Protective mechanism of Paeonol on central nervous system.

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.

Review of the Protective Mechanism of Paeonol on Cardiovascular Disease.

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.

Paeonol repurposing for cancer therapy: From mechanism to clinical translation.

Paeonol (PAE) is a natural phenolic monomer isolated from the root bark of Paeonia suffruticosa that has been widely used in the clinical treatment of some inflammatory-related diseases and cardiovascular diseases. Much preclinical evidence has demonstrated that PAE not only exhibits a broad spectrum of anticancer effects by inhibiting cell proliferation, invasion and migration and inducing cell apoptosis and cycle arrest through multiple molecular pathways, but also shows excellent performance in improving cancer drug sensitivity, reversing chemoresistance and reducing the toxic side effects of anticancer drugs. However, studies indicate that PAE has the characteristics of poor stability, low bioavailability and short half-life, which makes the effective dose of PAE in many cancers usually high and greatly limits its clinical translation. Fortunately, nanomaterials and derivatives are being developed to ameliorate PAE's shortcomings. This review aims to systematically cover the anticancer advances of PAE in pharmacology, pharmacokinetics, nano delivery systems and derivatives, to provide researchers with the latest and comprehensive information, and to point out the limitations of current studies and areas that need to be strengthened in future studies. We believe this work will be beneficial for further exploration and repurposing of this natural compound as a new clinical anticancer drug.

Paeonol enhances treatment of fluconazole and amphotericin B against oropharyngeal candidiasis through HIF-1α related IL-17 signaling.

Oropharyngeal candidiasis (OPC) is an oral infection mainly caused by Candida albicans, a dimorphic human opportunistic pathogen that can proliferate and invade the superficial oral epithelium using its hyphae. The filamentation of C. albicans is a hallmark of biofilm formation, accompanied by the occurrence of a hypoxic microenvironment. Paeonol (PAE) is a traditional medicine with multiple properties. In a previous study, we demonstrated the synergism of PAE plus Fluconazole (FLU) or Amphotericin B (AmB) against C. albicans in vitro and in vivo. This study aimed to explore the therapeutic mechanisms of drug combinations on OPC. In an established OPC mouse model, the culture of hypoxia was observed by calcofluor white and hypoxyprobe staining. The expression and levels of IL-17 signaling-associated genes and proteins (IL-17A and IL-23) were evaluated in tissue homogenates and EC109 cells. The results show that compared with the single therapy, PAE plus FLU or AmB can decrease fungal burden, restore mucosal integrity, and reduce the hypoxic microenvironment and inflammation in the OPC mice. Relative to infected mice, the drug combinations can also rectify the abnormal expression of hypoxia inducible factor (hif)-1α, il-17a, and il-23 mRNA. Meanwhile, compared with the infected EC109 cells treated with a single drug, PAE plus FLU or AmB significantly inhibited the mRNA and protein expression of HIF-1α, IL-17A, and IL-23. Taken together, the possible mechanism of PAE plus FLU or AmB can be attributed to the regulation of hypoxia-associated IL-17 signaling in OPC treatment.

Antioxidant Combo Therapy Protects White Matter After Traumatic Brain Injury.

Following traumatic brain injury (TBI), increased production of reactive oxygen species (ROS) and the ensuing oxidative stress promotes the secondary brain damage that encompasses both grey matter and white matter. As this contributes to the long-term neurological deficits, decreasing oxidative stress during the acute period of TBI is beneficial. While NADPH oxidase (NOX2) is the major producer of ROS, transcription factor Nrf2 that induces antioxidant enzymes promotes efficient ROS disposal. We recently showed that treatment with an antioxidant drug combo of apocynin (NOX2 inhibitor) and TBHQ (Nrf2 activator) protects the grey matter in adult mice subjected to TBI. We currently show that this antioxidant combo therapy given at 2 h and 24 h after TBI also protects white matter in mouse brain. Thus, the better functional outcomes after TBI in the combo therapy treated mice might be due to a combination of sparing both grey matter and white matter. Hence, the antioxidant combo we tested is a potent therapeutic option for translation in future.

Paeonol alleviates dextran sodium sulfate induced colitis involving Candida albicans-associated dysbiosis.

