Cell Biology and Toxicology最新文献

Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates both oxidative stress and mitochondrial biogenesis. Our previous study reported the cardioprotection of calycosin against triptolide toxicity through promoting mitochondrial biogenesis by activating nuclear respiratory factor 1 (NRF1), a coregulatory effect contributed by Nrf2 was not fully elucidated. This work aimed at investigating the involvement of Nrf2 in mitochondrial protection and elucidating Nrf2/NRF1 signaling crosstalk on amplifying the detoxification of calycosin. Results indicated that calycosin inhibited cardiomyocytes apoptosis and F-actin depolymerization following triptolide exposure. Cardiac contraction was improved by calycosin through increasing both fractional shortening (FS%) and ejection fraction (EF%). This enhanced contractile capacity of heart was benefited from mitochondrial protection reflected by ultrastructure improvement, augment in mitochondrial mass and ATP production. NRF1 overexpression in cardiomyocytes increased mitochondrial mass and DNA copy number, whereas NRF1 knockdown mitigated calycosin-mediated enhancement in mitochondrial mass. For nuclear Nrf2, it was upregulated by calycosin in a way of disrupting Nrf2-Keap1 (Kelch-like ECH associated protein 1) interaction, followed by inhibiting ubiquitination and degradation. The involvement of Nrf2 in mitochondrial protection was validated by the results that both Nrf2 knockdown and Nrf2 inhibitor blocked the calycosin effects on mitochondrial biogenesis and respiration. In the case of calycosin treatment, its effect on NRF1 and Nrf2 upregulations were respectively blocked by PGCα/Nrf2 and NRF1 knockdown, indicative of the mutual regulation between Nrf2 and NRF1. Accordingly, calycosin activated Nrf2/NRF1 and the signaling crosstalk, leading to mitochondrial biogenesis amplification, which would become a novel mechanism of calycosin against triptolide-induced cardiotoxicity.

Objective: Sevoflurane (Sevo), a commonly used inhalant anesthetic clinically, is associated with a worsened cancer prognosis, and we investigated its effect on RNA methylase tRNA aspartic acid methyltransferase 1 (TRDMT1) expression and ovarian cancer (OC) cell malignant phenotypes.

Methods: Human OC cells (OVCAR3/SKOV3) were pretreated with 3.6% Sevo and cultured under normal conditions for 48 h, with their viability assessed. After 2-h Sevo treatment or interference plasmid transfections to down-regulate TRDMT1/adenomatous polyposis coli (APC), changes in TRDMT1, APC and β-catenin expression, cell proliferative activity, cycle, apoptosis, migration, invasion, and 5-methylcytosine (m5C) methylation potential modification sites were evaluated. Additionally, APC mRNA m5C methylation level and stability, the binding of APC mRNA with TRDMT1, the binding intensity of APC and β-catenin, and β-catenin nuclear translocation were detected Lastly, Cyclin D1, cellular-myelocytomatosis viral oncogene (C-myc) and β-catenin protein levels, and ki67-positive rate were assessed.

Results: Sevo treatment boosted cell cycle, proliferation, migration and invasion, suppressed apoptosis and APC expression, and up-regulated C-myc, β-catenin, TRDMT1 and Cyclin D1 levels. Silencing TRDMT1 or β-catenin partially averted Sevo-mediated promotion effects on cell malignant biological behaviors. Lowly-expressed APC annulled the effect of silencing TRDMT1 and promoted cell malignant behaviors. Sevo enhanced APC mRNA m5C modification and degradation and activated the APC/β-catenin pathway by increasing TRDMT1, thus encouraging OC growth in vivo.

Conclusions: Sevo stimulated APC m5C modification and curbed its expression by up-regulating TRDMT1, which in turn activated the β-catenin pathway to stimulate OC cell cycle, invasion, proliferation, and migration and to suppress apoptosis.

Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation to regulate gene transcription, influencing the activity of T lymphocytes, NK cells, and macrophages in immune suppression, activating G protein-coupled receptor 81 for signal transduction, and serving as an energy substrate. The m⁶A modification represents the most prevalent post-transcriptional epigenetic alteration. It is regulated by m⁶A-related regulatory enzymes (including methyltransferases, demethylases, and recognition proteins) that control the transcription, splicing, stability, and translation of downstream target RNAs. Lactate-mediated lactylation at histone H3K18 can modulate downstream target m⁶A modifications by enhancing the transcriptional expression levels of m⁶A-related regulatory enzymes. These enzymes play a crucial role in the progression of diseases such as cancer, fibrosis (in both liver and lung), myocardial ischemia, cerebral hemorrhage, and sepsis. Furthermore, m⁶A-related regulatory enzymes are also subject to lactylation by lactate. In turn, these regulatory enzymes can influence key glycolytic pathway enzymes or modify lactate transporter MCT4 via m⁶A alterations to impact lactate levels and subsequently affect lactylation processes.

