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Paeonia suffruticosa (PS) and Paeonia lactiflora (PL) belong to the only genus in the family Paeoniaceae. Comparative analysis of the spatial metabolomes of PS and PL has rarely been performed. In this work, combined with multiple matrixes and dual-polarity detection, high mass resolution matrix-assisted laser desorption/ionization MS imaging (MALDI MSI) and MALDI tandem MSI were performed on the root sections of the two Paeonia species. The spatial distributions of many metabolites including monoterpene and paeonol glycosides, tannins, flavonoids, saccharides and lipids were systematically characterized. The ambiguous tissue distribution of the two isomers paeoniflorin and albiflorin were distinguished by tandem MSI using lithium salt doped 2,5-dihydroxybenzoate matrix. In addition, the major intermediates involved in the biosynthetic pathway of gallotannins were successfully localized and visualized in the root sections. High-mass resolution MALDI full-scan MSI provides comprehensive and accurate spatial distribution of metabolites. The analytical power of the technique was further tested in the tandem MSI of two isomers. The ion images of individual metabolites provide chemical and microscopic characteristics beyond morphological identification, and the detailed spatiochemical information could not only improve our understanding of the biosynthetic pathway of hydrolyzable tannins, but also ensure the safety and effectiveness of their medicinal use.

BackgroundPaeonol (Pae), a phenolic bioactive compound extracted from Cortex Moutan, exhibits numerous pharmacological properties, including anti-inflammatory, immunomodulatory, and antitumor activities. However, the precise mechanisms by which Pae influences protective autophagy in oral squamous cell carcinoma (OSCC) remain incompletely characterized.MethodsThis study assessed the effects of Pae treatment on proliferation, migration, and invasive potential of OSCC cells in vitro. Network pharmacology was employed to identify potential molecular targets of Pae involved in OSCC. Autophagic flux was analyzed using transmission electron microscopy alongside a dual-fluorescence reporter assay. Additionally, the combined effects of Pae with autophagy inhibitors were investigated.ResultsPae treatment promoted mitochondrial-dependent apoptosis and effectively inhibited epithelial–mesenchymal transition (EMT) by attenuating phosphorylation within the PI3K/AKT signaling pathway. Pae simultaneously initiated protective autophagy, confirmed by intact autophagic flux observed in CAL-27 and HSC-3 cells. Interference with this autophagic process through the autophagy inhibitor 3-methyladenine (3-MA) intensified apoptotic activity and markedly reduced OSCC cell proliferation.ConclusionPae suppressed OSCC cell proliferation and EMT and was associated with mitochondrial apoptosis and activation of autophagic flux, accompanied by reduced PI3K/AKT phosphorylation. Co-treatment with 3-methyladenine (3-MA) further decreased cell viability and enhanced apoptosis-associated changes, suggesting that pharmacological co-targeting of PI3K signaling and autophagy may potentiate Pae’s antitumor activity. Further studies are warranted to delineate the relative contributions of apoptosis and autophagy to Pae-induced cytotoxicity in OSCC.

Background This study aimed to investigate the potential mechanism of paeonol in the treatment of neuropathic pain. Methods Relevant mechanisms were explored through microglial pseudotime analysis and the use of specific inhibitors in cell experiments. In animal experiments, 32 SD rats were randomly divided into the sham operation group, the chronic constrictive injury (CCI) group, the ibuprofen group, and the paeonol group. We performed behavioral testing, ELISA, PCR, Western blotting, immunohistochemistry, and immunofluorescence analysis. Results The pseudotime analysis of microglia found that RhoA, Rock1, and p38MAPK were highly expressed in activated microglia, and the expression patterns of these genes were consistent with the expression trends of the M1 markers CD32 and CD86. Paeonol decreased the levels of M1 markers (IL1β, iNOS, CD32, IL6) and increased the levels of M2 markers (IL10, CD206, ARG‐1) in LPS‐induced microglia. The expression of iNOS, IL1β, RhoA, and Rock1 was significantly increased in LPS‐treated microglia, while paeonol decreased the expression of these proteins. Thermal hyperalgesia occurred after CCI surgery, and paeonol provided relief. In addition, paeonol decreased the levels of IL1β and IL8 and increased the levels of IL4 and TGF‐β in the serum of CCI rats. Paeonol decreased expression levels of M1 markers and increased expression levels of M2 markers in the spinal cord. Paeonol decreased IBA‐1, IL1β, RhoA, RhoA‐GTP, COX2, Rock1, and p‐p38MAPK levels in the spinal dorsal horn. Conclusion Paeonol relieves neuropathic pain by modulating microglial M1 and M2 phenotypes through the RhoA/p38 MAPK pathway. Experiment flow chart.

