Novel Neohesperidin Dihydrochalcone Analogue Inhibits Adipogenic Differentiation of Human Adipose-Derived Stem Cells through the Nrf2 Pathway

Abstract

Obesity, characterized by excess lipid accumulation, has emerged as a leading public health problem. Excessive, adipocyte-induced lipid accumulation raises the risk of metabolic disorders. Adipose-derived stem cells (ASCs) are mesenchymal stem cells (MSCs) that can be obtained from abundant adipose tissue. High fat mass could be caused by an increase in the size (hypertrophy) and number (hyperplasia) of adipocytes. Reactive oxygen species (ROS) are involved in the adipogenic differentiation of human adipose-derived stem cells (hASCs). Lowering the level of ROS is important to blocking or retarding the adipogenic differentiation of hASCs. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor that mediates various antioxidant enzymes and regulates cellular ROS levels. Neohesperidin dihydrochalcone (NHDC), widely used as artificial sweetener, has been shown to have significant free radical scavenging activity. In the present study, (E)-3-(4-chlorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (CTP), a novel NHDC analogue, was synthesized and examined to determine whether it could inhibit adipogenic differentiation. The inhibition of adipogenic differentiation in hASCs was tested using NHDC and CTP. In the CTP group, reduced Oil Red O staining was observed compared with the differentiation group. CTP treatment also downregulated the expression of PPAR-γ and C/EBP-α, adipogenic differentiation markers in hASCs, compared to the adipogenic differentiation group. The expression of FAS and SREBP-1 decreased in the CTP group, along with the fluorescent intensity (amount) of ROS. Expression of the Nrf2 protein was slightly decreased in the differentiation group. Meanwhile, in both the NHDC and CTP groups, Nrf2 expression was restored to the level of the control group. Moreover, the expression of HO-1 and NQO-1 increased significantly in the CTP group. Taken together, these results suggest that CTP treatment suppresses the adipogenic differentiation of hASCs by decreasing intracellular ROS, possibly through activation of the Nrf2 cytoprotective pathway. Thus, the use of bioactive substances such as CTP, which activates Nrf2 to reduce the cellular level of ROS and inhibit the adipogenic differentiation of hASCs, could be a new strategy for overcoming obesity.

Comparison between Traditional Chinese Medicine Constitution and Blood Biochemical Markers Associated with Left and Right Mammary Hyperplasia in Rural Areas of Southwest China

“…The representative compound of qingpi, neohesperidin, a flavonoid glycoside with a strong bitter taste [ 54 ], is also one of the most important natural flavonoid glycosides, with strong anti-inflammatory, anticancer, and cardiovascular protective effects [ 55 ]. Relevant research results show that neohesperidin can significantly inhibit the proliferation of breast cancer (MCF-7 cells) in a dose-dependent manner [ 56 ].…”

Bitter Orange (Citrus aurantium Linné) Improves Obesity by Regulating Adipogenesis and Thermogenesis through AMPK Activation

“…Neohesperidin, another well-known compound of the Citrus genus, also has an AMPK-dependent lipid-regulating effect in vivo and vitro [63]. Further studies reported the anti-adipogenic or anti-obese effect of naringin [64,65,66,67] and neohesperidin [68,69], nevertheless, none of these have established the effect of either compound on UCP1-mediated thermogenesis. Our LC-MS data suggests that these two constituents may be responsible for the AMPKα-dependent anti-adipogenic and thermogenic effect of CA, however, to clarify, further investigation should be carried out with different fractions and/or identified constituents.…”

The Role of NRF2 in Bone Metabolism – Friend or Foe?

“…Dendrobium officinale polysaccharides (DOPs) significantly promoted osteoblast differentiation and inhibited adipogenic differentiation of BMSCs by activating NRF2 pathway ( 78 ). The novel neohesperidin dihydrochalcone analogue inhibits adipogenic differentiation of human adipose-derived stem cells via the NRF2 pathway as well ( 79 ). Panax ginseng fruit protects against porphyromonas gingivalis lipopolysaccharide (PG-LPS)-induced osteoblastic differentiation injury in hPDLCs by activating the NRF2/HO-1 signaling pathway ( 80 ).…”