peoniflorin and Inflammation

Epidemiological studies have shown that the incidence, prevalence and mortality of atherosclerotic cardiovascular disease (ASCVD) are increasing globally. Atherosclerosis is characterized as a chronic inflammatory disease which involves inflammation and immune dysfunction.

Topics: Endothelial Cells; Glucosides; Humans; Inflammation; Monoterpenes

Increasing pharmacological evidence supports that paeoniflorin, a water-soluble monoterpene glycoside isolated from Paeonia lactiflora Pall. (Shaoyao in Chinese), has a wide range of medicinal properties including anti-inflammatory, antioxidant, antithrombotic, anticonvulsive, analgesic, cardioprotective, neuroprotective, hepatoprotective, antidepressant-like, antitumoral, and immune-regulatory activities; as well as enhancing cognition and attenuating learning impairment. In addition to pharmacodynamic studies, information on pharmacokinetics is also significant for the further development and utilization of paeoniflorin. The present review focuses on the absorption, distribution, metabolism, and excretion of paeoniflorin, especially main pharmacological activities of paeoniflorin on inflammation and immune function. According to the findings obtained both in vitro and in vivo, a broad application prospect has been opened for paeoniflorin. However, further studies are needed to clarity the direct molecular mechanisms and key targets underlying the beneficial effects of paeoniflorin on inflammation and immunity.

Topics: Animals; Anti-Inflammatory Agents; Glucosides; Humans; Immunologic Factors; Inflammation; Monoterpenes; Paeonia; Signal Transduction

Total glycoside of paeony (TGP) has been widely used to treat inflammation and immune diseases in China. Paeoniflorin (Pae) is the major active component of TGP. Although TGP has few adverse drug reactions, the slow onset and low bioavailability of Pae limit its clinical use. Enhanced efficacy without increased toxicity is pursued in developing new agents for inflammation and immune diseases. As a result, paeoniflorin-6'-O-benzene sulfonate (CP-25) derived from Pae, is developed in our group, and exhibits superior bioavailability and efficacy than Pae. Here we describe the development process and research advance on CP-25. The pharmacokinetic parameters of CP-25 and Pae were compared in vivo and in vitro. CP-25 was also compared with the first-line drugs methotrexate, leflunomide, and hydroxychloroquine in their efficacy and adverse effects in arthritis animal models and experimental Sjögren's syndrome. We summarize the regulatory effects of CP-25 on inflammation and immune-related cells, elucidate the possible mechanisms, and analyze the therapeutic prospects of CP-25 in inflammation and immune diseases, as well as the diseases related to its potential target G-protein-coupled receptor kinases 2 (GRK2). This review suggests that CP-25 is a promising agent in the treatment of inflammation and immune diseases, which requires extensive investigation in the future. Meanwhile, this review provides new ideas about the development of anti-inflammatory immune drugs.

Topics: Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Glucosides; Humans; Immunologic Factors; Inflammation; Lymphocytes; Mononuclear Phagocyte System; Monoterpenes; Sjogren's Syndrome

Inflammatory disorders result from abnormal immune response and their incidence has increased recently. Thus, there is an urgent need to discover new treatments for inflammatory disorders. In recent years, the natural products contained in Chinese herbs have attracted much attention worldwide owing to their anti-inflammatory effects. Paeoniflorin (PF) is a bioactive compound purified from the Chinese herb Paeonia lactiflora and reports have recently emerged suggesting the great potential of P. lactiflora as an agent to counter inflammatory disorders. The anti-inflammatory effects of PF have been revealed by in vitro studies and in vivo animal experiments of different inflammatory disorders, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and asthma. This review systematically describes the recent progress of studies on the mechanism of PF and its therapeutic potential in inflammatory disorders.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Glucosides; Humans; Inflammation; Monoterpenes

Parkinson's disease (PD) is a degenerative neurological disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the brain. The loss of the dopaminergic projection from the SNpc deprives the striatum of dopamine and results in a myriad of motor signs, including tremor, rigidity and ataxia. Although the stimulus for the initiation of the degenerative process is not understood, 80% of the dopaminergic neurons in the SNpc must be lost before the clinical symptoms of the disease are observed. This suggests that the degenerative process is initiated many years before clinical presentation of the disease. The neurodegeneration observed in PD is accompanied by inflammatory processes, and it has been suggested that anti-inflammatory drugs may be useful in slowing disease progression once the clinical signs of PD have been observed. This review summarizes and evaluates the progress that has been made in this area of research since 2006.

Topics: Animals; Anti-Inflammatory Agents; Benzoates; Bridged-Ring Compounds; Diterpenes; Drug Evaluation, Preclinical; Glucosides; Humans; Inflammation; Monoterpenes; Parkinson Disease; Phenanthrenes; Purines

The pathophysiological mechanism of acute kidney injury (AKI) is complicated, and effective drugs are still lacking. Ferroptosis is a newly discovered regulatory cell death mode characterized by the lethal accumulation of iron and reactive oxygen species-(ROS-)-dependent lipid hydroperoxides. In recent years, ferroptosis has been confirmed to be involved in the progression of AKI. Paeoniflorin (PF) is a traditional Chinese medicine that has protective effects on a variety of kidney diseases including AKI. However, the mechanism by which PF attenuates AKI is unclear. We detected that PF attenuated serum biochemical markers, histological damage, ferroptosis and inflammation in a dose-dependent manner in a mouse AKI model with bilateral renal artery ischemia-reperfusion (IR). Hypoxia-reoxygenation (HR)-induced ferroptosis and inflammation was also inhibited by PF in human renal tubular epithelial cells (HK2). RNA sequence analysis revealed that PF inhibited ferroptosis in HK2 cells by upregulating Slc7a11 in the glutathione pathway after HR treatment. PF failed to further protect cells with specific knockdown of Slc7a11 from ferroptosis under HR conditions. Consequently, these data indicated that PF prevention of ferroptosis in AKI requires dependence on Slc7a11. This study provided a scientific basis for the clinical search for drugs to prevent IR induced AKI.

Topics: Acute Kidney Injury; Amino Acid Transport System y+; Animals; Disease Models, Animal; Ferroptosis; Humans; Hypoxia; Inflammation; Ischemia; Mice; Reperfusion Injury

Staphylococcus haemolyticus (S. haemolyticus) is one of the most common coagulase-negative staphylococci (CoNS) isolates from bovine mastitis. Paeoniflorin (PF) shows anti-inflammatory effects on different inflammatory diseases in vitro studies and in vivo animal experiments. In this study, the viability of bovine mammary epithelial cells (bMECs) was detected by the cell counting kit-8 experiment. Subsequently, bMECs were induced with S. haemolyticus, and the induction dosage was determined. The expression of pro-inflammatory cytokines and toll-like receptor (TLR2) and nuclear factor kappa-B (NF-κB) signaling pathway-related genes were investigated by quantitative real-time PCR. The critical pathway proteins were detected by western blot. The results showed that the multiplicity of infection (MOI; the ratio of bacteria to bMECs) 5:1 of S. haemolyticus for 12 h could cause cellular inflammation, which was selected to establish the inflammatory model. Incubation with 50 μg/ml PF for 12 h was the best intervention condition for cells stimulated by S. hemolyticus. Quantitative real-time PCR and western blot analysis showed that PF inhibited the activation of TLR2 and NF-κB pathway-related genes and the expression of related proteins. Western blot results showed that PF suppressed the expression of NF-κB unit p65, NF-κB unit p50, and MyD88 in bMECs stimulated by S. haemolyticus. The inflammatory response pathway and molecular mechanism caused by S. haemolyticus on bMECs are related to TLR2-mediated NF-κB signaling pathways. The anti-inflammatory mechanism of PF may also be through this pathway. Therefore, PF is expected to develop potential drugs against CoNS-induced bovine mastitis.

