Anti-Fibrosis Effect of Panax ginseng and Inula japonica Formula in Human Pulmonary Fibroblasts.

Panax ginseng Meyer and Inula japonica Thunb. are well established in traditional medicine and are known for their therapeutic properties in managing a range of ailments such as diabetes, asthma, and cancer. Although P. ginseng and I. japonica can alleviate pulmonary fibrosis (PF), the anti-fibrosis effect on PF by the combination of two herbal medicines remains unexplored. Therefore, this study explores this combined effect. In conditions that were not cytotoxic, MRC-5 cells underwent treatment using the formula combining P. ginseng and I. japonica (ISE081), followed by stimulation with transforming growth factor (TGF)-ß1, to explore the fibroblast-to-myofibroblast transition (FMT). After harvesting the cells, mRNA levels and protein expressions associated with inflammation and FMT-related markers were determined to evaluate the antiinflammation activities and antifibrosis effect of ISE081. Additionally, the anti-migratory effects of ISE081 were validated through a wound-healing assay. ISE081 remarkably reduced the mRNA levels of interleukin (IL)-6, IL-8, α-smooth muscle actin (SMA), and TGF-ß1 in MRC-5 cells and suppressed the α-SMA and fibronectin expressions, respectively. Furthermore, ISE081 inhibited Smad2/3 phosphorylation and wound migration of MRC-5 cells. Under the same conditions, comparing those of ISE081, P. ginseng did not affect the expression of α-SMA, fibronectin, and Smad2/3 phosphorylation, whereas I. japonica significantly inhibited them but with cytotoxicity. The results indicate that the synergistic application of P. ginseng and I. japonica enhances the anti-fibrotic properties in pulmonary fibroblasts and concurrently diminishes toxicity. Therefore, ISE081 has the potential as a prevention and treatment herbal medicine for PF.

Ethanol Extracts from the Aerial Parts of Inula japonica and Potentilla chinensis Alleviate Airway Inflammation in Mice That Inhaled Particulate Matter 10 and Diesel Particulate Matter.

Air pollution causes various airway diseases. However, many commonly used treatments can have high risks of side effects or are costly. To examine the anti-inflammatory properties of Inula japonica Thunb. and Potentilla chinensis Ser., a mouse model was generated via inhalation of both particulate matter 10 and diesel particulate matter, and 30% ethanol extracts of either I. japonica (IJ) or P. chinensis (PC) and a mixture of both ethanol extracts (IP) were orally administered to BALB/c mice for 12 days. IJ, PC, and IP inhibited immune cell numbers and their regulation in both the bronchoalveolar lavage fluid (BALF) and lungs. These agents suppressed the levels of interleukin (IL)-1α, IL-17, tumor necrosis factor (TNF)-α, C-X-C motif chemokine ligand (CXCL)-1, and CXCL-2 in BALF, and also inhibited F4/80 and IL-1 receptor-associated kinase (IRAK)-1 in lungs. They reduced the gene expression of TNF-α, CXCL-1, inducible NOS, COX-2, Mucin 5AC, and transient receptor potential cation channel subfamily V member 1 in lungs. These extracts also reduced histopathological changes and inflammatory progression, manifested as decreased cell infiltration, collagen deposition, and respiratory epithelial cell thickness. I. japonica and P. chinensis show potential for development as pharmaceuticals that suppress inflammatory progression and alleviate airway inflammation diseases caused by air pollutants.

Ruptured organosilica nanocapsules immobilized acetylcholinesterase coupled with MnO2 nanozyme for screening inhibitors from Inula macrophylla.

