Cell Biology and Toxicology最新文献

Resistance to endocrine therapy remains a major challenge in treating prostate cancer (PCa), highlighting the need for alternative therapeutic approaches. In this study, we investigated the potential of Ginsenoside Rh2 to counteract such resistance by influencing the SIRT1-dependent deacetylation pathway, thereby modulating the equilibrium between estrogen receptor α (ERα) and androgen receptor (AR). We proposed that Rh2 may suppress therapy-resistant PCa progression by adjusting ERα/AR transcriptional dynamics. Through network pharmacology analysis, key anti-PCa targets of Rh2 were identified, with Cytoscape enrichment indicating a pivotal role in AR signaling modulation. Functional validation was performed using 3D tumor organoids and human PCa cell lines (C4-2B and LNCaP) treated with Rh2 to assess cellular behaviors and receptor deacetylation status. Additionally, xenograft mouse models were employed to evaluate Rh2's in vivo effects, based on tumor burden, serum PSA levels, and tissue histopathology. Rh2 treatment led to significant, dose- and time-dependent inhibition of PCa cell proliferation and metastatic traits, accompanied by restored ERα/AR balance through activation of SIRT1. In animal studies, Rh2 notably reduced tumor size, decreased PSA expression, and improved systemic health indicators. Collectively, our results suggest that Rh2 re-sensitizes PCa to endocrine therapy by targeting the SIRT1 pathway, positioning it as a promising phytochemical candidate for managing resistant PCa. This work provides mechanistic insights supporting Rh2's potential for clinical translation.

Background: Ischemic stroke (IS) stands as a principal contributor to high rates of sickness and death. The condition's pathological development is complicated, featuring mechanisms like mitochondrial impairment and the activation of microglial cells. A thorough grasp of these intricate processes is vital for creating successful treatment strategies.

Methods: We applied Weighted Gene Co-expression Network Analysis (WGCNA) to find gene sets with a strong correlation to IS. Integrated machine learning approachs were used to identify key mitochondrial-related genes (MRGs). From this analysis, SPTLC2 was identified as a pivotal MRG and was subsequently analyzed in detail using single-cell RNA sequencing (scRNA-seq) datasets. We performed functional confirmation using experimental stroke simulations, which included transient middle cerebral artery occlusion (tMCAO) in mice and in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) on primary microglia.

Results: WGCNA revealed two critical modules (yellow and blue) comprising 5348 genes, which were predominantly enriched in immune response, nerve regeneration, and lipid metabolism. We exhibited the robust and superior performance of MRGs in stroke prediction, which contributed to an optimal combination of ridge regression and random forest fitted on 18 MRGs. Subsequently, elevated expression of the SPTLC2 gene was observed in microglia following stroke. Functional studies and experimental validation demonstrated that SPTLC2 promoted microglial pro-inflammatory phenotype, metabolic reprogramming towards glycolysis, and exacerbated cell-cell communication alterations. SPTLC2-specific knockdown in myeloid cells using an adeno-associated virus (AAV) in our tMCAO model alleviated neurobehavioral deficits, reduced infarct volume, and improved mitochondrial function by elevating oxidative stress and mitigating mitochondrial membrane potential depolarization. Additionally, SPTLC2 was regulated by the transcription factor FLI1, and molecular docking identified potential drugs targeting SPTLC2, including Nystatin A3, Moxidectin, and Lumacaftor.

Conclusion: Our study highlights SPTLC2 as a critical mediator of microglial activation and metabolic reprogramming in ischemic stroke, providing a foundation for developing novel therapeutic strategies targeting SPTLC2 to improve stroke outcomes.

Fluorouracil (5-Fu)-based chemotherapy is a first-line treatment option for advanced colorectal cancer (CRC). However, long-term use of 5-Fu often leads to chemoresistance, which limits its therapeutic efficacy, highlighting the need for developing novel regimens to improve CRC treatment outcomes. In this study, we found that Tan IIA inhibits aerobic glycolysis in CRC cells via suppressing Skp2/Akt/HK2 signaling axis and thereby overcomes 5-Fu resistance. Specifically, Tan IIA induces ubiquitination-mediated Skp2 degradation by attenuating the interaction between USP2 and Skp2. Moreover, the combination of Tan IIA with USP2 inhibitor ML364 overcomes 5-Fu resistance in vitro and xenograft mouse models. This study elucidates a novel mechanism of 5-Fu resistance and offers a promising combination treatment option for overcoming chemoresistance.

