Genomics, Proteomics & Bioinformatics•2024•DOI: 10.1093/gpb/art_1118
Despite the success of antiretroviral therapy, human immunodeficiency virus (HIV) cannot be cured because of a reservoir of latently infected cells that evades therapy. To understand the mechanisms of HIV latency, we employed an integrated single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq) approach to simultaneously profile the transcriptomic and epigenomic characteristics of ~125,000 latently infected primary CD4+ T cells after reactivation using three different latency reversing agents. Differentially expressed genes and differentially accessible motifs were used to examine transcriptional pathways and transcription factor (TF) activities across the cell population. We identified cellular transcripts and TFs whose expression/activity was correlated with viral reactivation and demonstrated that a machine learning model trained on these data was 75%–79% accurate at predicting viral reactivation. Finally, we validated the role of two candidate HIV-regulating factors, FOXP1 and GATA3, in viral transcription. These data demonstrate the power of integrated multimodal single-cell analysis to uncover novel relationships between host cell factors and HIV latency.
Stem Cell Research & Therapy•2025•DOI: 10.1186/s13287-025-04378-3
Background Myocardial infarction (MI) is a severe disease that often associated with impaired angiogenesis and increased myocardial apoptosis. Mesenchymal stromal cells (MSCs) have been a promising candidate for treating myocardial infarction. However, functional heterogeneity of MSCs leads to inconsistent therapeutic efficiency and the current MSCs-based therapy lacks the concept and implementation of precision medicine. In this study, we compared the cardioprotective effect of UCMSCs and ADMSCs targeting the angiogenesis in a mouse MI model and screened out optimum MSCs candidate for precise clinical application. Methods The gene expression profiles of UCMSCs and ADMSCs were investigated through RNA sequencing analysis. To compare their angiogenic potential, we performed tube formation assay, Matrigel plug assays, and aortic ring assay, and analyzed pro-angiogenic genes via qPCR. Subsequently, UCMSCs and ADMSCs were respectively injected into myocardium after MI surgery in mice. On day 28 post-MI, echocardiography was performed to assess cardiac function. Histological analysis was performed to assess MSCs retention, angiogenesis, and myocardial apoptosis. Additionally, the anti-apoptosis effects mediated by MSCs were further evaluated using flow cytometry in hypoxia H9C2 and HL-1 cells. Results The RNA sequencing analysis revealed differences in gene expression related to angiogenesis and apoptosis pathways between UCMSCs and ADMSCs. UCMSCs presented greater pro-angiogenesis activity than ADMSCs in vitro and in vivo. Both of UCMSCs and ADMSCs improved cardiac function, decreased infarction area and inhibited cardiomyocyte apoptosis while promoting angiogenesis post-MI in mice. Notably, ADMSCs exerted a better cardioprotective function than UCMSCs and stronger anti-apoptotic effect on residual cardiomyocytes.
Stem Cell Research & Therapy•2024•DOI: 10.1186/s13287-024-03689-1
Background The clinical application of human bone-marrow derived mesenchymal stem cells (MSCs) for the treatment of refractory diseases has achieved remarkable results. However, there is a need for a systematic evaluation of the quality and safety of MSCs sourced from donors. In this study, we sought to assess one potential factor that might impact quality, namely the age of the donor. Methods We downloaded two data sets from each of two Gene Expression Omnibus (GEO), GSE39035 and GSE97311 databases, namely samples form young (<65 years of age) and old (>65) donor groups. Through, bioinformatics analysis and experimental validation to these retrieved data, we found that MSCs derived from aged donors can lead to differential expression of gene profiles compared with those from young donors, and potentially affect the function of MSCs, and may even induce malignant tumors. Results We identified a total of 337 differentially expressed genes (DEGs), including two upregulated and eight downregulated genes from the databases of both GSE39035 and GSE97311. We further identified 13 hub genes. Six of them, TBX15, IGF1, GATA2, PITX2, SNAI1 and VCAN, were highly expressed in many human malignancies in Human Protein Atlas database. In the MSCs in vitro senescent cell model, qPCR analysis validated that all six hub genes were highly expressed in senescent MSCs. Our findings confirm that aged donors of MSCs have