Publications by authors named "Tsong-Long Hwang"

331 Publications

Anti-Allergic, Anti-Inflammatory and Anti-Hyperglycemic Activity of Leaf Extract and Its Profiling Using LC/MS and GLC/MS.

Plants (Basel) 2021 May 31;10(6). Epub 2021 May 31.

Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Abbassia 11566, Egypt.

This study aims to comprehensively explore the phytoconstituents as well as investigate the different biological activities of (Iridaceae) for the first time. Metabolic profiling of the leaf methanol extract of (CAL) was carried out using HPLC-PDA-ESI-MS/MS. Twenty-nine compounds were annotated belonging to various phytochemical classes including organic acids, cinnamic acid derivatives, flavonoids, isoflavonoids, and fatty acids. Myricetin-3-O-rhamnoside was the major compound identified. GLC/MS analysis of the -hexane fraction (CAL-A) resulted in the identification of 45 compounds with palmitic acid (16.08%) and methyl hexadecanoic acid ester (11.91%) representing the major constituents. CAL-A exhibited a potent anti-allergic activity as evidenced by its potent inhibition of -hexosaminidase release triggered by A23187 and IgE by 72.7% and 48.7%, respectively. Results were comparable to that of dexamethasone (10 nM) in the A23187 degranulation assay showing 80.7% inhibition for -hexosaminidase release. Both the n-hexane (CAL-A) and dichloromethane (CAL-B) fractions exhibited potent anti-inflammatory activity manifested by the significant inhibition of superoxide anion generation and prohibition of elastase release. CAL showed anti-hyperglycemic activity vivo using streptozotocin-induced diabetic rat model by reducing fasting blood glucose levels (FBG) by 53.44% as compared with STZ-treated rats along with a substantial increase in serum insulin by 22.22%. Molecular modeling studies indicated that dicaffeoylquinic acid showed the highest fitting with free binding energies (∆G) of -47.24 and -60.50 Kcal/mol for human -amylase and -glucosidase, respectively confirming its anti-hyperglycemic activity. Thus, leaf extract could serve as an effective antioxidant natural remedy combating inflammation, allergy, and hyperglycemia.
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http://dx.doi.org/10.3390/plants10061118DOI Listing
May 2021

Cherbonolides M and N from a Formosan Soft Coral  .

Mar Drugs 2021 May 1;19(5). Epub 2021 May 1.

Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.

Two new isosarcophine derivatives, cherbonolides M () and N (), were further isolated from a Formosan soft coral . The planar structure and relative configuration of both compounds were established by the detailed analysis of the IR, MS, and 1D and 2D NMR data. Further, the absolute configuration of both compounds was determined by the comparison of CD spectra with that of isosarcophine (). Notably, cherbonolide N () possesses the unique cembranoidal scaffold of tetrahydrooxepane with the 12,17-ether linkage fusing with a -lactone. In addition, the assay for cytotoxicity of both new compounds revealed that they showed to be noncytotoxic toward the proliferation of A549, DLD-1, and HuCCT-1 cell lines. Moreover, the anti-inflammatory activities of both metabolites were carried out by measuring the -formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLF/CB)-induced generation of superoxide anion and elastase release in the primary human neutrophils. Cherbonolide N () was found to reduce the generation of superoxide anion (20.6 ± 6.8%) and the elastase release (30.1 ± 3.3%) in the fMLF/CB-induced human neutrophils at a concentration of 30 μM.
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http://dx.doi.org/10.3390/md19050260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170881PMC
May 2021

Randialic acid B and tomentosolic acid block formyl peptide receptor 1 in human neutrophils and attenuate psoriasis-like inflammation in vivo.

Biochem Pharmacol 2021 May 6;190:114596. Epub 2021 May 6.

Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33302, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City 24301, Taiwan. Electronic address:

Psoriasis is a long-lasting inflammatory skin disease lacking proper cure. Dysregulated activation of neutrophils is a major pathogenic factor in psoriasis. Formyl peptide receptor 1 (FPR1) triggers neutrophil activation in response to bacteria- or mitochondria-derived N-formyl peptides, but its significance in neutrophilic psoriasis remains unknown. In this study, we discovered two derivatives of ursolic acid, 3β-hydroxyurs-12,18-dien-28-oic acid (randialic acid B, RAB) and 3β-hydroxyurs-12,19-dien-28-oic acid (tomentosolic acid, TA), as FPR1 inhibitors in human neutrophils with ability to suppress psoriatic symptoms in mice. Both RAB and TA, triterpenoids of traditional medicinal plant Ilex kaushue, selectively inhibited reactive oxygen species production, elastase release, and CD11b expression in human neutrophils activated by FPR1, but not non-FPR1 agonists. Importantly, RAB and TA inhibited the binding of N-formyl peptide to FPR1 in human neutrophils, neutrophil-like THP-1 cells, and hFPR1-transfected HEK293 cells, indicating FPR1 antagonism. Moreover, in assays induced by various concentrations of FPR1 agonist, both RAB and TA acted competitively for its binding to the FPR1 receptor. The FPR1-downstream signaling such as Ca mobilisation and activation of Akt and MAPKs was also competitively inhibited. In addition, imiquimod-induced psoriasis-like symptoms, including epidermal hyperplasia, desquamation with scaling, neutrophil skin infiltration, and transepidermal water loss were significantly reduced by both RAB and TA. The results illustrate a possible role of human neutrophils FPR1 receptor in psoriasis-like inflammation. Accordingly, triterpenoids RAB and TA represent novel FPR1 antagonists and exhibit therapeutic potential for treating neutrophilic inflammatory skin diseases.
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http://dx.doi.org/10.1016/j.bcp.2021.114596DOI Listing
May 2021

Anti-Inflammatory Principles from the Needles of Hayata and In Silico Studies of Their Potential Anti-Aging Effects.

