Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04954-1
Neuroinflammation is a key pathogenic factor for neurodegenerative diseases. Mesenchymal stem cell (MSC) transplantation, as a potential strategy for regulating neuroinflammation, has received extensive attention. Our previous research revealed that compared with ordinary MSC, MSC pretreated with tanshinone IIA (TIIA), referred to as TIIA-MSC, exhibited superior anti-neuroinflammatory activity, but the mechanism of action remains unclear. To clarify the underlying mechanism, this study integrated in vitro and in vivo experiments and evaluated the therapeutic effect of TIIA-MSC in a triple-transgenic Alzheimer’s disease mouse model (3×Tg-AD mice) and explored its mechanism of action in a lipopolysaccharide (LPS)-induced BV2 microglial cell inflammation model. The results showed that TIIA-MSC could significantly improve the cognitive function of 3×Tg-AD mice, increase brain glucose metabolism levels, promote the recovery of synaptic and mitochondrial structures, and effectively alleviate neuroinflammatory responses. In vitro experiments further verified the superior inhibitory effect of TIIA-MSC on microglial cell activation and proinflammatory factor release. Mechanistic studies have indicated that the triggering receptor expressed on myeloid cells 2 (TREM2) is the key molecule that mediates this process. The knockdown of TREM2 expression significantly weakened the anti-inflammatory effect of TIIA-MSC, suggesting that TREM2 plays a central role in this process. Further analysis revealed that by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway downstream of TREM2, TIIA-MSC may promote the transformation of the functional state of microglia from mainly proinflammatory to having neuroprotective and repair properties. This study systematically revealed the molecular mechanism by which TIIA-MSC regulate microglial cell phenotypic transformation through the TREM2/PI3K/Akt pathway and exert anti-neuroinflammatory effects, providing new ideas and an experimental basis for expanding the application of MSC in the treatment of neurodegenerative diseases.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025171
Obesity-induced metabolic inflammation is a key driver of chronic kidney disease (CKD), with immune dysregulation, particularly among lymphocytes, contributing to early disease pathology. To explore the role of apolipoprotein A4 (Apoa4) in regulating immune cell metabolism and function, we establish high-fat diet-induced obese (DIO) models using wild-type and Apoa4-knockout (KO) mice. KO mice exhibit exacerbated insulin resistance and renal lipid accumulation. Single-cell RNA sequencing reveals that Apoa4 deletion remodeled the renal immune-metabolic landscape. This remodeling broadly compromises the immune functions of T, NK, and B cells, even as it expands the proportions of cytotoxic Gzma+ NK cells and Derl3+ plasma cells. Mechanistically, Apoa4 deletion aggravates metabolic dysregulation and oxidative stress and downregulates the expression levels of key effector genes, including Ifng and Il1b. Furthermore, the regulatory network activities of key transcription factors, such as Lef1 and Runx3 in Cd8+ T cells; Irf8, T-bet, and Eomes in NK cells; and Tcf4, Lmo2, and Xbp1 in B cells, are perturbed. CellChat analysis predicts disruptions in pro-inflammatory (IFN-II and IL-1), immunoregulatory (FASLG), and metabolic regulatory (ENHO and ANGPTL) signaling, alongside enhanced IL-2-mediated suppression. These findings are corroborated by flow cytometry, immunofluorescence staining, and qPCR. Our results establish Apoa4 as a crucial regulator of lymphocyte metabolic and immune homeostasis in the early stages of obesity-associated CKD.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025129
This is a corrigendum to the article 'Magnolol promotes the autophagy of esophageal carcinoma cells by upregulating HACE1 gene expression' published in Acta Biochimica et Biophysica Sinica 2024, 56(7): 1044–1054. In the original publication, the corresponding author's email address was personal. To comply with the institution's publishing policy, it has been changed from '[email protected]' to the institutional address '[email protected]'. The authors apologize for any confusion it may have caused.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025044
