwell assays, were conducted in A549 and NCI-H1975 cells with DNAJB1 knockdown.</p><p><strong>Results: </strong>Eight major cell populations were identified at the single-cell level, among which T/NK cells, particularly CD8+ effector memory T cells (CD8+ Tem), exhibited strong associations with neddylation. T/NK cells displayed extensive ligand-receptor-mediated interactions with other cell types. A transcription factor (TF)-target regulatory network was constructed, revealing that Surfactant Protein C (SFTPC), Lipopolysaccharide-Induced TNF Factor (LITAF), Serine/Threonine Kinase 17B (STK17B), Enah/Vasp-Like Protein (EVL), FYN Proto-Oncogene, Src Family Tyrosine Kinase (FYN), and Lymphocyte-Specific Protein 1 (LSP1) were associated with favorable prognosis, whereas DNAJB1 correlated with poor survival in LUAD patients. Pseudotime trajectories further delineated dynamic differentiation pathways of T/NK subsets and differential TF target expression across states. IHC analysis showed elevated DNAJB1 expression in tumors compared with adjacent normal tissues. Moreover, silencing DNAJB1 significantly inhibited proliferation, migration, and invasion in A549 and NCI-H1975 cells.</p><p><strong>Conclusion: </strong>This study identifies neddylation-associated cellular phenotypes and clinically relevant biomarkers in LUAD, providing new mechanistic insights and highlighting potential therapeutic targets for LUAD treatment.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"52485"},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083053","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":"Cell Senescence and the Aging Liver.","authors":"Roberta Pisu, Ezio Laconi, Fabio Marongiu","doi":"10.31083/FBL50660","DOIUrl":"https://doi.org/10.31083/FBL50660","url":null,"abstract":"<p><p>The liver has an enormous functional reserve, including a regenerative capacity that remains remarkable into old age, helping maintain liver function during physiological aging in the absence of specific disease processes. However, significant morphological and functional changes still occur in the aging liver, including the emergence and accumulation of senescent cells. While cell senescence is sometimes equated with aging at the cellular level, its precise role and significance in shaping the aged phenotype in tissues and the whole organism remain debated. Current evidence suggests that each cell type in the liver may contribute specifically to aging and age-associated morbidities. This review focuses on the \"heterogeneity of senescence\" and highlights the multifaceted role of cell senescence and its associated secretory patterns in aging. However, a better understanding of the complex interplay among cell types is essential for modulating the positive impact of senescence and delaying the emergence of age-associated changes.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"50660"},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083006","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":"Targeting Reductive Stress With Oxygen Enrichment Rescues Hippocampus-Dependent Memory Impairment after Acute Hypobaric Hypoxia.","authors":"Jiaojiao Ma, Miao Miao, Xiaohong Liu, Xiaohong Tian, Chenxu Zhang, Yuanzhe Li, Chengcheng Zhao, Juan Liu, Kangning Xie, Chi Tang, Mingming Zhai","doi":"10.31083/FBL54346","DOIUrl":"https://doi.org/10.31083/FBL54346","url":null,"abstract":"<p><strong>Background: </strong>High-altitude hypobaric hypoxia is known to impair cognitive function, but the underlying mechanistic role of impaired redox homeostasis in this context remains incompletely understood. This study investigated whether acute hypobaric hypoxia induces oxidative stress and redox dysregulation in the hippocampus, and whether oxygen enrichment can mitigate these impairments by restoring redox homeostasis.</p><p><strong>Methods: </strong>Spatial memory was assessed using the Morris water maze. Additionally, hippocampal morphology, redox status (including glutathione/oxidized glutathione [GSH/GSSG], the reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide [NADH/NAD+], and the reduced nicotinamide adenine dinucleotide phosphate/oxidized nicotinamide adenine dinucleotide phosphate [NADPH/NADP+] ratios, as well as antioxidant enzyme activity levels), and associated molecular pathways were analyzed.