Publications by authors named "Ki Sung Kang"

223 Publications

Identification of bioactive compounds from mulberry enhancing glucose-stimulated insulin secretion.

Bioorg Med Chem Lett 2021 May 10;43:128096. Epub 2021 May 10.

College of Korean Medicine, Gachon University, Seongnam 13120, Republic of Korea. Electronic address:

Previously, we isolated six heterocyclic compounds (1-6) from the fruits of mulberry trees (Morus alba L.) and determined that loliolide affords rat pancreatic islet β-cell (INS-1) protection against streptozotocin‑induced cytotoxicity. In the present study, we further investigated the effect of the six heterocyclic compounds (1-6) on glucose-stimulated insulin secretion (GSIS) in INS-1 cells. Among them, (R)‑5‑hydroxypyrrolidin‑2‑one(1) and indole (6) increased GSIS without inducing cytotoxicity. Additionally, compounds 1 and 6 enhanced the phosphorylation of total insulin receptor substrate-2, phosphatidylinositol 3-kinase, and Akt, and activated pancreatic and duodenal homeobox-1, which play a crucial role in β-cell functions related to insulin secretion. Collectively, these findings indicate that (R)‑5‑hydroxypyrrolidin‑2‑one(1) and indole (6), isolated from M. alba fruits, may be beneficial in managing type 2 diabetes.
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http://dx.doi.org/10.1016/j.bmcl.2021.128096DOI Listing
May 2021

Phytochemical Constituents of Medicinal Plants for the Treatment of Chronic Inflammation.

Authors:
Ki Sung Kang

Biomolecules 2021 Apr 30;11(5). Epub 2021 Apr 30.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Chronic inflammation increases the risk of several serious human diseases [...].
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http://dx.doi.org/10.3390/biom11050672DOI Listing
April 2021

Estrogenic Effects of Extracts and Isolated Compounds from Belowground and Aerial Parts of .

Mar Drugs 2021 Apr 11;19(4). Epub 2021 Apr 11.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Menopause, caused by decreases in estrogen production, results in symptoms such as facial flushing, vaginal atrophy, and osteoporosis. Although hormone replacement therapy is utilized to treat menopausal symptoms, it is associated with a risk of breast cancer development. We aimed to evaluate the estrogenic activities of (SA) and its compounds and identify potential candidates for the treatment of estrogen reduction without the risk of breast cancer. We evaluated the estrogenic and anti-proliferative effects of extracts of SA and its compounds in MCF-7 breast cancer cells. We performed an uterotrophic assay using an immature female rat model. Among extracts of SA, belowground part (SA-bg-E50) had potent estrogenic activity. In the immature female rat model, the administration of SA-bg-E50 increased uterine weight compared with that in the normal group. Among the compounds isolated from SA, 1,3-di---feruloyl-(-)-quinic acid () had significant estrogenic activity and induced phosphorylation at serine residues of estrogen receptor (ER)α. All extracts and compounds from SA did not increase MCF-7 cell proliferation. Compound is expected to act as an ERα ligand and have estrogenic effects, without side effects, such as breast cancer development.
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http://dx.doi.org/10.3390/md19040210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069246PMC
April 2021

Identification of gallic acid as a active ingredient of Syzygium aromaticum against tacrolimus-induced damage in renal epithelial LLC-PK1 cells and rat kidney.

Bioorg Med Chem Lett 2021 Jun 8;41:128012. Epub 2021 Apr 8.

College of Korean Medicine, Gachon University, Seongnam 13120, Republic of Korea. Electronic address:

Tacrolimus (FK506), a calcineurin inhibitor, is an effective immunosuppressive agent mainly used to lower the risk of organ rejection after allogeneic organ transplant. However, FK506-associated adverse effects, such as nephrotoxicity, may limit its therapeutic use. In this study, we confirmed that epigallocatechin-3-gallate (EGCG), sanguiin H-6, and gallic acid increased cell survival following FK506-induced cytotoxicity in renal epithelial LLC-PK1. Among these compounds, gallic acid exerted the strongest protective effect, further confirmed in the FK506-induced nephrotoxicity rat model. Additionally, we identified supporting evidence for the nephroprotective function of gallic acid using molecular docking and bioavailability investigations.
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http://dx.doi.org/10.1016/j.bmcl.2021.128012DOI Listing
June 2021

Neuroprotective Effect of Gallocatechin Gallate on Glutamate-Induced Oxidative Stress in Hippocampal HT22 Cells.

Molecules 2021 Mar 4;26(5). Epub 2021 Mar 4.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Oxidative stress leads to protein degeneration or mitochondrial dysfunction, causing neuronal cell death. Glutamate is a neurotransmitter that nerve cells use to send signals. However, the excess accumulation of glutamate can cause excitotoxicity in the central nervous system. In this study, we deciphered the molecular mechanism of catechin-mediated neuroprotective effect on glutamate-induced oxidative stress in mouse hippocampal neuronal HT22 cells. Cellular antioxidant activity was determined using the 1,1-diphenyl-picryl hydrazyl (DPPH) assay and 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) staining. Furthermore, the levels of intracellular calcium (Ca) as well as nuclear condensation and protein expression related to neuronal damage were assessed. All five catechins (epigallocatechin gallate, gallocatechin gallate (GCG), gallocatechin, epicatechin gallate, and epicatechin) showed strong antioxidant effects. Among them, GCG exhibited the highest neuroprotective effect against glutamate excitotoxicity and was used for further mechanistic studies. The glutamate-induced increase in intracellular Ca was reduced after GCG treatment. Moreover, GCG reduced nuclear condensation and the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinases (JNK) involved in cell death. The neuroprotective effect of GCG against glutamate-induced oxidative stress in HT22 cells was attributed to the reduction in intracellular free radicals and Ca influx and also the inhibition of phosphorylation of ERK and JNK. Furthermore, the antioxidant effect of GCG was found to be likely due to the inhibition of phosphorylation of ERK and JNK that led to the effective suppression of neurocytotoxicity caused by glutamate in HT22 cells.
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http://dx.doi.org/10.3390/molecules26051387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961752PMC
March 2021

Efficacy of Alpinumisoflavone Isolated from Fruit in Tumor Necrosis Factor-α-Induced Damage of Human Dermal Fibroblasts.

