International Journal of Biological Sciences最新文献

Genetic alterations that induce chromosomal instability (CIN) in colorectal cancer (CRC) cells result in partial impairments in a crucial cellular process, which present an opportunity for therapeutic exploitation in cancer treatment. In our effort to identify therapeutic vulnerability in PTEN-deficient CRC, we found that PTEN-deficient CRC cells exhibited elevated CIN phenotype and were hypersensitive to STAT3 inhibition. STAT3 inhibition induced a high level of abnormal spindle formation, causing mitotic arrest and death in PTEN-deficient CRC cells. Mechanistically, PTEN deficiency led to an increased phosphorylation in STAT3 and the hyperactivation of the downstream mitotic kinase PLK1, resulting in the formation of abnormal mitotic spindles and CIN. Inhibition of STAT3 strongly suppressed PLK1 phosphorylation in a STMN1-dependent manner, further inducing mitotic abnormalities in the cells. This irreparable mitotic defect triggered hyperactivation of the spindle assembly checkpoint and mitotic cell death in PTEN-deficient CRC cells. Collectively, our findings suggest that targeting STAT3-PLK1 axis represents a novel therapeutic approach for CRC cells with PTEN loss.

As a highly dynamic tissue, the endometrium undergoes complex remodeling during the menstrual cycle and pregnancy. Recent studies have revealed that cellular senescence plays a pivotal role in both physiological renewal (e.g., menstrual shedding, decidualization) and pathological disorders (e.g., endometriosis, intrauterine adhesions, thin endometrium) of the endometrium. Under physiological conditions, senescent cells contribute to tissue repair and embryo implantation through precise regulation. However, pathological accumulation of senescent cells drives chronic inflammation, fibrosis, and reproductive dysfunction. Here we aim to summarize the mechanism indicating endometrial senescence and elucidating their pleiotropic roles in both physiological homeostasis and pathological progression, while discussing emerging therapeutic strategies for clinical translation-including senolytics and SASP inhibitors.

More than half of Esophageal squamous cell carcinoma (ESCC) patients are at an advanced stage when first diagnosed, thus they do not benefit much from radical surgery. Single-cell RNA sequencing (scRNA-seq) data from patients with ESCC lymph node metastasis in our laboratory implied that ferroptosis might play an important role in ESCC metastasis. Ferroptosis was found to be a shared specific pathway between ESCC and adjacent non-tumor tissue, as well as between ESCC lymph node metastasis and adjacent non-tumor tissue, of which FTL was selected as the pivotal target gene within this common pathway. Bioinformatic analyses showed that FTL was highly expressed in both primary and metastatic sites than normal, and patients with high expression had poor prognosis, and its function was related to macrophages in TME. Functional studies have shown that FTL promoted tumor growth, tolerated oxidative stress, reduced the sensitivity of ESCC cells to ferroptosis, facilitated epithelial-mesenchymal transition (EMT) and recruited more macrophages to promote metastasis. Mechanism studies have shown that FTL promotes ESCC development and metastasis via NRF2 pathway and inhibits ferroptosis via NCOA4 protein. In vivo treatment, Brusatol, was found to inhibit FTL expression and have a significant inhibitory effect on ESCC growth and metastasis.

The mouse is the most widely used model organism for studying mammalian gonadal sex determination and related human disorders. However, a systematic and comprehensive comparison of human and mouse sex determination processes is lacking. Here, we performed an interspecies comparative analysis of the single-cell transcriptomic atlas of gonadal sex determination in mice and humans. Our results revealed major transcriptomic differences in each of the major cell types between human and mouse gonads. Only a small fraction of these genes shared a comparable expression profile, often genes known to be essential for gonadal sex determination. While the most differentiated gonadal cell types share similar transcriptomic signatures between humans and mice, poorly differentiated cells, such as somatic progenitors, show more divergent profiles. Ultimately, these comparisons will identify the genes and pathways for which the mouse is a suitable model to study human gonadal abnormalities and optimise the use of animal models.