Pigs, as crucial economic livestock species, possess remarkable reproductive traits and thus play a highly significant role in promoting the progress of the livestock industry. With the advent and application of CRISPR/Cas9 technology, researchers have explored genetic editing techniques to increase swine reproductive performance, flavour profiles, and nutritional attributes. Additionally, with respect to anatomy, physiology, immunology, and genomics as well as other traits, pigs exhibit remarkable similarities to humans. Genetically edited pigs play crucial roles in human disease models, xenotransplantation, breed improvement, vaccine development, and drug assessment. Common methods deployed in the preparation of genetically edited pigs include somatic cell nuclear transfer (SCNT), microinjection and sperm-mediated approaches. For example, Shen et al. [1] successfully generated P53-knockout Diannan miniature pigs using transcription activator-like effector nucleases combined with SCNT, offering a valuable resource for preclinical oncology research. In 2019, Chen et al. [2] employed microinjection to deliver Cas9 messenger ribonucleic acid (mRNA) and single guide ribonucleic acid (sgRNA) into the cytoplasm of fertilized eggs. These authors successfully obtained both the albinism phenotype and the combined phenotype of albinism and immunodeficiency in Tibetan miniature pigs. More recently, Tenihara et al. [3] introduced the CRISPR/Cas9 protein into fertilized porcine eggs via electroporation, enabling a simple, micromanipulation-free approach for generating gene-edited pigs. Among these methods, SCNT has gained extensive interest among researchers because of its reliability. An essential aspect of SCNT is the preparation of embryonic fibroblasts to serve as donor cells. Previously, the CRISPR/Cas9 plasmid editing system served as the predominant technique to generate genetically edited embryonic fibroblasts (Figure 1A) [4]. This approach, which is distinguished by its relative simplicity, high stability, and low cost, was formerly widely utilized in the production of gene-edited pigs. However, plasmid editing is associated with several notable limitations. First, it introduces resistance genes, posing risks of inaccurate gene editing, drug resistance and biosafety concerns. Second, during the CRISPR/Cas9 editing process, there is a possibility of ongoing editing due to deoxyribonucleic acid (DNA) integration. This continuous editing can increase the likelihood of off-target effects, random mutations, and interference with DNA repair mechanisms. Third, the acquisition of positive cell lines via the plasmid editing system typically demands an extended period of in vitro cultivation (lasting 3–4 weeks), which increases the risk of apoptosis and chromosomal aberrations. Consequently, plasmid-based transfection is now largely supplanted by ribonucleoprotein (RNP) systems for gene editing. RNP systems bypass plasmids, delivering the Cas9 protein and sgRNA directly into cells, reducing off-target effects and cytotoxicity [5]. In 2022, Xu et al. [6] developed the reporter RNA-enriched dual-sgRNA CRISPR/Cas9 ribonucleoprotein (RE-DSRNP) method, a transgene-free approach using CRISPR/Cas9 RNPs enriched with ATTO550-tracrRNA (IDT, Iowa, USA) as a fluorescent RNA probe (Figure 1B). This method reduced the time needed to generate donor cells from 3-4 weeks to one week, resulting in high-efficiency WIP1 gene knockouts and the production of pigs with male reproductive disorders. However, owing to genetic diversity, not all target genes achieve 95% editing efficiency, as demonstrated by the RE-DSRNP method, with some falling below 90%. For example, DOCK8, which belongs to the DOCK family, is an atypical guanine nucleotide exchange factor that plays a crucial role in immune responses. DOCK8 deficiency syndrome, a rare hereditary disorder, often leads to combined immunodeficiency and is characterized by elevated serum immunoglobulin E levels, increased eosinophil
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2024044
Esophagus cancer (EC) is one of the most aggressive malignant digestive system tumors and has a high clinical incidence worldwide. Magnolol, a natural compound, has anticancer effects on many cancers, including esophageal carcinoma, but the underlying mechanism has not been fully elucidated. Here, we first find that magnolol inhibits the proliferation of esophageal carcinoma cells and enhances their autophagy activity in a dose- and time-dependent manner. This study demonstrates that magnolol increases the protein levels of LC3 II, accompanied by increased HACE1 protein levels in both esophageal carcinoma cells and xenograft tumors. HACE1-knockout (KO) cell lines are generated, and the ablation of HACE1 eliminates the anti-proliferative and autophagy-inducing effects of magnolol on esophageal carcinoma cells. Additionally, our results show that magnolol primarily promotes HACE1 expression at the transcriptional level. Therefore, this study shows that magnolol primarily exerts its antitumor effect by activating HACE1-OPTN axis-mediated autophagy. It can be considered a promising therapeutic drug for esophageal carcinoma.