Antioxidants (Basel) 2021 Mar 25;10(4). Epub 2021 Mar 25.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

The skin is an important organ in the human body that protects the body from environmentally hazardous substances. Reactive oxygen species (ROS) cause inflammatory reactions and degradation of the extracellular matrix leading to skin aging and various cutaneous lesions. This study evaluated the potential of isoflavones isolated from fruit to prevent TNF-α-induced skin inflammation in normal human dermal fibroblasts (HDFs). It focused on alpinumisoflavone (AIF) that suppressed the accumulation of ROS and nitric oxide (NO) in tumor necrosis factor-alpha (TNF-α)-treated HDFs. AIF inhibited the TNF-α-induced increase in matrix metalloproteinase-1, decreased procollagen I α1, and suppressed pro-inflammatory mediators and pro-inflammatory cytokines, including NO synthase, cyclooxygenase-2, interleukin (IL)-1β, IL-6, and IL-8 that trigger inflammatory responses. AIF inhibited nuclear factor-κB and activating protein 1 mitogen-activated protein kinases that were increased by TNF-α stimulation. These results suggest that AIF may protect skin from aging and various cutaneous lesions.
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http://dx.doi.org/10.3390/antiox10040514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065416PMC
March 2021

Discovery and optimization of novel 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides as bifunctional antidiabetic agents stimulating both insulin secretion and glucose uptake.

Eur J Med Chem 2021 May 6;217:113325. Epub 2021 Mar 6.

College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea. Electronic address:

A novel series of 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides was designed, synthesized and evaluated for their biological activities on glucose-stimulated insulin secretion (GSIS). The cytotoxicity of all 41 novel compounds was screened to assess their pharmacological safety in pancreatic β-cells. A two-step optimization process was carried out to establish the structure-activity relationship for this class and subsequently we identified the most active analogue 26. Further modification study of 26 evidenced the necessity of N-hydrogens in the core architecture. Protein expression analysis suggested that 26 increases insulin secretion via the activation of the upstream effector of pancreatic and duodenal homeobox 1 (PDX-1), which is an important factor promoting GSIS. Moreover, the administration of 26 effectively augmented glucose uptake in C2C12 myotube cells via the suppression of Mitsugumin 53 (MG53), an insulin receptor substrate 1 (IRS-1) ubiquitination E3 ligase.
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http://dx.doi.org/10.1016/j.ejmech.2021.113325DOI Listing
May 2021

Estrogenic activity of ethyl gallate and its potential use in hormone replacement therapy.

Bioorg Med Chem Lett 2021 May 9;40:127919. Epub 2021 Mar 9.

Department of Korean International Medicine, College of Korean Medicine, Gachon University, Seongnam 13120, South Korea. Electronic address:

We aimed to compare the estrogenic activities of compounds isolated from Moutan Cortex Radicis (MRC, Paeonia suffruticosa Andrews) and identify their potential use in hormone replacement therapy. We quantified seven marker components (gallic acid, oxypaeoniflorin, paeoniflorin, ethyl gallate, benzoic acid, benzoylpaeoniflorin, and paeonol) in MRC using a high-performance liquid chromatography simultaneous analysis assay. To investigate the estrogenic activity of MRC and the seven marker components, an E-screen assay was conducted using the estrogen receptor (ER)-positive MCF-7 human breast cancer cell line. Among them, ethyl gallate caused cell proliferation in a concentration-dependent manner at concentrations above 25 µM and was clearly suppressed by combination treatment with the ER antagonist ICI 182,780. Therefore, ethyl gallate may be a compound of MRC that can increase the estrogenic effect in ER-positive MCF-7 cells.
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http://dx.doi.org/10.1016/j.bmcl.2021.127919DOI Listing
May 2021

Methyl Caffeate Isolated from the Flowers of (L.) Batsch Enhances Glucose-Stimulated Insulin Secretion.

Biomolecules 2021 02 14;11(2). Epub 2021 Feb 14.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Phenolic compounds from natural products are considered effective enhancers of insulin secretion to prevent and treat type 2 diabetes (T2DM). The flowers of (L.) Batsch also contain many phenolic compounds. In this study, the extract of flowers of (PRPE) exhibited an insulin secretion effect in a glucose-stimulated insulin secretion (GSIS) assay, which led us to isolate and identify the bioactive compound(s) responsible for these effects. Compounds isolated from PRPE were screened for their efficacy in INS-1 rat pancreatic β-cells. Among them, caffeic acid (5), methyl caffeate (6), ferulic acid (7), chlorogenic acid (8), naringenin (11), nicotiflorin (12), and astragalin (13) isolated from PRPE increased GSIS without inducing cytotoxicity. Interestingly, the GSIS effect of methyl caffeate (6) as a phenolic compound was similar to gliclazide, an antidiabetic sulfonylurea drug. Western blot assay showed that methyl caffeate (6) enhanced the related signaling proteins of the activated pancreatic and duodenal homeobox-1 (PDX-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ), but also the phosphorylation of the total insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and Akt, which influence β-cell function and insulin secretion. This study provides evidence that methyl caffeate (6) isolated from PRPE may aid in the management of T2DM.
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http://dx.doi.org/10.3390/biom11020279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917615PMC
February 2021

The Interrelationships between Intestinal Permeability and Phlegm Syndrome and Therapeutic Potential of Some Medicinal Herbs.