Antioxidants (Basel) 2021 Apr 13;10(4). Epub 2021 Apr 13.

Department of Forestry, National Chung-Hsing University, Taichung 402, Taiwan.

needle tea are very popular in Eastern countries such as Japan, Russia, Korea, and China. Pine needle tea is claimed to have significant anti-aging effects, but no clear evidence has supported this until now. In the present study, five undescribed compounds (-) as well as seventy-two known compounds were purified and characterized from the bioactive fraction of methanol extracts of needles. Most of the isolates were examined for their anti-inflammatory bioactivity by cellular neutrophil model and six compounds (, , , , , and ) exhibited a significant inhibition on superoxide anion generation and elastase release with IC values ranging from 3.3 ± 0.9 to 8.3 ± 0.8 μM. These anti-inflammatory ingredients were subjected to docking computing to evaluate their binding affinity on the ghrelin receptor, which played an important role in regulating metabolism, with anti-aging effects. Compounds , , and formed a stable complex with the ghrelin receptor via hydrogen bonds and different types of interactions. These results suggest the flavonoids are responsible for the potential anti-aging effects of pine needle tea.
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http://dx.doi.org/10.3390/antiox10040598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069155PMC
April 2021

Design and synthesis of β-carboline and combretastatin derivatives as anti-neutrophilic inflammatory agents.

Bioorg Chem 2021 Jun 26;111:104846. Epub 2021 Mar 26.

Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Division of Natural Products, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Chinese Herbal Medicine, Graduate Institute of Healthy Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan; College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, Taiwan. Electronic address:

A series of β-carboline derivatives was synthesized by the Pictet-Spengler reaction with or without the combretastatin skeleton. The structures of these derivatives were elucidated by spectroscopic techniques. All synthesized compounds were evaluated for their anti-inflammatory activity in human neutrophils. Among them, two compounds, NTU-228 and HK-72, showed significant inhibitory effects on N-formyl-Met-Leu-Phe (fMLF)-induced superoxide anion generation in human neutrophils with IC values of 5.58 ± 0.56 and 2.81 ± 0.07 μM, respectively. Neither NTU-228 nor HK-72 caused cytotoxicity in human neutrophils. NTU-228 inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and intracellular Ca levels ([Ca]) in fMLF-activated human neutrophils. Additionally, HK-72 selectively inhibited the fMLF-induced phosphorylation of p38 and [Ca] in human neutrophils. Molecular docking analysis showed a favorable binding affinity of HK-72 toward p38 MAPK. The proposed synthetic strategy opens up new opportunities for the synthesis of novel potential candidates against neutrophilic inflammation.
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http://dx.doi.org/10.1016/j.bioorg.2021.104846DOI Listing
June 2021

Monovalent antibody-conjugated lipid-polymer nanohybrids for active targeting to desmoglein 3 of keratinocytes to attenuate psoriasiform inflammation.

Theranostics 2021 4;11(10):4567-4584. Epub 2021 Mar 4.

Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.

To improve the treatment of psoriasiform inflammation, we developed actively targeted nanocarriers loaded with the phosphodiesterase 4 inhibitor AN2728. Phospholipid-poly(lactic--glycolic acid) nanohybrids were prepared and conjugated with monovalent anti-desmoglein 3 antibody to bind keratinocytes. The actively targeted nanohybrids were 229 nm in mean size with a nearly neutral surface charge. Flow cytometry and confocal microscopy showed a 9-fold increase in keratinocyte uptake of targeted nanohybrids relative to non-targeted nanoparticles. The nanoparticles localized mainly in lysosomes after internalization. AN2728-loaded antibody-conjugated nanocarriers inhibited cytokine/chemokine overexpression in activated keratinocytes without affecting cell viability. The targeted nanohybrids also suppressed neutrophil migration by reducing CXCL1 and CXCL2 release from keratinocytes. Following subcutaneous administration in mice, the nanohybrids distributed to the epidermis and hair follicles. In a psoriasis-like skin mouse model, the actively targeted nanoparticles were superior to free drug and non-targeted nanoparticles in mitigating skin inflammation. Intervention with the targeted nanosystem reduced the epidermal thickness of the psoriasiform lesion from 191 to 42 µm, decreased the Psoriasis Area Severity Index by 74%, restored barrier function, and returned chemokine levels to baseline. Our developed nanosystem was safe and demonstrated efficient targeting properties for the treatment of cutaneous inflammation.
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http://dx.doi.org/10.7150/thno.56995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978323PMC
March 2021

Cembranoids from Octocoral (von Marenzeller, 1886).

Mar Drugs 2021 Feb 27;19(3). Epub 2021 Feb 27.

Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944401, Taiwan.

Two cembranoids, including a new compound, lobocrassin I (), as well as a known analogue, lobohedleolide (), were obtained by solvent extraction from octocoral . This study employed a spectroscopic approach to establish the structures of these two cembranoids, and utilized single-crystal X-ray diffraction analysis to determine their absolute configurations. The results of biological activity assays demonstrated that cembranoid exhibited bioactivity against the protein expressions of inducible nitric oxide synthase (iNOS) lipopolysaccharide (LPS)-treated RAW 264.7 mouse macrophage cells.
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http://dx.doi.org/10.3390/md19030130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997245PMC
February 2021

5-Methoxybenzothiophene-2-Carboxamides as Inhibitors of Clk1/4: Optimization of Selectivity and Cellular Potency.

Molecules 2021 Feb 13;26(4). Epub 2021 Feb 13.

Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany.

