Acta biochimica et biophysica Sinica最新文献

The clinical use of doxorubicin (DOX) as a chemotherapeutic agent is limited by its cardiotoxic effects. Fibroblast growth factor (FGF) isoform 13, a distinct type of FGF, has been increasingly recognized as an important regulator of cardiovascular disease. However, its role in doxorubicin-induced cardiotoxicity remains unknown. Therefore, the objective of this study is to investigate the role and mechanism of FGF13 in doxorubicin-induced cardiac injury. C57BL/6 mice are used to establish Dox-induced cardiotoxicity models. The results reveal that mouse weight, cardiomyocyte cross-sectional area, ejection fraction and fractional shortening are decreased in the DOX group. In contrast, Fgf13 deficiency mitigates doxorubicin-mediated cardiotoxicity, as indicated by increased mouse weight, cardiomyocyte cross-sectional area, ejection fraction and fractional shortening. Mechanistically, the protein expressions of bax and cleaved caspase 3 are elevated in the DOX-treated group, along with decreased JC-1 fluorescence intensity and bcl-2 expression, whereas Fgf13 knockout prevents these alterations. In addition, Parkin, but not p53, interacts with FGF13 and is upregulated in response to Fgf13 deficiency in a mouse model of doxorubicin-induced cardiotoxicity. Overall, Fgf13 knockout attenuates doxorubicin-induced cardiomyocyte apoptosis and mitochondrial damage through the modulation of Parkin, indicating that FGF13 may serve as a promising therapeutic target for DOX-induced cardiotoxicity.

Doxorubicin (DOX) remains a cornerstone chemotherapeutic agent for malignancies, yet its clinical utility is severely limited by dose-dependent cardiotoxicity, which can lead to progressive left ventricular dysfunction and heart failure. Pleiotrophin (PTN), a heparin-binding growth factor with diverse physiological functions, regulates glucose and lipid metabolism and promotes oxidative energy pathways. However, whether PTN exerts protective effects against DOX-induced cardiotoxicity (DIC) remains unclear. In this study, we establish cellular and animal models of DIC. DOX administration induces pronounced myocardial injury in both models, characterized by impaired ventricular contractility, increased fibrotic remodeling, and reduced cell viability. Concurrently, PTN protein expression is significantly downregulated in cardiomyocytes under DOX treatment. Overexpression of PTN substantially alleviates these pathological changes. In vitro, PTN reduces mitochondrial oxidative stress and apoptosis while restoring energy production and cell viability. In vivo, PTN improves mitochondrial ultrastructure, decreases cardiomyocyte apoptosis, and enhances cardiac function. Mechanistically, PTN directly binds to SIRT1 and activates AMPK phosphorylation at Thr172, triggering a downstream cascade through the AMPK-PGC1α axis that reprograms mitochondrial energy metabolism and attenuates cardiotoxicity. In conclusion, the PTN-SIRT1 axis protects against DIC by reducing oxidative stress and promoting mitochondrial energy homeostasis via the AMPK/PGC1α pathway, highlighting its potential as a novel therapeutic target for preventing chemotherapy-related cardiac injury.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options due to the absence of hormone receptors and HER2 amplification. Immune checkpoint blockade, particularly targeting PD-1/PD-L1, has emerged as a promising therapeutic strategy. However, the response rate of TNBC patients to this monotherapy remains low. This study explores the systemic effect of PD-1 blockade on the immune and hematopoietic systems in 4T1 TNBC mice and demonstrates its limited efficacy in reducing the tumor burden and changing the number of tumor-infiltrating immune cells. However, PD-1 blockade increases systemic immune activity, as demonstrated by increased T cells and DCs in the peripheral blood, which may be associated with inflammatory side effects of this treatment. In addition, PD-1 blockade does not rescue the hematopoietic damage caused by TNBC, highlighting a limitation in long-term response. Furthermore, PD-1 blockade in tumor-free mice leads to an increase in hematopoietic stem/progenitor cells, suggesting that PD-1 blockade may yield better benefits post-tumor resection.