Abnormal expression of acetylcholinesterase (AChE) causes Alzheimer's disease (AD). Inhibiting AChE is a common strategy for reducing the degradation of neurotransmitter acetylcholine, in order to treat early-stage AD. Therefore, it is crucial to screen and explore AChE inhibitors which are safer and cause fewer side effects. Our research is focused on establishing a platform of ruptured organosilica nanocapsules (RONs) immobilized AChE coupled with an MnO2-OPD colorimetric assay, which could monitor AChE activity and screen AChE inhibitors. The fabricated RONs immobilized AChE possessed excellent pH and thermal stability. Huperzine A was introduced into the established platform to evaluate the inhibition kinetics of the immobilized AChE, which promoted its application in the screening of AChE inhibitors. The satisfactory results of enzyme inhibition kinetics proved the feasibility and applicability of the established method. Thus, the proposed platform was applied to screen AChE inhibitors from 14 compounds isolated from Inula macrophylla, and ß-cyclocostunolide (compound 4) demonstrated the best AChE inhibitory activity among these compounds. This work confirms the existence of chemical components that inhibit AChE activity in Inula macrophylla, and provides a new idea for the application of immobilized enzyme-nanozyme in the field of enzyme inhibitor screening.

Fermentation of Inula britannica using Lactobacillus plantarum SY12 increases of epigallocatechin gallate and attenuates toxicity.

This study aimed to increase epigallocatechin gallate (EGCG) levels and attenuate the toxicity in Inulabritannica by fermentation using Lactobacillus plantarum SY12. The optimal medium was composed of 10 g of I. britannica, 4 g of xylose, 5 g of soytone, and 5 g of beef extract. The predicted value of EGCG was 237.327 µg/mL. To investigate damage in HepG2 cell lines by I. britannica extracts (IE) or fermented I. britannica extracts (FIE), cell viability, mitochondria membrane potential, the expression of apoptosis and autophagy genes, and chemical composition were measured. FIE increased cell viability, regulation of the gene expression (decreased p53, p62, p-ERK 1/2, and p-p38; increased CDK2 and CDK4) compared with IE. These results were explained by an increase in 1,3-dicaffeoylquinic acid and a decrease in 1-O-caffeoylquinic acid, 1-O-acetylbritannilactone, and ergolide in FIE. In conclusion, these results indicated that fermentation can mitigate the toxicity in I. britannica.

Inula viscosa ameliorates acetic acid induced ulcerative colitis in rats.

Increased pro-inflammatory cytokines and oxidative stress contribute to the pathophysiology of ulcerative colitis (UC). Inula viscosa is a plant with antioxidant and anti-inflammatory properties. We investigated the effect of an ethanolic extract of I. viscosa on an experimental UC model created using acetic acid. Rats were divided into four groups of eight: group 1, control; group 2, 3% acetic acid group; group 3, 100 mg/kg sulfasalazine + 3% acetic acid group; group 4, 400 mg/kg I. viscosa + 3% acetic acid. I. viscosa and sulfasalazine were administered by oral gavage and 3% acetic acid was administered per rectum. We found that I. viscosa treatment decreased colon malondialdehyde, tumor necrosis factor-α, interleukin-1 beta and nuclear factor kappa B levels; it increased reduced glutathione, nuclear factor erythroid 2-related factor 2, heme oxygenase-1 and kelch-like ECH-associated protein 1 levels and glutathione peroxidase enzyme activity. Group 1 colon exhibited normal histological structure. Slight inflammatory cell infiltration and edema and insignificant slight erosion in crypts were detected in colon tissues of group 4. We found that I. viscosa reduced oxidative stress and inflammation, which was protective against UC by inducing the Nrf-2/Keap-1/HO-1 pathway in the colon.

Inula japonica ameliorated the inflammation and oxidative stress in LPS-induced acute lung injury through the MAPK/NF-κB and Keap1/Nrf2 signalling pathways.

OBJECTIVES: To investigate the protective effect and underlying mechanism of Inula japonica (TEIJ) in the treatment of acute lung injury (ALI). METHODS: Protective effects of TEIJ in the inflammation and oxidative stress were studied in lipopolysaccharide (LPS)-induced ALI mice. Meanwhile, Western blot and real-time qPCR were carried out to investigate the underlying mechanism of TEIJ for ALI as well as immunohistochemistry. KEY FINDINGS: TEIJ significantly alleviated the course of ALI via suppressing the interstitial infiltrated inflammatory cells, the increase of inflammatory factors and the decrease of anti-oxidative factors. TEIJ inactivated the MAPK/NF-κB signalling pathway to suppress the transcription of its downstream target genes, such as TNF-α, IL-6, etc. Meanwhile, TEIJ activated the Keap1/Nrf2 signalling pathway to regulate expression levels of Nrf2 and its target proteins. The results of LC-QTOF-MS/MS indicated potential active constituents of I. japonica, terpenoids and flavonoids. Additionally, terpenoids and flavonoids synergistically alleviated LPS-induced ALI depending on MAPK/NF-κB and Keap1/Nrf2 signalling pathways. CONCLUSION: I. japonica could be considered a potential agent to treat ALI via regulating the MAPK/NF-κB and Keap1/Nrf2 signalling pathways.

A Botanical Mixture Consisting of Inula japonica and Potentilla chinensis Relieves Obesity via the AMPK Signaling Pathway in 3T3-L1 Adipocytes and HFD-Fed Obese Mice.

Excessive lipid accumulation in white adipose tissue (WAT) is the major cause of obesity. Herein, we investigated the anti-obesity effect and molecular mechanism of a botanical mixture of 30% EtOH extract from the leaves of Inula japonica and Potentilla chinensis (EEIP) in 3T3-L1 preadipocytes and high-fat diet (HFD)-fed obese mice. In vitro, EEIP prevented lipid accumulation by downregulating the expression of lipogenesis-related transcription factors such as CCAAT/enhancer binding protein (C/EBP)α, peroxisome proliferator-activated receptor (PPAR)γ, and sterol regulatory element binding protein (SREBP)-1 via AMP-activated protein kinase (AMPK) activation and G0/G1 cell cycle arrest by regulating the Akt-mTOR pathways without inducing cytotoxicity. In vivo, EEIP significantly reduced body weight gain and body fat mass in the group administered concurrently with HFD (pre-) or administered during the maintenance of HFD (post-) including subcutaneous, gonadal, renal, and mesenteric fats, and improved blood lipid profiles and metabolic hormones. EEIP pre-administration also alleviated WAT hypertrophy and liver lipid accumulation by reducing C/EBPα, PPARγ, and SREBP-1 expression via AMPK activation. In the brown adipose tissue, EEIP pre-administration upregulated the expression of thermogenic factors. Furthermore, EEIP improved the HFD-induced altered gut microbiota in mice. Taken together, our data indicated that EEIP improves HFD-induced obesity through adipogenesis inhibition in the WAT and liver and is a promising dietary natural material for improving obesity.

Phytochemical constituents of Inula britannica as potential inhibitors of dihydrofolate reductase: A strategic approach against shigellosis.

Shigella dysenteriae type 1 is considered as an epidemic in different developing countries, which is responsible for the most severe form of bacterial dysentery. It habitually can develop to the most severe form of dysentery with deadly complications. Development of drugs against this disease is still ongoing. Therefore, we used in silico studies to screen the Inula britannica phytocompounds that are used in traditional Chinese and Kampo Medicines and have activities against different diseases. Spinacetin, eupatin, chrysoeriol and diosmetin were successfully passed through the docking-based screening and absorption, distribution, metabolism, excretion and toxicity (ADMET) filtration. The estimated docking affinities of eupatin, diosmetin, chrysoeriol and spinacetin with Dihydrofolate reductase type 1 (DHFR-1), were -6.5, -6.5, -6.3 and -6.1 kcal/mol, respectively. Which were selected for further investigations based on their favorable ADME/Tox characteristics. Then, the 100 ns molecular dynamics (MD) simulations of apo DHFR, spinacetin-DHFR, eupatin-DHFR, chrysoeriol-DHFR and diosmetin-DHFR complexes were carried out. The RMSD fluctuations of the spinacetin, eupatin, chrysoeriol and diosmetin inside the binding site were explored. Subsequently, the effect of binding Spinacetin, eupatin, chrysoeriol and diosmetin upon the dynamic stability of protein was assessed. Additionally, Principal Component Analysis (PCA) and Hydrogen bond analysis was performed for the apo protein and the protein ligand complexes. The results revealed that chrysoeriol and eupatin has good inhibitory effects against DHFR-1 as treatment for Shigella dysenteriae type when compared to other compounds under study. Hence this study implies that eupatin and chrysoeriol are a significantly potential drug like molecule for the treatment of Shigellosis and must undergo validation through in vivo and in vitro experiments.Communicated by Ramaswamy H. Sarma.

Alantolactone induces apoptosis in THP-1 cells through STAT3, survivin inhibition, and intrinsic apoptosis pathway.

Cancer is the second foremost cause of mortality in the world, and THP-1 cells play an important role in cancer progression. Alantolactone (ALT), a sesquiterpene lactone compound derived from Inula helenium, has a number of biological activities including antibacterial, antifungal, and anticancer. The current study was conducted to investigate the effects of ALT on THP-1 cells and its underlying molecular mechanisms. THP-1 cells were cultured and treated with ALT (20, 40 µM) for 12 hr, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, cell morphology, live/dead, and apoptosis assays were performed. The gene expressions at the protein level were checked through Western blot. Results show that ALT decreased cell viability and increased cell death and apoptosis. We found that ALT inhibited STAT3 and survivin expression. Furthermore, ALT induced mitochondrial-dependent apoptosis through a decrease in B-cell lymphoma-2 (Bcl-2) and Bcl-xL and increase in Bax expression, resulting in the release of cytochrome c (Cyt-c) from mitochondria. Cyt-c release from mitochondria further increased cleaved (cl) caspase-3 and cl-PARP expression and led the cells to apoptosis. Therefore, ALT might be a good therapy for the progression due to THP-1 cells.

Caffeoylquinic Acids, Cytotoxic, Antioxidant, Acetylcholinesterase and Tyrosinase Enzyme Inhibitory Activities of Six Inula Species from Bulgaria.

Chlorogenic (5-CQA), 1,5-, 3,5-, 4,5- and 3,4-dicaffeoylquinic (DCQA) acids were identified and quantified in the methanol extracts of Inula oculus-christi L., I. bifrons L., I. aschersoniana Janka var. aschersoniana, I. ensifolia L., I. conyza (Griess.) DC. and I. germanica L. by HPLC analysis. The amount of 5-CQA varied from 5.48 to 28.44 mg/g DE and the highest content was detected in I. ensifolia. 1,5-DCQA (4.05-55.25 mg/g DE) was the most abundant dicaffeoyl ester of quinic acid followed by 3,5-DCQA, 4,5-DCQA and 3,4-DCQA. The extract of I. ensifolia showed the highest total phenolic content (119.92±0.95 mg GAE/g DE) and exhibited the strongest DPPH radical scavenging activity (69.41±0.55 %). I. bifrons extract was found to be the most active sample against ABTS.+ (TEAC 0.257±0.012 mg/mL) and the best tyrosinase inhibitor. The studied extracts demonstrated a low inhibitory effect towards acetylcholinesterase and possessed low cytotoxicity in concentration range from 10 to 300 µg/mL toward non-cancer (MDCK II) and cancer (A 549) cells.

2α-Hydroxyeudesma-4,11(13)-Dien-8ß,12-Olide Isolated from Inula britannica Induces Apoptosis in Diffuse Large B-cell Lymphoma Cells.

