Stem Cell Research & Therapy•2025•DOI: 10.1186/s13287-025-04527-8
Background Although both pre-clinical and clinical studies show promising outcomes, resulting in rapid growth of clinical trials of MSC-based therapies in recent years, the heterogeneity and therapeutic inconsistency of MSCs have severely hampered their clinical applications. Purifying homogenous MSC populations with enhanced specific functions represents one promising approach. We have demonstrated recently that the CD317+ MSCs have enhanced anti-inflammatory functions and improved therapeutic efficacy and consistency.
Methods In the current study, we performed both in vitro and in vivo investigations to delineate whether and how CD317 regulates the immune modulation function of MSCs.
Results Our data here indicate that the CD317 directly contributes to the immune suppression function of MSCs stimulated by TNF-α through up-regulating TSG6 via CD317/lipid-raft/TNFR1 complex. The CD317 stabilizes the TNFR1 complex, resulting in hyper-activation of the NF-κB pathway and up-regulation of TSG6, which confers the therapeutic effects of MSCs on the mouse model of ALI (acute lung injury) and IBD (inflammatory bowel disease).
Conclusions Thus, the CD317 stabilizes TNFR1 and confers the anti-inflammatory functions of MSCs via NF-κB/TSG6 Pathway.
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.2025034
Proteinuria-induced damage to renal tubular epithelial cells is one of the main causes of diabetic kidney disease (DKD), and the clearance of overloaded albumin by lysosomes is crucial for maintaining the homeostasis of renal tubular epithelial cells. Therefore, lysosomal damage is closely related to the pathogenesis of DKD, but effective prevention and treatment measures are still lacking. Melatonin (MLT) is secreted by the pineal gland and can not only regulate circadian rhythms but also maintain lysosomal homeostasis. In this study, we demonstrate the presence of significant lysosomal damage in the renal tubules of DKD patients, which causes autophagy impairment and a concomitant oxidative stress imbalance; however, MLT can upregulate transcription factor EB (TFEB) to improve lysosomal damage and restore the biosynthesis of this organelle. Mechanistically, MLT may protect lysosomes via the upregulation of TFEB and the miR-205-5p-LRP-1 pathway in renal tubules, thus improving autophagy dysfunction and oxidative imbalance in DKD.
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2024078
Neural tube defects (NTDs) are characterized by the failure of neural tube closure during embryogenesis and are considered the most common and severe central nervous system anomalies during early development. Recent microRNA (miRNA) expression profiling studies have revealed that the dysregulation of several miRNAs plays an important role in retinoic acid (RA)-induced NTDs. However, the molecular functions of these miRNAs in NTDs remain largely unidentified. Here, we show that miR-10a-5p is significantly upregulated in RA-induced NTDs and results in reduced cell growth due to cell cycle arrest and dysregulation of cell differentiation. Moreover, the cell adhesion molecule L1-like (Chl1) is identified as a direct target of miR-10a-5p in neural stem cells (NSCs) in vitro, and its expression is reduced in RA-induced NTDs. siRNA-mediated knockdown of intracellular Chl1 affects cell proliferation and differentiation similar to those of miR-10a-5p overexpression, which further leads to the inhibition of the expressions of downstream ERK1/2 MAPK signaling pathway proteins. These cellular responses are abrogated by either increased expression of the direct target of miR-10a-5p (Chl1) or an ERK agonist such as honokiol. Overall, our study demonstrates that miR-10a-5p plays a major role in the process of NSC growth and differentiation by directly targeting Chl1, which in turn induces the downregulation of the ERK1/2 cascade, suggesting that miR-10a-5p and Chl1 are critical for NTD formation in the development of embryos.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025053
