Acta biochimica et biophysica Sinica最新文献

Obesity has emerged as a critical global health challenge, contributing to severe metabolic and neoplastic complications. However, most existing anti-obesity drugs exhibit significant adverse effects, necessitating the development of safer therapeutic alternatives. In this study, we evaluate the efficacy and safety of a flavonoid-rich medicinal herb extract (MHE) in a high-fat diet (HFD)-induced murine obesity model. Daily oral administration of MHE does not alter food intake or induce hepatic injury but significantly attenuates HFD-induced weight gain ( P < 0.05) and adiposity accumulation. Furthermore, MHE treatment improves systemic insulin sensitivity and glycemic control. Notably, MHE enhances whole-body energy expenditure, as evidenced by elevated oxygen consumption (VO ₂), carbon dioxide production (VCO ₂), and heat generation ( P < 0.01). Mechanistically, MHE selectively promotes the proliferation of beneficial gut microbiota, including Lactobacillus, Akkermansia, and Bifidobacterium species, resulting in increased production of the short-chain fatty acid propionate (PA). Elevated circulating PA levels subsequently stimulate the browning/beiging of inguinal white adipose tissue (iWAT) and upregulate thermogenic pathways. Collectively, our findings demonstrate that MHE exerts anti-obesity effects through gut microbiota modulation and adipose tissue remodeling, offering a promising natural alternative for obesity management.

Epstein-Barr virus (EBV) is now recognized as the definitive environmental driver of multiple sclerosis (MS), shifting the conceptual landscape of this autoimmune disorder to an infection-triggered model. In this review, we systematically evaluate the multidimensional evidence linking EBV to MS. This evidence ranges from epidemiological associations and the identification of mimotopes to emerging therapeutic strategies. We also discuss the broader implications of infection-driven immune dysregulation for autoimmune research. This pathogenic link is underpinned by molecular mimicry, where immune responses against the viral protein EBNA1 cross-react with the central nervous system (CNS) protein GlialCAM. Beyond this initial insult, EBV reprograms B cells to survive and proliferate abnormally, creating a compartmentalized viral reservoir within the CNS that sustains chronic neuroinflammation. These mechanistic insights catalyze a transition from broad immunosuppression to precision therapies targeting the EBV-MS axis, including CNS-penetrant kinase inhibitors and EBV-specific CAR-T cells. By integrating etiological discovery with mechanism-based intervention, the EBV-MS paradigm serves as a blueprint for transforming idiopathic autoimmune diseases into mechanistically tractable conditions with actionable therapeutic targets.

Macrophages play a pivotal role in bone regeneration, making their polarization a key target for immune regulation and therapeutic intervention. Modulating macrophage polarization represents a promising strategy for enhancing bone repair. Luteolin, a plant-derived flavonoid with well-documented anti-inflammatory properties, has been explored for its role in bone repair. However, its specific effects on macrophage polarization in bone repair remain unclear. This study investigates the role of luteolin in macrophage polarization and its underlying mechanisms. Our findings demonstrate that luteolin promotes M2 polarization while suppressing M1 polarization, as indicated by a reduction in the expression of pro-inflammatory markers, including IL-6 and iNOS, and an increase in the expression of anti-inflammatory factors, such as CD206, IL-10, and TGF-β. Mechanistically, luteolin inhibits STING oligomerization, thereby suppressing the STING-TBK1 pathway and mitigating downstream inflammatory responses. In vivo, in a mouse tibial bone defect model, luteolin effectively alleviates inflammation, facilitates angiogenesis, enhances collagen deposition, and improves bone density. Collectively, these findings highlight the potential of luteolin as a therapeutic agent for bone repair by modulating macrophage polarization and inhibiting STING-TBK1 signaling.