2α-Hydroxyeudesma-4,11(13)-dien-8ß,12-olide (HEDO), a eudesmane-type sesquiterpene lactone belonging to large group of plant terpenoids isolated from Inula britannica, displays cytotoxic activity against diffuse large B cell lymphoma cells in vitro. However, the molecular mechanism of the anticancer effect remains unclear. In this study, we showed that HEDO inhibits cell growth by inducing apoptosis in lymphoma cell lines through its antiproliferative activity. HEDO increases the depolarization of mitochondrial membrane potential and upregulated intracellular reactive oxygen species (ROS). Furthermore, we examined the cell cycle effect, and our results provided evidence that the arrest of the cell cycle at the SubG0/G1 phase plays an important role in the ability of HEDO to inhibit cell growth in Ontario Cancer Institute (OCI)-LY3 lymphoma cells by preventing nuclear factor-kappa B (NF-κB) signaling. In addition, HEDO induced apoptosis by instigating the activation of Bcl-2-associated X (BAX) and cleaved caspase-3, decreasing B-cell lymphoma 2 (BCL2), B-cell lymphoma-extra large (BCL-XL), and procaspase 3 expression levels. Based on these findings, we suggest that HEDO has potential as an anticancer drug of lymphoma by inducing ROS-dependent accumulation of SubG0/G1 arrest and apoptosis in OCI-LY3 cells.

Improved in vitro antioxidant properties and hepatoprotective effects of a fermented Inula britannica extract on ethanol-damaged HepG2 cells.

This study aimed to improve antioxidant effect and hepatoprotective effect of Inula britannica using fermentation. Epigallocatechin gallate (EGCG) in an I. britannica extract was found to be upregulated from 2.06 to 10.28 µg/mg during fermentation (p < 0.001). After fermentation, DPPH radical-scavenging ABTS radical-scavenging, and superoxide anion-scavenging abilities increased to 92.65%, 694.25 µM Trolox/mL, and 86.38%, respectively, at 500 µg/mL (p < 0.05). Cupric-ion-reducing capacity with formation of the Cu+-neocuproine complex increased by 5.88%, 6.38%, 3.24%, and 8.55% at 62.5 to 500 µg/mL. Ferric-ion-reducing capacity of the fermented extract increased by 20%, 7.16%, 3.85%, and 5.45% at each concentration (p < 0.05). Unfermented extracts yielded cell viability of 91.42%, 90.59%, 88.38%, and 79.17%, whereas the fermented extract yielded 100.28%, 99.66%, 96.15%, and 89.90%, respectively, at each concentration in ethanol-damaged HepG2 cells (p < 0.05). Additionally, the fermented extract decreased alanine transaminase activity from 117.2 to 61.7 U/mL in the ethanol-damaged HepG2 cell line (p < 0.01). Overall, both antioxidant and hepatoprotective effect increased by fermentation in I. britannica extract. These properties are expected to lead to new antioxidant agents via production of EGCG by fermentation.

Inhibitory effects of Inula britannica extract fermented by Lactobacillus plantarum KCCM 11613P on coagulase activity and growth of Staphylococcus aureus including methicillin-resistant strains.

The aim of this study was to evaluate the antimicrobial efficacy of fermented Inula britannica extract (FIBE) against Staphylococcus aureus strains including methicillin-resistant S. aureus (MRSA). I. britannica extract was fermented by Lactobacillus plantarum KCCM 11613P, and the pathogenicity of S. aureus strains was determined via assessment of coagulase, DNase, and hemolytic activities. Epicatechin concentration increased from 4.38 to 6.05 µg/mg during fermentation (p < 0.01). FIBE treatment inhibited coagulase release from S. aureus to levels below the inhibitory concentration. FIBE promoted the release of intracellular nucleic acids and N-phenyl-1-naphthylamine absorption. In three S. aureus strains, damaged cells exhibited 21.58, 16.79, and 17.65% decreases in membrane potential induced by cell membrane depolarization, respectively (p < 0.05). Upon FIBE treatment in culture, the minimum inhibitory concentration of FIBE exerted a bacteriostatic effect. In conclusion, FIBE possesses antimicrobial properties, including inhibition of virulence factors, damage to cell membranes, and inhibition of bacterial growth. PRACTICAL APPLICATIONS: Methicillin-resistant Staphylococcus aureus (MRSA) is a serious concern in hospitals because of its known antibiotic resistance. Vancomycin and tigecycline are used for treating MRSA, but the appearance of vancomycin-intermediate and multidrug-resistant strains of these bacteria has created a demand for new antimicrobial agents. This study demonstrates the effective application of Inula britannica and fermentation technology for developing natural antimicrobial agents against methicillin-resistant Staphylococcus aureus.

Discovery of SCY45, a Natural Small-Molecule MDM2-p53 Interaction Inhibitor.

The disruption of the MDM2-p53 interaction has been regarded as an attractive strategy for anticancer drug discovery. Here, the natural small-molecule SCY45 was identified as a potent MDM2-p53 interaction inhibitor based on fluorescence polarization and molecular modeling. SCY45 inhibited the MDM2-p53 interaction with an IC50 value of 4.93±0.08 µm. The structural modeling results showed that SCY45 not only had high structural similarity with nutlin-3a, a well-reported MDM2-P53 interaction inhibitor, but also bound to the p53 binding pocket of MDM2 with a binding mode similar to that of nutlin-3a. Moreover, SCY45 reduced the cell viability in cancer cells with MDM2 gene amplification. SCY45 showed the highest inhibition for SJSA-1 cells, which exhibit excessive MDM2 gene amplification, with an IC50 value of 7.54±0.29 µm, whereas SCY45 showed a weaker inhibition for 22Rv1 cells and A549 cells, which have a single copy of the MDM2 gene, with IC50 values of 18.47±0.75 µm and 31.62±1.96 µm, respectively.

Discovery of a non-stereoselective cytochrome P450 catalyzing either 8α- or 8ß-hydroxylation of germacrene A acid from the Chinese medicinal plant, Inula hupehensis.

Sesquiterpene lactones (STLs) are C15 terpenoid natural products with α-methylene γ-lactone moiety. A large proportion of STLs in Asteraceae species is derived from the central precursor germacrene A acid (GAA). Formation of the lactone rings depends on the regio-(C6 or C8) and stereoselective (α- or ß-)hydroxylations of GAA, producing STLs with four distinct stereo-configurations (12,6α-, 12,6ß-, 12,8α-, and 12,8ß-olide derivatives of GAA) in nature. Curiously, two configurations of STLs (C12,8α and C12,8ß) are simultaneously present in the Chinese medicinal plant, Inula hupehensis. However, how these related yet distinct STL stereo-isomers are co-synthesized in I. hupehensis remains unknown. Here, we describe the functional identification of the I. hupehensis cytochrome P450 (CYP71BL6) that can catalyze the hydroxylation of GAA in either 8α- or 8ß-configuration, resulting in the synthesis of both 8α- and 8ß-hydroxyl GAAs. Of these two products, only 8α-hydroxyl GAA spontaneously lactonizes to the C12,8α-STL while the 8ß-hydroxyl GAA remains stable without lactonization. Chemical structures of the C12,8α-STL, named inunolide, and 8ß-hydroxyl GAA were fully elucidated by nuclear magnetic resonance analysis and mass spectrometry. The CYP71BL6 displays 63-66% amino acid identity to the previously reported CYP71BL1/2 catalyzing GAA 6α- or 8ß-hydroxylation, indicating CYP71BL6 shares the same evolutionary lineage with other stereoselective cytochrome P450s, but catalyzes hydroxylation in a non-stereoselective manner. We observed that the CYP71BL6 transcript abundance correlates closely to the accumulation of C12,8-STLs in I. hupehensis. The identification of CYP71BL6 provides an insight into the biosynthesis of STLs in Asteraceae.

Metabolomic Profile of the Genus Inula.