a significant effect on gene expression profiles. The MSCs from old donors have the potential to cause a variety of malignancies. These TBX15, IGF1, GATA2, PITX2, SNAI1, VCAN genes could be used as potential biomarkers to diagnosis aging state of donor MSCs, and evaluate whether MSCs derived from an aged donor could be used for therapy in the clinic. Our findings provide a diagnostic basis for the clinical use of MSCs to treat a variety of diseases. Conclusions Therefore, our findings not only provide guidance for the safe and standardized use of MSCs in the clinic for the treatment of various diseases, but also provide insights into the use of cell regeneration approaches to reverse aging and support rejuvenation.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025042
This study elucidates the mechanisms by which cancer-associated fibroblast (CAF)-derived platelet-derived growth factor C (PDGFC) promotes the progression of lung adenocarcinoma (LUAD) and explores the impact of PDGFC on immune regulation within the tumor microenvironment (TME). Our results show that there is higher expression of PDGFC in CAFs than in nontumor tissue fibroblasts (NFs) and that higher expression of PDGFC is correlated with poor prognosis in LUAD patients. Furthermore, CAF-derived PDGFC promotes epithelial-mesenchymal transition (EMT) in cancer cells as well as matrix metalloproteinase 2 (MMP2) expression through the PDGF receptor A (PDGFRA)-mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Moreover, our study demonstrates that CAF-derived PDGFC is essential for the activation and infiltration of fibroblasts in the TME, as well as the inflammatory infiltration of different immune cell types and the immunosuppressive conditions within the TME. In particular, PDGFC induces increased PDGFRA expression in both tumor cells and fibroblasts, which can lead to reciprocally positive feedback to accelerate malignant tumor progression. This discovery provides a novel TME-targeted strategy for LUAD treatment.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025016
CRISPR-Cas nucleases have been extensively used in molecular detections, especially highly sensitive nucleic acid detections. In these detections, Cas nucleases are programmed by the guide RNA to respond to the detection targets and cleave the chemically labelled molecular beacons by the trans-cleavage activity to produce the detection signal. To improve sensitivity, nucleic acid amplification technologies are usually introduced to give a pre-amplification of the nucleic acid targets, increasing the detection sensitivity extraordinarily. Polymerase chain reaction (PCR) technology has been used for pre-amplification in laboratories, and isothermal amplification technologies are applied to meet point-of-care testing (POCT) needs because they avoid the use of sophisticated thermal cycling devices. The recombinase polymerase amplification (RPA) technology that amplifies nucleic acid targets isothermally at 37–42°C has been combined with CRISPR-Cas nucleases to establish advantageous nucleic acid detection assays, e.g., the SHERLOCK, which combines with Cas13a, and the DETECTR, which combines with Cas12a. It has been challenging to integrate Cas nucleases and RPA in a one-pot reaction system because the cleavage activity of Cas stimulated by even small amounts of the targets can interfere with amplification by digesting the primers or the newly amplified fragments. Thus, many assays based on Cas nucleases and RPA are in a two-step setting, with pre-amplification and Cas cleavage being isolated as two independent procedures. The two-step setting ensures that amplification and cleavage occur under favorable conditions but sacrifices operational convenience and introduces the risk of cross-contamination. In efforts to establish one-pot RPA-Cas assays, many strategies have been applied, including the use of photocontrolled guide RNA to activate the Cas nuclease at a preferred timepoint, the use of a suboptimal protospacer adjacent motif (PAM) to suppress Cas activity, the generation of dynamic aqueous multiphase with sucrose or glycerol to partially separate the two reactions, and extensive optimization of the RPA-CRISPR reaction system to achieve a subtle balance between the two reactions. In this study, a one-pot CRISPR-Cas12b and RPA combined assay with a temperature switch (CRATS) was established utilizing the reaction temperature difference between RPA and CRISPR-Cas12b cleavage. The Cas12b used in this study, AaCas12b, is a type V-B CRISPR‒Cas nuclease from Alicyclobacillus acidiphilus. It has a bi-lobed architecture consisting