International Journal of Biological Sciences最新文献

Chronic stress is closely associated with gastrointestinal disorders. However, the impact of stress-related neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT) on the intestines under chronic stress conditions remains poorly understood. This study aims to elucidate the mechanisms by which 5-HT affects mitochondrial biogenesis and intestinal barrier integrity during chronic stress. Employing a chronic restraint stress (CRS) mouse model, we observed elevated intestinal 5-HT levels, altered colonic mucosal structure, and disrupted tight junctions. The increase in 5-HT was associated with up-regulated serotonin synthesis enzymes and downregulated serotonin reuptake transporters, indicating an imbalance in serotonin homeostasis imbalance caused by chronic stress. Furthermore, serotonin exacerbated oxidative stress and impaired tight junction protein expression, highlighting its role in promoting intestinal barrier dysfunction. Experiments with cells in vitro demonstrated that 5-HT impairs mitochondrial biogenesis by inhibiting the AMPK-PGC-1α axis via 5-HT₇ receptors and the cAMP-PKA pathway. Pharmacological inhibition of serotonin synthesis or 5-HT₇ receptors alleviated the intestinal barrier damage caused by 5-HT and chronic stress, restoring mitochondrial biogenesis. These findings provide compelling evidence that serotonin exacerbates chronic stress-induced intestinal barrier disruption by inhibiting the AMPK-PGC-1α axis, paving the way for novel therapeutic interventions targeting the detrimental effects of serotonin on the intestine, particularly under chronic stress conditions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic, progressive liver disease that encompasses a spectrum of steatosis, steatohepatitis (or MASH), and fibrosis. Evidence suggests that dietary restriction (DR) and sleeve gastrectomy (SG) can lead to remission of hepatic steatosis and inflammation through weight loss, but it is unclear whether these procedures induce distinct metabolic or immunological changes in MASLD livers. This study aims to elucidate the intricate hepatic changes following DR, SG or sham surgery in rats fed a high-fat diet as a model of obesity-related MASLD, in comparison to a clinical cohort of patients undergoing SG. Single-cell and single-nuclei transcriptome analysis, spatial metabolomics, and immunohistochemistry revealed the liver landscape, while circulating biomarkers were measured in serum samples. Artificial intelligence (AI)-assisted image analysis characterized the spatial distribution of hepatocytes, myeloid cells and lymphocytes. In patients and experimental MASLD rats, SG improved body mass index, circulating liver injury biomarkers and triglyceride levels. Both DR and SG attenuated liver steatosis and fibrosis in rats. Metabolism-related genes (Ppara, Cyp2e1 and Cyp7a1) were upregulated in hepatocytes upon DR and SG, while SG broadly upregulated lipid metabolism on cholangiocytes, monocytes, macrophages, and neutrophils. Furthermore, SG promoted restorative myeloid cell accumulation in the liver not only ameliorating inflammation but activating liver repair processes. Regions with potent myeloid infiltration were marked with enhanced metabolic capacities upon SG. Additionally, a disruption of periportal hepatocyte functions was observed upon DR. In conclusion, this study indicates a dynamic cellular crosstalk in steatotic livers of patients undergoing SG. Notably, PPARα- and gut-liver axis-related processes, and metabolically active myeloid cell infiltration indicate intervention-related mechanisms supporting the indication of SG for the treatment of MASLD.

Prostate cancer presents as an immunologically "cold" malignancy, characterized by a lack of response to immunotherapy in the majority of patients. The dysfunction of prostate tumor metabolism is recognized as a critical factor in immune evasion, resulting in reduced effectiveness of immunotherapeutic interventions. Despite this awareness, the precise molecular mechanisms underpinning metabolic dysregulation in prostate cancer and its intricate relationship with immune evasion remain incompletely elucidated. In this study, we introduce the multi-drug resistance protein ABCC4/MRP4 as a key player prominently expressed in prostate cancer, exerting a pivotal role in suppressing the activity of intratumoral CD8⁺ T cells. Depletion of ABCC4 in prostate cancer cells halts the release of prostaglandin E2 (PGE2), a molecule that diminishes the population of CD8⁺ T cells and curtails their cytotoxic capabilities. Conversely, constraining the activation of PGE2 signaling in CD8⁺ T cells effectively improved the efficacy of prostate cancer treatment with PD-1 blockade. During this process, downregulation of the JAK1-STAT3 pathway and depolarization of mitochondria emerge as crucial factors contributing to T cell anergy. Collectively, our research identifies the ABCC4-PGE2 axis as a promising target for reversing dysfunction within tumor-infiltrating lymphocytes (TILs) and augmenting the suboptimal responsiveness to immunotherapy in prostate cancer.