Plants have a long history as therapeutics in the treatment of human diseases and have been used as source of medicines for ages. Searching for new biologically active natural products, many plants and herbs are screened for natural products with pharmacological activities. In this field, the genus Inula, which comprises more than 100 species, several of them being used in traditional medicine, is very important, especially due to the finding that several of the isolated pure secondary metabolites proved to possess important biological activities. Inula species have been reported as rich sources of sesquiterpene lactones, including eudesmanes, germacranes, guaianes, and dimeric structures, and since 2006 ca. 400 secondary metabolites, including more than 100 new natural products, some of them with relevant pharmacological activities, have been identified. Herein, we critically compile and update the information regarding the types of secondary metabolites found in the genus Inula and the progress in their isolation.

[Analysis on morphological characteristics, photosynthetic characteristics and chemical constituents of Inula lineariifolia from different populations].

Twelve populations of Inula lineariifolia were used as materials to measure morphological characteristics, photosynthetic parameters and chemical constituents. It aims to provide a theoretical basis for germplasm resources evaluation. The results showed that I. lineariifolia had relatively rich morphological diversity, there were significant differences of morphological characteristics, photosynthetic parameters and chemical constituents among populations. There was positive correlation on morphological characteristics and P(n). Twelve populations were divided into three-type. The three populations of Xuyi, Mingguang and Fengyang were of narrower-longer leaf, bigger biomass,better photosynthetic and higher chemical constituents. Then they were classified for a similar group. It proved that the three populations were more suitable for cultivation and promotion.

Inhibitory Effects of JEUD-38, a New Sesquiterpene Lactone from Inula japonica Thunb, on LPS-Induced iNOS Expression in RAW264.7 Cells.

We isolated JEUD-38, a new sesquiterpene lactone from Inula japonica Thunb. JEUD-38 dramatically attenuated lipopolysaccharide (LPS)-induced nitric oxide (NO) production. Consistent with this finding, the protein expression of inducible nitric oxide synthase (iNOS) was blocked by JEUD-38 in a concentration-dependent manner. To elucidate the mechanism, we examined the effect of JEUD-38 on LPS-stimulated nuclear factor-κB (NF-κB) nuclear translocation, inhibitory factor-κB (IκB) phosphorylation, and degradation. JEUD-38 reduced the translocation of p65, via abrogating IκB-α phosphorylation and degradation. In addition, JEUD-38 inhibited LPS-stimulated phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. Since iNOS as well as the upstream NF-κB and MAPKs are known to be closely involved in inflammation, these results suggest that JEUD-38 is a promising candidate for prevention and therapy of inflammatory diseases.