of an α-helical recognition lobe containing the REC domains and a nuclease lobe containing the WED, RuvC and Nuc domains. As a dual-RNA-guided DNA endonuclease, Cas12b can be guided by a chimeric single-guide (sg) RNA, and its trans-cleavage activity is specifically activated by the DNA target and results in nonspecific cleavage of single-stranded (ss) DNA molecules, which can be used to produce detection signals if the ssDNA is appropriately labelled as the molecular beacon. As the temperature for RPA is 37°C and the trans-cleavage of Cas12b is active at 60°C, CRATS uses temperature switching to adjust the major on-going reaction in the one-pot system and realizes sequential amplification of the target and cleavage reactions for signal detection. The detection target of this study, monkeypox virus, is an infectious pathogen that has caused the announcement of the Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) twice in recent years. In this one-pot CRATS assay, the reaction reagents of CRISPR-Cas12b and RPA are mixed in a single tube. After the addition of the sample containing the detection target, the reaction was carried out at 37°C for 20 min for amplification, followed by 60°C for 20 min for Cas12b cleavage. The fluorescently labelled molecular beacon is cleaved by Cas12b to release the FAM fluorophore from quenching, producing a fluorescence signal that is visualized under blue light. CRATS shows a high sensitivity of 100 copies of the target DNA per reaction and good specificity, providing a novel strategy of temperature switching to integrate CRISPR-Cas and RPA in a one-pot reaction system. Moreover, it provides a POCT-friendly tool for the detection of the important infectious pathogen monkeypox virus.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2025207
O-GlcNAcylation, a prevalent reversible post-translational modification, intricately alters non-histone proteins, influencing the organization of gene transcriptional regulation within the accessible chromatin environment. This nucleoplasmic landscape, characterized by histone-free regions, fundamentally enables O-GlcNAc-mediated modulation through dynamic accessibility. However, unraveling the O-GlcNAc-open chromatin interplay that governs sophisticated transcriptional regulatory networks remains constrained by current techniques, which lack the resolution to probe this spatiotemporal crosstalk. Here, we report a general strategy to systematically and chemoselectively profile O-GlcNAc-associated chromatin accessibility on a genome-wide scale (COCA-seq). Through comprehensive validation across low- and high-throughput levels, we demonstrate COCA-seq’s dual fidelity in both O-GlcNAc chemoselectivity and open chromatin specificity. We employ it to delve into doxorubicin resistance for breast cancer, scrutinizing pivotal regulatory genes and transcription factors implicated in this complex biological event. By integrating bulk RNA-seq with COCA-seq, we offer a multiomics perspective, shedding light on related biological processes and pathways like drug efflux and stress homeostasis, thereby uncovering potential mechanisms by which O-GlcNAc-associated open chromatin orchestrates tumor drug resistance. COCA-seq emerges as a general and versatile tool across various biological contexts, poised to reveal the landscape of O-GlcNAc-associated open chromatin regions across the genome and decipher the significance of glycosylation behind it.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2025136
Tumor cells exhibit a notable ability to adapt to constantly changing microenvironments and possess distinct metabolic traits during metastasis. This study aims to establish a melanoma lung metastasis model in mice to elucidate the metabolic mechanisms involved in early-stage metastasis prior to treatment. The male C57BL/6 mice are divided into five groups based on time intervals of 6, 24, 72, and 120 h post-injection (SKCM-M groups) of melanoma cells, as well as a normal control group (NOR group). Our results demonstrate that platelet activation mainly occurs in the initial phases of metastasis to help tumor cells survive. NMR-based metabolomics analysis of mouse lung tissues identifies distinct metabolites and pathways associated with early-stage metastasis, revealing significant alterations in energy and amino acid metabolism during tumor progression. Further analysis indicates that methylxanthine and allantoin could serve as potential biomarkers for monitoring the early progression of tumor metastasis in cancer patients, providing novel insights into early diagnostic strategies for lung metastasis.