Hepatocellular carcinoma (HCC), the predominant type of primary liver cancer, represents an extremely aggressive malignancy. The induction of cuproptosis has developed into a favorable therapeutic direction for HCC, considering its strong association with HCC. Sanguinarine (San), a benzophenanthridine alkaloid derived from traditional herbs such as Chelidonium majus L., demonstrates broad-spectrum anticancer activities against various cancer cell types. However, the precise molecular mechanisms underlying its effects in the treatment of HCC remain largely undefined. This investigation seeks to examine the anti-HCC effects of San and to explore the mechanisms underlying these effects through the induction of cuproptosis. In vitro experiments demonstrate that San markedly inhibits the proliferation, movement, and epithelial-mesenchymal transition of HCC cells while enhancing their apoptosis. In vivo, San notably impedes tumor growth and upregulates the cuproptosis signature markers ferredoxin 1 (FDX1), oligomeric dihydrolipoamide S-acetyltransferase (DLAT), and heat shock protein 70 (HSP70) in HCC xenograft tumor models. Mechanistically, San induces proteotoxic stress and cuproptosis in HCC cells by increasing copper concentration, upregulating the expression of FDX1, lipoic acid synthetase (LIAS), HSP70, and lipoylated DLAT aggregation, and simultaneously reducing mitochondrial membrane potential and intracellular glutathione and pyruvate levels. Moreover, the combination of San with copper ionophores (Elesclomol-CuCl ₂) exhibits synergistic effects in promoting cuproptosis. FDX1 silencing markedly diminishes San-induced suppression of cell proliferation and FDX1 and HSP70 levels in HCC cells. Additionally, molecular docking analysis predicts that San exhibits the highest potential for binding with FDX1. Surface plasmon resonance experiments and cellular thermal shift assay confirm that San strongly interacts with FDX1 and markedly enhances the thermostability of FDX1. In conclusion, our findings indicate that San substantially inhibits the progression of HCC by targeting FDX1/LIAS/DLAT/HSP70 axis-dependent cuproptosis.

Dendritic cells (DCs) exhibit the capacity to elicit either immune activation or tolerance, contingent upon diverse induction conditions. However, the crucial factors governing the induction of tolerogenic dendritic cells (Tol-DCs) remain obscure. Our study demonstrates that the combined use of docosahexaenoic acid (DHA) and the mammalian target of rapamycin inhibitor PP242 (comb-DHA) markedly hinders DC maturation while maintaining DC phagocytic capabilities in an immature state, thereby enabling substantial and sustained DHA accumulation within cells. Upon withdrawal of exogenous drug intervention, we observe that the retained DHA within the DCs facilitates delayed activation of p-AKT ^Ser473 and PTDSS2-related pathways, ultimately leading to the induction of a novel type of Tol-DC, comb-DHA-DC. These Tol-DCs display significantly reduced expression of costimulatory molecules and possess the ability to profoundly inhibit T-cell proliferation. Adoptive transfer of comb-DHA-DCs suppresses allograft rejection reactions. In summary, our findings reveal a novel strategy for inducing Tol-DCs and present a promising therapeutic avenue for enhancing graft tolerance.

Pearl protein extracted from freshwater mussels has been shown to inhibit tyrosinase activity. However, the unclear inhibitory mechanism and associated conformational changes limit their practical applications. In this study, peptides from the crude extract of pearl powder are analyzed via liquid chromatography-tandem mass spectrometry (LC-MS/MS). These peptides are subsequently assessed for their tyrosinase inhibitory potential via molecular docking techniques. Notably, experiments reveal that a small-molecule peptide effectively prevents the interaction between 3,4-dihydroxyphenylalanine (L-DOPA) and tyrosinase, impeding the formation of dopaquinone. The peptide GLGGGLAGAGGADGA (95P, 1099.54 Da) shows particular promise, with synthesized 95P inhibiting both the monophenolase and diphenolase activities of tyrosinase, with IC ₅₀ values of 30.97 ± 0.75 μM and 64.62 ± 3.08 μM,respectively. 95P inhibits tyrosinase activity in a mixed competitive and reversible manner. Molecular dynamics simulations suggest that 95P stabilizes 5M8N, impeding structural contraction identified by model number 5M8N. In conclusion, 95P is a powerful and stable tyrosinase inhibitor with the potential to be used as a skin whitening agent in the pharmaceutical field and an anti-browning agent in the food industry.