The genus Inula and their metabolites: from ethnopharmacological to medicinal uses.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Inula comprises more than one hundred species widespread in temperate regions of Europe and Asia. Uses of this genus as herbal medicines have been first recorded by the Greek and Roman ancient physicians. In the Chinese Pharmacopoeia, from the 20 Inula spp. distributed in China, three are used as Traditional Chinese medicines, named Tumuxiang, Xuanfuhua and Jinfeicao. These medicines are used as expectorants, antitussives, diaphoretics, antiemetics, and bactericides. Moreover, Inula helenium L. which is mentioned in Minoan, Mycenaean, Egyptian/Assyrian pharmacotherapy and Chilandar Medical Codex, is good to treat neoplasm, wound, freckles and dandruff. Many other Inula spp. are used in Ayurvedic and Tibetan traditional medicinal systems for the treatment of diseases such as bronchitis, diabetes, fever, hypertension and several types of inflammation. This review is a critical evaluation of the published data on the more relevant ethnopharmacological and medicinal uses of Inula spp. and on their metabolites biological activities. This study allows the identification of the ethnopharmacological knowledge of this genus and will provide insight into the emerging pharmacological applications of Inula spp. facilitating the prioritirization of future investigations. The corroboration of the ethnopharmacological applications described in the literature with proved biological activities of Inula spp. secondary metabolites will also be explored. MATERIALS AND METHODS: The major scientific databases including ScienceDirect, Medline, Scopus and Web of Science were queried for information on the genus Inula using various keyword combinations, more than 180 papers and patents related to the genus Inula were consulted. The International Plant Name Index was also used to confirm the species names. RESULTS: Although the benefits of Inula spp. are known for centuries, there are insufficient scientific studies to certify it. Most of the patents are registered by Chinese researchers, proving the traditional use of these plants in their country. Although a total of sixteen Inula species were reported in the literature to have ethnopharmacological applications, the species Inula cappa (Buch.-Ham. ex D.Don) DC., Inula racemosa Hook.f., Inula viscosa (L.) Aiton [actually the accepted name is Dittrichia viscosa (L.) Greuter], Inula helenium, Inula britannica L. and Inula japonica Thunb. are the most frequently cited ones since their ethnopharmacological applications are vast. They are used to treat a large spectrum of disorders, mainly respiratory, digestive, inflammatory, dermatological, cancer and microbial diseases. Fifteen Inula spp. crude extracts were investigated and showed interesting biological activities. From these, only 7 involved extracts of the reported spp. used in traditional medicine and 6 of these were studied to isolate the bioactive compounds. Furthermore, 90 bioactive compounds were isolated from 16 Inula spp. The characteristic compounds of the genus, sesquiterpene lactones, are involved in a network of biological effects, and in consequence, the majority of the experimental studies are focused on these products, especially on their cytotoxic and anti-inflammatory activities. The review shows the chemical composition of the genus Inula and presents the pharmacological effects proved by in vitro and in vivo experiments, namely the cytotoxic, anti-inflammatory (with focus on nitric oxide, arachidonic acid and NF-κB pathways), antimicrobial, antidiabetic and insecticidal activities. CONCLUSIONS: Although there are ca. 100 species in the genus Inula, only a few species have been investigated so far. Eight of the sixteen Inula spp. with ethnopharmacological application had been subjected to biological evaluations and/or phytochemical studies. Despite Inula royleana DC. and Inula obtusifolia A. Kerner are being used in traditional medicine, as far as we are aware, these species were not subjected to phytochemical or pharmacological studies. The biological activities exhibited by the compounds isolated from Inula spp., mainly anti-inflammatory and cytotoxic, support some of the described ethnopharmacological applications. Sesquiterpene lactone derivatives were identified as the most studied class, being britannilactone derivatives the most active ones and present high potential as anti-inflammatory drugs, although, their pharmacological effects, dose-response relationship and toxicological investigations to assess potential for acute or chronic adverse effects should be further investigated. The experimental results are promising, but the precise mechanism of action, the compound or extract toxicity, and the dose to be administrated for an optimal effect need to be investigated. Also human trials (some preclinical studies proved to be remarkable) should be further investigated. The genus Inula comprises species useful not only in medicine but also in other domains which makes it a high value-added plant.

Variability of antioxidant and antibacterial effects of essential oils and acetonic extracts of two edible halophytes: Crithmum maritimum L. and Inula crithmoїdes L.

This work aimed to assess the richness of the food halophytes Crithmum maritimum and Inula crithmoїdes on phenolics and essential oils (EOs) and to evaluate the antioxidant and antibacterial potential of these metabolites. Results displayed that extract of I. crithmoїdes possesses considerable contents of phenolic compounds (14.1mg GAE.g⁻¹ DW) related to important antioxidant activities (IC50 = 13 µg ml⁻¹ for the DPPH test) as compared to C. maritimum. C. maritimum EOs composition is dominated by oxygenated monoterpenes, while I. crithmoїdes one is mainly consisted by monoterpene hydrocarbons. EOs have low antioxidant activity as compared to acetone extracts; nevertheless, they show best antimicrobial activity. A significant variability is also depicted between the provenances of each species and depended on the chemical nature of antioxidant and antibacterial molecules as well as the used tests.