Hepatocyte-derived liver progenitor-like cells (HepLPCs) exhibit a remarkable capacity to support liver function by detoxifying ammonia, promoting native liver regeneration, and suppressing inflammation, which leads to improvements in the recovery and survival of animals with acute liver failure (ALF). However, the mechanism through which HepLPCs promote liver regeneration is unclear. Here, we isolated HepLPC-derived extracellular vesicles (HepLPC-EVs) from conditioned media and performed microRNA sequencing analysis. Our results showed HepLPC-EVs promoted liver regeneration in mice with carbon tetrachloride or acetaminophen induced ALF. Cell cycle progression and proliferation of primary human hepatocytes were promoted after coculture with HepLPC-EVs. Exosomal miRNA sequencing confirmed that HepLPC-EVs were enriched with miR-183-5p, which played an essential role in ameliorating ALF. Mechanistically, HepLPC-derived exosomal miR-183-5p negatively regulated the expression of the target gene FoxO1, activated the Akt/GSK3β/β-catenin signaling pathway, and thereby promoted liver regeneration and restoration of normal liver function. These results indicate that during ALF, HepLPC-Exos mediate liver regeneration mainly through a paracrine exosome-dependent mechanism and these effects accelerate liver regeneration and lead to the restoration of normal liver function.

Background: Gilteritinib is a commonly used targeted drug for acute myeloid leukemia (AML), but the emergence of gilteritinib resistance greatly reduces the therapeutic effect. RING finger protein 38 (RNF38), a protein with RING Finger domain and E3 ubiquitin ligase activity, has been implicated in tumorigenesis and drug resistance. However, the role and mechanism of RNF38 in the gilteritinib resistance of AML remains unclear.

Methods: Normal AML cells were treated with gilteritinib to construct gilteritinib-resistant cells (MV4-11/Gilteritinib and MOLM-13/Gilteritinib). CCK8 assay, TUNEL staining and EdU assay were used to assess gilteritinib resistance, cell apoptosis and proliferation. The protein levels of autophagy-related markers, RNF38 and LIM homeobox transcription factor 1 alpha (LMX1A) were determined by western blot. Also, RNF38 and LMX1A mRNA levels were tested using qRT-PCR. Autophagic flux was assessed using mRFP-GFP-LC3 labeling, and autophagosome numbers was counted under transmission electron microscopy. Co-IP assay was employed to analyze interaction between RNF38 and LMX1A. The effects of LMX1A and RNF38 on AML tumorigenesis were analyzed by in vivo experiments.

Results: In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG132.

Conclusions: RNF38 induced autophagy to promote gilteritinib resistance in AML by increasing the ubiquitination of LMX1A.

Ferroptosis represents a newly programmed cell death, and the process is usually accompanied with iron-dependent lipid peroxidation. Importantly, ferroptosis is implicated in a myriad of diseases. Recent literature suggests a potential position of ferroptosis in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD), the most widespread liver ailment worldwide. Intriguingly, several functional genes and metabolic pathways central to ferroptosis are regulated by nuclear factor erythroid-derived 2-like 2 (NRF2). In current work, we aim to identify protocatechuic acid (PCA), a primary metabolite of antioxidant polyphenols, as a potent NRF2 activator and ferroptosis inhibitor in the hepatic lipotoxicity and steatosis models. Herein, both NRF2^+/+ and NRF2^-/- cell lines and mice were used to analyze the importance of NRF2 in PCA function, and hepatic lipotoxicity and steatosis models were induced by palmitic acid and high-fat diet respectively. Our results indicated that ferroptosis was mitigated by PCA intervention in hepatic cells. Furthermore, PCA exhibited therapeutic efficacy against ferroptosis, as well as hepatic lipotoxicity and steatosis. The protective role of PCA was predominantly mediated through NRF2 activation, potentially elucidating a pivotal mechanism underlying PCA's therapeutic impact on MAFLD. Additionally, the augmented mitochondrial TCA cycle activity observed in hepatic lipotoxicity and steatosis models was ameliorated by PCA, in part via NRF2-dependent pathways, further bolstering PCA's anti-ferroptosis properties. Collectively, our findings underscore PCA's potential in alleviating hepatic ferroptosis, lipotoxicity and steatosis via inducing activation of NRF2 signaling pathway, offering a promising strategy for the therapy of MAFLD as well as related lipid metabolic disorders.

Significant advancements in cardiovascular and metabolic disease research have been made with the CREB3 protein family. Studies have revealed that members of this family are crucial in the development of these diseases, contributing to the regulation of lipid metabolism, inflammation, and vascular function. These studies provide useful information for future therapeutic strategies in cardiovascular and metabolic diseases.

