Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment but can cause severe cardiotoxicity. Anti-inflammatory and cardioprotective effects of sinomenine have been documented in existing research. However, it remains unclear what role sinomenine plays in myocardial injury induced by PD-1 inhibitors. Myocardial injury in mice, induced by PD-1 inhibitors, was used to establish an experimental model. After administering sinomenine to the mice, assessments of cardiac function were conducted using echocardiographic techniques. Histological examination and ELISA were performed to evaluate myocardial injury, inflammation, and mitochondrial dysfunction. The expression of key proteins in the TLR4/NF-κB pathway was determined via Western blotting. Treatment with sinomenine notably enhanced cardiac function and mitigated myocardial injury in mice subjected to PD-1 inhibitors. It also attenuated myocardial inflammation and mitochondrial dysfunction. Mechanistic studies shed light on the fact that the activation of the TLR4/NF-κB pathway was inhibited by sinomenine. The alleviation of PD-1 inhibitor-induced myocardial injury by sinomenine is achieved through the reduction of inflammation and the restoration of mitochondrial function, with this process being regulated by the inhibition of the TLR4/NF-κB signaling pathway. These observations imply that sinomenine has the potential to serve as a therapeutic option for managing cardiotoxicity linked to immune checkpoint inhibitors.
Various cellular stressors inhibit translation initiation and promote ribosome disassembly, thereby transiently inducing stress granules (SGs), dynamic ribonucleoprotein condensates that contain mRNAs and RNA-binding proteins. Although SG assembly is usually reversible, dysregulated SG dynamics can trigger the formation of persistent ubiquitin-positive protein inclusions. There is increasing evidence that this conversion of SGs into insoluble aggregates represents a central pathogenic mechanism in neurodegenerative proteinopathies, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) and Tau are causative factors in ALS and AD, respectively, and both localize to SGs under stress conditions. During disease progression, TDP-43 or Tau within SGs undergoes pathological changes that promote the formation of neurotoxic inclusions, which propagate neuronal dysfunction and death. This review summarizes recent advances in understanding the molecular factors that regulate SG assembly and disassembly, as well as the pathological processes that drive the conversion of SGs into aggregates associated with neurodegenerative diseases. Particular emphasis is placed on the role of the ubiquitin-specific protease 10 (USP10), which modulates SG dynamics and has been mechanistically implicated in both ALS and AD. Finally, we discuss the therapeutic potential of targeting these pathways to mitigate neurodegenerative disease progression.
Pyruvate kinase M (PKM) catalyzes the conversion of phosphoenolpyruvate to pyruvate in glycolysis and exists as two splice isoforms, PKM1 and PKM2, generated from alternative splicing of mutually exclusive exons 9 or 10, respectively. The expression balance between PKM1 and PKM2 is tightly regulated in a cell-type-specific manner. PKM1 is predominantly expressed in tissues such as skeletal muscle, heart, and brain, whereas PKM2 is prevalent in most other tissues and various cancer cells. Despite its importance, the trans-acting factors promoting exon 9 selection in a tissue-specific context remain largely unknown. Here, using a multi-color splicing reporter system for cell-based cDNA screening, we identified PUF60 as a novel trans-acting factor that promotes PKM1-type splicing. We also demonstrated that PUF60 induction and the resulting splicing switch are essential for myotube formation during C2C12 differentiation. This study establishes PUF60 as a critical regulator of muscle-specific splicing and provides new insights into the fundamental mechanisms governing skeletal muscle differentiation.
