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Botrytis cinerea may cause gray mold in fruits and vegetables. Paeonol, an active component of traditional Chinese medicine, could suppress various microbial growth. However, reports on its effect on B. cinerea have not yet been documented. In this paper, we demonstrated that paeonol completely inhibited B. cinerea growth at 250 mg/L, corroborated by the observation of irregular morphological alterations in B. cinerea exposed to paeonol. Notably, the investigation of the operating mechanism revealed that paeonol induced cell death by disrupting the cell membrane, potentially mediated by the interaction between paeonol and ergosterol from the membrane. Further studies indicated that paeonol decreased ergosterol content and the expression of certain genes involved in ergosterol biosynthesis was significantly downregulated. In addition, paeonol treatment reduced the gray mold of cherry tomatoes. Meanwhile, compared to the control treatment, paeonol treatment could reduce weight loss and maintain higher contents of total soluble solid (TSS) and ascorbic acid, leading to a higher quality of the stored cherry tomato. Together, the data indicate that paeonol was effective as an alternative agent targeting disrupting the cell membrane to control gray mold and prolong the shelf life of cherry tomatoes, suggesting that paeonol could be used as a natural antifungal compound during postharvest storage. [ABSTRACT FROM AUTHOR]

Paeonol is a principle bioactive compound separated from the root bark of Cortex Moutan and has been shown to confer various biological functions, including antineuroinflammation and neuroprotection. Inflammation, blood–brain barrier (BBB), permeability, and apoptosis are three major underlying mechanisms involved in early brain injury (EBI) postsubarachnoid hemorrhage (SAH). This study aimed to detect the roles and mechanisms of paeonol in EBI following SAH. A SAH model was established by an endovascular perforation method in Sprague‐Dawley rats. The localizations of HMGB1 and p65 were identified by immunofluorescence staining. Protein levels were measured by western blot analysis. The serum levels of HMGB1 and the levels of inflammatory cytokines in the brain cortex were evaluated by ELISA. Hematoxylin and eosin staining was conducted to detect neuronal degeneration. Brain water content and Evans blue extravasation were assessed to determine EBI. Neuronal apoptosis was examined by TUNEL. Paeonol deacetylated HMGB1 by upregulating SIRT1 level. SIRT1 inhibition attenuated the protective effects of paeonol against neurological dysfunctions, brain edema, and BBB disruption. SIRT1 inhibition rescued the paeonol‐induced inhibition in inflammatory response. The paeonol‐induced decrease in neuronal apoptosis was restored by SIRT1 inhibitor. The paeonol‐mediated deactivated TLR4/MyD88/NF‐κB pathway was activated by SIRT1 inhibitor. Paeonol alleviates the SAH injury in rats by upregulating SIRT1 to inactivate the HMGB1/TLR4/MyD88/NF‐κB pathway. [ABSTRACT FROM AUTHOR]

Cortex Moutan is the root bark of the buttercup plant Paeonia suffruticosa Andr, of Ranunculaceae family. It has been utilized in Chinese medicine for thousands of years to treat a multitude of diseases, and traditional Chinese documents allege that it has heat-clearing, antipyretic, anti-inflammatory and detoxicating properties. Paeonol is a bioactive substance extracted from Cortex Moutan, which is considered to be one of its most effective metabolites. Recent studies have illustrated that paeonol treatment can alleviate skin damage, relieve the inflammatory response in patients with numerous dermatological conditions, and inhibit anomalous proliferation of skin tissue. Accordingly, paeonol may serve as a potential therapeutic agent for a variety of skin conditions. This review summarizes the physicochemical properties and pharmacokinetics (PK) characteristics of paeonol, and mechanisms of operation in diverse skin diseases, including dermatitis, psoriasis, pruritus, photoaging, hyperpigmentation, and hyperplasticscar. Additionally, much of the evidence is based on animal experiments. Furthermore, it explores the prospects of enhancing paeonol's efficacy through extraction, synthesis, and formulation innovations, as well as strategies to overcome its limitations in dermatological therapy. This review aims to provide a more reliable theoretical basis for the clinical application of paeonol. [ABSTRACT FROM AUTHOR]

BACKGROUND: The natural product paeonol is a rich and sustainable natural bioresource, and its derivatives have various unique biological efficacy. As is well known, Schiff bases are a class of organic compounds with a wide range of biological activities, including anti‐fungal, insecticidal, anti‐viral, and nematicidal. RESULTS: To discover biorational natural product‐based pesticides, nine intermediates (2–10), 12 sulfonylhydrazones (11a–11c, 12a–12c, 13a–13c, and 14a–14c) and 20 benzylidene hydrazones (18a–18r, 19a, and 20a) were synthesized by structural modification of paeonol, and their structures were characterized by proton nuclear magnetic resonance (1H NMR), carbon‐13 (13C) NMR, and high‐resolution mass spectrometry (HRMS). The stereochemical configurations of compounds 14a, 18d, and 18r were unambiguously confirmed by single‐crystal X‐ray diffraction. Furthermore, bioactivities of these compounds as anti‐oomycete, anti‐fungal, and nematicidal agents against three serious agricultural pests, Phytophthora capsici, Fusarium graminearum, and Heterodera glycines were evaluated. Among all tested compounds: (i) compound 7 exhibited promising anti‐oomycete against Phytophthora capsici, with a half maximal effective concentration (EC50) value of 15.81 mg L−1; (ii) compounds 2, 7, 10, and 19a displayed promising anti‐fungal against F. graminearum, with EC50 values of 12.22, 14.72, 23.39, and 33.10 mg L−1, respectively; (iii) ten compounds (12a–12c, 14c, 18g–18j, 18m, and 19a) showed significant nematicidal activity against H. glycines, with median lethal concentration (LC50) values all less than 30.00 mg L−1. Especially for compound 18g, its LC50 value is the smallest, at 12.65 mg L−1. CONCLUSION: The research results indicate that introducing nitro groups at the C5 position of paeonol, or introducing halogens at both C5 and C3 positions, can significantly enhance its biological activity against Phytophthora capsici, F. graminearum, and H. glycines. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Abstract To investigate the role of miR-223-3p in the modulatory effect of paeonol (Pae) on high glucose (HG)-induced endothelial cell apoptosis. HG (25 mmol/L) was used to induce cellular damage and apoptosis in the mouse cardiac microvascular endothelial cells (MCMECs). Various concentration of Pae was tested and 60 μmol/L Pae was selected for the subsequent studies. MCMECs were transfected with exogenous miR-223-3p mimics or anti-miR-223-3p inhibitors. Cell viability was assessed by MTT assay and apoptosis was quantified by flow cytometry. The expression of miR-223-3p and NLRP3 mRNA was measured using real-time quantitative RT-PCR, and protein level of NLRP3 and apoptosis-related proteins was detected by immunoblotting. Pae significantly attenuated HG-induced apoptosis of MCMECs in a concentration-dependent manner. In addition, Pae (60 µmol/L) significantly reversed HG-induced down-regulation of miR-223-3p and up-regulation of NLRP3. Pae (60 µmol/L) also significantly blocked HG-induced up-regulation of Bax and Caspase-3 as well as down-regulation of Bcl-2. Moreover, exogenous miR-223-3p mimics not only significantly attenuated HG-induced apoptosis, but also significantly suppressed NRLP-3 and pro-apoptotic proteins in the MCMECs. In contrast, transfection of exogenous miR-223-3p inhibitors into the MCMECs resulted in not only significantly increased apoptosis of the cells, but also significant suppression of NLRP3 and pro-apoptotic proteins in the cells. Pae attenuated HG-induced apoptosis of MCMECs in a concentration-dependent manner. MiR-223-3p may mediate the modulatory effects of Pae on MCMEC survival or apoptosis through targeting NLRP3 and regulating apoptosis-associated proteins.

