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

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-1ß-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-1ß (IL-1ß), 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.

Liuweidihuang Pill Alleviates Inflammation of the Testis via AMPK/SIRT1/NF-κB Pathway in Aging Rats.

Liuweidihuang Pill (LP) is a traditional Chinese herbal formula that is often used in clinical practice to treat kidney deficiency syndrome. The present study investigated the antiaging effects of LP in a D-galactose- (D-Gal-) induced subacute aging rat model. The study also attempted to explore whether anti-inflammatory mechanisms that underpin the antiaging effects are mediated by the AMPK/SIRT1/NF-κB signaling pathway. Rats were subcutaneously injected with D-Gal at a dosage of 100 mg/kg/d for 8 weeks. Upon successful induction of aging in the rats, the animal was administered LP at 0.9 g/kg/d by gavage for 4 weeks. Proteins of the testis were subsequently examined by western blot analysis, and associated locations in the testicular tissue were determined by immunohistochemistry. We observed that LP exerted antiaging effects in aging rats following the activation of AMPK/SIRT1. It was also observed that LP inhibited the expression of NF-κB, thereby further attenuating inflammation of the testis. Therefore, LP can alleviate inflammation of the testis via the AMPK/SIRT1/NF-κB pathway in aging rats.

A new periplogenin cardenolide from the seeds of Antiaris toxicaria.

A new periplogenin cardenolide, periplogulcoside (1), together with three known cardenolides, was isolated from the seeds of Antiaris toxicaria. The structure of the new compound was characterized as periplogenin-3-O-ß-D-glucopyranosyl-(1 → 4)-ß-D-glucopyranoside (1) by spectroscopic methods including 1D and 2D NMR, HR-TOF-MS, and CD spectrometry, and the known compounds were identified by comparison of their NMR and HR-TOF-MS data with those reported in the literature. Compound 1 showed significant cytotoxicity against Hela and HepG-2 cell lines.