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PubMed1999

Novel derivatives of phenethyl-5-bromopyridylthiourea and dihydroalkoxybenzyloxopyrimidine are dual-function spermicides with potent anti-human immunodeficiency virus activity.

Sexually active women represent the fastest growing HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) risk group. In an effort to develop a vaginal microbicidal contraceptive potentially capable of preventing HIV transmission as well as providing fertility control, we have synthesized novel non-nucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT) and examined them for dual-function anti-HIV and spermicidal activity. Structure-based drug design by use of a computer docking procedure for the NNI binding pocket generated from nine RT-NNI crystal structures led to the synthesis of three novel NNIs: N-[2-(2, 5-dimethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (D-PBT); N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (F-PBT); and 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-on e (S-DABO). The anti-HIV activity of these NNIs was compared with that of trovirdine and virucidal/spermicide, nonoxynol-9 (N-9), by measuring viral RT activity and p24 antigen production as markers of viral replication using HTLVIIIB-infected human peripheral blood mononuclear cells (PBMCs). The effects on sperm motion kinematics and sperm membrane integrity were examined by computer-assisted sperm analysis and by confocal laser scanning microscopy (CLSM), respectively. The growth-inhibitory effects of NNI versus N-9 against normal human ectocervical and endocervical epithelial cells were tested using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. All three NNIs were potent inhibitors of purified recombinant HIV RT and abrogated HIV replication in PBMCs at nanomolar concentrations (IC50 < 1 nM) when compared with N-9 or trovirdine (IC50 values of 2.2 microM and 0.007 microM, respectively). Two NNIs, F-PBT and S-DABO, also exhibited concentration- and time-dependent spermicidal activity. The drug concentration required to inhibit sperm motility by 50% (EC50 values) for the lead compound F-PBT versus N-9 was 147 microM and 81 microM, respectively. Sperm-immobilizing activity induced by F-PBT and S-DABO was rapid (t1/2 = 7-13 min) and irreversible. Unlike that of N-9, spermicidal activity of F-PBT and S-DABO was not accompanied by loss of acrosomal membrane as detected by fluorescent-lectin binding assay and CLSM. Whereas N-9 was cytotoxic to normal human ectocervical and endocervical cells at spermicidal doses, both F-PBT and S-DABO were selectively spermicidal. We conclude that as potent anti-HIV agents with spermicidal activity and reduced cytotoxicity, F-PBT and S-DABO show unique clinical potential to become the active ingredients of a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Sesquiterpenes with various carbon skeletons from Ligularia virgaurea spp. oligocephala.

Two new 8,9-seco-cacalol-type sesquiterpene lactones, ligulolide C (1 and 2) and six known sesquiterpenes, adenostylide (3 and 4), cacalol (5), 1 -hydroxy-2-(3'-pentenyl)-3,7-dimethylbenzofuran (6), 1beta, 6alpha-dihydroxy-4(14)-eudesmene (7) and (+)-oplopanone (8), have been isolated from an extract of the whole plant of Ligularia virgaurea spp. oligocephala. The structures of 1 and 2 were confirmed by spectroscopic methods including 1D and 2D NMR spectra. A discussion of biogenesis of 1 and 2 was described. Cytotoxicity against selected cancer cells human promyelocytic leukemia (HL-60), human ovarian (HO-8910) and human lung epithehial (A-549) of compounds 1-8 were measured in vitro.

Antineoplastic Agents, Phytogenic↗
PubMed1977

Disorders of phagocyte function: biochemical aspects.