Background/Aim: Skin wound healing is a physiological process restoring the structural and functional integrity of injured skin. During this process, wound management preventing bacterial infection and complications is important for the regeneration of skin layers and adnexa, as well as the protective function of the skin. Therefore, the development of an effective ointment to promote wound healing without complications is beneficial. Materials and Methods: This study developed Raepenol™ cream, comprising a base cream and natural compounds including paeonol, D-panthenol and extract of Centella asiatica, and assessed its therapeutic effect in wound healing. A rat model of skin wound healing and a mouse model of imiquimod-induced pruritus were employed. The effect of Raepenol™ cream was evaluated by wound size and histological analysis, including the integrity of skin structures and inflammatory response. Results: Raepenol™ cream treatment effectively restored the structural integrity of the skin in rats, including wound closure, regeneration of skin adnexa, and reconstitution of collagen, comparable to commercial ointment. Additionally, Raepenol™ cream significantly suppressed pruritus by inhibiting mast cell infiltration or retention in the inflammatory site of mouse ears. Conclusion: Raepenol™ cream effectively promoted wound healing and relieved pruritus in animal models. These results suggest that it could be a promising option for wound care and pruritus relief, offering potential advantages over current ointments. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Shenyang Pharmaceutical University is the property of Shenyang Pharmaceutical University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

To investigate the role of miR-223-3p in the modulatory effect of paeonol (Pae) on high glucose (HG)-induced endothelial cell apoptosis. HG (25 mmol/L) was used to induce cellular damage and apoptosis in the mouse cardiac microvascular endothelial cells (MCMECs). Various concentration of Pae was tested and 60 μmol/L Pae was selected for the subsequent studies. MCMECs were transfected with exogenous miR-223-3p mimics or anti-miR-223-3p inhibitors. Cell viability was assessed by MTT assay and apoptosis was quantified by flow cytometry. The expression of miR-223-3p and NLRP3 mRNA was measured using real-time quantitative RT-PCR, and protein level of NLRP3 and apoptosis-related proteins was detected by immunoblotting. Pae significantly attenuated HG-induced apoptosis of MCMECs in a concentration-dependent manner. In addition, Pae (60 µmol/L) significantly reversed HG-induced down-regulation of miR-223-3p and up-regulation of NLRP3. Pae (60 µmol/L) also significantly blocked HG-induced up-regulation of Bax and Caspase-3 as well as down-regulation of Bcl-2. Moreover, exogenous miR-223-3p mimics not only significantly attenuated HG-induced apoptosis, but also significantly suppressed NRLP-3 and pro-apoptotic proteins in the MCMECs. In contrast, transfection of exogenous miR-223-3p inhibitors into the MCMECs resulted in not only significantly increased apoptosis of the cells, but also significant suppression of NLRP3 and pro-apoptotic proteins in the cells. Pae attenuated HG-induced apoptosis of MCMECs in a concentration-dependent manner. MiR-223-3p may mediate the modulatory effects of Pae on MCMEC survival or apoptosis through targeting NLRP3 and regulating apoptosis-associated proteins. [ABSTRACT FROM AUTHOR]

Apocynin (AP) and paeonol (PA) are low molecular weight phenolic compounds with a broad array of anti-inflammatory and immunoregulatory effects. This study assessed of a fixed-dose combination of APPA in people with symptomatic knee osteoarthritis (OA). A multi-center, randomized, placebo-controlled, double-blind phase 2a trial enrolled participants with radiographic knee OA (Kellgren-Lawrence, KL, grades 2–3) and pain ≥40/100 on WOMAC pain subscale, and evaluated the efficacy and safety of oral APPA over a 28-day period. APPA 800 mg or matching placebo was administered twice daily in a 1:1 ratio. Post-hoc analyses explored the response to APPA in sub-groups with more severe pain and structural severity. The two groups were comparable at baseline; 152 subjects were enrolled and 148 completed the trial. There was no statistically significant difference between groups with respect to the primary outcome, WOMAC pain (mean difference between groups was −0.89, 95% CI: −5.62, 3.84, p = 0.71), nor WOMAC function or WOMAC total. However, predefined subgroup analyses of subjects with symptoms compatible with nociplastic/neuropathic pain features showed a statistically significant effect of APPA compared to placebo. Adverse events (mainly gastrointestinal) were mild to moderate. Treatment with APPA 800 mg twice daily for 28 days in subjects with symptomatic knee OA was not associated with significant symptom improvement compared to placebo. The treatment was well-tolerated and safe. While the study was not powered for such analysis, pre-planned subgroup analyses showed a significant effect of APPA in subjects with nociplastic pain/severe OA, indicating that further research in the effects of APPA in appropriate patients is warranted. [ABSTRACT FROM AUTHOR]

Paeonol, a naturally bioactive phenolic ingredient predominantly isolated from Paeonia suffruticosa, has recently garnered significant interest as an anti-tumor agent against diverse carcinomas including non-small cell lung cancer (NSCLC). However, the anti-tumor mechanism of paeonol in NSCLC remains unclear. Cell viability, caspase-3 activity, and apoptosis were evaluated using CCK-8 assay, Caspase-3 Colorimetric Assay Kit, and flow cytometry analysis, respectively. GSE186218 was downloaded from NCBI Gene Expression Omnibus (GEO). The common genes were screened using GEO2R and Draw Venn Diagram software. Expression of troponin C type 1 (TNNC1), scavenger receptor class A member 5 (SCARA5), phosphorylated protein kinase B (AKT) (p-AKT) and AKT was examined using GEPIA database, qRT-PCR and western blot analysis. Paeonol treatment concentration-dependently inhibited cell viability and increased caspase-3 activity and apoptotic rate in NSCLC cells. Only 5 overlapping genes including TNNC1 and SCARA5 were obtained among 232 upregulated genes in GSE186218, 200 underexpressed genes in TCGA-LUAD, and 200 underexpressed genes in TCGA-LUSC according to the Venn diagram software. TNNC1 and SCARA5, two known tumor suppressors, were significantly downregulated in LUAD and LUSC tissues and NSCLC cells. Paeonol dose-dependently upregulated TNNC1 and SCARA5 expression in NSCLC cells. Paeonol suppressed the AKT pathway by upregulating TNNC1 and SCARA5 expression. AKT inhibitor attenuated the effects of TNNC1 or SCARA5 knockdown on the anti-tumor activity of paeonol. In conclusion, paeonol exhibited anti-cancer activity in NSCLC cells through inactivating the AKT pathway by upregulating TNNC1 or SCARA5. [ABSTRACT FROM AUTHOR]

Botrytis cinerea may cause gray mold in fruits and vegetables. Paeonol, an active component of traditional Chinese medicine, could suppress various microbial growth. However, reports on its effect on B. cinerea have not yet been documented. In this paper, we demonstrated that paeonol completely inhibited B. cinerea growth at 250 mg/L, corroborated by the observation of irregular morphological alterations in B. cinerea exposed to paeonol. Notably, the investigation of the operating mechanism revealed that paeonol induced cell death by disrupting the cell membrane, potentially mediated by the interaction between paeonol and ergosterol from the membrane. Further studies indicated that paeonol decreased ergosterol content and the expression of certain genes involved in ergosterol biosynthesis was significantly downregulated. In addition, paeonol treatment reduced the gray mold of cherry tomatoes. Meanwhile, compared to the control treatment, paeonol treatment could reduce weight loss and maintain higher contents of total soluble solid (TSS) and ascorbic acid, leading to a higher quality of the stored cherry tomato. Together, the data indicate that paeonol was effective as an alternative agent targeting disrupting the cell membrane to control gray mold and prolong the shelf life of cherry tomatoes, suggesting that paeonol could be used as a natural antifungal compound during postharvest storage.

Cortex Moutan is the root bark of the buttercup plant Paeonia suffruticosa Andr, of Ranunculaceae family. It has been utilized in Chinese medicine for thousands of years to treat a multitude of diseases, and traditional Chinese documents allege that it has heat-clearing, antipyretic, anti-inflammatory and detoxicating properties. Paeonol is a bioactive substance extracted from Cortex Moutan, which is considered to be one of its most effective metabolites. Recent studies have illustrated that paeonol treatment can alleviate skin damage, relieve the inflammatory response in patients with numerous dermatological conditions, and inhibit anomalous proliferation of skin tissue. Accordingly, paeonol may serve as a potential therapeutic agent for a variety of skin conditions. This review summarizes the physicochemical properties and pharmacokinetics (PK) characteristics of paeonol, and mechanisms of operation in diverse skin diseases, including dermatitis, psoriasis, pruritus, photoaging, hyperpigmentation, and hyperplasticscar. Additionally, much of the evidence is based on animal experiments. Furthermore, it explores the prospects of enhancing paeonol’s efficacy through extraction, synthesis, and formulation innovations, as well as strategies to overcome its limitations in dermatological therapy. This review aims to provide a more reliable theoretical basis for the clinical application of paeonol.