Bone metastasis is a significant contributor to the poor prognosis in prostate cancer. Recent evidence highlights the pivotal role of pseudouridine synthases in solid tumor progression, yet the specific enzyme driving prostate cancer metastasis remains unidentified. This study uncovers a novel regulatory mechanism of the FOXA1/PUS1/EIF3b signaling axis in prostate cancer bone metastasis. We identified elevated PUS1 expression in prostate cancer tissues, correlating with higher clinical grade and worse prognosis. Knockdown of PUS1 inhibited metastasis independently of its enzymatic activity, with EIF3b acting as a downstream effector, protected from ubiquitin-mediated degradation by PUS1. Overexpression of EIF3b countered the metastasis suppression due to PUS1 knockdown. Additionally, FOXA1 was shown to enhance PUS1 expression by binding to its promoter. Mogroside IV-E, a specific PUS1 inhibitor, demonstrated potent anti-metastatic effects by reducing PUS1 expression. Our findings highlight the FOXA1/PUS1/EIF3b axis as a critical mediator of prostate cancer bone metastasis and suggest that targeting this pathway could be a promising therapeutic strategy.

Large-scale phase III clinical trials of Olaparib have revealed benefits for ovarian cancer patients with BRCA gene mutations or homologous recombination deficiency (HRD). However, fewer than 50% of ovarian cancer patients have both BRCA mutations and HRD. Therefore, improving the effect of Olaparib in HR-proficient patients is of great clinical value. Here, a combination strategy comprising Olaparib and CDK12-IN-3 effectively inhibited the growth of HR-proficient ovarian cancer in cell line, patient-derived organoid (PDO), and mouse xenograft models. Furthermore, the combination strategy induced severe DNA double-strand break (DSB) formation, increased NHEJ activity in the G2 phase, and reduced HR activity in cancer cells. Mechanistically, the combination treatment impaired Ku80 poly(ADP-ribosyl)ation (PARylation) and phosphorylation, resulting in PARP1-Ku80 complex dissociation. After dissociation, Ku80 occupancy at DSBs and the resulting Ku80-primed NHEJ activity were increased. Owing to Ku80-mediated DNA end protection, MRE11 and Rad51 foci formation was inhibited after the combination treatment, suggesting that this treatment suppressed HR activity. Intriguingly, the combination strategy expedited cGAS nuclear relocalization, further suppressing HR and, conversely, increasing genomic instability. Moreover, the inhibitory effect on cell survival persisted after drug withdrawal. These findings provide a rationale for the clinical application of CDK12-IN-3 in combination with Olaparib.

Various cancer treatment approaches that inhibit the activity of the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis, a key player in tumor immune evasion, have been developed. We show that the immunomodulatory small tellurium complexes AS101 (ammonium trichloro(dioxoethylene-o,o')tellurate) and SAS (octa-O-bis(R,R)-tartarate ditellurane) suppress PD-L1 expression in a variety of human and mouse malignant cells via the modulation of α4β1 very late antigen-4 (VLA-4) integrin activity. Consequently, the expression of pAkt and its downstream effector pNFκB are inhibited. Additionally, SAS promotes the death of mouse malignant cells by activated syngeneic splenocytes or CD8⁺ T cells, preventing the development of chemoresistance in malignant cells. Moreover, AS101 and SAS may increase, at least in part, chemosensitivity through inhibition of the VLA-4/IL-10/PD-L1 pathway. Additionally, AS101 or SAS treatment of B16/F10 melanoma-bearing mice decreased tumor cell PD-L1 expression, leading to increased CD8⁺ T-cell infiltration into the tumors and tumor shrinkage. Combination treatment with an αPD-1 antibody and either tellurium compound significantly increased the antitumor efficacy of immunotherapy. Overall, VLA-4 integrin signaling is critical for tumor immune evasion and is a potential target for cancer treatment. Finally, AS101 or SAS, biologically active tellurium compounds, can effectively enhance the therapeutic efficacy of αPD-1-based cancer immunotherapy.

Macrophages are the most abundant alternative immune cells in the tumor microenvironment (TME). The cross-talk between macrophages and tumor cells provides an important shelter for the occurrence and development of tumors. As an important information transfer medium, exosomes play an important role in intercellular communication. Nonetheless, how exosomal lncRNAs coordinate the communication between tumor cells and immune cells in hepatocellular carcinoma (HCC) is incompletely understood. We found that HCC exosomes-derived antisense RNA of SLC16A1(SLC16A1-AS1) promoted the malignant progression of HCC by regulating macrophage M2-type polarization. Mechanistically, the HCC exosomal SLC16A1-AS1 enhanced mRNA stabilization of SLC16A1 in macrophage by promoting the interaction between 3' untranslated regions (3'UTR) of SLC16A1 mRNA and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1). As a lactate transporter, SLC16A1 accelerated lactate influx and then activated c-Raf/ERK signaling to induce M2 polarization of macrophages. Reciprocally, M2 macrophages secreted IL-6 to activate STAT3 and then induce METTL3 transcription in HCC cells, which increasing m6A methylation and stabilization of SLC16A1-AS1. In turn, the reciprocal SLC16A1-AS1/IL-6 signaling between HCC cells and M2 macrophages promoted the proliferation, invasion and glycolysis of HCC cells. Our study highlights that exosomal SLC16A1-AS1 acts as a signaling message that induces lactate-mediated M2 polarization of macrophages, and implies that SLC16A1-AS1 might be an applicable target for therapeutic treatment of HCC.