Krüppel-like factors (KLFs) are a family of 18 transcriptional regulators characterized by three highly conserved C2H2 zinc fingers at their C-terminal regions. KLF7, a member of this family, plays a crucial role in cell proliferation, differentiation, and the development of the nervous system, adipogenesis, diabetes, and various cancers. Studies have shown that KLF7 aggravates metabolic disorders by impeding insulin secretion and sensitivity. The nuclear factor kappa-B (NF-κB) signaling cascade is essential for inflammatory responses, while fatty acid β-oxidation is vital for metabolism. Both are linked to insulin resistance, obesity, and cardiovascular diseases. A functional link between KLF7 and the NF-κB signaling pathway has been demonstrated. In rheumatoid arthritis, KLF7 activates NF-κB signaling pathway, leading to increased cell proliferation and the production of proinflammatory cytokines, including interleukin 6 (IL-6), IL-1β, and IL-17A. In adipose tissue, KLF7 may initiate NF-κB signaling pathway by upregulating protein kinase Cζ, causing significant IL-6 secretion. KLF7 also reduces oleate-induced lipid droplets in chicken preadipocytes, indicating its role in fatty acid metabolism. Studies in mice showed that KLF7 regulates the transcription of genes of the rate-limiting glycolytic enzyme phosphofructokinase liver type (PFKL) and the fatty acid β-oxidation enzyme acyl-CoA dehydrogenase long-chain (ACADL) in cardiomyocytes independently of peroxisome proliferator-activated receptor (PPAR) γ, thereby altering heart metabolism. Additionally, KLF7 may promote cervical cancer progression by enhancing fatty acid utilization efficiency at least via ACADL upregulation. Overall, KLF7 is crucial for the regulation of fatty acid β-oxidation. KLF7 is a ring-shaped protein with zinc fingers forming the protruding part of ring surface. The lack of the third zinc finger domain in KLF7 affected its function in chicken preadipocytes. However, the importance of zinc finger domains for the regulatory function of human KLF7 remains unclear. In this study, we engineered an overexpression vector for wild-type KLF7 (pCMV-myc-KLF7_WT) and three vectors for KLF7 mutants with different zinc finger deletions (pCMV-myc-KLF7_D1, pCMV-myc-KLF7_D2, and pCMV-myc-KLF7_D3). These vectors were constructed using primers shown in Supplementary Table S1 and cDNA from HEK293T cells. Western blot analysis in the HEK293T, Ishikawa, HeLa, and EC109 cells (Pricella, Wuhan, China) showed that, unlike cells transfected with the empty vector (EV) of pCMV-myc (Clontech, Mountain View, USA), Myc-tagged proteins appeared at expected sizes in cells transfected with either the wild-type KLF7 or any of the three mutant KLF7 overexpression plasmids after 48 h (Figure 1A and Supplementary Figure S1). The impacts of overexpressing various KLF7 isoforms on gene transcription related to the NF-κB signaling pathway and fatty acid β-oxidation were evaluated using luciferase reporter assays, real-time PCR, and western blot analysis in Ishikawa, HeLa, and EC109 cells 48 h post-transfection. Details of the luciferase reporter assay transfection protocol are provided in Supplementary Table S2, the oligonucleotide sequences for real-time PCR are shown in Supplementary Table S3, and the antibodies for western blot analysis are listed in Supplementary Table S4. Compared to EV group, wild-type KLF7 overexpression significantly boosted NF-κB pathway activity in HeLa and EC109 cells (P < 0.05, Figure 1B). Furthermore, wild-type KLF7 overexpression significantly elevated IL-6 and TNF-α expressions in Ishikawa and HeLa cells (P < 0.05, Figure 1C), confirming previous findings that KLF7 enhances inflammation via the NF-κB pathway [4,5]. Cells transfected with KLF7 overexpression plasmids lacking zinc fingers showed significant differences in NF-κB pathway activities compared to those transfected with the wild-type KLF7 overexpression plasmid (P < 0.05, Figure 1B). In HeLa and EC109 cells, the absence of zinc fingers reduced NF-κB signaling activity, with the reduction proportional to the number of zinc fingers lost (P < 0.05, Figure 1B). In Ishikawa cells, losing one or two zinc fingers increased NF-κB activity compared to the wild-type KLF7 (P < 0.05, Figure 1B). Additionally, the ability of KLF7 overexpression to increase IL-6 and TNF-α expression decreased with the loss of zinc fingers.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21249