Inflammatory bowel disease (IBD), which consists of ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disorder of the gastrointestinal tract. Occurrence and development of UC have been associated with multiple potential causative factors, which include fungal dysbiosis. Growing evidence reveals that Candida albicans-associated dysbiosis is correlated with clinical deterioration in UC. Paeonol (PAE) is a commonly used traditional medicine with multiple reported properties including effective alleviation of UC. In this study, a murine UC model was established by colonizing mice with additional C. albicans via gavage prior to dextran sodium sulfate (DSS) administration. Effects of PAE treatment were also assessed at initiation and in preestablished C. albicans-associated colitis. The results showed that C. albicans supplementation could aggravate disease activity index (DAI), compromise mucosal integrity, exacerbate fecal and tissue fungal burdens, increase serum ß-glucan and anti-Saccharomyces cerevisiae antibody (ASCA) levels, promote serum and colonic tissue pro-inflammatory cytokine secretion (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-8) and decrease the anti-inflammatory cytokine IL-10 level. It also stimulated Dectin-1, TLR2 and TLR4 as well as expression of their downstream effector NF-κB in colonic tissue. After PAE treatment, the adverse impacts of C. albicans on colitis were relieved, via decreased receptor-associated local and systemic inflammation. Our study suggests that PAE should be a candidate for treatment of fungal dysbiosis-associated UC and may act through the Dectin-1/NF-κB pathway in collaboration with TLR2 and TLR4. LAY SUMMARY: Candida albicans is believed to be an important stimulator in ulcerative colitice (UC) development. Suppressing the growth of intestinal C. albicans can be contributory to the amelioration of UC. Paeonol (PAE) is a commonly used traditional medicine with multiple biological functions. In this study, we observed that PAE could alleviate symptoms in mice UC model accompanying with burden reduction of C. albicans. Therefore, we suppose that PAE can be a candidate in the treatment of C. albicans-associated UC.

Hyperbaric oxygen preconditioning and the role of NADPH oxidase inhibition in postischemic acute kidney injury induced in spontaneously hypertensive rats.

Renal ischemia/reperfusion injury is a common cause of acute kidney injury (AKI) and hypertension might contribute to the increased incidence of AKI. The purpose of this study was to investigate the effects of single and combined hyperbaric oxygen (HBO) preconditioning and NADPH oxidase inhibition on oxidative stress, kidney function and structure in spontaneously hypertensive rats (SHR) after renal ischemia reperfusion injury. HBO preconditioning was performed by exposing to pure oxygen (2.026 bar) twice a day for two consecutive days for 60 minutes, and 24h before AKI induction. For AKI induction, the right kidney was removed and ischemia was performed by clamping the left renal artery for 45 minutes. NADPH oxidase inhibition was induced by apocynin (40 mg/kg b.m., intravenously) 5 minutes before reperfusion. AKI significantly increased renal vascular resistance and reduced renal blood flow, which were significantly improved after apocynin treatment. Also, HBO preconditioning, with or without apocynin treatment showed improvement on renal hemodynamics. AKI significantly increased plasma creatinine, urea, phosphate levels and lipid peroxidation in plasma. Remarkable improvement, with decrease in creatinine, urea and phosphate levels was observed in all treated groups. HBO preconditioning, solitary or with apocynin treatment decreased lipid peroxidation in plasma caused by AKI induction. Also, combined with apocynin, it increased catalase activity and solitary, glutathione reductase enzyme activity in erythrocytes. While AKI induction significantly increased plasma KIM- 1 levels, HBO preconditioning, solitary or with apocynin decreased its levels. Considering renal morphology, significant morphological alterations present after AKI induction were significantly improved in all treated groups with reduced tubular dilatation, tubular necrosis in the cortico-medullary zone and PAS positive cast formation. Our results reveal that NADPH oxidase inhibition and hyperbaric oxygen preconditioning, with or without NADPH oxidase inhibition may have beneficial effects, but their protective role should be evaluated in further studies.

Apocynin Dietary Supplementation Delays Mouse Ovarian Ageing.

