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1.
Bioorg Chem ; 108: 104562, 2021 03.
Article in English | MEDLINE | ID: mdl-33358389

ABSTRACT

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 IC50 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.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Coriolaceae/chemistry , Enzyme Inhibitors/pharmacology , Fruiting Bodies, Fungal/chemistry , Pancreatic Elastase/antagonists & inhibitors , Triterpenes/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Humans , Molecular Structure , Neutrophils/drug effects , Neutrophils/metabolism , Pancreatic Elastase/metabolism , Structure-Activity Relationship , Triterpenes/chemistry , Triterpenes/isolation & purification
2.
Molecules ; 25(22)2020 Nov 17.
Article in English | MEDLINE | ID: mdl-33213112

ABSTRACT

This study investigates the application of the paramagnetic shift reagent tris(dipivaloylmethanato)-europium(III) in NMR spectral studies of permethoxyacridone alkaloids (1-3) and pyranoacridone alkaloids (4-6). The induced chemical shifts (∆δ) of all protons were observed for the same molecule, and were compared to deduce the positions resulting from the distance nearby the Eu(dpm)3. Assignment of the H-2, H-4 and H-8 of polysubstituted acridones could be distinguished based on the least-squares method of lanthanide-induced shifts plotted against the mole ratios of Eu(dpm)3 to the substrate. The developed method is not only potentially useful for determining the planar structures of polysubstituted compounds, such as acridones, anthraquinones, xanthones, flavonoids, and phenanthrenes, but also applicable for their stereochemistry.


Subject(s)
Acridones/chemistry , Alkaloids/chemistry , Lanthanoid Series Elements/chemistry , Proton Magnetic Resonance Spectroscopy , Europium/chemistry
3.
Bioorg Med Chem Lett ; 30(13): 127224, 2020 07 01.
Article in English | MEDLINE | ID: mdl-32359855

ABSTRACT

Four new sesquiterpenes (1-4), one new alkaloid (5), and one new benzenoid glycoside (6) were characterized from Lindera aggregata, and their structures were elucidated according to their spectrometric analytical data. Among these isolates, 3 and 4 were constructed as possessing unprecedented carbon skeletons from the natural source. Some of these purified constituents were examined for their anti-inflammatory bioactivity. Among the tested compounds, linderaggredin C (3), (+)-N-methyllaurotetanine, and (+)-isoboldine displayed the significant inhibition of superoxide anion generation in human neutrophils with IC50 values of 7.45 ± 0.74, 8.36 ± 0.11, and 5.81 ± 0.59 µM, respectively.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Lindera/chemistry , Sesquiterpenes/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Humans , Molecular Structure , Neutrophils/drug effects , Pancreatic Elastase/metabolism , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Superoxides/metabolism
4.
RSC Adv ; 9(59): 34184-34195, 2019 Oct 23.
Article in English | MEDLINE | ID: mdl-35530004

ABSTRACT

Twelve undescribed sesquiterpenoids, fomitopins A-L (1-12), were isolated via bioassay-guided purification from the bracket fungus Fomitopsis pinicola (Sw.) P. Karst, and this fungus have been reported to exhibit anti-microbial and anti-inflammatory activities. The structures of 1-12 were elucidated by spectroscopic and spectrometric analyses and their absolute configurations were further confirmed by ECD simulations. Ten isolated compounds were evaluated for their anti-inflammatory potential and compound 11 exhibited the most significant inhibition of superoxide anion generation and elastase release with IC50 values of 0.81 ± 0.15 and 0.74 ± 0.12 µM. These newly purified sesquiterpenoids could be potential candidates for further anti-inflammatory studies.

5.
J Food Drug Anal ; 26(3): 1105-1112, 2018 07.
Article in English | MEDLINE | ID: mdl-29976403

ABSTRACT

Lycii Fructus, a solanaceous drug, is widely used as functional foods and in Traditional Chinese Medicine. Samples collected from different regions of China have been found to be not identical in chemical compositions which might affect the biological activities. Although many chromatographic and spectrometric methods have been reported to determine the concentration of betaine and other bioactive amino acids, disturbance resulted from other polar substances with low UV-absorbance and expensive mass facilities reduced the applicability of these techniques. In the present study, the strong cation exchange solid phase extraction procedure incorporated with 1H NMR was successfully developed as a rapid and reliable method that can simultaneously determine betaine, citric acid, threonine, alanine, and proline in various Lycii Fructus. In addition, ERETIC 2 method based on PULCON principle was also applied and compared with conventional method. This feasible and practical method offers a very powerful tool for the quality control of commercial Lycii Fructus from different sources.