</p><p><strong>Results: </strong>Following 3 days of hypoxia exposure, rats exhibited impaired spatial memory retention, increased neuronal apoptosis, and reduced neuronal viability in the hippocampal cornu ammonis 1 [CA1] region. The hippocampus displayed significantly altered redox status, characterized by elevated GSH/GSSG, NADH/NAD+, and NADPH/NADP+ ratios, upregulated antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase [GPX]), and decreased superoxide levels. These changes are consistent with an adaptive nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response and a shift toward a reductive state. Notably, oxygen enrichment rescued cognitive deficits, attenuated neuronal apoptosis, and normalized redox ratios and the microtubule-associated protein 1A/1B-light chain 3-II/microtubule-associated protein 1A/1B-light chain 3-I (LC3B-II/ LC3B-I) ratio.</p><p><strong>Conclusions: </strong>Hypoxia-induced redox dysregulation is closely associated with cognitive impairment. Oxygen enrichment alleviates these deficits by modulating the Nrf2-mediated adaptive response and restoring redox homeostasis, thereby supporting further investigation of oxygen enrichment as a potential neuroprotective strategy.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"54346"},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082982","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":"Mosaic Loss of Chromosome Y (LOY): From Genomic Instability to Disease and Single-Cell Detection.","authors":"Ruslan Kalendar","doi":"10.31083/FBL55248","DOIUrl":"https://doi.org/10.31083/FBL55248","url":null,"abstract":"<p><p>Mosaic loss of chromosome Y (LOY) is the acquired absence of the Y chromosome in a fraction of cells, is most readily observed in the haematopoietic compartment, and represents the most common form of clonal mosaicism in older men. Once dismissed as a benign correlate of aging, LOY is now recognized as a clinically meaningful biomarker associated with reduced survival and an expanding range of age-related disorders, including multiple solid and haematological cancers, cardiovascular disease, Alzheimer's disease, and type 2 diabetes mellitus. Large-scale genome-wide analyses have shown that susceptibility to LOY is highly heritable and associated with genes involved in cell cycle regulation, the DNA damage response, and apoptosis, supporting a model in which detectable LOY in blood reflects broader genomic instability across tissues. In parallel, functional studies in genetically engineered mice have demonstrated that haematopoietic LOY can contribute causally to pathologic processes such as cardiac fibrosis, indicating that loss of dosage-sensitive Y-linked genes in immune cells may exert direct effects rather than merely serving as a passive marker. Progress in this field has been constrained by detection methods that are laborious, costly, or insufficiently sensitive at low mutant cell fractions. This constraint is now easing on two fronts. Haplotype- and coverage-based callers can detect LOY from whole-genome and exome sequencing data generated for other purposes, extending measurement to ancestrally diverse cohorts and tumour genomes, while newer single-cell droplet-based approaches permit accurate quantification of LOY and its female counterpart, mosaic loss of chromosome X (LOX), at single-cell resolution. Here, we summarize the biology, genetic architecture, disease associations, and proposed mechanisms of LOY and discuss how improved detection may help clarify its causal contribution to human aging and disease.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"55248"},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083033","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":"Leucine-Rich Repeat Domains in the Class III Adenylyl Cyclase of Fungi: Some Features of the Sequences and Structures.","authors":"Norio Matsushima, Dashdavaa Batkhishig","doi":"10.31083/FBL50167","DOIUrl":"https://doi.org/10.31083/FBL50167","url":null,"abstract":"<p><p>Fungal adenylyl cyclase (AC) converts adenosine triphosphate (ATP) to the second messenger 3',5'-cyclic AMP (cAMP). Class III ACs contain multiple domains, including the adenylyl cyclase domain and a leucine-rich repeat domain (LRR), through