Hyoscyamus albus nortropane alkaloids reduce hyperglycemia and hyperinsulinemia induced in HepG2 cells through the regulation of SIRT1/NF-kB/JNK pathway

Abstract

Background Chronic superphysiological glucose and insulin concentrations are known to trigger several tissue and organ failures, including insulin resistance, oxidative stress and chronic low-grade inflammation. Hence, the screening for molecules that may counteract such conditions is essential in current existing therapeutic strategies, thereby the use of medicinal plant derivatives represents a promising axis in this regard. Methods In this study, the effect of a selected traditional medicinal plant, Hyoscyamus albus from which, calystegines have been isolated, was investigated in an experimental model of hyperinsulinemia and hyperglycemia induced on HepG2 cells. The mRNA and protein expression levels of different insulin signaling, gluconeogenic and inflammatory pathway- related molecules were examined. Additionally, cell viability and apoptosis, oxidative stress extent and mitochondrial dysfunctions were assayed using flow cytometric and qRT-PCR techniques. Results Treatment of IR HepG2 cells with calystegines strongly protected the injured cells from apoptosis, oxidative stress and mitochondrial integrity loss. Interestingly, nortropane alkaloids efficiently regulated the impaired glucose metabolism in IR HepG2 cells, through the stimulation of glucose uptake and the modulation of SIRT1/Foxo1/G6PC/mTOR pathway, which is governing the hepatic gluconeogenesis. Furthermore, the alkaloidal extract restored the defective insulin signaling pathway, mainly by promoting the expression of Insr at the mRNA and protein levels. What is more, treated cells exhibited significant mitigated inflammatory response, as evidenced by the modulation and the regulation of the NF- κB/JNK/TLR4 axis and the downstream proinflammatory cytokines recruitment. Conclusion Overall, the present investigation demonstrates that calystegines from Hyoscyamus albus provide cytoprotection to the HepG2 cells against insulin/glucose induced insulin resistance and apoptosis due to the regulation of SIRT1/Foxo1/G6PC/mTOR and NF-κB/JNK/TLR4 signaling pathways.

Exercise alleviates diabetic complications by inhibiting oxidative stress-mediated signaling cascade and mitochondrial metabolic stress in GK diabetic rat tissues

“…Exercise training caused a significant decrease in activity in the kidney, though no significant change was observed in the liver. Activation of the PI3K/Akt/Glut-4 pathway has been known to be significantly involved in the regulation of insulin signaling and glucose metabolism and defects in the insulin signaling pathway, which lead to glucose homeostasis could lead to insulin resistance ( Marinho et al, 2014 ; Rai et al, 2019 ; Kowalczuk et al, 2021 ; John et al, 2022 ). Our current study also showed activation of Akt and improved expression of Glut-4 protein after exercising, implying improved glucose homeostasis and increased insulin sensitivity.…”

Flavonoid compound from Agrimonia Pilosa Ledeb improves adipose insulin resistance by alleviating oxidative stress and inflammation

“…Akt, a downstream target of PI3K, is triggered by the activation of insulin receptor in insulin signal pathway and facilitates the uptake of glucose with GLUT. Besides, the increased PI3K activity and activated Akt also can increase the insulin-stimulated glucose disposal [7]. Therefore, stopping JNK/PI3K/Akt pathway is an approach of stopping oxidative and in ammatory insult at the initiation of IR and T2DM.…”

“…In addition, JNK, as the common point of oxidative stress and in ammation, its phosphorylation can trigger the serine phosphorylation of IRS-1 and lead to IR. These series of reports clearly provide evidence that ROS and in ammatory factors can phosphorylate JNK [7], and controlling JNK may play an indispensable role in preventing IR [8]. Taken all of these together, alleviating oxidative stress and in ammation may be e cient and reliable in preventing IR and T2DM.…”

The Signaling Pathways Induced by Exosomes in Promoting Diabetic Wound Healing: A Mini-Review

“…Hyperglycemia can trigger oxidative stress and promote the production of pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), which can result in the activation of the NF-kB pathway and further promote the synthesis of inflammatory factors, disrupting diabetic wound healing [ 69 ]. Fan et al showed that HBMMSCS-derived exosomes (HBMMSCS-exos) significantly inhibited the expression of pro-apoptotic proteins and pro-inflammatory factors, while the expression of anti-apoptotic proteins and anti-inflammatory factors was up-regulated in lipopolysaccharide (LPS)-induced PC12 cell apoptosis [ 70 ].…”