Subject(s)
Drugs, Chinese Herbal/chemistry , Lycium/chemistry , Proton Magnetic Resonance Spectroscopy/methods , Amino Acids/chemistry , China , Fruit/chemistry , Quality Control
6.
Int J Mol Med ; 41(4): 2420-2428, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29328426

ABSTRACT

Ginger (Zingiber officinale Roscoe) is a popular Chinese herbal medicine, which is considered to warm the stomach and dispel cold in traditional Chinese medicine. Ginger is widely used to treat stomach disorders, and it has been reported to exhibit antithrombotic activity via the inhibition of platelet aggregation and thromboxane B2 production in vitro. Cardiovascular disease is associated with the aberrant functioning of the heart and circulatory system; the relatively narrow vessels of the circulation are commonly affected and blocked by atherosclerosis, which may result in angina or heart attack. Numerous drugs and medicines are used to treat myocardial infarction; however, they are often associated with numerous side effects. Therefore, it is important to identify substitutive drugs with no unbearable side effects. In the present study, the relaxant effects of ginger crude extract (GCE) were determined on porcine coronary arteries. The DPPH radical scavenging assay, lucigenin­enhanced chemiluminescence assay and western blot analysis were used to individually detect antioxidant assay of ginger extraction or superoxide anion produced by endothelial cells and molecular signaling. The results indicated that GCE induced relaxation of porcine coronary arteries in an endothelium­dependent manner. GCE increased vasoprotection via the suppression of nitric oxide synthase and cyclooxygenase. In addition, GCE possessed antioxidant ability, as determined using 1,1­diphenyl­2­picrylhydrazyl and lucigenin­enhanced chemiluminescence assays. Taken together, the present study demonstrated that GCE exerts marked vasoprotective effects and free radical­scavenging activities in porcine coronary arteries.


Subject(s)
Antioxidants/pharmacology , Coronary Vessels/drug effects , Plant Extracts/pharmacology , Vasodilator Agents/pharmacology , Zingiber officinale/chemistry , Animals , Antioxidants/chemistry , Biphenyl Compounds/metabolism , Coronary Vessels/physiology , Nitric Oxide/metabolism , Nitric Oxide Synthase/metabolism , Picrates/metabolism , Plant Extracts/chemistry , Signal Transduction/drug effects , Soluble Guanylyl Cyclase/metabolism , Swine , Vasodilator Agents/chemistry
7.
Molecules ; 22(6)2017 Jun 09.
Article in English | MEDLINE | ID: mdl-28598384

ABSTRACT

A series of chromatographic separations performed on the ethanol extracts of the peels of Citrus grandis has led to the characterization of forty compounds, including seventeen coumarins, eight flavonoids, two triterpenoids, four benzenoids, two steroids, one lignan, one amide, and five other compounds, respectively. The chemical structures of the purified constituents were identified on the basis of spectroscopic elucidation, including 1D- and 2D-NMR, UV, IR, and mass spectrometric analysis. Most of the isolated compounds were examined for their inhibition of superoxide anion generation and elastase release by human neutrophils. Among the isolates, isomeranzin (3), 17,18-dihydroxybergamottin (12), epoxybergamottin (13), rhoifolin (19), vitexicarpin (22) and 4-hydroxybenzaldehyde (29) displayed the most significant inhibition of superoxide anion generation and elastase release with IC50 values ranged from 0.54 to 7.57 µM, and 0.43 to 4.33 µM, respectively. In addition, 7-hydroxy-8-(2'-hydroxy-3'-methylbut-3'-enyl)coumarin (8) and 17,18-dihydroxybergamottin (12) also exhibited the protection of neurons against A-mediated neurotoxicity at 50 µM.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Citrus/chemistry , Coumarins/pharmacology , Flavonoids/pharmacology , Neuroprotective Agents/pharmacology , Triterpenes/pharmacology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/toxicity , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Cell Death/drug effects , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Complex Mixtures/chemistry , Coumarins/chemistry , Coumarins/isolation & purification , Flavonoids/chemistry , Flavonoids/isolation & purification , Fruit/chemistry , Humans , Leukocyte Elastase/antagonists & inhibitors , Leukocyte Elastase/metabolism , Lignans/chemistry , Lignans/isolation & purification , Lignans/pharmacology , Neurons/cytology , Neurons/drug effects , Neuroprotective Agents/chemistry , Neuroprotective Agents/isolation & purification , Neutrophils/cytology , Neutrophils/drug effects , Neutrophils/metabolism , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/toxicity , Primary Cell Culture , Rats , Rats, Sprague-Dawley , Steroids/chemistry , Steroids/isolation & purification , Steroids/pharmacology , Superoxides/antagonists & inhibitors , Superoxides/chemistry , Triterpenes/chemistry , Triterpenes/isolation & purification , Waste Products
8.
J Nat Prod ; 80(4): 1055-1064, 2017 04 28.
Article in English | MEDLINE | ID: mdl-28218000