Sepsis-induced cardiomyopathy (SICM), a critical contributor to the high mortality rate associated with sepsis, involves complex pathophysiological mechanisms that remain incompletely elucidated. In recent years, dysregulation of bidirectional signaling communication between mitochondria and the nucleus has been recognized as a pivotal factor in the pathogenesis of SICM. The anterograde signaling pathways-including the PGC-1α/NRF1/NRF2 axis, SIRT3-mediated deacetylation, and TFAM-dependent mitochondrial DNA (mtDNA) maintenance-are suppressed by inflammation and metabolic disturbances. This suppression leads to impaired mitochondrial biogenesis and disrupted energy metabolism. Concurrently, within retrograde signaling pathways, molecular mediators such as reactive oxygen species (ROS), mtDNA, and calcium signaling activate pro-inflammatory and apoptotic pathways, notably NF-κB and cGAS-STING. This activation establishes a vicious cycle perpetuating inflammation and cellular damage. Although current targeted interventions aimed at modulating mitochondrial-nuclear crosstalk have demonstrated some efficacy in animal models, their clinical translation faces significant challenges. These include the dynamic nature of the disease, substantial interindividual variability, and difficulties in achieving targeted delivery. This review summarizes the mechanisms of mitochondrial-nuclear bidirectional signaling in SICM and explores potential therapeutic targets, aiming to provide novel insights for SICM treatment strategies.

Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that significantly impairs recovery in elderly surgical patients. While astrocyte activation has been implicated in various neurodegenerative disorders, its dynamic changes and precise role in POCD pathogenesis remain poorly understood. In this study, we observed selective activation of astrocytes (but not microglia) in the hippocampal CA1 region of POCD model mice at postoperative day 3, accompanied by marked downregulation of the atypical chemokine receptor CXCR7. Notably, both astrocyte-specific CXCR7 overexpression in the hippocampal CA1 region and systemic administration of the CXCR7 agonist AMD3100 effectively attenuated astrocyte activation, reduced neuroinflammation, and significantly improved synaptic plasticity and cognitive performance in aged surgical mice. Furthermore, chemogenetic inhibition of hippocampal astrocytes during the perioperative period similarly ameliorated neuroinflammatory responses and cognitive deficits. Our findings demonstrate that surgery induces reactive astrogliosis in the hippocampal CA1 region through CXCR7 downregulation, ultimately leading to synaptic dysfunction and cognitive impairment. These results identify CXCR7 as a promising therapeutic target for POCD prevention.

4-Nonylphenol (NP) is an environmental endocrine disruptor widely used in consumer products. Previous studies have shown that NP can interfere with hormone synthesis and metabolism in humans and animals, leading to male reproductive dysfunction. This study utilized the scRNA-seq method to evaluate cell populations and their heterogeneity, aiming to elucidate the toxic mechanisms of NP exposure on testicular cells. We demonstrate, for the first time, the transcriptomic characteristics of testicular single cells in adolescent mice exposed to NP. Adolescent mice, initially exposed at 4 weeks of age, were subsequently analyzed at sexual maturity after a continuous exposure period of 3 months. The blank control and NP-exposed groups underwent scRNA-seq analysis, identifying ten cell populations. The results showed that after NP exposure, the number of germline cells was remarkably reduced compared to the control group. NP exposure significantly decreased the protein expression of the four common differentially expressed genes (DEGs) (Cmtm2b, Rpl28, Adam32, and Pgam2). The DEGs enriched in the GO functions of the four germline cell types were spermatogenesis and spermatid development. KEGG analysis showed that the DEGs were enriched in the oxidative phosphorylation, and ROS signaling pathways. Further analysis of intercellular interactions revealed that NP exposure altered intercellular communication between germ cells, with the NECTIN3-NECTIN2 receptor-ligand interactions activating between spermatogonia, Sertoli, and Leydig cells. Germ cells bind to Sertoli and Leydig cells via NECTIN3-NECTIN2 receptor ligands. Somatic cells bind to RS and ES through GRN-SORT1 receptor ligands. CADM1-CADM1 receptor-ligand interactions enhances between germ and Sertoli cells. Our study provides new insights into the potential impacts of NP on spermatogenesis and sperm function, emphasizing the importance of environmental hormones in male fertility issues.