The initial stage of alcoholic liver disease (ALD) is hepatic steatosis. Recent studies have highlighted a possible role for Apoptosis-stimulating protein 2 of p53 (ASPP2) in regulating hepatic lipid metabolism in nonalcoholic fatty liver (NAFLD). However, whether ASPP2 regulates alcohol-induced lipid accumulation and its mechanisms remain unclear. To explore that, we establish an alcoholic liver injury model in vivo and in vitro. The clinical specimens were collected from liver tissues of patients with alcoholic liver disease. Lipid metabolism was detected by HE staining, oil red O staining and qPCR; and ASPP2-peroxisome proliferator-activated receptor γ (PPARγ) signaling pathways were detected by western blot and immunohistochemical staining. We found that both ASPP2 and PPARγ expression increased in patients and mouse models with ALD. We also discovered the reduction of ASPP2 significantly inhibited the expression of PPARγ and alleviated alcohol-induced hepatic lipid accumulation and liver injury in vivo and in vitro. Mechanistically, the PPARγ agonist reversed the protective effect of ASPP2 downregulation on hepatic steatosis and liver injury, while the opposite results were observed using PPARγ inhibitor. In conclusion, ASPP2 exacerbates ethanol-induced lipid accumulation and hepatic injury by upregulating the PPARγ signaling pathway, thus promoting the occurrence and development of ALD.

Gastric cancer (GC) is the fifth most common cancer worldwide, particularly prevalent in Asia, especially in China, where both its incidence and mortality rates are significantly high. Meanwhile, nanotechnology has demonstrated great potential in the treatment of GC. In particular, nanodrug delivery systems have improved therapeutic efficacy and targeting through various functional modifications, such as targeting peptides, tumor microenvironment responsiveness, and instrument-based methods. For instance, silica (SiO₂) has excellent biocompatibility and can be used as a drug carrier, with its porous structure enhancing drug loading capacity. Polymer nanoparticles regulate drug release rates and mechanisms by altering material composition and preparation methods. Lipid nanoparticles efficiently encapsulate hydrophilic drugs and promote cellular uptake, while carbon-based nanoparticles can be used in biosensors and drug delivery. Targets such as integrins, HER2 receptors, and the tumor microenvironment have been used to improve drug efficacy in GC treatment. Nanodrug delivery techniques not only enhance drug efficacy and delivery capabilities but also selectively target tumor cells. Currently, there is a lack of systematic summarization and synthesis regarding the relationship between nanodrug delivery systems and GC treatment, which to some extent hinders researchers and clinicians from efficiently searching for and referencing related studies, thereby reducing work efficiency. This study aims to systematically summarize the existing research on the relationship between nanodrug delivery systems and GC treatment, making it easier for professionals to search and reference, and thereby promoting further research on the role of nanodrug delivery systems and their clinical applications in GC. This review discusses the applications of functionalized nanocarriers in the treatment of GC in recent years, including surface modifications with targeted markers, the combination of phototherapy, chemotherapy, and immunotherapy, along with their advantages and challenges. It also examines the future prospects of targeted nanomaterials in GC treatment. The review particularly focuses on the combined application of nanocarriers in multiple treatment modalities, such as phototherapy, chemotherapy, and immunotherapy, demonstrating their potential in multimodal treatments. Furthermore, it thoroughly explores the specific challenges that nanocarriers face in GC treatment, such as biocompatibility, drug release control, and clinical translation issues, while providing a systematic outlook on future developments. Additionally, this study emphasizes the potential value and feasibility of nanocarriers in clinical applications, contrasting with most reviews that focus on basic research. Through these innovations, we offer new perspectives and directions for the development of nanotechnology in the treatment of GC.

Zinc finger protein 384 (ZNF384) is a highly conserved transcribed gene associated with the development of multiple tumors, however, its role and mechanism in serous ovarian cancer (SOC) are unknown. We first confirmed that ZNF384 was abnormally highly expressed in SOC tissues by bioinformatics analysis and immunohistochemistry. We further used lentivirus packaging and transfection techniques to construct ZNF384 overexpression or knockdown cell lines, and through a series of cell function experiments, gradually verified that ZNF384 promoted a series of malignant behaviors of SOC cell proliferation, migration, and invasion. By establishing a xenotransplantation model in nude mice, it was confirmed that ZNF384 promoted the progress of SOC in vivo. Mechanistically, Overexpression of ZNF384 enhanced the transcriptional activity of Lin-28 homolog B (LIN28B), which promoted the malignant behavior of SOC cells. In addition, LIN28B could regulate the expression of the downstream factor ubiquitin D (UBD) in SOC cells, further promoting the development of SOC. This study shows that ZNF384 aggravates the malignant behavior of SOC cells through the LIN28B/UBD axis, which may be used as a diagnostic biomarker for patients with SOC.