Topics: Animals; Anti-Inflammatory Agents; Cattle; Cattle Diseases; Epithelial Cells; Female; Inflammation; Mammary Glands, Animal; Mastitis, Bovine; NF-kappa B; Signal Transduction; Staphylococcus haemolyticus; Toll-Like Receptor 2; Toll-Like Receptors

Paeonia lactiflora Pall has been used in Chinese Medicine for thousands of years, especially having anti-inflammatory, sedative, analgesic and other ethnic pharmacological effects. Moreover, Paeoniflorin is the main active ingredient of the Paeonia lactiflora Pall, and most are used in the treatment of inflammation-related autoimmune diseases. In recent years, studies have found that Paeoniflorin has a therapeutic effect on a variety of kidney diseases.. Cisplatin (CIS) is limited in clinical use due to its serious side effects, such as renal toxicity, and there is no effective method for prevention. Paeoniflorin (Pae) is a natural polyphenol which has a protective effect against many kidney diseases. Therefore, our study is to explore the effect of Pae on CIS-induced AKI and the specific mechanism.. Firstly, CIS induced acute renal injury model was constructed in vivo and in vitro, and Pae was continuously injected intraperitoneally three days in advance, and then Cr, BUN and renal tissue PAS staining were detected to comprehensively evaluate the protective effect of Pae on CIS-induced AKI. We then combined Network Pharmacology with RNA-seq to investigate potential targets and signaling pathways. Finally, affinity between Pae and core targets was detected by molecular docking, CESTA and SPR, and related indicators were detected in vitro and in vivo.. In this study, we first found that Pae significantly alleviated CIS-AKI in vivo and in vitro. Through network pharmacological analysis, molecular docking, CESTA and SPR experiments, we found that the target of Pae was Heat Shock Protein 90 Alpha Family Class A Member 1 (Hsp90AA1) which performs a crucial function in the stability of many client proteins including Akt. RNA-seq found that the KEGG enriched pathway was PI3K-Akt pathway with the most associated with the protective effect of Pae which is consistent with Network Pharmacology. GO analysis showed that the main biological processes of Pae against CIS-AKI include cellular regulation of inflammation and apoptosis. Immunoprecipitation further showed that pretreatment with Pae promoted the Hsp90AA1-Akt protein-protein Interactions (PPIs). Thereby, Pae accelerates the Hsp90AA1-Akt complex formation and leads to a significant activate in Akt, which in turn reduces apoptosis and inflammation. In addition, when Hsp90AA1 was knocked down, the protective effect of Pae did not continue.. In summary, our study suggests that Pae attenuates cell apoptosis and inflammation in CIS-AKI by promoting Hsp90AA1-Akt PPIs. These data provide a scientific basis for the clinical search for drugs to prevent CIS-AKI.

Topics: Acute Kidney Injury; Cisplatin; HSP90 Heat-Shock Proteins; Humans; Inflammation; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

Macrophages M1 polarization involved in the process of renal inflammatory injury, is a well-established hallmark of chronic kidney disease (CKD). Paeoniflorin (PF), a water-soluble monoterpene glycoside extracted from Paeonia lactiflora, revealed renal anti-inflammatory activities in our previous study. However, the potential molecular mechanism of PF on CKD remains unknown.. The present study aims to investigate the regulation of PF on macrophage polarization in CKD.. A CKD model was established by cationic bovine serum albumin and a murine macrophage cell line RAW264.7 induced with lipopolysaccharide (LPS) were used to clarify the underlying mechanisms of PF in CKD.. Results showed that PF exhibited favorable protective effects on CKD model mice by promoting renal function, ameliorating renal pathological injury and podocyte damage. Furthermore, PF inhibited the infiltration of M1 macrophage marker CD68 and iNOS in kidney tissue, but increased the proportion of M2 macrophage marker CD206. In RAW264.7 cells stimulated with LPS, the levels of cytokines including IL-6, IL-1β, TNF-α, MCP-1 were lessened under PF treatment, while the levels of Arg1, Fizz1, IL-10 and Ym-1 were augmented. These results indicated that PF promoted macrophage polarization from M1 to M2 in vivo and in vitro. More importantly, PF repaired the damaged mitochondria through increasing mitochondrial membrane potential and reducing ROS accumulation. The mitophagy-related proteins PINK1, Parkin, Bnip3, P62 and LC3 were up-regulated by PF, accompanied by the incremental expressions of Krüppel-like transcription factor 4 (KLF4). Moreover, the promotion of mitophagy and inhibition of M1 macrophage polarization owing to PF were reversed by mitophagy inhibitor Mdivi-1 or silencing KLF4.. Overall, PF suppressed renal inflammation by promoting macrophage polarization from M1 to M2 and inducing mitophagy via regulating KLF4. It is expected to provide a new strategy for exploring the effects of PF in treating CKD.

Topics: Animals; Inflammation; Kidney; Lipopolysaccharides; Macrophages; Mice; Mitophagy; Monoterpenes; Nephritis; Renal Insufficiency, Chronic

Baojin Chenfei formula (BCF), a Chinese herbal formula, has significant effects on improving the clinical symptoms of patients with silicosis. However, its active compounds and the underlying mechanisms have not yet fully been elucidated.. This study aimed to explore the underlying mechanisms of BCF in treating silicosis.. The rat model of silicosis was developed via a single intratracheal instillation of SiO. BCF significantly alleviated SiO. Active compounds of BCF, such as glycyrrhetic acid and paeoniflorin, could suppress inflammatory response by the MAPK pathway and suppress fibroblast activation by the EGFR-PI3K-AKT pathway. These might be the mechanisms of BCF in treating silicosis.

Topics: Animals; Drugs, Chinese Herbal; ErbB Receptors; Fibrosis; Glycyrrhetinic Acid; Inflammation; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Silicon Dioxide; Silicosis

Asthma characterized by airway remodeling is a multiple pulmonary disease, which is associated with various physiological processes including inflammation reaction, immune response, oxidative stress and autophagy.. This study aimed to investigate whether these processes are modulated by the total glucosides of Paeonia lactiflora Pall (TGP), and its active compound paeoniflorin (PF) with anti-inflammatory and immune-regulatory effects could alleviate ovalbumin (OVA)-induced mouse asthma.. In vivo, models of mouse asthma were established by intraperitoneally with a mixture of OVA and aluminum hydroxide, plus a single nasal injected with OVA to female C57BL/6 mice. The results were observed with PET imaging, TEM, RT-PCR, western blotting. In vitro, CD4. TGP, either in its crude or processed form, and PF effectively ameliorated lung injury in mice induced by OVA, regulated immune/inflammatory response by inhibiting the release of pro-inflammatory cytokines, thereby decreasing Th2 cell proportion, inhibited oxidative stress by recovering mitochondrial membrane potential and regulating metabolic activity in dose-dependent manner. Moreover, PF could inhibit autophagy by regulating mitochondrial function. In addition, the therapeutic effects of TGP and PF on pulmonary injury in asthmatic mice were not affected by processing.. PF may be a valuable agent in ameliorating inflammation and immune response in asthmatic mice, and the possible mechanism involved in this response rang may from oxidative stress to autophagy.

Topics: Animals; Asthma; Autophagy; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Female; Glucosides; Immunity; Inflammation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monoterpenes; Ovalbumin; Oxidative Stress

Sepsis is caused by bacterial infections or viral infections. Clinically, there exist confirmed or highly suspected infection foci. Mortality caused by septic shock remains in a high rate even though antibiotic treatment works effectively. In this study, we treat THP-1 cells with 1 ug/mL LPS (lipopolysaccharide) and add paeoniflorin or LR-12 inhibitor. TREM-1 (triggering receptor expressed on myeloid cells-1), IL-6, IL-1

Topics: Glucosides; Humans; Inflammation; Lipopolysaccharides; Monoterpenes; NF-kappa B; THP-1 Cells; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha

Acute liver injury (ALI) is a poor prognosis and high mortality complication of sepsis. Paeoniflorin (PF) has remarkable anti-inflammatory effects in different disease models. Here, we explored the protective effect and underlying molecular mechanisms of PF against lipopolysaccharide (LPS)-induced ALI. Sprague-Dawley rats received intraperitoneal (i.p.) injection of PF for 7 days, 1 h after the last administration, and rats were injected i.p. 10 mg/kg LPS. PF improved liver structure and function, reduced hepatic reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels, and increased superoxide dismutase (SOD) activity. Western blot analysis suggested that PF significantly inhibited expression of inflammatory cytokines (TNF-α, IL-1β, and IL-18) and inhibited activation of the NLRP3 inflammasome. PF or mitochondrial ROS scavenger (mito-TEMPO) significantly improved liver mitochondrial function by scavenging mitochondrial ROS (mROS), restoring mitochondrial membrane potential loss and increasing level of ATP and enzyme activity of complex I and III. In addition, PF increased expression of sirtuin-1 (SIRT1), forkhead box O1 (FOXO1a) and manganese superoxide dismutase (SOD2), and increased FOXO1a nuclear retention. However, the inhibitor of SIRT1 (EX527) abolished the protective effect of PF. Taken together, PF promotes mROS clearance to inhibit mitochondrial damage and activation of the NLRP3 inflammasome via SIRT1/FOXO1a/SOD2 signaling.