ABSTRACT

Fifty compounds were isolated from the fruits of Forsythia suspensa, including 13 new compounds characterized as eight new diterpenoids (1-8), three new lignans (9-11), a new iridoid (12), and a new triterpenoid (13). Their structures were established on the basis of spectroscopic and spectrometric analysis. Most of the isolated compounds were examined for their anti-inflammatory activity in vitro. The results showed that several compounds displayed significant inhibition of fMLP/CB-induced superoxide anion generation and elastase release, with IC50 values ranging from 0.6 ± 0.1 to 8.6 ± 0.8 µg/mL and from 0.8 ± 0.3 to 7.3 ± 1.1 µg/mL, respectively.


Subject(s)
Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Diterpenes/isolation & purification , Diterpenes/pharmacology , Forsythia/chemistry , Fruit/chemistry , Lignans/isolation & purification , Lignans/pharmacology , Anti-Inflammatory Agents/chemistry , Diterpenes/chemistry , Humans , Lignans/chemistry , Molecular Structure , Neutrophils/drug effects , Pancreatic Elastase/drug effects , Pancreatic Elastase/metabolism , Superoxides/metabolism , Taiwan
9.
J Recept Signal Transduct Res ; 37(1): 1-7, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27309957

ABSTRACT

Minoxidil is clinically used to prevent hair loss. However, its effect on Ca2+ homeostasis in prostate cancer cells is unclear. This study explored the effect of minoxidil on cytosolic-free Ca2+ levels ([Ca2+]i) and cell viability in PC3 human prostate cancer cells. Minoxidil at concentrations between 200 and 800 µM evoked [Ca2+]i rises in a concentration-dependent manner. This Ca2+ signal was inhibited by 60% by removal of extracellular Ca2+. Minoxidil-induced Ca2+ influx was confirmed by Mn2+-induced quench of fura-2 fluorescence. Pre-treatment with the protein kinase C (PKC) inhibitor GF109203X, PKC activator phorbol 12-myristate 13 acetate (PMA), nifedipine and SKF96365 inhibited minoxidil-induced Ca2+ signal in Ca2+ containing medium by 60%. Treatment with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-ditert-butylhydroquinone (BHQ) in Ca2+-free medium abolished minoxidil-induced [Ca2+]i rises. Conversely, treatment with minoxidil abolished BHQ-induced [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 abolished minoxidil-evoked [Ca2+]i rises. Overnight treatment with minoxidil killed cells at concentrations of 200-600 µM in a concentration-dependent fashion. Chelation of cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM (BAPTA/AM) did not prevent minoxidil's cytotoxicity. Together, in PC3 cells, minoxidil induced [Ca2+]i rises that involved Ca2+ entry through PKC-regulated store-operated Ca2+ channels and PLC-dependent Ca2+ release from the endoplasmic reticulum. Minoxidil-induced cytotoxicity in a Ca2+-independent manner.


Subject(s)
Antihypertensive Agents/pharmacology , Apoptosis/drug effects , Calcium Signaling/drug effects , Calcium/metabolism , Cell Proliferation/drug effects , Minoxidil/pharmacology , Prostatic Neoplasms/pathology , Humans , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Tumor Cells, Cultured
10.
Toxicol Mech Methods ; 26(8): 580-587, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27790936

ABSTRACT

Tricyclic antidepressants (TCA) have been clinically prescribed in the auxiliary treatment of cancer patients. Although protriptyline, a type of TCA, was used primarily in the clinical treatment of mood disorders in cancer patients, the effect of protriptyline on physiology in human osteosarcoma is unknown. This study examined the effect of protriptyline on cytosolic free Ca2+ concentrations ([Ca2+]i) and viability in MG63 human osteosarcoma cells. Protriptyline between 50 and 250 µM evoked [Ca2+]i rises concentration-dependently. Protriptyline induced influx of Mn2+, indirectly implicating Ca2+ influx. Protriptyline-evoked Ca2+ entry was inhibited by nifedipine by 20% but was not altered by econazole, SKF96365, GF109203X, and phorbol-12-myristate-13-acetate (PMA). In Ca2+-free medium, treatment with protriptyline inhibited the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin-evoked [Ca2+]i rises. Conversely, treatment with thapsigargin inhibited 45% of protriptyline-evoked [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 failed to alter protriptyline-evoked [Ca2+]i rises. Protriptyline at 50-250 µM decreased cell viability, which was not reversed by pretreatment with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Collectively, our data suggest that in MG63 cells, protriptyline induced [Ca2+]i rises by evoking Ca2+ release from the endoplasmic reticulum and other stores in a PLC-independent manner, and Ca2+ entry via a nifedipine-sensitive Ca2+ pathway. Protriptyline also caused Ca2+-independent cell death.