Biomolecules 2021 02 15;11(2). Epub 2021 Feb 15.

Department of Oriental Internal Medicine, Gangnam Weedahm Oriental Hospital, 402 Samsung-ro, Gangnam-gu, Seoul 06185, Korea.

The gastrointestinal (GI) tract has an intriguing and critical role beyond digestion in both modern and complementary and alternative medicine (CAM), as demonstrated by its link with the immune system. In this review, we attempted to explore the interrelationships between increased GI permeability and phlegm, an important pathological factor in CAM, syndrome, and therapeutic herbs for two disorders. The leaky gut and phlegm syndromes look considerably similar with respect to related symptoms, diseases, and suitable herbal treatment agents, including phytochemicals even though limitations to compare exist. Phlegm may be spread throughout the body along with other pathogens via the disruption of the GI barrier to cause several diseases sharing some parts of symptoms, diseases, and mechanisms with leaky gut syndrome. Both syndromes are related to inflammation and gut microbiota compositions. Well-designed future research should be conducted to verify the interrelationships for evidence based integrative medicine to contribute to the promotion of public health. In addition, systems biology approaches should be adopted to explore the complex synergistic effects of herbal medicine and phytochemicals on conditions associated with phlegm and leaky gut syndromes.
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http://dx.doi.org/10.3390/biom11020284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918952PMC
February 2021

Protective Effect of Osmundacetone against Neurological Cell Death Caused by Oxidative Glutamate Toxicity.

Biomolecules 2021 02 22;11(2). Epub 2021 Feb 22.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Oxidative stress is one of the main causes of brain cell death in neurological disorders. The use of natural antioxidants to maintain redox homeostasis contributes to alleviating neurodegeneration. Glutamate is an excitatory neurotransmitter that plays a critical role in many brain functions. However, excessive glutamate release induces excitotoxicity and oxidative stress, leading to programmed cell death. Our study aimed to evaluate the effect of osmundacetone (OAC), isolated from (Thunb.) Hylander, against glutamate-induced oxidative toxicity in HT22 hippocampal cells. The effect of OAC treatment on excess reactive oxygen species (ROS), intracellular calcium levels, chromatin condensation, apoptosis, and the expression level of oxidative stress-related proteins was evaluated. OAC showed a neuroprotective effect against glutamate toxicity at a concentration of 2 μM. By diminishing the accumulation of ROS, as well as stimulating the expression of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), OAC triggered the self-defense mechanism in neuronal cells. The anti-apoptotic effect of OAC was demonstrated through its inhibition of chromatin condensation, calcium accumulation, and reduction of apoptotic cells. OAC significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 kinases. Thus, OAC could be a potential agent for supportive treatment of neurodegenerative diseases.
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http://dx.doi.org/10.3390/biom11020328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926874PMC
February 2021

(-)-Leucophyllone, a Tirucallane Triterpenoid from Enhances Insulin Secretion in INS-1 Cells.

Plants (Basel) 2021 Feb 24;10(3). Epub 2021 Feb 24.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Phytochemical examination of the MeOH extract from the stems and stem bark of (Cornaceae) led to the isolation and verification of a tirucallane triterpenoid, (-)-leucophyllone, as a major component. Its structure was elucidated using NMR spectroscopy and liquid chromatography-mass spectrometry. The effect of (-)-leucophyllone on insulin secretion in INS-1 cells was investigated. (-)-Leucophyllone increased glucose-stimulated insulin secretion (GSIS) at concentrations showing no cytotoxic effect in rat INS-1 pancreatic β-cells. Moreover, we attempted to determine the mechanism of action of (-)-leucophyllone in the activation of insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), Akt, and pancreatic and duodenal homeobox-1 (PDX-1). Treatment of INS-1 cells with (-)-leucophyllone markedly increased the expression of these proteins. Our findings indicate the potential of (-)-leucophyllone as an antidiabetic agent.
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http://dx.doi.org/10.3390/plants10030431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996230PMC
February 2021

Effects of estrogen inhibition formula herbal mixture for danazol-induced precocious puberty in female rats: an experimental study with network pharmacology.

Integr Med Res 2021 Sep 16;10(3):100708. Epub 2020 Dec 16.

Department of Pediatrics, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea.

Background: This study aimed at determining the effect of the herbal mixture estrogen inhibition formula (EIF) and its possible mechanisms by precocious puberty animal models and network pharmacology-based analysis.

Methods: Precocious puberty animal models were established by a single injection of 300 μg danazol, then female rats were administered EIF, vaginal openings were monitored, uterus and pituitary indices were determined. The levels of ALP, E2, LH, and FSH were measured using ELISA kits. Real-time PCR was performed to evaluate the mRNA expression of GnRH, UNC5C, and netrin-1 in hypothalamic tissues. We applied network pharmacological analysis to predict potential targets and pathways of EIF.