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2024128
Glycosylphosphatidylinositol (GPI) is a highly conserved post-translational modification in eukaryotes, which is essential for anchoring various proteins to the cell surface. Dysfunction of GPI biogenesis leads to human diseases, such as inherited GPI deficiency (IGD) caused by germline mutations in GPI-related genes. With accumulating reports on individuals with IGD, there has been increasing interest and studies on disease mechanism, diagnosis, and therapy. This review outlines the biosynthetic pathway of GPI-anchored proteins (GPI-APs) and summarizes clinical IGD cases from a molecular perspective. We also review current diagnostic and therapeutic approaches for IGD. Finally, we discuss future research directions to facilitate the understanding and treatment of GPI-related disorders.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024171
Ozone (O3), a prevalent atmospheric pollutant, can induce lung injury. However, the molecular mechanisms of O3-induced acute lung inflammatory injury remain unclear. In this study, we investigate the abnormal changes in and molecular mechanism of mitochondrial homeostasis in alveolar macrophages (AMs) in O3-induced acute lung inflammatory injury mice. Mitochondria and mitochondrial reactive oxygen species (mtROS) are labeled with Mito-Tracker® Deep Red and MitoSOX Red, respectively. Mitochondrial DNA (mtDNA) in AMs from the bronchoalveolar lavage fluid (BALF) is detected via real-time PCR, and the expressions of mitochondrial fusion/fission-related and biogenesis-related proteins in AMs are determined via immunofluorescence staining. Our data show that in O3-induced acute lung inflammatory injury mice, the number of AMs and the protein expression of the NLRP3 inflammasome complex in the lung tissue are increased. In AMs from O3-exposed mice, the number of mitochondria, mtROS, and fission-related protein DRP1 are increased, but the levels of Na+-K+-ATPase, fusion-related protein OPA1, biogenesis-related protein NRF1 and mtDNA are significantly decreased. Compared with that in O3-exposed WT mice, lung inflammation is attenuated, especially the indicators of mitochondrial homeostatic imbalance in AMs, which are alleviated in NLRP3‒/‒ and Caspase-1‒/‒ mice after O3 exposure. These findings indicate that the NLRP3 inflammasome-mediated imbalance in mitochondrial homeostasis in AMs contributes to O3-induced acute lung inflammatory injury. This study may provide a new target for the prevention of lung inflammation induced by O3.
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2024047
The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ligase complex in which the ubiquitin-like (UBL) domains of SHARPIN and HOIL-1L interact with HOIP to determine the structural stability of LUBAC. The interactions between subunits within LUBAC have been a topic of extensive research. However, the impact of the LTM motif on the interaction between the UBL domains of SHARPIN and HOIL-1L with HOIP remains unclear. Here, we discover that the absence of the LTM motif in the AlphaFold2-predicted LUBAC structure alters the HOIP-UBA structure. We employ GeoPPI to calculate the changes in binding free energy (ΔG) caused by single-point mutations between subunits, simulating their protein-protein interactions. The results reveal that the presence of the LTM motif decreases the interaction between the UBL domains of SHARPIN and HOIL-1L with HOIP, leading to a decrease in the structural stability of LUBAC. Furthermore, using the AlphaFold2-predicted results, we find that HOIP (629‒695) and HOIP-UBA bind to both sides of HOIL-1L-UBL, respectively. The experiments of Gromacs molecular dynamics simulations, SPR and ITC demonstrate that the elongated domain formed by HOIP (629‒695) and HOIP-UBA, hereafter referred to as the HOIP (466‒695) structure, interacts with HOIL-1L-UBL to form a structurally stable complex. These findings illustrate the collaborative interaction between HOIP-UBA and HOIP (629‒695) with HOIL-1L-UBL, which influences the structural stability of LUBAC.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21225
BACKGROUND: The crescent sign is a significant radiological feature in the progression of steroid-induced osteonecrosis of the femoral head (SIONFH), indicating the separation and defect of articular cartilage and subchondral bone. The appearance of the crescent sign is associated with the mid-to-late stages of the disease and poor prognosis. However, studies on the specific pathological characteristics and progression patterns of articular cartilage in SIONFH remain unclear. OBJECTIVE: To observe the pathological features of articular cartilage in specimens from different stages of SIONFH, explore the progression and pathological mechanisms, and elucidate the formation mechanism of the crescent sign, providing a theoretical basis for optimizing hip-preserving strategies. METHODS: Femoral head specimens were collected from patients with SIONFH who underwent total hip arthroplasty at the First Affiliated Hospital of Guangzhou University of Chinese Medicine from 2021 to 2024. According to the ARCO staging, they were divided into mild, moderate, and severe collapse groups, with fresh femoral neck fracture specimens as controls. All specimens were cut coronally, and the folded cartilage surface in the necrotic area was taken; control group took corresponding