Clks have been shown by recent studies to be promising targets for cancer therapy, as they are considered key regulators in the process of pre-mRNA splicing, which in turn affects every aspect of tumor biology. In particular, Clk1 and -4 are overexpressed in several human tumors. Most of the potent Clk1 inhibitors reported in the literature are non-selective, mainly showing off-target activity towards Clk2, Dyrk1A and Dyrk1B. Herein, we present new 5-methoxybenzothiophene-2-carboxamide derivatives with unprecedented selectivity. In particular, the introduction of a 3,5-difluoro benzyl extension to the methylated amide led to the discovery of compound (cell-free IC = 12.7 nM), which was four times more selective for Clk1 over Clk2 than the previously published flagship compound . Moreover, showed an improved growth inhibitory activity with T24 cells (GI = 0.43 µM). Furthermore, a new binding model in the ATP pocket of Clk1 was developed based on the structure-activity relationships derived from new rigidified analogues.
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http://dx.doi.org/10.3390/molecules26041001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918793PMC
February 2021

The study on structure-activity relationship between chromone derivatives and inhibition of superoxide anion generating from human neutrophils.

Bioorg Med Chem Lett 2021 03 27;36:127822. Epub 2021 Jan 27.

School of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC. Electronic address:

Over activation of neutrophils has been linked to many inflammatory diseases; one of critical pathologic mechanisms is that generation and exocellular release of superoxide anion from neutrophils results in peripheral tissues damage. Besides, in this study, 2-(3,5-dimethoxyphenoxy)-5,7-dimethoxy-chromen-4-one (4), a 2-phexnoychromone from our compound bank, was demonstrated to have the moderate inhibitory effect on superoxide anion generating. Therefore, serial chromones substituted with phenols or 3-flourothiophenol were designed, synthesized, and examined for suppression of superoxide anion generation. In accordance with the results, the methoxy group at 7 position (R) of the chromone, as well as a hydrogen bond donor at a meta site of the phenyl ring greatly impacted on the activity. 2-(3-fluorophenyl)sulfanyl-7-methoxy-chromen-4-one (16), a successful example of bioisosteres from a phenol to a thiophenol, exhibited prominent anti-inflammatory effects with the IC value against superoxide anion generation of 5.0 ± 1.4 μM.
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http://dx.doi.org/10.1016/j.bmcl.2021.127822DOI Listing
March 2021

An Anti-Inflammatory 2,4-Cyclized-3,4-Secospongian Diterpenoid and Furanoterpene-Related Metabolites of a Marine Sponge sp. from the Red Sea.

Mar Drugs 2021 Jan 16;19(1). Epub 2021 Jan 16.

Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.

Chemical investigation of a Red Sea sp. led to the isolation of four new compounds, i.e., 17-dehydroxysponalactone (), a carboxylic acid, spongiafuranic acid A (), one hydroxamic acid, spongiafuranohydroxamic acid A (), and a furanyl trinorsesterpenoid 16--irciformonin G (), along with three known metabolites (-)-sponalisolide B (), 18-nor- 3,17-dihydroxy-spongia-3,13(16),14-trien-2-one (), and cholesta-7-ene-3β,5α-diol-6-one (). The biosynthetic pathway for the molecular skeleton of and related compounds was postulated for the first time. Anti-inflammatory activity of these metabolites to inhibit superoxide anion generation and elastase release in -formyl-methionyl-leucyl phenylalanine/cytochalasin B (fMLF/CB)-induced human neutrophil cells and cytotoxicity of these compounds toward three cancer cell lines and one human dermal fibroblast cell line were assayed. Compound was found to significantly reduce the superoxide anion generation and elastase release at a concentration of 10 μM, and compound was also found to display strong inhibitory activity against superoxide anion generation at the same concentration. Due to the noncytotoxic activity and the potent inhibitory effect toward the superoxide anion generation and elastase release, and can be considered to be promising anti-inflammatory agents.
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http://dx.doi.org/10.3390/md19010038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830757PMC
January 2021

Neutrophil elastase inhibitor (MPH-966) improves intestinal mucosal damage and gut microbiota in a mouse model of 5-fluorouracil-induced intestinal mucositis.

Biomed Pharmacother 2021 Feb 26;134:111152. Epub 2020 Dec 26.

Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan. Electronic address:

Background: 5-Fluorouracil (5-FU)-based chemotherapy is first-line chemotherapy for colorectal cancer. However, 5-FU-induced intestinal mucositis (FUIIM) is a common adverse effect that severely impairs drug tolerance and results in poor patient health.

Methods: Male C57BL/6 mice were given 5-FU (50 mg/kg/day, i.p.) and treated with MPH-966 (5 and 7.5 mg/kg/day, p.o.) for five days. The body weight loss and the amount of food intake, and histopathological findings were recorded and analyzed. In addition, the neutrophil infiltration, levels of neutrophil serine proteases and pro-inflammatory cytokines, and tight junction proteins expression in intestinal tissues were determined. The ecology of gut microbiota was performed through next-generation sequencing technologies.

Results: Neutrophil elastase (NE) overexpression is a key feature in FUIIM. This study showed that treatment with the specific NE inhibitor MPH-966 (7.5 mg/kg/day, p.o.) significantly reversed 5-FU-induced loss in body weight and food intake; reversed villous atrophy; significantly suppressed myeloperoxidase, NE, and proteinase 3 activity; and reduced pro-inflammatory cytokine expression in an FUIIM mouse model. In addition, MPH-966 prevented 5-FU-induced intestinal barrier dysfunction, as indicated by the modulated expression of the tight junction proteins zonula occludin-1 and occludin. MPH-966 also reversed 5-FU-induced changes in gut microbiota diversity and abundances, specifically the Firmicutes-to-Bacteroidetes ratio; Muribaculaceae, Ruminococcaceae, and Eggerthellaceae abundances at the family level; and Candidatus Arthromitus abundance at the genus level.

