Integrated serum pharmacochemistry and network pharmacology analyses reveal the bioactive metabolites and potential functional mechanism of Piper longum L. in the treatment of gastric ulcer in rats

doi:10.5246/jcps.2024.02.013

Abstract

Abstract:

The fruit of Piper longum L. (PL) is widely utilized in China for medicinal and dietary purposes, and it is also used in Ayurvedic medicine in India to treat gastric disorders and other ailments. In the present study, a strategy combining serum pharmacochemistry with network pharmacology was proposed to screen the bioactive metabolites derived from PL and explore their potential functional mechanisms. The strategy primarily involved investigating the anti-gastric ulcer activities, network pharmacology analysis, and metabolite identification. The results demonstrated the efficacy of PL in protecting against ethanol-induced gastric ulcers. Through network pharmacology approaches, potential drug-disease common targets were identified. GO enrichment analysis predicted that PL might influence multiple biological processes, such as lipid metabolism and inflammatory response. KEGG enrichment analysis suggested the involvement of the TNF and AGE-RAGE signaling pathways. Molecular docking further indicated that the synergistic effect of sesamin, piperine, and other ingredients could be the main contributors to PL’s anti-inflammatory and antibacterial activities. Additionally, the serum pharmacochemistry of PL was established, enabling the screening of absorbed components and metabolites for their anti-gastric ulcer activity. A total of 23 prototypes and 17 metabolites were found to significantly contribute to the anti-gastric ulcer activity, suggesting that these bioactive compounds could serve as potential active components of PL. Overall, this investigation provided an experimental foundation to support the clinical application of PL in gastric ulcer therapy.

Key words: Serum pharmacochemistry, Network pharmacology, Metabolite, Piper longum L., Gastric ulcer

Supporting:

Hong Zhang, Shasha Zhang, Huanyun Wang, Yue Liang, Shikui Wu, Lijun Sun, Huimin Xia, Yunxia Bai, Huiwen Zhang. Integrated serum pharmacochemistry and network pharmacology analyses reveal the bioactive metabolites and potential functional mechanism of Piper longum L. in the treatment of gastric ulcer in rats[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(2): 156-168.

Figures/Tables 8

Table 1. Mass spectra properties of the absorbed components and their tentative identification results.

Table 2. Mass spectra properties of the metabolized components and their tentative identification results.