Subject(s)
Antidepressive Agents, Tricyclic/toxicity , Calcium/metabolism , Osteoblasts/drug effects , Protriptyline/toxicity , Cell Line, Tumor , Cell Survival/drug effects , Cytosol/drug effects , Cytosol/metabolism , Dose-Response Relationship, Drug , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Humans , Osteoblasts/metabolism , Osteoblasts/pathology
11.
Chin J Physiol ; 59(5): 268-275, 2016 Oct 31.
Article in English | MEDLINE | ID: mdl-27604137

ABSTRACT

NPC15199 is a synthesized compound that inhibits inflammation in some models. However, whether NPC15199 affects Ca²âº homeostasis in human gastric cancer is unclear. This study examined the effect of NPC15199 on cytosolic free Ca²âº concentrations ([Ca²âº]i) and viability in SCM1 human gastric cancer cells. The Ca²âº-sensitive fluorescent dye fura-2 was used to measure [Ca²âº]i. NPC15199 evoked [Ca²âº]i rises concentration-dependently. The response was reduced by removing extracellular Ca²âº. NPC15199-evoked Ca²âº entry was not inhibited by store-operated channel inhibitors (nifedipine, econazole and SKF96365) and protein kinase C (PKC) activator (phorbol 12-myristate 13 acetate, PMA), or PKC inhibitor (GF109203X). In Ca²âº-free medium, treatment with the endoplasmic reticulum Ca²âº pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) nearly abolished NPC15199-evoked [Ca²âº]i rises. Conversely, treatment with NPC15199 also nearly abolished thapsigargin or BHQ-evoked [Ca²âº]i rises. Inhibition of phospholipase C (PLC) with U73122 did not affect NPC15199-evoked [Ca²âº]i rises. NPC15199 at concentrations of 100-900 µM induced concentration-dependent, Ca²âº-independent decrease in viability. Together, in SCM1 cells, NPC15199 induced [Ca²âº]i rises that involved Ca²âº entry through PKC-insensitive non-store-operated Ca²âº channels and PLC-independent Ca²âº release from the endoplasmic reticulum. NPC15199 also induced Ca²âº-independent cell death.


Subject(s)
Calcium Signaling/drug effects , Fluorenes/therapeutic use , Leucine/analogs & derivatives , Stomach Neoplasms/drug therapy , Cell Death/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Fluorenes/pharmacology , Humans , Leucine/pharmacology , Leucine/therapeutic use , Type C Phospholipases/metabolism
12.
Toxicol Mech Methods ; 26(5): 327-33, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27310574

ABSTRACT

The phenolic compound 2,5-dimethylphenol is a natural product. 2,5-Dimethylphenol has been shown to affect rat hepatic and pulmonary microsomal metabolism. However, the effect of 2,5-dimethylphenol on Ca(2+ )signaling and cyotoxicity has never been explored in any culture cells. This study explored the effect of 2,5-dimethylphenol on cytosolic free Ca(2+ )levels ([Ca(2+)]i) and cell viability in PC3 human prostate cancer cells. 2,5-Dimethylphenol at concentrations between 500 µM and 1000 µM evoked [Ca(2+)]i rises in a concentration-dependent manner. This Ca(2+ )signal was inhibited by approximately half by the removal of extracellular Ca(2+). 2,5-Dimethylphenol-induced Ca(2+ )influx was confirmed by Mn(2+)-induced quench of fura-2 fluorescence. Pretreatment with the protein kinase C (PKC) inhibitor GF109203X, nifedipine or the store-operated Ca(2+ )entry inhibitors (econazole or SKF96365) inhibited 2,5-dimethylphenol-induced Ca(2+ )signal in Ca(2+)-containing medium by ∼30%. Treatment with the endoplasmic reticulum Ca(2+ )pump inhibitor thapsigargin in Ca(2+)-free medium abolished 2,5-dimethylphenol-induced [Ca(2+)]i rises. Conversely, treatment with 2,5-dimethylphenol abolished thapsigargin-induced [Ca(2+)]i rises. Inhibition of phospholipase C (PLC) with U73122 reduced 2,5-dimethylphenol-evoked [Ca(2+)]i rises by ∼80%. 2,5-Dimethylphenol killed cells at concentrations of 350-1000 µM in a concentration-dependent fashion. Chelation of cytosolic Ca(2+ )with 1,2-bis(2-aminophenoxy)ethane-N, N, N', N'-tetraacetic acid/AM (BAPTA/AM) did not prevent 2,5-dimethylphenol's cytotoxicity. Together, in PC3 cells, 2,5-dimethylphenol induced [Ca(2+)]i rises that involved Ca(2+ )entry through PKC-regulated store-operated Ca(2+ )channels and PLC-dependent Ca(2+ )release from the endoplasmic reticulum. 2,5-Dimethylphenol induced cytotoxicity in a Ca(2+)-independent manner.


