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.

A hydroalcoholic extract of Senecio nutans SCh. Bip (Asteraceae); its effects on cardiac function and chemical characterization.

ETHNOPHARMACOLOGY RELEVANCE: The plant Senecio nutans SCh. Bip. is used by Andean communities to treat altitude sickness. Recent evidence suggests it may produce vasodilation and negative cardiac inotropy, though the cellular mechanisms have not been elucidated. PURPOSE: To determinate the mechanisms action of S. nutans on cardiovascular function in normotensive animals. METHODS: The effect of the extract on rat blood pressure was measured with a transducer in the carotid artery and intraventricular pressure by a Langendorff system. The effects on sheep ventricular intracellular calcium handling and contractility were evaluated using photometry. Ultra-high-performance liquid-chromatography with diode array detection coupled with heated electrospray-ionization quadrupole-orbitrap mass spectrometric detection (UHPLC-DAD-ESI-Q-OT-MSn) was used for extract chemical characterization. RESULTS: In normotensive rats, S. nutans (10 mg/kg) reduced mean arterial pressure (MAP) by 40% (p < 0.05), causing a dose-dependent coronary artery dilation and decreased left ventricular pressure. In isolated cells, S. nutans extract (1 µg/ml) rapidly reduced the [Ca2+]i transient amplitude and sarcomere shorting by 40 and 49% (p < 0.001), respectively. The amplitude of the caffeine evoked [Ca2+]i transient was reduced by 24% (p < 0.001), indicating reduced sarcoplasmic reticulum (SR) Ca2+ content. Sodium-calcium exchanger (NCX) activity increased by 17% (p < 0.05), while sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) activity was decreased by 21% (p < 0.05). LC-MS results showed the presence of vitamin C, malic acid, and several antioxidant phenolic acids reported for the first time. Dihydroeuparin and 4-hydroxy-3-(3-methylbut-2-enyl) acetophenone were abundant in the extract. CONCLUSION: In normotensive animals, S. nutans partially reduces MAP by decreasing heart rate and cardiac contractility. This negative inotropy is accounted for by decreased SERCA activity and increased NCX activity which reduces SR Ca2+ content. These results highlight the plant's potential as a source of novel cardio-active phytopharmaceuticals or nutraceuticals.

Diterpene glycosides, acetophenone glycosides and tannins from polar extracts of the root of Euphorbia fischeriana with cytotoxicity and antibacterial activities.

The phytochemical study on Euphorbia fischeriana, a folk medicinal plant in China, led to the isolation of eight undescribed glycosides, including two diterpene glycosides, three acetophenone glycosides and three tannins together with eight known ones. Their planar structures were elucidated by extensive analyses of 1D, 2D NMR experiments and HRESIMS. The absolute configurations were determined by NOESY experiments, ECD calculations. All undescribed compounds were evaluated for their cytotoxicity and antibacterial activities in vitro. Two diterpene glycosides (1-2) showed cytotoxic activity with IC50 values ranging from 5.4 to 16.2 µM toward Hep-G2, Hep-3B, A549, NCI-H460 and AGS cells. Tannins (6-8) showed the significant antibacterial activity with MIC values in the range of 1.56-6.25 µg/mL.

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.

Imidazolylacetophenone oxime-based multifunctional neuroprotective agents: Discovery and structure-activity relationships.

Alzheimer's disease (AD) possesses a complex pathogenetic mechanism. Nowadays, multitarget agents are considered to have potential in effectively treating AD via triggering molecules in functionally complementary pathways at the same time. Here, based on the screening (∼1400 compounds) against neuroinflammation, an imidazolylacetophenone oxime ether (IOE) was discovered as a novel hit. In order to obtain SARs, a series of imidazolylacetophenone oxime derivatives were constructed, and their C=N bonds were confirmed as the Z configuration by single crystals. These derivatives exhibited potential multifunctional neuroprotective effects including anti-neuroinflammatory, antioxidative damage, metal-chelating, inhibition of acetylcholinesterase (AChE) properties. Among these derivatives, compound 12i displayed the most potent inhibitory activity against nitric oxide (NO) production with EC50 value of 0.57 µM 12i can dose-dependently suppress the expression of iNOS and COX-2 but not change the expression of HO-1 protein. Moreover, 12i exhibited evidently neuroprotective effects on H2O2-induced PC12 cells damage and ferroptosis without cytotoxicity at 10 µM, as well as selectively metal chelating properties via chelating Cu2+. In addition, 12i showed a mixed-type inhibitory effect on AChE in vitro. The structure-activity relationships (SARs) analysis indicated that dioxolane groups on benzene ring and rigid oxime ester can improve the activity. Parallel artificial membrane permeation assay (PAMPA) also verified that 12i can overcome the blood-brain barrier (BBB). Overall, this is the first report on imidazolylacetophenone oxime-based multifunctional neuroprotective effects, suggesting that this type of compounds might be novel multifunctional agents against AD.