Advanced maternal age is associated with higher infertility rates, pregnancy-associated complications, and progeny health issues. The ovary is considered the main responsible for these consequences due to a continuous decay in follicle number and oocyte quality. Intracellular imbalance between oxidant molecules and antioxidant mechanisms, in favour of the former, results in oxidative stress (OS) that is believed to contribute to ovarian ageing. This work is aimed at evaluating whether an age-related increase in ovarian OS, inflammation, and fibrosis may contribute to tissue dysfunction and whether specific antioxidant supplementation with a NADPH oxidase inhibitor (apocynin) could ameliorate them. Mice aged 8-12 weeks (reproductively young) or 38-42 weeks (reproductively aged) were employed. Aged mice were divided into two groups, with one receiving apocynin (5 mM) in the drinking water, for 7 weeks, upon which animals were sacrificed and their ovaries collected. Ovarian structure was similar at both ages, but the ovaries from reproductively aged mice exhibited lipofuscin deposition, enhanced fibrosis, and a significant age-related reduction in primordial and primary follicle number when compared to younger animals. Protein carbonylation and nitration, and markers of OS were significantly increased with age. Moreover, mRNA levels of inflammation markers, collagens, metalloproteinases (MMPs), and tissue inhibitor MMPs (TIMPs) were upregulated. Expression of the antifibrotic miRNA29c-3p was significantly reduced. Apocynin supplementation ameliorated most of the age-related observed changes, sometimes to values similar to those observed in young females. These findings indicate that there is an age-related increase in OS that plays an important role in enhancing inflammation and collagen deposition, contributing to a decline in female fertility. Apocynin supplementation suggests that the imbalance can be ameliorated and thus delay ovarian ageing harmful effects.

Anticonvulsant and Neuroprotective Effects of Paeonol in Epileptic Rats.

Paeonol is the main active compound in the root bark extract of the peony tree, and it has antioxidative and anti-inflammatory effects. Recent studies have reported the neuroprotective effects of paeonol including its capacity in improving impaired memory. However, the effect of paeonol on epilepsy is yet to be demystified. We aimed to investigate the therapeutic effect of paeonol in epilepsy and its relationship with oxidative stress damage and neuronal loss in the rat brain to reveal the underlying mechanisms of epileptic seizures. A rat model for chronic epilepsy was established, and the seizure scores of the rats in different groups were recorded. The seizure duration and the seizure onset latency were used to evaluate the anticonvulsant effects of paeonol. Terminal deoxynucleotidyl transferase dUTP nick end-labeling staining, Nissl staining and H/E staining were used to evaluate the effects of paeonol on neuronal loss and apoptosis in epileptic rats. The colorimetric assessment of malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, catalase activity and total antioxidant capacity of paeonol were used in assessing paeonol's effect on oxidative stress in epileptic rats. Evaluation of Caspase-3 mRNA and protein expression levels were determined using western blot and quantitative real-time (RT-q)PCR. In this study, we found that paeonol reduced the seizure scores of epileptic rats and attenuated the duration and onset latency of seizures. Paeonol can also increase the activities of total antioxidant capacity, SOD and catalase activity and reduce MDA content as well. This suggests that paeonol can improve the level of oxidative stress in rats. More significantly, paeonol can improve neuronal loss and apoptosis in epileptic rats. These results indicate that paeonol has anticonvulsant and neuroprotective effects in epileptic rats. This effect may be caused by reducing oxidative stress.

Paeonol ameliorates monosodium urate-induced arthritis in rats through inhibiting nuclear factor-κB-mediated proinflammatory cytokine production.

Moutan Cortex has been widely used to treat various types of arthritis in traditional Chinese medicine. Paeonol is isolated as an active ingredient from Moutan Cortex. However, the effect and potential mechanism of paeonol on gouty arthritis have not been evaluated. In this study, rats were treated intragastrically with paeonol for consecutive 7 days. On Day 5, rats were intra-articularly injected with monosodium urate (MSU) crystals in the ankle joints to induce MSU-induced arthritis (MIA). Paw volume was detected at various time points. Gait score was measured at 24 hr after MSU crystal injection. Ankle joints were collected for evaluation of histological score and expression of proinflammatory cytokines using hematoxylin and eosin staining and immunohistochemistry staining, respectively. Nuclear level of nuclear factor (NF)-κBp65 in synovial tissues was analyzed by western blot assay. NF-κB DNA-binding activity was measured by enzyme linked immunosorbent assay. Paeonol markedly lowered the paw volume, gait score, and histological score in MIA rats. Mechanistically, paeonol markedly reduced the expression of TNF-α, IL-1ß, and IL-6 in synovial tissues of MIA rats. In addition, the elevated level of p65 in nucleus and NF-κB DNA-binding activity in synovial tissues of MIA rats were reduced significantly by paeonol treatment. These findings suggest that paeonol exerts anti-inflammatory effect in MIA rats through inhibiting expression of proinflammatory cytokines and NF-κB activation.

