SUMMARY
Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment (TME) induces immune dysfunctional tumor-infiltrating DCs (TIDCs), characterized with both increased intracellular lipid content and mitochondrial respiration. The underlying mechanism, however, remains largely unclear. Here, we report that fatty acid-carrying tumor-derived exosomes (TDEs) induce immune dysfunctional DCs to promote immune evasion. Mechanistically, peroxisome proliferator activated receptor (PPAR) α responds to the fatty acids delivered by TDEs, resulting in excess lipid droplet biogenesis and enhanced fatty acid oxidation (FAO), culminating in a metabolic shift toward mitochondrial oxidative phosphorylation, which drives DC immune dysfunction. Genetic depletion or pharmacologic inhibition of PPARα effectively attenuates TDE-induced DC-based immune dysfunction and enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in DCs and reveals that PPARα lies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target.
Mitochondrial biogenesis is one of the generally accepted regulatory mechanisms in the heart under chronic hypoxia. The precise quantity and quality control of mitochondria is critical for the survival and function of cardiomyocytes. Mitochondrial autophagy, also known as mitophagy, which selectively eliminates dysfunctional and unwanted mitochondria, is the most important type of mitochondrial quality control. However, the detailed molecular mechanisms of mitophagy in cardiomyocytes have been largely undefined. The present study investigated the role of adenosine 5′-monophosphate-activated protein kinase (AMPK) in mitophagy regulation in cardiomyocytes under chronic hypoxia. H9c2 cells were cultured under hypoxic conditions (1% O2) for different time periods. Mitochondrial biogenesis was confirmed and hypoxia was found to induce the collapse of mitochondrial membrane potential (ΛΨm) and increase the number of dysfunctional mitochondria. As expected, mitochondrial autophagy was increased significantly in cardiomyocytes exposed to hypoxic conditions for 48 h. AMPK was activated under hypoxia. Notably, when the activation of AMPK was enhanced by the AMPK agonist AICAR, mitochondrial autophagy was increased accordingly. By contrast, when AMPK activation was blocked, mitochondrial autophagy was decreased and cardiomyocyte apoptosis was increased. In conclusion, in the present study, mitophagy was activated and played a crucial role in cardioprotection under chronic hypoxia. AMPK was involved in mitophagy regulation, thereby providing a potential therapeutic target for heart diseases associated with chronic hypoxia.
Microtubule-associated serine/threonine kinase 1 (MAST1) is a central driver of cisplatin resistance in human cancers. However, the molecular mechanism regulating MAST1 levels in cisplatin-resistant tumors is unknown. Through a proteomics screen, we identified the heat shock protein 90 B (hsp90B) chaperone as a direct MAST1 binding partner essential for its stabilization. Targeting hsp90B sensitized cancer cells to cisplatin predominantly through MAST1 destabilization. Mechanistically, interaction of hsp90B with MAST1 blocked ubiquitination of MAST1 at lysines 317 and 545 by the E3 ubiquitin ligase CHIP and prevented proteasomal degradation. The hsp90B-MAST1-CHIP signaling axis and its relationship with cisplatin response were clinically validated in cancer patients. Furthermore, combined treatment with a hsp90 inhibitor and the MAST1 inhibitor lestaurtinib further abrogated MAST1 activity and consequently enhanced cisplatin-induced tumor growth arrest in a patient-derived xenograft model. Our study not only uncovers the regulatory mechanism of MAST1 in tumors but also suggests a promising combinatorial therapy to overcome cisplatin resistance in human cancers.
Dysfunction of the calcium balancing system and disruption of calcium distribution can induce abnormal intracellular calcium overload, further causing serious damage and even cell death, which provides a potential therapeutic approach for tumor treatment. Herein, a nano-platform, which includes UCNPs-Ce6@RuR@mSiO 2 @PL-HA NPs (UCRSPH) and SA-CaO 2 nanoparticles, is prepared for improving the tumor micro-environment (TME), Ca 2+ signal disturbance as well as enhanced photodynamic tumor therapy (PDT). UCRSPH combined with SA-CaO 2 can alter TME and relieve hypoxia of the tumor to realize self-reinforcing PDT under near-IR irradiation (980 nm). The ruthenium red (RuR) in the UCRSPH NPs can be released to the cytoplasm after endocytosis of the nanoparticles, target Ca 2+ channel proteins on the endoplasmic reticulum and mitochondria, sarcoplasmic reticulum Ca 2+ -ATPase (SERCA), and mitochondrial calcium uniporter (MCU). The combined participation of nanoparticles and RuR promotes Ca 2+ imbalance and cytoplasmic calcium overload with the assistance of CaO 2 , and provides tumor cells higher sensitivity to PDT. Furthermore, the nano-platform also provides fluorescence imaging and calcification computed tomography imaging for in vivo treatment guidance. In conclusion, this image-guided nano-platform show potential for highly specific, efficient combined therapy against tumor cells with minimal side-effects to normal cells by integrating TME improvement, self-reinforcing PDT, and Ca 2+ signal disturbance.
Nitric oxide (NO) gas treatment offers a promising strategy for tumor therapy, however, its practical application was still be limited for the poor efficacy and biotoxicity which were caused by...
Induction of cardiomyocyte proliferation, the most promising approach to reverse myocardial attrition, has been gaining importance as a therapy for cardiovascular disease. Hypoxia and macrophages were previously independently reported to promote cardiomyocyte proliferation in mice. However, whether hypoxia promotes cardiomyocyte proliferation in humans, and the association between hypoxia and macrophages in cardiomyocyte proliferation, have not to the best of our knowledge been previously investigated. The present study investigated the cardiomyocyte proliferation in 22 acyanotic and 29 cyanotic patients. Cardiomyocyte proliferation in a hypoxic mouse model (15% O2) was subsequently performed and the macrophage subsets were analyzed. A C-C chemokine receptor type 2 (CCR2) inhibitor was used to increase the number of resident macrophages in order to investigate the effect of macrophages on cardiomyocyte proliferation. The results demonstrated that cardiomyocyte proliferation in the cyanotic infant group was significantly increased compared with the acyanotic infant group and the hypoxia-treated C57BL/6J neonates confirmed the hypoxia-induced cardiomyocyte proliferation. However, hypoxia did not induce the proliferation of isolated cardiomyocytes. Notably, hypoxia treatment increased the number of cardiac resident macrophages in neonate hearts. Furthermore, increasing the number of resident macrophages significantly enhanced cardiomyocyte proliferation. In conclusion, postnatal hypoxia promoted cardiomyocyte proliferation in humans and animals, and cardiac resident macrophages may be involved in this process. Therefore, this novel mechanism may provide a promising strategy for cardiovascular disease treatment.
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