Paeonol exhibits a wide range of pharmacological activities, such as anti-inflammatory, antidiabetic as well as pain-relieving activities. However, its intrinsic properties, such as low water solubility, poor stability and low oral bioavailability, restrict its clinical application. The current study aimed to optimize paeonol-loaded ethosomal formulation and characterize it in terms of encapsulation efficiency (EE), vesicle size (VS), zeta potential (ZP) and polydispersity index (PDI), in addition to differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FT-IR) studies. Here, paeonol-loaded ethosomes were prepared by the injection method and optimized by the single-factor test and central composite design-response surface methodology. The optimized paeonol-loaded ethosomes had an EE of 84.33 ± 1.34%, VS of 120.2 ± 1.3 nm, negative charge of −16.8 ± 0.36 mV, and PDI of 0.131 ± 0.006. Ethosomes showed a spherical morphology under the transmission electron microscope (TEM). DSC, XRD and FT-IR results indicated that paeonol was successfully incorporated into the ethosomes. In-vitro transdermal absorption and skin retention of paeonol from paeonol-loaded ethosomes were 138.58 ± 9.60 µg/cm2 and 52.60 ± 7.90 µg/cm2, respectively. With reasonable skin tolerance, ethosomes could be a promising vehicle for transdermal delivery of paeonol.

The study investigated the immunity and antioxidant potential of paeonol by employing a hepatocellular carcinoma (HCC) rat model. Three doses of paeonol (20, 40, 60 mg/kg b.w. orally) were administrated to diethylnitrosamine (DEN)-induced HCC rats. Results showed that paeonol significantly reduced the serum AST, ALT, ALP, GGT, AFU and liver MDA levels, increased serum WBC, TP, ALB, A/G, TNF-α and IFN-γ and liver antioxidant enzymes activities (SOD, CAT, GSH-Px, GR) in HCC rats. Altogether, these results suggest that the paeonol could effectively decrease oxidative injury and improve immunity function in HCC rats.

Paeonol is a biologically active component purified from the root bark of Cortex Moutan that exerts pharmacological effects on the cervical cancer. In this study, we aim to evaluate the anti-cervical cancer capacity of paeonol and to investigate the mechanism driving its anti-cervical cancer effect. Paeonol administration markedly restrained the proliferation and caused apoptosis in HeLa cells. Furthermore, paeonol treatment resulted in a mitochondrial dysfunction in HeLa cells, including the inducing of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, and the release of cytochrome c. Moreover, the Bcl-2/Bax proportion was obviously downregulated and cleaved caspase-3 expression was evaluated through paeonol treatment. Additionally, the expression of p-PI3K and p-Akt was noticeably reduced in response to paeonol treatment in HeLa cells. Our findings indicated that paeonol exerts an anticancer potential in HeLa cells, at least in a manner, via triggering the mitochondrial pathway of cellular apoptosis by inhibiting PI3K/Akt signaling. Thus, paeonol has great potential as a promising therapeutic compound to resist human cervical cancer.

AbstractPaeonol, a major ingredient isolated from Moutan Cort, has various pharmacological effects. Our previous studies have shown that paeonol can exert antioxidant and anti-inflammatory therapeutic effects on ethanol-induced experimental gastric ulcer (GU). Therefore, in this study, we designed two GU models in rats induced by pyloric ligation (PL) and acetic acid and evaluated the protective effects of paeonol and gastroretention tablets of paeonol (GRT-Ps; 24, 48, and 96 mg/kg) on GU in rats and the effect of paeonol (48 mg/kg) on the intestinal flora. In vivo experiments showed that paeonol or GRT-Ps remarkably reduced gastric mucosal damage in a dose-dependent manner in the different types of models and improved the superoxide dismutase (SOD) activity and the malondialdehyde (MDA) content. And in fact, the sustained-release effect of GRT-Ps is more conducive to the improvement of GU compared with the rapid clearance of free drugs. In the PL-induced model, gastric secretion parameters, that is, pH and total acid, showed significant differences compared with the model group. In addition, paeonol treatment can improve the richness and diversity of the intestinal flora and increase the amount of beneficial bacteria, such as Lactobacillus. Paeonol and its stable sustained-release tablet GRT-Ps can promote ulcer healing by inhibiting oxidative stress and regulating the intestinal flora. This study can provide basis for the clinical treatment of GU with paeonol.