Topics: Animals; Chemical and Drug Induced Liver Injury; Glucosides; Inflammasomes; Inflammation; Lipopolysaccharides; Liver; Monoterpenes; Nerve Tissue Proteins; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Sirtuin 1; Superoxide Dismutase

Topics: Animals; Cell Proliferation; Colitis; Complement C1q; Dextran Sulfate; Disease Models, Animal; Glucosides; Inflammation; Interleukin-10; Intestinal Mucosa; Macrophages; Mice; Mice, Inbred C57BL; Monoterpenes; Stem Cells

Treatment of chronic inflammatory pain remains a major goal in the clinic. It is thus of prime importance to characterize inherent pathophysiological pathways to design new therapeutic strategies and analgesics for pain management. Paeoniflorin (PF), a monoterpenoid glycoside from Paeonia lactiflora Pallas plants, possesses promising anti-nociceptive property. However, therapeutic effect and underlying mechanism of action of PF on inflammatory pain have not yet been fully elucidated. In this study, we aim to investigate the analgesic effect further and clarify its mechanism of action of PF on complete freund's adjuvant (CFA)-evoked inflammatory pain.. Twenty-four male mice were divided into 3 groups: sham, CFA, and CFA + PF groups (n = 8/group). Mice were treated with normal saline or PF (30 mg/kg) for 11 days. Footpad swelling (n = 8/group), mechanical (n = 8/group) and thermal hypersensitivity (n = 8/group) were measured to evaluate the analgesic effect of PF on CFA-injected mice. At the end of the animal experiment, blood and L4-L6 dorsal root ganglion neurons were collected to assess the therapeutic effect of PF on CFA-induced inflammatory pain. Next, hematoxylin and eosin, quantitative realtime PCR, ELISA, capsaicin and dimethyl succinate induced pain test (n = 8/group), motor coordination test (n = 8/group), tail flicking test (n = 8/group), pyruvate and succinate dehydrogenase assay (n = 6/group), immunohistochemical staining, were performed to clarify the action mechanism of PF on CFA-evoked inflammatory pain. Besides, the effect of PF on TRPV1 was evaluated by whole-cell patch clamp recording on primary neurons (n = 7). Finally, molecular docking further performed to evaluate the binding ability of PF to TRPV1.. PF significantly relieved inflammatory pain (P < 0.001) and paw edema (P < 0.001) on a complete Freund adjuvant (CFA)-induced peripheral inflammatory pain model. Furthermore, PF inhibited neutrophil infiltration (P < 0.01), IL-1β increase (P < 0.01), and pain-related peptide substance P release (P < 0.001). Intriguingly, CFA-induced succinate aggregation was notably reversed by PF via modulating pyruvate and SDH activity (P < 0.01). In addition, PF dampened the high expression of subsequent succinate receptor SUCNR1 (P < 0.01), HIF-1α (P < 0.05), as well as the activation of NLPR3 inflammasome (P < 0.05) and TRPV1 (P < 0.05). More importantly, both capsaicin and dimethyl succinate supplementation obviously counteracted the pain-relieving effect of PF and TRPV1 (P < 0.01 or P < 0.001).. Our findings suggest that PF can significantly relieve CFA-induced paw swelling, as well as mechanical and thermal hyperalgesia. PF alleviated inflammatory pain partly through inhibiting the activation of TRPV1 and succinate/SUCNR1-HIF-1α/NLPR3 pathway. Furthermore, we found that PF exerted its analgesic effect without affecting motor coordination and pain-related cold ion-channels. In summary, this study may provide valuable evidence for the potential application of PF as therapeutic strategy for inflammatory pain treatment.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Capsaicin; Freund's Adjuvant; Ganglia, Spinal; Glucosides; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Male; Mice; Monoterpenes; Neurons; Receptors, G-Protein-Coupled; Succinic Acid; TRPV Cation Channels

The activation of macrophages and the release of inflammatory cytokines are the main reasons for the progress of systemic lupus erythematosus (SLE). MicroRNA (miRNA)-124 is involved in the regulation of macrophages and is a key regulator of inflammation and immunity.. To explore whether paeoniflorin (PF) regulates the biological functions of macrophages depends on miR-124.. RT-PCR, WB, ELISA, CCK-8 and flow cytometry were used to evaluate that PF regulated the biological functions of THP-1 cells through miR-124.. PF significantly inhibited the proliferation while promotes the apoptosis of THP-1 cells, and inhibited the release of IL-6, TNF-α and IL-1βin THP-1 cells. RT-PCR results shown that PF up-regulated the expression of miR-124 in THP-1 cells. Functional recovery experiments showed that compared with the LPS + mimic-NC group, LPS + miR-124 mimic significantly inhibited the proliferation and the release of IL-6, TNF-α and IL-1β, but promoted the apoptosis of THP-1 cells. In addition, compared with the LPS + PF + inhibitor-NC group, LPS + PF + miR-124 inhibitor significantly promoted the proliferation and the release of IL-6, TNF-α and IL-1β, but inhibited the apoptosis of THP-1 cells.. By down-regulating miR-124, PF inhibits the proliferation and inflammation of THP-1 cells, and promotes the apoptosis of THP-1 cells.

Topics: Apoptosis; Cell Proliferation; Flow Cytometry; Gene Expression Regulation, Neoplastic; Glucosides; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Lupus Erythematosus, Systemic; Macrophages; MicroRNAs; Monoterpenes; Signal Transduction; Transcriptional Activation; Tumor Necrosis Factor-alpha

The role of Paeoniflorin on hepatic fibrosis and the specific mechanisms has not yet been elucidated. Therefore, we explored whether Paeoniflorin exerted protective effects on carbon tetrachloride (CCl4)-induced hepatic fibrosis and the underlying mechanisms.. A model of hepatic fibrosis was induced by intraperitoneally injecting with CCl4 (10% 5 μl/g) twice a week for 7 weeks. To explore the effects of Paeoniflorin, mice were treated with Paeoniflorin (100 mg/kg) by gavage once a day at 1 week after modeling until they were sacrificed.. Paeoniflorin remarkably improved liver function and histopathological changes of hepatic tissues in CCl4-induced liver injury. Besides, the serum MAO enzyme activity and hydroxyproline contents were notably decreased following the intervention of Paeoniflorin. The decreased expression of Vimentin, α-SMA, Col1a and Desmin manifested the inhibition of the hepatic stellate cells (HSCs) activation. Interestingly, Paeoniflorin intervention significantly upregulated the expression of heme oxygenase-1, and attenuated the inflammatory cytokines production as well as the CCl4-induced oxidative stress imbalance.. Paeoniflorin could effectively alleviate CCl4-induced hepatic fibrosis by upregulation of heme oxygenase-1, and it might be a new effective option for the comprehensive treatment of hepatic fibrosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbon Tetrachloride; Cytokines; Disease Models, Animal; Glucosides; Heme Oxygenase-1; Hepatic Stellate Cells; Inflammation; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Monoterpenes; Oxidative Stress; Up-Regulation

SiNiSan (SNS) is an ancient Chinese herbal prescription, and the current clinical treatment of irritable bowel syndrome (IBS) is effective. In the previous study of the research team, the multi-functional co-synergism of SNS against IBS was presented. Some potential drug targets and candidate ligands were predicted.. This study attempts to explore the crucial ingredient combinations from SNS formula and reveal their synergistic mechanism for IBS therapy.. In present study, a comprehensive strategy was performed to reveal IBS related pathways and biological modules, and explore synergistic effects of the ingredients, including ADME (absorption, distribution, metabolism, excretion) screening, Text mining, Venn analysis, Gene ontology (GO) analysis, Pathway cluster analysis, Molecular docking, Network construction and Experimental verification in visceral hypersensitivity (VHS) rats.. Three compressed IBS signal pathways were derived from ClueGO KEGG analysis of 63 IBS genes, including Neuroactive ligand-receptor interaction, Inflammatory mediator regulation of TRP (transient receptor potential) channels and Serotonergic synapse. A multi-module network, composed of four IBS therapeutic modules (psychological, inflammation, neuroendocrine and cross-talk modules), was revealed by Target-Pathway network. Nine kernel targets were considered closely associated with the IBS pathways, including ADRA2A, HTR2A, F2RL1, F2RL3, TRPV1, PKC, PKA, IL-1Β and NGF. In silico analysis revealed that three crucial ingredients (synephrine, paeoniflorin and naringin) were assumed to coordinate the network of those IBS therapeutic modules by acting on these kernel targets in the important pathways. In vivo experimental results showed that the crucial ingredient combinations synergistically affected the expressions of the kernel biological molecules, and improved the minimum capacity threshold of AWR in VHS rats.. The study proposes the important IBS associated pathways and the network regulation mechanisms of the crucial ingredients. It reveals the multi-target synergistic effect of the crucial ingredient combinations for the novel therapy on IBS.