Subject(s)
Calcium Signaling/drug effects , Calcium/metabolism , Xylenes/pharmacology , Calcium Channels/metabolism , Cell Culture Techniques , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Humans , Male , Manganese/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Time Factors , Type C Phospholipases/metabolism
13.
J Biochem Mol Toxicol ; 30(11): 539-547, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27252039

ABSTRACT

The effect of protriptyline on Ca2+ physiology in human hepatoma is unclear. This study explored the effect of protriptyline on [Ca2+ ]i and cytotoxicity in HepG2 human hepatoma cells. Protriptyline (50-150 µM) evoked [Ca2+ ]i rises. The Ca2+ entry was inhibited by removal of Ca2+ . Protriptyline-induced Ca2+ entry was confirmed by Mn2+ -induced quench of fura-2 fluorescence. Except nifedipine, econazole, SKF96365, GF109203X, and phorbol 12-myristate 13 acetate did not inhibit Ca2+ entry. Treatment with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) inhibited 40% of protriptyline-induced response. Treatment with protriptyline abolished BHQ-induced response. Inhibition of phospholipase C (PLC) suppressed protriptyline-evoked response by 70%. At 20-40 µM, protriptyline killed cells which was not reversed by the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Together, in HepG2 cells, protriptyline induced [Ca2+ ]i rises that involved Ca2+ entry through nifedipine-sensitive Ca2+ channels and PLC-dependent Ca2+ release from endoplasmic reticulum. Protriptyline induced Ca2+ -independent cell death.


Subject(s)
Antidepressive Agents, Tricyclic/pharmacology , Calcium/metabolism , Cell Death/drug effects , Protriptyline/pharmacology , Calcium/agonists , Cations, Divalent , Econazole/pharmacology , Egtazic Acid/analogs & derivatives , Egtazic Acid/pharmacology , Fluorescent Dyes , Fura-2 , Hep G2 Cells , Humans , Hydroquinones/pharmacology , Imidazoles/pharmacology , Indoles/pharmacology , Ion Transport/drug effects , Kinetics , Maleimides/pharmacology , Manganese/pharmacology , Nifedipine/pharmacology , Protriptyline/antagonists & inhibitors , Spectrometry, Fluorescence , Tetradecanoylphorbol Acetate/analogs & derivatives , Tetradecanoylphorbol Acetate/pharmacology , Type C Phospholipases/antagonists & inhibitors , Type C Phospholipases/metabolism
14.
Chin J Physiol ; 59(3): 148-55, 2016 Jun 30.
Article in English | MEDLINE | ID: mdl-27188467

ABSTRACT

This study explored the effect of deltamethrin, a pesticide, on intracellular free Ca²âº concentration ([Ca²âº]i) in PC3 human prostate cancer cells. Deltamethrin at concentrations between 5 µM and 20 µM evoked [Ca²âº]i rises in a concentration-dependent manner. This Ca²âº signal was inhibited by 22% by removal of extracellular Ca²âº. Nifedipine, econazole, and SKF96365 also inhibited the Ca²âº signal. Treatment with the endoplasmic reticulum Ca²âº pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) in Ca²âº-free medium nearly abolished deltamethrin-induced [Ca²âº]i rises. Treatment with deltamethrin also inhibited most of BHQ-induced [Ca²âº]i rises. Inhibition of phospholipase C (PLC) with U73122 failed to alter deltamethrin-evoked [Ca²âº]i rises. Deltamethrin killed cells at concentrations of 20-100 µM in a concentration-dependent fashion. Chelation of cytosolic Ca²âº with 1,2-bis (2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid/acetoxymethyl ester (BAPTA/AM) did not prevent deltamethrin's cytotoxicity. Together, in PC3 human prostate cancer cells, deltamethrin induced [Ca²âº]i rises that involved Ca²âº entry through store-operated Ca²âº channels and PLC-independent Ca²âº release from the endoplasmic reticulum. Deltamethrin induced cytotoxicity in a Ca²âº-independent manner.