Investigation on the antitumor effects of paeonol against renal cell carcinoma based on network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Renal cell carcinoma (RCC) is the most common cancer of the urinary system, the current treatments for RCC are unsatisfactory. Paeonol is the main pharmacologically active ingredient of the traditional Chinese medicine (TCM) moutan cortex (Paeonia suffruticosa Andrews) and Paeonia albiflora Pall, and has been used in TCM to treat various diseases including cancer. However, the underlying therapeutic mechanisms of paeonol in RCC have not been investigated yet. AIM OF THE STUDY: This study aimed to explore the potential antitumor effects and mechanisms of paeonol on RCC based on network pharmacology and experimental validation. MATERIALS AND METHODS: Network pharmacological analysis was performed to predict the potential targets and mechanism of paeonol against RCC. The antitumor effects and the priority targets of paeonol against RCC were further assessed by in vitro experiments. RESULTS: 104 intersection targets shared by paeonol and RCC were collected, 15 hub genes were obtained, among these genes, VEGFA expression was higher in RCC, and the higher expression of IL-6 or lower expression of AKT1, JUN, MAPK1, and MAPK8 were correlated to the shorter overall survival (OS) in RCC patients. GO and KEGG analyses suggested that the genes were mainly enriched in the positive regulation of cell death and apoptosis pathway. In vitro experiments showed that paeonol inhibited 786-O cell proliferation, migration, invasion, and promoted apoptosis. When 786-O cells were treated with paeonol, the expression of Bax increased while Bcl-2 and VEGFA decreased. CONCLUSION: The present study demonstrated that paeonol might play an essential role in RCC by regulating cell proliferation, apoptosis, metastasis, and invasion through the Bcl-2/Bax signaling pathway and VEGFA, providing a theoretical and experimental scientific basis for future investigations of the antitumor effects of paeonol against RCC.

Natural Benzo/Acetophenones as Leads for New Synthetic Acetophenone Hybrids Containing a 1,2,3-Triazole Ring as Potential Antifouling Agents.

Marine biofouling is a natural process that represents major economic, environmental, and health concerns. Some booster biocides have been used in biofouling control, however, they were found to accumulate in environmental compartments, showing negative effects on marine organisms. Therefore, it is urgent to develop new eco-friendly alternatives. Phenyl ketones, such as benzophenones and acetophenones, have been described as modulators of several biological activities, including antifouling activity (AF). In this work, acetophenones were combined with other chemical substrates through a 1,2,3-triazole ring, a strategy commonly used in Medicinal Chemistry. In our approach, a library of 14 new acetophenone-triazole hybrids was obtained through the copper(I)-catalyzed alkyne-azide cycloaddition "click" reaction. All of the synthesized compounds were evaluated against the settlement of a representative macrofouling species, Mytilus galloprovincialis, as well as on biofilm-forming marine microorganisms, including bacteria and fungi. The growth of the microalgae Navicula sp. was also evaluated after exposure to the most promising compounds. While compounds 6a, 7a, and 9a caused significant inhibition of the settlement of mussel larvae, compounds 3b, 4b, and 7b were able to inhibit Roseobacter litoralis bacterial biofilm growth. Interestingly, acetophenone 7a displayed activity against both mussel larvae and the microalgae Navicula sp., suggesting a complementary action of this compound against macro- and microfouling species. The most potent compounds (6a, 7a, and 9a) also showed to be less toxic to the non-target species Artemia salina than the biocide Econea®. Regarding both AF potency and ecotoxicity activity evaluation, acetophenones 7a and 9a were put forward in this work as promising eco-friendly AF agents.

