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Peucedanum japonicum Thunberg (PJT) has been used in traditional medicine to treat colds, coughs, fevers and other inflammatory diseases. The goal of this study was to investigate whether 3'-isovaleryl-4'-senecioylkhellactone (IVSK) from PJT has anti-inflammatory effects on lung epithelial cells. Anti-inflammatory effects of IVSK was evaluated using phorbol 12-myristate 13-acetate (PMA)-stimulated A549 cells and regular human lung epithelial cells as a reference. IVSK reduced the secretion of inflammatory mediators, interleukin (IL)-8 and monocyte chemoattractant protein-1 (MCP-1) and the mRNA expression of IL-6, IL-8, MCP-1 and IL-1β. Additionally, it inhibited the phosphorylation of IκB kinase (IKK), p65, Iκ-Bα and mitogen-activated protein kinases (MAPKs) p38, JNK, and ERK in A549 cells stimulated with PMA. Moreover, the binding affinity of activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) was significantly reduced in the luciferase assay, and nuclear translocation was markedly inhibited by IVSK in the immunocytochemistry. These findings indicate that IVSK can protect against inflammation through the AP-1 and NF-κB pathway and could possibly be used as a lead compound for the treatment of inflammatory lung diseases.

Lagerstroemia ovalifolia Teijsm. & Binn. (LO) (crape myrtle) has reportedly been used as traditional herbal medicine (THM) in Java, Indonesia. Our previous study revealed that the LO leaf extract (LOLE) exerted anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Based on this finding, the current study aimed to evaluate the protective effects of LOLE in a mouse model of LPS-induced acute lung injury (ALI). The results showed that treatment with LPS enhanced the inflammatory cell influx into the lungs and increased the number of macrophages and the secretion of the inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) of mice. However, these effects were notably abrogated with LOLE pretreatment. Furthermore, the increase of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1) expression in the lung tissues of mice with ALI was also reversed by LOLE. In addition, LOLE significantly suppressed the LPS-induced activation of the MAPK/NF-κB signaling pathway and led to heme oxygenase-1 (HO-1) induction in the lungs. Additionally, in vitro experiments showed that LOLE enhanced the expression of HO-1 in RAW264.7 macrophages. The aforementioned findings collectively indicate that LOLE exerts an ameliorative effect on inflammatory response in the airway of ALI mice.

Objective We investigated whether purpurin inhibits various pathways of inflammation leading to atopic dermatitis. Introduction 1,2,4-Trihydroxyanthraquinone, commonly called purpurin, is an anthraquinone that is a naturally occurring red/yellow dye. Purpurin is a highly antioxidative anthraquinone and previous studies have reported antibacterial, anti-tumor, and anti-oxidation activities in cells and animals. However, the skin inflammatory inhibition activity mechanism study of purpurin has not been elucidated in vitro. Methods In this study, we investigated the anti-inflammatory activity of purpurin in HaCaT (human keratinocyte) cell lines stimulated with a mixture of tumor necrosis factor-alpha (TNF-α)/Interferon-gamma (IFN-γ). The inhibitory effect of Purpurin on cytokines (IL-6, IL-8, and IL-1β) and chemokine (TARC, MDC, and RANTES) was confirmed by ELISA and RT-qPCR. We investigated each signaling pathway and the action of inhibitors through western blots. Results The expression levels of cytokines and chemokines were dose-dependently suppressed by purpurin treatment in TNF-α/IFN-γ-induced HaCaT cells from ELISA and real-time PCR. Purpurin also inhibited protein kinase B (AKT), mitogen-activated protein kinase (MAPKs), and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) activation in TNF-α/IFN-γ-stimulated HaCaT cells. Additionally, there was a synergistic effect when purpurin and inhibitor were applied together, and inflammation was dramatically reduced. Conclusion Therefore, these results demonstrate that purpurin exhibits anti-inflammatory and anti-atopic dermatitis activity in HaCaT cells.

A number of species of the genus Trichilia (Meliaceae) exhibit anti-inflammatory effects. However, the effect of Trichilia martiana C. DC. (TM) on lipopolysaccharide (LPS)-induced inflammation has not, to the best of our knowledge, yet been determined. Therefore, in the present study, the anti-inflammatory effect of TM on LPS-stimulated RAW264.7 macrophages was evaluated. The ethanol extract of TM (TMEE) significantly inhibited LPS-induced nitric oxide (NO), prostaglandin 2 (PGE2), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). TMEE also reduced the levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and IL-6. The upregulation of mitogen-activated protein kinases (MAPKs) and NF-κB activation was revealed to be downregulated following TMEE pretreatment. Furthermore, TMEE was indicated to lead to the nucleus translocation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1). In H292 airway epithelial cells, the pretreatment of TMEE significantly downregulated the production of LPS-stimulated IL-1β, and TMEE was indicated to increase the expression of HO-1. In animal models exhibiting LPS-induced acute lung injury (ALI), treatment with TMEE reduced the levels of macrophages influx and TNF-α production in the bronchoalveolar lavage fluid (BALF) of ALI mice. Additionally, TMEE significantly downregulated the activation of ERK, JNK and IκB, and upregulated the expression of HO-1 in the lungs of ALI mice. In conclusion, the results of the current study demonstrated that TMEE could exert a regulatory role in the prevention or treatment of the endotoxin-mediated inflammatory response.

Sophora flavescens is used as a traditional herbal medicine to modulate inflammatory responses. However, little is known about the impact of (‐)‐maackiain, a compound derived from S. flavescens, on the activation of inflammasome/caspase‐1, a key factor in interleukin‐1β (IL‐1β) processing. Here, we report that (‐)‐maackiain potently amplified caspase‐1 cleavage in macrophages in response to nigericin (Nig). In macrophages primed with either lipopolysaccharide or monophosphoryl lipid A, Nig‐mediated caspase‐1 cleavage was also markedly promoted by (‐)‐maackiain. Notably, (‐)‐maackiain induced the production of vimentin, an essential mediator for the activation of the NOD‐, LRR‐, and pyrin domain‐containing protein 3 inflammasome, thereby contributing to promotion of the formation of the inflammasome complex to activate caspase‐1. Taken together, our data suggest that (‐)‐maackiain exerts an immunostimulatory effect by promoting IL‐1β production via activation of the inflammasome/caspase‐1 pathway. Thus, the potent inflammasome‐activating effect of (‐)‐maackiain may be clinically useful as an acute immune‐stimulating agent., Proinflammatory cytokine interleukin‐1β (IL‐1β) plays critical roles in defending against infections. Sophora flavescens‐derived (‐)‐maackiain potently amplifies caspase‐1 cleavage in response to nigericin. Notably, (‐)‐maackiain promotes caspase‐1 cleavage and IL‐1β production even in monophosphoryl lipid A‐primed macrophages. The potent inflammasome‐activating effect of (‐)‐maackiain may be clinically useful as an acute immune‐stimulating agent.

Methyl p-hydroxycinnamate (MH), an esterified derivative of p-Coumaric acid exerts anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Based on these effects, the present study investigated the protective role of MH in a mouse model of LPS-induced acute respiratory distress syndrome (ARDS). The results demonstrated that administration of LPS (5 mg/kg intranasally) markedly increased the neutrophil/macrophage numbers and levels of inflammatory molecules (TNF-α, IL-6, IL-1β and reactive oxygen species) in the bronchoalveolar lavage fluid (BALF) of mice. On histological examination, the presence of inflammatory cells was observed in the lungs of mice administered LPS. LPS also notably upregulated the secretion of monocyte chemoattractant protein-1 and protein content in BALF as well as expression of inducible nitric oxide synthase in the lungs of mice; it also caused activation of p38 mitogen-activated protein kinase (MAPK) and NF-κB signaling. However, MH treatment significantly suppressed LPS-induced upregulation of inflammatory cell recruitment, inflammatory molecule levels and p38MAPK/NF-κB activation, and also led to upregulation of heme oxygenase-1 (HO-1) expression in the lungs of mice. In addition, the ability of MH to induce HO-1 expression was confirmed in RAW264.7 macrophages. Taken together, the findings of the present study indicated that MH may exert protective effects against airway inflammation in ARDS mice by inhibiting inflammatory cell recruitment and the production of inflammatory molecules.

Ethnopharmacological Relevance. Atopic dermatitis is a chronic inflammatory skin disease. Lagerstroemia ovalifolia Teijsm. & Binn. (LO) has traditionally been used as an herbal medicine for anti-inflammatory diseases. The effect of LO on atopic dermatitis has not been verified scientifically. We investigated the effects of CHCl3 fraction number 5 of LO (LOC) on atopic dermatitis through cell-based experiments. HaCaT cells were treated with tumor necrosis factor-alpha (TNFα)/interferon-gamma (IFNγ) to induce an inflammatory reaction. Proinflammatory cytokines, interleukin- (IL-) 6, IL-8, and IL-1β and chemokines such as thymus and activation-regulated chemokine (TARC/CCL17), monocyte chemoattractant protein 1 (MCP1/CCL2), and macrophage-derived chemokine (MDC/CCL22) were measured by RT-PCR and ELISA. In addition, the degree of phosphorylation and activation of JAK/STAT1, PI3K/AKT, and nuclear factor-kappa B (NF-κB) were measured by western blot and luciferase assays. The production of inflammatory cytokines and chemokines and activation of the JAK/STAT1, PI3K/AKT, and NF-κB pathways were induced by TNFα/IFNγ in HaCaT cells. Under these conditions, LOC treatment inhibited the production of targeted cytokines and chemokines and decreased the phosphorylation and activation of JAK/STAT1, PI3K/AKT, and NF-κB. These results suggest that LOC reduces the production of proinflammatory cytokines and chemokines by suppressing the JAK/STAT1, PI3K/AKT, and NF-κB pathways. Therefore, LOC may have potential as a drug for atopic dermatitis.

3,4,5‑Trihydroxycinnamic acid (THCA) exhibits anti‑inflammatory activity in acute or chronic inflammatory disorders, such as acute lung injury and asthma. The present study investigated the anti‑inflammatory activity of THCA in a tumor necrosis factor‑α/interferon‑γ (TI) mixture‑stimulated human keratinocyte cell line. The results of ELISA and reverse transcription‑quantitative PCR revealed that THCA reduced the secretion and mRNA expression levels of interleukin (IL)‑6; IL‑8; thymus and activation‑regulated chemokine; macrophage‑derived chemokine; regulated upon activation, normal T cell expressed and secreted; and monocyte chemoattractant protein‑1 in TI mixture‑stimulated HaCaT cells. In addition, the results of western blot analysis demonstrated that THCA exerted inhibitory activity on the activation of AKT, ERK and nuclear factor‑κB in TI mixture‑stimulated HaCaT cells. Furthermore, THCA upregulated the expression levels of heme oxygenase‑1 and NAD(P)H:quinone oxidoreductase 1, and the activation of nuclear factor erythroid 2‑related factor 2 in HaCaT cells. These results demonstrated that THCA may exhibit anti‑inflammatory activity in activated HaCaT cells.

Pistacia weinmannifolia (PW) has been used in traditional Chinese medicine to treat headaches, dysentery, enteritis and influenza. However, PW has not been known for treating respiratory inflammatory diseases, including chronic obstructive pulmonary disease (COPD). The present in vitro analysis confirmed that PW root extract (PWRE) exerts anti-inflammatory effects in phorbol myristate acetate- or tumor necrosis factor α (TNF-α)-stimulated human lung epithelial NCI-H292 cells by attenuating the expression of interleukin (IL)-8, IL-6 and Mucin A5 (MUC5AC), which are closely associated with the pulmonary inflammatory response in the pathogenesis of COPD. Thus, the aim of the present study was to evaluate the protective effect of PWRE on pulmonary inflammation induced by cigarette smoke (CS) and lipopoly-saccharide (LPS). Treatment with PWRE significantly reduced the quantity of neutrophils and the levels of inflammatory molecules and toxic molecules, including tumor TNF-α, IL-6, IL-8, monocyte chemoattractant protein-1, neutrophil elastase and reactive oxygen species, in the bronchoalveolar lavage fluid of mice with CS- and LPS-induced pulmonary inflammation. PWRE also attenuated the influx of inflammatory cells in the lung tissues. Furthermore, PWRE downregulated the activation of nuclear factor-κB and the expression of phosphodiesterase 4 in the lung tissues. Therefore, these findings suggest that PWRE may be a valuable adjuvant treatment for COPD.

Physalis peruviana L. (PP) is well known for its various properties, including its antioxidant property. In our previous study, the protective effects of PP against cigarette smoke‑induced airway inflammation were confirmed. The purpose of the present study was to evaluate the anti‑inflammatory effect of PP against ovalbumin (OVA)‑induced airway inflammation. Treatment with PP inhibited the numbers of eosinophils and the levels of inflammatory cytokines, including interleukin (IL)‑4, IL‑5 and IL‑13, in the bronchoalveolar lavage fluid (BALF) of animal models with OVA‑induced allergic asthma. PP also significantly decreased the production of total immunoglobulin E in the serum. Lung sections stained with hematoxylin and eosin revealed that the influx of inflammatory cells was decreased in the lungs of mice treated with PP compared with cells in the OVA group. The increased expression levels of monocyte chemoattractant protein‑1 (MCP‑1) and T cell marker KEN‑5 were also reduced following PP treatment in the lung tissues compared with those in the OVA group. The PAS staining results showed that PP attenuated the overproduction of mucus in the lung. Additionally, western blot analysis revealed that PP significantly downregulated the activation of nuclear factor‑κB/p38 mitogen‑activated protein kinase/c‑Jun N‑terminal kinase, and upregulated the expression of heme oxgenase‑1 in the lungs. In an in vitro experiment, PP effectively reduced the levels of LPS‑stimulated MCP‑1 in a concentration‑dependent manner. Taken together, these results indicate that PP has considerable potential in the treatment of allergic asthma.

Pyrus pyrifolia Nakai (P. pyrifolia) has been traditionally used in East Asia to treat diseases such as phlegm, cough, hangover, and fever. However, there is no investigation that evaluates the biological activities of the leaves of P. pyrifolia. This study aims at describing the anti-inflammatory effects of PP, a bioactive fraction from the leaves of P. pyrifolia, in lipopolysaccharide (LPS)-stimulated THP-1 cells. Initially, PP decreased the protein and RNA expression of TNF-α, MCP-1, IL-8, and IL-6 induced by LPS. Moreover, PP attenuated the phosphorylation of p38, JNK, and ERK. In addition, after stimulation with LPS, the degradation of IκB-α was suppressed by PP, and the phosphorylation of IκB-α and p65 was suppressed by PP. Additionally, PP increased HO-1, which controls the production of inflammatory molecules, by activating Nrf2. These results indicated that PP could be used as an anti-inflammatory drug to promote wellness.

Macrophages play an important role in the innate and adaptive immune responses of organ systems, including the lungs, to particles and pathogens. Cumulative results show that macrophages contribute to the development and progression of acute or chronic inflammatory responses through the secretion of inflammatory cytokines/chemokines and the activation of transcription factors in the pathogenesis of inflammatory lung diseases, such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ARDS related to COVID-19 (coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), allergic asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). This review summarizes the functions of macrophages and their associated underlying mechanisms in the development of ALI, ARDS, COVID-19-related ARDS, allergic asthma, COPD, and IPF and briefly introduces the acute and chronic experimental animal models. Thus, this review suggests an effective therapeutic approach that focuses on the regulation of macrophage function in the context of inflammatory lung diseases.

Ethnopharmacological Relevance. Atopic dermatitis is a chronic inflammatory skin disease. Lagerstroemia ovalifolia Teijsm. & Binn. (LO) has traditionally been used as an herbal medicine for anti-inflammatory diseases. The effect of LO on atopic dermatitis has not been verified scientifically. We investigated the effects of CHCl3 fraction number 5 of LO (LOC) on atopic dermatitis through cell-based experiments. HaCaT cells were treated with tumor necrosis factor-alpha (TNFα)/interferon-gamma (IFNγ) to induce an inflammatory reaction. Proinflammatory cytokines, interleukin- (IL-) 6, IL-8, and IL-1β and chemokines such as thymus and activation-regulated chemokine (TARC/CCL17), monocyte chemoattractant protein 1 (MCP1/CCL2), and macrophage-derived chemokine (MDC/CCL22) were measured by RT-PCR and ELISA. In addition, the degree of phosphorylation and activation of JAK/STAT1, PI3K/AKT, and nuclear factor-kappa B (NF-κB) were measured by western blot and luciferase assays. The production of inflammatory cytokines and chemokines and activation of the JAK/STAT1, PI3K/AKT, and NF-κB pathways were induced by TNFα/IFNγ in HaCaT cells. Under these conditions, LOC treatment inhibited the production of targeted cytokines and chemokines and decreased the phosphorylation and activation of JAK/STAT1, PI3K/AKT, and NF-κB. These results suggest that LOC reduces the production of proinflammatory cytokines and chemokines by suppressing the JAK/STAT1, PI3K/AKT, and NF-κB pathways. Therefore, LOC may have potential as a drug for atopic dermatitis.

Pyrus pyrifolia Nakai (P. pyrifolia) has been traditionally used in East Asia to treat diseases such as phlegm, cough, hangover, and fever. However, there is no investigation that evaluates the biological activities of the leaves of P. pyrifolia. This study aims at describing the anti-inflammatory effects of PP, a bioactive fraction from the leaves of P. pyrifolia, in lipopolysaccharide (LPS)-stimulated THP-1 cells. Initially, PP decreased the protein and RNA expression of TNF-α, MCP-1, IL-8, and IL-6 induced by LPS. Moreover, PP attenuated the phosphorylation of p38, JNK, and ERK. In addition, after stimulation with LPS, the degradation of IκB-α was suppressed by PP, and the phosphorylation of IκB-α and p65 was suppressed by PP. Additionally, PP increased HO-1, which controls the production of inflammatory molecules, by activating Nrf2. These results indicated that PP could be used as an anti-inflammatory drug to promote wellness.

There is an increasing interest in natural products and their derivatives with therapeutic benefits and less side effects compared to steroid therapy. Benzofuran derivatives display biological effects including anti-inflammatory effects. The present study aims to investigate whether (3-(7-methoxy-2-p-tolyl benzofuran-5-yl) propan-1-ol) (DK-1108), new synthetic benzofuran compound exerts anti-asthmatic effects in vitro and in vivo. DK-1108 strongly reduced the production of inflammatory mediators, cytokines and chemokines in RAW264.7 and A549 cells. DK-1108 significantly regulated the levels of AKT/MAPKs/c-Jun activation, AP-1 luciferase activity and ICAM-1 expression. Furthermore, DK-1108 effectively suppressed the adhesion of A549 and EOL-1 cells. In OVA-induced asthmatic mice, DK-1108 decreased the levels of IL-5/IL-13/IgE production, eosinophils/macrophages influx, ICAM-1/MCP-1 expression, mucus secretion and airway hyperresponsiveness (AHR). These effects of DK-1108 were accompanied by downregulation of MAPKs activation. Therefore, we suggest that DK-1108 exerts protective effect against airway inflammation and mucus overproduction, and therefore could be valuable therapeutic agent for treatment in asthma.

Breast cancer is one of the most common cancers in women and is associated with a high mortality rate. The majority of deaths resulting from breast cancer are attributable to metastatic growth; in addition, chemoresistance is a major concern in the treatment of patients with breast cancer. However, limited drugs are available for the treatment of metastatic breast cancer. In this study, the chemoadjuvant effects of a methanolic extract from the leaves of Pseudolysimachion rotundum var. subintegrum (NC13) and an active component isolated from the plant, verminoside (Vms), were evaluated. Furthermore, their potent anti-metastatic activities were validated in vitro and in vivo in animal models. The anti-metastatic and chemosensitizing activities of NC13 and Vms on cisplatin treatment were found to be partly mediated by suppression of the epithelial–mesenchymal transition of cancer cells. Collectively, our results implied that NC13 and its bioactive component Vms could be developed as effective chemoadjuvants in combination with conventional therapeutics.

Background: The type three secretion system (T3SS) is a major virulence system of Pseudomonas aeruginosa (P. aeruginosa). The effector protein Exotoxin S (ExoS) produced by P. aeruginosa is secreted into the host cells via the T3SS. For the purpose of screening the inhibitors with regard to ExoS secretion, we developed the sandwich-type enzyme-linked immunosorbent assay (ELISA) system. From the initial screening, quercetin was selected because it has the prominent effect of ExoS inhibition and also is known to have anti-inflammatory and antioxidant effects on mammalian cells.Results: In this study, we investigated the effects of quercetin on the expression and secretion of ExoS using the ELISA and Western blot analysis methods. The results showed that the secretion of ExoS was significantly decreased by 10, 20uM quercetin. Also, pscF and popD, which are composed of the T3SS needle, are reduced by quercetin at the mRNA level, and we confirmed the inhibitory effect of quercetin on cytokines in P. aeruginosa-infected H292 cells by real-time polymerase chain reaction (PCR). Conclusion: Collectively, quercetin inhibits the secretion of ExoS by reducing both ExoS production and the expression of the needle protein of T3SS. Furthermore, these results suggest that quercetin has the potential to be used as an anti-toxic treatment for the disease caused by P. aeruginosa infection.

A number of species of the genus

3,4,5-Trihydroxycinnamic acid (THCA) has been reported to possess anti-inflammatory activity. However, the effect of THCA for treating allergic asthma was unknown. Therefore, in the present study, the anti-asthmatic effects of THCA were studied in both in vitro and in vivo studies. In phorbol 12-myristate 13-acetate (PMA)-stimulated A549 airway epithelial cells, THCA pretreatment decreased the mRNA expression and secretion of interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecules 1 (ICAM-1), and reduced the mRNA expression of matrix metalloproteinase 9 (MMP-9). THCA also inhibited PMA-induced protein kinase B (AKT), mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) activation in A549 cells. In lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, THCA pretreatment suppressed the mRNA expression of ICAM-1 and MMP-9. In addition, THCA suppressed the adhesion of EOL and A549 cells. In ovalbumin (OVA)-administered asthmatic mice, THCA exerted inhibitory activity on IL-5, IL-13, and MCP-1 in bronchoalveolar lavage fluid (BALF) and on OVA-specific immunoglobulin E (IgE) in serum. THCA attenuated the numbers of inflammatory cells in BALF and the influx of inflammatory cell in lung tissues. Furthermore, THCA downregulated the levels of inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2), and leukotriene B4 (LTB4) expression, mucus production and CREB phosphorylation as well as Penh value. These effects were accompanied by suppression of AKT, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-κB activation. Therefore, the results of the current study suggest that THCA may be a valuable adjuvant or therapeutic in the prevention or treatment of allergic asthma.

3,4,5-Trihydroxycinnamic acid (THCA), a derivative of hydroxycinnamic acid, has been reported to exert anti-inflammatory and antioxidant activities. However, its anti-inflammatory effects in chronic obstructive pulmonary disease (COPD) have not yet been elucidated. Therefore, we explored the protective effects of THCA on pulmonary inflammation in an experimental COPD model elicited by cigarette smoke (CS) and lipopolysaccharide (LPS). Oral administration of THCA significantly inhibited the activity of elastase, the release of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO) and the numbers of neutrophils and macrophages in the bronchoalveolar lavage fluid (BALF) of experimental COPD mice. THCA also exerted inhibitory effects on the recruitment of inflammatory cells, the levels of PAS positive cells and cAMP-response-element-binding protein (CREB) activation, and the expression of phosphodiesterase 4 (PDE4) in the lungs of experimental COPD mice. In addition, THCA exerted a regulatory effect on the activation of p38, ERK and nuclear factor-κB (NF-κB) in the lungs of experimental COPD mice. THCA also significantly upregulated the expression of NAD(P)H dehydrogenase (quinone 1) 1 (NQO1) and the activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) in the lungs of mice. Furthermore, THC restored the reduction of NAD-dependent protein deacetylase sirtuin-1 (SIRT1) in the lungs of experimental COPD mice. In phorbol myristate acetate (PMA)-stimulated A549 or H292 airway epithelial cells, pretreatment of THCA dose-dependently inhibited the generation of IL-6. THCA also led to increased NQO1 expression in H292 cells. Collectively, these protective effects of antioxidant THCA were notably excellent and are thought to be associated with the downregulation of MAPK (partial)/NF-κB signaling and upregulation of NQO1 and SIRT1 expression.

Ethnopharmacological relevance The leaves, bark, and flowers of Paulownia tomentosa Steud. have been widely used as a traditional medicine in East Asia to treat inflammatory and infectious diseases. Aim of the study We investigated the protective effect of the methanol stem bark extract of P. tomentosa using an animal model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Materials and methods The UPLC Q-TOF-MS profiles for the methanol extract of P. tomentosa stem bark showed that verbascoside and isoverbascoside were the predominant compounds. Raw 264.7 cells were used for inhibitory effects of cytokine production in vitro. C57BL/6 N mice were administered intranasally with LPS (10 μg/per mouse) to induce ALI. H&E staining was used to evaluate histological changes in the lung. Results Treatment with P. tomentosa stem bark extract (PTBE) suppressed the production of IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophages, and the recruitment of neutrophils and macrophages in the BALF of mice with LPS-induced ALI. PTBE also decreased the levels of reactive oxygen species (ROS) and pro-inflammatory cytokines in the BALF. PTBE reduced the levels of nitric oxide (NO) in the serum and of inducible nitric oxide synthase (iNOS) in the lung of ALI mice. PTBE also attenuated the infiltration of inflammatory cells and the expression of monocyte chemoattractant protein-1 (MCP-1) in the lung. In addition, PTBE suppressed the activation of NF-κB and the reduced expression of superoxide dismutase 3 (SOD3) in the lung. Conclusion The results suggest that PTBE has a protective effect on LPS-induced ALI.

// Na-Rae Shin 1, * , Ji-Won Park 2, * , In-Chul Lee 3 , Je-Won Ko 1 , Sung-Hyeuk Park 1 , Joong-Sun Kim 4 , Jong-Choon Kim 1 , Kyung-Seop Ahn 2 and In-Sik Shin 1 1 College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, Gwangju 500-757, Republic of Korea 2 Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea 3 Natural Product Research Center, Jeonbuk Branch, Korea Research Institute of Biosciences and Biotechnology, Jeongeup 580-185, Republic of Korea 4 Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan 619-953, Republic of Korea * These authors contributed equally to this work Correspondence to: In-Sik Shin, email: dvmmk79@gmail.com Kyung-Seop Ahn, email: ksahn@kribb.re.kr Keywords: melatonin, cigarette smoke, pulmonary fibrosis, TGF-β1, MAPK Received: August 01, 2017 Accepted: September 22, 2017 Published: October 09, 2017 ABSTRACT Cigarette smoke (CS) is the most important risk factor in the development of chronic obstructive pulmonary disease (COPD). Pulmonary fibrosis is an irreversible response and important feature of COPD. In this study, we investigated the effects of melatonin on fibrotic response in development of COPD using a CS and lipopolysaccharide (LPS) induced COPD model and cigarette smoke condensate (CSC)-stimulated NCI-H292 cells, a human mucoepidermoid cell line. Mice were exposed to CS for 1 h per day (8 cigarettes per day) from day 1 to day 7 and were treated intranasally with LPS on day 4. Melatonin (10 or 20 mg/kg) was injected intraperitoneally 1 h before CS exposure. Melatonin decreased the inflammatory cell counts in bronchoalveolar lavage fluid (BALF), with a reduction in transforming growth factor (TGF)-β1. Melatonin inhibited the expression of TGF-β1, collagen I and SMAD3 phosphorylation in lung tissue exposed to CS and LPS. In CSC-stimulated H292 cells, melatonin suppressed the elevated expression of fibrotic mediators induced by CSC treatment. Melatonin reduced the expression of TGF-β1, collagen I, SMAD3 and p38 phosphorylation in CSC-stimulated H292 cells. In addition, cotreatment with melatonin and TGF-β1 inhibitors significantly limited fibrotic mediators, with greater reductions in the expression of TGF-β1, collagen I, SMAD3 and p38 phosphorylation than those of H292 cells treated with TGF-β1 inhibitor alone. Taken together, melatonin effectively inhibited fibrotic responses induced by CS and LPS exposure, which was related to the downregulation of TGF-β1. Therefore, our results suggest that melatonin may suppress the pulmonary fibrotic response induced by CS.

Few studies have reported on the antioxidant and anti-inflammatory properties of coumestrol (CM). In this study, CM not only significantly attenuated inflammation in acute lung injury (ALI) mice but also reduced the production of nitric oxide (NO), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and suppressed nuclear factor-kappaB (NF-κB) activation in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Interestingly, treatment with CM significantly attenuated the infiltration of inflammatory cells into the lung. CM decreased the levels of pro-inflammatory molecules, such as reactive oxygen species (ROS), TNF-α and IL-6, in the bronchoalveolar lavage fluid (BALF) of ALI mice. CM also inhibited the release of NO in the serum and reduced the expression of monocyte chemoattractant protein-1 (MCP-1) in the lung. In addition, CM suppressed the activation of NF-κB and the reduced expression of superoxide dismutase 3 (SOD3) in the lung. Our findings suggest that CM possesses protective effects in an ALI animal model.

As part of an ongoing search for active compounds against pulmonary inflammation, a polyacetylene was isolated from Dendropanax morbifera leaves. The polyacetylene (9Z, 16S)-16-Hydroxy-9,17-octadecadiene-12,14-diynoic acid) was isolated from the chloroform fraction of methanolic extract of D. morbifera leaves based on the IL-6 inhibitory activity evaluated in NCI-H292 cells. In the murine model of cigarette smoke (CS) and lipopolysaccharide (LPS)-induced airway inflammation, the polyacetylene significantly attenuated the infiltration of inflammatory cells in BALF (broncoalveolar lavage fluid) and in the lung. In addition, this compound reduced ROS (reactive oxygen species) production and NE (neutrophil elastase) activity, and decreased the release of proinflammatory cytokines (TNF-α, IL-6) in BALF. Furthermore, the polyacetylene reduced mucus secretion and the activation of ERK, p-38 and NF-κB in the lung. These findings suggest that the polyacetylene might be valuable constituent of D. morbifera as a material for functional food alleviating pulmonary inflammation disease such as COPD.

Natural product drugs, or botanical drugs, are drugs composed of natural substances which have constituents with healthenhancing or medicinal activities. In Korea, government-led projects brought attention to botanical drugs invigorating domestic botanical drug industry. Foreign markets, as well, are growing bigger as the significance of botanical drugs stood out. To follow along with the tendency, Korea puts a lot of effort on developing botanical drugs suitable for global market. However, standards for approving drug sales vary by countries. And also, thorough standardization, certification, clinical studies and data of these will be required as well as data confirming safety and effectiveness. Meanwhile, as an international exchange in botanical drug market continues, the importance of plant resources was emphasized. Thus countries' ownership of domestic natural resources became vital. Not only establishing a systematic method to secure domestic plant resources, but also cooperation with other countries on sharing natural resources is essential to procure natural resources effectively. Korea started to show visible results with botanical drugs, and asthma/COPD treatment made out of speedwell is one example. Sufficient investment and government's active support for basic infrastructure for global botanical drugs will bring Korea to much higher level of botanical drug development. [BMB Reports 2017; 50(3): 111-116].

Ethnopharmacological relevance A standardized bark extract of Pinus pinaster Aiton (Pycnogenol®; PYC) used as an herbal medicine to treat various diseases in Europe and North America. Aim of the study This study evaluates the ability of PYC to inhibit chronic obstructive pulmonary disease (COPD) in the cigarette smoke extract (CSE)-stimulated human airway epithelial cell line NCI-H292 and in a cigarette smoke (CS) and lipopolysaccharide (LPS)-induced mouse model. Methods To induce COPD, the mice intranasally received LPS on day 4 and were exposed to CS for 1 h per day (total eight cigarettes per day) from days 1–7. The mice were administered PYC at a dose of 15 mg/kg and 30 mg/kg 1 h before CS exposure. Results In the CSE-stimulated NCI-H292 cells, PYC significantly inhibited Erk phosphorylation, sp1 expression, MUC5AC, and pro-inflammatory cytokines in a concentration-dependent manner, as evidenced by a reduction in their mRNA levels. Co-treatment with PYC and Erk inhibitors markedly reduced the levels inflammatory mediators compared to only PYC-treatment. In the COPD mice model, PYC decreased the inflammatory cell count and the levels of pro-inflammatory cytokines in the broncho-alveolar lavage fluid compared with COPD mice. PYC attenuated the recruitment of inflammatory cells in the airways and decreased the expression levels of Erk phosphorylation and sp1. PYC also inhibited the expression of myeloperoxidase and matrix metalloproteinases-9 in lung tissue. Conclusion Our results indicate that PYC inhibited the reduction in the inflammatory response in CSE-stimulated NCI-H292 cells and the COPD mouse model via the Erk-sp1 pathway. Therefore, we suggest that PYC has the potential to treat COPD.

Gnaphalium affine has long been used as a vegetable and as a traditional medicine to treat various diseases in East Asia. In this work, the human neutrophil elastase inhibitory activity and anti-inflammatory effects of the lead phytochemicals isolated from G . affine and their effects on respiratory disease agents were evaluated in vitro . Through activity-guided fractionation, eight compounds ( 1 – 8 ) with different scaffolds were isolated from the EtOAc fraction of G . affine extract (GAE) . The GAE inhibited LPS-induced NO production with different potencies. The highest potency for the inhibition of NO, iNOS, and pro-inflammatory cytokine production was found in isolated compounds ( 1 – 8 ). A series of isolated compounds demonstrated modest to high inhibition of HNE with IC 50 values of 2.3–46.1 µM. In particular, luteolin-4′- O -β- d -(6″- E -caffeoyl)-glucoside ( 7 ) showed noncompetitive inhibition kinetics against HNE. The results of this study support the traditional use of polyphenol-rich products in the prevention and treatment of respiratory disease.

Benzofuran derivatives have wide range of biological activities as anti-oxidant, anti-inflammatory and anticonvulsant agent. In this study, we investigated whether the novel benzofuran derivative, DK-1014 has the anti-inflammatory effects on macrophage and lung epithelial cells and anti-asthmatic effects on ovalbumin-treated mice. A series of 2-arylbenzofuran analogues were synthesized and evaluated for NO and interleukin-6 (IL-6) inhibition in LPS-stimulated Raw264.7 cells. Of these analogues, compounds 8, 22a, 22d, and 22 f (DK-1014) exhibited notable inhibitory activity with respect to IL-6 and NO production. In particular, compound DK-1014 strongly reduced IL-6, IL-8, and MMP-9 mRNA expression and IL-6, IL-8, and MCP-1 production in phorbol myristate acetate stimulated A549 cells, reduced MAPKs phosphorylation and c-fos translocation, and attenuated AKT, p70S6K and GSK phosphorylation. In vivo experiments were also performed on ovalbumin-sensitized and challenged BALB/c mice. DK-1014 reduced the airway hyperresponsiveness, inflammatory cell counts and cytokine levels (IL-4, 5, 13) in bronchial alveolar lavage fluid (BALF) and immunoglobulin E in serum, and attenuated inflammatory cell infiltration and mucus hypersecretion in lung tissue. These findings indicate that DK-1014 can protect against allergic airway inflammation through the AP-1 and AKT/mTOR pathways and could be useful source for the development of a therapeutic agent for asthma.

Linalool is a natural product present in fruits and aromatic plants with biological activities. Researchers have reported that the inhalation of linalool exerts anti-inflammatory activities. In this study, we examined the therapeutic effects of linalool on airway inflammation and mucus overproduction in mice with allergic asthma. Oral administration of linalool significantly inhibited the levels of eosinophil numbers, Th2 cytokines and immunoglobulin E (IgE) caused by ovalbumin (OVA) exposure. Linalool exerted preventive effects against the influx of inflammatory cells and mucus hypersecretion in the lung tissues. Linalool also dose-dependently decreased the levels of inducible nitric oxide synthase (iNOS) expression and protein kinase B (AKT) activation in the lung tissues. Linalool effectively downregulated the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) caused by OVA exposure. Furthermore, linalool exerted inhibitory effect on OVA-induced airway hyperresponsiveness (AHR). In the in vitro study, the increased secretion of MCP-1 was attenuated with linalool treatment in lipopolysaccharide (LPS)-stimulated H292 airway epithelial cells. In conclusion, linalool effectively exerts a protective role in OVA-induced airway inflammation and mucus hypersecretion, and its protective effects are closely related to the downregulation of inflammatory mediators and MAPKs/NF-κB signaling.

Pistacia weinmannifolia (Anacardiaceae) has been used in herbal medicine for the treatment of influenza, dysentery and enteritis in China. It was recently observed that P. weinmannifolia root extract (PWRE) exerts anti‑inflammatory effects both in in vitro and in vivo models. Based on the results from previous studies, the present study investigated the protective effect of PWRE on airway inflammation and mucus hypersecretion. Treatment with PWRE significantly decreased the number of eosinophils and the levels of Th2 cytokines, such as interleukin (IL)‑4, IL‑5 and IL‑13, in the bronchoalveolar lavage fluid (BALF) of OVA‑exposed mice. PWRE decreased the high serum levels of total and OVA‑specific immunoglobulin E. PWRE also effectively inhibited the influx of inflammatory cells into the lung, as well as airway mucus hypersecretion. In addition, the increased level of monocyte chemoattractant protein‑1 was significantly decreased with the PWRE treatment in the BALF of OVA‑exposed mice and in lipopolysaccharide‑stimulated RAW264.7 macrophages. These protective effects of PWRE on OVA‑induced pulmonary inflammation were accompanied by the downregulation of mitogen associated protein kinases and nuclear factor‑κB activation. Thus, the results from the present study indicate that PWRE could be valuable adjuvant for the treatment of asthma.