Globally, gastric cancer (GC) ranks among the deadliest malignancies due to frequent late-stage detection, metastatic dissemination, and resistance to therapies. Emerging evidence highlights N⁶-methyladenosine (m⁶A) modification, orchestrated by methyltransferase-like 3 (METTL3), as a pivotal epigenetic driver of GC pathogenesis. While METTL3 is implicated in promoting tumorigenesis, metastasis, and chemoresistance, a systematic synthesis of its multi-layered regulatory networks and clinical relevance remains elusive. This review comprehensively deciphers METTL3's dual roles as an oncogene and RNA modifier, elucidating its mechanisms in reprogramming GC progression through m⁶A-dependent RNA stability, translation, and non-coding RNA interactions. We reveal novel axes such as HOXA10-TGFβ /Smad-METTL3, METTL3/IGF2BP3-HDGF-glycolysis, and METTL3-YTHDF1- PARP1-driven chemoresistance, underscoring its cross-talk with oncogenic signaling and metabolic reprogramming. Crucially, we pioneer a clinical perspective by evaluating METTL3's diagnostic potential as a biomarker and its therapeutic vulnerability in immunotherapy and NSAID-based strategies. Our analysis identifies METTL3 as a central node in GC's molecular landscape, bridging epigenetic dysregulation with malignant phenotypes and therapy failure. These insights not only redefine METTL3's role in GC but also provide a roadmap for targeting m⁶A machinery in precision oncology.

Interleukin (IL)-1β and IL-18 are involved in the inflammatory response of wear-induced osteolysis. The production and secretion of these interleukins are regulated by the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein (NLRP3) inflammasome. Uptake of wear particles can lead to mitochondrial damage, the production of reactive oxygen species (ROS), and stress in the endoplasmic reticulum (ER), resulting in an increased production of the ER stress key factor DNA damage-inducible transcript 3 (DDIT3). This factor is known to inhibit the mitophagy of dysfunctional mitochondria, inducing the generation of ROS. All these factors are known to activate the NLRP3 inflammasome. In this study, we investigated the influence of cobalt-chromium-molybdenum particles (CoCr) on the activation of the NLRP3 inflammasome in human osteoblasts (hOBs). Also, this research aimed to examine the impact of particles on mitochondria and the activation of the inflammasome. HOBs were primed with CoCr particles or tumor necrosis factor (TNF). After the incubation period, the cells were again treated with CoCr particles for activation. To test whether particle-induced DDIT3 upregulation has an effect on mitophagy and regulation of the NLRP3 inflammasome in hOBs, cells were additionally treated with the mitophagy agonist carbonyl cyanide-3-chlorophenylhydrazone (CCCP). Treatment of hOBs with metallic particles increased pyroptosis, which was accompanied by the release of IL-18. Further particle exposure damaged and inhibited the degradation of mitochondria. Activating the mitophagy with CCCP in hOBs reduced the inflammatory response to particles and TNF. These findings indicate that particle-induced inflammation can be influenced by maintaining mitochondrial function.

The Aryl Hydrocarbon Receptor (AHR) is a crucial mediator of cellular responses upon exposure to environmental pollutants. Initially described as central activator in xenobiotic metabolism, recent research has unveiled additional layers of complexity in AHR function and regulation. The circadian rhythm is a fundamental regulatory process that modulates various physiological processes, including AHR activity. Our recent findings show that AHR-dependent gene induction is subject to circadian rhythmicity. While some studies suggest a circadian AHR gene transcription in various tissues, a comprehensive mechanistic understanding of the circadian AHR regulation remains elusive. This mechanistic study aimed to elucidate the circadian regulation of AHR target gene induction upon dioxin treatment in human breast cells. To acquire a more profound understanding of the intricacies of AHR regulation, we conducted a systematic analysis of the molecular co-factors and their interactions in circadian synchronized cells. Our results show circadian regulation of AHR transcriptional activity at the CYP1A1 promoter upon dioxin treatment. This appears to be orchestrated by the core clock components BMAL1/CLOCK, which directly interact with AHR in circadian synchronized cells. Additionally, we identified SP1 as an important positive and p23 as an essential negative regulator of circadian AHR activity. The understanding of these interactions is crucial for elucidating the molecular relationship between the circadian clock and cellular responses to environmental stimuli. Such knowledge is of vital importance for the application of New Approach Methods (NAMs) as part of a weight-of-evidence (WoE) approach in the next generation of risk assessments.