Intensive laboratory investigation of patients with recurrent infections, and with infections with microbial species not usually considered to be pathogenic, have led to the identification of several defects in granulocyte function. The two functions of granulocytes which have received most attention in the past decade have been locomotion (especially response to chemotactic stimulation) and microbicidal activity. Defective granulocyte chemotaxis has been demonstrated in patients with clinical manifestations suggesting abnormalities related to vasoactive amines, i.e., patients with eczema and extreme IgE hyperimmunoglobulinemia. The depressed granulocyte chemotactic responsiveness found in these patients can be reproduced in vitro when histamine and beta adrenergic agents are incubated with control granulocytes. Since these compounds have been shown to increase levels of intracellular cyclic AMP in other cells, there appears to be an association between cyclic nucleotide metabolism and regulation of granulocyte locomotion. Defective granulocyte microbicidal activity is found in patients with chronic granulomatous disease and it has been shown that there is little increase in oxidative metabolism during phagocytosis by these cells. Methods for quantitating the oxidative metabolism of granulocytes and monocytes include oxygen uptake, reduction of nitroblue tetrazolium, formate oxidation, and chemiluminescence response during phagocytosis. Since products of oxygen metabolism, i.e., hydrogen peroxide, superoxide or singlet oxygen do not accumulate in granulocyte phagocytic vacuoles, intracellular microbes are not killed (except bacterial species that produce hydrogen peroxide). The biochemical basis for defective oxidative metabolism in granulocytes from patients with chronic granulomatous disease appears to be associated with abnormal nucleotide oxidase activity.

Blood Bactericidal Activity↗
PubMed2005

Responses of European eel (Anguilla anguilla L.) circulating phagocytes to an in situ closed pulp mill effluent exposure and its association with organ-specific peroxidative damage.

The effect of bleached kraft pulp mill effluent (BKPME) persistent compounds on phagocyte activities and its organ-specific influence in gill, kidney and liver was studied in European eel (Anguilla anguilla L.). Eels were caged and plunged at 3 different sites-50 m (site 1), 100 m (site 2) and 2,000 m (site 3) away from the end of the closed BKPME discharging channel for 8 and 48 h. Gill, head kidney and peritoneum phagocytes oxidative burst activity (OBA) was measured by the nitroblue tetrazolium reduction assay whereas lipid peroxidation (LPO) in eel gill, kidney and liver was measured by thiobarbituric acid reaction. A significant gill OBA induction was found at 8h on site 2, and on sites 1, 2 and 3 at 48 h exposure. However, in head kidney and peritoneal exudate phagocytes, OBA induction was significant only at sites 2 and 3 after 48 h exposure. In those particular sites, a significant increase in gill, kidney and liver LPO was measured that is assumed to result from OBA induction. Considering OBA and LPO, gill is the most affected tissue compared to kidney and liver. Gill vulnerability towards peroxidative damage was demonstrated at 8h on site 2 and at 48 h on sites 1, 2 and 3, whereas in kidney was observed at sites 2 and 3 only at 48 h. Liver LPO increased at site 2 only after 48 h exposure. Our results demonstrate that the OBA activation pattern in gill and kidney is associated with the induced peroxidative damage extent in those organ, together with water pollution the exposure route, resulting from previous BKPME effluent sediment contamination which may affect the activation pattern of circulating fish phagocytes.

Anguilla↗
PubMed2003

Identification of novel inhibitors of BCR-ABL tyrosine kinase via virtual screening.

Inhibition of BCR-ABL tyrosine kinase activity has shown to be essential for the treatment of chronic myelogenous leukemia (CML). However, drug resistance has quickly arisen in recent clinical trials for STI571 (Gleevec), which is the first approved drug of CML by inhibiting ABL tyrosine kinase. It is desirable to develop new types of ABL tyrosine kinase inhibitors that may overcome this drug resistance problem. Here we present the discovery of novel inhibitors targeted at the catalytic domain of ABL tyrosine kinase by using three-dimensional database searching techniques. From a database containing 200,000 commercially available compounds, the top 1000 compounds with the best DOCK energy score were selected and subjected to structural diversity and drug likeness analysis, 15 compounds were submitted for biological assay. Eight out of the 15 showed inhibitory activity against K562 cells with IC(50) value ranging from 10 to 200 microM. Two promising compounds showed inhibition in further ABL tyrosine phosphorylation assay. It is anticipated that those two compounds can serve as lead compounds for further drug design and optimization.

Binding Sites↗
PubMed2004

Neuroprotective effects of Ptychopetalum olacoides Bentham (Olacaceae) on oxygen and glucose deprivation induced damage in rat hippocampal slices.