Results: EIF delayed danazol-induced early vaginal opening. In the onset model, EIF reduced the increased levels of serum ALP, E2, LH, and FSH; as well as mRNA expressions of GnRH, Netrin-1, and UNC5C. Moreover, long-term administration of EIF not only diminished all impaired factors but also had no effect on the normal development of the animals. The gene set enrichment analysis showed that the targets of EIF are mainly associated with the GnRH signaling and ovarian steroidogenesis pathways.

Conclusion: EIF could be used in preclinical research for the treatment of precocious puberty by the inhibition of HPGA pre-maturation.
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http://dx.doi.org/10.1016/j.imr.2020.100708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903350PMC
September 2021

Preventive Effects of Anthraquinones Isolated from an Endophytic Fungus, sp. JS-0367 in Tumor Necrosis Factor-α-Stimulated Damage of Human Dermal Fibroblasts.

Antioxidants (Basel) 2021 Jan 30;10(2). Epub 2021 Jan 30.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Reactive oxygen species (ROS) are a major causative factor of inflammatory responses and extracellular matrix degradation. ROS also cause skin aging and diverse cutaneous lesions. Therefore, antioxidants that inhibit the generation of ROS may be beneficial in the relief of skin aging and diseases. We investigated the anti-skin aging effect of anthraquinones from cultures of sp., an endophytic fungus isolated from L. using human dermal fibroblasts (HDFs). We preferentially evaluated the preventive effects of anti-oxidative anthraquinones (, ) against the generation of ROS, nitric oxide (NO), and prostaglandins-E (PGE). Among them, 1,3-dihydroxy-2,8-dimethoxy-6-methylanthraquinone () suppressed the generation of ROS, NO, and PGE in tumor necrosis factor-alpha (TNF-α)-stimulated HDFs. Compound reversed the TNF-induced increase in matrix metalloproteinase (MMP)-1 and a decrease in procollagen I α1 (COLIA1). It also suppressed inducible NO synthase, cyclooxygenase-2, interleukin (IL)-1β, IL-6, and IL-8, which upregulate inflammatory reactions. Mechanistically, compound suppressed nuclear factor-κB, activator protein 1, and mitogen-activated protein kinases in TNF-α-stimulated HDFs. These results suggest that compound may be beneficial for improving skin aging and diverse cutaneous lesions.
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http://dx.doi.org/10.3390/antiox10020200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910856PMC
January 2021

Anti-Inflammatory Effect of on Ethanol-Induced Gastric Ulcer: Analytical, In Vitro and In Vivo Studies for the Identification of Action Mechanism and Active Compounds.

Plants (Basel) 2021 Feb 9;10(2). Epub 2021 Feb 9.

Korean Medicine, Gachon University, Seongnam-si, Gyeonggi-do 13120, Korea.

is widely used as traditional medicine in East Asia. However, its effects against inflammation and gastric ulcers have not been reported yet. We analyzed anti-inflammatory activity and its molecular mechanisms of using RAW264.7 cells line, then evaluated the curative efficacy in rats with acute gastric ulcers. Nitric oxide and IL-6 production was measured using Griess reagent and an ELISA kit. Inducible nitric oxide synthase (iNOS), interleukin (IL)-6, and mucin (MUC)1, MUC5AC, and MUC6 mRNA were determined by SYBR Green or Taqman qRT-PCR methods. The phosphorylation of ERK, JNK, p38, and c-Jun protein were detected by western blotting. RW0117 inhibited LPS-induced NO and IL-6 production. The mRNA levels of iNOS and IL-6 were strongly suppressed. The phosphorylation of ERK, JNK, and c-Jun decreased by treatment with RW0117. Oral administration of RW0117 recovered the amount of mucin mRNA and protein level that was decreased due to gastric ulcers by HCl-EtOH. exhibited strong anti-inflammatory effects and contributed to the modulation of HCl-EtOH-induced gastric ulcer in rats.
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http://dx.doi.org/10.3390/plants10020332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914715PMC
February 2021

Protective Effect of γ-mangostin Isolated from the Peel of against Glutamate-Induced Cytotoxicity in HT22 Hippocampal Neuronal Cells.

Biomolecules 2021 01 27;11(2). Epub 2021 Jan 27.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-lo, Gwanak-gu, Seoul 08826, Korea.

The aim of the present study was to examine the protective effect of γ-mangostin, a component of the mangosteen shell, against oxidative damage to nerve cells induced by excessive glutamate, a known excitatory neurotransmitter. To investigate the effect of γ-mangostin on apoptosis, 5 mM of glutamate was used to induce apoptotic cell death in mouse hippocampal HT22 cells. In this study, γ-mangostin was found to exert a stronger protection than N-acetyl cysteine against glutamate-induced cell damage. γ-Mangostin showed prevented glutamate-induced apoptosis in HT22 cells by reducing the production of reactive oxygen species and stimulating the expression of heme oxygenase-1 protein. In addition, glutamate significantly induced the accumulation of intracellular calcium ions, whereas treatment with γ-mangostin markedly reduced it. Hoechst 33342 staining showed an improvement in glutamate-induced nuclear condensation following γ-mangostin treatment. Furthermore, the number of annexin V-positive cells was significantly reduced following treatment with γ-mangostin. Western blot analysis showed the inhibition of glutamate-induced mitogen-activated protein kinase phosphorylation by γ-mangostin. γ-mangostin also inhibited the regulation of the intrinsic mitochondrial apoptotic pathway. Thus, the results of this study suggest that γ-mangostin is an active ingredient of mangosteen and exerts neuroprotective activities in HT22 cells.
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http://dx.doi.org/10.3390/biom11020170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910862PMC
January 2021

The Chemical Constituents from Fruits of Walt. and Their α-Glucosidase Inhibitory Activity and Insulin Secretion Effect.

Molecules 2021 Jan 12;26(2). Epub 2021 Jan 12.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Catalpa pod has been used in traditional medicine for the treatment of diabetes mellitus in South America. Studies on the constituents of Catalpa species have shown that it is rich in iridoids. In the present study, three previously undescribed compounds (-), including two secoiridoid derivatives along with twelve known compounds, were isolated from the fruits of Walt. In addition, fully assigned C-NMR of 5,6-dihydroxy-7,4'-dimethoxyflavone-6--sophoroside () is reported for the first time in the present study. The structures of compounds were determined on the basis of extensive spectroscopic methods, including UV, IR, 1D, and 2D NMR, mass spectroscopy, and CD spectroscopic data. All the isolated compounds were evaluated for α-glucosidase inhibitory activity. Among the tested compounds, compounds , , and exhibited significant inhibitory activity against α-glucosidase enzyme assay. Meanwhile, the effect of compounds , , and on glucose-stimulated insulin secretion (GSIS) was measured using pancreatic β-cells. Compounds , , and exhibited non-cytotoxicity-stimulated insulin secretion in INS-1 cells. The expression levels of proteins associated with β-cell function and insulin secretion such as phosphorylation of total insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), Akt, activated pancreatic duodenal homeobox-1 (PDX-1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) were increased in INS-1 cells after treatment with compounds , , and . The findings of the present study could provide a scientific warrant for their application as a potential antidiabetic agent.
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http://dx.doi.org/10.3390/molecules26020362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826643PMC
January 2021

Metabolite Profile of Cucurbitane-Type Triterpenoids of Bitter Melon (Fruit of ) and Their Inhibitory Activity against Protein Tyrosine Phosphatases Relevant to Insulin Resistance.

J Agric Food Chem 2021 Feb 6;69(6):1816-1830. Epub 2021 Jan 6.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.

Qualitative analysis of cucurbitane-type triterpenoids of bitter melon (fruit of L.) using ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry revealed 27 promising cucurbitane-type triterpenoids, and LC/MS-guided chemical analysis of fruit extract led to the isolation and structural characterization of 22 cucurbitane-type triterpenoids (), including 8 new cucurbitane-type triterpenoidal saponins, yeojoosides A-H (). The structures of the new compounds () were elucidated by spectroscopic methods, including 1D and 2D NMR and high-resolution electrospray ionization mass spectrometry. Their absolute configurations were assigned by quantum chemical electronic circular dichroism calculations, chemical reactions, and DP4+ analysis using gauge-including atomic orbital NMR chemical shift calculations. All isolated compounds () were examined for inhibitory activity against protein tyrosine phosphatases relevant to insulin resistance. Nine compounds (, , , , , , , , and ) showed selective inhibitory effects of over 70% against PTPN2. The present results suggested that these compounds would be potential antidiabetic agents.
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http://dx.doi.org/10.1021/acs.jafc.0c06085DOI Listing
February 2021

Protective Effect of Shikimic Acid against Cisplatin-Induced Renal Injury: In Vitro and In Vivo Studies.

Plants (Basel) 2020 Dec 1;9(12). Epub 2020 Dec 1.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Nephrotoxicity is a serious side effect of cisplatin, which is one of the most frequently used drugs for cancer treatment. This study aimed to assess the renoprotective effect of extract and its bioactive compound (shikimic acid) against cisplatin-induced renal injury. An in vitro assay was performed in kidney tubular epithelial cells (LLC-PK1) with 50, 100, and 200 µg/mL extract and 25 and 50 µM shikimic acid, and cytotoxicity was induced by 25 µM cisplatin. BALB/c mice (6 weeks old) were injected with 16 mg/kg cisplatin once and orally administered 25 and 50 mg/kg shikimic acid daily for 4 days. The results showed that the extract reversed the decrease in renal cell viability induced by cisplatin, whereas it decreased the reactive oxidative stress accumulation and apoptosis in LLC-PK1 cells. Shikimic acid also reversed the effect on cell viability but decreased oxidative stress and apoptosis in renal cells compared with the levels in the cisplatin-treated group. Furthermore, shikimic acid protected against kidney injury in cisplatin-treated mice by reducing serum creatinine levels. The protective effect of shikimic acid against cisplatin-mediated kidney injury was confirmed by the recovery of histological kidney injury in cisplatin-treated mice. To the best of our knowledge, this study is the first report on the nephroprotective effect of extract and its mechanism of action against cisplatin-induced renal injury.
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http://dx.doi.org/10.3390/plants9121681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759863PMC
December 2020

Colletotrichalactones A-Ca, unusual 5/6/10-fused tricyclic polyketides produced by an endophytic fungus, Colletotrichum sp. JS-0361.

Bioorg Chem 2020 12 3;105:104449. Epub 2020 Nov 3.