Chronic hyperglycemia-driven protein glycation in diabetes is a key pathogenic factor in vascular endothelial injury. This study demonstrates the multifaceted protective profile of aminoguanidine (AMG) against diabetes-induced vascular injury. As a carbonyl scavenger, AMG effectively traps methylglyoxal (MGO), inhibiting advanced glycation end products (AGEs) formation while preserving endothelial glycocalyx integrity and permeability. Mechanistically, AMG suppresses NF-κB-mediated inflammation, upregulates the eNOS/NO pathway, and restores CD31 expression, collectively mitigating oxidative stress, apoptosis and impaired proliferation in human umbilical vein endothelial cells (HUVECs). Metabolomic profiling further reveals AMG's capacity to alleviate MGO-induced metabolic dysregulation by modulating critical pathways, including glutathione metabolism and the TCA cycle. In diabetic mice, AMG attenuates site-specific glycation adducts on plasma albumin and demonstrates significant therapeutic efficacy by improving endothelial-dependent vasodilation via the eNOS/NO pathway, reducing vascular fibrosis and basement membrane thickening, and suppressing NF-κB-driven inflammatory responses. These integrated findings establish AMG as a promising therapeutic candidate with multifaceted protective effects against diabetic vascular injury.

The recombination-activating gene (RAG) complex initiates adaptive immunity by catalyzing V(D)J recombination to generate diverse antigen receptors. While the catalytic function of the RAG core is well defined, its regulatory interactions and physiological roles remain poorly understood due to limited knowledge of RAG-associated proteins. The RAG complex forms a heterotetramer of two RAG1 and RAG2 subunits, yet the individual contributions of each subunit remain unclear. Here, we use TurboID-mediated proximity labelling to map the human RAG interactome. By fusing TurboID to RAG1 or RAG2, we identify 88 RAG1- and 146 RAG2-associated proteins, with only 23 shared proteins, indicating distinct sets of proximal proteins. Although RAG1 and RAG2 are thought to exert their physiological functions by forming a complex, they display distinct potential interaction networks, suggesting subunit-specific functions and revealing their spatial proximity to each subunit. These findings uncover distinct RAG1 and RAG2 interaction landscapes and establish a framework for exploring broader RAG functions in immunity.

Human embryonic kidney (HEK) 293 cells are widely used for recombinant protein production because of their efficient posttranslational modification capabilities. However, their large-scale culture is often limited by metabolic stress and early apoptosis, leading to insufficient protein yields. In this study, we aim to increase protein expression through the coordinated modulation of metabolic and apoptotic pathways. Using CRISPR/Cas9 technology, we target and knockout the genes of ornithine decarboxylase antizyme 1 (OAZ1), which regulates polyamine metabolism, and caspase 8-associated protein 2 (CASP8AP2), an apoptosis-related protein. We successfully construct an OAZ1/ CASP8AP2 double-knockout HEK293 cell line. Following transfection with the knockout vector and screening of single-cell clones, multiple levels of validation confirm the successful gene knockout. The results show that the double-knockout cells exhibit significantly reduced apoptosis rates. Furthermore, the production of recombinant secreted alkaline phosphatase (SEAP) and vitronectin (VN) increases by 2.1 folds and 2.9 folds, respectively, compared with those in wild-type cells. Metabolic profiling reveals that the cell cycle is arrested in the G1/G0 phase, accompanied by increased specific consumption and production rates of key metabolites. This study demonstrates that concurrent inhibition of apoptosis and optimization of metabolism effectively enhances recombinant protein production in HEK293 cells, suggesting a novel strategy for improving HEK293 cell-based expression.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive nature and high propensity to metastasize, resulting in a low overall survival rate. Identifying effective molecular targets for treatment and enhancing sensitivity to gemcitabine (GEM) could significantly improve the management of PDAC patients. SUZ12 has been implicated in the progression of several malignancies, but its associations with PDAC, ferroptosis and GEM sensitivity remain unclear. To investigate the relationship between SUZ12 and PDAC, bioinformatics analyses are performed, and the results reveal that higher levels of SUZ12 expression in patients with PDAC are associated with poor prognosis. Studies using in vitro cell lines and in vivo xenograft mouse models show that SUZ12 promotes cell proliferation and increases the tumor-forming ability of PDAC cell lines. The mechanistic basis by which SUZ12 regulates PDAC involves its binding to the transcription factor YBX1 and subsequent recruitment of the complex to the NCOA4 promoter region. This recruitment mediates the epigenetic silencing of NCOA4 through the deposition of the repressive histone mark trimethylation of histone H3 at lysine 27 (H3K27me3) at the promoter. Consequently, this silencing enhances the cellular antioxidant capacity and suppresses ferroptosis in PDAC. SUZ12 expression is found to be elevated in GEM-resistant (GR) PDAC cells, and decrease of SUZ12 levels increases GEM sensitivity in PDAC cells. The combination of SUZ12 knockout with GEM shows enhanced synergistic effects in cancer therapy and sensitizes GR cells to GEM, providing new insights into overcoming GEM resistance and highlighting SUZ12 as a potential target for clinical intervention in PDAC patients.