Alcoholic infusions of Ptychopetalum olacoides Bentham (PO, Olacaceae) are used in traditional medicine by patients presenting age associated symptoms and those recovering from stroke. The aim of this study is to evaluate the neuroprotective properties of PO ethanol extract (POEE) using hippocampal slices from Wistar rats exposed to oxygen and glucose deprivation (OGD, followed by reoxygenation). Mitochondrial activity, an index of cell viability, was assessed by the MTT assay; in addition, the free radicals content was estimated by the use of dichlorofluorescein diacetate as probe. The OGD ischemic condition significantly impaired cellular viability, and increased free radicals generation. In non-OGD slices, incubation with POEE (0.6 microg/ml) increased (approximately 40%) mitochondrial activity, without affecting free radicals levels. In comparison to OGD controls, slices incubated with POEE (0.6 microg/ml) during and after OGD exposure had significantly increased cellular viability. In addition, at this same concentration, POEE prevented the increase of free radicals content induced by OGD. In view of the fact that respiratory chain inhibition and increased generation of free radicals are major consequences of the ischemic injury, this study suggests that Ptychopetalum olacoides contains useful neuroprotective compounds and, therefore, deserves further scrutiny.

Animals↗
PubMed1997

Estimation of the chemosensitizing activity of modulators of multi-drug resistance via combined simultaneous analysis of sigmoidal dose-response curves.

The potency of modulators which re-establish sensitivity of resistant tumour cells to cytotoxic drugs is not usually described by ED50 values, even though such values are needed for comparison of modulator activity. Various methods are reported for the determination of ED50 values of propafenone-type modulators of multi-drug resistance in cytotoxicity assays. Best results were obtained by using a combined simultaneous analysis of dose-response curve families. This approach enables calculation of statistically highly significant ED50 values without any data reduction directly from the original data points obtained in daunomycin cytotoxicity assays. The method also enables extrapolation of the ED50 values of compounds with low activity or poor solubility, or both.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1983

Generation of hydrogen peroxide and superoxide anion from active metabolites of naphthylamines and aminoazo dyes: its possible role in carcinogenesis.

Autoxidation of active metabolites of naphthylamine and aminoazo dyes in neutral buffer generated hydrogen peroxide (H2O2) and superoxide anion (O-.2), as detected by the titanium sulfate method and nitro blue tetrazolium method, respectively. 2-Amino-1-naphthol, 1-amino-2-naphthol, 1-amino-4-naphthol, N-hydroxy-2-aminonaphthalene, N-hydroxy-1-aminonaphthalene, N-hydroxy-4-aminoazobenzene and N-hydroxy-4-methylaminoazobenzene generated H2O2 and O-.2, whereas 1-nitrosonaphthalene, 2-nitrosonaphthalene, 1-naphtylamine, 2-naphthylamine and non-carcinogenic aminonaphthols and naphthols generated no active oxygens. Catalase and superoxide dismutase were used to identify the formation of these active oxygens. For all compounds tested except nitrosonaphthalenes, good parallelism was found between the active oxygen formation and convertibility to free radicals. These results suggest a possible role of free radicals and subsequently formed active oxygens in aromatic amine carcinogenesis.

Animals↗
PubMed2000

Hepatotoxicity of camptothecin derivatives in a primary culture system of rat hepatocytes.

The topoisomerase I inhibitors are a new class of antineoplastic agents currently under clinical development. Among these compounds there are some camptothecin (CPT) derivatives with improved toxicity profiles and antitumor activity: irinotecan (CPT-11) and topotecan (TPT), particularly active against colon, lung and ovarian cancer. The aim of this study was to evaluate the cytotoxicity of CPT, CPT-11, its metabolite SN38 and TPT in a primary culture system of rat hepatocytes. Cytotoxicity was evaluated by measuring the leakage of lactate dehydrogenase (LDH) into the medium and by assessing cell viability in terms of tetrazolium salts (MTT) reduction by mitochondrial dehydrogenase activity. Our results showed that cytotoxicity was limited in the case of short drug exposure. There was a significant and time-dependent increase in LDH leakage and a significant time- and dose-dependent decrease in MTT reduction after 3 h of incubation (p<0.01). In the treatments with doses related to peak plasma levels, CPT-11 was less responsible for the observed in vitro hepatotoxicity than its metabolite SN38; TPT had lower LDH leakage compared to SN38 and CPT-11 but showed significant and early (3 h) decrease in MTT reduction: this may mean a different mechanism of cellular damage. These results demonstrate that CPT derivatives are directly toxic to liver cells in a distinct time- and dose-related response.