Sudden unexpected death in epilepsy (SUDEP) is a critical concern, with seizure-induced respiratory arrest (S-IRA) being a major contributing factor. The serotonergic (5-HT) and noradrenergic (NE) neurons have emerged as key modulators of SUDEP, yet the network-level interactions and specific mechanisms underlying their protective roles remain poorly defined. This study is the first to demonstrate a synergistic effect of 5-HT and NE in mitigating S-IRA and SUDEP using DBA/1 mice. Through a combination of pharmacological interventions, calcium signal recordings, and optogenetics, results show that elevating 5-HT and NE levels via 5-hydroxytryptophan and the norepinephrine reuptake inhibitor atomoxetine significantly reduced SUDEP incidence, with evidence of a robust synergistic interaction. Furthermore, venlafaxine, a selective serotonin-norepinephrine reuptake inhibitor, enhances the cooperative regulation of 5-HT and NE, further supporting their combined protective role. Crucially, the dorsal raphe-locus coeruleus-pre-Bötzinger complex (DR-LC-PBC) neural network is demonstrated as a critical pathway underlying this modulation. Targeted administration of the 5-HT2A/NE α-1 receptor antagonist and agonist into the PBC reveal their pivotal roles in mediating the protective effects of 5-HT and NE. Our study reveals that serotonergic and noradrenergic systems synergistically regulate SUDEP, and further identifies that the DR-LC-PBC neural circuit exerts a protective effect through activation of 5-HT2A and NE-α1 receptors within the PBC.

Circadian rhythm disruption has been increasingly implicated in asthma and glucocorticoid (GC) resistance. In this study, we discovered that disruption of the brain and muscle ARNT-like 1 (BMAL1), a significant activator of the circadian clock transcription, not only exacerbated allergic inflammation but also induced GC resistance. The absence of BMAL1 intensified airway inflammation by activating the NF-κB and AP-1 pathways and also impaired the anti-inflammatory effect of GC. Our findings indicated that the deletion of BMAL1 reduced the phosphorylation level of the GC receptor (GR-Ser211), which has a direct effect on the efficacy of GC and serves as a key indicator of GR activation. Additionally, BMAL1 has a negative regulatory effect on the phosphatase dual specificity protein phosphatase 4 (DUSP4) of p38 mitogen-activated protein kinase (p38MAPK), which plays a crucial role in the phosphorylation of GR. Consequently, our findings suggest that the absence of BMAL1 results in the resistance of airway epithelial cells to GC due to the inhibition of GR phosphorylation via the DUSP4-p38MAPK axis in HDM-induced asthma. We demonstrated that the inhibition of DUSP4 restored GR activation and improved GC responsiveness, highlighting a potential therapeutic strategy for GC resistance driven by circadian disruption. Regulating the sleep disorder and circadian rhythm of patients with asthma could become a potential treatment to increase GC sensitivity.

Background: In non-small cell lung cancer (NSCLC), lymph node (LN) metastasis is a crucial prognostic factor. Asparagine synthetase (ASNS) plays a crucial role in cellular aspartate metabolism and promotes LN metastasis. However, the mechanisms by which LN metastasis affects immune microenvironment remodeling in situ and tumor-draining LNs (TdLNs), as well as the role of ASNS in this process remains unclear. Methods: LN metastatic lung cancer cell lines were established through in vivo selection in a murine model and subsequently analyzed via metabolomic profiling. ASNS expression and its role in modulating immunogenicity were assessed using transcriptomic analysis, western blotting, and immunohistochemistry. Metabolomic profiling, combined with in vitro stimulation assays, identified key metabolic regulators involved in the axis. Furthermore, T-cell kinetics were monitored via flow cytometry, multiplex immunofluorescence and patient datasets. Tissue samples from NSCLC patients with LN metastases following neoadjuvant immunotherapy were employed to validate findings. Results: Elevated aspartate metabolism and ASNS expression were observed in LN metastasis based on metabolomic analyses of LN metastatic lung cancer cell lines and immunohistochemistry of tissue samples from LN metastasis, intrapulmonary implantation, LN injection models and NSCLC patients-derived samples. Higher ASNS expression in LN metastases correlated with enhanced immunogenicity. Mechanically, ASNS promoted the expression of major histocompatibility complex through α-aminobutyric acid auto-secretion in lung cancer cells. Moreover, in vivo and clinical studies revealed that metastatic tumor areas with high ASNS expression facilitated the formation of lymphocyte niches conducive to CD8+T cell activation, memory, and stemness within metastatic TdLNs, particularly in the vicinity of metastatic foci, thus reshaping the immune landscape in both tumors in situ and metastatic LNs. Clinical research confirmed that high ASNS expression in LN metastases correlated with improved efficacy of neoadjuvant immunotherapy in NSCLC patients. Conclusions: ASNS promotes anti-tumor immunity in NSCLC via regulating immunogenicity of cancer cells and immune microenvironment remodeling in metastatic TdLNs. Lung cancer cell-intrinsic ASNS appears to be a promising marker for anti-PD-1-based neoadjuvant immunotherapy.