The influence of apocynin, lipoic acid and probiotics on antioxidant enzyme levels in the pulmonary tissues of obese asthmatic mice.

Bronchial asthma and obesity are common health problems. Obesity is already responsible for 300,000 deaths per year. AIMS: The aim of the present study was to assess whether apocynin, alpha lipoic acid and probiotic administration in combination with low-fat diet supplementation influences the levels of antioxidant enzymes in the pulmonary tissues of obese asthmatic mice. MAIN METHODS: The study was performed on male C57/BL6 mice divided into 10 groups: (I) control; (II) asthma; (III) obesity; (IV) asthma + obesity; (V) asthma + obesity + apocynin p.o. 15 mg/kg/day for 12 weeks; (VI) asthma + obesity + low-fat diet for 12 weeks; (VII) asthma + obesity + low-fat diet for 12 weeks with apocynin p.o. 15 mg/kg/day; (VIII) asthma + obesity + low-fat diet with probiotics for 12 weeks; (IX) asthma + obesity + low-fat diet for 12 weeks with lipoic acid p.o. 100 mg/kg/day for 12 weeks; (X) asthma + obesity + standard diet with probiotics for 12 weeks. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activity were examined. The administration of apocynin alone and apocynin in combination with a low-fat diet resulted in a significant increase in SOD values (respectively p < 0.001; p = 0.010). Application of probiotics resulted in a decrease in CAT activity (p = 0.037) and an increase in GPx activity (p < 0.001) compared to obese asthmatic mice. The administration of lipoic acid resulted in an increase in GR activity (p = 0.024 vs. control). KEY FINDINGS: Supplementation containing apocynin, lipoic acid and probiotics has a positive influence on the antioxidant capacity of the pulmonary tissues of obese asthmatic mice. SIGNIFICANCE: These results may contribute to the development of new therapeutic approaches.

Protection of paeonol against epirubicin-induced hepatotoxicity: A metabolomic study.

Paeonol extracted from the Moutan Cortex, possesses hepatoprotective activity against epirubicin (EPI)-induced liver damage. This study evaluated the protective effect of paeonol on EPI-induced hepatotoxicity and explored the underlying metabolomic mechanism. Breast tumor-bearing mice were randomly divided into three groups: control, EPI, and EPI + paeonol treatment. Mice received a tail i.v. injection of EPI every other day for 3 cycles or/and intragastrically (i.g.) administered paeonol daily for 6 days. Hematoxylin-eosin (HE) staining and biochemical detection were used to determine the degree of damage. A gas chromatography-mass spectrometry (GC-MS) technique was established to determine the metabolites. PLS-DA and PCA were used to investigate metabolic changes. HE staining and biochemical detection results showed that EPI caused serious liver damage while paeonol ameliorated it. The results of mass spectrogram, partial least squares-discriminate analysis (PLS-DA), and principal component analysis (PCA) demonstrated that lipid, amino acid, and energy metabolism involving seven metabolites were obviously changed by EPI and reversed by paeonol. Additionally, paeonol inhibited EPI-induced activation of adenosine monophosphate activated protein kinase/mammalian target of Rapamycin (AMPK/mTOR) signalling pathway. Our results demonstrated the hepatoprotective effect of paeonol on EPI-induced hepatotoxicity in mice, provided potential biomarkers for early assessment of EPI-induced liver injury and illuminated the metabolic mechanism underlying paeonol-related hepatic protection.

The natural phenolic compounds as modulators of NADPH oxidases in hypertension.

