Stearoyl CoA Desaturase 1 and Inositol-Requiring Protein 1α Determine the Efficiency of Oleic Acid in Alleviating Silica Nanoparticle-Induced Insulin Resistance.

Despite the widespread use of silica nanoparticles (SiNPs), their metabolic impact and mechanisms of action have not been well studied. Exposure to SiNPs induces insulin resistance (IR) in hepatocytes by endoplasmic reticulum (ER) stress via inositol-requiring protein 1α (IRE1α) activation of c-Jun N-terminal kinases (JNK). It has been well established that stearoyl CoA desaturase (SCD1) and its major product oleic acid elicited beneficial effects in restoring ER homeostasis. However, the potential coordination of SCD1 and IRE1α in determining SiNP regulation of insulin signaling is unclear. Herein, we investigated the effects of SCD1 and oleic acid on IR induced by SiNPs or thapsigargin in hepatocytes. SCD1 overexpression or oleic acid efficiently reversed SiNP-induced ER stress and IR, whereas the effects of thapsigargin treatment could not be restored. Thapsigargin diminished SCD1 protein levels, leading to the accumulation of IRE1α and sustained activation of the IRE1α/JNK pathway. Moreover, knockdown of activating transcription factor 4 (ATF4) upstream of SCD1 suppressed SiNP-induced SCD1 expression, rescued the activated IRE1α, and inhibited insulin signaling but was not able to restore the effects of thapsigargin. Collectively, downregulation of SCD1 and excess accumulation of IRE1α protein prevented the beneficial effects of exogenous oleic acid on IR induced by ER stress. Our results provide valuable mechanistic insights into the synergic regulation of IR by SiNPs and ER stress and suggest a combinational strategy to restore ER homeostasis by targeting SCD1 and IRE1α proteins, as well as supplementation of unsaturated fatty acids.

Sheng-Mai Yin exerts anti-inflammatory effects on RAW 264.7 cells and zebrafish.

ETHNOPHARMACOLOGICAL RELEVANCE: Sheng-Mai Yin (SMY), a famous traditional Chinese medicine formula, has been commonly used in China for centuries to treat various diseases, such as inflammation-related diseases. However, the anti-inflammatory activity of SMY and its potential mechanisms still have not yet been clearly understood. AIM OF THE STUDY: In this study, we aimed to determine the anti-inflammatory effect of SMY and explore its underlying mechanisms both on RAW 264.7 cells and zebrafish. MATERIALS AND METHODS: The levels of pro-inflammatory cytokines IL-6 and TNF-α secreted by RAW 264.7 cells were measured by ELISA. The protein expressions of IκBα, p-IκBα (Ser32), STAT3 and p-STAT3 (Tyr705) were determined by Western blotting. And the nuclear translocation of NF-κB p65 in LPS-induced RAW 264.7 macrophage cells was detected by confocal microscopy. Moreover, the in vivo anti-inflammatory effect of SMY and its potential mechanisms were further investigated by survival analysis, hematoxylin-eosin staining (H&E), observation of neutrophil migration and quantitative real-time PCR (qRT-PCR) analysis in zebrafish inflammatory models. RESULTS: SMY reduced the release of IL-6 and TNF-α, inhibited the phosphorylation of IκBα and STAT3 as well as the nuclear translocation of NF-κB p65 in LPS-induced RAW 264.7 cells. Furthermore, the increased survival, decreased infiltration of inflammatory cells and the attenuated migration of neutrophils together suggested the in vivo anti-inflammatory effects of SMY. More importantly, SMY reduced the gene expressions of pro-inflammatory cytokines and suppressed LPS-induced up-regulation of NF-κB, IκBα and STAT3 in zebrafish inflammatory models. CONCLUSION: SMY exerts significant anti-inflammatory effects with a potential mechanism of inhibiting the NF-κB and STAT3 signal pathways. Our findings suggest a scientific rationale of SMY to treat inflammatory diseases in clinic.