Conclusion: These data indicate that NE inhibitor is a key treatment candidate to alleviate FUIIM by regulating abnormal inflammatory responses, intestinal barrier dysfunction, and gut microbiota imbalance.
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http://dx.doi.org/10.1016/j.biopha.2020.111152DOI Listing
February 2021

Antiinflammatory triterpenoids from the fruiting bodies of Fomitopsis pinicola.

Bioorg Chem 2021 Mar 16;108:104562. Epub 2020 Dec 16.

School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Department of Pharmacy, College of Pharmacy and Health Care, Tajen University, Pingtung 907, Taiwan. Electronic address:

Twelve undescribed lanostane-type triterpenes, and twenty-two known triterpenes were isolated and identified from a medicinal bracket fungus Fomitopsis pinicola (Sw.) P. Karst. The structures of these compounds were determined by spectroscopic and spectrometric analyses. The antiinflammatory potential of thirty-two triterpene compounds was evaluated using neutrophils as an assay model, and pinicolasin J was the most potent inhibitor of superoxide anion generation and elastase release, with IC values of 1.81 ± 0.44 and 2.50 ± 0.64 μM, respectively. This study provides scientific insight into the nutritional supplement value and medicinal development of Fomitopsis pinicola.
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http://dx.doi.org/10.1016/j.bioorg.2020.104562DOI Listing
March 2021

Recent advances in the field of caloric restriction mimetics and anti-aging molecules.

Ageing Res Rev 2021 03 24;66:101240. Epub 2020 Dec 24.

Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, CA, USA. Electronic address:

Caloric restriction (CR) mimetics are molecules that produce beneficial effects on health and longevity in model organisms and humans, without the challenges of maintaining a CR diet. Conventional CR mimetics such as metformin, rapamycin and spermidine activate autophagy, leading to recycling of cellular components and improvement of physiological function. We review here novel CR mimetics and anti-aging compounds, such as 4,4'-dimethoxychalcone, fungal polysaccharides, inorganic nitrate, and trientine, highlighting their possible molecular targets and mechanisms of action. The activity of these compounds can be understood within the context of hormesis, a biphasic dose response that involves beneficial effects at low or moderate doses and toxic effects at high doses. The concept of hormesis has widespread implications for the identification of CR mimetics in experimental assays, testing in clinical trials, and use in healthy humans. We also discuss the promises and limitations of CR mimetics and anti-aging molecules for delaying aging and treating chronic diseases.
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http://dx.doi.org/10.1016/j.arr.2020.101240DOI Listing
March 2021

Secoiridoid Glucosides and Anti-Inflammatory Constituents from the Stem Bark of .

Molecules 2020 Dec 14;25(24). Epub 2020 Dec 14.

Faculty of Pharmacy, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan.

Qin Pi ( Roxb.) is commercially used in healthcare products for the improvement of intestinal function and gouty arthritis in many countries. Three new secoiridoid glucosides, (8)-4''--methylligstroside (), (8)-4''--methyldemethylligstroside (), and 3'',4''-di--methyl-demethyloleuropein (), have been isolated from the stem bark of , together with 23 known compounds (-). The structures of the new compounds were established by spectroscopic analyses (1D, 2D NMR, IR, UV, and HRESIMS). Among the isolated compounds, (8)-4''--methylligstroside (), (8)-4''--methyldemethylligstroside (), 3'',4''-di--methyldemethyloleuropein (), oleuropein (), aesculetin (), isoscopoletin (), aesculetin dimethyl ester (), fraxetin (), tyrosol (), 4-hydroxyphenethyl acetate (), and (+)-pinoresinol () exhibited inhibition (IC ≤ 7.65 μg/mL) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leuckyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds , , , , , and inhibited fMLP/CB-induced elastase release with IC ≤ 3.23 μg/mL. In addition, compounds , , , , and showed potent inhibition with IC values ≤ 27.11 μM, against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation. The well-known proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), were also inhibited by compounds , , and . Compounds , , and displayed an anti-inflammatory effect against NO, TNF-α, and IL-6 through the inhibition of activation of MAPKs and IκBα in LPS-activated macrophages. In addition, compounds , , and stimulated anti-inflammatory M2 phenotype by elevating the expression of arginase 1 and Krüppel-like factor 4 (KLF4). The above results suggested that compounds , , and could be considered as potential compounds for further development of NO production-targeted anti-inflammatory agents.
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http://dx.doi.org/10.3390/molecules25245911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764309PMC
December 2020

Aqueous Extract of Kan-Lu-Hsiao-Tu-Tan Ameliorates Collagen-Induced Arthritis in Mice by Inhibiting Oxidative Stress and Inflammatory Responses.

Life (Basel) 2020 Nov 27;10(12). Epub 2020 Nov 27.

Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan.

Background: Kan-Lu-Hsiao-Tu-Tan (KLHTT) exhibits anti-psoriatic effects through anti-inflammatory activity in mice. However, the therapeutic effects of KLHTT on rheumatoid arthritis (RA), another significant autoimmune inflammatory disorder, have not been elucidated. Herein, we explored the anti-arthritic effects of KLHTT on collagen-induced arthritis (CIA) in mice.

Methods: KLHTT was extracted by boiling water and subjected to spectroscopic analysis. Chicken collagen type II (CII) with complete Freund's adjuvant was intradermally injected to induce CIA in DBA/1J mice. Anti-CII antibody, cytokines, malondialdehyde (MDA), and hydrogen peroxide (HO) were measured using ELISA, thiobarbituric acid reactive substances, and a hydrogen peroxide assay kit. Splenocyte proliferation was tested using thymidine incorporation. Th1 and Th17 cells were analyzed by flow cytometry.

Results: Oral KLHTT treatment (50 and 100 mg/kg) ameliorated mouse CIA by decreasing the levels of interleukin (IL)-1β, IL-6, IL-17A, and tumour necrosis factor-α in the paw homogenates and serum. KLHTT also suppressed anti-CII antibody formation, splenocyte proliferation, and splenic Th1 and Th17 cell numbers. Additionally, KLHTT showed antioxidant activity by reducing the concentrations of MDA and HO in paw tissues.

Conclusions: The therapeutic effects of KLHTT in CIA mice were through regulating oxidative stress and inflammatory responses. Our results suggest that KLHTT has potential to treat RA.
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http://dx.doi.org/10.3390/life10120313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760413PMC
November 2020

Anti-Inflammatory Cembranoids from a Formosa Soft Coral .

Mar Drugs 2020 Nov 19;18(11). Epub 2020 Nov 19.

Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan.

The present investigation on chemical constituents of the soft coral resulted in the isolation of seven new cembranoids, cherbonolides F-L (-). The chemical structures of - were determined by spectroscopic methods, including infrared, one- and two-dimensional (1D and 2D) NMR (COSY, HSQC, HMBC, and NOESY), MS experiments, and a chemical reduction of hydroperoxide by triphenylphosphine. The anti-inflammatory activities of - against neutrophil proinflammatory responses were evaluated by measuring their inhibitory ability toward -formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLF/CB)-induced superoxide anion generation and elastase release in primary human neutrophils. The results showed that all isolates exhibited moderate activities, while cherbonolide G () and cherbonolide H () displayed a more active effect than others on the inhibition of elastase release (48.2% ± 6.2%) and superoxide anion generation (44.5% ± 4.6%) at 30 µM, respectively.
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http://dx.doi.org/10.3390/md18110573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699541PMC
November 2020

Novel Caryophyllane-Related Sesquiterpenoids with Anti-Inflammatory Activity from (Linnaeus, 1758).

Mar Drugs 2020 Nov 6;18(11). Epub 2020 Nov 6.

Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-sen University, Kaohsiung 804201, Taiwan.

Two previously undescribed caryophyllane-related sesquiterpenoids, antipacids A () and B (), with a novel bicyclo[5.2.0] core skeleton, and known compound clovane-2β,9α-diol (), along with rumphellolide L (), an esterified product of and , were isolated from the organic extract of octocoral . Their structures, including the absolute configurations were elucidated by spectroscopic and chemical experiments. In vivo anti-inflammatory activity analysis indicated that antipacid B () inhibited the generation of superoxide anions and the release of elastase by human neutrophils, with IC values of 11.22 and 23.53 μM, respectively, while rumphellolide L () suppressed the release of elastase with an IC value of 7.63 μM.
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http://dx.doi.org/10.3390/md18110554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694975PMC
November 2020

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease.

Front Pharmacol 2020 9;11:572009. Epub 2020 Oct 9.

Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

This review describes targeting neutrophils as a potential therapeutic strategy for acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 (COVID-19), a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutrophil counts are significantly elevated in patients with COVID-19 and significantly correlated with disease severity. The neutrophil-to-lymphocyte ratio can serve as a clinical marker for predicting fatal complications related to ARDS in patients with COVID-19. Neutrophil-associated inflammation plays a critical pathogenic role in ARDS. The effector functions of neutrophils, acting as respiratory burst oxidants, granule proteases, and neutrophil extracellular traps, are linked to the pathogenesis of ARDS. Hence, neutrophils can not only be used as pathogenic markers but also as candidate drug targets for COVID-19 associated ARDS.
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http://dx.doi.org/10.3389/fphar.2020.572009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583590PMC
October 2020

Imperatorin Alleviates Psoriasiform Dermatitis by Blocking Neutrophil Respiratory Burst, Adhesion, and Chemotaxis Through Selective Phosphodiesterase 4 Inhibition.

Antioxid Redox Signal 2020 Dec 3. Epub 2020 Dec 3.

Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

Neutrophil infiltration and increased oxidative stress are involved in the pathogenesis and severity of psoriasis. Although the therapy of psoriasis remains elusive, targeting treatment to reduce oxidative stress is considered a potential option. Our study demonstrates the anti-inflammatory effects of a natural furocoumarin, imperatorin, on activated human neutrophils and psoriasiform dermatitis in mice. Imperatorin inhibited superoxide anion generation, neutrophil adhesion, and migration in -formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-stimulated human neutrophils. Further studies showed that imperatorin induced a decrease in cAMP-specific phosphodiesterase (PDE) activity, and increased intracellular cAMP levels and protein kinase A (PKA) activity in human neutrophils. The enzyme activities of PDE4 subtypes, but not PDE3 and PDE7, were inhibited by imperatorin. Furthermore, imperatorin inhibited the phosphorylation of protein kinase B (Akt), extracellular regulated kinase (ERK), and c-Jun -terminal kinase (JNK), as well as Ca mobilization in fMLF-stimulated neutrophils. These suppressive effects of imperatorin on cell responses and signaling were reversed by PKA inhibitor, suggesting that cAMP/PKA is involved in the anti-inflammatory effects of imperatorin. studies of imiquimod- and interleukin-23-induced mouse psoriasiform dermatitis demonstrated that imperatorin alleviated skin desquamation, epidermal thickening, keratinocyte hyperproliferation, and neutrophil infiltration. Our results demonstrate that imperatorin inhibits human neutrophil respiratory burst, adhesion, and migration through the elevation of cAMP/PKA to inhibit Akt, ERK, JNK, and Ca mobilization. Imperatorin is a natural inhibitor of PDE4A/B/C and may serve as a lead for developing new therapeutics to treat neutrophilic psoriasis.
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http://dx.doi.org/10.1089/ars.2019.7835DOI Listing
December 2020

Understanding the role of neutrophils in acute respiratory distress syndrome.

Biomed J 2020 Sep 10. Epub 2020 Sep 10.

Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, Taiwan. Electronic address:

Acute respiratory distress syndrome (ARDS) is difficult to treat and is associated with a high mortality rate. The most severe form of coronavirus disease 2019 (COVID-19) also leads to life-threatening ARDS. Neutrophil counts are positively correlated with disease severity in ARDS. Neutrophil activation not only plays a significant role in immune defense against infections, but also causes tissue damage and leads to inflammatory diseases. Activated neutrophils rapidly migrate to inflamed lung tissue, releasing toxic granular contents and generating neutrophil extracellular traps. In the last few decades, it has become apparent that neutrophils occupy a central role in ARDS pathology. In this review, we summarize the neutrophil inflammatory responses and their relationships to ARDS. According to the current literature, understanding the function of neutrophils may be helpful in the treatment of ARDS.
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http://dx.doi.org/10.1016/j.bj.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481802PMC
September 2020

Qualitative and Quantitative Analysis of Ukrainian Species: A Fresh Look on Their Antioxidant Content and Biological Activities.

Molecules 2020 Oct 8;25(19). Epub 2020 Oct 8.

Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.

The major groups of antioxidant compounds (isoflavonoids, xanthones, hydroxycinnamic acids) in the rhizome methanol extracts of four Ukrainian sp. (, , , and ) were qualitatively and quantitatively analyzed using HPLC-DAD and UPLC-MS/MS. Gallic acid, caffeic acid, mangiferin, tectoridin, irigenin, iristectorigenin B, irisolidone, 5,6-dihydroxy-7,8,3',5'-tetramethoxyisoflavone, irisolidone-7---d-glucopyranoside, germanaism B, and nigricin were recognized by comparing their UV/MS spectra, chromatographic retention time (tR) with those of standard reference compounds. and showed the highest total amount of phenolic compounds. Germanaism B was the most abundant component in the rhizomes of (7.089 ± 0.032 mg/g) and (6.285 ± 0.030 mg/g). The compound analyses showed good calibration curve linearity (r > 0.999) and low detection and quantifications limit. These results validated the method for its use in the simultaneous quantitative evaluation of phenolic compounds in the studied sp. and rhizomes exhibited antioxidant activity, as demonstrated by the HPLC-ABTS system and NRF2 expression assay and anti-inflammatory activity on respiratory burst in human neutrophils. Moreover, the extracts showed anti-allergic and cytotoxic effects against cancer cells. Anti-coronavirus 229E and lipid formation activities were also evaluated. In summary, potent antioxidant marker compounds were identified in the examined sp.
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http://dx.doi.org/10.3390/molecules25194588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582944PMC
October 2020

Resveratrol, a Molecule with Anti-Inflammatory and Anti-Cancer Activities: Natural Product to Chemical Synthesis.

Curr Med Chem 2020 09 17. Epub 2020 Sep 17.

Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 33302. Taiwan.

Background: Resveratrol, a natural polyphenol product, is used in plant defense from fungal and microbial aggression. It is found naturally, especially in plants such as grapes, peanuts, and berries. It has the highest concentrations in blueberries, mulberries, blackberries, and the skin of red grapes. Resveratrol has various pharmacological properties such as anti-inflammatory, cytoprotective, and antineoplastic activities.

Methods: We conducted a literature survey using standard tools such as Google, Reaxys, Scifinder, Scihub, and patent Espacenet to compile the biosynthetic pathways, all organic synthetic methods, and biological activities reported for resveratrol till date.

Results: More than one hundred research articles and patents were referred to write this review. About twenty-five of them are related to chemical synthesis, and the rests are about the source, pharmacological activity, and other properties of resveratrol. This study reveals that many common pathways are involved in various pharmacological activities, which can be useful for treating various diseases based on the pathways involved. Reactions such as Pfitzner-Moffatt oxidation, WittigHorner condensation, Mizoroki-Heck, Perkin, Wittig, etc. have been used in resveratrol synthesis. A structure-activity relationship was also established based on its analogs and derivatives.

Conclusion: This review examined and reported all the published biological activities and chemical syntheses of resveratrol apart from the biosynthetic pathway. Due to its valuable biological activities, various synthetic approaches have been reported till date. The reported synthetic operations are suitable for large-scale industrial production. Moreover, these comprehensive synthetic procedures could be utilized in the preparation of stilbenes and other related compounds in future endeavors.
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http://dx.doi.org/10.2174/0929867327999200918100746DOI Listing
September 2020

Phytochemical Investigation and Anti-Inflammatory Activity of the Leaves of var. .

Molecules 2020 Sep 10;25(18). Epub 2020 Sep 10.

School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

In a series of anti-inflammatory screenings of lauraceous plants, the methanolic extract of the leaves of var. (Hayata) J.C. Liao showed potent inhibition on both superoxide anion generation and elastase release in human neutrophils. Bioassay-guided fractionation of the leaves of var. led to the isolation of twenty compounds, including six new butanolides, machinolides A-F (-), and fourteen known compounds (-). Their structures were characterized by 1D and 2D NMR, UV, IR, CD, and MS data. The absolute configuration of the new compounds were unambiguously confirmed by single-crystal X-ray diffraction analyses (, , and ) and Mosher's method (, , and ). In addition, lignans, (+)-eudesmin (), (+)-methylpiperitol (), (+)-pinoresinol (), and (+)-galbelgin () exhibited inhibitory effects on -formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation in human neutrophils with IC values of 8.71 ± 0.74 μM, 2.23 ± 0.92 μM, 6.81 ± 1.07 μM, and 7.15 ± 2.26 μM, respectively. The results revealed the anti-inflammatory potentials of Formosan var.
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http://dx.doi.org/10.3390/molecules25184149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570621PMC
September 2020

BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells.