The T cell receptor (TCR) initiates signaling by specifically recognizing peptide-MHC complexes, triggering the phosphorylation of CD3 chain immunoreceptor tyrosine-based activation motifs (ITAMs). This recruits kinases such as ZAP70, triggering a tightly regulated signaling cascade that governs T cell activation, differentiation, and effector functions. In contrast, the chimeric antigen receptor (CAR) is a synthetic construct that bypasses MHC restriction by fusing an antigen-binding domain with intracellular signaling modules (usually CD3ζ and co-stimulatory domains) from the TCR complex and other receptors. CAR-T cell therapy has revolutionized the treatment of hematologic malignancies, resulting in durable remission of B-cell leukemia, lymphoma, and multiple myeloma. However, its efficacy in solid tumors is limited by intrinsic barriers: poor CAR-T-cell trafficking/infiltration into tumors, the immunosuppressive tumor microenvironment (TME), intratumoral metabolic competition, and tumor antigen heterogeneity/loss. To improve CAR-T-cell function in solid tumors, numerous studies have explored multiple strategies: engineering CARs to boost immune synapse formation via optimized receptor clustering, increasing the ITAM number/strength to amplify downstream signaling, and incorporating novel/multiple co-stimulatory domains to sustain T-cell activation and persistence. Additionally, approaches include the use of CAR-T cells that secrete pro-inflammatory cytokines, epigenetic reprogramming to preserve T-cell stemness and functionality, and the use of synthetic biology tools for tunable/logic-gated CAR activation. Here, we summarize the current understanding of CAR signaling dynamics and highlight recent breakthrough strategies designed to overcome these challenges in solid tumors. These advances narrow the liquid-solid tumor efficacy gap, holding promise for better clinical outcomes in patients with solid malignancies and a new era of personalized immunotherapy.

The immune system orchestrates a delicate balance between robust defense against pathogens and restraint to prevent tissue damage, with T cells serving as central mediators of adaptive immunity. The canonical pathway for T-cell activation hinges on the precise recognition of peptide antigens presented by major histocompatibility complex (MHC) molecules via the T-cell receptor (TCR), which is complemented by essential co-stimulatory signals. However, this model alone cannot fully explain the nuanced contextualization of immune responses, particularly how T cells integrate signals related to the nature of the threat. Pattern recognition receptors (PRRs), which are traditionally studied in innate immune cells, are recognized as critical regulators of T cell function, challenging the conventional dichotomy between innate and adaptive immunity. T cell-intrinsic PRR signaling integrates endogenous danger signals and microbes to modulate critical processes, including cytokine production, proliferation, and polarization, thereby shaping immune responses and disease outcomes in contexts ranging from viral infections to chronic inflammation and cancer. However, the molecular mechanisms underlying PRR-mediated T cell regulation and their contributions to immune homeostasis or pathology remain incompletely understood. This study investigates the role of T cell-intrinsic PRR signaling in shaping immune responses and its implications for disease. By elucidating key signaling pathways and their impact on T cell function, we aim to offer novel insights into the complex regulation of T cell-mediated immunity and uncover an underappreciated paradigm for immune-related disorders, providing new insights into the pathogenesis of inflammatory and neoplastic diseases.