Ginsenoside Re Protects against Serotonergic Behaviors Evoked by 2,5-Dimethoxy-4-iodo-amphetamine in Mice via Inhibition of PKCδ-Mediated Mitochondrial Dysfunction.

It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.

Chemical and genetic rescue of in vivo progranulin-deficient lysosomal and autophagic defects.

In 2006, GRN mutations were first linked to frontotemporal dementia (FTD), the leading cause of non-Alzheimer dementias. While much research has been dedicated to understanding the genetic causes of the disease, our understanding of the mechanistic impacts of GRN deficiency has only recently begun to take shape. With no known cure or treatment available for GRN-related FTD, there is a growing need to rapidly advance genetic and/or small-molecule therapeutics for this disease. This issue is complicated by the fact that, while lysosomal dysfunction seems to be a key driver of pathology, the mechanisms linking a loss of GRN to a pathogenic state remain unclear. In our attempt to address these key issues, we have turned to the nematode, Caenorhabditis elegans, to model, study, and find potential therapies for GRN-deficient FTD. First, we show that the loss of the nematode GRN ortholog, pgrn-1, results in several behavioral and molecular defects, including lysosomal dysfunction and defects in autophagic flux. Our investigations implicate the sphingolipid metabolic pathway in the regulation of many of the in vivo defects associated with pgrn-1 loss. Finally, we utilized these nematodes as an in vivo tool for high-throughput drug screening and identified two small molecules with potential therapeutic applications against GRN/pgrn-1 deficiency. These compounds reverse the biochemical, cellular, and functional phenotypes of GRN deficiency. Together, our results open avenues for mechanistic and therapeutic research into the outcomes of GRN-related neurodegeneration, both genetic and molecular.

Paeonolide as a Novel Regulator of Core-Binding Factor Subunit Alpha-1 in Bone-Forming Cells.

Paeonia suffruticosa has been extensively used as a traditional medicine with various beneficial effects; paeonolide (PALI) was isolated from its dried roots. This study aimed to investigate the novel effects and mechanisms of PALI in pre-osteoblasts. Here, cell viability was evaluated using an MTT assay. Early and late osteoblast differentiation was examined by analyzing the activity of alkaline phosphatase (ALP) and by staining it with Alizarin red S (ARS). Cell migration was assessed using wound healing and Boyden chamber assays. Western blot and immunofluorescence analyses were used to examine the intracellular signaling pathways and differentiation proteins. PALI (0.1, 1, 10, 30, and 100 µM) showed no cytotoxic or proliferative effects in pre-osteoblasts. In the absence of cytotoxicity, PALI (1, 10, and 30 µM) promoted wound healing and transmigration during osteoblast differentiation. ALP staining demonstrated that PALI (1, 10, and 30 µM) promoted early osteoblast differentiation in a dose-dependent manner, and ARS staining showed an enhanced mineralized nodule formation, a key indicator of late osteoblast differentiation. Additionally, low concentrations of PALI (1 and 10 µM) increased the bone morphogenetic protein (BMP)-Smad1/5/8 and Wnt-ß-catenin pathways in osteoblast differentiation. Particularly, PALI (1 and 10 µM) increased the phosphorylation of ERK1/2 compared with BMP2 treatment, an FDA-approved drug for bone diseases. Furthermore, PALI-mediated early and late osteoblast differentiation was abolished in the presence of the ERK1/2 inhibitor U0126. PALI-induced RUNX2 (Cbfa1) expression and nuclear localization were also attenuated by blocking the ERK1/2 pathway during osteoblast differentiation. We suggest that PALI has biologically novel activities, such as enhanced osteoblast differentiation and bone mineralization mainly through the intracellular ERK1/2-RUNX2 signaling pathway, suggesting that PALI might have therapeutic action and aid the treatment and prevention of bone diseases, such as osteoporosis and periodontitis.

Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures.

Notch1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to development of resistance, thus restricting its clinical efficacy. Here, we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta. We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.

Acetovanillone prevents cyclophosphamide-induced acute lung injury by modulating PI3K/Akt/mTOR and Nrf2 signaling in rats.