Topics: Animals; Data Mining; Drugs, Chinese Herbal; Flavanones; Glucosides; Humans; Inflammation; Interleukin-6; Irritable Bowel Syndrome; Male; Molecular Docking Simulation; Monoterpenes; Proto-Oncogene Proteins c-raf; Rats, Sprague-Dawley; Signal Transduction; Synephrine; Transient Receptor Potential Channels

Paeoniflorin (PF) has been demonstrated to have an anti-allergic and anti-inflammatory effect in the treatment of allergic contact dermatitis (ACD). However, its clinical application is hampered by the lacking of comprehensive mechanical explanation. This research aimed to study the effect of PF on the proliferation, apoptosis and cytokines secretion as well as the expression of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways of T lymphocytes activation in vitro and in vivo. We found that PF depressed human T lymphocytes activation via inhibition ofinterferon-gamma (IFN-γ) production and NF-κB/IκBα and p38 MAPK signaling pathway in vitro, also PF could attenuate such ACD responses by inhibiting the production of IFN-γ and NF-κB/IκBα pathway in T lymphocytes of ACD mouse model, suggesting that PF might be useful for the treatment of T cell-mediated allergic inflammatory disorders such as ACD. This would make PF a promising T cell-targeted drug candidate for further study because of its immunosuppressive and anti-inflammatory effects.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Dermatitis, Allergic Contact; Disease Models, Animal; Glucosides; Humans; Inflammation; Interferon-gamma; Monoterpenes; NF-kappa B; NF-KappaB Inhibitor alpha; Signal Transduction; T-Lymphocytes

Lipopolysaccharide (LPS) is a toxic component of the outer membrane of gram-negative bacteria that can activate the blood coagulation system, leading to disseminated intravascular coagulation (DIC). DIC is a syndrome characterized by thromboembolism and multiple organ failure. Herein, the beneficial effect of paeoniflorin (PF) on the alleviation of LPS-induced DIC was investigated with an experimental DIC mouse model. Briefly, mice were randomly divided into the following six groups: (1) control; (2) LPS; (3) heparin; (4) low-PF treatment; (5) medium-PF treatment; and (6) high-PF treatment. The histological morphology of the liver and kidney was observed, and the coagulation indicators (such as prothrombin time), function indicators (such as alanine transferase), and inflammatory factors (such as TNF-α) were detected. Additionally, an in vitro cell inflammation model using RAW 264.7 murine macrophages was established. Activation of the nuclear factor kappa B (NF-κB) signaling pathway and tumor necrosis factor-α (TNF-α) were determined by western blotting. Based on our findings, PF could significantly improve the histological morphology of the liver and kidney, indicating that PF protects the liver and kidney against damage induced by LPS. Additionally, PF improved the function and coagulation indicators and reduced the production of inflammatory factors. In vitro, PF inhibited the expression of TNF-α by suppressing NF-κB signaling pathway activation. Collectively, our findings support the hypothesis that PF has anti-inflammatory and anticoagulation effects for the alleviation of LPS-induced DIC. PF is thus a potential co-treatment option for DIC.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Blood Coagulation; Disease Models, Animal; Disseminated Intravascular Coagulation; Glucosides; Inflammation; Lipopolysaccharides; Macrophages; Mice; Monoterpenes; NF-kappa B; RAW 264.7 Cells; Signal Transduction; Tumor Necrosis Factor-alpha

LPS has been widely used to induce inflammatory pain, attributing to production of inflammatory cytokines and sensitization of nociceptors. Paeoniflorin (PF) possesses anti-nociceptive property, but its effect on LPS-induced inflammatory pain has not been investigated. In this study, we aimed to investigate the analgesic effect of PF on an inflammatory pain mouse model and explore the underlying mechanisms. LPS-induced inflammatory pain model was established in C57BL/6J mice after PF treatment. Then, thermal hyperalgesia, neutrophil infiltration, inflammatory cytokine production, intracellular Ca

Topics: Animals; Calcium; Cytokines; Edema; Glucosides; Inflammasomes; Inflammation; Inflammation Mediators; Lipopolysaccharides; Macrophages; Male; Mice, Inbred C57BL; Models, Biological; Monoterpenes; Neutrophils; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Nociception; Pain; Protein Kinase C; Transcription, Genetic; TRPV Cation Channels

There are challenges in the treatment of chronic inflammatory diseases of oral mucosa. Both paeoniflorin (PF) and baicalin (BAI) exert anti-inflammatory effects, but the mechanism underlying their combined effects is still unclear. Here, we explored the anti-inflammatory function of the PF-BAI combination in the oral inflammatory response.. The CCK-8 assay was used to determine the proliferative capacity of HOKs with PF and BAI. Enzyme-linked immunosorbent (ELISA), Western blotting, reverse transcription polymerase chain reaction, and confocal immunofluorescence were performed to study the anti-inflammatory effects of PF-BAI in LPS-stimulated human oral keratinocytes (HOKs). Immunohistochemistry and ELISA were performed to detect the levels of NF-κB p65, IKKα and IL-6, TNF-α in OLP and healthy tissues.. Compared to PF or BAI alone, the combination of PF-BAI at 5 µg/ml downregulated secretion of inflammatory cytokines more effectively (p < .05). Combined PF-BAI decreased NF-κB p65 and IκBα protein phosphorylation, leading to reduce nuclear translocation of NF-κB p65. Higher expression of TNF-α, IL-6, NF-κB p65, and IKKα were observed in OLP than in HC tissues (p < .01).. The optimal combination concentration of PF and BAI at 5 µg/ml may have a positive effect on the treatment of oral inflammatory diseases, providing a novel therapeutic approach.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Flavonoids; Glucosides; Humans; Inflammation; Inflammation Mediators; Lichen Planus, Oral; Lipopolysaccharides; Monoterpenes; NF-kappa B; Periodontitis

Inflammatory bowel disease (IBD) in humans is closely related to bacterial infection and the disruption of the intestinal barrier. Paeoniflorin (PF), a bioactive compound from Paeonia lactiflora Pallas plants, exerts a potential effect of anti-inflammatory reported in various researches. However, the effect of PF on intestinal barrier function and its related mechanisms has not been identified. Here, we investigate the PF potential anti-inflammatory effect on lipopolysaccharide (LPS)-stimulated human Caco-2 cell monolayers and explore its underlying key molecular mechanism. In this context, PF significantly increased TEER value, decreased intestinal epithelium FITC-dextran flux permeability, and restored the expressions of occludin, ZO-1, and claudin5 in LPS-induced Caco-2 cell. In vitro, treatment of PF significantly inhibited LPS-induced expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9). In addition, we found that PF suppressed nuclear factor kappa B (NF-κB) signaling via activating the Nrf2/HO-1 signaling pathways in ILPS-stimulated Caco-2 cells. Our findings indicate that PF has an inhibitory effect on endothelial injury. Our findings suggested that PF has an anti-inflammatory effect in ILPS-stimulated Caco-2 cells, which might be a potential therapeutic agent against IBD and intestinal inflammation.

Topics: Anti-Inflammatory Agents; Caco-2 Cells; Glucosides; Humans; Inflammation; Intestinal Mucosa; Intestines; Lipopolysaccharides; Monoterpenes; Permeability; Unilamellar Liposomes

Hyperglycemia fluctuation is associated with diabetes mellitus (DM) complications when compared to persistent hyperglycemia. Previous studies have shown that paeoniflorin (PF), through its antiapoptosis, anti-inflammation, and antithrombotic properties, effectively protects against cardiovascular and cerebrovascular disease. However, the mechanism underlying the protection from PF against vascular injuries induced by hyperglycemia fluctuations remains poorly understood. Herein, we investigated the potential protective role of PF on human umbilical vein endothelial cells (HUVECs) subjected to intermittent glucose levels

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Diabetes Mellitus, Experimental; Disease Models, Animal; Glucosides; Human Umbilical Vein Endothelial Cells; Humans; Hyperglycemia; Inflammation; Male; Monoterpenes; Oxidative Stress; Protective Agents; Protein Kinase C beta; Rats, Sprague-Dawley; Vascular System Injuries

Postoperative pain is a common form of acute pain that, if not managed effectively, can become chronic pain. Evidence has shown that glia, especially microglia, mediate neuroinflammation, which plays a vital role in pain sensitization. Moreover, toll-like receptor 4 (TLR4), the tumor necrosis factor receptor (TNF-R), the interleukin-1 receptor (IL-1R), and the interleukin-6 receptor (IL-6R) have been considered key components in central pain sensitization and neuroinflammation. Therefore, we hypothesized that activation of the body's endogenous "immune brakes" will inhibit these receptors and achieve inflammation tolerance as well as relieve postoperative pain. After searching for potential candidates to serve as this immune brake, we identified and focused on the suppressor of cytokine signaling 3 (SOCS3) gene. To regulate SOCS3 expression, we used paeoniflorin to induce heat shock protein 70 (HSP70)/TLR4 signaling. We found that paeoniflorin significantly induced SOCS3 expression both in vitro and in vivo and promoted the efflux of HSP70 from the cytoplasm to the extracellular environment. Furthermore, paeoniflorin markedly attenuated incision-induced mechanical allodynia, and this effect was abolished by small interfering RNAs targeting SOCS3. These findings demonstrated an effective and safe strategy to alleviate postoperative pain.

