Punicalagin, a Pomegranate‐Derived Ellagitannin, Suppresses Obesity and Obesity‐Induced Inflammatory Responses Via the Nrf2/Keap1 Signaling Pathway

Abstract

Scope Punicalagin (PCG) is one of the most abundant phytochemicals found in pomegranates. The effects and mechanistic action of PCG on obesity and obesity‐induced inflammatory and oxidant responses are investigated in vitro and in vivo. Methods and results The effect of PCG on adipogenesis is examined using Oil red O staining. The effects and mechanism of action of PCG on inflammatory responses are determined in adipocyte‐conditioned medium (ACM)‐cultured macrophages, a cell‐to‐cell contact system, and a transwell system. The effects of PCG on obesity and obesity‐induced inflammatory/oxidant responses are examined in high‐fat diet (HFD)‐fed mice. PCG effectively suppresses lipid accumulation in adipocytes and adipocyte‐induced inflammatory responses in adipocyte‐macrophage co‐culture systems. Small interfering RNA (siRNA) transfection indicates that the PCG‐mediated anti‐inflammatory effect is exerted via the nuclear factor erythroid 2‐related factor 2/Kelch‐like ECH‐associated protein 1(Nrf2/Keap1) pathway. PCG administration results in a significant reduction in body and white adipose tissue (WAT) weights. PCG favorably regulates pro‐ and anti‐inflammatory cytokines, downregulating nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB). Immunohistochemical (IHC) analysis demonstrates that PCG differentially modulates the distribution of complement component 3 receptor 4 subunit (CD11c) and cluster of differentiation 206 (CD206). PCG regulates the level of antioxidant and oxidant molecules by activating Nrf2/Keap1 signaling. Conclusions PCG ameliorates obesity and obesity‐induced inflammatory responses via activation of Nrf2/Keap1 signaling, suggesting that PCG has potential as an oral agent to control obesity‐mediated diseases.

Punicalagin Protects Human Retinal Pigment Epithelium Cells from Ultraviolet Radiation-Induced Oxidative Damage by Activating Nrf2/HO-1 Signaling Pathway and Reducing Apoptosis

“…In fact, the translocation of Nrf2 can also cause an increase in the transcription of the Bcl-2 gene, which translates into a raise of Bcl-2 protein levels and a decrease of Bax, with a consequent decrease in apoptosis and increase in cell survival [ 39 ]. Despite scant information in the literature on this topic, our findings agree with current knowledge about PUN and its anti-oxidative action via Nrf2 pathways observed in other experimental models both in vivo and in vitro [ 24 , 40 , 41 ]. Interestingly, PUN has no effects on ARPE-19 cells in absence of photo-oxidative stress, such as UV-A rays.…”

“…The concentration 10 μM was chosen based on the following evidence: (a) we conducted cell viability studies to evaluate the cytotoxicity of PUN in ARPE-19 for 24 h: no toxicity was found in the range 1–20 µM [Control: 100%; 1 µM PUN: 95% ± 3.7%; 5 µM PUN: 96% ± 2.8%; 10 µM PUN: 98% ± 2.4%; 20 µM PUN: 95% ± 4.1%; the results are expressed as percentage of control and represented by mean ± SEM ( n = 3)]; (b) our recent study showed that the concentration of 10 μM of PUN was effective, but not maximal, in counteracting cellular oxidative stress. In fact, the PUN given in the range 0.5–20 μM protected the cells from oxidative damage in a concentration-dependent manner, recovering cell viability to about 85% at 10 μM [ 16 ]; (c) the scientific literature review about ellagitannins supports the hypothesis that this concentration is the most appropriate and effective in contrasting different oxidative stresses in numerous cell lines [ 22 , 23 , 24 , 25 ].…”

“…To date, it is well known that PUN possesses antioxidant, anti-inflammatory, antidiabetic, anti-proliferative, anti-angiogenic, and anti-cancer properties. Moreover, many of the PUN’s beneficial effects have been widely related to the modulation of various and important signaling pathways and to the expression of genes responsible for the therapeutic effects mentioned above [ 24 , 25 , 26 , 27 , 28 ]. Nevertheless, the results presented in this study demonstrate for the first time that PUN has an antioxidant action on the RPE and a probable antiapoptotic effect, modulating the protein expression of Bax and Bcl2.…”

Beneficial Fatty Acid Ratio of Salvia hispanica L. (Chia Seed) Potentially Inhibits Adipocyte Hypertrophy, and Decreases Adipokines Expression and Inflammation in Macrophage

“…Most interestingly, insulin resistance-and obesity-associated immune disorder progressive proteins, such as, LTB-4R, STAT6, IL-4 and TNF-α levels, have been suppressed by chia seed treatment. Our findings are in line with Kang et al [37] that punicalagin has been proven for its anti-obesity effect and obesity-induced inflammatory responses via the Nrf2/Keap1 Signaling Pathway.…”

Medicinal Plant Polyphenols Attenuate Oxidative Stress and Improve Inflammatory and Vasoactive Markers in Cerebral Endothelial Cells during Hyperglycemic Condition

“…For T. bentzoe plant extract, the predominant polyphenols identified were gallic and ellagic acids as well as their sugar conjugates comprising the ellagitannins punicalin and punicalagin. Interestingly, these compounds may represent unique ellagitannins from specific dietary sources, like pomegranate, and be responsible for most of the antioxidant properties that were attributed to this fruit [ 53 , 54 ]. Altogether, our UPLC-ESI-MS-MS results demonstrate that the polyphenol composition was dependent on the medicinal plant considered.…”