Apoptosis最新文献

Pyroptosis is a new type of programmed cell death that plays an important role in neuronal injury after subarachnoid hemorrhage (SAH). The effect of natural compounds in SAH has attracted much attention. Hsperetin has been found to have neuroprotective effects in ischemic stroke, but its role in SAH has not been studied. An in vivo model of SAH in male C57BL/6 mice is constructed by the endovascular perforation method, and the heme intervention HT22 cells simulate the in vitro SAH model. After administration of hesperetin, SAH grade, brain water content (BWC), modified garcia score, neurobehavior tests, cerebral blood flow, transmission electron microscope, western blot, and immunofluorescence staining were conducted. Our study found that hesperetin significantly alleviated neurobehavioral deficits, improved cerebral blood flow, and reduced the expression of NLRP3, GSDMD-N, Caspase-1, ASC, IL-18, which were also demonstrated in vitro. Mechanistically, hesperetin notably promoted mitophagy by regulating DHCR24 and BACE1, thereby inhibiting neuronal pyroptosis. This effect was eliminated by U18666A and 3-MA administration. Our findings demonstrated that hesperetin alleviated neuronal pyroptosis by promoting mitophagy via DHCR24/BACE1 to provide neuroprotective effects on EBI. These results suggest that hesperetin has the potential to be a therapeutic target for SAH.

Chemotherapy failure caused by adriamycin (ADM) and imatinib (IM) resistance remains a critical challenge in the treatment of chronic myeloid leukemia (CML). In this study, a novel compound 4, 4’-(selenophene-2, 5-diyl)bis(3-fluorophenol) (Se-1) with estrogen receptor regulation and selenium anticancer activity was applied to reverse drug resistance of CML. Se-1 exhibited superior inhibitory activity against resistant K562/ADM cells compared to sensitive K562 cells. The growth of K562/ADM in xenograft mouse was suppressed by Se-1 treatment. The anti-leukemia mechanism of Se-1 was tested by western-blot, flow cytometry, molecular docking and fluorescence imaging. The apoptosis rate was increasing after Se-1 treatment, meanwhile proteins of Cleaved PARP and Cleaved Caspase3 were up-regulated and Bcl-2 was down-regulated. In addition, the autophagy was activated through increasing of autophagy vesicles and proteins of LC3-II and P62, and inactivating of mTOR protein. Moreover, estrogen receptor α (ERα), ERK and P38 were activated, the proteins of PI3K and AKT1 were decreased. Overall, Se-1 exerted anti-CML effects through multi-mechanism interaction, which was expected to advance the research in reversing ADM and IM resistance of chronic myeloid leukemia.

Triple-negative breast cancer (TNBC) is characterized by a highly immunosuppressive tumor microenvironment (TME), which contributes to its poor clinical outcomes. Tumor-associated macrophages (TAMs) constitute a major cellular component of the TME, and the dominance of immunosuppressive M2 phenotype, rather than the pro-inflammatory M1 phenotype, plays a pivotal role in maintaining immune evasion. Reprogramming TAMs from M2 to M1 phenotype represents a promising therapeutic strategy for reversing immunosuppression in TME. In the current study, our findings demonstrated that JQ1, a bromodomain and extra-terminal motif (BET) protein inhibitor, effectively promotes macrophage polarization toward the M1 phenotype both in vitro and in vivo. Furthermore, JQ1 enhances the cytotoxic and phagocytic capacity of TAMs. Mechanistic studies revealed that JQ1 inhibits PPARγ signaling, thereby shifting TAMs toward the M1 phenotype and subsequently promoting T cell-mediated antitumor immunity. Importantly, treatment with JQ1 in combination with anti-CD47 antibody synergistically suppressed 4T1 tumor growth. Our findings uncovered a novel immunomodulatory function of JQ1 in reprogramming TAMs polarization within the TNBC TME and provided a compelling rationale for targeting BET proteins in cancer immunotherapy.

N6-methyladenosine (m6A) RNA modification plays a pivotal role in gynaecological cancers by regulating tumor initiation, progression, and therapeutic resistance. m6A RNA modification include writers (METTL3/14, RBM15, ZC3H13, WTAP), which catalyze methylation; erasers (ALKBH5, FTO), which remove methyl groups; and readers (YTHDC1, YTHDF1/2/3, IGF2BP1/2/3, HNRNPC/G, HNRNPA2BP1), which interpret m6A marks to regulate the RNA fate. These regulators alter basic RNA metabolism, such as splicing, mRNA stability, translation, and degradation. In gynaecological cancers, both oncogenic and tumor suppressive signaling pathways are also altered by these regulators. Due to their diagnostic, prognostic and predictive value, m6A regulators have emerged as promising biomarkers in gynaecological cancers in recent years. This review highlights the role of m6A regulators and critically evaluates their biomarker and clinical potential in gynaecological cancers.

Circular RNAs (circRNAs) have been identified as important mediators of tumorigenesis and tumor progression. This study focuses on circAGFG1, a circRNA with elevated N6-methyladenosine (m6A) modification, and its role in triple-negative breast cancer (TNBC). Fluorescence in situ hybridization and qPCR analyses revealed that circAGFG1 is significantly upregulated in TNBC tissues and in the TNBC cell line MDA-MB-231. Functional characterization using loss-of-function and gain-of-function strategies in two TNBC cell lines demonstrated that circAGFG1 promotes oncogenic phenotypes. Specifically, knockdown in MDA-MB-231 cells suppressed proliferation, invasion, migration, and G1/S phase transition, while its overexpression in MDA-MB-468 cells promoted these processes. Mechanistically, western blotting and PCR analyses indicated that circAGFG1 modulates the expression of epithelial-mesenchymal transition markers N-cadherin and α-SMA. Furthermore, we identified that YTHDF3, an m6A reader protein upregulated in TNBC, upregulates circAGFG1 expression by enhancing its transcript stability. Finally, dual-luciferase reporter assays confirmed that circAGFG1 acts as a sponge for miR-1299, thereby potentially modulating the miR-1299 signaling pathway. Collectively, our findings delineate the critical role of the circAGFG1 in promoting TNBC progression, highlighting its potential as a novel therapeutic target.