Hepatic stellate cell (HSC) activation is a key event in extracellular matrix accumulation, causing hepatic fibrosis. Therefore, identifying chemicals that inhibit HSC activation is an important therapeutic strategy for hepatic fibrosis. The aim of this study was to investigate the therapeutic effects of paeonol on HSC activation. In LX-2 cells, paeonol inhibited the expression of collagen and decreased the expression of HSC activation markers. In mice with thioacetamide-induced liver fibrosis, paeonol treatment decreased the serum levels of aspartate aminotransferase and alanine transaminase and mRNA expression of α-smooth muscle actin, platelet-derived growth factor-β, and connective-tissue growth factor. Investigation of the underlying molecular mechanism of paeonol showed that paeonol inhibits the SMAD2/3 and STAT3 signaling pathways that are important for HSC activation. On the basis of these results, paeonol should be investigated and developed further for hepatic fibrosis treatment. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology. It is marked by the production of pathogenic autoantibodies and the deposition of immune complexes. Lupus nephritis (LN) is a prevalent and challenging clinical complications of SLE. Cortex Moutan contains paeonol as its main effective component. In this study, using the animal model of SLE induced by R848, it was found that paeonol could alleviate the lupus-like symptoms of lupus mouse model induced by R848 activating TLR7, reduce the mortality and ameliorate the renal damage of mice. In order to explore the mechanism of paeonol on lupus nephritis, we studied the effect of paeonol on the polarization of Raw264.7 macrophages in vitro. The experimental results show that paeonol can inhibit the polarization of macrophages to M1 and promote their polarization to M2, which may be related to the inhibition of MAPK and NF-κB signaling pathways. Our research provides a new insight into paeonol in the treatment of lupus nephritis, which is of great importance for the treatment of systemic lupus erythematosus and its complications. • Paeonol can inhibit the polarization of macrophages to M1 and promote their polarization to M2. • MAPK and NF-κB signaling pathway may be an important way to regulate M1/M2 polarization of macrophages. • Feasibility analysis of intervention of paeonol in lupus nephritis. [ABSTRACT FROM AUTHOR]

Introduction: Ischemic stroke is the second most common chronic disease worldwide and is associated with high morbidity and mortality. Thromboembolism and platelet aggregation are the most characteristic features of stroke. Other than aspirin, no standard, accepted, or effective treatment for acute ischemic stroke has been established. Consequently, it is essential to identify novel therapeutic compounds for this condition. Methods: In this study, novel ozagrel/paeonol-containing codrugs were synthesized and characterized using 1H-NMR, 13C-NMR, and mass spectroscopy. Their antiplatelet aggregation activity was evaluated, with compound PNC3 found to exhibit the best effect. Subsequently, studies were conducted to assess its neuroprotective effect, pharmacokinetic properties and model its binding mode to P2Y12 and TXA2, two proteins critical for platelet aggregation. Results: The results indicated that PNC3 has good bioavailability and exerts protective effects against oxygen-glucose deprivation injury in PC12 cells. Molecular docking analysis further demonstrated that the compound interacts with residues located in the active binding sites of the target proteins. Conclusion: The codrugs synthesized in this study display promising pharmacological activities and have the potential for development as an oral formulation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cerebrovascular diseases involve neuronal damage, resulting in degenerative neuropathy and posing a serious threat to human health. The discovery of effective drug components from natural plants and the study of their mechanism are a research idea different from chemical synthetic medicines. Paeonol is the main active component of traditional Chinese medicine Paeonia lactiflora Pall. It widely exists in many medicinal plants and has pharmacological effects such as anti‐atherosclerosis, antiplatelet aggregation, anti‐oxidation, and anti‐inflammatory, which keeps generally used in the treatment of cardiovascular and cerebrovascular diseases. Based on the therapeutic effects of Paeonol for cardiovascular and cerebrovascular diseases, this article reviewed the pharmacological effects of Paeonol in Alzheimer's disease, Parkinson's disease, stroke, epilepsy, diabetes encephalopathy, and other neurological diseases, providing a reference for the research of the mechanism of Paeonol in central nervous system diseases. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory disease leading to various vascular diseases. Vascular smooth muscle cell (VSMC) senescence promotes atherosclerotic inflammation and the formation of plaque necrosis core, in part through telomere damage mediated by a high-fat diet. Our previous research found that paeonol, a potential anti-inflammatory agent extracted from Cortex Moutan, could significantly improve VSMCs dysfunction. However, the impact of paeonol on the senescence of VSMCs remains unexplored. This study presents the protective effects of paeonol on VSMCs senescence, and its potential activity in inhibiting the progression of atherosclerosis in vivo and in vitro. Sirtuin 1 (SIRT1) is a nuclear deacetylase involved in cell proliferation, senescence, telomere damage, and inflammation. Here, SIRT1 was identified as a potential target of paeonol having anti-senescence and anti-atherosclerosis activity. Mechanistic studies revealed that paeonol binds directly to SIRT1 and then activates the SIRT1/P53/TRF2 pathway to inhibit VSMCs senescence. Our results suggested that SIRT1-mediated VSMCs senescence is a promising druggable target for atherosclerosis, and that pharmacological modulation of the SIRT1/P53/TRF2 signaling pathway by paeonol is of potential benefit for patients with atherosclerosis. [ABSTRACT FROM AUTHOR]

Background Stroke is a cardiovascular disease that seriously endangers human health, which is characterized by high prevalence, disability and mortality rates. Peony bark is the dried root bark of peony in the buttercup family, which has the effect of clearing heat and cooling blood, activating blood circulation and resolving blood stasis. Paeonol (PAE) is the main active ingredient of peony bark, has been confirmed to have neuroprotective effect under hypoglycemia and hypoxia conditions. Objective To observe the effect and neurobiological mechanism of gastric administration of paeonol solution on improving behavioral dysfunction caused by middle cerebral artery occlusion (MCAO) , a kind of stroke, in a mouse model. Methods The study was conducted from December 2019 to December 2021. Twenty SPF male C57BL/6 mice were randomized into SHAM group (n=10) and model group (MCAO group, n=10) . The MCAO model was formed by intraluminal suture method. After 24 hours of modeling, the neurological function of each group was evaluated by Longa Score. Laser Speckle Contrast Imaging was used to monitor the changes of cerebral blood flow after MCAO. TTC staining was used in the pathological examination of cerebral infarction in MCAO mice. For investigating the protective effect of PAE on behavioural dysfunction of MCAO mice, 50 SPF male C57BL/6 mice were randomly grouped into SHAM group (n=10) , model+corn oil group (n=20) , and model+PAE group (n=20) . After the verification of model stability at 24 hours following the modeling, the model+PAE group received intragastric administration of PAE and corn oil solution in a concentration of 100 mg·kg-1· d-1, and the other two groups were gavaged with equal amounts of corn oil. Then on the 28th day after of modelling, survival curve was plotted to assess the survival status of mice in the three groups; the neurological recovery of mice was determined using the Longa Score; the area of cerebral infarction was examined by Nissl staining. The behavioural changes in motor sensory function were tested at five time points: the day before modeling, and 7, 14, 21 and 28 days after modelling. For exploring the mechanism of PAE improving behavioural dysfunction in MCAO mice, 30 SPF male C57BL/6 mice were randomly divided into SHAM group (n=6) , model+corn oil group (n=12) and model+PAE group (n=12) . After verifying the model stability at 24 hours following the modeling, the model+PAE group received intragastric administration of PAE and corn oil solution in a concentration of 100 mg·kg-1· d-1, and the other two groups were gavaged with an equal amount of corn oil. The expression of interleukin 1β (IL-1β) protein in the striatum of mouse brain was measured by Western blotting on the second day after modelling to investigate whether PAE could reduce the inflammatory response in the brain during the acute period. The expression of ionized calcium-binding adapter molecule 1 (IBA1) and glial fibrillary acidic protein (GFAP) in the penumbra was measured by immunofluorescence on the 14th day after modelling. Results The 28-day survival rate was 66.47% for the model+corn oil group, and 81.43% for model+PAE group. Log-rank test showed that the 28-day survival curve significantly differed across SHAM group, model+corn oil group, and model+PAE group (χ2=1.436, P

