PMID: 

Inflammation. 2017 Oct ;40(5):1698-1706. PMID: 28695367

Abstract Title: 

Paeonol Inhibits IL-1β-Induced Inflammation via PI3K/Akt/NF-κB Pathways: In Vivo and Vitro Studies.

Abstract: 

Paeonol, the main active component isolated from the root of Paeonia suffruticosa, has been reported to have anti-inflammatory properties. However, the effects of paeonol on osteoarthritis (OA) remain unclear. The aim of this study was to investigate the anti-inflammatory effects and mechanism of paeonol in IL-1β-induced human OA chondrocytes as well as mice OA models. Human OA chondrocytes were pretreated with different concentrations of paeonol 2 h prior to IL-1β (10 ng/mL) stimulation for 24 h. Nitric oxide (NO) production was determined by Griess method. The levels of prostaglandin E2 (PGE2), matrix metalloproteinase 1 (MMP-1), MMP-3, and MMP-13 were assessed by ELISA. Inducible nitric oxide synthase (INOS), COX-2, and PI3K/Akt/NF-κB-related signaling molecules production were measured by Western blot. In vivo, mice OA models were established by destabilization of the medial meniscus. One month after surgery, mice in paeonol-treated group were given intraperitoneal injection of paeonol in 30 mg/kg every day, while mice of vehicle-treated group were injected with DMSO under the same conditions. Hematoxylin and eosin as well as Safranin-O staining were applied to assess the severity ofcartilage lesions. The results showed that pretreatment with paeonol could inhibit IL-1β-induced NO and PGE2 production. Meanwhile, the overproduction of INOS, COX-2, MMP-1, MMP-3, and MMP-13 were also reversed by paeonol. Moreover, paeonol was found to inhibit IL-1β-induced NF-κB activation, PI3K, and AKT phosphorylation. In vivo, treatment with paeonol exhibited less cartilage degradation and lower Osteoarthritis Research Society International scores in mice OA models. In conclusion, these results suggest that paeonol may be a potential therapeutic agent in the treatment of OA.

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PMID: 

Inflammopharmacology. 2017 Aug 10. Epub 2017 Aug 10. PMID: 28799079

Abstract Title: 

Protective effects of paeonol on inflammatory response in IL-1β-induced human fibroblast-like synoviocytes and rheumatoid arthritis progression via modulating NF-κB pathway.

Abstract: 

Various investigations have demonstrated that human fibroblast-like synoviocytes rheumatoid arthritis (HFLS-RA) take part in the chronic inflammatory responses and RA progression. Inhibition of synovium activation and inflammatory processes may represent a therapeutic target to alleviate RA. Paeonol, a major natural product, has many biological and pharmacological activities. However, its protective effects against RA considering HFLS-RA have not been explored. In this study, anti-inflammatory effects of paeonol were detected in interleukin-1β (IL-1β)-treated HFLS-RA. Our results demonstrated that paeonol had no effect on cell survival and IL-1β-induced proliferation in HFLS-RA. Pretreatment with paeonol significantly suppressed the production of pro-inflammatory TNF-α, IL-6 and IL-1β, and the expressions of matrix metalloproteinase-1/-3 in vitro and in vivo. Mice treated with paeonol (10 mg/kg) remarkablely attenuated arthritic symptoms based on clinical arthritis scores and histopathology in collagen-induced arthritis mice. Furthermore, the TLR4 expression and NF-κB p65 activation were inhibited by paeonol in vitro and invivo. Our findings illustrated that paeonol had significantly suppressed inflammation effects in synovial tissues and RA progression. The potential mechanism might be based on the attenuation TLR4-NF-κB activation. These collective results indicated that paeonol might be a promising therapeuticagent for alleviating RA progress through inhibiting inflammations and NF-κB signalling pathway.

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PMID: 

Biomed Pharmacother. 2017 Nov ;95:914-921. Epub 2017 Sep 10. PMID: 28910961

Abstract Title: 

Paeonol alleviates interleukin-1β-induced inflammatory responses in chondrocytes during osteoarthritis.

