A discovery of clinically approved Panlongqi Tablet for repositioning to treat osteoarthritis by inhibiting PI3K/AKT activation

Lu Wang; Panyu Xu; Ying Xu; Ruiqin Cui; Yibo Yang; Zhao Zou; Hanqian Du; Chunyan Zhu; Guoxin Zhang; Tengfei Han; Na Lin

doi:10.1016/j.phymed.2022.154360

A discovery of clinically approved Panlongqi Tablet for repositioning to treat osteoarthritis by inhibiting PI3K/AKT activation

Phytomedicine. 2022 Oct:105:154360. doi: 10.1016/j.phymed.2022.154360. Epub 2022 Jul 28.

Authors

Lu Wang¹, Panyu Xu², Ying Xu³, Ruiqin Cui⁴, Yibo Yang², Zhao Zou², Hanqian Du², Chunyan Zhu², Guoxin Zhang², Tengfei Han⁵, Na Lin⁶

Affiliations

¹ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, PR China; Ningxia Medical University, No.1160, Shengli Street, Xingqing District, Yinchuan 750004, PR China.
² Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, PR China.
³ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, PR China. Electronic address: yxu@icmm.ac.cn.
⁴ Ningxia Medical University, No.1160, Shengli Street, Xingqing District, Yinchuan 750004, PR China.
⁵ Shanxi Panlong Pharmaceutical Group Co., Ltd, No.2801, Ba LiuEr Road, Baqiao District, Shanxi 710000, PR China.
⁶ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, PR China. Electronic address: nlin@icmm.ac.cn.

PMID: 35964457
DOI: 10.1016/j.phymed.2022.154360

Abstract

Background: Panlongqi Tablet (PLQT) is a Chinese patent drug composed of 29 kinds of traditional Chinese medicines. Clinical practice has shown that PLQT can relieve osteoarthritis-caused joint pain, but its effects and mechanisms in other pathological links of osteoarthritis have not been characterized.

Purpose: The purpose of this study is to reposition the pharmacodynamic effects of PLQT through network pharmacology analysis combined with experimental validation, and also to preliminarily explore its possible mechanism.

Methods: On the basis of integrating the relevant targets of PLQT in multiple drug databases and osteoarthritis-related targets in the disease database, an interaction network of related genes was constructed. The hub candidate targets of PLQT in the treatment of osteoarthritis were determined by calculating the main network topological characteristics, The specific functions and pathways of these targets acting on osteoarthritis were modularly analyzed. In addition, the modified Hulth-induced rat model of osteoarthritis and IL-1β-induced in vitro model of osteoarthritis were established to further validate the potential efficacy and possible mechanism of PLQT.

Results: A total of 138 key targets related to osteoarthritis were selected based on topological parameters, and their biological functions were mainly enriched in four over-expressed modules of cartilage degeneration, inflammatory response, immune response, and subchondral bone metabolism. The hub candidate targets had the highest enrichment degree in the TLR4-RAC1-PIK3CA-Akt-NFκB signaling axis of the PI3K/Akt signaling pathway. In vivo results showed that PLQT treatment significantly inhibited the degeneration of proteoglycan and collagen in the cartilage of osteoarthritis rats, suppressed chondrocyte apoptosis, and reduced the Mankin score of joints. Moreover, PLQT alleviated synovial inflammation, reduced the Krenn score of synovium, inhibited the formation of osteophytes in osteoarthritis rats, reduced the bone mineral density (BMD), fractional bone volume (BV/TV), and trabecular thickness (Tb.Th.), as well as increased the trabecular separation (Tb.Sp.) of subchondral bone and the thickness of the subchondral bone plate (SBP.Th.). PLQT suppressed the expressions of TLR4, RAC1, PIK3CA, p-Akt, MMP-13, and ADAMTS-5 in the cartilage, and inhibited the expression of NFκB p65 in the chondrogenic nucleus. Meanwhile, as downstream effector factors of the predictive pathways, the levels of serum interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nitric oxide (NO), and prostaglandin E₂ (PGE₂) were decreased after PLQT treatment. In vitro results also showed that PLQT could inhibit the expression of key proteins and downstream effector factors of the signaling axis, and this inhibition disappeared when pathway agonists were added.

Conclusion: PLQT exerted pharmacological effects on the key pathological links of osteoarthritis including chondrocyte apoptosis, extracellular matrix degradation, inflammation, and subchondral bone metabolism by inhibiting the TLR4-RAC1-PIK3CA-Akt-NFκB axis-related proteins.

Keywords: Cartilage; Inflammation; Network pharmacology; Osteoarthritis; Panlongqi Tablet (PLQT); Subchondral bone.

MeSH terms

Animals
Class I Phosphatidylinositol 3-Kinases
Drugs, Chinese Herbal
Inflammation
NF-kappa B
Osteoarthritis*
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Rats
Toll-Like Receptor 4*

Substances

Drugs, Chinese Herbal
NF-kappa B
Toll-Like Receptor 4
panlongqi
Class I Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt