Hispidulin Alleviates Mast Cell-Mediated Allergic Airway Inflammation through FcεR1 and Nrf2/HO-1 Signaling Pathway.

Allergic asthma is a type 2 immune-response-mediated chronic respiratory disease. Mast cell activation influences the pathogenesis and exacerbation of allergic asthma. Therefore, the development of mast cell-targeting pharmacotherapy is important for managing allergic airway inflammation. We investigated the efficacy of hispidulin (HPD), natural flavone, in a mast-cell-mediated ovalbumin (OVA)-induced allergic airway inflammation model. HPD alleviated symptoms of allergic asthma and decreased the levels of immunoglobulin (Ig) E, type 2 inflammation, immune cell infiltration, and mast cell activation in the lung. Furthermore, in vivo analysis confirmed the efficacy of HPD through the evaluation of IgE-mediated allergic responses in a mast cell line. HPD treatment inhibited mast cell degranulation through inhibition of the FcεR1 signaling pathway and suppressed the expression of inflammatory cytokines (TNF-α, IL-4, IL-6, and IL-13) through suppression of the NF-κB signaling pathway. The antioxidant effects of HPD in activated mast cells were identified through modulation of antioxidant enzymes and the Nrf2/HO-1 signaling pathway. In conclusion, HPD may be a potential therapeutic candidate for allergic airway inflammation of asthma and acts by suppressing mast cell activation and oxidative stress.

The bioflavonoid hispidulin effectively attenuates T helper type 2-driven allergic lung inflammation in the ovalbumin-induced allergic asthma mouse model.

BACKGROUND: Allergic asthma affects nearly 300 million people worldwide and causes ahigh burden of disability and death. Effective treatments rely heavily on corticosteroids, which are associated with various complications. So, the alternative treatment is of significance. Hispidulin is a bioflavonoid found in herbs that were used in traditional medicine to treat inflammatory diseases, including asthma. This study aims to investigate the efficacy of hispidulin compound in the treatment of allergic lung inflammation using the mouse model of allergic asthma. METHODS: BALB/c mice were sensitized and challenged with chicken egg ovalbumin. Cells and cytokines from bronchoalveolar lavage (BAL) fluid were examined. Lung tissues were collected for histologic study. Mouse splenic CD4+ cells were cultured to observe the effect of hispidulin on T-helper 2 (Th2) cell differentiation in vitro. RESULTS: Hispidulin treatment could alleviate allergic airway inflammation as evidenced by a significant reduction in the inflammatory cell count and Th2 cytokines interleukin (IL)-4, IL-5, IL-13 in BAL fluid. Histologic examination of lung tissues revealed lower inflammatory cell infiltration to the bronchi and less airway goblet cell hyperplasia in the treatment group compared to the control group. At the cellular level, hispidulin (25, 50, and 100 µM) was found to directly suppress the differentiation and proliferation of Th2 cells and to suppress the production of Th2 cytokines, such as IL-4, IL-5, and IL-13, in vitro. CONCLUSIONS: Hispidulin treatment was shown to effectively decrease type 2 lung inflammation in an ovalbumin-induced allergic asthma mouse model by directly suppressing Th2 cell differentiation and functions.

Hispidulin exerts a protective effect against oleic acid induced-ARDS in the rat via inhibition of ACE activity and MAPK pathway.

This study investigates the protective role of Hispidulin on acute respiratory distress syndrome (ARDS) in rats. Rats were divided into three groups: control, ARDS, ARDS+ Hispidulin. The ARDS models were established by injecting rats with oleic acid. Hispidulin (100 mg/kg) was injected i.p. an hour before ARDS. Myeloperoxidase (MPO), Interleukin-8 (IL-8), Mitogen-activated protein kinases (MAPK), Lipid Peroxidation (LPO), Superoxide Dismutase (SOD), Glutathione (GSH), and Angiotensin-converting enzyme (ACE) were determined by ELISA. Tumor necrosis factor-alpha (TNF-α) expression was described by RT-qPCR. Caspase-3 immunostaining was performed to evaluate apoptosis. Compared with the model group, a significant decrease was observed in the MPO, IL-8, MAPK, ACE, LPO levels, and TNF-α expression in the ARDS+ Hispidulin group. Moreover, reduced caspase-3 immunoreactivity and activity of ACE were detected in the Hispidulin+ARDS group. The protective effect of Hispidulin treatment may act through inhibition of the ACE activity and then regulation of inflammatory cytokine level and alteration of apoptosis.