BACKGROUND: Hypertension is a major public health problem worldwide. It is an important risk factor for other cardiovascular diseases such as coronary artery disease, stroke, heart failure, atrial fibrillation, peripheral vascular disease, chronic kidney disease, and atherosclerosis. PURPOSE: There is strong evidence that excess ROS-derived NADPH oxidase (NOX) is an important agent in hypertension. It augments blood pressure in the presence of other pro-hypertensive factors such as angiotensin II (Ang II), an important and potent regulator of cardiovascular NADPH oxidase, activates NOX via AT1 receptors. NADPH oxidase, a multi-subunit complex enzyme, is considered as a key source of ROS production in the vasculature. The activation of this enzyme is needed for assembling Rac-1, p40phox, p47phox and p67phox subunits. Since, hypertensive patients need to control blood pressure for their entire life and because drugs and other chemicals often induce adverse effects, the use of natural phenolic compounds which are less toxic and potentially beneficial may be good avenues of addition research in our understand of the underlying mechanism involved in hypertension. This review focused on several natural phenolic compounds as berberine, thymoquinone, catechin, celastrol, apocynin, resveratrol, curcumin, hesperidine and G-hesperidine, and quercetin which are NOX inhibitors. In addition, structure activity relationship of these compounds eventually as the most inhibitors was discussed. METHODS: This comprehensive review is based on pertinent papers by a selective search using relevant keywords that was collected using online search engines and databases such as ScienceDirect, Scopus and PubMed. The literature mainly focusing on natural products with therapeutic efficacies against hypertension via experimental models both in vitro and in vivo was identified. RESULTS: It has been observed that these natural compounds prevent NADPH oxidase expression and ROS production while increasing NO bioavailability. It have been reported that they improve hypertension due to formation of a stable radical with ROS-derived NADPH oxidase and preventing the assembly of NOX subunites. CONCLUSION: It is clear that natural phenolic compounds have some potential inhibitory effect on NADPH oxidase activity. In comparison to other phenolic plant compounds, the structural variability of the flavonoids should off different impacts on oxidative stress in hypertension including inhibition of nadph oxidase and direct scavenging of free radicals.

Beneficial Effects Exerted by Paeonol in the Management of Atherosclerosis.

Atherosclerosis, a chronic luminal stenosis disorder occurred in large and medium arteries, is the principle pathological basis of cardiovascular diseases with the highest morbidity and mortality worldwide. In oriental countries, traditional Chinese medicine Cortex Moutan has been widely used for the treatment of atherosclerosis-related illnesses for thousands of years. Paeonol, a bioactive monomer extracted from Cortex Moutan, is an important pharmacological component responsible for the antiatherosclerotic effects. Numerous lines of findings have established that paeonol offers beneficial roles against the initiation and progression of atherosclerotic lesions through inhibiting proatherogenic processes, such as endothelium damage, chronic inflammation, disturbance of lipid metabolism, uncontrolled oxidative stress, excessive growth, and mobilization of vascular smooth muscle cells as well as abnormality of platelet activation. Investigations identifying the atheroprotective effects of paeonol present substantial evidence for potential clinical application of paeonol as a therapeutic agent in atherosclerosis management. In this review, we summarize the antiatherosclerotic actions by which paeonol suppresses atherogenesis and provide newly insights into its atheroprotective mechanisms and the future clinical practice.

3,5-Di-C-ß-D-glucopyranosyl phloroacetophenone, a major component of Melicope ptelefolia, suppresses fibroblast activation and alleviates arthritis in a mouse model: Potential therapeutics for rheumatoid arthritis.

Melicope ptelefolia has been traditionally used to treat rheumatism and fever. The present study aimed to investigate the therapeutic effect of 3,5­di­C­ß­D­glucopyranosyl phloroacetophenone (ßGP), a main component of M. ptelefolia, on rheumatoid arthritis (RA). A model of collagen­induced arthritis (CIA) was established in mice using the RAW 264.7 murine macrophage cell line and mouse embryonic fibroblasts (MEFs). The clinical scores of arthritis, swelling, histopathological findings, and micro­computed tomography in CIA mouse paws were assessed. The levels of anti­type II collagen antibody and cytokines were determined in the plasma and cell culture supernatant, respectively. Protein and gene expression levels were analyzed by western blot and reverse transcription­quantitative polymerase chain reaction analyses. ßGP significantly decreased the gross arthritic scores of CIA mice and joint swelling, and decreased articular inflammation, cartilage degradation and bone erosion. However, ßGP did not exert any effect on anti­type II collagen immunoglobulin G plasma levels or inflammatory cytokine expression in macrophages. ßGP significantly suppressed the expression of interleukin­6 and leukemia inhibitory factor and decreased the phosphorylation of signal transducer and activator of transcription 3, and expression of receptor activator of nuclear factor­κB ligand in tumor necrosis factor­α­stimulated MEFs and in CIA mouse paws. Osteoclast­related gene expression was significantly reduced in CIA mouse paws. Taken together, ßGP suppressed the development of RA by regulating the activation of synovial fibroblasts.