Topics: Animals; Cytokines; Drug Tolerance; Glucosides; HSP70 Heat-Shock Proteins; Hyperalgesia; Inflammation; Mice; Microglia; Monoterpenes; Neuralgia; Neuroglia; Neuroimmunomodulation; Pain, Postoperative; Rats; Rats, Sprague-Dawley; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Toll-Like Receptor 4

Paeoniflorin (PF) is known to have anti-inflammatory and paregoric effects, but the mechanism underlying its analgesic effect remains unclear. The aim of this study was to clarify the effect of PF on Freund's complete adjuvant (CFA)-induced inflammatory pain and explore the underlying molecular mechanism.. An inflammatory pain model was established by intraplantar injection of CFA in C57BL/6J mice. After intrathecal injection of PF daily for 8 consecutive days, thermal and mechanical withdrawal thresholds, the levels of inflammatory factors TNF-α, IL-1β and IL-6, microglial activity, and the expression of Akt-NF-κB signaling pathway in the spinal cord tissue were detected by animal ethological test, cell culture, enzyme-linked immunosorbent assay, immunofluorescence histochemistry, and western blot.. PF inhibited the spinal microglial activation in the CFA-induced pain model. The production of proinflammatory cytokines was decreased in the central nervous system after PF treatment both in vivo and in vitro. PF further displayed a remarkable effect on inhibiting the activation of Akt-NF-κB signaling pathway in vivo and in vitro.. These results suggest that PF is a potential therapeutic agent for inflammatory pain and merits further investigation.

Topics: Actin Cytoskeleton; Animals; Anti-Inflammatory Agents; Cell Line; Central Nervous System; Disease Models, Animal; Freund's Adjuvant; Glucosides; Inflammation; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Microglia; Monoterpenes; NF-kappa B; Pain; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Necrosis Factor-alpha

Diabetic retinopathy (DR) is a serious-threatening complication of diabetes and urgently needed to be treated. Evidence has accumulated indicating that microglia inflammation within the retina plays a critical role in DR. Microglial matrix metalloproteinase 9 (MMP-9) has an important role in the destruction of the integrity of the blood-retinal barrier (BRB) associated with the development of DR. MMP-9 was also considered important for regulating inflammatory responses. Paeoniflorin, a monoterpene glucoside, has a potent immunomodulatory effect on microglia. We hypothesized that paeoniflorin could significantly suppress microglial MMP-9 activation induced by high glucose and further relieve DR. BV2 cells were used to investigate the effects and mechanism of paeoniflorin. The activation of MMP-9 was measured by gelatin zymography. Cell signaling was measured by western blot assay and immunofluorescence assay. High glucose increased the activation of MMP-9 in BV2 cells, which was abolished by HMGB1, TLR4, p38 MAPK, and NF-κB inhibition. Phosphorylation of p38 MAPK induced by high glucose was decreased by TLR4 inhibition in BV2 cells. Paeoniflorin induced suppressor of cytokine signaling 3 (SOCS3) expression and reduced MMP-9 activation in BV2 cells. The effect of paeoniflorin on SOCS3 was abolished by the TLR4 inhibitor. In streptozotocin (STZ)-induced diabetes mice, paeoniflorin induced SOCS3 expression and reduced MMP-9 activation. Paeoniflorin suppressed STZ-induced IBA-1 and IL-1β expression and decreased STZ-induced high blood glucose level. In conclusion, paeoniflorin suppressed high glucose-induced retinal microglia MMP-9 expression and inflammatory response via inhibition of the TLR4/NF-κB pathway through upregulation of SOCS3 in diabetic retinopathy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Diabetic Retinopathy; Glucose; Glucosides; Inflammation; Matrix Metalloproteinase 9; Mice; Microglia; Monoterpenes; NF-kappa B; Retina; Suppressor of Cytokine Signaling 3 Protein; Toll-Like Receptor 4

Paeoniflorin is traditionally used to treat inflammatory disorders. In our laboratory, we have scientifically validated the anti-inflammatory effect of paeoniflorin. In this study, it has been aimed to evaluate in vivo anti-inflammatory effect of paeoniflorin isolated from the dried peeled root of Paeonia lactiflora Pall. It was further intended to find out the probable mechanism of anti-inflammatory effect of paeoniflorin. The anti-inflammatory effect of paeoniflorin (15, 30 and 45mg/kg) was measured employing TNBS-induced ulcerative colitis model of acute inflammation. The TNBS injection resulted significant colitis formation when compared with un-injected mice. The anti-inflammatory effects of paeoniflorin for ulcerative colitis were assessed by body weight, colonic weight and length, macroscopic scores, and histopathological examinations. In addition, the colonic tissue levels of inflammation markers, including myeloperoxidase (MPO), IL-2, IL-6, IL-10, IL-12, IL-1β, TNF-α and IFN-γ were also determined to assess the effect of paeoniflorin. In addition, western blot demonstrated that paeoniflorin inhibited NF-kappaB signaling pathway and apoptosis in TNBS-induced ulcerative colitis tissues. In conclusion, all the findings of this study suggested that paeoniflorin has the anti-inflammatory effect in ulcerative colitis via inhibiting MAPK/NF-kappaB pathway and apoptosis in mice.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Colitis, Ulcerative; Colon; Cytokines; Extracellular Signal-Regulated MAP Kinases; Glucosides; Humans; Inflammation; Male; Mice; Mice, Inbred BALB C; Monoterpenes; NF-kappa B; Paeonia; Signal Transduction; Trinitrobenzenesulfonic Acid

Paeoniflorin, a type of bioactive monoterpene glucoside in Paeoniae Radix, possesses anti-oxidative, anti-inflammatory and anti-hyperglycaemic properties. However, the underlying mechanism of paeoniflorin in treating atherosclerosis is unclear. A rat model of high-fat diet-induced atherosclerosis and palmitic acid (PA)-treated vascular smooth muscle cells (VSMCs) were used in this study. The serum concentrations of total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) were determined, and the results indicated that paeoniflorin remarkably lowered the levels of TC, TG and LDL-C induced by a high-fat diet. Histopathological results showed that paeoniflorin significantly improved the pathological changes in the aorta. In addition, paeoniflorin also maintained a normal weight gain speed. Subsequently, the effects of paeoniflorin on the production of inflammatory cytokines (IL-1β, IL-6 and TNF-α) were detected by qPCR and ELISA. The qPCR and ELISA results showed that paeoniflorin decreased the levels of these inflammatory cytokines. Moreover, the expression of TLR4 and its downstream pathway molecules was measured by Western blot. The results indicated that paeoniflorin significantly reduced the expression of TLR4 and MyD88 as well as the phosphorylation of IκBα and NF-κB p65. Taken together, these results suggested that paeoniflorin could alleviate atherosclerotic inflammation by inhibiting the TLR4/MyD88/NF-κB pathway. Therefore, paeoniflorin may be a potential therapy for atherosclerosis.

Topics: Animals; Atherosclerosis; Diet, High-Fat; Glucosides; Inflammation; Monoterpenes; Myeloid Differentiation Factor 88; NF-kappa B; Rats; Toll-Like Receptor 4

Topics: 1-Naphthylisothiocyanate; Animals; Bile; Biomarkers; Carrier Proteins; Cholestasis; Edema; Glucosides; Inflammation; Liver; Liver Function Tests; Male; Monoterpenes; Necrosis; Neutrophil Infiltration; NF-kappa B; Rats; Rats, Sprague-Dawley

Paeoniflorin, the main active component of the peony plant, exerts various pharmacological effects. Recently, research on the effect of paeoniflorin on the nervous system has gained more attention. The aim of the present study was to determine whether paeoniflorin exerts a protective effect that improves Alzheimer's disease (AD) via inflammation and apoptosis in the cerebral cortex of a transgenic mouse model of AD. Transgenic mice were used to construct the model of AD and were treated with paeoniflorin. The Morris water maze test was used to analyze cognitive function in AD mice. The protein expression levels of nuclear factor‑κB, tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6 and caspase‑3 were examined with commercial kits. Expression levels of B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax), phosphorylated (p)‑Akt and p‑p38 mitogen‑activated protein kinase (p‑p38 MAPK) in AD were evaluated by western blotting. The neuroprotective effects of paeoniflorin significantly improved cognitive function and ameliorated patterns of escape distance and escape latency in AD mice. Furthermore, the effects of paeoniflorin decreased inflammation and caspase‑3 activity, and inhibited cell death via increasing the Bcl‑2/Bax ratio and p‑Akt expression levels, and downregulating p‑p38 MAPK expression in AD mice.