College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea. Electronic address:

Three unusual polyketides with a 5/6/10-fused ring system, named colletotrichalactones A-Ca (1-3a), were isolated from cultures of the endophytic fungus, Colletotrichum sp. JS-0361, which was isolated from a leaf of Morus alba. Their structures, including their absolute stereochemistries, were completely established using extensive spectroscopic methods together with a chemical reaction utilizing competing enantioselective acylation coupled with LC/MS. Compounds possessing this ring skeleton were previously reported in three studies. Our rigorous chemical investigation revealed the complete configuration of this skeleton, which agreed with the results for glabramycin B with this ring skeleton established by computational chemistry and enantioselective synthesis in previous reports. 1 and 2 had unstable aldehyde groups that were easily converted to acetal groups in the presence of solvents. Meanwhile, compound 3a, with terminal acetal functionality, was deduced to be an artefact originating from compound 3 with a terminal aldehyde group. Compounds 1 and 3a displayed moderate-to-potent cytotoxic activities against MCF7 cells with ICs of 35.06 and 25.20 µM, respectively.
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http://dx.doi.org/10.1016/j.bioorg.2020.104449DOI Listing
December 2020

Neuroprotective Effect of Tricyclic Pyridine Alkaloids from SSF2, against Glutamate-Induced Oxidative Stress and Apoptosis in the HT22 Hippocampal Neuronal Cell Line.

Antioxidants (Basel) 2020 Nov 11;9(11). Epub 2020 Nov 11.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Excessive glutamate damages neuronal cells via the accumulation of intracellular reactive oxygen species (ROS), calcium ion (Ca) influx, depolarization of mitochondrial membrane potential, and apoptosis, which may result in the development of chronic neurodegenerative diseases. In this study, we evaluated the effects of 4,6'-anhydrooxysporidinone isolated from endophytic fungus SSF2 on glutamate-induced cytotoxicity, accumulation of intracellular ROS, increases in superoxide anion production, Ca, depolarization of mitochondrial membrane potential, and apoptotic cell death in hippocampal HT22 cells. 2',7'-Dichlorofluorescin diacetate (H2DCFDA) staining was used to determine the intracellular reactive oxygen species concentration and dihydroethidine (DHE) staining was used to determine the superoxide radical. Expression of the nuclear factor-erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was analyzed by Western blot. Fluo-4 staining was used to determine the intracellular Ca levels. In order to explore mitochondrial membrane potential, tetramethylrhodamine methyl ester (TMRM) staining was used. Apoptotic cell death was evaluated using Annexin-V/propidium iodide (PI) staining and TUNEL staining. Expression of the cytochrome release and cleaved caspase-9, -3 was analyzed by Western blot. Here, we were able to isolate 4,6'-anhydrooxysporidinone from endophytic fungus, SSF2, which was shown to protect HT22 cells from glutamate-induced cytotoxicity, accumulation of intracellular ROS, increases in superoxide anion production, Ca, and depolarization of mitochondrial membrane potential. In addition, 4,6'-anhydrooxysporidinone enhanced the expressions of Nrf2 and HO-1. It also inhibited the apoptotic cell death through the inhibition of cytochrome release and cleaved caspase-9, -3 in glutamate-treated HT22 cells. Therefore, our results provide ample evidence of the neuroprotective properties of 4,6'-anhydrooxysporidinone.
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http://dx.doi.org/10.3390/antiox9111115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698086PMC
November 2020

Identification of Anti-Inflammatory Compounds from Hawaiian Noni ( L.) Fruit Juice.

Molecules 2020 Oct 27;25(21). Epub 2020 Oct 27.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Noni ( L.) fruit juice has been used in Polynesia as a traditional folk medicine and is very popular worldwide as a functional food supplement. In this study, compounds present in Hawaiian Noni fruit juice, with anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were identified. Five compounds were isolated using a bioassay-driven technique and phytochemical analysis of noni fruit juice: asperulosidic acid (), rutin (), nonioside A (), (2,4,7)-deca-2,4,7-trienoate-2--β-d-glucopyranosyl-β-d-glucopyranoside (), and tricetin (). The structures of these five compounds were determined via NMR spectroscopy and LC/MS. In an anti-inflammatory assay, compounds - inhibited the production of nitric oxide (NO), which is a proinflammatory mediator, in LPS-stimulated macrophages. Moreover, the mechanisms underlying the anti-inflammatory effects of compounds - were investigated. Parallel to the inhibition of NO production, treatment with compounds - downregulated the expression of IKKα/β, I-κBα, and NF-κB p65 in LPS-stimulated macrophages. Furthermore, treatment with compounds - downregulated the expression of nitric oxide synthase and cyclooxygenase-2. Thus, these data demonstrated that compounds - present in noni fruit juice, exhibited potential anti-inflammatory activity; these active compounds may contribute preventively and therapeutically against inflammatory diseases.
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http://dx.doi.org/10.3390/molecules25214968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662328PMC
October 2020

Preventive Effect of Muscone against Cisplatin Nephrotoxicity in LLC-PK1 Cells.

Biomolecules 2020 10 15;10(10). Epub 2020 Oct 15.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Cisplatin, one of the most common antitumor agents, is widely applied to treat various cancerous diseases and is included in the World Health Organization Model List of Essential Medicines. Cisplatin therapy is used to treat 10-20% of all cancerous cases, and its cure rate is especially high in testicular cancer (over 90%). However, a major side effect of this anticancer drug is nephrotoxicity, limiting treatment effect and reducing the quality of life in cancer patients. Muscone, an odoriferous constituent of musk, was confirmed to inhibit cisplatin-induced LLC-PK1 kidney proximal tubule cell death in a dose-dependent manner. In term of renal protective mechanism, muscone inhibited cisplatin oxidative toxicity by decreasing reactive oxygen species (ROS) level and stimulating HO-1 expression. Muscone also exerted anti-inflammation effect through inhibition of p38 phosphorylation. Furthermore, muscone mitigated cisplatin-induced apoptosis in LLC-PK1 cells via both intrinsic and extrinsic pathways by inhibiting pro-apoptotic protein Bax expression, and cleaved caspase-3, 7, and 8; and increase of anti-apoptotic protein Bcl-2 level. In addition, the anti-apoptotic effect of muscone also was enhanced by preventing p53 expression and its phosphorylation. Our study showed that muscone may be a potential protective agent against cisplatin-induced nephrotoxicity.
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http://dx.doi.org/10.3390/biom10101444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602442PMC
October 2020

Potential Anti-Skin Aging Effect of (-)-Catechin Isolated from the Root Bark of var. in Tumor Necrosis Factor-α-Stimulated Normal Human Dermal Fibroblasts.