BACKGROUND: In recent years, numerous studies have shown that physical activity significantly promotes neural plasticity, contributing to improvements in cognitive abilities and neurological health. However, the current state and dynamic evolution of the research field on "physical activity and neural plasticity" have not been systematically organized and analyzed. This lack of comprehensive understanding may hinder accurate predictions regarding the future development trends in this area. OBJECTIVE: Using bibliometric methods, we analyzed the dynamic evolution trajectory of research topics in the field of physical activity and neural plasticity, organized the development trends and the evolution of the knowledge framework in this area, and provided directional references for subsequent research. METHODS: Relevant literature was retrieved from the Web of Science Core Collection database (www.webofscience.com) using the following search strategy: TS=(("physical activity" OR exercise OR "motor activity" OR "physical exercise" OR "aerobic exercise" OR "physical training") AND ("neuroplasticity" OR "brain plasticity" OR "neural plasticity" OR "cognitive plasticity" OR "brain adaptability")). A total of 2,098 eligible articles were included. Co-word analysis and visualization were performed using SciMAT software to generate keyword topic overlay maps, strategic coordinate maps, and topic evolution path maps, revealing the dynamic evolution process of research topics in this field. RESULTS AND CONCLUSION: (1) Research in the field of physical activity and neural plasticity is flourishing, with increasingly in-depth studies and ample room for future development. (2) The field comprises five main evolution directions: "physical activity", "adult rats", "stem cells", "individual differences", and "randomized controlled trials", forming 15 sub-evolution paths. (3) Topics such as "older adults", "animal models", and "disease" may become future research focuses. (4) Therefore, it is recommended that future research employ randomized controlled trials and optimized animal model designs to investigate the long-term effects and mechanisms of physical activity on neural plasticity and cognitive function, and focus on clinical validation of multimodal interventions in special populations.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026020
The insulin receptor (IR) is central to the regulation of glucose and lipid metabolism. Although insulin is its primary ligand, insulin-like growth factors I and II (IGF-I and IGF-II) also engage IR, albeit with reduced affinity. The structural basis of cooperative ligand binding, however, has remained poorly understood. Here, we report cryo-Electron Microscopy (cryo-EM) structures of IR in complex with insulin, IGF-I, and IGF-II, revealing that all three ligands engage the receptor at overlapping binding sites and can induce a conserved T-shaped quaternary assembly involving four ligand molecules at site 1/1′ and site 2/2′. Despite this shared overall architecture, distinct ligand-specific conformational changes are observed. Notably, IGF-I and IGF-II adopt different binding sequence at site 1 and site 2 compared to insulin, suggesting unique interaction dynamics. These structural insights highlight divergent mechanisms of ligand recognition and cooperative binding, providing a deeper understanding of hormone-induced conformational modulation of the IR.
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.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025066
Chromosome congression and spindle assembly are essential for genomic stability, and their dysregulation is linked to tumorigenesis. WDR5, a core component of the MLL methyltransferase complex, directly binds Kif2A to regulate mitotic events, but the structural basis of this interaction remained unresolved. Here, the crystal structure of WDR5 in complex with a Kif2A-derived peptide (residues 114–122) was determined at 1.85 Å resolution. Kif2A engages both the WIN and S7 sites of WDR5 via Arg117 and Ser121; Ser121 forms hydrogen bonds with WDR5 Tyr191 and Lys259, inducing Tyr191 rotation and opening the S7 pocket. Structures of WDR5 with truncated or mutated Kif2A peptides and a WDR5 Y191F variant reveal the dynamic nature of Tyr191. Anti-WDR5 compounds exhibit a similar binding mode at the WIN-S7 site. Mutagenesis combined with isothermal titration calorimetry (ITC) assays underscore the critical roles of Arg117 and Ser121 in mediating Kif2A–WDR5 binding. These findings provide atomic-level insights into the non-canonical mitotic function of the MLL/WDR5 complex and highlight WIN-S7 sites as promising therapeutic targets for diseases associated with chromosomal instability, such as cancers.