Chunkun Yang,1,* Jiawen Cheng,1,* Qinwei Zhu,2 Qingquan Pan,2 Kui Ji,2 Jun Li1 1Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Department of Emergency, Weifang Hospital of Traditional Chinese Medicine, Weifang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Li, Email gamyylj@163.comAbstract: Cardiovascular disease (CVD) is one of the leading causes of death in the world. Paeonol(Pae) is a phenolic component extracted from peony bark, peony root and Xu Changqing. Studies have shown that Pae can protect cardiomyocytes by inhibiting oxidative stress, promoting mitochondrial fusion, regulating mitochondrial autophagy and inhibiting inflammation. In addition, Pae improves ventricular remodeling by inhibiting myocardial apoptosis, hypertrophy and fibrosis. Pae also has a good protective effect on blood vessels by inhibiting vascular inflammation, reducing the expression of adhesion molecules, inhibiting vascular proliferation, and inhibiting oxidative stress and endoplasmic reticulum stress(ERS). Pae also has the effect of anti-endothelial cell senescence, promoting thrombus recanalization and vasodilating. In conclusion, the molecular targets of Pae are very complex, and the relationship between different targets and signaling pathways cannot be clearly explained, which requires us to use systems biology methods to further study specific molecular targets of Pae. It has to be mentioned that the bioavailability of Pae is poor, and some nanotechnology-assisted drug delivery systems improve the therapeutic effect of Pae. We reviewed the protective mechanism of paeonol on the cardiovascular system, hoping to provide help for drug development in the treatment of CVD.Keywords: paeonol, oxidative stress, inflammation, mitochondrial fusion, adhesion, autophagy

Background: Oxidative stress has been shown to play a critical role in the pathogenesis of hypertension. Paeonol, a major phenolic component extracted from Moutan Cortex, exerts a beneficial effect in preventing cardiovascular disease via reducing oxidative stress. The present study investigated the protective mechanism of paeonol against high blood pressure in spontaneous hypertension rats (SHRs). Methods: Wistar-Kyoto (WKY) rats and SHRs received vehicle or peaonol in the drinking water for 5 weeks. Blood pressure was measured by tail-cuff plethysmography and oxidative stress in kidney and vascular tissue was examined by enzyme-linked immunosorbed assay. The functions of angiotensin II type 1 receptors (AT1R) in the kidney and mesenteric artery were measured by natriuresis and vasoconstrictor response, respectively. Results: Compared with vehicle-treated WKY rats, vehicle-treated SHRs exhibited higher blood pressure, increased oxidative stress, accompanied by exaggerated diuretic and natriuretic responses to candesartan (AT1 receptor antagonist) and vasoconstrictor responses to angiotensin II (Ang II). Moreover, SHRs had higher ACE and AT1R in the kidney and mesenteric artery, and higher Ang II and lower renin levels. Interestingly, paeonol treatment reduced the candesartan-induced increase in diuresis and natriuresis and vasoconstrictor responses to Ang II, and lowered blood pressure in SHRs, accompanied by reducing AT1R protein expression in the kidney and mesenteric artery of SHR, and Ang II levels in plasma and increasing renin levels in renal cortex. In addition, these changes were associated with reducing oxidative stress. Conclusions: The present study suggests that paeonol improves renal and vascular AT1R functions by inhibition of oxidative stress, thus lowering blood pressure in SHRs. [ABSTRACT FROM AUTHOR]

Paeonol (2-hydroxy-4-methoxyphenylacetophenone) is a natural phenolic component isolated from the root bark of peony with multiple pharmacological activities and has been proven to have anti-cancer effects. The objective of this study is to investigate the influence mechanism of paeonol on the proliferatory and apoptotic activities of ovarian cancer (OC) cells by modulating the transforming growth factor beta (TGF-β)/Smad3 pathway. The SKOV3 cells were pretreated with various concentrations of paeonol (0, 25, 50, 100, 200, 400 µg/mL) for 48 hours to determine the optimal experimental concentration of paeonol. Following this, the TGF-β overexpression vector was constructed and transfected into the SKOV3 cells. The assessment of cell proliferation, invasion, and migration was conducted through MTT, colony formation, flow cytometry, transwell, and wound-healing experiments. The detection of TGF-β/Smad3 pathway-related proteins and apoptosis-related proteins (B-cell lymphoma (Bcl-2) Bcl-2-associated X protein (Bax)) was performed using Western blot analysis. Paeonol exhibited a significant inhibitory effect on SKOV3 cell viability when administered at concentrations ranging from 50-400 µg/mL, with an IC50 value of 200 µg/mL. Within the concentration range of 50 to 200 µg/mL, paeonol exhibited a dose-dependent effect on the progression of SKOV3 cells, including a reduction in the anti-apoptotic protein Bcl-2, an increase in the pro-apoptotic protein Bax (P<0.05), inhibition of cell migration and invasion (P<0.05), and promotion of cell apoptosis (P<0.05), particularly at a concentration of 200 µg/mL. These effects were found to be more pronounced. The aforementioned effects of paeonol can be ascribed to its inhibition of the TGFb/Smad3 pathway, according to a mechanistic viewpoint. It is noteworthy that the inhibitory impact of paeonol on SKOV3 cell progression is counteracted by the elevation of TGF-β levels following overexpression. We conclude that paeonol exerts regulatory effects on the TGF-β/Smad3 pathway, leading to the inhibition of proliferation, migration, and invasion of OC cells, thereby attenuating malignant behavior of cancer cells. [ABSTRACT FROM AUTHOR]

Aleuroglyphus ovatus, a common mite harming stored grain, poses a threat to human health. Paeonol is the main component isolated from peony roots and exhibits various medicinal values. In our previous study, we found that paeonol shows strong acaricidal activity. In the present study, the acaricidal mechanism of paeonol against A. ovatus was uncovered through RNA-seq transcriptomics and TMT proteomics. According to the transcriptomics results, paeonol treatment noticeably up-/downregulated genes associated with "oxidoreductase activity" (peptidase activity, ATPase activity, and hydrolase activity). As shown by proteomic analysis, concordant changes were identified in proteins linked with hydrolase activity, serine-type peptidase activity, antioxidant activity, and oxidoreductase activity. Paeonol target proteins were FMO, ACAD8, GPX, CTSL, and PRSS1, as determined by transcriptomicsproteomics correlation analysis. We propose that paeonol may play an acaricidal role by interfering with enzyme activities in A. ovatus, especially serine-type peptidase, thereby causing an imbalance in amino acid ratios and eventually leading to the death of A. ovatus. However, the specific mechanism of action needs to be further studied. In addition, we verified the key enzymes at the transcriptional level. [ABSTRACT FROM AUTHOR]

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Gut microbiota dysbiosis is an avenue for the promotion of atherosclerosis (AS) and this effect is mediated partly via the circulating microbial metabolites. More microbial metabolites related to AS vascular inflammation, and the mechanisms involved need to be clarified urgently. Paeonol (Pae) is an active compound isolated from Paeonia suffruticoas Andr. with anti-AS inflammation effect. However, considering the low oral bioavailability of Pae, it is worth exploring the mechanism by which Pae reduces the harmful metabolites of the gut microbiota to alleviate AS. In this study, ApoE−/− mice were fed a high-fat diet (HFD) to establish an AS model. AS mice were administrated with Pae (200 or 400 mg·kg−1) by oral gavage and fecal microbiota transplantation (FMT) was conducted. 16S rDNA sequencing was performed to investigate the composition of the gut microbiota, while metabolomics analysis was used to identify the metabolites in serum and cecal contents. The results indicated that Pae significantly improved AS by regulating gut microbiota composition and microbiota metabolic profile in AS mice. We also identified α -hydroxyisobutyric acid (HIBA) as a harmful microbial metabolite reduced by Pae. HIBA supplementation in drinking water promoted AS inflammation in AS mice. Furthermore, vascular endothelial cells (VECs) were cultured and stimulated by HIBA. We verified that HIBA stimulation increased intracellular ROS levels, thereby inducing VEC inflammation via the TXNIP/NLRP3 pathway. In sum, Pae reduces the production of the microbial metabolite HIBA, thus alleviating the ROS/TXNIP/NLRP3 pathway-mediated endothelial inflammation in AS. Our study innovatively confirms the mechanism by which Pae reduces the harmful metabolites of gut microbiota to alleviate AS and proposes HIBA as a potential biomarker for AS clinical judgment. [ABSTRACT FROM AUTHOR]