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-026-04954-1
Neuroinflammation is a central pathogenic driver of neurodegenerative diseases, including Alzheimer's disease (AD), for which therapeutic options remain limited. Mesenchymal stem cell (MSC) transplantation has emerged as a potential strategy to modulate neuroinflammation, but its efficacy is constrained by suboptimal anti-inflammatory potency. Prior work demonstrated that MSCs pretreated with tanshinone IIA (TIIA-MSC) exhibit superior anti-neuroinflammatory activity compared with naïve MSCs, yet the underlying mechanism remained undefined. This study integrated in vitro and in vivo experiments to evaluate TIIA-MSC in a triple-transgenic AD mouse model (3×Tg-AD) and to dissect mechanisms in a lipopolysaccharide (LPS)-induced BV2 microglial inflammation model. TIIA-MSC significantly improved cognitive function, increased brain glucose metabolism, promoted recovery of synaptic and mitochondrial structures, and alleviated neuroinflammatory responses in 3×Tg-AD mice. In vitro, TIIA-MSC more effectively inhibited microglial activation and proinflammatory factor release. Mechanistic analyses identified triggering receptor expressed on myeloid cells 2 (TREM2) as the key mediator: TREM2 knockdown significantly attenuated the anti-inflammatory effect of TIIA-MSC. Downstream, activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway promoted microglial transformation from a predominantly proinflammatory phenotype toward a neuroprotective, reparative state. These findings systematically reveal that TIIA-MSC regulate microglial phenotypic conversion through the TREM2/PI3K/Akt axis, providing mechanistic rationale and experimental basis for expanding MSC applications in neurodegenerative disease therapy.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025171
Obesity-induced metabolic inflammation drives chronic kidney disease (CKD), with lymphocyte dysregulation contributing to early pathology. We established high-fat diet-induced obese (DIO) models in wild-type and Apoa4-knockout (KO) mice to investigate apolipoprotein A4 (Apoa4) in immune-metabolic regulation. KO mice exhibited exacerbated insulin resistance and renal lipid accumulation. Single-cell RNA sequencing (scRNA-seq) of renal immune cells revealed that Apoa4 deletion remodeled the immune-metabolic landscape, compromising T, NK, and B cell functions while expanding cytotoxic Gzma+ NK cells and Derl3+ plasma cells. Mechanistically, Apoa4 deletion aggravated metabolic dysregulation and oxidative stress, downregulating effector genes including Ifng and Il1b. Transcription factor regulatory networks were perturbed: Lef1 and Runx3 in Cd8+ T cells; Irf8, T-bet, and Eomes in NK cells; and Tcf4, Lmo2, and Xbp1 in B cells. CellChat predicted disrupted pro-inflammatory (IFN-II, IL-1), immunoregulatory (FASLG), and metabolic (ENHO, ANGPTL) signaling, with enhanced IL-2-mediated suppression. Flow cytometry, immunofluorescence, and qPCR validated these findings. Sequencing depth averaged 278,276 reads/cell (WT) and 197,768 reads/cell (KO), ensuring robust detection of low-abundance transcripts despite modest cell capture. Apoa4 is a critical regulator of lymphocyte metabolic and immune homeostasis in early obesity-associated CKD.