Trastuzumab (TRZ), a monoclonal antibody targeting the ErbB2 protein, significantly improves the prognosis of patients with ErbB2-positive breast or gastric cancer; however, its cardiotoxicity substantially limits its clinical applicability in certain patient populations. TRZ-induced cardiotoxicity (TIC) primarily arises from ErbB2 signaling blockade, compromising cardiomyocyte repair mechanisms and functional integrity. This inhibition further compromises the cellular antioxidant capacity, leading to the accumulation of reactive oxygen species (ROS) and triggering a cascade of downstream events, including apoptosis, inflammatory responses, ferroptosis, autophagy dysfunction, and pyroptosis. Based on the aforementioned mechanisms, researchers have conducted in-depth investigations into the molecular pathways involved in TIC. To date, decades of research have identified several keys signaling pathways implicated in TIC, including PI3K/Akt, MAPK, STATs, AMPK, mTOR, MDM2/p53, NLRP3, and NF-κB. Furthermore, a number of potential therapeutic agents targeting key molecules in TIC have been explored. However, these findings have not yet been summarized. Therefore, this review aims to comprehensively consolidate existing knowledge on TIC, elucidate its regulatory mechanisms, and provide insights for developing novel cardioprotective strategies.

Background

Pyroptosis contributes significantly to neuronal death following ischemic stroke. This study investigated whether lactylation of heat shock protein family A member 8 (HSPA8) modulates neuronal pyroptosis after ischemic/reperfusion injury.

Research design and methods

Both in vitro oxygen-glucose deprivation/reperfusion (OGD/R) models and in vivo transient middle cerebral artery occlusion (tMCAO) mouse models were established to assess the functional significance of HSPA8 lactylation at lysine 524 (K524).

Results

HSPA8 expression and lactylation increased following ischemic/reperfusion injury both in vitro and in vivo. K524 was the predominant lactylation site, regulated by p300 acetyltransferase and histone deacetylases. The lactylation-mimetic K524Q mutant significantly reduced pyroptosis markers (NLRP3, GSDMD, cleaved caspase-1) and pyroptotic cell death compared to wild-type or K524R mutant. In tMCAO mice, neuronal expression of HSPA8-K524Q reduced infarct volume and suppressed pyroptosis more effectively than K524R. Mechanistically, HSPA8 lactylation at K524 enhanced its interaction with the E3 ubiquitin ligases PARK2 and ARIH2, promoting NLRP3 ubiquitination and degradation.

Conclusions

HSPA8 lactylation at K524 is a critical regulator of neuronal pyroptosis and ischemic brain injury. This modification facilitates E3 ligase-mediated NLRP3 degradation and suppression of inflammasome activation. Targeting protein lactylation pathways may offer a promising therapeutic strategy for neuroprotection in ischemic stroke.

5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutic agents for various cancers, including cholangiocarcinoma (CCA) and colorectal cancer (CRC). However, its therapeutic efficiency has remained unsatisfactory. A better understanding of the molecular mechanisms underlying 5-FU responsiveness is therefore crucial for developing more effective treatment strategies and improving patient survival. Mixed lineage kinase domain-like protein (MLKL), a key regulator of necroptosis, has been implicated in cancer progression and therapeutic response. However, the exact roles of MLKL in modulating chemotherapy response, particularly 5-FU, has also remained unknown. Through a comprehensive bioinformatics analysis, we identified a significant association between high MLKL expression and poor therapeutic outcomes in CCA and CRC patients treated with 5-FU. Moreover, higher MLKL expression was detected in CRC patients who were clinically unresponsive to 5-FU-based treatments compared to responders, suggesting a crucial role of MLKL in mediating 5-FU response. Of particular interest, MLKL depletion sensitized CRC cells to 5-FU and enhanced its tumor-suppressive effects in a xenograft mouse model by promoting apoptosis. We propose that MLKL suppression potentiate TNF-α/TNFR-I-mediated apoptotic signaling, potentially by prolonging TNFR-I retention within the early endosome and delaying its degradation upon 5-FU treatment. Notably, silencing of TNFR-I attenuated 5-FU-induced cell death in MLKL-knockdown cells. These findings provide novel insights into previously unrecognized roles of MLKL in modulating 5-FU responsiveness and highlight MLKL as a potential predictive and therapeutic target to improve 5-FU efficacy in precision cancer therapy.

Ferroptosis, a distinct form of regulated cell death, has attracted significant attention due to its critical role at the intersection of cellular metabolism, redox biology, and various human diseases. Macrophages play a key role in maintaining systemic iron balance, and their specific polarization states influence the regulation of ferroptotic processes. However, the therapeutic potential of ferroptosis in cancer is frequently limited by tumor-associated macrophages (TAMs), representing a significant challenge in applying immunotherapy to hematologic malignancies. Notably, inducing ferroptosis in macrophages themselves also holds therapeutic promise. This review synthesizes recent advances in macrophage ferroptosis research to clarify its role in disease pathogenesis. Importantly, we highlight the translational potential of the ferroptosis-TAM axis, suggesting that biomarker-guided modulation of this pathway, via novel nanocarriers or combination treatments, represents a paradigm-shifting strategy to overcome drug resistance and restore antitumor immunity in hematologic malignancies.