Biomedicines 2020 Sep 4;8(9). Epub 2020 Sep 4.

Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan.

Activation of hepatic stellate cells (HSCs) is a critical pathogenic feature of liver fibrosis and cirrhosis. BAY 41-2272 is a canonical non-nitric oxide (NO)-based soluble guanylyl cyclase (sGC) stimulator that triggers cyclic guanosine monophosphate (cGMP) signaling for attenuation of fibrotic disorders; however, the impact of BAY 41-2272 on HSC activation remains ill-defined. Transforming growth factor (TGF)β and its downstream connective tissue growth factor (CTGF or cellular communication network factor 2, CCN2) are critical fibrogenic cytokines for accelerating HSC activation. Here, we identified that BAY 41-2272 significantly inhibited the TGFβ1-induced mRNA and protein expression of CTGF in mouse primary HSCs. Indeed, BAY 41-2272 increased the sGC activity and cGMP levels that were potentiated by two NO donors and inhibited by a specific sGC inhibitor, ODQ. Surprisingly, the inhibitory effects of BAY 41-2272 on CTGF expression were independent of the sGC/cGMP pathway in TGFβ1-activated primary HSCs. BAY 41-2272 selectively restricted the TGFβ1-induced phosphorylation of Akt but not canonical Smad2/3 in primary HSCs. Together, we illustrate a unique framework of BAY 41-2272 for inhibiting TGFβ1-induced CTGF upregulation and HSC activation via a noncanonical Akt-dependent but sGC/cGMP-independent pathway.
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http://dx.doi.org/10.3390/biomedicines8090330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554962PMC
September 2020

Secondary Metabolites and Bioactivities of Isolated from .

ACS Omega 2020 Aug 14;5(33):20991-20999. Epub 2020 Aug 14.

Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Five new polyketides, asperochrapyran () and asperochralactones A-D (-), along with 12 known polyketides (-), were obtained from the fungal strain . Structures of all isolates were elucidated by their spectroscopic parameters. The relative configurations of the new compounds were deduced by the data of coupling constants and NOESY spectra. The absolute configurations were determined by the comparison of experimental and calculated ECD spectra. Moreover, the plausible biosynthesis pathway of major isolates was proposed as well. Anti-inflammatory activity of compounds and - were evaluated with human neutrophils in response to the stimulation of formyl-methionyl-leucyl phenylalanine (fMLP). Asperlactone (), aspyrone (), and (-)-(3)-mellein () exerted superoxide anion inhibition at 30 ± 9%, 29 ± 9%, and 26 ± 12%, respectively, at 10 μM. The capacities of asperlactone (), aspilactonol B (), penicillic acid (), and (-)-(3)-mellein () in elastase release inhibition were revealed as 25 ± 4%, 38 ± 8%, 25 ± 5%, and 34 ± 9%, respectively, at 10 μM.
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http://dx.doi.org/10.1021/acsomega.0c02489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450643PMC
August 2020

Mechanism of Nanoformulated Graphene Oxide-Mediated Human Neutrophil Activation.

ACS Appl Mater Interfaces 2020 Sep 26;12(36):40141-40152. Epub 2020 Aug 26.

Graduate Institute of Natural Products, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.

Understanding the molecular mechanisms of graphene oxide (GO)-based biomaterials is important for logical biomedical applications. Previous studies have revealed biointeractions between GO and immune effector cells, but the effects on neutrophils, crucial cells in the immune system, have not been thoroughly discussed. In this study, GO nanoformulations were synthesized with different functional groups, including GO, GO-carboxylated (GO-COOH), and PEGylated GO (GO-PEG), with different surface features, which were elucidated using imaging methods and surface-sensitive quantitative spectroscopic techniques, including atomic force microscopy (AFM), transmission electron microscopy (TEM), and X-ray photoemission spectroscopy (XPS). The GO-based nanoformulations elicited reactive oxygen species (ROS) generation and neutrophil extracellular trap (NET) formation in human neutrophils. Nanoformulated GO stimulates NET development via the formation of ROS. An endocytosis study revealed that nanoformulated GO facilitated internalization by neutrophils via macropinocytosis and actin-dependent phagocytosis. Importantly, calcium mobilization and phosphorylation proteins such as mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38) and AKT were involved in the activation of neutrophils. These findings offer the first verification that nanoformulated GO exhibits direct effects on human neutrophils.
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http://dx.doi.org/10.1021/acsami.0c12490DOI Listing
September 2020

Lophatherum gracile Brongn. attenuates neutrophilic inflammation through inhibition of JNK and calcium.

J Ethnopharmacol 2021 Jan 12;264:113224. Epub 2020 Aug 12.

Research Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, 33303, Taiwan; Graduate Institute of Natural Products, School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, 33302, Taiwan; Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, 33303, Taiwan; Department of Anaesthesiology, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, 24301, Taiwan. Electronic address:

Ethnopharmacological Relevance: Lophatherum gracile Brongn. (L. gracile) has been long used in traditional herbal medicine to clinically clear heat, disinhibit dampness, and treat inflammation. However, the effect of L. gracile on the activation of human neutrophils remains unclear.

Aim Of The Study: The aim of current study is to investigate the anti-inflammatory properties of L. gracile extract (LGE) in N-formyl-methionyl-leucyl-phenylalanine (fMLF)-induced activation of human neutrophils.

