The Beneficial Effects of Chinese Herbal Monomers on Ameliorating Diabetic Cardiomyopathy via Nrf2 Signaling

Figures

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  Figure 1. Oxidative stress in the pathogenesis of DCM (created with BioRender.com). In patients with diabetes, the main abnormalities of the inner environment are hyperglycemia, systemic insulin insistence, and hyperinsulinemia. Oxidative stress could trigger mitochondrial dysfunction and endoplasmic reticulum stress, and impair calcium handling and increase Ca2+ sensitivity and Ca2+ influx. ROS/RNS could impact both β-cells and cardiac cells leading to cell death and dysfunction. ROS: reactive oxygen species; RNS: reactive nitrogen species.

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  Figure 2. The crosstalk between Nrf2 and NF-κB signaling pathway (created with BioRender.com). (a) Nrf2-dependent antioxidant genes could block TLR and TNF-dependent signaling. (b) Nrf2 and NQO1 inhibit the priming step of NLRP3, and suppress caspase-1 cleavage and IL-1β generation. (c) Keap1 could ubiquitinate IKK and be targeted by 15d-PGJ2. (d) Nrf2 and NF-κB could compete to combine with CBP. Nrf2: nuclear factor erythroid-2 related factor 2; NF-κB: nuclear factor-κB; HO-1: heme oxygenase-1; NQO1: NAD(P)H quinone dehydrogenase-1; TLR: toll-like receptors; TNFR: tumor necrosis factor receptor; NLRP3: nucleotide-binding oligomerization domain-like receptor protein 3; IL-1β: interleukin-1β; Keap1: kelch-like ECH-associated protein 1; IKK: inhibitors of NF-κB kinase; CBP: cAMP-response-element-binding protein-binding protein.

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  Figure 3. The crosstalk between Nrf2 and other signaling pathways (created with BioRender.com). (a) AMPK could phosphorylate both Nrf2 (active) and GSK3β (deactivate) to prevent Nrf2 ubiquitinated by GSK3β to improve the nuclear accumulation of Nrf2. AMPK could promote autophagic degradation of Keap1. Besides, AMPK could activate SIRT1 to regulate Nrf2. (b) Akt could phosphorylate GSK3β to prompt nuclear accumulation of Nrf2. Furthermore, CK2 could not only activate Akt signaling pathway but also could directly phosphorylate Nrf2 to enhance its stability. (c) ERK, JNK, and p38 are always observed accompany by suppression of Nrf2. But the underlying mechanism is unclear. (d) Nrf2 could reduce MMP-9 to decrease the levels of TGF-β. Besides, Smad7 could form a complex type I receptor, and it recruits Smurf 1/2 to activate the type I receptor, thus negatively regulating TGF-β signaling pathway. And Nrf2 could enhance the level of Smad7. AMPK: adenosine monophosphate-activated protein kinase; GSK3β: glycogen synthase kinase 3β; SIRT: silent information regulator 1; Akt: phosphatidylinositol 3-kinase-protein kinase B; CK2: ceramide-protein kinase C ζ-casein kinase 2; ERK: extracellular…