Hispidulin: a promising anticancer agent and mechanistic breakthrough for targeted cancer therapy.

Cancer is a complex disease characterized by dysregulated cell growth and division, posing significant challenges for effective treatment. Hispidulin, a flavonoid compound, has shown promising biological effects, particularly in the field of anticancer research. The main objective of this study is to investigate the anticancer properties of hispidulin and gain insight into its mechanistic targets in cancer cells. A comprehensive literature review was conducted to collect data on the anticancer effects of hispidulin. In vitro and in vivo studies were analyzed to identify the molecular targets and underlying mechanisms through which hispidulin exerts its anticancer activities. Hispidulin has shown significant effects on various aspects of cancer, including cell growth, proliferation, cell cycle regulation, angiogenesis, metastasis, and apoptosis. It has been observed to target both extrinsic and intrinsic apoptotic pathways, regulate cell cycle arrest, and modulate cancer progression pathways. The existing literature highlights the potential of hispidulin as a potent anticancer agent. Hispidulin exhibits promising potential as a therapeutic agent for cancer treatment. Its ability to induce apoptosis and modulate key molecular targets involved in cancer progression makes it a valuable candidate for further investigation. Additional pharmacological studies are needed to fully understand the specific targets and signaling pathways influenced by hispidulin in different types of cancer. Further research will contribute to the successful translation of hispidulin into clinical settings, allowing its utilization in conventional and advanced cancer therapies with improved therapeutic outcomes and reduced side effects.

[Effect of Hispidulin on Proliferation and Apoptosis of Leukemia K562 Cells by Up-Regulating IL-37].

OBJECTIVE: To investigate the effect and underlying mechanism of hispidulin on the proliferation and apoptosis of leukemia K562 cells. METHODS: K562 cells were cultured in vitro and treated with 0, 5, 25 or 100 µmol/L hispidulin for 24 h. Cell proliferation and apoptosis were detected by CCK-8 and flow cytometry, respectively. Western blot was used to assess the expression of Bax, Bcl-2 and interleukin (IL)-37 proteins. Bone marrow mononuclear cells were extracted from 17 chronic myeloid leukemia patients and 21 healthy individuals by Ficoll-Hypaque density gradient method, and the expression of IL-37 protein was measured by Western blot. K562 cells with IL-37 overexpression or knockdown were constructed, and then treated with 0 or 100 µmol/L hispidulin for 24 h. Cell proliferation, apoptosis and protein expression of Bax and Bcl-2 were determined in the same way as above. RESULTS: After K562 cells were treated with hispidulin, the cell inhibition rate, apoptosis rate, and the protein expression of Bax and IL-37 were significantly increased (P <0.05), but the cell proliferation and expression of Bcl-2 protein were decreased (P <0.05). The expression of IL-37 protein in bone marrow mononuclear cells of the leukemia patient was 0.24±0.03, which was significantly lower than 0.91±0.05 of healthy controls (P <0.05). Overexpression of IL-37 significantly promoted inhibition rate, apoptosis rate, and expression of Bax protein in K562 cells (P <0.05), but suppressed the expression of Bcl-2 protein (P <0.05). In addition, knockdown of IL-37 could reverse the effects of hispidulin on proliferation and apoptosis of K562 cells. CONCLUSION: Hispidulin inhibits the proliferation and induces apoptosis of leukemia K562 cells, which may be related to the up-regulation of IL-37 protein in cells.

Hispidulin Inhibits the Vascular Inflammation Triggered by Porphyromonas gingivalis Lipopolysaccharide.

Hispidulin is a natural bioactive flavonoid that has been studied for its potential therapeutic properties, including its anti-inflammatory, antioxidant, and neuroprotective effects. The aim of this study was to explore whether hispidulin could inhibit the endothelial inflammation triggered by Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS). The adhesion of monocytes to the vascular endothelium was evaluated through in vitro and ex vivo monocyte adhesion assays. We analyzed the migration of monocytes across the endothelial layer using a transmigration assay. The results showed that treatment with hispidulin decreased the P. gingivalis LPS-induced adhesion of monocytes to endothelial cells and their migration by suppressing the P. gingivalis LPS-triggered expression of intercellular adhesion molecule-1 (ICAM-1) through downregulating nuclear factor-қB (NF-қB). In addition, hispidulin inhibited P. gingivalis LPS-induced mitogen-activated protein kinases (MAPKs) and AKT in endothelial cells. Altogether, the results indicate that hispidulin suppresses the vascular inflammation induced by P. gingivalis LPS. Mechanistically, it prevents the adhesion of monocytes to the vascular endothelium and migration and inhibits NF-қB, MAPKs, and AKT signaling in endothelial cells.

Effect of Hispidulin on Proliferation and Apoptosis of Leukemia K562 Cells by Up-Regulating IL-37 / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect and underlying mechanism of hispidulin on the proliferation and apoptosis of leukemia K562 cells.@*METHODS@#K562 cells were cultured in vitro and treated with 0, 5, 25 or 100 μmol/L hispidulin for 24 h. Cell proliferation and apoptosis were detected by CCK-8 and flow cytometry, respectively. Western blot was used to assess the expression of Bax, Bcl-2 and interleukin (IL)-37 proteins. Bone marrow mononuclear cells were extracted from 17 chronic myeloid leukemia patients and 21 healthy individuals by Ficoll-Hypaque density gradient method, and the expression of IL-37 protein was measured by Western blot. K562 cells with IL-37 overexpression or knockdown were constructed, and then treated with 0 or 100 μmol/L hispidulin for 24 h. Cell proliferation, apoptosis and protein expression of Bax and Bcl-2 were determined in the same way as above.@*RESULTS@#After K562 cells were treated with hispidulin, the cell inhibition rate, apoptosis rate, and the protein expression of Bax and IL-37 were significantly increased (P <0.05), but the cell proliferation and expression of Bcl-2 protein were decreased (P <0.05). The expression of IL-37 protein in bone marrow mononuclear cells of the leukemia patient was 0.24±0.03, which was significantly lower than 0.91±0.05 of healthy controls (P <0.05). Overexpression of IL-37 significantly promoted inhibition rate, apoptosis rate, and expression of Bax protein in K562 cells (P <0.05), but suppressed the expression of Bcl-2 protein (P <0.05). In addition, knockdown of IL-37 could reverse the effects of hispidulin on proliferation and apoptosis of K562 cells.@*CONCLUSION@#Hispidulin inhibits the proliferation and induces apoptosis of leukemia K562 cells, which may be related to the up-regulation of IL-37 protein in cells.

Flavonoids and phenylethanoids from the flowers and leaves of Aeschynanthus species and cultivars (Gesneriaceae).

Forty-one flavones, each one of flavonol, chalcone and dihydroflavonol, two flavanones, and four phenylethanoids were isolated from corollas, calyces and leaves of two Aeschynanthus species, A. fulgens and A. pulcher, and six cultivars, 'Mahligai', 'Mona Lisa', SoeKa', 'Redona', 'Freshya' and 'Bravera'. Flavonoids were mainly the glucuronides and/or methylglucuronides based on hispidulin, nepetin, pectolinarigenin, 6-hydroxyluteolin, scutellarein, apigenin and luteolin, and identified by UV spectra, HR-MS, LC-MS, acid hydrolysis, NMR, and/or HPLC and TLC comparisons with authentic samples. Of these flavonoids, twelve, i.e. hispidulin 7,4'-di-O-glucuronide, 7,4'-di-O-methylglucuronide, 7-O-methylglucuronide-4'-O-glucuronide, 7-O-glucuronide-4'-O-methylglucuronide, 7-O-glucosyl-(1 â†’ 2)-glucuronide and 8-C-glucoside, nepetin 7,4'-di-O-glucuronide, 7-O-glucuronide-4'-O-methylglucuronide and 7-O-methylglucuronide-4'-O-glucuronide, pectolinarigenin 7-O-glucosyl-(1 â†’ 2)-glucuronide and 7-O-xylosyl-(1 â†’ 2)-(6″-malonylglucoside), and 6-hydroxyluteolin 7,4'-di-O-glucuronide, were previously undescribed.

Natural flavone hispidulin protects mice from Staphylococcus aureus pneumonia by inhibition of α-hemolysin production via targeting AgrAC.

The emergence of drug-resistant Staphylococcus aureus (S. aureus) has limited drug options for the clinical treatment of S. aureus infections. Considering recent reports, therapeutic strategies targeting bacterial virulence hold great promise, and alpha-hemolysin (encoded by hla), a critical virulence factor of S. aureus, plays a vital role during bacterial infection. Herein, we demonstrated that hispidulin effectively inhibited the hemolytic activity of S. aureus USA300 without suppressing bacterial growth, along with inhibiting hla transcription and expression in a dose-dependent manner. As heptamer formation is essential for hla-mediated invasion of cells, nevertheless, hispidulin did not affect the deoxycholate-induced oligomerization of hla, suggesting that hispidulin did not affect the protein activity of hla. In vitro assays illustrated that hispidulin bound to agrAC, a crucial protein in quorum sensing. Meanwhile, hispidulin alleviated A549 cell damage caused by S. aureus USA300 and reduced lactate dehydrogenase release. In vivo studies showed that hispidulin had a protective effect against pneumonia caused by S. aureus USA300 in mice. S. aureus did not develop resistance to hispidulin in the short term. Interestingly, our research indicated that hispidulin synergized with the antibacterial activity of cefoxitin. These results showed that hispidulin effectively inhibited α-hemolysin expression by inhibiting the agr quorum sensing of S. aureus. It has promise as an agent to treat S. aureus infection.

The potential effects and mechanisms of hispidulin in the treatment of diabetic retinopathy based on network pharmacology.

BACKGROUND: Diabetic retinopathy (DR), one of the most common and severe microvascular complication of diabetes mellitus (DM), is mainly caused by diabetic metabolic disorder. So far, there is no effective treatment for DR. Eriocauli Flos, a traditional Chinese herb, has been used in treating the ophthalmic diseases including DR. However, the active ingredients and molecular mechanisms of Eriocauli Flos to treat diabetic retinopathy remain elusive. METHODS: Here, the systems pharmacology model was developed via constructing network approach. 8 active components which were screened by oral bioavailability (OB ≥ 30%) and drug-likeness (DL ≥ 0.18) and 154 targets were selected from Eriocauli Flos through TCMSP database. Another 3593 targets related to DR were obtained from Genecards, OMIM, TTD, and Drugbank databases. The 103 intersecting targets of DR and Eriocauli Flos were obtained by Draw Venn Diagram. In addition, protein-protein interaction network was established from STRING database and the compound-target network was constructed by Cytoscape which screened top 12 core targets with cytoNCA module. Then the overlapping targets were analyzed by GO and KEGG enrichment. Moreover, two core targets were selected to perform molecular docking simulation. Subsequently, CCK8 assay, RT-PCR and Western blotting were applied to further reveal the mechanism of new candidate active component from Eriocauli Flos in high glucose-induced HRECs. RESULTS: The results showed that the overlapping targets by GO analysis were enriched in cellular response to chemical stress, response to oxidative stress, response to reactive oxygen species, reactive oxygen species metabolic process and so on. Besides, the overlapping targets principally regulated pathways such as AGE-RAGE signaling pathway in diabetic complications, lipid atherosclerosis, fluid shear stress and atherosclerosis, and PI3K-Akt signaling pathway. Molecular docking exhibited that VEGFA and TNF-α, had good bindings to the great majority of compounds, especially the compound hispidulin. In vitro, hispidulin ameliorated high-glucose induced proliferation by down-regulating the expression of p-ERK, p-Akt, and VEGFA; meanwhile inhibited the mRNA levels of TNF-α. CONCLUSIONS: In this study, through network pharmacology analysis and experimental validation, we found that hispidulin maybe has a potential targeted therapy effect for DR by decreasing the expression of p-Akt, p-ERK, and VEGFA, which resulted in ameliorating the proliferation in HRECs.

Phytochemical Combination (p-Synephrine, p-Octopamine Hydrochloride, and Hispidulin) for Improving Obesity in Obese Mice Induced by High-Fat Diet.

Obesity treatment efficiency can be increased by targeting both central and peripheral pathways. In a previous study, we identified two natural compounds (hispidulin and p-synephrine) that affect adipocyte differentiation. We tested whether obesity treatment efficiency may be improved by adding an appetite-controlling agent to the treatment in the present study. Alkaloids, such as p-octopamine, are adrenergic agonists and are thus used as dietary supplements to achieve weight loss. Here, we assessed anti-obesity effects of a mixture of p-synephrine, p-octopamine HCl, and hispidulin (SOH) on murine preadipocyte cells and on mice receiving a high-fat diet (HFD). SOH showed stronger inhibition of the formation of red-stained lipid droplets than co-treatment with hispidulin and p-synephrine. Moreover, SOH reduced the expression of adipogenic marker proteins, including CCAAT/enhancer-binding protein alpha, CCAAT/enhancer-binding protein beta, and peroxisome proliferator-activated receptor gamma. In the HFD-induced obesity model, body weight and dietary intake were lower in mice treated with SOH than in the controls. Additionally, liver weight and the levels of alanine aminotransferase and total cholesterol were lower in SOH-treated mice than in the controls. In conclusion, our results suggest that consumption of SOH may be a potential alternative strategy to counteract obesity.

Synergistic immunosuppressive effect of hispidulin and nepetin mixtures on human T lymphocytes.

BACKGROUND: Clerodendrum petasites S. Moore predominantly contains hispidulin (His) and nepetin (Nep) which are immunosuppressive potentials. Although the effect of individual compounds was previously confirmed, a cumulative suppression of these flavonoid mixtures is unknown. This study thus investigated their inhibitory effects and cytotoxicity on T cells by using His:Nep ratios following a naturally occurring dose (3:1) and optimized doses (1:1 and 1:3). MATERIALS AND METHODS: Anti-CD3/28 stimulated peripheral blood mononuclear cells were treated with individual compounds and their mixtures. Changes in early cell activation markers in activated T cells and apoptosis were analyzed by a flow cytometer. RESULTS: Mixtures at 3:1 suppressed CD69 and CD25 expression in CD4+ and CD8+ T cells in a dose-dependent manner. At the highest concentration of 200 µM His + 66.7 µM Nep, over 90% inhibition was observed for CD25 expression in CD4+ and CD8+ T cells, whereas a lesser effect was observed for CD69 expression. A dose-dependent inhibition was still observed when using 1:1 and 1:3 ratios. Interestingly, 80-97% inhibition were observed in CD69 and CD25 expression without inducing cell death after treated with the highest doses of each ratio (66.7 µM His + 200 µM Nep and 200 µM His + 200 µM Nep). These mixtures were also exhibited a better suppression than individual compounds. CONCLUSIONS: The optimized mixture of His and Nep at 66.7:200 µM is suggested for further study due to a greater suppressive effect than a single compound or a naturally-occurring dose.

Antioxidant properties of hispidulin.

There are conflicting reports on the antioxidant activity of hispidulin. Antioxidant activity of hispidulin was evaluated using assays of ABTS• reduction, ferric ion reducing antioxidant power (FRAP) assay, DPPH reduction assay, and protection of erythrocyte membranes against lipid peroxidation and protein thiol oxidation. ABTS• reduction assay pointed to the involvement of all three phenol groups of hispidulin in ABTS• reduction. The reactivity of hispidulin in the FRAP assay and DPPH reduction assay was low (0.09 and 0.019 of the reactivity of Trolox). However, hispidulin was effective in protection against erythrocyte membrane lipid peroxidation and highly effective in protection against erythrocyte membrane protein thiol group oxidation (more effective than Trolox). These results point to the necessity of caution in extrapolating the antioxidant activity evaluated in simple cell-free systems on more complex systems.

Combined Anti-Adipogenic Effects of Hispidulin and p-Synephrine on 3T3-L1 Adipocytes.

Hispidulin is abundant in Arrabidaea chica, Crossostephium chinense, and Grindelia argentina, among others. p-Synephrine is the main phytochemical constituent of Citrus aurantium. It has been used in combination with various other phytochemicals to determine synergistic effects in studies involving human participants. However, there have been no reports comparing the anti-adipogenic effects of the combination of hispidulin and p-synephrine. The current study explores the anti-adipogenic effects of hispidulin alone and in combination with p-synephrine in a murine preadipocyte cell line, 3T3-L1. Co-treatment resulted in a greater inhibition of the formation of red-labeled lipid droplets than the hispidulin or p-synephrine-alone treatments. Co-treatment with hispidulin and p-synephrine also significantly inhibited adipogenic marker proteins, including Akt, mitogen-activated protein kinases, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha, glucocorticoid receptor, and CCAAT/enhancer-binding protein ß. Although further studies are required to assess the effects of each drug on pharmacokinetic parameters, a combination treatment with hispidulin and p-synephrine may be a potential alternative strategy for developing novel anti-obesity drugs.

Anti-Proliferative and Anti-Migratory Activities of Hispidulin on Human Melanoma A2058 Cells.

Melanoma represents less than 5% of skin cancers, but is the most lethal, mainly because of its high-metastatic potential and resistance to various therapies. Therefore, it is important to develop effective treatments, especially chemotherapeutic drugs with cytotoxicity, anti-metastaticity, and few side effects. One such natural product is hispidulin, a flavone distributed in plants of the Asteraceae. Previous studies have demonstrated that hispidulin has various pharmacological benefits, such as anti-tumor, anti-inflammation, and anti-allergic effects. This study aims to explore the effects of hispidulin against melanoma in vitro and in vivo. Results revealed that hispidulin selectively decreased the cell viability of A2058 cells in a dose- and time-dependent manner. Hispidulin induced cells accumulated in the sub-G1 phase via activating caspase 8 and 9, increased cleaved caspase 3, and cleaved PARP expression. Hispidulin was able to decrease AKT and ERK phosphorylation, which facilitated cell growth and survival. Moreover, hispidulin promoted reactive oxygen species generation in cells and suppressed cell migration through downregulated matrix metalloproteinase-2 expression. Hispidulin significantly inhibited tumor growth in a xenograft model. Based on these results, hispidulin produces its anti-melanoma effects by inducing cancer cell apoptosis and reducing its migration. Therefore, we suggest hispidulin as a potent therapeutic candidate for melanoma treatment.

The Effect of Hispidulin, a Flavonoid from Salvia plebeia, on Human Nasopharyngeal Carcinoma CNE-2Z Cell Proliferation, Migration, Invasion, and Apoptosis.

Nasopharyngeal carcinoma (NPC) is a common malignant head and neck tumor. Drug resistance and distant metastasis are the predominant cause of treatment failure in NPC patients. Hispidulin is a flavonoid extracted from the bioassay-guided separation of the EtOH extract of Salvia plebeia with strong anti-proliferative activity in nasopharyngeal carcinoma cells (CNE-2Z). In this study, the effects of hispidulin on proliferation, invasion, migration, and apoptosis were investigated in CNE-2Z cells. The [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay and the colony formation assay revealed that hispidulin could inhibit CNE-2Z cell proliferation. Hispidulin (25, 50, 100 µM) also induced apoptosis in a dose-dependent manner in CNE-2Z cells. The expression of Akt was reduced, and the expression of the ratio of Bax/Bcl-2 was increased. In addition, scratch wound and transwell assays proved that hispidulin (6.25, 12.5, 25 µM) could inhibited the migration and invasion in CNE-2Z cells. The expressions of HIF-1α, MMP-9, and MMP-2 were decreased, while the MMPs inhibitor TIMP1 was enhanced by hispidulin. Moreover, hispidulin exhibited potent suppression tumor growth and low toxicity in CNE-2Z cancer-bearing mice at a dosage of 20 mg/kg/day. Thus, hispidulin appears to be a potentially effective agent for NPC treatment.

Hispidulin alleviates 2,4-dinitrochlorobenzene and house dust mite extract-induced atopic dermatitis-like skin inflammation.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder that affects 10-20% of the world's population. Therefore, the discovery of drugs for the treatment of AD is important for human health. Hispidulin (HPD; also known as scutellarein 6-methyl ether or dinatin) is a natural flavone that exerts anti-inflammatory effects. In the present study, the effectiveness of HPD on AD-like skin inflammation was investigated. We used a mouse AD model through repeated exposure of mice to 2,4-dinitrochlorobenzene and house dust mite extract (Dermatophagoides farinae extract, DFE) to the ears. In addition, tumor necrosis factor-α and interferon-γ-activated keratinocytes (HaCaT cells) were used to investigate the underlying mechanism of HPD action. Oral administration of HPD alleviated AD-like skin inflammations: it reduced ear thickness; serum immunoglobulin (Ig)E, DFE-specific IgE, and IgG2a levels; and inflammatory cell infiltration. HPD reduced the expression of pro-inflammatory cytokines and chemokines through inhibition of signal transducer and activator of transcription 1 nuclear factor-κB in HaCaT cells. Taken together, these results suggest that HPD could be a potential drug candidate for the treatment of AD.