Materials And Methods: Superoxide anion generation and elastase release were estimated by spectrophotometry. A series of signaling pathways including mitogen-activated protein kinases (MAPKs) and protein kinase B (Akt), as well as calcium mobilization were studied by Western blot analysis and spectrofluorometry.

Results: Our experimental results indicated that the nontoxic dosage of LGE does-dependently inhibited the fMLF-induced superoxide anion (O) generation, elastase release, CD11b expression, adhesion, and chemotactic migration in human neutrophils. LGE selectively inhibited the fMLF-induced phosphorylation of JNK but not p38, ERK, or Akt in human neutrophils. LGE also decreased the intracellular Ca levels ([Ca]) in fMLF-activated human neutrophils. However, a specific JNK inhibitor inhibited the fMLF-induced O generation and CD11b expression, but it had no effect on [Ca] in human neutrophils.

Conclusions: LGE exhibited anti-inflammatory activities in fMLF-activated human neutrophils. The pharmacological mechanisms of LGE-repressed neutrophilic inflammation were through two independent pathways, JNK signaling and calcium mobilization. Our results suggested that LGE holds the potential to be developed as an anti-inflammatory botanical medicine.
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http://dx.doi.org/10.1016/j.jep.2020.113224DOI Listing
January 2021

Anti-Inflammatory and Antibacterial Activity Constituents from the Stem of .

Molecules 2020 Jul 25;25(15). Epub 2020 Jul 25.

School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

One new dibenzocycloheptene, validinol (), and one butanolide firstly isolated from the natural source, validinolide (), together with 17 known compounds were isolated from the stem of . Among the isolates, lincomolide A (), secosubamolide (), and cinnamtannin B1 () exhibited potent inhibition on both superoxide anion generation (IC values of 2.98 ± 0.3 µM, 4.37 ± 0.38 µM, and 2.20 ± 0.3 µM, respectively) and elastase release (IC values of 3.96 ± 0.31 µM, 3.04 ± 0.23 µM, and 4.64 ± 0.71 µM, respectively) by human neutrophils. In addition, isophilippinolide A (), secosubamolide (), and cinnamtannin B1 () showed bacteriostatic effects against in in vitro study, with minimal inhibitory concentration (MIC) values at 16 μg/mL, 16 μg/mL, and 500 μg/mL, respectively. Further investigations using the in vivo ear infection model showed that the intraperitoneal administration of the major component cinnamtannin B1 () reduced immune cell infiltration and pro-inflammatory cytokines TNF-α and IL-6 at the infection sites. The results demonstrated the potential of cinnamtannin B1 () for acne therapy. In summary, these results demonstrated the anti-inflammatory potentials of Formosan during bacterial infections.
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http://dx.doi.org/10.3390/molecules25153382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435785PMC
July 2020

Briarenols Q-T: Briaranes from A Cultured Octocoral (Kükenthal, 1908).

Mar Drugs 2020 Jul 24;18(8). Epub 2020 Jul 24.

Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944401, Taiwan.

Our continuous chemical study of a cultured octocoral led to the isolation of four new briarane diterpenoids, briarenols Q-T (-). The structures of new metabolites - were established by spectroscopic methods, and compounds and were found to inhibit the generation of inducible nitric oxide synthase (iNOS) from RAW 264.7 stimulated by lipopolysaccharides (LPS).
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http://dx.doi.org/10.3390/md18080383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460508PMC
July 2020

Anti-inflammatory, hepatoprotective and antioxidant activity of ellagitannin isolated from Melaleuca styphelioides.

Phytochemistry 2020 Sep 16;177:112429. Epub 2020 Jun 16.

Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, 33302, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan, 33302, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, 24301, Taiwan. Electronic address:

Ellagitannins have a marked antioxidant effect and can prevent liver injury induced by free radicals. An undescribed ellagitannin named styphelioidin was isolated from Melaleuca styphelioides Sm. The structure of styphelioidin was elucidated by using various spectroscopic methods. The hepatoprotective activity of styphelioidin (25, 50, and 100 μM) was tested using the CCl-challenged HepG2 cell model by measuring alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in HepG2 cells treated with styphelioidin for 1 h followed by 40 mM CCl. Glutathione (GSH), superoxide dismutase activity (SOD) and lipid peroxidation (MDA) were evaluated to determine the mechanisms of the hepatoprotective activity. Styphelioidin significantly reduced the levels of ALT, AST, and MDA at all tested concentrations. Moreover, it conferred a marked increase in the GSH levels and the SOD activity compared to the CCl-treated groups. Styphelioidin also exerted DPPH· radical-scavenging effects with an IC value of 3.67 μM. Results indicated the hepatoprotective therapeutic potential of styphelioidin comparable to silymarin. Moreover, anti-inflammatory activity was assessed and styphelioidin inhibited fMLF/CB-induced elastase release in human neutrophils with IC 2.51 μM. Cell-free experiments with human neutrophil elastase indicated a direct enzymatic inhibitory effect of styphelioidin on the enzyme activity (IC 2.58 μM). The potential of styphelioidin to interact with human neutrophil elastase binding sites was further confirmed by molecular docking of styphelioidin into human neutrophil elastase crystal structure using AutoDock 4.2. Styphelioidin represents a potent hepatoprotective and antioxidant agent with effects on ALT, AST, MDA, GSH, and SOD comparable to silymarin. The beneficial anti-elastase properties hold the potential for drug development against elastase-related inflammatory diseases. This study highlights a promising natural hepatoprotective and anti-inflammatory candidate derived from M. styphelioides.
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http://dx.doi.org/10.1016/j.phytochem.2020.112429DOI Listing
September 2020