Transmissible gastroenteritis virus (TGEV), an enteropathogenic α-coronavirus, causes severe disruption of the intestinal epithelium and diarrhea in neonatal piglets. Despite growing evidence linking mitochondrial dysfunction to coronavirus-induced inflammation, the role of mitophagy-mediated mitochondrial regulation in TGEV pathogenesis remains largely unclear. Here, we conducted a screening of a series of natural plant compounds in TGEV-infected porcine intestinal epithelial cells and identified quercetin, a plant-derived flavonoid, as a potent antiviral candidate. Quercetin significantly alleviated TGEV-induced cytopathic effects and reduced viral load, without directly inactivating viral particles. Interestingly, TGEV infection triggered excessive activation of PINK1/Parkin-mediated mitophagy, leading to mitochondrial membrane potential loss, mitochondrial reactive oxygen species (mtROS) accumulation, and suppression of respiratory chain components, which subsequently activated the NF-κB and JAK/STAT signaling pathways. However, quercetin restored mitochondrial function by suppressing mitophagy overactivation, preserving mitochondrial membrane potential and mtDNA levels, and attenuating oxidative stress. Moreover, functional interference assays revealed that the anti-inflammatory efficacy of quercetin was dependent on its ability to maintain mitochondrial homeostasis and inhibit pathological mitophagic flux. These findings were validated in a TGEV-infected piglet model, where excessive mitophagy correlated closely with intestinal inflammation signaling activation. Collectively, our results not only indicated a novel mechanism of mitophagy-driven mitochondrial dysfunction in TGEV pathogenesis, but also suggested that quercetin may serve as a potential mitochondria-targeted natural compound for mitigating coronavirus-induced intestinal inflammation.

Human pluripotent stem cells (hPSCs) can generate specific cell types for therapeutic applications. Since cell therapy often requires billions of cells for transplantation, it is essential to maximize differentiation efficiency to optimize both cell yield and quality. Cardiomyocytes are commonly induced in static culture with limited expandability. In this study, we explored the impact of cell adhesion remodeling on hPSC cell fate determination. We reveal that cell passaging at critical time points drives cardiac cell fate even without traditional cardiac inducers. Cardiac fate is specified while cells proliferate continuously. Cell adhesion remodeling leads to a 10-fold increase of cardiomyocyte yield with high purity in comparison to traditional static culture. AMPK activation and PI3K/AKT inhibition were observed following cell passaging. The impact of cell passaging can be mimicked by Src and FAK inhibition, suggesting critical roles of integrin signaling pathway in passaging-driven cardiac differentiation. Transcriptome analysis suggests that cell adhesion remodeling enhances the expression of critical cardiac genes associated with maturation. This study highlights that cell adhesion remodeling significantly impacts cell fate during in vitro differentiation. Our study provides an ideal method for high-yield, high-purity cardiomyocyte production, and offers a useful potential strategy for generating other cell types through directed differentiation.

Lactobacillus paracasei abundance is markedly reduced in gastric cancer (GC) tissues, suggesting its potential protective role. From healthy gastric tissue of a GC patient, we isolated a novel strain, L. paracasei ZJUZ2-3, which exerted potent antitumor effects. Intratumoral injection of live ZJUZ2-3, but not heat-killed bacteria, attenuated gastrointestinal tumor growth in mice. Conditioned medium from ZJUZ2-3 similarly inhibited cancer cell proliferation, implicating a secreted metabolite. Metabolomic profiling identified indole-3-acetic acid (IAA) as the key bioactive compound. Consistent with this, genetic knockout of trpA (essential for IAA biosynthesis) in ZJUZ2-3 abolished its antitumor efficacy. IAA alone recapitulated the tumor-suppressive effects both in vitro and in vivo. Mechanistically, IAA activated the aryl hydrocarbon receptor (AHR), which then competitively bound to metadherin (MTDH). This interaction blocked MTDH phosphorylation and the subsequent activation of NF-κB signaling. Crucially, depletion of either AHR or MTDH abrogated IAA's efficacy, underscoring the essential role of this axis. Furthermore, ZJUZ2-3 synergized with conventional chemotherapy, potentiating tumor regression. While this study lacks humanized immune models and exploration of strain-specificity, our findings identify L. paracasei ZJUZ2-3 and its effector metabolite IAA as promising precision microbiome-based therapeutics targeting the AHR-MTDH-NF-κB pathway for adjuvant treatment of GC.