Abstract Doxorubicin (DOX) is a widely used anticancer agent, but its use carries the risk of cardiotoxicity. The underlying mechanisms of DOX-induced cardiac injury involve multiple interconnected processes, including oxidative stress, inflammatory activation, apoptosis, dysregulation of metal ion homeostasis, mitochondrial dysfunction, and impaired autophagy. The p38 mitogen-activated protein kinase (p38 MAPK) pathway functions as a stress-response central hub that integrates these signals and orchestrates downstream cellular outcomes via phosphorylation-dependent signaling cascades. This review summarizes current evidence on the molecular mechanisms of DOX-induced cardiotoxicity (DIC), with a focus on the pivotal role of the p38 MAPK pathway. We further discuss natural compounds that mitigate DIC via modulation of p38 MAPK signaling and examine emerging evidence on sex-specific cardioprotective effects mediated by distinct p38 MAPK isoforms. In addition, we briefly discuss the role of DOX nanoformulations in reducing cardiotoxicity, offering new insights into the mitigation of DIC.
Bingjie Zhao, Meng-Yao Tang, Jiedong Zhou et al.· International Journal of Gen...· 0 citations
Stanniocalcin-1 (STC-1) is a multifunctional glycoprotein; however, its role in protecting intestinal epithelial cells against oxidative injury has not been completely elucidated. This study investigated the cytoprotective effects and underlying molecular mechanisms of STC-1 overexpression in porcine intestinal epithelial (IPEC-J2) cells subjected to tert-butyl hydroperoxide (TBHP)-induced oxidative stress. IPEC-J2 cells were transfected with pcDNA3.1/STC-1 prior to TBHP challenge. STC-1 overexpression markedly rescued cells from TBHP-induced cytotoxicity and cell death, and was associated with a reduced Bax/Bcl-2 ratio. Concurrently, elevated STC-1 expression dramatically suppressed intracellular reactive oxygen species and mitochondrial superoxide accumulation while preserving the mitochondrial membrane potential. These physiological improvements were accompanied by enhanced total antioxidant capacity and activities of key antioxidant enzymes. Mechanistically, STC-1 overexpression enhanced autophagic flux and promoted Pink1/Parkin-mediated mitophagy to eliminate dysfunctional mitochondria. Furthermore, STC-1 upregulation potentiated the AMPK–Nrf2/Sirt1 signaling axis and the subsequent transcriptional upregulation of mitochondrial quality control markers, including FoxO1, PGC-1α, and TFAM, under stress conditions. Collectively, these findings demonstrate that STC-1 safeguards porcine intestinal cells against oxidative injury by orchestrating a cooperative defense network encompassing ROS scavenging, mitochondrial homeostasis, and antioxidant defense amplification via the AMPK–Nrf2/Sirt1 pathway, highlighting a potential therapeutic target for preventing stress-associated intestinal disorders in piglets.
Liming Wu, Yan Bin, Yu-Bei Wei et al.· Animals· 0 citations