Yang Wang,1,&ast; Zheng Wang,1,&ast; Xiao Wu,1,&ast; Song Zhu,2,&ast; Qiru Guo,1 Zhong Jin,1 Zixian Chen,3 Delai Zhang,2 Wangming Hu,1 Huan Xu,1 Liangqin Shi,1 Lan Yang,1 Yong Wang1 1College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 3School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yong Wang, College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China, Tel +86 18280350393, Email yongwang1008@hotmail.com; wangyong@cdutcm.edu.cnPurpose: Dysfunction of endothelium is associated with multiple pathological vascular diseases. However, how to regulate reendothelialization after vascular injury is not well defined. This study aims to determine whether and how Paeonol controls reendothelialization following artery injury.Methods: The endothelium of murine carotid artery was denuded by catheter guide wires injury. H&E staining and IF staining were performed to determine whether Paeonol is critical for reendothelialization. BRDU Incorporation Assay, Boyden Chamber Migration Assay, Tube Formation Assay, and Spheroid Sprouting Assay were used to investigate whether Paeonol is involved in regulating proliferation and migration of endothelial cells. The underlying mechanism of how Paeonol regulates reendothelialization was determined by Molecular docking simulation and CO-IP Assay.Results: Paeonol treatment significantly inhibits neointima formation in carotid artery ligation model by promoting proliferation and migration of endothelial cells. Mechanistically, Paeonol enhances c-Myc expression, consequently interacts with VEGFR2 results in activating VEGF signaling pathway, and eventually promotes reendothelialization after vascular injury.Conclusion: Our data demonstrated that Paeonol plays a critical role in regulating vascular reendothelialization, which may be therapeutically used for treatment of pathological vascular diseases.Graphical Abstract: Keywords: Paeonol, c-Myc, VEGFR2, vascular injury, reendothelialization

Introduction: The anti-cancer medication doxorubicin (Dox) is largely restricted in clinical usage due to its significant cardiotoxicity. The only medication approved by the FDA for Dox-induced cardiotoxicity is dexrazoxane, while it may reduce the sensitivity of cancer cells to chemotherapy and is restricted for use. There is an urgent need for the development of safe and effective medicines to alleviate Dox-induced cardiotoxicity. Objectives: The objective of this study was to determine whether Paeonol (Pae) has the ability to protect against Dox-induced cardiotoxicity and if so, what are the underlying mechanisms involved. Methods: Sprague-Dawley rats and primary cardiomyocytes were used to create Dox-induced cardiotoxicity models. Pae's effects on myocardial damage, mitochondrial function, mitochondrial dynamics and signaling pathways were studied using a range of experimental methods. Results: Pae enhanced Mfn2-mediated mitochondrial fusion, restored mitochondrial function and cardiac performance both in vivo and in vitro under the Dox conditions. The protective properties of Pae were blunted when Mfn2 was knocked down or knocked out in Dox-induced cardiomyocytes and hearts respectively. Mechanistically, Pae promoted Mfn2-mediated mitochondria fusion by activating the transcription factor Stat3, which bound to the Mfn2 promoter in a direct manner and up-regulated its transcriptional expression. Furthermore, molecular docking, surface plasmon resonance and co-immunoprecipitation studies showed that Pae’s direct target was PKCε, which interacted with Stat3 and enabled its phosphorylation and activation. Pae-induced Stat3 phosphorylation and Mfn2-mediated mitochondrial fusion were inhibited when PKCε was knocked down. Furthermore, Pae did not interfere with Dox's antitumor efficacy in several tumor cells. Conclusion: Pae protects the heart against Dox-induced damage by stimulating mitochondrial fusion via the PKCε-Stat3-Mfn2 pathway, indicating that Pae might be a promising therapeutic therapy for Dox-induced cardiotoxicity while maintaining Dox's anticancer activity.

Premenstrual dysphoric disorder (PMDD) is a periodic psychiatric disorder with high prevalence in women of childbearing age, seriously affecting patients' work and life. Currently, the international first-line drugs for PMDD have low efficiency and increased side effects. Paeonol, a major component of the traditional Chinese medicine Cortex Moutan, has been applied in treating PMDD in China with satisfactory results, but the therapeutic mechanism is not fully understood. This study aims to evaluate the therapeutic effects and pharmacological mechanisms of paeonol on the main psychiatric symptoms and hippocampal damage in PMDD. We established a premenstrual irritability rat model by the resident-intruder paradigm and performed elevated plus maze and social interactions. And we employed the HE and Nissl staining techniques to observe the therapeutic effect of paeonol on hippocampal damage in PMDD rats. Subsequently, Elisa, qRT-PCR Array, Western Blotting, and cell models were utilized to elucidate the underlying molecular mechanisms through which paeonol intervenes in treating PMDD. In this study, we demonstrated the therapeutic effects of paeonol on irritability, anxiety, and social withdrawal behaviors in rats. In addition, we found that paeonol significantly reduced the serum corticosterone (CORT) level, improved hippocampal morphological structure and neuron number, and reduced hippocampal neuron apoptosis in PMDD rats. Paeonol reduced GRM5, GABBR2, β-arrestin2, and GRK3 expression levels in hippocampal brain regions of PMDD rats and activated the cAMP/PKA signaling pathway. Inhibitor cell experiments showed that paeonol specifically ameliorated hippocampal injury by modulating the β-arrestin2/PDE4-cAMP/PKA signaling pathway. The present study demonstrates, for the first time, that paeonol exerts a therapeutic effect on periodic psychotic symptoms and hippocampal injury in PMDD through inhibiting GRM5/GABBR2/β-arrestin2 and activating cAMP-PKA signaling pathway. These findings enhance our understanding of the pharmacological mechanism underlying paeonol and provide a solid scientific foundation for its future clinical application.

Diabetic ulcer is usually seen in people with uncontrolled blood sugar. Reportedly, many factors such as impaired glucose metabolism, and macrovascular and microvascular diseases caused angiogenesis disorders and delayed the healing of diabetic ulcers, thus affecting the body's metabolism, nutrition, and immune function. This study aimed to explore the effect of paeonol on skin wound healing in diabetic rats and the related mechanism. A rat model of diabetic ulcer was established. High glucose-treated mouse skin fibroblasts were co-cultured with M1 or M2- polarized macrophages treated with or without paeonol. H&E and Masson staining were used to reveal inflammatory cell infiltration and collagen deposition, respectively. Immunohistochemistry visualized the expression of Ki67, CD31, and vascular endothelial growth factor (VEGF). Western blot was used to detect interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-4, IL-10, CD31, VEGFA, and collagen I/III. The expression of iNOS and arginase 1 was revealed by immunofluorescence staining. Paeonol treatment augmented collagen deposition and the expression of Ki67, CD31, VEGF, and macrophage M2 polarization markers (IL-4 and IL-10) and reduced wound area, inflammatory cell infiltration, and macrophage M1 polarization markers (IL-1β and TNF-α) in the ulcerated area. In vitro, paeonol treatment promoted M2-polarization and repressed M1-polarization in macrophages, thereby improving the repair of cell damage induced by high glucose. Paeonol accelerates the healing of diabetic ulcers by promoting M2 macrophage polarization and inhibiting M1 macrophage polarization. [ABSTRACT FROM AUTHOR]