Abstract: 

Interleukin-1β (IL-1β)-induced inflammatory responses in chondrocytes play an important role in the pathogenesis of osteoarthritis (OA). Searching medicines that affect IL-1β-mediated chondrocytes function is critical in developing therapies for OA. Paeonol, as an important component in traditional Chinese medicine, has anti-inflammatory activity and can offer therapy for a multitude of inflammatory-related diseases. The purpose of this study was to investigate whether paeonol could alleviate the progression of OA through inhibition of IL-1β-induced inflammatory responses in chondrocytes. The cell counting kit-8 assay, 5-ethynil-2'-deoxyuridine staining, hoechst 33258 staining and flow cytometric staining were used to observe the chondrocytes proliferation and apoptosis. Western blot and quantitative real-time PCR were applied to examine the expression of extracellular matrix and cartilage degrading enzymes. Reactive oxygen species (ROS) production was monitored by 2',7'-dichlorodihydrofluoresce in diacetate staining. Furthermore, paeonol was intra-articularly injected into joint capsule in destabilized medial meniscus (DMM)-induced OA rat model for 8 and 12 weeks. The results showed that paeonol could negatively affect IL-1β-mediate chondrocyte apoptosis and proliferation. Application of paeonol attenuated the secretion of cartilage extracellular matrix and cartilage degrading enzymes induced by IL-1β in chondrocytes. Increasing of ROS production by IL-1β was obviously alleviatedby paeonol. Besides, paeonol alleviated DMM-induced articular cartilage degeneration in vivo. Taken together, we concluded that paeonol might be used as therapeutic agent for treating OA.

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PMID: 

Exp Ther Med. 2017 Oct ;14(4):3213-3220. Epub 2017 Aug 3. PMID: 28912871

Abstract Title: 

Paeonol enhances the sensitivity of human ovarian cancer cells to radiotherapy-induced apoptosis due to downregulation of the phosphatidylinositol-3-kinase/Akt/phosphatase and tensin homolog pathway and inhibition of vascular endothelial growth factor.

Abstract: 

Radiotherapy is a vital and effective method to treat solid tumors. However, in many tumor types, development of resistance of cancer cells and cytotoxicity in normal tissues presents a major therapeutic problem. It is therefore crucial to identify and develop novel sensitizing agents that may improve the response to radiation therapy without causing any adverse effects. The present study aimed to investigate whether paeonol, a bioactive flavonoid, was able to confer sensitivity to radiation in human ovarian cancer cells. The human ovarian cancer cell lines SKOV-3 and OVCAR-3 were exposed to varying doses of radiation (2, 4 or 6 Gy) in the presence or absence of paeonol (25, 50 or 100µM). Radiosensitivity was assessed by measuring cell viability using a CCK-8 assay and Annexin V/PI staining. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α (HIF-1α), proteins of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and apoptotic pathway proteins [caspase-3, Bcl-2-associated death promoter, B-cell lymphoma (Bcl)-2, Bcl-2-associated X and Bcl-extra large (Bcl-xL)] were also assessed. Paeonol treatment enhanced apoptosis of SKOV-3 and OVCAR-3 cells that were exposed to radiation. The expression of Bcl-2 and Bcl-xL were markedly upregulatedin these cells. Treatment with paeonol concentrations of 50 and 100 µM caused a significant downregulation of VEGF, HIF-1α and PI3K/Akt pathway proteins. Paeonol effectively enhanced the sensitivity of ovarian cancer cells to radiation by significantly altering regulation of the proteins of the PI3K/Akt pathway, in addition to downregulating VEGF and HIF-1α.

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PMID: 

Int J Nanomedicine. 2017 ;12:6605-6616. Epub 2017 Sep 7. PMID: 28924345

Abstract Title: 

Delivery of paeonol by nanoparticles enhances its in vitro and in vivo antitumor effects.

Abstract: 

Paeonol (Pae; 2'-hydroxy-4'-methoxyacetophenone) has attracted intense attention as a potential therapeutic agent against various cancers. However, the use of Pae is limited owing to its hydrophobicity. Recently, biodegradable polymeric nanoparticles with amphiphilic copolymers have been used as drug carriers; these have better bioavailability and are promising tumor-targeted drug delivery systems. In the current study, we prepared Pae-loaded nanoparticles (Pae-NPs) with amphiphilic block copolymers using nanoprecipitation. The physiochemical characteristics and antitumor effects of nanoparticles were evaluated in different cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed substantial inhibition of cell growth by Pae-NPs. Moreover, lower doses of Pae-NPs inhibited cell growth more efficiently than the equivalent doses of free Pae. Inhibition was characterized by significant elevation of intracellular reactive oxygen species and subsequent inhibition of Akt and regulation of apoptotic proteins, which could be partly reversed by pretreatment with the antioxidant N-acetylcysteine. In vivo results also demonstrated that Pae-NPs could exert much stronger antitumor effects than free Pae. Therefore, Pae-NPs represent a promising delivery system to overcome the low solubility of Pae and enable its use in treating cancer.