PDIA5 is responsible for modification of disulfide bonds of proteins. However, its impact on the malignant progression of glioblastoma multiforme (GBM) remains unknown. We analyzed the expression and prognostic significance of PDIA5 in cohorts of GBM and clinical samples. The PDIA5 protein was significantly overexpressed in GBM tissues, and higher expression of PDIA5 was statistically associated with a worse prognosis in patients with GBM. Transcriptional data from PDIA5 knockdown GBM cells revealed that downstream regulatory genes of PDIA5 were enriched in malignant regulatory pathways and PDIA5 enhanced the proliferative and invasive abilities of GBM cells. By constructing a PDIA5 CXXC motif mutant plasmid, we found CCAR1 was the vital downstream factor of PDIA5 in regulating GBM malignancy in vitro and in vivo. Additionally, RUNX1 bound to the promoter region of PDIA5 and regulated gene transcription, leading to activation of the PDIA5/CCAR1 regulatory axis in GBM. The RUNX1/PDIA5/CCAR1 axis significantly influenced the malignant behavior of GBM cells. In conclusion, this study comprehensively elucidates the crucial role of PDIA5 in the malignant progression of GBM. Downregulating PDIA5 can mitigate the malignant biological behavior of GBM both in vitro and in vivo, potentially improving the efficacy of treatment for clinical patients with GBM.

Background: Cellular senescence has emerged as a pivotal focus in cardiovascular research. This study investigates the previously unrecognized role of cellular senescence in septic cardiomyopathy (SCM) and evaluates senomorphic therapy using ruxolitinib (Rux) as a potential treatment option. Methods: We employed lipopolysaccharide (LPS)-induced neonatal rat cardiomyocytes (NRCMs) and two mouse models-LPS-induced and cecal ligation and puncture (CLP)-induced SCM models-to assess Rux's effects. RNA sequencing, western blotting (WB), quantitative polymerase chain reaction (qPCR), immunofluorescence, immunohistochemistry, senescence-associated β-galactosidase (SA-β-gal) assay, and other techniques were utilized to investigate underlying mechanisms. Results: Senescence-associated secretory phenotype (SASP) and cellular senescence markers were markedly elevated in LPS-induced NRCMs and SCM animal models, confirmed by the SA-β-gal assay. Rux treatment attenuated SASP in vitro and in vivo, alongside downregulation of senescence markers. Moreover, Rux-based senomorphic therapy mitigated mitochondrial-mediated apoptosis, improved cardiac function in SCM mice, restored the balance of antioxidant system, and reduced reactive oxygen species (ROS) levels. Rux treatment restored mitochondrial membrane potential, mitigated mitochondrial morphological damage, and upregulated mitochondrial complex-related gene expression, thereby enhancing mitochondrial function. Additionally, Rux treatment ameliorated SCM-induced mitochondrial dynamic dysfunction and endoplasmic reticulum stress. Mechanistically, Rux inhibited JAK2-STAT3 signaling activation both in vitro and in vivo. Notably, low-dose Rux and ABT263 showed comparable efficacy in mitigating SCM. Conclusions: This study highlighted the potential significance of cellular senescence in SCM pathogenesis and suggested Rux-based senomorphic therapy as a promising therapeutic approach for SCM.

Mitophagy selectively eliminates damaged or dysfunctional mitochondria, playing a crucial role in maintaining mitochondrial quality control. However, it remains unclear whether mitophagy can be fully activated and how it evolves after SCI. Our RNA-seq analysis of animal samples from sham and 1, 3, 5, and 7 days post-SCI indicated that mitophagy was indeed inhibited during the acute and subacute early stages. In vitro experiments showed that this inhibition was closely related to excessive production of reactive oxygen species (ROS) and the downregulation of BNIP3. Excessive ROS led to the blockage of mitophagy flux, accompanied by further mitochondrial dysfunction and increased neuronal apoptosis. Fortunately, ligustilide (LIG) was found to have the ability to reverse the oxidative stress-induced downregulation of BNIP3 and enhance mitophagy through BNIP3-LC3 interaction, alleviating mitochondrial dysfunction and ultimately reducing neuronal apoptosis. Further animal experiments demonstrated that LIG alleviated oxidative stress and mitophagy inhibition, rescued neuronal apoptosis, and promoted tissue repair, ultimately leading to improved motor function. In summary, this study elucidated the state of mitophagy inhibition following SCI and its potential mechanisms, and confirmed the effects of LIG-enhanced mitophagy through BNIP3-LC3, providing new therapeutic targets and strategies for repairing SCI.