Antioxidants (Basel) 2020 Oct 13;9(10). Epub 2020 Oct 13.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Reactive oxygen species (ROS) are generated during skin aging, including intrinsic (chronologic aging) and extrinsic aging (photoaging). Therefore, antioxidants that inhibit ROS generation can delay skin aging. In this study, we evaluated the potential anti-skin aging effect of (-)-phenolic compounds isolated from the root bark of var. . We preferentially investigated the possible preventive effects of isolates against the degradation of skin extracellular matrix. Among the isolates, (-)-catechin suppressed the activity of collagenase MMP-1, and reversed the degradation of collagen induced by tumor necrosis factor-α (TNF-α) in normal human dermal fibroblast. This action mechanism of (-)-catechin was validated by the suppression of tumor necrosis factor-α-induced accumulation of ROS and activation of mitogen-activated protein kinases, protein kinase B (Akt), and cyclooxygenase-2 (COX-2). The proinflammatory cytokines upregulate inflammatory reactions, and ultimately promote aging-related reactions. In this milieu, we demonstrated that (-)-catechin decreased the expression and secretion of proinflammatory cytokines, including interleukin (IL)-1β and IL-6. In conclusion, (-)-catechin is a candidate to ameliorate both intrinsic and extrinsic skin aging.
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http://dx.doi.org/10.3390/antiox9100981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601800PMC
October 2020

Chemical Constituents from the Aerial Parts of and Their Protective Activities on Glutamate-Induced HT22 Cell Death.

J Nat Prod 2020 10 29;83(10):3149-3155. Epub 2020 Sep 29.

Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine (KIOM), Naju 58245, Republic of Korea.

A new phenolic glucoside, (7,9)-3-hydroxyavenalumic acid-3--[6'--()-caffeoyl]-β-d-glucopyranoside (), and three new acetylated flavone glycosides, acacetin-7--[β-d-glucopyranosyl(1″″→2″)-4‴--acetyl-α-l-rhamnopyranosyl(1‴→6″)]-β-d-glucopyranoside (), acacetin-7--[6″″--acetylβ-d-glucopyranosyl(1″″→2″)-3‴--acetyl-α-l-rhamnopyranosyl(1‴→6″)]-β-d-glucopyranoside (), and acacetin-7--[3″″,6″″-di--acetylβ-d-glucopyranosyl(1″″→2″)-4‴--acetyl-α-l-rhamnopyranosyl(1‴→6″)]-β-d-glucopyranoside (), as well as 34 known compounds (, , , and -) were isolated from the aerial parts of . The chemical structures of the new compounds were determined by spectroscopic/spectrometric data interpretation using NMR and HRESIMS. The neuroprotective effect of the isolated compounds was evaluated by a cell viability assay on HT22 murine hippocampal neuronal cells. Among them, 23 compounds, including new substances and , exhibited neuroprotective effects against glutamate-induced HT22 cell death. In particular, compounds , , , , , , , and presented potent neuroprotective effects with EC values of 1.5-8.3 μM.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00756DOI Listing
October 2020

Calvatianone, a Sterol Possessing a 6/5/6/5-Fused Ring System with a Contracted Tetrahydrofuran B-Ring, from the Fruiting Bodies of .

J Nat Prod 2020 09 17;83(9):2737-2742. Epub 2020 Sep 17.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.

is an extremely rare mushroom with a limited number of studies on its chemical components and biological activities published. Here we report the isolation of a novel sterol, calvatianone (), possessing a 6/5/6/5-fused ring system with a contracted tetrahydrofuran B-ring, and four known steroids (-) from the fruiting bodies of . The structure of calvatianone including its absolute configuration was determined by NMR spectroscopic analyses, HR-ESIMS, gauge-including atomic orbital NMR chemical shift calculations, and ECD calculations. Ergosterol peroxide () and cyathisterol () suppressed the cell viability increase induced by 17β-estradiol in MCF-7 breast cancer cell lines, suggesting a possible approach for these compounds to serve as ERα antagonists.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00673DOI Listing
September 2020

Evaluation of Anti-Colitis Effect of KM1608 and Biodistribution of Dehydrocostus Lactone in Mice Using Bioimaging Analysis.

Plants (Basel) 2020 Sep 10;9(9). Epub 2020 Sep 10.

College of Korean Medicine, Gachon University, Seongnam-si, Gyeonggi-do 13120, Korea.