Hispidulin modulates epithelial-mesenchymal transition in breast cancer cells.

Breast cancer is the most commonly diagnosed cancer worldwide. Despite the use of chemotherapeutic drugs, drug resistance has been observed in numerous patients with breast cancer. Epithelial-mesenchymal transition (EMT) is an important initiation step in the process of metastasis, whereby cancer cells move away from the original tumor site. Therefore, the discovery of new substances that suppress EMT is a promising avenue for cancer treatment. The present study investigated the effect of hispidulin, a polyphenolic flavonoid, on EMT in human breast cancer cells in vitro (MCF-7 and HCC38). The EMT-associated mRNA and protein expression levels were measured using reverse transcription-quantitative PCR or western blot analysis. Hispidulin treatment increased the expression levels of EMT-associated epithelial markers and decreased the expression levels of mesenchymal markers in both cells. Transforming growth factor-ß1 (TGF-ß1) treatment increased breast cancer cell viability (assessed via MTS assay) and EMT induction. However, hispidulin and TGF-ß1 co-treatment increased the expression levels of E-cadherin and occludin, while downregulating vimentin expression. Additionally, hispidulin treatment inhibited TGF-ß1-induced Smad2/3 signaling and cell migration in both breast cancer cell lines. Overall, the current findings suggested that hispidulin may inhibit EMT and cell migration by suppressing the Smad2/3 signaling pathway in breast cancer cells.

Hispidulin inhibits proliferation, migration, and invasion by promoting autophagy via regulation of PPARγ activation in prostate cancer cells and xenograft models.

Prostate cancer (PCa) is one of the important factors of cancer deaths especially in the western countries. Hispidulin (4',5,7-trihydroxy-6-methoxyflavone) is a phenolic flavonoid compound proved to possess anticancer properties, but its effects on PCa are left to be released. The aims of this study were to investigate the effects and the relative mechanisms of Hispidulin on PCa development. Hispidulin administration inhibited proliferation, invasion, and migration, while accelerated apoptosis in Du145 and VCaP cells, which was accompanied by PPARγ activation and autophagy enhancement. The beneficial effects of Hispidulin could be diminished by PPARγ inhibition. Besides, Hispidulin administration suppressed PCa tumorigenicity in Xenograft models, indicating the anticancer properties in vivo. Therefore, our work revealed that the anticancer properties of Hispidulin might be conferred by its activation on PPARγ and autophagy.

The antiaging property of aqueous extract of Millingtonia hortensis flowers in aging neuron.

Cellular senescence is the key mediator of cellular dysfunction before undergoing degenerative disease such as Alzheimer's disease. The aging process was mainly by the overactivation of senescence associated ß-galactosidase (SA-ß-gal) enzyme before mediated several negative responses, including intracellular reactive oxygen species (ROS) production, cellular senescence regulation, and death prior encourage synaptic loss. Thus, in the recent work, we evaluated the in vitro effects of aqueous extract of Millingtonia hortensis L. (MH) from flower in hydrogen peroxide (H2O2)-induced senescence in SK-N-SH cells. Herein, we demonstrated that MH significantly increased cell viability and decreased both of apoptotic cells and ROS production in a dose-dependent manner comparing to aging group (P < 0.01) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, and ROS assay. Furthermore, the number of SA-ß-gal-positive cells was also reduced in MH treatment (P < 0.01) together with the promotion of Sirt-1 protein. Importantly, MH also promoted the synaptic plasticity by decreased acetylcholinesterase activity and increased synaptophysin expression in aging neurons comparing to aging group (P < 0.01). Hispidulin (the active ingredient in MH) was also revealed the similarly effects to MH. Therefore, we suggested that MH might be beneficially for neurodegenerative disease that caused by aging.