Paeonol attenuates acute lung injury by inhibiting HMGB1 in lipopolysaccharide-induced shock rats.

High-mobility group box 1 (HMGB1) is a highly conserved DNA-binding nuclear protein that facilitates gene transcription and the DNA repair response. However, HMGB1 may be released by necrotic cells as well as activated monocytes and macrophages following stimulation with lipopolysaccharide (LPS), interleukin-1ß (IL-1ß), or tumor necrosis factor-α (TNF-α). Extracellular HMGB1 plays a critical role in the pathogenesis of acute lung injury (ALI) through activating the nuclear transcription factor κB (NF-κB) P65 pathway, thus, it may be a promising therapeutic target in shock-induced ALI. Paeonol (Pae) is the main active component of Paeonia suffruticosa, which has been used to inhibit the inflammatory response in traditional Chinese medicine. We have proven that Pae inhibits the expression, relocation and secretion of HMGB1 in vitro. However, the role of Pae in the HMGB1-NF-κB pathway remains unknown. We herein investigated the role of Pae in LPS-induced ALI rats. In this study, LPS induced a marked decrease in the mean arterial pressure (MAP) and survival rate (only 25% after 72 h), and induced severe pathological changes in the lung tissue of rats, which was accompanied by elevated expression of HMGB1 and its downstream protein NF-κB P65. Treatment with Pae significantly improved the survival rate (>60%) and MAP, and attenuated the pathological damage to the lung tissue in ALI rats. Western blotting revealed that Pae also inhibited the total expression of HMGB1, NF-κB P65 and TNF-α in the lung tissue of ALI rats. Moreover, Pae increased the expression of HMGB1 in the nucleus, inhibited the production of HMGB1 in the cytoplasm, and decreased the expression of P65 both in the nucleus and cytoplasm of lung tissue cells in LPS-induced ALI rats. The results were in agreement with those observed in the in vitro experiment. These findings indicate that Pae may be a potential treatment for ALI through its repression of the HMGB1-NF-κB P65 signaling pathway.

Apocynin combined with drugs as coadjuvant could be employed to prevent and/or treat the chronic kidney disease.

A worldwide public health problem is chronic kidney disease (CKD) presenting alarming epidemiological data. It currently affects about 10% of the adult population worldwide and has a high mortality rate. It is now known that oxidative stress represents one of the most important mechanisms in its pathophysiology, from the early stages to the terminal phase. Oxidation increases inflammation and reduces the capacity of NO• to relax vascular smooth muscle, in part by decreasing bioavailability of tetrahydrobiopterin (BH4), leading to endothelial dysfunction and high blood pressure, and due to the limited effectiveness of existing treatments, new drugs are needed to prevent and/or treat these mechanisms. The aim of this study was to test apocynin in a 5/6 nephrectomy mouse model of CKD to investigate whether its known antioxidant effect can improve the disease outcome. This effect results from the inhibition of NADPH oxidase and consequently a reduced production of the superoxide anion ([Formula: see text]). Animals were divided into five groups: sham, 5/6 nephrectomy only, and 5/6 nephrectomy followed by treatment with captopril, losartan or apocynin. The parameters evaluated were blood pressure and markers of oxidative stress ([Formula: see text]) and endothelial function (BH4). There were significantly lower levels of [Formula: see text] and a greater availability of serum BH4 in the apocynin-treated animals versus the control group and the two other drug treatments. The present findings suggest that apocynin in conjunction with a coadjuvant for modulating blood pressure may be useful for controlling the progression of CRF.

Evaluation of LPS-Induced Acute Lung Injury Attenuation in Rats by Aminothiazole-Paeonol Derivatives.

