Discovery of caffeoylisocitric acid as a Keap1-dependent Nrf2 activator and its effects in mesangial cells under high glucose

Wang

et al. 2023

Mol Med

Background Pancreatic beta cell dysfunction and activated macrophage infiltration are early features in type 1 diabetes pathogenesis. A tricarboxylic acid cycle metabolite that can strongly activate NF-E2-related factor 2 (Nrf2) in macrophages, itaconate is important in a series of inflammatory-associated diseases via anti-inflammatory and antioxidant properties. However, its role in type 1 diabetes is unclear. We used 4-octyl itaconate (OI), the cell-permeable itaconate derivate, to explore its preventative and therapeutic effects in mouse models of type 1 diabetes and the potential mechanism of macrophage phenotype reprogramming. Methods The mouse models of streptozotocin (STZ)-induced type 1 diabetes and spontaneous autoimmune diabetes were used to evaluate the preventative and therapeutic effects of OI, which were performed by measuring blood glucose, insulin level, pro- and anti-inflammatory cytokine secretion, histopathology examination, flow cytometry, and islet proteomics. The protective effect and mechanism of OI were examined via peritoneal macrophages isolated from STZ-induced diabetic mice and co-cultured MIN6 cells with OI-pre-treated inflammatory macrophages in vitro. Moreover, the inflammatory status of peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients was evaluated after OI treatment. Results OI ameliorated glycemic deterioration, increased systemic insulin level, and improved glucose metabolism in STZ-induced diabetic mice and non-obese diabetic (NOD) mice. OI intervention significantly restored the islet insulitis and beta cell function. OI did not alter the macrophage count but significantly downregulated the proportion of M1 macrophages. Additionally, OI significantly inhibited MAPK activation in macrophages to attenuate the macrophage inflammatory response, eventually improving beta cell dysfunction in vitro. Furthermore, we detected higher IL-1β production upon lipopolysaccharide stimulation in the PBMCs from type 1 diabetes patients, which was attenuated by OI treatment. Conclusions These results provided the first evidence to date that OI can prevent the progression of glycemic deterioration, excessive inflammation, and beta cell dysfunction predominantly mediated by restricting macrophage M1 polarization in mouse models of type 1 diabetes.

Section: Discussionmentioning

confidence: 99%

4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes

Wang

et al. 2023

Mol Med

“…Also, TGGR only increased Cat mRNA expression in female flies. The Keap1-Nrf2 signal transduction pathway plays a highly conserved role in regulating oxidative stress ( Yao et al, 2022 ). Under normal physiological conditions, Nrf2 binds to the cytoplasmic inhibitor, Keap1, and exists in the cytoplasm, maintaining low transcriptional activity ( Luo et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Studies on the Regulation and Molecular Mechanism of Panax Ginseng Saponins on Senescence and Related Behaviors of Drosophila melanogaster

Liu

Zhang

et al. 2022

Front. Aging Neurosci.

In an increasingly aged global population, achieving healthy life expectancy through natural and safe drug interventions is highly desirable. Here we show that total ginsenosides (TGGR), the main active components in the traditional Chinese medicine, ginseng, promote longevity across species. In Drosophila, an intriguing effect of TGGR on lifespan was the relatively narrow treatment window to elicit long-term benefits. TGGR administration during early adulthood, and especially during midlife, was sufficient to extend lifespan in both sexes. TGGR did not increase lifespan by reducing food intake or reproductive capacity; rather, TGGR increased the fertility of male Drosophila. TGGR augmented healthspan readouts associated with youth and with healthy aging, such as motility, intestinal barrier integrity, and biorhythm homeostasis. TGGR treatment also improved some types of stress resistance in both sexes, including increased tolerance to starvation and oxidation, and shifting “aged” gene expression patterns toward “healthy” patterns seen in the young. Gene expression, pharmacological and genetic epistatic analyses demonstrated that TGGR effects require normal expression of genes involved in insulin, TOR and MAPK signaling. The positive effects of TGGR on both healthspan and lifespan, coupled with its mechanism of action via evolutionarily conserved signaling pathways, demonstrate it to be a promising anti-aging drug.

“…It was proven in several studies that Nrf2 exerted anti-in ammatory and antioxidative functions by regulating MAPK pathway activity. It was suggested that Nrf2 activation mitigated oxidative stress and in ammation in mesangial cells caused by high glucose through inhibiting MAPK signaling (47). Moreover, sulforaphane exerted anti-neuroin ammatory effects on LPS-activated microglia through Nrf2-HO-1 pathway activation and JNK-AP-1-NF-κB pathway inhibition (48).…”

Section: Discussionmentioning

confidence: 99%

4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes

Wang

et al. 2022

Preprint

Background: Pancreatic beta cell dysfunction and activated macrophage infiltration are early features in type 1 diabetes pathogenesis. A tricarboxylic acid cycle metabolite that can strongly activate NF-E2-related factor 2 (Nrf2) in macrophages, itaconate is important in a series of inflammatory-associated diseases by anti-inflammatory and antioxidant properties. However, its role in type 1 diabetes is unclear. We used 4-octyl itaconate (OI), the cell-permeable itaconate derivate, to explore its preventative and therapeutic effects in mouse models of type 1 diabetes and the potential mechanism of macrophage phenotype reprogramming. Methods: The mouse model of streptozotocin (STZ) induced type 1 diabetes and spontaneous autoimmune diabetes were used to evaluate the preventative and therapeutic effects of OI, which were performed by measuring blood glucose, insulin level, pro- and anti-inflammatory cytokine secretion, histopathology examination, flow cytometry, and islet proteomics. The protective effect and mechanism of OI were further examined via peritoneal macrophages isolated from STZ-induced diabetic mice and co-cultured MIN6 cells with OI-pre-treated inflammatory macrophages in vitro. Moreover, the inflammatory status of peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients was evaluated after OI treatment. Results: OI ameliorated glycemic deterioration, increased systemic insulin level, and improved glucose metabolism in STZ-induced diabetic mice and non-obese diabetic (NOD) mice. Meanwhile, the islet insulitis and beta cell function were significantly restored by OI intervention. Indeed, OI did not change the count of macrophages but significantly downregulated the proportion of M1 macrophages. In addition, OI significantly inhibited MAPK activation in macrophages to attenuate the macrophage inflammatory response, eventually improving beta cell dysfunction in vitro. We also found higher IL-1β production upon lipopolysaccharide stimulation in the PBMCs from type 1 diabetes patients, which was attenuated by OI treatment. Conclusions: These results provided the first evidence to date that OI can prevent the progression of glycemic deterioration, excessive inflammation, and beta cell dysfunction predominantly mediated by restricting macrophage M1 polarization in mouse models of type 1 diabetes.