Cyclophosphamide (CP) is a medication used as an anticancer drug and to suppress the immune system. However, its clinical applications are restricted because of the toxic and adverse side effects. The present study investigated the protective effect of acetovanillone (AV), a natural NADPH oxidase inhibitor, against acute lung injury (ALI) induced by CP. Rats were administered AV (100 mg/kg) for 10 days and a single injection of CP (200 mg/kg) at day 7. At the end of the experiment, the animals were sacrificed, and lung samples were collected for analyses. CP caused ALI manifested by the histopathological alterations. Lipid peroxidation and NADPH oxidase activity were increased, whereas GSH and antioxidant enzymes were decreased in the lung of CP-intoxicated rats. Oral administration of AV prevented CP-induced lung injury and oxidative stress and enhanced antioxidant defenses. AV downregulated Keap1 and upregulated Nrf2, GCLC, HO-1, and SOD3 mRNA. In addition, AV boosted the expression of PI3K, Akt, mTOR, and cytoglobin. In vitro, AV showed a synergistic anticancer effect when combined with CP. In conclusion, AV protected against CP-induced ALI by attenuating oxidative stress and boosting Nrf2/HO-1 and PI3K/Akt/mTOR signaling. Therefore, AV might represent a promising adjuvant to prevent lung injury in patients receiving CP.

Paeonol prevents migration and invasion, and promotes apoptosis of cervical cancer cells by inhibiting 5­lipoxygenase.

Cervical cancer is a common public health issue with high morbidity worldwide. Paeonol (Pae) has been recognized as a traditional Chinese medicine used for the treatment of various cancer types. However, whether Pae could exert a protective effect on cervical cancer remains to be investigated. The aim of the present study was to explore the role of Pae in cervical cancer cells and identify the potential mechanism. Cell Counting Kit­8 and colony­formation assays were conducted to test the proliferation of HeLa cells. Additionally, wound healing and transwell assays were used to detect the migratory and invasive abilities of cells. The plasmid that overexpressed 5­lipoxygenase (5­LO) or control vector was constructed and transfected into the cells. Subsequently, flow cytometry was used to monitor the apoptotic rate of cells. The expression levels of apoptosis­associated proteins and 5­LO were detected using western blot analysis. Reverse transcription­quantitative PCR analysis detected the expression of 5­LO. Pae inhibited the proliferation, invasion and migration of HeLa cells, promoted cell apoptosis and downregulated the expression of 5­LO. Overexpression of 5­LO, however, attenuated these effects. Thus, Pae could inhibit the proliferation, migration and invasion, as well as promote apoptosis of HeLa cells by regulating the expression of 5­LO.

Paeonol administration alleviates cognitive deficits and attenuates neural pathological changes in APP/PS1 mice.

Alzheimer's disease typically presents with impaired cognition and pathological morphologic changes, including the accumulation of amyloid-ß plaques. Disease-modifying drugs are in urgent need as neuroprotective therapies. Exploration of novel therapeutics for alleviating symptoms of Alzheimer's disease has found promise in plant extracts of functional phenols. Paeonol is a water-soluble phenolic substance that has been shown to confer diverse biological effects, including neuroprotection. An Alzheimer's disease model of APP/PS1 double transgenic mice was used in this study, and the therapeutic effects of paeonol were assessed after three weeks' administration. It was found that paeonol treatment significantly increased behavioral performance in the Morris water maze test and increased discrimination rate in the novel object recognition test compared to vehicle-treated APP/PS1 mice. Histologically, paeonol treatment significantly alleviated the Aß plaque burden, reduced neural loss, inhibited microglia activation, and decreased neuroinflammation in the brain of APP/PS1 mice. In addition, a number of Alzheimer's disease-related synaptic plasticity deficits were ameliorated. The present results indicate that paeonol significantly relieved amyloid-ß deposition and amyloid-ß -mediated neuropathology in the brain of APP/PS1 mice, suggesting the potential of paeonol as a preventive and therapeutic agent for Alzheimer's disease.

Design, synthesis of Cinnamyl-paeonol derivatives with 1, 3-Dioxypropyl as link arm and screening of tyrosinase inhibition activity in vitro.