Topics: Alzheimer Disease; Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cerebral Cortex; Cognition; Disease Models, Animal; Glucosides; Inflammation; Mice, Transgenic; Monoterpenes; Neuroprotective Agents; Phosphorylation; Proto-Oncogene Proteins c-akt

The study is to investigate the effects of paeoniflorin (PA) on renal function in cyclophosphamide-induced mice. Mice were injected with intraperitoneal cyclophosphamide (CYP, 200mg/kg) or saline respectively. Mice were treated with PA (15, 30mg/kg/day) or vehicle for the next 7 days. Then, mice were sacrificed to analyze the biochemical, histological parameters and mechanism research. Our results shown that PA significantly decreased the urine levels of uric acid and creatinine, serum and kidney levels of cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), PA also obviously attenuated the histological changes of the kidney tissues caused by CYP. Moreover, Western blot demonstrated that PA increased the AMPK levels and inhibited NF-κB signaling pathway and apoptosis in CYP-stimulated kidney tissues. In conclusion, PA might be considered as an effective agent in the amelioration of the kidney toxicity resulting from CYP treatment.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cyclophosphamide; Dose-Response Relationship, Drug; Glucosides; Inflammation; Kidney; Male; Mice; Mice, Inbred BALB C; Monoterpenes

Paeoniflorin (PF) is the main active component of the commonly used Traditional Chinese Medicine peony, Paeonia Suffruticosa. PF has diverse biological functions and exhibits anti‑oxidative, anti‑inflammatory and anti‑apoptotic activity. Inducible nitric oxide synthase (iNOS) is a catalyzing enzyme that is involved in the synthesis of nitric oxide (NO). NO has an important regulatory role in the cardiovascular, immune and nervous systems. PF has previously been demonstrated to inhibit the gene expression of iNOS. The present study aimed to identify a potentially novel cytoprotective function of PF, and to elucidate its effects against myocardial ischemic damage in a rat model of acute myocardial infarction (AMI). PF was able to significantly decrease the myocardial infarct size as well as the activities of creatine kinase (CK), the MB isoenzyme of CK, lactate dehydrogenase and cardiac troponin T. In addition, in the PF‑treated groups, the expression levels of tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6 and nuclear factor‑κB were markedly inhibited. Furthermore, treatment with PF inhibited the activities and protein expression levels of iNOS. Decreased caspase‑3 and caspase‑9 activities were also observed in the AMI rat model treated with various doses of PF. The results of the present study indicated that the cardioprotective effects of PF may be associated with the inhibition of inflammation and iNOS signaling pathways.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Caspase 3; Caspase 9; Creatine Kinase; Creatine Kinase, MB Form; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Glucosides; Inflammation; L-Lactate Dehydrogenase; Medicine, Chinese Traditional; Monoterpenes; Myocardial Infarction; NF-kappa B; Nitric Oxide Synthase Type II; Paeonia; Rats; Rats, Sprague-Dawley; Signal Transduction; Troponin T

Alzheimer's disease (AD) is associated with the inflammatory response in response to amyloid β-peptide (Aβ). Previous studies have suggested that paeoniflorin (PF) shows anti-inflammatory and neuroprotective effects in inflammation-related diseases. However, the impacts of PF on AD have not been investigated. In the present study, we showed that a 4-week treatment with PF could significantly inhibit Aβ burden, Aβ-induced over activation of astrocytes and microglia, downregulation of proinflammatory cytokines, and upregulation of anti-inflammatory cytokines in the brain. In addition, we demonstrated that chronic treatment with PF inhibited the activation of glycogen synthase kinase 3β (GSK-3β) and reversed neuroinflammtory-induced activation of nuclear factor-kappa B (NF-κB) signaling pathways. Moreover, PF exerted inhibitory effects on NALP3 inflammasome, caspase-1, and IL-1β. Collectively, in the present study, we demonstrated that PF exhibits neuroprotective effects in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice via inhibiting neuroinflammation mediated by the GSK-3β and NF-κB signaling pathways and nucleotide-binding domain-like receptor protein 3 inflammasome. Thus, these results suggest that PF might be useful to intervene in development or progression of neurodegeneration in AD through its anti-inflammatory and anti-amyloidogenic effects.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Glucosides; Inflammation; Inflammation Mediators; Male; Memory Disorders; Mice; Mice, Transgenic; Monoterpenes; Paeonia; Plaque, Amyloid; Presenilin-1

Paeonia lactiflora Pall is one of the most well-known herbs in China, Korea, and Japan for more than 1,200 years. Paeoniflorin, the major bioactive component of peony root, has recently been reported to have anticolitic activity. However, the underlying molecular mechanism is unclear. The present study was to explore the possible mechanism of paeoniflorin in attenuating dextran sulfate sodium (DSS)-induced colitis. Pre- and coadministration of paeoniflorin significantly reduced the severity of colitis and resulted in downregulation of several inflammatory parameters in the colon, including the activity of myeloperoxidase (MPO), the levels of TNF-α and IL-6, and the mRNA expression of proinflammatory mediators (MCP-1, Cox2, IFN-γ, TNF-α, IL-6, and IL-17). The decline in the activation of NF-κB p65, ERK, JNK, and p38 MAPK correlated with a decrease in mucosal Toll-like receptor 4 (TLR4) but not TLR2 or TLR5 expression. In accordance with the in vivo results, paeoniflorin downregulated TLR4 expression, blocked nuclear translocation of NF-κB p65, and reduced the production of IL-6 in LPS-stimulated mouse macrophage RAW264.7 cells. Transient transfection assay performed in LPS-stimulated human colon cancer HT-29 cells indicated that paeoniflorin inhibits NF-κB transcriptional activity in a dose-dependent manner. TLR4 knockdown and overexpression experiments demonstrated a requirement for TLR4 in paeoniflorin-mediated downregulation of inflammatory cytokines. Thus, for the first time, the present study indicates that paeoniflorin abrogates DSS-induced colitis via decreasing the expression of TLR4 and suppressing the activation of NF-κB and MAPK pathways.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Biological Availability; Bridged-Ring Compounds; Colitis; Dextran Sulfate; Drugs, Chinese Herbal; Gene Expression Profiling; Glucosides; HT29 Cells; Humans; Inflammation; Interleukin-6; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; Models, Animal; Monoterpenes; NF-kappa B; Paeonia; Peroxidase; Protein Biosynthesis; Toll-Like Receptor 4; Transcriptional Activation; Tumor Necrosis Factor-alpha

Cardiac remodeling is a key determinant in the clinical course and outcome of heart failure and characterized by cardiac hypertrophy, fibrosis, cardiomyocyte apoptosis and inflammation. The anti-inflammatory, anti-apoptotic and anti-fibrotic effects of paeoniflorin have been identified in various types of tissue and cells. However, the role of paeoniflorin in cardiac remodeling remains unclear. We performed aortic banding (AB) in mice to induce a cardiac remodeling model in response to pressure overload. Paeoniflorin (20 mg/kg) was administered by daily intraperitoneal (i.p.) injection. Paeoniflorin treatment promoted the survival rate and improved cardiac function of mice at 8 weeks post surgery. AB-induced cardiac hypertrophy, as assessed by heart weight, gross heart, HE and WGA staining, cross-sectional area of cardiomyocyte and mRNA expresssion of hypertrophic makers, was attenuated by paeoniflorin. Paeoniflorin also inhibited collagen deposition, expression of TGFβ, CTGF, collagen Iα and collagen IIIα, and phosphorylation of Smad2 and Smad3 in the heart exposed to pressure overload. Cardiomyocyte apoptosis and induction of Bax and cleaved caspase3 in response to AB were suppressed by paeoniflorin. Furthermore, paeoniflorin decreased the quantity of CD68+ cells, protein levels of TNF-α and IL-1β, and phosphorylation of IκBα and NFκB-p65 in the heart after AB. In conclusion, paeoniflorin attenuated cardiac hypertrophy, fibrosis, apoptosis and inflammation, and improved left ventricular function in pressure overloaded mice. The cardioprotective effect of paeoniflorin is associated with the inhibition of TGFβ/Smads and NF-κB pathways.

