PM_2.5 is particulate matter with a diameter of 2.5 μm or less. Airway macrophages are the key players regulating PM_2.5-induced inflammation. High molecular weight hyaluronan (HMW-HA) has previously been shown to exert protective effects on PM_2.5-induced acute lung injury and inflammation. However, little is known about the detailed mechanism. In this study, we aimed to determine whether HMW-HA alleviates PM_2.5-induced pulmonary inflammation by modulating macrophage polarization. The levels of M1 biomarkers TNF-α, IL-1β, IL-6, CXCL1, CXCL2, NOS2 and CD86, as well as M2 biomarkers IL-10, MRC1, and Arg-1 produced by macrophages were measured by ELISA, qPCR, and flow cytometry. In addition, the amount of M1 macrophages in lung tissues was examined by immunofluorescence of CD68 and NOS2. We observed a decline in PM_2.5-induced M1 polarization both in macrophages and lung tissues when HMW-HA was administered simultaneously. Meanwhile, western blot analysis revealed that PM_2.5-induced JNK and p38 phosphorylation was suppressed by HMW-HA. Furthermore, in vitro and in vivo studies showed that co-stimulation with HMW-HA and PM_2.5 promoted the expression and release of IL-10, but exhibited limited effects on the transcription of MRC1 and ARG1. In conclusion, our results demonstrated that HMW-HA ameliorates PM_2.5-induced lung inflammation by repressing M1 polarization through JNK and p38 pathways and promoting the production of pro-resolving cytokine IL-10.

Background: Sirtuin 3 (SIRT3) is a key mitochondrial regulator that functions as an oncogene in breast cancer, where its overexpression drives chemoresistance. Targeting SIRT3 offers a strategy to overcome resistance mechanisms and improve chemotherapy efficacy. Methods: We utilized molecular docking-based virtual screening to identify SIRT3 inhibitors from a natural product library. Candidates were validated via molecular dynamics simulations and binding assays. Efficacy was tested in breast cancer cells and an orthotopic mouse model by assessing cell viability, apoptosis, mitochondrial function, and tumor growth during cisplatin treatment. Results: Jionoside B1 was identified as a potent SIRT3 inhibitor that suppresses enzymatic activity, leading to increased SOD2 acetylation. In breast cancer cells, Jionoside B1 significantly enhanced cisplatin sensitivity by promoting ROS accumulation, disrupting mitochondrial potential, and triggering apoptosis. In vivo, the combination of Jionoside B1 and cisplatin inhibited tumor growth more effectively than cisplatin alone. Conclusions: Jionoside B1 sensitizes breast cancer cells to cisplatin by inhibiting SIRT3-mediated oxidative stress defense. These findings highlight Jionoside B1 as a promising therapeutic candidate for combination chemotherapy to enhance cisplatin responsiveness in breast cancer.