Objective To discuss the effect of paeonol on the proliferation, migration and chemokinereceptor4 (CXCR4) /signal transducer and activators of transcription3 (STAT3) pathway of the human osteosarcoma (OS) MG-63 cells, and to clarify its possible mechanism. Methods The MG-63 cells were cultured in vitro and divided into control group (without drug intervention) and different concentrations of paeonol groups (given 10, 20, 40, 80, 160，and 320 mg·L－1 paeonol, respectively) .The survival rates of the MG-63 cells in various groups were detected by CCK-8 method and the half inhibitory concentration (IC50) value was selected as the drug concentration for subsequent experiment. The MG-63 cells were divided into control group (without drug treatment) and paeonol group (given 215.8 mg·L－1 paeonal).The expression levels of CXCR4, interleukin 6 (IL-6), and phosphorylated STAT3 (p-STAT3)，and STAT3 proteins in the MG-63 cells in various groups were detected by Western blotting method.The MG-63 cells were divided into control group, paeonol group, paeonol+empty group (given 215.8 mg·L－1 paeonol+empty plasmid), and paeonol+overexpression group (given 215.8 mg·L－1 paeonol+CXCR4 over-expression plasmid) . The scratch healing rates of the MG-63 cells in various groups were detected by cell scratch experiment, the clone formation rates the MG-63 cells in various groups were detected by cloning formation experiment, and the expression levels of CXCR4, IL-6, p-STAT3, and STAT3 proteins in the MG-63 cells in various groups were detected by Western blotting method. Results Compared with control group, the survival rates of the MG-63 cells treated in 40, 80, 160, and 320 mg·L－1 paeonol groups were decreased (P<0.05), and the IC50 value of paeonol was 215.8 mg·L－1. Compared with control group, the expression levels of CXCR4, IL-6, and p-STAT3 proteins in the MG-63 cells in paeonol group were decreased (P<0.05). Compared with control group, the scratch healing rates and clone formation rates of the MG-63 cells in paeonol group and paeonol+empty group were decreased (P<0.05), and the expression levels of CXCR4, IL-6, and p-STAT3 proteins in the MG-63 cells were decreased (P<0.05); compared with paeonol group，the scratch healing rate, clone formation rate, expression levels of CXCR4, IL-6, p-STAT3，and STAT3 proteins in the MG-63 cells in paeonol+empty group had no significant differences (P>0.05); compared with paeonol group, the scratch healing rate and clone formation rate of the MG-63 cells in paeonol+overexpression group were increased (P<0.05), and the expression levels of CXCR4, IL-6 and p-STAT3 proteins were increased (P<0.05) . Conclusion Paeonol can inhibit the proliferation, migration，and clonogenic ability of the MG-63 cells, and its mechanism may be related to the regulation of CXCR4/STAT3 signal pathway. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

[Objectives] To study the coating process of paeonol sustained release pills by extrusion-spheronization method taking ethyl cellulose as the coating material. [Methods] Paeonol pills were made by Âuari AW-95 Full Automatic Pill Making Machine. Coating of paeonol sustained release pills was prepared by Auari Mini Pill Polishing Machine. The prescription and process factors of paeonol sustained release pills coating were investigated by single factor experiment and orthogonal experiment. The release of paeonol sustained release pills was determined according to the cumulative release curve of paeonol. [ Results] The prepared paeonol sustained release pills released slowly within 24 h, and the release rate reached 80% in 12 h. [Conclusions] The prepared paeonol sustained release pills basically meet the 24 h sustained release standard, and can be further developed and applied. [ABSTRACT FROM AUTHOR]

Cancer represents one of the leading causes of mortality worldwide. Conventional clinical treatments include radiation therapy, chemotherapy, immunotherapy, and targeted therapy. However, these treatments have inherent limitations, such as multidrug resistance and the induction of short- and long-term multiple organ damage, ultimately leading to a significant decrease in cancer survivors' quality of life and life expectancy. Paeonol, a nature active compound derived from the root bark of the medicinal plant Paeonia suffruticosa, exhibits various pharmacological activities. Extensive research has demonstrated that paeonol exhibits substantial anticancer effects in various cancer, both in vitro and in vivo. Its underlying mechanisms involve the induction of apoptosis, the inhibition of cell proliferation, invasion and migration, angiogenesis, cell cycle arrest, autophagy, regulating tumor immunity and enhanced radiosensitivity, as well as the modulation of multiple signaling pathways, such as the PI3K/AKT and NF-κB signaling pathways. Additionally, paeonol can prevent adverse effects on the heart, liver, and kidneys induced by anticancer therapy. Despite numerous studies exploring paeonol's therapeutic potential in cancer, no specific reviews have been conducted. Therefore, this review provides a systematic summary and analysis of paeonol's anticancer effects, prevention of side effects, and the underlying mechanisms involved. This review aims to establish a theoretical basis for the adjunctive strategy of paeonol in cancer treatment, ultimately improving the survival rate and enhancing the quality of life for cancer patients. [ABSTRACT FROM AUTHOR]

Background: Liver injury due to ischemia/reperfusion (I/R) is a major challenge during liver surgery. Effects of paeonol pretreatment on partial hepatic I/R injury were assessed in this study. Methods: Male Wistar rats were allocated into sham, vehicle-I/R, and paeonol-I/R groups. Paeonol, 100 mg/kg/day, was administered by gavage. After 10 days, rats of I/R groups were subjected to partial I/R of the liver. Blood samples were collected for assessment of alanine and aspartate aminotransferases as well as gamma glutamyl transferases. Liver samples were taken for detection of tumor necrosis factor-α (TNF-α) and malondialdhyde (MDA) levels as well as superoxide dismutase (SOD) activity. The mRNA expression of toll-like receptor-4 (TLR4), myeloid differentiation factor 88 (MyD88), high mobility group box 1 (HMG-1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) were assessed in the liver. Hematoxylin& eosin stained liver sections were examined. Expressions of nuclear factor kappa B (NF-κB) and autophagy markers (LC3 II, P62) were assessed in immunostained sections. Results: Liver I/R increased serum transferases and tissue MDA, TNF-α, TLR4, HMGB-1, MyD88, NF-κB, LC3 II, P62 levels with hydropic degeneration and cellular infiltration in the liver while decreased SOD activity and PPAR-γ mRNA expression. These alterations were attenuated by paeonol pretreatment. Conclusions: Paeonol pretreatment alleviated liver I/R injury through inhibition of autophagy and TLR4/MyD88/NF-κB pathways. [ABSTRACT FROM AUTHOR]

Aberrant glycolytic reprogramming is involved in lung cancer progression by promoting the proliferation of non-small cell lung cancer cells. Paeonol, as a traditional Chinese medicine, plays a critical role in multiple cancer cell proliferation and inflammation. Acyl-CoA dehydrogenase (ACADM) is involved in the development of metabolic diseases. N6-methyladenosine (m6A) modification is important for the regulation of messenger RNA stability, splicing, and translation. Here, we investigated whether paeonol regulates the proliferation and glycolytic reprogramming via ACADM with m6A modification in A549 cells (human non-small cell lung cancer cells). Cell counting kit 8, 5-Bromo-2-deoxyuridine, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, flow cytometry analysis, western blotting and seahorse XFe24 extracellular flux analyzer assays showed that paeonol had a significant inhibitory effect against A549 cell proliferation and glycolysis. Mechanistically, ACADM was a functional target of paeonol. We also showed that the m6A reader YTH domain containing 1 plays an important role in m6A-modified ACADM expression, which is negatively regulated by paeonol, and is involved in A549 cell proliferation and glycolytic reprogramming. These results indicated the central function of paeonol in regulating A549 cell glycolytic reprogramming and proliferation via m6A modification of ACADM. [ABSTRACT FROM AUTHOR]

This study aimed to obtain paeonol with high purity by using the combination of steam distillation and antisolvent recrystallization (ASR) and to reduce the energy consumption and CO2 emission in the preparation process. First, different experimental parameters were optimized by response surface methodology (RSM). Under the optimal conditions, the purity and yield of the as‐obtained paeonol were about 98% and 56.97%, respectively. The physicochemical properties of purified paeonol were tested, showing consistency with those of standard paeonol. The energy consumption and CO2 emission of the preparation process of ASR and single‐solvent recrystallization were also investigated. Results showed that the energy consumption and CO2 emission of ASR were about 4.41 J/mg and 0.006 kg/mg, respectively, which were 6.89 J/mg and 0.0095 kg/mg lower than those of ethanol recrystallization, respectively, and 50.22 J/mg and 0.0144 kg/mg lower than methanol those of recrystallization, respectively. The above results showed that ASR could obtain paeonol with high purity in a high‐efficiency, low‐energy, and environmentally protective manner. [ABSTRACT FROM AUTHOR]