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PMID: 

Chem Biol Interact. 2018 Apr 25 ;286:17-25. Epub 2018 Mar 2. PMID: 29505745

Abstract Title: 

Cardioprotective effect of paeonol against epirubicin-induced heart injury via regulating miR-1 and PI3K/AKT pathway.

Abstract: 

Cardiotoxicity is a dose-dependent side effect of epirubicin that restricts its clinical utility in cancer chemotherapy. Paeonol is an active constituent with various biological activities, including the protection of antineoplastic-induced toxicities. In the present study, we investigated the protective effect of paeonol on epirubicin-induced cardiotoxicity and explored the underlying mechanism. A series of methods were used including a MTT assay, flow cytometry, echocardiography, TUNEL staining, a dual-luciferase reporter assay, immunofluorescence, RT-PCR and Western blotting. The results indicate that paeonol improves cardiac dysfunction, relieves histopathological changes, alleviates inflammation, reduces myocardial apoptosis and increases autophagy. Further studies suggest that paeonol upregulates the decreased expression of miR-1 caused by epirubicin and thus inhibits the activation of PI3K/AKT/mTOR and NF-κB pathways. In conclusion, paeonol effectively ameliorates myocardial injury by increasing miR-1 expression to suppress the PI3K/AKT/mTOR and NF-kB signalling pathways.

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PMID: 

Mol Med Rep. 2017 Nov ;16(5):7513-7519. Epub 2017 Sep 21. PMID: 28944890

Abstract Title: 

Paeonol exerts potential activities to inhibit the growth, migration and invasion of human gastric cancer BGC823 cells via downregulating MMP‑2 and MMP‑9.

Abstract: 

Paeonol (Pae) is an herbal extract that has attracted extensive attention for its anti‑cancer effects demonstrated by a number of studies, which have predominantly demonstrated inhibition of cell proliferation and induction of apoptosis. The influence of Pae on cancer cell metastasis has been less widely reported. The present study aimed to investigate the under‑reported effectsof Pae on the growth, invasion and migration of poorly differentiated BGC823 gastric cancer cells with strong invasive and metastatic abilities. The anti‑proliferative and pro‑apoptotic effects of Pae on BGC823 cells were verified by Cell Counting kit‑8 and Annexin V‑fluorescein isothiocyanate/propidium iodide assays. Cell scratch‑wound healing and Transwell methods were applied, and it was demonstrated that Pae could exert inhibitory activities on the invasion and migration of BGC823 cells. Furthermore, it was indicated by western blot analysis that Pae could downregulate the protein expression levels of matrix metalloproteinase (MMP)‑2 and ‑9 in a concentration‑dependent manner, which may support a novel potential mechanism accounting for its anti‑cancer effects on gastric cancer.

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PMID: 

J Ethnopharmacol. 2019 Nov 7:112325. Epub 2019 Nov 7. PMID: 31707049

Abstract Title: 

Effect of Zataria multiflora on serum cytokine levels and pulmonary function tests in sulfur mustard-induced lung disorders: A randomized double-blind clinical trial.

Abstract: 

ETHNOPHARMACOLOGICAL RELEVANCE: Zataria multiflora (Z. multiflora) belongs to the Lamiaceae family and has several traditional uses owing to its antiseptic, aesthetic, antispasmodic, analgesic, and antidiarrheal properties.AIM OF THE STUDY: We aimed to investigate the effect of Z. multiflora on serum cytokine levels and pulmonary function tests (PFT) in patients exposed to sulfur mustard (SM) for a long term (27-30 years).MATERIALS AND METHODS: Thirty-five patients were randomly assigned to the placebo group (P) and two experimental groups treated with Z. multiflora extracts, i.e., 5 and 10 mg/kg/day (Z5 and Z10). Serum levels of cytokines including IL (2, 4, 6, 8, and 10) and IFN-γ as well as PFT indices such as maximum mid-expiratory flow (MMEF) and maximum expiratory flow at 25, 50, and 75% of vital capacity (VC) (MEF25, 50, and 75) were assessed at the beginning (phase 0) and at the end of 4 and 8 weeks (phases I and II, respectively) after starting the treatment.RESULTS: Serum levels of IL-2, IL-6, and IL-8 were significantly decreased, while serum levels of IL-10 and IFN-γ were significantly increased in the Z5 and Z10 treatment groups in phases I and II as compared to those in phase 0 (p 