area. Hematoxylin-eosin staining and Safranin O-fast green staining were used for morphological observation, immunohistochemistry and western blot for biomarker expression, and apoptosis kit for apoptosis level. RESULTS AND CONCLUSION: (1) Gross observation: The control group showed smooth cartilage surface without folds or hyperplasia, no separation or defect between articular cartilage and subchondral bone, and tough texture. In SIONFH specimens, obvious folds were visible on the cartilage surface, with separation and defects between articular cartilage and subchondral bone, and a loose sensation on pressing. (2) Pathological observation: In the control group, chondrocytes in each layer were arranged neatly, cartilage matrix stained uniformly, tidemark was intact and continuous, calcified cartilage layer and subchondral bone connection was clear and complete, and bone trabeculae were arranged neatly. In SIONFH specimens, chondrocytes were disorganized, empty lacunae increased, matrix staining loss of varying degrees, tidemark duplication and loss, calcified cartilage layer showed numerous cavities and sclerosis, with granulation tissue invasion into cavities, separation and defects between calcified cartilage and subchondral bone, and abundant proliferative granulation tissue in subchondral bone trabecular spaces. (3) Immunohistochemistry: In SIONFH specimens, positive staining of Runt-related transcription factor 2, matrix metalloproteinase 13, matrix metalloproteinase 3, and collagen type I alpha 2 chain increased in calcified cartilage layer and deep cartilage; vascular endothelial growth factor A, hypoxia-inducible factor 1 alpha, interleukin-1 beta, and tumor necrosis factor alpha positive staining increased in subchondral bone trabecular spaces and deep cartilage granulation and scar tissue. (4) Western blot results showed decreased expression of collagen type II alpha 1 chain and SOX9, and increased expression of Runt-related transcription factor 2, matrix metalloproteinase 13, hypoxia-inducible factor 1 alpha, and vascular endothelial growth factor A in SIONFH specimens. (5) Caspase3/7 activity in SIONFH samples was significantly higher than that in the control group, positively correlated with the degree of collapse. (6) These results indicate that articular cartilage lesions in SIONFH mainly concentrate in the deep cartilage and calcified cartilage around the necrotic area. Necrosis of subchondral bone leads to changes in local microenvironment and elastic modulus, causing sclerosis of calcified cartilage. With continued weight-bearing, stress concentration at the necrosis-sclerosis junction leads to brittle fracture, which is the starting point of fracture. Bone and cartilage fracture leads to destruction of the subchondral cortical bone barrier, and invasion of granulation tissue from subchondral bone trabecular spaces directly stimulates calcified cartilage and deep cartilage, resulting in terminal differentiation, apoptosis, matrix degradation, and cavity formation of chondrocytes, leading to decreased repair capacity of articular cartilage. The diseased cartilage cannot properly interlock with subchondral bone, and with disease progression, extensive separation and defects eventually appear between bone and cartilage, manifesting as the crescent sign on imaging.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21316
BACKGROUND: The therapeutic potential of Toddalia asiatica in rheumatoid arthritis has garnered increasing attention, yet its mechanisms remain incompletely elucidated. OBJECTIVE: To investigate the underlying mechanisms of Toddalia asiatica in treating rheumatoid arthritis using bioinformatics combined with molecular dynamics simulation. METHODS: Active ingredients of Toddalia asiatica and their targets were retrieved. Drug targets were intersected with rheumatoid arthritis-related targets, followed by enrichment analysis of the overlapping genes. Molecular docking and molecular dynamics simulation were performed to validate the binding mechanisms of core active ingredients with key targets. RESULTS AND CONCLUSION: Through literature retrieval, 22 core active ingredients of Toddalia asiatica and their key targets against rheumatoid arthritis were identified. Enrichment analysis indicated that Toddalia asiatica may exert therapeutic effects by modulating disease-related signaling pathways (including cancer, infectious diseases, metabolic diseases, and cardiovascular diseases) as well as biological pathways related to metabolism, immunity, and inflammation. Meanwhile, the main components Dihydrochelerythrine and 8-Methoxychelerythrine specifically target phospholipase C gamma 2 (PLCG2) and mitogen-activated protein kinase 8 (MAPK8), respectively, suggesting that Toddalia asiatica may exert anti-rheumatoid arthritis effects through synergistic multi-pathway regulation.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21356