Subject(s)
Calcium/metabolism , Insecticides/pharmacology , Nitriles/pharmacology , Prostatic Neoplasms/metabolism , Pyrethrins/pharmacology , Apoptosis/drug effects , Calcium Channel Blockers/pharmacology , Calcium Signaling/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Chelating Agents/pharmacology , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Enzyme Inhibitors/pharmacology , Humans , Male , Nitriles/antagonists & inhibitors , Pyrethrins/antagonists & inhibitors , Type C Phospholipases/antagonists & inhibitors
15.
Chem Biol Interact ; 252: 61-73, 2016 May 25.
Article in English | MEDLINE | ID: mdl-27060209

ABSTRACT

Gallic acid, a polyhydroxylphenolic compound, is widely distributed in various plants, fruits and foods. It has been shown that gallic acid passes into blood brain barrier and reaches the brain tissue of middle cerebral artery occlusion rats. However, the effect of gallic acid on Ca(2+) signaling in glia cells is unknown. This study explored whether gallic acid affected Ca(2+) homeostasis and induced Ca(2+)-associated cytotoxicity in DBTRG-05MG human glioblastoma cells and CTX TNA2 rat astrocytes. Gallic acid (20-40 µM) concentration-dependently induced cytotoxicity and intracellular Ca(2+) level ([Ca(2+)]i) increases in DBTRG-05MG cells but not in CTX TNA2 cells. In DBTRG-05MG cells, the Ca(2+) response was decreased by half by removal of extracellular Ca(2+). In Ca(2+)-containing medium, gallic acid-induced Ca(2+) entry was inhibited by store-operated Ca(2+) channel inhibitors (2-APB, econazole and SKF96365). In Ca(2+)-free medium, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin abolished gallic acid-induced [Ca(2+)]i increases. Conversely, incubation with gallic acid also abolished thapsigargin-induced [Ca(2+)]i increases. Inhibition of phospholipase C with U73122 abolished gallic acid-induced [Ca(2+)]i increases. Gallic acid significantly caused cytotoxicity in DBTRG-05MG cells, which was partially prevented by prechelating cytosolic Ca(2+) with BAPTA-AM. Moreover, gallic acid activated mitochondrial apoptotic pathways that involved ROS production. Together, in DBTRG-05MG cells but not in CTX TNA2 cells, gallic acid induced [Ca(2+)]i increases by causing Ca(2+) entry via 2-APB, econazole and SKF96365-sensitive store-operated Ca(2+) entry, and phospholipase C-dependent release from the endoplasmic reticulum. This Ca(2+) signal subsequently evoked mitochondrial pathways of apoptosis that involved ROS production.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Astrocytes/drug effects , Brain Neoplasms/drug therapy , Calcium/metabolism , Gallic Acid/pharmacology , Glioblastoma/drug therapy , Animals , Astrocytes/metabolism , Brain Neoplasms/metabolism , Cations, Divalent/metabolism , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Glioblastoma/metabolism , Homeostasis/drug effects , Humans , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Rats , Reactive Oxygen Species/metabolism
16.
Eur J Pharmacol ; 780: 243-51, 2016 Jun 05.
Article in English | MEDLINE | ID: mdl-27038520

ABSTRACT

Ellagic acid, a natural phenol compound found in numerous fruits and vegetables, causes various physiological effects in different cell models. However, the effect of this compound on Ca(2+) homeostasis in liver cells is unknown. This study examined the effect of ellagic acid on intracellular Ca(2+) concentration ([Ca(2+)]i) and established the relationship between Ca(2+) signaling and cytotoxicity in liver cells. The data show that ellagic acid induced concentration-dependent [Ca(2+)]i rises in HepG2 human hepatoma cells, but not in HA22T, HA59T human hepatoma cells or AML12 mouse hepatocytes. In HepG2 cells, this Ca(2+) signal response was reduced by removing extracellular Ca(2+) and was inhibited by store-operated Ca(2+) channel blockers (2-APB, econazole or SKF96365) and the protein kinase C (PKC) inhibitor GF109203X. In Ca(2+)-free medium, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin abolished ellagic acid-induced [Ca(2+)]i rises. Conversely, incubation with ellagic acid abolished thapsigargin-induced [Ca(2+)]i rises. Inhibition of phospholipase C (PLC) with U73122 also abolished ellagic acid-induced [Ca(2+)]i rises. Ellagic acid (25-100µM) concentration-dependently caused cytotoxicity in HepG2, HA22T or HA59T cells, but not in AML12 cells. Furthermore, this cytotoxic effect was partially prevented by prechelating cytosolic Ca(2+) with BAPTA-AM only in HepG2 cells. Together, in HepG2 cells, ellagic acid induced [Ca(2+)]i rises by inducing PLC-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via PKC-sensitive store-operated Ca(2+) channels. Moreover, ellagic acid induced Ca(2+)-associated cytotoxicity.


Subject(s)
Antineoplastic Agents/pharmacology , Calcium/metabolism , Ellagic Acid/pharmacology , Homeostasis/drug effects , Animals , Biological Transport/drug effects , Calcium Channel Blockers/pharmacology , Cell Survival/drug effects , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Hep G2 Cells , Humans , Manganese/metabolism , Mice , Protein Kinase C/antagonists & inhibitors , Type C Phospholipases/metabolism
17.
Food Chem Toxicol ; 91: 151-66, 2016 May.
Article in English | MEDLINE | ID: mdl-27016494

ABSTRACT

Oleuropein, a phenolic compound found in the olive leaf (Olea europaea), has been shown to have biological activities in different models. However, the effects of oleuropein on Ca(2+) homeostasis, cytotoxicity, cell cycle distribution and ROS signaling in liver cells have not been analyzed. Oleuropein induced [Ca(2+)]i rises only in HepG2 cells but not in AML12, HA22T or HA59T cells due to the different status of 3-hydroxy-3-methylglutaryl-CoA reductase expression. In HepG2 cells, this Ca(2+) signaling response was reduced by removing extracellular Ca(2+), and was inhibited by the store-operated Ca(2+) channel blockers 2-APB and SKF96365. In Ca(2+)-free medium, pretreatment with the ER Ca(2+) pump inhibitor thapsigargin abolished oleuropein-induced [Ca(2+)]i rises. Oleuropein induced cell cycle arrest which was associated with the regulation of p53, p21, CDK1 and cyclin B1 levels. Furthermore, oleuropein elevated intracellular ROS levels but reduced GSH levels. Treatment with the intracellular Ca(2+) chelator BAPTA-AM or the antioxidant NAC partially reversed oleuropein-induced cytotoxicity. Together, in HepG2 cells, oleuropein induced [Ca(2+)]i rises by releasing Ca(2+) from the ER and causing Ca(2+) influx through store-operated Ca(2+) channels. Moreover, oleuropein induced Ca(2+)-associated cytotoxicity that involved ROS signaling and cell cycle arrest. This compound may offer a potential therapy for treatment of human hepatoma.


Subject(s)
Calcium/metabolism , Cell Cycle/drug effects , Homeostasis/drug effects , Iridoids/pharmacology , Plant Leaves/chemistry , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Hep G2 Cells , Humans , Iridoid Glucosides , Iridoids/isolation & purification , Olea/chemistry
18.
Tumour Biol ; 37(4): 4665-78, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26508031

ABSTRACT

Esculetin (6,7-dihydroxycoumarin), a derivative of coumarin compound, is found in traditional medicinal herbs. It has been shown that esculetin triggers diverse cellular signal transduction pathways leading to regulation of physiology in different models. However, whether esculetin affects Ca(2+) homeostasis in breast cancer cells has not been explored. This study examined the underlying mechanism of cytotoxicity induced by esculetin and established the relationship between Ca(2+) signaling and cytotoxicity in human breast cancer cells. The results showed that esculetin induced concentration-dependent rises in the intracellular Ca(2+) concentration ([Ca(2+)]i) in ZR-75-1 (but not in MCF-7 and MDA-MB-231) human breast cancer cells. In ZR-75-1 cells, this Ca(2+) signal response was reduced by removing extracellular Ca(2+) and was inhibited by the store-operated Ca(2+) channel blocker 2-aminoethoxydiphenyl borate (2-APB). In Ca(2+)-free medium, pre-treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) abolished esculetin-induced [Ca(2+)]i rises. Conversely, incubation with esculetin abolished TG-induced [Ca(2+)]i rises. Esculetin induced cytotoxicity that involved apoptosis, as supported by the reduction of mitochondrial membrane potential and the release of cytochrome c and the proteolytic activation of caspase-9/caspase-3, which were partially reversed by pre-chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). Moreover, esculetin increased the percentage of cells in G2/M phase and regulated the expressions of p53, p21, CDK1, and cyclin B1. Together, in ZR-75-1 cells, esculetin induced [Ca(2+)]i rises by releasing Ca(2+) from the ER and causing Ca(2+) influx through 2-APB-sensitive store-operated Ca(2+) entry. Furthermore, esculetin activated Ca(2+)-associated mitochondrial apoptotic pathways that involved G2/M cell cycle arrest. Graphical abstract The summary of esculetin-evoked [Ca(2+)]i rises and -activated Ca(2+)-associated mitochondrial apoptotic pathways that involved cell cycle arrest. The natural coumarin derivative esculetin caused Ca(2+) influx via 2-APB-sensitive store-operated Ca(2+) entry and induced Ca(2+) release from the endoplasmic reticulum. Moreover, esculetin activated the mitochondrial pathway of apoptosis in a Ca(2+)-associated manner that involved G2/M arrest.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Umbelliferones/pharmacology , Breast Neoplasms/drug therapy , Calcium , Calcium Signaling , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , G1 Phase Cell Cycle Checkpoints , Humans , Inhibitory Concentration 50 , Membrane Potential, Mitochondrial/drug effects , Mitochondria
19.
Environ Toxicol ; 31(3): 314-28, 2016 Mar.
Article in English | MEDLINE | ID: mdl-25258189

