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Ilex asprella aqueous extracts exert in vivo anti-inflammatory effects by regulating the NF-κB, JAK2/STAT3, and MAPK signaling pathways.
J Ethnopharmacol. 2018 Oct 28; 225:234-243.JE

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Ilex asprella (Hook. et Arn.) Champ. ex Benth. (IA) is a representative medicinal plant from the South of the Five Ridges of China. Its roots (RIA) and stems (SIA) have been traditionally used for the inflammation-related diseases, such as acute and chronic pharyngitis, cough, and sore throats.

AIM OF THE STUDY

To evaluate the in vivo anti-inflammatory effects of IA extracts to provide evidence for its traditional use and to enhance the knowledge of the medicinal properties of IA.

MATERIALS AND METHODS

Models of xylene-induced ear edema in mice and carrageenan-induced paw edema in rats were used for the pharmacological evaluations. The mice were randomly divided into eight groups (n = 10 per group): a model group, a positive control group [dexamethasone (Dex), 10 mg/kg, intragastrically (i.g.)], RIA aqueous extract groups with three dosages (30, 15, and 7.5 mg/kg, i.g.), and SIA aqueous extract groups with three dosages (60, 30, and 15 mg/kg, i.g.). The rats were randomly divided into eight groups (n = 6 per group): a model group, a positive control group [acetylsalicylic acid (ASA), 300 mg/kg, i.g.], RIA groups with three dosages (80, 40, and 20 mg/kg, i.g.) and SIA aqueous extract groups with three dosages (160, 80, and 40 mg/kg, i.g.). Histological examinations of the ear and paw tissues were observed by hematoxylin-eosin (HE) staining, and neutrophil elastase levels were assessed in ear tissues by immunohistochemical analysis. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured by ELISAs, and expression levels of TNF-α, IL-6, and IL-1β in rat paw tissues were measured by RT-PCR. The signal transduction proteins p65, IκBα, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), p38 mitogen-activated protein kinases (p38), extracellular regulated protein kinases (ERK1/2), and c-Jun N-terminal kinase (JNK) in the rat paw tissues were investigated by western blot analyses. RIA and SIA were characterized by HPLC and LC-MS analyses, and the components were confirmed by comparison with isolated compounds.

RESULTS

Intragastric administration with RIA (30 mg/kg) and SIA (60, 30 mg/kg) significantly mitigated ear edema in mice. RIA administration at 80 and 40 mg/kg reduced paw edema in rats 2‒3 h after injection. SIA administration with 160 mg/kg inhibited paw edema in rats after the injection of carrageenan for 1‒4 h, and SIA administration at 80 mg/kg inhibited paw edema after the injection of carrageenan for 2‒4 h. Meanwhile, RIA (80, 40 mg/kg) and SIA (160, 80 mg/kg) reduced inflammatory cell infiltration in the ear and paw tissues and infiltration of neutrophil leukocytes in rat paw tissues. RIA (80, 40, and 20 mg/kg) and SIA (160, 80, and 40 mg/kg) notably inhibited the increases of TNF-α, IL-6 and IL-1β in the serum and mRNA expression in the rat paw tissues. RIA (80, 40 mg/kg) and SIA (160, 80 mg/kg) reduced the p-p65/p-IκBα, p-JAK2/p-STAT3, and p-p38/p-ERK1/2/p-JNK levels in the pathological tissues of the animals. Phenolic acids and triterpenoids likely contributed to the anti-inflammatory activity.

CONCLUSIONS

Both RIA and SIA aqueous extracts showed anti-inflammatory effects in vivo in a dose-independent manner (20‒80 and 40‒160 mg/kg, respectively). The underlying mechanisms are mediated by inhibiting the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β via regulation of the NF-κB, JAK2/STAT3, and MAPK signaling pathways. The present results provided pharmacological evidence that stems are alternative medicinal parts of IA but function at different doses. Additionally, this study supports the use of IA as an anti-inflammatory herbal medicine.

Authors+Show Affiliations

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, PR China. Electronic address: yxy920512@163.com.School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, PR China. Electronic address: lily19870721@163.com.School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, PR China. Electronic address: dbz0828@163.com.School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, PR China. Electronic address: zfy2401@163.com.School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, PR China. Electronic address: fengxiao931209@163.com.School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, PR China. Electronic address: zhxg6666@163.com.School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, PR China. Electronic address: ahssfxgt@163.com.SANJIU Medical & Pharmaceutical Co., Ltd., Shenzhen 518029, PR China. Electronic address: xingjianyong@999.com.cn.SANJIU Medical & Pharmaceutical Co., Ltd., Shenzhen 518029, PR China. Electronic address: gulf@999.com.cn.School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, PR China. Electronic address: pengfeitu@vip.163.com.School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, PR China. Electronic address: xingyunchai@yeah.net.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29981433