Context Paeonol (PAE) is the main phytochemical from Cortex Moutan. Its main pharmacological effects are anti-inflammatory and antioxidant, but its cardioprotective effect is unclear.Objective The study investigates the effects and underlying mechanisms of PAE on transverse aortic constriction (TAC)-induced heart failure (HF) in mice.Materials and methods C57BL/6 mice were randomly divided into five groups: sham, TAC, PAE10 (TAC + PAE 10 mg/kg), PAE20 (TAC + PAE 20 mg/kg) and PAE 50 (TAC + PAE 50 mg/kg). Paeonol was intragastrically administered to mice for 4 weeks. Mice were anaesthetized with pentobarbital sodium and underwent cardiac echocardiography using echocardiography system. Serum levels of atrial natriuretic peptide (ANP), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Myocardial apoptosis was detected with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining. Haematoxylin–eosin (H&E) and Masson’s staining were used for histopathological evaluation. Western and quantitative real-time PCR (qRT-PCR) were performed to detect levels of apoptosis and fibrosis-related proteins.Results Echocardiography showed PAE improved cardiac function (LVEF: TAC, 52.3±6.8%; PAE20, 65.8±3.6%; PAE50, 71.4±2.5%) and H&E staining showed PAE alleviated myocardial injury (TAC: 1170.3 ± 134.6 μm2; PAE50: 576.0 ± 53.5 μm2). Western and qRT-PCR results showed that PAE down-regulated the levels of ANP, BNP and α-MHC. In addition, TUNEL and western results showed PAE significantly inhibited apoptosis. Masson and western results showed PAE inhibited cardiac hypertrophy. Western results showed the ERK1/2/JNK pathway could be inhibited by PAE.Discussion and conclusions Paeonol regulates ERK1/2/JNK to improve cardiac function, which provides theoretical support for the extensive clinical treatment of HF.

Abstract Preeclampsia (PE) is a multisystemic and placental inflammatory disease that causes maternal and infant health issues. As one of the active components in peony root extract, paeonol (Pae) exerts anti‐apoptosis and anti‐inflammatory effects. Nonetheless, the protective role of Pae in PE has not yet been characterized. A mouse model of PE was constructed through tail vein injection of 1 mg/d phosphatidylserine/dioleoyl‐phosphatidycholine suspension. The levels of inflammatory cytokines in the placenta were examined via enzyme‐linked immunosorbent assay (ELISA). The mRNA levels of inflammatory cytokines (TNF‐α, IL‐6, IFN‐γ, and IL‐4) and apoptosis markers (Bax, Bcl‐2, and caspase‐3) were tested using quantitative reverse transcription‐polymerase chain reaction (qRT–PCR). Western blot analysis was performed to detect the protein levels of apoptosis markers and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway‐related molecules. Here, Pae repressed the inflammatory response in the placenta of PE‐like mouse models, as demonstrated by the decreased concentrations and mRNA levels of TNF‐α, IL‐6, and IFN‐γ and the increased concentrations and mRNA levels of IL‐4. Apoptosis in the placentas of PE‐like mouse models was attenuated by Pae, as manifested by the downregulated mRNA and protein levels of Bax and cleaved‐caspase‐3 and the upregulated Bcl‐2. Administration of Pae inhibited the phosphorylation of JAK2 and STAT3 in the placental tissues of PE mice. The JAK2/STAT3 pathway agonist (SC‐39100) reversed Pae treatment‐mediated suppression of placental inflammation and apoptosis in PE mice. Overall, Pae inhibits the JAK2/STAT3 signaling pathway to attenuate placental inflammation and apoptosis in PE mice.

Flavonoids have good pharmacological activity and are widely used, but the yield of extracted flavonoids is low and the price is high. In order to explore the new technology of artificial synthesis of flavonoids and synthesis of new flavonoids, natural product paeonol was used as the raw material, and alkali catalyzed condensation reaction between m-hydroxybenzaldehyde and paeonol was carried out to construct intermediate product Ⅰ. Then, at high temperature, dimethyl sulfoxide (DMSO) was used as a solvent, and iodine was catalyzed to induce its oxidation and cyclization to obtain the target product Ⅱ. The structure of the product was determined through comprehensive analysis such as UV, IR, elemental analysis, and nuclear magnetic resonance. The changes in UV spectra of product Ⅰ and product Ⅱ in different concentrations of acid, alkali, and salt solutions were investigated and the reasons were analyzed. The results show that product Ⅰ is 2′,3-dihydroxy-4′-methoxychalone, with a yield of 82.2%. Its UV spectrum varies in different concentrations of acid, alkali, and salt solutions, and it could react with low concentrations of NaOH solution. The product could exist stably within 30 minutes and also easily interact with KNO3 solution, resulting in unstable products. Product Ⅱ is 7-methoxy-3′- hydroxyflavone, with a yield of 92. 0% . It can exist stably for a long time in HCl (4.0 mol / L), NaOH, and KNO3 solutions. This synthesis process overcomes the problem of protecting hydroxyl groups in condensation reactions and achieves efficient synthesis of 7- methoxy-3′-hydroxyflavones. Product Ⅰ failed to form a 4-chromone structure, with one phenolic hydroxyl group on each AB ring. Its stability is greatly affected by the environment, especially in alkaline environments. When using product Ⅰ, the storage environment should be controlled, and the pH should not be higher than 7. Product Ⅱ has a stable conjugated structure, which is less affected by the environment and can also exist stably in strong acid environments. This study has guiding and reference value for the production and application of flavonoids. [ABSTRACT FROM AUTHOR]

The abnormal immune response mediated by malignant melanoma is related to PD1. Paeonol has pharmacological antitumor activity. Previous studies have indicated that paeonol induces tumor cell apoptosis, but its underlying mechanism in tumor immunity remains unknown. In this study, malignant melanoma was established in normal and thymectomized mice to determine the important role of the thymus in the antitumor effects of paeonol. Paeonol-treated thymocytes were cocultured with melanoma cell spheres to further evaluate the regulatory role of thymocytes in tumor immune dysfunction. Studies have shown that PD1 may be targeted by miR-139–5p. Our results revealed that tumor-induced thymic atrophy was significantly accompanied by high PD1 expression and low miR-139–5p expression. Interestingly, paeonol significantly reversed thymic atrophy and largely protected thymocytes against low PD1 expression and high miR-139–5p expression. Dual-luciferase assays indicated that miR-139–5p interacted with the 3′ untranslated region (3′-UTR) of PD1. These results showed that paeonol alleviates PD1-mediated antitumor immunity by reducing miR-139–5p expression and demonstrated a novel mechanism for melanoma immunotherapy. • We have demonstrated through both in vivo and in vitro experiments that paeonol can suppress the progression of melanoma by decreasing the expression of PD1, which is mediated by miR-139–5p in thymocytes. This is a novel pharmacological effect of paeonol in tumor immune regulation, and it provides a new avenue for further exploration of tumor immune regulation therapies and drug development. [ABSTRACT FROM AUTHOR]