Topics: Animals; Apoptosis; Benzoates; Biomarkers; Bridged-Ring Compounds; Cardiomegaly; Fibrosis; Glucosides; Heart; Inflammation; Male; Mice; Mice, Inbred C57BL; Monoterpenes; Myocytes, Cardiac; NF-kappa B; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Ventricular Function, Left; Ventricular Remodeling

Chronic activation of microglial cells endangers neuronal survival through the release of various proinflammatory and neurotoxic factors. Paeoniflorin (PF), a water-soluble monoterpene glycoside found in the root of Paeonia lactiflora Pall, has a wide range of pharmacological functions, such as anti-oxidant, anti-inflammatory, and anti-cancer effects. Neuroprotective potential of PF has also been demonstrated in animal models of neuropathologies. Here, we have examined the efficacy of PF in the repression of inflammation-induced neurotoxicity and microglial inflammatory response. In organotypic hippocampal slice cultures, PF significantly blocked lipopolysaccharide (LPS)-induced hippocampal cell death and productions of nitric oxide (NO) and interleukin (IL)-1β. PF also inhibited the LPS-stimulated productions of NO, tumor necrosis factor-α, and IL-1β from primary microglial cells. These results suggest that PF possesses neuroprotective activity by reducing the production of proinflammatory factors from activated microglial cells.

Topics: Animals; Anti-Inflammatory Agents; Benzoates; Brain; Bridged-Ring Compounds; Cell Death; Glucosides; Hippocampus; Immunologic Factors; Inflammation; Interleukin-1beta; Lipopolysaccharides; Microglia; Monoterpenes; Neuroprotective Agents; Nitric Oxide; Rats; Tumor Necrosis Factor-alpha

Paeoniflorin (PF) extracted from the root of Paeonia lactiflora pall, displays anti-inflammation properties in several animal models. Adhesion molecules are important for the recruitment of leucocyte to the vessel wall and involved in the pathogenesis of various autoimmune and inflammatory diseases. Herein, we investigate the effects of PF on adhesion molecule expression in a mouse model of cutaneous Arthus reaction and cultured human dermal microvascular endothelial cells (HDMECs). We showed that PF significantly ameliorated the immune complex (IC) induced vascular damage, leucocyte infiltrates and adhesion molecules expression. Furthermore, PF markedly blocked tumor necrosis factor-α (TNF-α)-induced E-selectin and intercellular adhesion molecule-1 (ICAM-1) expression in HDMECs at both mRNA and protein levels. PF also suppressed TNF-α-induced adhesion of polymorphonuclear leucocytes (PMNs) to HDMECs. Finally, western blot data revealed that PF can inhibit the phosphorylation of p38, JNK in TNF-α-treated HDMECs. These data suggest that PF, as an anti-inflammatory agent, can downregulate adhesion molecules expression. PF may be a candidate medicine for the treatment of IC-induced inflammatory response.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigen-Antibody Complex; Arthus Reaction; Autoimmunity; Benzoates; Bridged-Ring Compounds; Cell Adhesion; Cells, Cultured; Disease Models, Animal; E-Selectin; Endothelial Cells; Gene Expression Regulation; Glucosides; Humans; Inflammation; Intercellular Adhesion Molecule-1; Leukocytes; Male; MAP Kinase Kinase 4; Mice; Mice, Inbred BALB C; Microcirculation; Monoterpenes; p38 Mitogen-Activated Protein Kinases; Real-Time Polymerase Chain Reaction; Skin; Tumor Necrosis Factor-alpha; Vascular Diseases

Paeonia suffruticosa, an important traditional herbal medicine, has been reported to prevent the pathogenesis of diabetic nephropathy through modulating advanced glycation end products-induced inflammatory and oxidative stress responses. However, little was known about the protective effect of the two major compounds in P. suffruticosa, paeoniflorin and oxypaeoniflora, on advanced glycation end products-induced mesangial cell damage. In the present study, we investigated the protective activities of paeoniflorin and oxypaeoniflora on advanced glycation end product-induced oxidative stress and inflammation in mesangial cells HBZY-1. The IC50 values of paeoniflorin and oxypaeoniflora for inhibiting 2,2'-azinobis-(3-thylbenzothiazoline-6-sulfonic acid) formation were 4.197 × 10-4 M and 1.002 × 10-4 M, respectively. The pretreatment with paeoniflorin and oxypaeoniflora (10-8-10-4 M) significantly increased advanced glycation end product-induced glutathione peroxidase and catalase activities. In the coculture system of HBZY-1 and macrophages, paeoniflorin and oxypaeoniflora could inhibit remarkably the migration of macrophages. Furthermore, paeniflorin and oxypaeniflora attenuated markedly advanced glycation end products-induced inflammation cytokines interleukin-6 and monocyte chemoattractant protein-1 levels in ELISA and western blot analysis in a dose-dependent manner. Taken together, our data provided the reliable evidence that paeniflorin and oxypaeniflora were able to attenuate advanced glycation end products-induced oxidative damage and inflammation in mesangial cells. Paeniflorin and oxypaeniflora might therefore have a beneficial effect in the treatment of diabetic nephropathy.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Benzoates; Bridged-Ring Compounds; Catalase; Chemokine CCL2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Glucosides; Glutathione Peroxidase; Glycation End Products, Advanced; Inflammation; Inhibitory Concentration 50; Interleukin-6; Macrophages; Mesangial Cells; Monoterpenes; Oxidative Stress; Paeonia; Phytotherapy; Rats

TNFα plays an important role in the adipocyte dysfunction, including lipolysis acceleration, insulin resistance and changes of adipokines. Recently, we showed that paeoniflorin attenuates adipocyte lipolysis and inhibits the phosphorylation of ERK, JNK, IKK stimulated by TNFα. However, the effects of paeoniflorin on adipocytes insulin resistance and changes of adipokines remain unknown. The aim of the current study was to investigate the role of paeoniflorin in preventing insulin resistance or inflammation in 3T3-L1 adipocytes treated with TNFα. Our results showed that paeoniflorin restored insulin-stimulated [(3)H]2-DOG uptake, which was reduced by TNFα, with concomitant restoration in serine phosphorylation of IRS-1 and insulin-stimulated phosphorylation of AKT in adipocytes. Paeoniflorin attenuated TNFα-mediated suppression of the expressions of PPARγ and PPARγ target genes, and the improvement of paeoniflorin on TNFα-induced insulin resistance was attenuated by GW9662, an antagonist of PPARγ activity. Moreover, paeoniflorin could inhibit the expressions and secretions of IL-6 and MCP-1 from adipocytes induced by TNFα. These results, together with our previous data, indicate that paeoniflorin exerts a beneficial effect on adipocytes to prevent TNFα-induced insulin resistance and inflammatory adipokine release. Our studies provide important evidence for an ability of paeoniflorin in amelioration of TNFα-induced adipocyte dysfunction, which would be helpful to clarify its potential role in the treatment of obesity.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Anilides; Animals; Benzoates; Bridged-Ring Compounds; Chemokine CCL2; Drugs, Chinese Herbal; Gene Expression; Glucose; Glucosides; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Interleukin-6; Mice; Monoterpenes; Obesity; Paeonia; Phosphorylation; PPAR gamma; Proto-Oncogene Proteins c-akt; Tumor Necrosis Factor-alpha

Obesity is associated with a state of chronic, low-grade inflammation. It is considered that the paracrine loop involving free fatty acid (FFA) and tumor necrosis factor (TNF)α between adipocytes and macrophages establishes an inflammatory vicious cycle that augments the inflammatory changes and insulin resistance in obese adipose tissue. Paeoniflorin (PF), one of the major components of Paeony root, has been shown to have anti-inflammatory effects in vivo. We investigated the effect of PF on the production of FFA and TNFα in the interaction between adipocytes and macrophages. Coculture of 3T3-L1 adipocytes and RAW 264.7 macrophages markedly enhanced the production of TNFα and FFA compared with the control cultures, however, treatment with PF dose-dependently inhibited the production. We further examined the effects of PF on TNFα-stimulated adipocyte lipolysis and on FFA-induced macrophage TNFα expression. PF inhibited TNFα-stimulated adipocyte lipolysis in a dose-dependent manner, which was compatible with suppressed phosphorylation of TNFα-activated ERK1/2 and preserved downregulation of perilipin. Palmitate, one of the most important saturated FFAs, induced macrophage TNFα upexpression, but PF partially attenuated the effect. These results indicate that PF exhibits anti-inflammatory properties by inhibiting the vicious cycle between adipocytes and macrophages. PF may be useful for ameliorating the inflammatory changes in obese adipose tissue.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Bridged-Ring Compounds; Cell Line; Fatty Acids, Nonesterified; Glucosides; Inflammation; Insulin Resistance; Lipolysis; Macrophages; Mice; Monoterpenes; Tumor Necrosis Factor-alpha