Citation

Yang, Xinyao, et al. "Ilex Asprella Aqueous Extracts Exert in Vivo Anti-inflammatory Effects By Regulating the NF-κB, JAK2/STAT3, and MAPK Signaling Pathways." Journal of Ethnopharmacology, vol. 225, 2018, pp. 234-243.
Yang X, Gao X, Du B, et al. Ilex asprella aqueous extracts exert in vivo anti-inflammatory effects by regulating the NF-κB, JAK2/STAT3, and MAPK signaling pathways. J Ethnopharmacol. 2018;225:234-243.
Yang, X., Gao, X., Du, B., Zhao, F., Feng, X., Zhang, H., Zhu, Z., Xing, J., Han, Z., Tu, P., & Chai, X. (2018). Ilex asprella aqueous extracts exert in vivo anti-inflammatory effects by regulating the NF-κB, JAK2/STAT3, and MAPK signaling pathways. Journal of Ethnopharmacology, 225, 234-243. https://doi.org/10.1016/j.jep.2018.06.037
Yang X, et al. Ilex Asprella Aqueous Extracts Exert in Vivo Anti-inflammatory Effects By Regulating the NF-κB, JAK2/STAT3, and MAPK Signaling Pathways. J Ethnopharmacol. 2018 Oct 28;225:234-243. PubMed PMID: 29981433.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ilex asprella aqueous extracts exert in vivo anti-inflammatory effects by regulating the NF-κB, JAK2/STAT3, and MAPK signaling pathways. AU - Yang,Xinyao, AU - Gao,Xiaoli, AU - Du,Bingzhao, AU - Zhao,Feng, AU - Feng,Xiao, AU - Zhang,Hexinge, AU - Zhu,Zhixiang, AU - Xing,Jianyong, AU - Han,Zhengzhou, AU - Tu,Pengfei, AU - Chai,Xingyun, Y1 - 2018/07/04/ PY - 2018/03/28/received PY - 2018/06/25/accepted PY - 2018/7/8/pubmed PY - 2018/11/14/medline PY - 2018/7/8/entrez KW - Anti-inflammation KW - Ilex asprella KW - JAK2/STAT3 KW - MAPK KW - NF-κB SP - 234 EP - 243 JF - Journal of ethnopharmacology JO - J Ethnopharmacol VL - 225 N2 - ETHNOPHARMACOLOGICAL RELEVANCE: Ilex asprella (Hook. et Arn.) Champ. ex Benth. (IA) is a representative medicinal plant from the South of the Five Ridges of China. Its roots (RIA) and stems (SIA) have been traditionally used for the inflammation-related diseases, such as acute and chronic pharyngitis, cough, and sore throats. AIM OF THE STUDY: To evaluate the in vivo anti-inflammatory effects of IA extracts to provide evidence for its traditional use and to enhance the knowledge of the medicinal properties of IA. MATERIALS AND METHODS: Models of xylene-induced ear edema in mice and carrageenan-induced paw edema in rats were used for the pharmacological evaluations. The mice were randomly divided into eight groups (n = 10 per group): a model group, a positive control group [dexamethasone (Dex), 10 mg/kg, intragastrically (i.g.)], RIA aqueous extract groups with three dosages (30, 15, and 7.5 mg/kg, i.g.), and SIA aqueous extract groups with three dosages (60, 30, and 15 mg/kg, i.g.). The rats were randomly divided into eight groups (n = 6 per group): a model group, a positive control group [acetylsalicylic acid (ASA), 300 mg/kg, i.g.], RIA groups with three dosages (80, 40, and 20 mg/kg, i.g.) and SIA aqueous extract groups with three dosages (160, 80, and 40 mg/kg, i.g.). Histological examinations of the ear and paw tissues were observed by hematoxylin-eosin (HE) staining, and neutrophil elastase levels were assessed in ear tissues by immunohistochemical analysis. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured by ELISAs, and expression levels of TNF-α, IL-6, and IL-1β in rat paw tissues were measured by RT-PCR. The signal transduction proteins p65, IκBα, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), p38 mitogen-activated protein kinases (p38), extracellular regulated protein kinases (ERK1/2), and c-Jun N-terminal kinase (JNK) in the rat paw tissues were investigated by western blot analyses. RIA and SIA were characterized by HPLC and LC-MS analyses, and the components were confirmed by comparison with isolated compounds. RESULTS: Intragastric administration with RIA (30 mg/kg) and SIA (60, 30 mg/kg) significantly mitigated ear edema in mice. RIA administration at 80 and 40 mg/kg reduced paw edema in rats 2‒3 h after injection. SIA administration with 160 mg/kg inhibited paw edema in rats after the injection of carrageenan for 1‒4 h, and SIA administration at 80 mg/kg inhibited paw edema after the injection of carrageenan for 2‒4 h. Meanwhile, RIA (80, 40 mg/kg) and SIA (160, 80 mg/kg) reduced inflammatory cell infiltration in the ear and paw tissues and infiltration of neutrophil leukocytes in rat paw tissues. RIA (80, 40, and 20 mg/kg) and SIA (160, 80, and 40 mg/kg) notably inhibited the increases of TNF-α, IL-6 and IL-1β in the serum and mRNA expression in the rat paw tissues. RIA (80, 40 mg/kg) and SIA (160, 80 mg/kg) reduced the p-p65/p-IκBα, p-JAK2/p-STAT3, and p-p38/p-ERK1/2/p-JNK levels in the pathological tissues of the animals. Phenolic acids and triterpenoids likely contributed to the anti-inflammatory activity. CONCLUSIONS: Both RIA and SIA aqueous extracts showed anti-inflammatory effects in vivo in a dose-independent manner (20‒80 and 40‒160 mg/kg, respectively). The underlying mechanisms are mediated by inhibiting the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β via regulation of the NF-κB, JAK2/STAT3, and MAPK signaling pathways. The present results provided pharmacological evidence that stems are alternative medicinal parts of IA but function at different doses. Additionally, this study supports the use of IA as an anti-inflammatory herbal medicine. SN - 1872-7573 UR - https://www.unboundmedicine.com/medline/citation/29981433/Ilex_asprella_aqueous_extracts_exert_in_vivo_anti_inflammatory_effects_by_regulating_the_NF_κB_JAK2/STAT3_and_MAPK_signaling_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-8741(18)31105-X DB - PRIME DP - Unbound Medicine ER -