Inflammatory bowel disease (IBD) is a chronic relapsing disorder modulated by numerous factors. Recent failures of drugs targeting single factors suggest that multitargeting drugs could be useful for the treatment of IBD. Natural medicines may be an alternative option for the treatment of IBD, owing to the complex nature of the disease. However, most natural medicines have poor in vitro and in vivo translational potential because of inadequate pharmacokinetic study. KM1608, a mixture of the medicinal plants , , and , was examined for its anti-colitis effects and biodistribution using bioimaging. Dehydrocostus lactone, as a marker compound, was analyzed to assess the biodistribution of KM1608. KM1608 significantly attenuated the disease activity of dextran sodium sulfate-induced colitis in mice and suppressed inflammatory mediators such as myeloperoxidase, proinflammatory cytokines (TNF-α and IL-6), and the Th2-type cytokine IL-4 in the colon. Optical fluorescence imaging revealed that KM1608 was distributed in the intestinal area as a target organ. Collectively, our findings suggest that KM1608 is a potential therapeutic formulation for IBD.
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http://dx.doi.org/10.3390/plants9091175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570101PMC
September 2020

Bioactive Phytochemicals Isolated from Enhances Glucose-Stimulated Insulin Secretion by Inducing PDX-1.

Plants (Basel) 2020 Aug 24;9(9). Epub 2020 Aug 24.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Chocolate vine () is consumed as a fruit and is also used in traditional medicine. In order to identify the bioactive components of , a phytosterol glucoside stigmasterol-3--β-d-glucoside (1), three triterpenoids maslinic acid (2), scutellaric acid (3), and hederagenin (4), and three triterpenoidal saponins akebia saponin PA (5), hederacoside C (6), and hederacolchiside F (7) were isolated from a 70% EtOH extract of the fruits of (AKQU). The chemical structures of isolates 1-7 were determined by analyzing the 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data. Here, we evaluated the effects of AKQU and compounds 1-7 on insulin secretion using the INS-1 rat pancreatic β-cell line. Glucose-stimulated insulin secretion (GSIS) was evaluated in INS-1 cells using the GSIS assay. The expression levels of the proteins related to pancreatic β-cell function were detected by Western blotting. Among the isolates, stigmasterol-3--β-d-glucoside (1) exhibited strong GSIS activity and triggered the overexpression of pancreas/duodenum homeobox protein-1 (PDX-1), which is implicated in the regulation of pancreatic β-cell survival and function. Moreover, isolate 1 markedly induced the expression of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), insulin receptor substrate-2 (IRS-2), phosphoinositide 3-kinase (PI3K), and Akt, which regulate the transcription of PDX-1. The results of our experimental studies indicated that stigmasterol-3--β-d-glucoside (1) isolated from the fruits of can potentially enhance insulin secretion, and might alleviate the reduction in GSIS during the development of T2DM.
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http://dx.doi.org/10.3390/plants9091087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570369PMC
August 2020

Anti-Apoptotic and Antioxidant Effects of 3-Iso-Tanapartholide Isolated from Against Iodixanol-Induced Kidney Epithelial Cell Death.

Biomolecules 2020 06 5;10(6). Epub 2020 Jun 5.

College of Korean Medicine, Gachon University, Seongnam 13120, Korea.

Iodixanol is a non-ionic iso-osmolar contrast agent, but it is a risk factor for kidney damage and increases morbidity and mortality. In this study, we investigated the effect of 9 sesquiterpenes isolated from mugwort () in contrast agent-induced cytotoxicity in LLC-PK1 cells. Cells were exposed to nine sesquiterpene compounds for 2 h, followed by incubation with iodixanol for 3 h. Cell viability was assessed using the Ez-Cytox assay. The level of reactive oxygen species was measured using 2',7'-dichlorodihydrofluorescein diacetate staining. Apoptotic cell death was detected using annexin V/PI staining. In addition, immunofluorescence staining and western blotting were performed using antibodies against proteins related to apoptosis, oxidative stress, and MAPK pathways. The most effective 3-iso-tanapartholide (compound ) among the 9 sesquiterpene compounds protected LLC-PK1 cells from iodixanol-induced cytotoxicity, oxidative stress, and apoptotic cell death. Pretreatment with compound reversed iodixanol-induced increases in the expression of JNK, ERK, p38, Bax, caspase-3, and caspase-9. It also reversed the iodixanol-induced decrease in Bcl-2 expression. Furthermore, pretreatment with compound caused nuclear translocation of Nrf2 and upregulated HO-1 via the Nrf2 pathway in iodixanol-treated LLC-PK1 cells. Thus, we demonstrated here that compound isolated from has the potential to effectively prevent iodixanol-induced kidney epithelial cell death via the caspase-3/MAPK pathways and HO-1 via the Nrf2 pathway.
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http://dx.doi.org/10.3390/biom10060867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356648PMC
June 2020

Phallac acids A and B, new sesquiterpenes from the fruiting bodies of Phallus luteus.

J Antibiot (Tokyo) 2020 10 29;73(10):729-732. Epub 2020 May 29.

Natural Product Research Laboratory, School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

Phallus luteus (Phallaceae), previously known as Dictyophora indusiata, is an edible and medicinal mushroom. As part of a continuing project to discover structurally and/or biologically novel natural products from wild mushrooms, we aimed to perform a chemical investigation of the methanol extract of P. luteus combined with a liquid chromatography-mass spectrometry-guided analysis coupled to an in-house UV spectral library. Two new sesquiterpenes, phallac acids A (1) and B (2), were isolated and determined. The chemical structure of the new natural products was unambiguously determined using a combination of 1D and 2D NMR and high-resolution electrospray ionization mass spectrometry data. To our knowledge, this is the first study to report linear sesquiterpene carboxylic acids from P. luteus. The new compounds were evaluated for α-glucosidase inhibitory activities where phallac acid B (2) showed α-glucosidase inhibitory potential (IC value of 94.89 ± 5.57 μM) compared with the standard acarbose (IC value of 26.23 ± 1.31 μM).
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http://dx.doi.org/10.1038/s41429-020-0328-zDOI Listing
October 2020