which multiple signals are integrated into the cAMP-Protein Kinase A (PKA) signaling response. This review focuses on the sequences and structural features of the LRR domains. To this end, we analyzed LRR domain sequences from ACs in the phyla <i>Ascomycota</i>, <i>Mucoromycota</i>, <i>Basidiomycota</i>, <i>Blastocladiomycota</i>, <i>Zoopagomycota</i>, and <i>Chytridiomycota</i>. Protein structures were also predicted using AlphaFold2. More than 99% of individual LRR domains consist of 23 repeats with an additional parallel β-strand at the C-terminus. The repeat unit length (RUL) is mainly 23 or 24 residues. The most distinctive feature is the presence of non-LRR island region (IR) interrupting the LRRs between the 16th and the 17th units. The IRs may be roughly classified into two groups. The first group IRs, which, for example, are identified in ACs from <i>Saccharomyces cerevisiae</i> and <i>Candida albicans</i> belonging to the phylum <i>Ascomycota</i>, are relatively short; the IR lengths are within 10 to 50 residues. The second group IRs, which are identified in many ACs from the phyla <i>Ascomycota</i>, <i>Mucoromycota</i>, <i>Basidiomycota</i>, and <i>Zoopagomycota</i> are long; the IRs range from 50 to 220 residues. Most of the long IRs are regarded as intrinsically disordered regions. The AC LRR domains adopt typical solenoid structures in which the IRs form bulges or loops in a non-globular conformation. Two possibilities are discussed for the role of IRs in AC LRR domains. This review proposes a new subclass of fungal class III ACs, which includes a forkhead-associated domain.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"50167"},"PeriodicalIF":3.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083118","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":"Ergothioneine Attenuates Ovariectomy-Induced Bone Loss in Association With Reduced Oxidative Stress and Enhanced Type H Vessel-Related Angiogenesis.","authors":"Xinping Wang, Yuanzhang Xiao, Renwei Liu, Yingchao Cai, Wuyang Liu, Kai Zhao","doi":"10.31083/FBL54657","DOIUrl":"https://doi.org/10.31083/FBL54657","url":null,"abstract":"<p><strong>Background: </strong>Ergothioneine (EGT) has been reported to alleviate estrogen deficiency-induced osteoporosis, but whether this protection is accompanied by alterations in the bone microvasculature accompany this protection remain unknown. Therefore, this study aimed to examine the effects of EGT in ovariectomized (OVX) mice, with particular attention to type H vessels.</p><p><strong>Methods: </strong>A total of 18 female C57BL/6J mice were randomly assigned to the sham, OVX, and OVX + EGT groups (n = 6 each). EGT was initiated 24 h after OVX and administered for 12 weeks. Femoral structure was evaluated using micro-computed tomography, hematoxylin and eosin staining, immunohistochemistry, and immunofluorescence. Meanwhile, serum assays were used to characterize bone turnover and oxidative stress. In addition, mouse bone-derived type H endothelial cells were exposed to EGT. The localization of organic cation transporter novel type 1 (OCTN1) was examined by immunofluorescence. Angiogenic activity was measured in Matrigel, while OCTN1 gene and protein expression were assessed by reverse-transcription quantitative polymerase chain reaction and Western blotting, respectively.</p><p><strong>Results: </strong>In OVX mice, EGT increased bone mineral density and improved trabecular microarchitecture. Serum superoxide dismutase activity and glutathione concentrations were higher after EGT administration, whereas advanced oxidation protein products and malondialdehyde levels were lower. Bone sections also showed a larger CD31⁺ vascular area, more osterix-positive (Osx⁺) osteogenic cells, and a closer spatial association between these signals. EGT increased OCTN1 expression <i>in vitro</i> and promoted angiogenesis.</p><p><strong>Conclusions: </strong>Early administration of EGT alleviated OVX-induced bone loss. This effect may be linked to reduced oxidative stress and enhanced angiogenesis related to type H vessels.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 9","pages":"54657"},"PeriodicalIF":3.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082938","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}