Protective Effects of Punicalagin on Osteoporosis by Inhibiting Osteoclastogenesis and Inflammation via the NF-κB and MAPK Pathways

Wang, Wei; Bai, Jiaxiang; Zhang, Wenhao; Ge, Gaoran; Wang, Qing; Liang, Xiaoyao; Li, Ning; Gu, Ye; Li, Meng; Xu, Wei; Yang, Huilin; Xu, Yaozeng; Zhou, Jun

doi:10.3389/fphar.2020.00696

Cited by 24 publications

(23 citation statements)

References 40 publications

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“…Targeting the ERK MAPK signaling pathway has been employed as a therapeutic strategy to treat cancer and neurological diseases, highlighting its importance in the regulation of these diseases [ 76 , 77 ]. Similarly, although there has yet to be an available therapeutic strategy that is designed to specifically target the ERK MAPK signaling pathway to treat osteoporosis, various other strategies such as estrogen, rhein-derived thioamide (RT), prostaglandin E2 (PGE2), and Src inhibitors, to name a few, have mechanisms involved in the regulation of the ERK MAPK signaling pathway [ 74 , 78 , 79 , 80 , 81 , 82 ]. Estrogen and PGE2 activate ERK to promote osteoblast differentiation, but estrogen also activates ERK to inhibit osteoclast differentiation, as mentioned above [ 74 , 81 ].…”

Section: Discussionmentioning

confidence: 99%

A Synthetic Peptide, CK2.3, Inhibits RANKL-Induced Osteoclastogenesis through BMPRIa and ERK Signaling Pathway

Nguyen

Kelly

Wood

et al. 2020

JDB

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The skeletal system plays an important role in the development and maturation process. Through the bone remodeling process, 10% of the skeletal system is renewed every year. Osteoblasts and osteoclasts are two major bone cells that are involved in the development of the skeletal system, and their activity is kept in balance. An imbalance between their activities can lead to diseases such as osteoporosis that are characterized by significant bone loss due to the overactivity of bone-resorbing osteoclasts. Our laboratory has developed a novel peptide, CK2.3, which works as both an anabolic and anti-resorptive agent to induce bone formation and prevent bone loss. We previously reported that CK2.3 mediated mineralization and osteoblast development through the SMAD, ERK, and AKT signaling pathways. In this study, we demonstrated the mechanism by which CK2.3 inhibits osteoclast development. We showed that the inhibition of MEK by the U0126 inhibitor rescued the osteoclast development of RAW264.7 induced by RANKL in a co-culture system with CK2.3. We observed that CK2.3 induced ERK activation and BMPRIa expression on Day 1 after stimulation with CK2.3. While CK2.3 was previously reported to induce the SMAD signaling pathway in osteoblast development, we did not observe any changes in SMAD activation in osteoclast development with CK2.3 stimulation. Understanding the mechanism by which CK2.3 inhibits osteoclast development will allow CK2.3 to be developed as a new treatment for osteoporosis.

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Section: Discussionmentioning

confidence: 99%

A Synthetic Peptide, CK2.3, Inhibits RANKL-Induced Osteoclastogenesis through BMPRIa and ERK Signaling Pathway

Nguyen

Kelly

Wood

et al. 2020

JDB

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“…Punicalagin (PUN) is a polyphenol isolated from pomegranate and displays a variety of pharmacological activities, of which antioxidant and anti-inflammatory are the most important [125,126]. It seems that antioxidant activity of PUN is mediated via its impact on Nrf2 signaling pathway.…”

Section: Natural Compounds In Ameliorating Doxorubicin-mediated Toxicitymentioning

confidence: 99%

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

et al. 2021

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Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.

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“…Previously, it was reported that punicalagin would be beneficial in some diseases, including Alzheimer's disease [ 27 ], memory impairment [ 28 ], and endometritis [ 29 ], which is due to its inhibitory effects on MAPK and NF- κ B activation. Punicalagin treatment effectively inhibits proinflammatory cytokine, nuclear factor κ B (NF- κ B), and mitogen-activated protein kinase (MAPK) expression in vitro in osteoporosis [ 30 ]. Punicalagin which has potent anti-inflammatory effects could be beneficial for ankylosing spondylitis like chronic progressive inflammatory conditions.…”

Section: Introductionmentioning

confidence: 99%

Punicalagin Exerts Protective Effects against Ankylosing Spondylitis by Regulating NF-κB-TH17/JAK2/STAT3 Signaling and Oxidative Stress

Feng

Yang

Wang

et al. 2020

BioMed Research International

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Background. Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by sacroiliitis and spinal rigidity of the axial joints. The role of oxidative stress and increased proinflammatory cytokines is well documented in AS pathogenesis. Punicalagin (2,3-hexahydroxydiphenoyl-gallagyl-D-glucose), an ellagitannin widely present in pomegranates, is found to exhibit potent anti-inflammatory, antiproliferative, and antioxidative effects. The present study was undertaken to investigate the effects of punicalagin in a rodent model of AS. Methods. BALB/c mice induced spondylitis were sacrificed 24 h after the last injection of proteoglycan extract. Histological scoring was done to assess the degree of the disease. The expression of JAK2/STAT3 proteins and proteins of the nuclear factor-κB (NF-κB) pathway was determined by immunoblotting. Serum levels of inflammatory mediators—TNF-α, IL-1β, IL-6, IL-17A, and IL-23—were assessed. Levels of lipid peroxidation and reactive oxygen species (ROS) were quantified. Antioxidant status as a measure of activities of antioxidant enzymes—catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)—was determined. Results. Punicalagin effectively improved antioxidant status and decreased lipid peroxidation, ROS production, and serum levels of inflammatory mediators. NF-κB pathway and JAK2/STAT3 signaling were significantly (p<0.05) downregulated. Punicalagin effectively regulated the production of cytokines by the Th17 cells and the IL-17A/IL-23 axis. Conclusion. The observations suggest that punicalagin exerts a protective role in AS via reducing oxidative stress and regulating NF-κB/TH17/JAK2/STAT3 signal. Punicalagin thus could be explored further as a potent candidate compound in the treatment of AS.

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Protective Effects of Punicalagin on Osteoporosis by Inhibiting Osteoclastogenesis and Inflammation via the NF-κB and MAPK Pathways

Cited by 24 publications

References 40 publications

A Synthetic Peptide, CK2.3, Inhibits RANKL-Induced Osteoclastogenesis through BMPRIa and ERK Signaling Pathway

A Synthetic Peptide, CK2.3, Inhibits RANKL-Induced Osteoclastogenesis through BMPRIa and ERK Signaling Pathway

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Punicalagin Exerts Protective Effects against Ankylosing Spondylitis by Regulating NF-κB-TH17/JAK2/STAT3 Signaling and Oxidative Stress

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