Doxorubicin (Dox)-induced cardiomyopathy (DIC) is characterized by severe myocardial damage that can progress to dilated cardiomyopathy and potentially lead to heart failure. No effective prevention or treatment strategies are available for DIC. Sauchinone, a diastereomeric lignan isolated from Saururus chinensis, is known for its notable anti-inflammatory effects. However, a paucity of research on sauchinone in relation to heart disease exists, particularly regarding its role in DIC, which remains unclear. This study aimed to assess the therapeutic potential of sauchinone in alleviating cardiac injury and elucidate its potential molecular mechanism in DIC. Male C57BL/6J mice were used to construct chronic and acute DIC models in vivo. The mice were administered sauchinone intragastrically concurrently with the first injection of Dox to evaluate the therapeutic effect of sauchinone on DIC. H9c2, a rat cardiomyocyte cell line, was treated with various concentrations of sauchinone in conjunction with Dox to assess the protective effects of sauchinone on cardiomyocyte injury in vitro. Supplementation with exogenous sauchinone mitigated Dox-induced cardiac atrophy, cardiac fibrosis, and ventricular remodeling, while preserving cardiac function. Sauchinone reduced Dox-induced abnormal apoptosis both in vitro and in vivo. Additionally, sauchinone restored mitochondrial function and decreased reactive oxygen species levels, which may be attributed to its activation of nuclear factor erythroid 2-related factor 2 (NRF2) signaling, thereby attenuating Dox-induced oxidative damage. Furthermore, sauchinone significantly inhibited the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and reduced the cardiac infiltration of inflammatory factors, thereby alleviating oxidative stress and inhibiting the progression of DIC. The NLRP3 agonist nigericin abolished DIC progression, while the NLRP3 antagonist MCC950 further enhanced the beneficial effects of sauchinone on DIC progression both in vivo and in vitro. The key novel finding of the present study is that the use of sauchinone, a diastereomeric lignan isolated from Saururus chinensis, effectively limits the progression of DIC. Specifically, sauchinone not only alleviates Dox-induced chronic cardiac injury but also significantly delays the progression of acute DIC. Mechanistically, inactivation of the NLRP3 inflammasome and NRF2-mediated antioxidant pathways have been identified as two critical signaling pathways regulated by sauchinone, which plays a vital role in blocking the progression of DIC. Sauchinone holds promise as a potential therapeutic approach for DIC or dilated cardiomyopathy.

Aims: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cell (VSMC) proliferation, migration, oxidative stress, and neointima formation of vascular injury. Methods: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation, and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of the carotid artery in mice. Results: Asprosin overexpression promoted VSMC oxidative stress, proliferation, and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant (N-Acetylcysteine, NAC), NADPH oxidase 1 (NOX1) inhibitor ML171, or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, whereas asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation, and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation, and migration were enhanced by Nrf2 inhibitor ML385 but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation, and vascular remodeling in mice. Innovation and Conclusion: Asprosin promotes oxidative stress, proliferation, and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress, and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury. Antioxid. Redox Signal. 41, 488–504.

The chemotherapy agent doxorubicin (DOX) is significantly constrained in its clinical application due to its notable cardiotoxicity. Dexrazoxane is the only drug approved by the FDA for the prevention of DOX-induced carditoxicity; however, it may also diminish the sensitivity of cancer cells to DOX chemotherapy. Consequently, there is an urgent need for the development of safe and effective therapeutic agents to mitigate the cardiotoxic effects induced by DOX. In this study, C57BL/6J mice and H9C2 cardiomyocytes were employed to establish models of DOX-induced cardiotoxicity. We examined the effects of herbacetin on myocardial damage, cardiac function, oxidative stress, ferroptosis and the associated signaling pathways using a variety of experimental techniques. Our results demonstrated that herbacetin mitigated DOX-induced myocardial damage and cardiac dysfunction both in vivo and in vitro. Mechanistically, herbacetin inhibits oxidative stress and lipid peroxidation by directly binding to tyrosine 342 of acyl-CoA synthetase long-chain family member 4 (ACSL4). This interaction inhibits lipid peroxidation and ferroptosis, suggesting that herbacetin may serve as a promising ferroptosis inhibitor and therapeutic agent for diseases associated with ferroptosis. This study underscores the therapeutic potential of herbacetin in DOX-induced cardiotoxicity and highlights the importance of modulating ACSL4 activity and inhibiting lipid peroxidation in diseases associated with ferroptosis.