Paeoniflorin (PF), the principal component of Paeoniae Radix prescribed in traditional Chinese medicine, has been reported to exhibit many pharmacological effects including protection against ischemic injury. However, the mechanisms underlying the protective effects of PF on cerebral ischemia are still under investigation. The present study showed that PF treatment for 14 days could significantly inhibit transient middle cerebral artery occlusion (MCAO)-induced over-activation of astrocytes and microglia, and prevented up-regulations of pro-inflamamtory mediators (TNFα, IL-1β, iNOS, COX(2) and 5-LOX) in plasma and brain. Further study demonstrated that chronic treatment with PF suppressed the activations of JNK and p38 MAPK, but enhanced ERK activation. And PF could reverse ischemia-induced activation of NF-κB signaling pathway. Moreover, our in vitro study revealed that PF treatment protected against TNFα-induced cell apoptosis and neuronal loss. Taken together, the present study demonstrates that PF produces a delayed protection in the ischemia-injured rats via inhibiting MAPKs/NF-κB mediated peripheral and cerebral inflammatory response. Our study reveals that PF might be a potential neuroprotective agent for stroke.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Astrocytes; bcl-2-Associated X Protein; Benzoates; Brain; Brain Ischemia; Bridged-Ring Compounds; Cerebral Infarction; Cyclooxygenase 2; Cytochromes c; Disease Models, Animal; Gene Expression Regulation; Glucosides; Hippocampus; Inflammation; Interleukin-1beta; Lipoxygenase; Male; Microglia; Mitogen-Activated Protein Kinases; Monoterpenes; Neurons; NF-kappa B; Nitric Oxide Synthase Type II; Proto-Oncogene Proteins c-bcl-2; Rats; Signal Transduction; Tumor Necrosis Factor-alpha

The present study aims to explore the effects of paeoniflorin (PF), a monoterpene glycoside isolated from the roots of Paeonia lactiflora Pallas, on acute lung injury (ALI) and the possible mechanisms.. ALI was induced in mice by an intratracheal instillation of lipopolysaccharide (LPS, 1 mg/kg), and PF was injected intraperitoneally 30 min prior to LPS administration. After 24 h, lung water content, histology, microvascular permeability and proinflammatory cytokines in the bronchoaveolar lavage fluid were evaluated.. It was shown that PF (50, 100 mg/kg) could alleviate LPS-induced ALI, evidenced by reduced pulmonary edema, improved histological changes, and attenuated inflammatory cell accumulation in the interstitium and alveolar space as well as microvascular permeability. It also markedly down-regulated the expressions of proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α at both transcription and protein levels. Additionally, PF inhibited the phosphorylations of p38 MAP kinase (p38) and c-Jun NH2-terminal kinase (JNK) but not extracellular signal-regulated kinase (ERK), and prevented the activation of nuclear factor-kappa B (NF-κB) in the lung tissues.. The findings suggest that PF is able to alleviate ALI, and the underlying mechanisms are probably attributed to decreasing the production of proinflammatory cytokines through down-regulation of the activation of p38, JNK and NF-κB pathways in lung tissues.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Bridged-Ring Compounds; Extracellular Signal-Regulated MAP Kinases; Glucosides; Inflammation; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Lung Injury; Male; Mice; Mice, Inbred ICR; Microcirculation; Monoterpenes; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Permeability; Phosphorylation; Pulmonary Edema; Signal Transduction; Time Factors

The present study was carried out to investigate the effects of paeoniflorin in cultured RAW264.7 cell line as well as in an experimental model of sepsis induced by cecal ligation and puncture, and intraperitoneal injection (i.p.) of lipopolysaccharide in rats. Results showed that paeoniflorin concentration-dependently down-regulated the levels of TNF-alpha, IL-6 and high-mobility group-box 1 protein in lipopolysaccharide-induced RAW264.7 cell, inhibited the IkappaB kinase pathway and modulated NF-kappaB. Intravenous injection (i.v.) of paeoniflorin alone or in combination with imipenem reduced i.p. of lipopolysaccharide or cecal ligation and puncture-induced lethality in rats. In addition, serum levels of TNF-alpha, IL-6, high-mobility group-box 1 protein, triggering receptor expressed on myeloid cells and endotoxin were down-regulated; by contrast, serum levels of IL-10 were up-regulated. Amelioration of hemodynamics, decrease of enzyme levels, decrease of myeloperoxidase in lung, liver, and small intestine were also found after paeoniflorin injection. These data indicate that the anti-sepsis effect of paeoniflorin was mediated by decreasing local and systemic levels of a wide spectrum of inflammatory mediators. This work provides the first evidence that paeoniflorin has the capacity to inactivate inflammatory response in sepsis and the anti-inflammatory mechanism of paeoniflorin may inhibit activation of the NF-kappaB pathway by inhibiting IkappaB kinase activity.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Blood Urea Nitrogen; Bridged-Ring Compounds; Cecum; Cell Line; Clinical Enzyme Tests; DNA-Binding Proteins; Endotoxins; Glucosides; Hemodynamics; Imipenem; Inflammation; Inflammation Mediators; Intestine, Small; Lactic Acid; Liver; Lung; Macrophages; Male; Membrane Glycoproteins; Mice; Monoterpenes; Peroxidase; Rats; Rats, Sprague-Dawley; Receptors, Immunologic; Shock, Septic; Triggering Receptor Expressed on Myeloid Cells-1

Paeony root has long been used for its anti-inflammatory effects. In this study, the effects of albiflorin, paeoniflorin, and paeonol, compounds from paeony root, on gene expression profiles were examined in macrophages challenged with the inflammation inducer lipopolysaccharide (LPS).. The RAW264.7 macrophages were treated with LPS in the presence or absence of albiflorin, paeoniflorin, or paeonol. Global mRNA expression levels were detected by using an oligonucleotide microarray platform covering the mouse whole genome.. Treatment with LPS caused expression level changes in 1,270 genes by 2 folds or more. Paeonol attenuated the induction level of 355 LPS-responsive genes. Classification of the genes targeted by paeonol according to the Panther group analysis revealed 20 biological processes, 24 molecular functions, and 22 signaling pathways. The Panther signaling pathways highly affected by paeonol included the 'inflammation mediated by chemokine and cytokine signaling', 'interleukin signaling', and 'Toll receptor signaling'.. Our results demonstrate that paeonol has extensive inhibitory effects on the regulation of inflammation associated gene expression by LPS in macrophages. In addition, the predominant effect of paeonol among the tested compounds suggests that paeonol may be a major ingredient for the anti-inflammatory effect of paeony root.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Bridged-Ring Compounds; Cells, Cultured; Chemokines; Drugs, Chinese Herbal; Gene Expression Profiling; Gene Expression Regulation; Glucosides; Inflammation; Interleukins; Lipopolysaccharides; Macrophages; Mice; Monoterpenes; Oligonucleotide Array Sequence Analysis; Toll-Like Receptors

1. This study examined whether Paeoniflorin (PF), the major active components of Chinese herb Paeoniae alba Radix, has neuroprotective effect in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). 2. Subcutaneous administration of PF (2.5 and 5 mg kg(-1)) for 11 days could protect tyrosine hydroxylase (TH)-positive substantia nigra neurons and striatal nerve fibers from death and bradykinesia induced by four-dose injection of MPTP (20 mg kg(-1)) on day 8. 3. When given at 1 h after the last dose of MPTP, and then administered once a day for the following 3 days, PF (2.5 and 5 mg kg(-1)) also significantly attenuated the dopaminergic neurodegeneration in a dose-dependent manner. Post-treatment with PF (5 mg kg(-1)) significantly attenuated MPTP-induced proinflammatory gene upregulation and microglial and astrocytic activation. 4. Pretreatment with 0.3 mg kg(-1) 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A1 receptor (A1AR) antagonist, 15 min before each dose of PF, reversed the neuroprotective and antineuroinflammatory effects of PF. 5. In conclusion, this study demonstrated that PF could reduce the MPTP-induced toxicity by inhibition of neuroinflammation by activation of the A1AR, and suggested that PF might be a valuable neuroprotective agent for the treatment of PD.

Topics: Animals; Benzoates; Bridged-Ring Compounds; Corpus Striatum; Dopamine; Glucosides; Inflammation; Mice; Monoterpenes; Nerve Fibers; Neurons; Neuroprotective Agents; Neurotoxicity Syndromes; Parkinsonian Disorders; Receptor, Adenosine A1; Substantia Nigra