References 20

[1]	Wang, H.R.; Jiang, H.L.; Zhao, J.Y.; Liu, X.N.; Li, T.E.; Chai, J.P.; Meng, M.; Pan, T.; Xu, K.Y.; Wang, F.C. Acupuncture therapy for gastric ulcer. Medicine. 2021, 100, e27656.
[2]	Ketut Adnyana, I. Gastric ulcer healing effect of wild honey and its combination with Turmeric (Curcuma domestica Val.) Rhizome on male Wistar rats. J. Chin. Pharm. Sci. 2014, 23, 844–849.
[3]	Yadav, V.; Krishnan, A.; Vohora, D. A systematic review on Piper longum L.: bridging traditional knowledge and pharmacological evidence for future translational research. J. Ethnopharmacol. 2020, 247, 112255.
[4]	Dinat, S.; Orchard, A.; Van Vuuren, S. A scoping review of African natural products against gastric ulcers and Helicobacter pylori. J. Ethnopharmacol. 2023, 301, 115698.
[5]	Meghwal, M.; Goswami, T.K. Piper nigrum and piperine: an update. Phytother. Res. 2013, 27, 1121–1130.
[6]	Shityakov, S.; Bigdelian, E.; Hussein, A.A.; Hussain, M.B.; Tripathi, Y.C.; Khan, M.U.; Ali Shariati, M. Phytochemical and pharmacological attributes of piperine: a bioactive ingredient of black pepper. Eur. J. Med. Chem. 2019, 176, 149–161.
[7]	Kim, N.; Nam, M.; Kang, M.S.; Lee, J.O.; Lee, Y.W.; Hwang, G.S.; Kim, H.S. Piperine regulates UCP₁ through the AMPK pathway by generating intracellular lactate production in muscle cells. Sci. Rep. 2017, 7, 41066.
[8]	Toshio, M.; Hisashi, M.; Itadaki, Y.; Yutana, P.; Masayuki, Y. New amides and gastroprotective constituents from the fruit of Piper chaba. Planta Med. 2004, 70, 152–159.
[9]	Lee, S.W.; Rho, M.C.; Park, H.R.; Choi, J.H.; Kang, J.Y.; Lee, J.W.; Kim, K.; Lee, H.S.; Kim, Y.K. Inhibition of diacylglycerol acyltransferase by alkamides isolated from the fruits of Piper longum and Piper nigrum. J. Agric. Food Chem. 2006, 54, 9759–9763.
[10]	Al-Sayed, E.; Gad, H.A.; El-Kersh, D.M. Characterization of four Piper essential oils (GC/MS and ATR-IR) coupled to chemometrics and their anti-Helicobacter pylori activity. ACS Omega. 2021, 6, 25652–25663.
[11]	Sun, C.R.; Pei, S.F.; Pan, Y.J.; Shen, Z.Q. Rapid structural determination of amides inPiper longum by high-performance liquid chromatography combined with ion trap mass spectrometry. Rapid Commun. Mass Spectrom. 2007, 21, 1497–1503.
[12]	Li, K.Y.; Fan, Y.P.; Wang, H.; Fu, Q.; Jin, Y.; Liang, X.M. Qualitative and quantitative analysis of an alkaloid fraction from Piper longum L. using ultra-high performance liquid chromatography-diode array detector-electrospray ionization mass spectrometry. J. Pharm. Biomed. Anal. 2015, 109, 28–35.
[13]	Luca, S.V.; Minceva, M.; Gertsch, J.; Skalicka-Woźniak, K. LC-HRMS/MS-based phytochemical profiling of Piper spices: global association of piperamides with endocannabinoid system modulation. Food Res. Int. 2021, 141, 110123.
[14]	Liao, C.P.; Ge, S.S.; Alatan, C.H.; Gao Y.; Tu, Y. Piper longum L’s research progress and the prediction of quality markers. Chin. J. Tradit. Chin. Med. 2022, 19, 5182–5192.
[15]	Yu, L.J.; Wei, C.X.; Wang, Y.; Gong, G.H.; Xu, Y.N. Sugemule-3 protects against isoprenaline-induced cardiotoxicity in vitro. Pharmacogn. Mag. 2017, 13, 517–522.
[16]	Li, K.Y.; Fan, Y.P.; Wang, H.; Fu, Q.; Jin, Y.; Liang, X.M. Qualitative and quantitative analysis of an alkaloid fraction from Piper longum L. using ultra-high performance liquid chromatography-diode array detector-electrospray ionization mass spectrometry. J. Pharm. Biomed. Anal. 2015, 109, 28–35.
[17]	Li, K.Y.; Zhu, W.Y.; Fu, Q.; Ke, Y.X.; Jin, Y.; Liang, X.M. Purification of amide alkaloids from Piper longum L. using preparative two-dimensional normal-phase liquid chromatography × reversed-phase liquid chromatography. Anal. 2013, 138, 3313–3320.
[18]	Lee, S.W.; Kim, M.S.; Park, M.H.; Park, S.J.; Lee, W.S.; Chang, J.S.; Rho, M.C. Alkamides from Piper longum and Piper nigrum as inhibitors of IL-6 action. Bull. Korean Chem. Soc. 2010, 31, 921–924.
[19]	Umeda-Sawada, R.; Ogawa, M.; Igarashi, O. The metabolism and distribution of sesame lignans (sesamin and episesamin) in rats. Lipids. 1999, 34, 633–637.
[20]	Li, Y.; Li, M.; Wang, Z.; Wen, M.; Tang, J. Identification of the metabolites of piperine via hepatocyte incubation and liquid chromatography combined with diode-array detection and high-resolution mass spectrometry. Rapid Commun Mass Spectrom. 2020, 34, e8947.