ABSTRACT

Arsenic trioxide is an old drug and has been used for a long time in traditional Chinese and Western medicines. However, the cancer treatment of arsenic trioxide has heart and vascular toxicity. The cytotoxic effects of arsenic trioxide and its molecular mechanism in human umbilical mesenchymal stem cells (HUMSC) and human bone marrow-derived mesenchymal stem cells (HMSC-bm) were investigated in this study. Our results showed that arsenic trioxide significantly reduced the viability of HUMSC and HMSC-bm in a concentration- and time-dependent manner. Arsenic trioxide is able to induce apoptotic cell death in HUMSC and HMSC-bm, as shown from the results of morphological examination, flow cytometric analyses, DAPI staining and comet assay. The appearance of arsenic trioxide also led to an increase of intracellular free calcium (Ca(2+) ) concentration and the disruption of mitochondrial membrane potential (ΔΨm). The caspase-9 and caspase-3 activities were time-dependently increased in arsenic trioxide-treated HUMSC and HMSC-bm. In addition, the proteomic analysis and DNA microarray were carried out to investigate the expression level changes of genes and proteins affected by arsenic trioxide treatment in HUMSC. Our results suggest that arsenic trioxide induces a prompt induction of ER stress and mitochondria-modulated apoptosis in HUMSC and HMSC-bm. A framework was proposed for the effect of arsenic trioxide cytotoxicity by targeting ER stress.


Subject(s)
Apoptosis/drug effects , Bone Marrow Cells/drug effects , Endoplasmic Reticulum Stress/physiology , Fetal Blood/cytology , Mesenchymal Stem Cells/drug effects , Oxides/toxicity , Apoptosis/genetics , Arsenic Trioxide , Arsenicals , Bone Marrow Cells/physiology , Caspase 3/metabolism , Caspase 9/metabolism , Cells, Cultured , Endoplasmic Reticulum Stress/drug effects , Fetal Blood/drug effects , Humans , Membrane Potential, Mitochondrial/drug effects , Mesenchymal Stem Cells/physiology , Mitochondria/drug effects , Mitochondria/metabolism , Proteome/analysis , Proteome/drug effects , Signal Transduction/drug effects
20.
J Nat Prod ; 78(11): 2521-30, 2015 Nov 25.
Article in English | MEDLINE | ID: mdl-26523463

ABSTRACT

Eight new clausenamides, including three γ-lactams (1-3), four δ-lactams (4-7), and an amide (8), and seven known lactams, including compounds 9-11, which were purified from natural sources for the first time, were characterized from the leaves of Clausena lansium. Their structures were elucidated using spectroscopic methods, and the absolute configurations were determined using electronic circular dichroism and single-crystal X-ray diffraction analyses with Cu Kα radiation. Compound 2 (50 µM) protected 22.24% of cortical neurons against Aß25-35-induced cell death.


Subject(s)
Clausena/chemistry , Lactams/isolation & purification , Lignans/isolation & purification , Neuroprotective Agents/isolation & purification , Amyloid beta-Peptides/pharmacology , Carbazoles , Lactams/chemistry , Lignans/chemistry , Molecular Structure , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Nuclear Magnetic Resonance, Biomolecular , Peptide Fragments/pharmacology , Plant Leaves/chemistry , Stereoisomerism , Vietnam
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