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PMID: 

Med Sci Monit. 2017 Oct 3 ;23:4740-4748. Epub 2017 Oct 3. PMID: 28972959

Abstract Title: 

Role of Paeonol in an Astrocyte Model of Parkinson's Disease.

Abstract: 

BACKGROUND Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Inflammation and neural degeneration are implicated in the pathogenesis of PD. Paeonol has been verified to attenuate inflammation. MATERIAL AND METHODS 1-methyl-4-phenylpyridnium ion (MPP+, 100μM) was used to induce the cell model of PD in primary cultured astrocytes. Astrocyte cell viability and apoptosis were determined by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry (FCM), respectively. Protein levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthases (iNOS) in culture medium were tested by enzyme-linked immunosorbent (ELISA) assay. Protein levels of casapse-1, COX2, iNOS, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, and phosphorylated Jun N-terminal kinase (p-JNK)/phosphorylated extracellular signal-regulated kinase (p-ERK)/p-P38 were examined by Western blot. RESULTS Pretreatment with paeonol remarkably rescued MPP+-induced cell viability reduction, up-regulation of cell apoptosis, caspase-1 activity, COX-2, iNOS, and Bax/Bcl-2 ratio in primary astrocytes. Furthermore, paeonol repressed MPP+ -induced elevation of p-JNK/p-ERK in primary cultured astrocytes. CONCLUSIONS The present study found that paeonol protected cells from apoptosis by repressing the activation of the JNK/ERK related signalling pathway induced by MPP+ in astrocytes. We propose that paeonol is a neuroprotective agent for the treatment of PD patients, with great promise in the future.

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PMID: 

J Pharmacol Exp Ther. 2018 03 ;364(3):420-432. Epub 2017 Dec 19. PMID: 29259041

Abstract Title: 

Paeonol Attenuates LPS-Induced Endothelial Dysfunction and Apoptosis by Inhibiting BMP4 and TLR4 Signaling Simultaneously but Independently.

Abstract: 

Inflammatory injury of the endothelium leads to apoptosis and endothelial dysfunction. The current study explored the effect and mechanisms of paeonol in inflammation-induced apoptosis and endothelial dysfunction induced by lipopolysaccharides (LPSs). The effects of paeonol on LPS-induced inflammatory injury were assessed by Western blotting, flow cytometry and reactive oxygen species (ROS) measurement in human umbilical vein endothelial cells (HUVECs) and C57BL/6J mice. Vascular reactivity of isolated mouse aortae was examined using wire myographs. The exposure of HUVECs to LPS increased the protein presence of Toll-like receptor 4 (TLR4), bone morphogenic protein 4 (BMP4), BMP receptor type 1A, nicotinamide adenine dinucleotide phosphate oxidase subunit 2, mitogen-activated protein kinase (MAPK), inducible nitric oxide synthase (iNOS), and cleaved caspase 3, as well as decreased it in phosphorylated endothelial nitric oxide synthase; these effects were prevented by treatment with paeonol. Similarly, cotreatment with paeonol reversed BMP4-induced apoptosis in HUVECs. Relaxation in response to the endothelium-dependent vasodilator acetylcholine were impaired in mouse aortae after exposure to LPSs; this endothelial dysfunction was reversed by cotreatment with paeonol, noggin (a BMP4 inhibitor), TAK242 (TLR4 antagonist), apocynin (an ROS scavenger), MAPK inhibitors, and AG (an iNOS inhibitor). BMP4 small interfering RNAs (siRNAs) abolished LPS-induced upregulation of BMP4 and cleaved caspase 3 protein, but not in cells treated with TLR4 siRNA and vice versa. The silencing of TLR4 and BMP4 abolished the inhibitory effects of paeonol on LPS-induced activation of cleaved caspase 3. The present results demonstrate that paeonol reduces LPS-induced endothelial dysfunction and apoptosis by inhibiting TLR4 and BMP4 signaling independently.

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