[Display omitted] • Paeonol promotes Mfn2-mediated mitochondrial fusion in doxorubicin-treated hearts. • Mfn2 knockdown or knockout blunts the protective effects of paeonol. • Paeonol increases Mfn2 expression via Stat3-mediated transcription. • Paeonol activates Stat3-Mfn2 signaling pathway via upregulating PKCε. • Paeonol does not interfere with doxorubicin's antitumor efficacy. The anti-cancer medication doxorubicin (Dox) is largely restricted in clinical usage due to its significant cardiotoxicity. The only medication approved by the FDA for Dox-induced cardiotoxicity is dexrazoxane, while it may reduce the sensitivity of cancer cells to chemotherapy and is restricted for use. There is an urgent need for the development of safe and effective medicines to alleviate Dox-induced cardiotoxicity. The objective of this study was to determine whether Paeonol (Pae) has the ability to protect against Dox-induced cardiotoxicity and if so, what are the underlying mechanisms involved. Sprague-Dawley rats and primary cardiomyocytes were used to create Dox-induced cardiotoxicity models. Pae's effects on myocardial damage, mitochondrial function, mitochondrial dynamics and signaling pathways were studied using a range of experimental methods. Pae enhanced Mfn2-mediated mitochondrial fusion, restored mitochondrial function and cardiac performance both in vivo and in vitro under the Dox conditions. The protective properties of Pae were blunted when Mfn2 was knocked down or knocked out in Dox-induced cardiomyocytes and hearts respectively. Mechanistically, Pae promoted Mfn2-mediated mitochondria fusion by activating the transcription factor Stat3, which bound to the Mfn2 promoter in a direct manner and up-regulated its transcriptional expression. Furthermore, molecular docking, surface plasmon resonance and co-immunoprecipitation studies showed that Pae's direct target was PKCε, which interacted with Stat3 and enabled its phosphorylation and activation. Pae-induced Stat3 phosphorylation and Mfn2-mediated mitochondrial fusion were inhibited when PKCε was knocked down. Furthermore, Pae did not interfere with Dox's antitumor efficacy in several tumor cells. Pae protects the heart against Dox-induced damage by stimulating mitochondrial fusion via the PKCε-Stat3-Mfn2 pathway, indicating that Pae might be a promising therapeutic therapy for Dox-induced cardiotoxicity while maintaining Dox's anticancer activity. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the protective effect of paeonol (pae) on an angiotensin II (AngII)-induced cardiac hypertrophy mouse model. First, AngII mouse models were constructed and randomly grouped into the control (con), AngII, and AngII + Pae groups. Compared with that in the blank group, the surface area of myocardial cells in the AngII group increased significantly. In contrast to that in the AngII group, the cardiomyocyte surface area in the Pae group was significantly reduced. Ultrasound results showed that the myocardial function of mice in the AngII group was decreased compared with that in the Con group, while the myocardial function of mice in the Pae treatment was significantly improved. Moreover, the Fe2+ and lipid peroxide levels of primary cardiomyocytes were significantly increased after treatment with AngII and were significantly decreased after the addition of Pae. Compared with those in the Con group, cristae were reduced and the outer membrane was lost in the myocardial tissues of the AngII group, and myocardial MDA, ROS, and Fe2+ levels were increased. However, myocardial damage was significantly alleviated after Pae treatment, and myocardial MDA, ROS, and Fe2+ levels were reduced. Moreover, in myocardial tissue, AngII reduced the protein levels of xCT and GPX4, while the levels of both xCT and GPX4 were increased after Pae treatment. In conclusion, Pae protected the hearts of AngII mice by upregulating the protein expression of xCT and GPX4 and resisting AngII-induced ferroptosis in cardiomyocytes.

Atherosclerosis is a chronic inflammatory disease leading to various vascular diseases. Vascular smooth muscle cell (VSMC) senescence promotes atherosclerotic inflammation and the formation of plaque necrosis core, in part through telomere damage mediated by a high-fat diet. Our previous research found that paeonol, a potential anti-inflammatory agent extracted from Cortex Moutan, could significantly improve VSMCs dysfunction. However, the impact of paeonol on the senescence of VSMCs remains unexplored. This study presents the protective effects of paeonol on VSMCs senescence, and its potential activity in inhibiting the progression of atherosclerosis in vivo and in vitro. Sirtuin 1 (SIRT1) is a nuclear deacetylase involved in cell proliferation, senescence, telomere damage, and inflammation. Here, SIRT1 was identified as a potential target of paeonol having anti-senescence and anti-atherosclerosis activity. Mechanistic studies revealed that paeonol binds directly to SIRT1 and then activates the SIRT1/P53/TRF2 pathway to inhibit VSMCs senescence. Our results suggested that SIRT1-mediated VSMCs senescence is a promising druggable target for atherosclerosis, and that pharmacological modulation of the SIRT1/P53/TRF2 signaling pathway by paeonol is of potential benefit for patients with atherosclerosis.

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.

Objective: The purpose of this randomized controlled trial was to compare the efficacy of a toothpaste containing paeonol, potassium nitrate, and strontium chloride with control toothpaste on dentine hypersensitivity (DH). Methods: DH patients who had at least two sensitive teeth and did not use desensitization toothpaste in the past 3 months were randomly allocated to either test or control group. The toothpaste containing paeonol, potassium nitrate, and strontium chloride was used in the test group, while the placebo toothpaste used in control group. The outcome measures included Yeaple probe score and Schiff Index score at 4 and 8 weeks. The patients, personnel and assessors were blinded to the allocation. The differences in Yeaple probe score and Schiff Index score between groups were analyzed with ANOVA. Results: 91 eligible subjects were randomized. 88 of them completed 8-week follow-up and were analyzed (45 in the test group and 43 in the control group). In both groups, the Yeaple probe score showed an upward trend, while the Schiff sensitivity score showed a downward trend. At week 8, the Yeaple probe score had increased by 30.22 g in the test group, and the Schiff Index score had decreased by 0.89. Compared with the control group, the Yeaple probe score in the test group increased by 286.85% from baseline, and the Schiff Index score decreased by 42.96%, showing a statistically significant difference. Five cases of adverse events were observed. Conclusion: The toothpaste containing paeonol, potassium nitrate, and strontium chloride was effective against DH. Clinical significance: This combination of paeonol, potassium nitrate and strontium chloride could be a novel functional ingredient choice for anti-hypersensitivity products in future. Registration: The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2000041417).

Paeonol (PAE) is a hydrophobic drug. In this study, we encapsulated paeonol in a lipid bilayer of liposomes (PAE-L), which delayed drug release and increased drug solubility. When PAE-L was dispersed in gels (PAE-L-G) based on a poloxamer matrix material for local transdermal delivery, we observed amphiphilicity, reversible thermal responsiveness, and micellar self-assembly behavior. These gels can be used for atopic dermatitis (AD), an inflammatory skin disease, to change the surface temperature of the skin. In this study, we prepared PAE-L-G at an appropriate temperature for the treatment of AD. We then assessed the gel's relevant physicochemical properties, in vitro cumulative drug release, and antioxidant properties. We found that PAE-loaded liposomes could be designed to increase the drug effect of thermoreversible gels. At 32 °C, PAE-L-G could change from solution state to gelatinous state at 31.70 ± 0.42 s, while the viscosity was 136.98 ± 0.78 MPa.S and the free radical scavenging rates on DPPH and H2O2 were 92.24 ± 5.57% and 92.12 ± 2.71%, respectively. Drug release across the extracorporeal dialysis membrane reached 41.76 ± 3.78%. In AD-like mice, PAE-L-G could also relieve skin damage by the 12th day. In summary, PAE-L-G could play an antioxidant role and relieve inflammation caused by oxidative stress in AD. [ABSTRACT FROM AUTHOR]

Background: The management of diabetes mellitus-induced erectile dysfunction (DMED) is progressively becoming tricky due to the surge in the number of patients and the poor efficiency of phosphodiesterase type 5 inhibitors in DMED. Paeonol (Pae), as a traditional Chinese medicine, has been more and more widely used in the treatment of diabetic complications. However, whether Pae could be a potential therapeutic drug of DMED needs to be further evaluated. Objectives: To investigate the pharmacological effect and possible mechanism of Pae in the treatment of DMED. Methods: Intraperitoneal streptozotocin injection and an apomorphine test were used to construct the model of DMED. Seventeen DMED rats were divided into two groups: DMED group (n = 8) and DMED+Pae group (Pae; 100 mg/kg/d; oral administration; n = 9). In addition, there were still 10 normal age-matched male rats as control group. Four weeks later, the cavernous nerve electric stimulation was carried out to measure the erectile response. Moreover, the corpus cavernosum smooth muscle cells (CCSMCs) were primarily isolated and exposed to high glucose (HG) stimulation, Pae treatment and glycyrrhizin (GL; the selective inhibitor of HMGB1). After an incubation for 1 week, the CCSMCs were harvested for detection. Results: The impairment of erectile function was observed in DMED rats compared with control samples, accompanied by the upregulation of HMGB1/RAGE/NF-κB Pathway. The lower nitric oxide and cGMP level and the higher level of inflammation, fibrosis, and apoptosis were also observed in DMED rats. It showed contrast that Pae treatment could improve the erectile function, as well as histologic alteration and related molecular changes. In addition, Pae could downregulate the HMGB1/RAGE/NF-κB pathway to regulate the apoptosis and inflammation levels of CCSMCs in high-glucose conditions, which is similar to the results of GL treatment. Conclusion: Pae alleviated ED in DMED rats, likely by inhibiting HMGB1/RAGE/NF-κB Pathway, inflammatory, apoptosis, and fibrotic activity, and moderating endothelial dysfunction. Our study provide evidence for a potential new therapy for DMED. [ABSTRACT FROM AUTHOR]