Animals↗
PubMed1996

Revalidation of the in vitro alkaline elution/rat hepatocyte assay for DNA damage: improved criteria for assessment of cytotoxicity and genotoxicity and results for 81 compounds.

The in vitro alkaline elution/rat hepatocyte assay is a sensitive assay for genotoxicity, measured as DNA strand breaks induced in primary cultures of rat hepatocytes after 3-h treatments with test compounds. Since DNA degradation can be rapid and extensive in dead and/or dying cells, the original criteria for a positive result in the assay were that a compound induce a 3.0-fold or greater increase in the elution slope (for the terminal phase of alkaline elution from 3 to 9 h) in the absence of significant cytotoxicity (defined as relative cell viability of less than 70% by trypan blue dye exclusion; TBDE). Recently we have shown that false-positive results can still be obtained due to cytotoxicity when loss of membrane integrity is a late event in toxic cell death relative to the induction of endonucleolytic DNA degradation. To improve the ability of the assay to discriminate between genotoxic vs. cytotoxic effects of chemicals, we have evaluated additional assays of cytotoxicity including cell adenosine triphosphate (ATP) and potassium (K+) content, tetrazolium dye reduction (MTT), TBDE after a further 3-h recovery incubation without test chemicals (delayed toxicity), cell blebbing and endonucleolytic DNA degradation (double-strand breaks; DSBs) assessed by pulsed-field gel electrophoresis (PFGE). We have also evaluated 2 parameters derived from the elution data which can indicate extensive, cytotoxicity-induced DNA degradation: the fraction of the DNA recovered in the neutral lysis/rinse fraction and the gamma-intercept of the extrapolation of the 3-9-h segment of the elution curve. Twenty-eight rodent non-carcinogens that are negative (or inconclusive) in the Ames assay with no, or limited, other evidence of genotoxicity, and 33 genotoxins, most of which are also carcinogens, were evaluated. The results showed that DNA degradation as measured by a 1-h PACE (Programmed Autonomously Controlled Electrodes)/PFGE assay was a sensitive indicator of cytotoxicity which correlated well with results of the other cytotoxicity indicators. The delayed TBDE (after a 3-h recovery), intracellular potassium and ATP assays as well as the gamma-intercept parameter were also shown to be sensitive and in some cases complementary measures of cytotoxicity. Using new criteria based on these data of an induced slope (treatment slope-negative control slope) of 0.020 for the 3- to 9-h elution period and cytotoxicity limits of 70% relative viability for the delayed TBDE assay and 50% for intracellular ATP content, the assay scores the genotoxicity of these 61 reference compounds with an overall accuracy of 92%. Test results using these new criteria are provided for an additional 20 compounds (5 non-genotoxic carcinogens and 15 compounds whose genotoxic and carcinogenic potential are unknown or equivocal).

Adenosine Triphosphate↗
PubMed1995

Ibuprofen protects rat livers from oxygen-derived free radical-mediated injury after tourniquet shock.