Rationale Increasing evidence has suggested that major depressive disorder (MDD) is highly associated with brain-derived neurotrophic factor (BDNF) levels, dendrites atrophy, and loss of dendritic spines, especially in emotion-associated brain regions including the hippocampus. Paeonol is a kind of polyphenols natural product with a variety of therapeutic effects. Recent studies have reported its antidepressant effects. However, it is unclear what signaling pathways contribute to improve MDD. Objective The present study investigated the effect of Paeonol on hippocampal neuronal morphology and its possible signaling pathways in chronic unpredictable mild stress (CUMS) rat model. Methods Using CUMS rat model, the antidepressant-like effect of Paeonol was validated via depression-related behavioral tests. Neuronal morphology in hippocampal CA1 and DG was assessed using ImageJ’s Sholl plugin and RESCONSTRUCT software. BDNF signaling pathway-related molecules was determined by Western blotting. Results Paeonol attenuated CUMS-induced depression-like behaviors, which were accompanied by hippocampal neuronal morphological alterations. After Paeonol treatment for 4 weeks, the dendritic length and complexity and the density of dendritic spines markedly increased in the hippocampal CA1 and the dentate gyrus (DG). However, CUMS or Paeonol treatment does not selectively affect dendritic spine types. Simultaneously, administration of Paeonol deterred CUMS-induced cofilin1 activation that is essential for remolding of dendritic spines. The induction of CUMS downregulated BDNF levels and upregulated Rac1/RhoA levels; however, the tendency of these was inhibited by treatment with Paeonol. Conclusion Our data suggest that BDNF-Rac1/RhoA pathway may be involved in attenuation of CUMS-induced behavioral and neuronal damage by Paeonol that may represent a novel therapeutic agent for depression.

Moutan Cortex (MC) is a traditional Chinese medicine that contains abundant medicinal components, such as paeonol, paeoniflorin, etc. Paeonol is the main active component of MC. In this study, paeonol was extracted from MC through an ultrasound-assisted extraction process, which is based on single-factor experiments and response surface methodology (RSM). Subsequently, eight macroporous resins of different properties were used to purify paeonol from MC. The main components of the purified extract were identified by ultra-performance liquid chromatography–quadrupole–time of flight–mass spectrometry (UPLC-Q-TOF-MS/MS). The results indicate the optimal parameters are as follows: liquid-to-material ratio 21:1 mL/g, ethanol concentration 62%, ultrasonic time 31 min, ultrasonic temperature 36 °C, ultrasonic power 420 W. Under these extraction conditions, the actual yield of paeonol was 14.01 mg/g. Among the eight tested macroporous resins, HPD-300 macroporous resin was verified to possess the highest adsorption and desorption qualities. The content of paeonol increased from 6.93% (crude extract) to 41.40% (purified extract) after the HPD-300 macroporous resin treatment. A total of five major phenolic compounds and two principal monoterpene glycosides were characterized by comparison with reference compounds. These findings will make a contribution to the isolation and utilization of the active components from MC.

Paeonol (2'-hydroxy-4'-methoxyacetophenone), isolated from moutan cortex, is an active component and has been shown to have anti-atherosclerotic and anti-proliferation effects on vascular smooth muscle cells (VSMCs). However, the possible role of Paeonol in protecting against VSMC proliferation as related to autophagy has yet to be elucidated. The athero-protective effects of Paeonol were evaluated in apoE mice. The effects of Paeonol on VSMC proliferation and autophagy were examined by staining α-SMA and LC3II spots in the media layer of apoE mice, respectively. CCK8 and BrdU assays were used to investigate the effects of Paeonol on cell proliferation . The autophagic levels in VSMCs were evaluated by detecting LC3II accumulation and p62 degradation by immunoblot analysis. To investigate if Paeonol could prevent VSMCs proliferation through autophagy induction, we tested the change in autophagy and cell proliferation by inhibition of autophagy. The levels of the AMPK/mTOR pathway in autophagy regulation were detected by immunoblot analysis. An AMPK inhibitor and si-AMPK transfection in VSMCs was used to confirm whether AMPK activity plays a key role in autophagy regulation of Paeonol. experiments confirmed that Paeonol restricted atherosclerosis development and decreased the amount of VSMCs in the media layer of apoE mice. Paeonol increased protein levels of LC3II and the presence of autophagosomes in the media layer of arteries, which implies that Paeonol may induce VSMCs autophagy . Paeonol showed potential in inhibiting ox-LDL-induced proliferation experiments. Paeonol dose-dependently enhanced the formation of acidic vesicular organelles and autophagosmomes, up-regulated the expression of LC3II and increased p62 degradation. The autophagy inhibitor CQ obviously attenuated Paeonol-induced autophagy and the anti-proliferation effect in VSMCs. In addition, Paeonol induced phosphorylation of AMPK and reduced phosphorylation of mTOR. An AMPK inhibitor reversed the Paeonol-induced p-mTOR/mTOR decrease. Paeonol induced LC3II conversion, increased p62 degradation and inhibited cell proliferation in VSMCs, the effects of which were abolished by si-AMPK. These results imply that Paeonol inhibits proliferation of VSMCs by up-regulating autophagy, and activating the AMPK/mTOR signaling pathway, providing new insights into the anti-atherosclerosis activity of Paeonol.