This study aimed to obtain tyrosinase inhibitors for treating hyperpigmentation. A series of cinnamyl ester analogues were designed and synthesized with cinnamic acid (CA) and peaonol compounds. The safety, melanin content and inhibitory effects of all target compounds were evaluated. In the enzymatic activity test, the inhibitory rate of compounds 8, 13 and 14 had stronger inhibitory activity with the IC50 values of 20.7 µM, 13.98 µM and 15.16 µM, respectively than the positive drug kojic acid (IC50 with 30.83 µM). The cytotoxicity evaluation showed that compounds 13 and 14 have higher safety than the other compounds to the proliferation of B16F10 cells. The result of the melanocyte test supported that compound13 has stronger cellular tyrosinase inhibitory activity than kojic acid and arbutin at 100 µM and 200 µM. The enzyme kinetics mechanism revealed that compound 13 was a non-competitive inhibitor while compounds 8 and 14 were mixed inhibitors. For the experiments of melanin content and tyrosinase activity in the B16F10 melanona cells, the inhibition rates of compounds 8, 14 and 13 were with 19.62%, 20.59% and 23.83%, respectively. In addition, compound 13 revealed the highest inhibitory activity to tyrosinase in the melanocyte with inhibition rates of 23.83%, which was better than kojic acid and arbutin (19.21% and 20.45%) at the same concentration. In the anti-melanogenesis experiment, compounds 8 and 13 had better anti-melanin effects than kojic acid from 25 µM to 100 µM. In summary, the results indicated that compounds 8, 13 and 14 had better tyrosinase inhibitory activity and anti-melanogenesis activity. Especially, the compound 13 has potentiality to develop novel tyrosinase inhibitors and whitening agents. The docking studies results revealed that the functional group of compound 13 mostly depends on the phenolic hydroxyl moiety, and its hydroxyl group did not insert into the active site of tyrosinase, which was in agreement with the results of the kinetics study.

New lignans and acetophenone derivatives with α-glucosidase inhibitory activity from the leaves of Melicope patulinervia.

Four new lignans, patulinones A-D (1-4) and three new acetophenone derivatives, patulinones E-G (5-7) were isolated from the leaves of Melicope patulinervia. Their structures were elucidated on the basis of the interpretation of HR-ESIMS, NMR, CD data. All the isolated compounds were evaluated for α-glucosidase inhibitory activity. Of the isolates, compound 4 was found to exhibit the strongest inhibition against α-glucosidase with IC50 value of 6.02 ± 0.46 µM.

Cepharanthine and Curcumin inhibited mitochondrial apoptosis induced by PCV2.

BACKGROUND: Porcine circovirus type 2 (PCV2) is an immunosuppressive pathogen with high prevalence rate in pig farms. It has caused serious economic losses to the global pig industry. Due to the rapid mutation of PCV2 strain and co-infection of different genotypes, vaccination could not eradicate the infection of PCV2. It is necessary to screen and develop effective new compounds and explore their anti-apoptotic mechanism. The 13 natural compounds were purchased, with a clear plant origin, chemical structure and content and specific biological activities. RESULTS: The maximum no-cytotoxic concentration (MNTC) and 50% cytotoxic concentration (CC50) of 13 tested compounds were obtained by the cytopathologic effect (CPE) assay and (3-(4,5-dimethyithiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method in PK-15 cells. The results of qPCR and Western blot showed that, compared with the PCV2 infected group, the expression of Cap in Paeonol (0.4 mg/mL and 0.2 mg/mL), Cepharanthine (0.003 mg/mL, 0.0015 mg/mL and 0.00075 mg/mL) and Curcumin (0.02 mg/mL, 0.001 mg/mL and 0.005 mg/mL) treated groups were significantly lowered in a dose-dependent manner. The results of Annexin V-FITC/PI, JC-1, Western blot and ROS analysis showed that the expression of cleaved caspase-3 and Bax were up-regulated Bcl-2 was down-regulated in Cepharanthine or Curcumin treated groups, while ROS and MMP value were decreased at different degrees and the apoptosis rate was reduced. In this study, Ribavirin was used as a positive control. CONCLUSIONS: Paeonol, Cepharanthine and Curcumin have significant antiviral effect. And the PCV2-induced Mitochondrial apoptosis was mainly remitted by Cepharanthine and Curcumin.

Effects of Paeonol and Gastroretention Tablets of Paeonol on Experimental Gastric Ulcers and Intestinal Flora in Rats.

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