Rats subjected to tourniquet shock suffer a severe form of circulatory shock, tissue and organ oxidative stress, and final multiple system organ failure (MSOF) and death of the animals within 24 h of tourniquet release. The oxidative damage observed in hind-limb muscle tissue after reperfusion does not by itself account for the final systemic and lethal MSOF. We have postulated that organ failure has its genesis in a primary perfusion abnormality, e.g. the hind limbs, which is followed by secondary hypoperfusion of other organs, such as the liver, as has been shown to be the case in several septic shock models. It has also been shown that injured or necrotic tissue can activate neutrophils, Küpffer cells, platelets, and both the complement and coagulation cascades. In turn, complement activation also leads to neutrophil and Küpffer cell activation as assessed by their capacity to generate oxyradicals. Herein we have evaluated the potential protective effect of ibuprofen on hepatic oxygen-derived free radical production, as well as its effects on both polymorphonuclear leucocyte (PMN) activation and liver infiltration. The protective effect of ibuprofen on hepatic oxidative injury was assessed by determining total thiol groups (SH), thiobarbituric acid-reactive substances (TBARS), and by the release of aspartic acid (AsT) and alanine (AIT) aminotransferases in control animals, in animals subjected to 5 h of tourniquets, and in animals after 2 h of hind-limb reperfusion. Liver infiltration by PMNs was determined by histology after staining with eosin-hematoxylin, and PMN activation by their capacity to reduce nitro blue tetrazolium (NBT).(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1997

Antioxidant activities of some extracts of Thymus zygis.

The antioxidant activities of methanol and ethyl ether extracts obtained from Thymus zygis, collected during the flowering or non-flowering period, were evaluated and compared. To investigate this potential, extracts were tested on their capacity to react with diphenylpicrylhydrazyl (DPPH) in a homogeneous medium, and to inhibit Fe2+/ascorbate-induced membrane lipid peroxidation, as estimated by the formation of thiobarbituric acid-reactive substances (TBARS). Although methanol extracts reduce DPPH radicals more efficiently than ethyl ether extracts, suggesting a potent radical scavenger activity, the ethyl ether extracts were found to be most active in inhibiting lipid peroxidation in sarcoplasmic reticulum (SR) membranes. In addition, both extracts present peroxyl and superoxide radical scavenging activities. Peroxyl radicals were generated by the water soluble 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) azoinitiator, and the scavenging activities of the extracts were measured by the inhibition of cis-parinaric acid (PnA) fluorescence decay in SR. Superoxide radicals were generated either by an enzymatic or a non-enzymatic system, and the scavenger ability was evaluated by the inhibition of nitroblue tetrazolium reduction. Methanolic extracts are more potent as scavengers of peroxyl and superoxide radicals than the ethyl ether extracts. Apparently, there is a relationship between antioxidant potency and the total phenolic groups content in each extract.

Amidines↗
PubMed1993

Effects of novel retinoic acid compound, 9-cis-retinoic acid, on proliferation, differentiation, and expression of retinoic acid receptor-alpha and retinoid X receptor-alpha RNA by HL-60 cells.

Retinoic acid modulates proliferation and differentiation of a wide variety of normal and leukemic cells through two distinct families of transcriptional factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). A stereoisomer of retinoic acid, 9-cis-retinoic acid, is a high-affinity ligand for RXR and binds efficiently to RAR. In contrast, all-trans-retinoic acid interacts 40-fold less efficiently with RXR as compared with RAR. To clarify the biologic role of retinoic acid compounds (all-trans,- 9-cis-, and 13-cis-retinoic acid) in hematopoietic cells, we studied their effects on clonal growth, differentiation, and expression of RAR-alpha and RXR-alpha genes in HL-60 cells. At very low concentrations (10(-15) to 10(-12) mmol/L), each retinoid enhanced clonal growth of HL-60 cells. These concentrations of the retinoids had no capacity to induce differentiation of leukemic cells as measured by ability either to reduce nitroblue tetrazolium and to express CD11b antigens, suggesting that retinoids at very low concentrations may stimulate proliferation of leukemic cells rather than induce their differentiation. These findings may help explain why patients with acute promyelocytic leukemia may relapse while receiving retinoic acids. With continuous therapy, retinoids are metabolized rapidly with increased urinary excretion, lowering their plasma levels to a range that may stimulate proliferation without inducing differentiation of leukemic cells. In contrast, we found that at higher concentrations (> or = 10(-11) mmol/L) each retinoid inhibited clonal growth, reduced c-myc RNA levels, and induced differentiation of HL-60 cells. 9-cis-retinoic acid was a slightly more potent inducer of differentiation than all-trans-retinoic acid; the mechanism for this increased potency and its clinical potential requires additional studies. Steady-state levels of RAR-alpha mRNA in HL-60 cells were not affected by either 9-cis- and all-trans-retinoic acid. In contrast, 9-cis-retinoic acid, but not all-trans-retinoic acid, reduced RXR-alpha mRNA accumulation in a dose-dependent manner.