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Disruption of vascular smooth muscle cell (VSMC) homeostasis plays a vital role in triggering TAD. ELA (ELABELA) is a novel endogenous ligand for APJ (angiotensin receptor AT1–related receptor protein). However, the effects of ELA on TAD formation and development remain elusive. METHODS: Four-week-old C57BL/6J male mice were treated with β-aminopropionitrile monofumarate or β-aminopropionitrile monofumarate combined with Ang II (angiotensin II) to induce TAD models, and the aortic rupture occurred mainly in the descending thoracic region. ELA or saline was infused via osmotic minipumps into mice for 4 weeks. Transcriptomic studies and VSMC-derived conditioned medium were used to investigate the downstream molecular mechanisms of ELA. RESULTS: ELA infusion mitigated TAD development and prevented aortic media degradation in mice, which was reversed by APJ antagonist ML221. Exogenous ELA prevented the disruption of VSMC homeostasis under PDGF (platelet-derived growth factor) stimulation in VSMCs. Based on transcriptomic studies, we showed that ELA significantly inhibits NLRP3 (NLR family pyrin domain-containing 3)/IL (interleukin)-1β pathway activation and modulates NET (neutrophil extracellular trap) formation in vivo and in vitro. In human neutrophils, ELA significantly inhibited NETs’ formation, which is prevented by reactive oxidative species supplementation. Using VSMC-derived conditioned medium, we showed that NLRP3/IL-1β–related NETs’ formation connects cellular signaling from VSMCs to neutrophils, leading to disruption of VSMC homeostasis. Notably, ELA was downregulated in both plasma and aortic tissues of human TAD, and lower plasma ELA levels were associated with an increased risk of TAD. CONCLUSIONS: We provide evidence that ELA prevents TAD progression and aortic medial degeneration, primarily by maintaining VSMC homeostasis, which may be linked to the inhibition of NETosis in neutrophils and NLRP3/IL-1β–related cellular signaling between VSMCs and neutrophils. ELA shows promise as a target for pharmacological therapy and diagnostic TAD management.

Pathological cardiac hypertrophy is associated with intricate changes that can eventually lead to heart failure. Galangin is a natural flavonoid derived from the rhizome of the galangal plant that has shown protective effects against a variety of cardiomyopathies. Galangin undergoes methylation at the third hydroxyl position to form Galangin 3-methyl ether (G3-ME), thus increasing its lipophilicity, thereby facilitating its cellular entry and regulatory effects. In this study, we investigated the effects of G3-ME on hypertrophic cardiomyopathy (HCM) and the underlying mechanisms. Two established transgenic mouse models of HCM, i.e., Myh6^R404Q and Tnnt2^R109Q mice, were used for in vivo studies. For in vitro experiments, H9c2, a rat cardiomyocyte cell line, along with human embryonic stem cell-derived cardiomyocytes (hESC-CMs), were exposed to angiotensin II (Ang II, 1 μM). We showed that G3-ME (2.5–20 μM) dose-dependently inhibited the expression of pathological cardiac hypertrophy marker genes Nppa and Nppb in Ang II-treated H9c2 cells. G3-ME (5 μM) effectively mitigated the Ang II-induced expansion of H9c2 cells and hESC-CMs. In the two HCM mouse models, administration of G3-ME (20 or 50 mg·kg⁻¹·d⁻¹, i.g.) for 4 weeks significantly improved the cardiac hypertrophy phenotype. By conducting RNA sequencing combined with network pharmacology, we identified histone deacetylase 2 (HDAC2) as the direct target of G3-ME in H9c2 cells. We demonstrated that G3-ME inhibited both the phosphorylation of HDAC2 and the PI3K-AKT signaling pathway during the cardiac hypertrophy process in vivo and in vitro. Knockdown of HDAC2 resulted in inhibition of cardiac hypertrophy, whereas its overexpression facilitated cardiac hypertrophy through the PI3K-AKT signaling pathway. In conclusion, G3-ME attenuates pathological cardiac hypertrophy in vivo and in vitro by targeting HDAC2, leading to the inactivation of the PI3K-AKT signaling pathway. G3-ME may serve as a promising option for addressing hypertrophic cardiomyopathy.

Background: Clinical data indicate that at least half of patients with malignancies receive radiotherapy. While radiotherapy effectively kills tumor cells, it is also associated with significant ionizing radiation (IR) damage. Moreover, the increasing emissions of nuclear pollutants raise concerns about the potential exposure of more individuals to the risks associated with IR. The Chinese term for amniotic fluid (AF) is rooted in the Yin–Yang theory of traditional Chinese medicine, where it symbolizes the inception of human life. Chick early AF (ceAF), a natural product, has shown promise in the field of regenerative medicine. There have been no studies investigating the potential efficacy of ceAF in the treatment of IR-induced damage. This study aims to assess the therapeutic potential of ceAF in alleviating IR-induced damage and elucidate its potential molecular mechanism. Methods: In vivo experiments were conducted on 8-week-old male C57BL/6J mice to investigate the effects of ceAF in a radiation injury model induced by whole-body irradiation with X-rays (6 Gy) for 5 min. The ceAF was extracted from chicken embryos aged 7–9 days. Results: We found that the supplementation of ceAF reduces mortality induced by IR, improves exercise capacity in IR mice, and reverses IR-induced skin damage. IR leads to varying degrees of volume atrophy and weight loss in the major internal organs of mice. However, ceAF intervention effectively mitigates IR-induced organ damage, with a notable impact on the spleen. The supplementation of ceAF enhances spleen hematopoietic and immune functions by reducing oxidative stress, alleviating inflammatory responses, and preventing splenic DNA damage from IR exposure, ultimately leading to an overall improvement in health. Conclusions: ceAF effectively alleviates body damage induced by IR, and our findings provide new perspectives and therapeutic strategies for mitigating IR-induced damage.