BACKGROUND: Stem cells show a great potential in oral tissue regeneration but face challenges such as immune rejection and tumor formation. Exosomes are nanoscale extracellular vesicles secreted by cells, reducing immunogenicity and tumor risks while maintaining stem cell functions, such as promoting angiogenesis and tissue repair. OBJECTIVE: To summarize the mechanisms and roles of exosomes in oral tissue regeneration, explore exosome engineering strategies and the challenges and future directions in the application of exosomes in oral regenerative medicine. METHODS: The relevant literature published from the WanFang and PubMed databases from their inception to 2025 was searched using Chinese search terms “stem cells, exosomes, dental pulp regeneration, periodontal regeneration” and English search terms “exosomes, stem cells, dentistry, regenerate.” Finally, 94 articles were included for review and analysis. RESULTS AND CONCLUSION: (1) Exosomes have lower immunogenicity and no tumorigenic risk compared with stem cells. They are more stable and easier to store and transport. Additionally, exosomes can penetrate dense tissues for targeted delivery, avoiding ethical and immune rejection issues associated with stem cell therapy, making them a safer and more effective treatment option. (2) Exosomes have shown significant efficacy in regenerating dental pulp, periodontal tissues, craniofacial bone, salivary glands, nerves, and skin, promoting tissue repair and regeneration through multiple mechanisms, demonstrating broad application prospects. (3) Engineering strategies such as preconditioning, isolation and purification, and targeted modification can enhance exosome function, improving therapeutic potential and clinical feasibility. However, current technologies still have limitations, and further optimization is needed to promote widespread application of exosomes.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21342
BACKGROUND: Although cell transplantation offers a promising approach for the treatment of myocardial infarction, the low transplantation rate limits its application. Therefore, promoting the proliferation of transplanted cells and reducing apoptosis are the key issues to be solved urgently to improve the therapeutic effect. OBJECTIVE: To investigate the effects of non-coding RNA-activated by DNA damage (NORAD) on the proliferation of human induced pluripotent stem cell-derived cardiomyocytes and their apoptosis induced by oxygen-glucose deprivation/reoxygenation, as well as the effects of transplanting NORAD-overexpressing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-NORADOECMs) on cardiac function in a murine model of myocardial infarction. METHODS: The expression of NORAD in the hearts of mice at different ages (3 days old and 8 weeks old) was measured by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). A cellular model of hiPSC-NORADOECMs was established by infecting human induced pluripotent stem cells with a lentiviral vector designed to specifically upregulate NORAD, followed by directed differentiation into cardiomyocytes. The overexpression efficiency was confirmed by RT-qPCR. Proliferation was assessed by immunofluorescence staining for Ki67. Apoptosis was induced by oxygen-glucose deprivation/reoxygenation (OGD/R). Intracellular reactive oxygen species (ROS) levels were measured by flow cytometry, and the expression of apoptosis-related proteins (Bax, Bcl-2, Cleaved Caspase-3) was detected by western blot. In vivo, hiPSC-NORADOECMs were transplanted into the infarcted myocardium of mice, and cardiac function was evaluated by echocardiography after 4 weeks. RESULTS AND CONCLUSION: NORAD expression was significantly higher in 3-day-old neonatal mouse hearts compared with 8-week-old adult hearts. hiPSC-NORADOECMs were successfully generated, showing increased Ki67 expression compared with control cells. Overexpression of NORAD inhibited OGD/R-induced ROS production, decreased Bax and Cleaved Caspase-3 protein levels, and increased Bcl-2 levels. Transplantation of hiPSC-NORADOECMs significantly improved cardiac function in myocardial infarction mice. These findings indicate that NORAD overexpression promotes hiPSC-CM proliferation and inhibits apoptosis by reducing ROS production, thereby enhancing the reparative capacity of hiPSC-CMs in myocardial infarction.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025042
Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, with late-stage 5-year survival rates below 50%. Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) drive progression, yet the molecular mediators of CAF-tumor crosstalk are incompletely defined. This study identifies platelet-derived growth factor C (PDGFC) as a critical CAF-secreted factor that promotes epithelial-mesenchymal transition (EMT) and immunosuppression in LUAD. Analysis of patient specimens revealed elevated PDGFC expression in CAFs relative to nontumor tissue fibroblasts (NFs), and high PDGFC levels correlated with poor prognosis. Mechanistically, CAF-derived PDGFC activates the PDGF receptor A (PDGFRA)-mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway in cancer cells, inducing EMT and matrix metalloproteinase 2 (MMP2) expression. PDGFC also stimulates PDGFRA expression in both tumor cells and fibroblasts, establishing a reciprocal positive feedback loop that accelerates fibrotic TME remodeling and malignant progression. Immunologically, PDGFC promotes infiltration and polarization of immunosuppressive cell populations, including CD4+ Treg cells, M2 macrophages, and N2 neutrophils, while restraining immunocompetent NK cells. Immunoinhibitors TGFB1, CSF1R, PD-L1, PD-L2, KDR, IL10RB, and HAVCR2 may synergize with PDGFC in modulating immunosuppression. These findings position PDGFC as a diagnostic indicator and potential immunotherapy target for LUAD, offering a novel TME-targeted therapeutic strategy.