Recombinant antibodies, primarily produced in Chinese hamster ovary (CHO) cells, are widely used to treat various diseases. For industrial production, a rapid and efficient method to screen stable, high-expressing clones is essential. However, conventional screening based on random integration is often cumbersome and labor intensive. This study establishes a novel strategy for generating stable, high-yielding clones by combining a MAR-based piggyBac (PB) transposon semitargeted integration system with blasticidin (BSD) selection. Compared to the random integrated vector pMAR-mAb, the MAR-PB system increases the titers (3.95- to 5.61-fold) and specific protein productivity (Qp; 4.28- to 6.07-fold) of four monoclonal antibodies in stable cell pools. When compared to PB-only vectors, the MAR-PB transposon system enhances the titers (by up to 2.50-fold) and Qp (1.96- to 2.77-fold), respectively. The increased antibody production correlates with elevated mRNA expression. Furthermore, this approach increases the proportion of high-expressing clones by more than 10-fold and significantly improves volumetric yield. Importantly, this approach promotes the long-term stability of recombinant mAb expression for over 60 generations. Transcriptome analysis reveals that the system modulates genes involved in DNA binding, transcriptional regulation, and protein binding. In conclusion, the MAR-based PB transposon system combined with BSD selection presents a significant improvement for efficiently generating high-yielding and stable CHO cell clones, offering a valuable tool for recombinant antibody production.

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.

Chimeric antigen receptor T (CAR-T) cell therapy achieves remarkable success in hematological cancers, but its efficacy is severely limited in solid tumors by formidable obstacles including physical barriers, the highly immunosuppressive tumor microenvironment (TME), and antigen escape. To address these persistent challenges, chimeric antigen receptor-macrophage (CAR-M) therapy emerges as a promising alternative, leveraging intrinsic advantages of macrophages like unparalleled tumor infiltration, powerful phagocytosis, and high plasticity. The evolution of CAR-M is primarily defined by the intracellular signaling domain. CAR-M exerts its anti-tumor effects through multifaceted mechanisms, including direct enhanced phagocytosis and tumor cell killing, TME remodeling by repolarizing to a pro-inflammatory M1-like phenotype, releasing anti-tumor effectors, and degrading the extracellular matrix (ECM), and the activation of adaptive immunity via efficient antigen presentation. Despite its promise, CAR-M faces hurdles such as TME physical barriers and the potential for M2-like re-education. Current optimization strategies focus on enhancing tumor infiltration, overcoming immunosuppression with "armored" CAR-Ms, and improving safety with suicide switches. Encouraging pre-clinical data accelerates CAR-M into early-phase clinical trials for solid tumors, and the platform's utility is also being explored beyond oncology in infectious, autoimmune, and neurodegenerative diseases.

Exposure to chronic hypobaric hypoxia provokes marked alterations in the gut microbiota and its metabolome, yet the functional significance of histidine-derived metabolites in hypobaric hypoxic pulmonary hypertension (PH) remains underexplored. Here, we employ 16S rDNA, metagenomic, and untargeted metabolomic sequencing to characterize longitudinal shifts in the fecal microbiota and metabolites during hypobaric hypoxic PH development in Sprague-Dawley rats. Fecal carnosine levels and the abundance of its producer, Ruminococcus bromii, both decrease significantly over 28 days of hypobaric hypoxia ( P  < 0.05). Spearman correlation shows that carnosine is inversely correlated with the percentage of pulmonary arteriole media thickness (MT%; r = -0.8741, P  < 0.001). Therapeutic supplementation with carnosine restores systemic and pulmonary antioxidant defenses and attenuates vascular remodeling without altering right ventricular pressures. In vitro, carnosine inhibits hypoxia-induced pulmonary artery smooth muscle cell (PASMC) proliferation and migration and suppresses nuclear factor erythroid 2-related factor 2 (Nrf2) accumulation. These findings reveal dynamic gut-lung crosstalk in hypobaric hypoxic PH and nominate carnosine as a metabolite-based intervention to mitigate hypoxia-driven pulmonary vascular remodeling.