Paeonol is a key phenolic compound in the root bark of Moutan Cortex Radicis that has been used in traditional Chinese Medicine to ameliorate inflammation. A series of aminothiazole-paeonol derivatives (APDs) were synthesized in this work and subjected to preliminary evaluation in cells followed by verification in animals. Quantification of monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) in culture media of LPS-activated A549 cells, a lung epithelial adenocarcinoma cell line, were used to investigate the anti-inflammatory capability of APDs. ALI-bearing rats were employed to verify therapeutic efficacy of APDs according to observations of total cells, protein amounts, MCP-1 and IL-6 in bronchoalveolar lavage fluid (BALF). Histopathological examinations of lung tissues were consequently applied for validation of APDs. Among these compounds, 2-(2-aminothiazol-4-yl)-5-methoxyphenol (4) had the most potent activity, showing comparable inhibition of MCP-1/IL-6 and superior elimination of neutrophil infiltration and protein exudation in lungs compared to others as well as dexamethasone. This study demonstrated a comprehensive strategy to evaluate APDs through integration of cell-based screening and animal-based verification. In order to fulfill unmet needs of treating acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), APDs introduced in this work could be promising lead compounds to develop high potent anti-inflammation agents.

Paeonol alleviates interleukin-1ß-induced inflammatory responses in chondrocytes during osteoarthritis.

Interleukin-1ß (IL-1ß)-induced inflammatory responses in chondrocytes play an important role in the pathogenesis of osteoarthritis (OA). Searching medicines that affect IL-1ß-mediated chondrocytes function is critical in developing therapies for OA. Paeonol, as an important component in traditional Chinese medicine, has anti-inflammatory activity and can offer therapy for a multitude of inflammatory-related diseases. The purpose of this study was to investigate whether paeonol could alleviate the progression of OA through inhibition of IL-1ß-induced inflammatory responses in chondrocytes. The cell counting kit-8 assay, 5-ethynil-2'-deoxyuridine staining, hoechst 33258 staining and flow cytometric staining were used to observe the chondrocytes proliferation and apoptosis. Western blot and quantitative real-time PCR were applied to examine the expression of extracellular matrix and cartilage degrading enzymes. Reactive oxygen species (ROS) production was monitored by 2',7'-dichlorodihydrofluoresce in diacetate staining. Furthermore, paeonol was intra-articularly injected into joint capsule in destabilized medial meniscus (DMM)-induced OA rat model for 8 and 12 weeks. The results showed that paeonol could negatively affect IL-1ß-mediate chondrocyte apoptosis and proliferation. Application of paeonol attenuated the secretion of cartilage extracellular matrix and cartilage degrading enzymes induced by IL-1ß in chondrocytes. Increasing of ROS production by IL-1ß was obviously alleviated by paeonol. Besides, paeonol alleviated DMM-induced articular cartilage degeneration in vivo. Taken together, we concluded that paeonol might be used as therapeutic agent for treating OA.

Paeonol Inhibits IL-1ß-Induced Inflammation via PI3K/Akt/NF-κB Pathways: In Vivo and Vitro Studies.

Paeonol, the main active component isolated from the root of Paeonia suffruticosa, has been reported to have anti-inflammatory properties. However, the effects of paeonol on osteoarthritis (OA) remain unclear. The aim of this study was to investigate the anti-inflammatory effects and mechanism of paeonol in IL-1ß-induced human OA chondrocytes as well as mice OA models. Human OA chondrocytes were pretreated with different concentrations of paeonol 2 h prior to IL-1ß (10 ng/mL) stimulation for 24 h. Nitric oxide (NO) production was determined by Griess method. The levels of prostaglandin E2 (PGE2), matrix metalloproteinase 1 (MMP-1), MMP-3, and MMP-13 were assessed by ELISA. Inducible nitric oxide synthase (INOS), COX-2, and PI3K/Akt/NF-κB-related signaling molecules production were measured by Western blot. In vivo, mice OA models were established by destabilization of the medial meniscus. One month after surgery, mice in paeonol-treated group were given intraperitoneal injection of paeonol in 30 mg/kg every day, while mice of vehicle-treated group were injected with DMSO under the same conditions. Hematoxylin and eosin as well as Safranin-O staining were applied to assess the severity of cartilage lesions. The results showed that pretreatment with paeonol could inhibit IL-1ß-induced NO and PGE2 production. Meanwhile, the overproduction of INOS, COX-2, MMP-1, MMP-3, and MMP-13 were also reversed by paeonol. Moreover, paeonol was found to inhibit IL-1ß-induced NF-κB activation, PI3K, and AKT phosphorylation. In vivo, treatment with paeonol exhibited less cartilage degradation and lower Osteoarthritis Research Society International scores in mice OA models. In conclusion, these results suggest that paeonol may be a potential therapeutic agent in the treatment of OA.