Cell Differentiation↗
PubMed2003

Organic phenyl arsonic acid compounds with potent antileukemic activity.

A series of 12 organic arsonic acid compounds has been synthesized and evaluated against human B-lineage (NALM-6) and T-lineage (MOLT-3) acute lymphoblastic leukemia (ALL) cell lines. The lead compounds 2-trichloromethyl-4-[4'-(4"-phenylazo)phenylarsonic acid]aminoquinazoline (compound 19, PHI-P518; IC(50)=1.1+/-0.5 microM against NALM-6 and 2.0+/-0.8 microM against MOLT-3) and 2-methylthio-4-(2'-phenylarsonic acid)aminopyrimidine (compound 15, PHI-P381; IC(50)=1.5+/-0.3 microM against NALM-6 and 2.3+/-0.5 microM against MOLT-3) exhibited potent antileukemic activity at low micromolar concentrations.

Antineoplastic Agents↗
PubMed1995

Vitamin D3 analogs: effect on leukemic clonal growth and differentiation, and on serum calcium levels.

In vitro, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) induces differentiation of HL-60 cells and inhibits their proliferation as well as the proliferation of leukemic cells from patients. In vivo, the survival of mice challenged with syngeneic leukemic cells is enhanced by treatment with 1,25(OH)2D3. Patients treated with 1,25(OH)2D3 develop hypercalcemia at a serum level of 2 x 10(-10) mol/l which is a concentration too low to achieve an antileukemic effect in vitro. Several interesting vitamin D3 analogs have recently been developed. We initially examined the effect of 1,25(OH)2-16ene-23yne-19-nor-26,27-F6-D3 and 24a,26a,27a-tri-homo-22,24-diene-1-alpha,25-(OH)2-D3 on clonal growth and differentiation of HL-60 cells. Each of the analogs had comparable effects on clonal growth with 50% inhibition (ED50) at concentrations of 0.2-0.5 x 10(-9) M; 1,25(OH)2D3 was about 20- to 50-fold less active in inhibiting growth. Differentiation was determined by induction of superoxide production, as measured by nitroblue tetrazolium (NBT) reduction and by expression of a macrophage-specific enzyme (alpha napthyl acetate esterase (ANAE)). The 24a,26a,27a-tri-homo-22,24-diene-1-alpha,25-(OH)2-D3 and 1,25(OH)2-16ene-23yne-19-nor-26,27-F6-D3 were about 5- to 14-fold more potent than 1,25(OH)2D3. The hypercalcemia inducing side-effects of these analogs and three other previously identified, extremely potent vitamin D3 compounds, as well as 1,25(OH)2D3, were studied. The analogs were administered intraperitoneally every other day (qod) for 5 weeks; serum was collected weekly and Ca2+ measured by atomic absorption spectrophotometry. The highest tolerated dose of each analog leaving all mice alive was for 1,25(OH)2D3: 0.25 micrograms; 1,25(OH)2-24a,26a,27a-tri-homo-22,24-diene-D3: 0.25 micrograms; and 1,25(OH)2-16ene-23yne-19-nor-26,27-F6-D3: 0.0625 micrograms. Another hexafluoro compound with potent abilities to induce differentiation (1,25(OH)2-16ene-23yne-26,27-F6-D3) was very toxic, all mice died in the second week while receiving 0.0625 micrograms qod. Prior studies showed that the most potent compound in inducing differentiation of HL-60 was 1,25(OH)2-20-epi-D3; but it is very toxic as only one mouse survived a dose of > or = 0.0125 micrograms qod for 5 weeks. 1,25(OH)2-16ene-23yne-D3 is an extremely active inducer of differentiation but, on the other hand, it has low potential to produce hypercalcemia; mice maintained normal serum calcium levels even while receiving 2 micrograms qod for 5 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

In vitro antibacterial and anti-inflammatory effects of honokiol and magnolol against Propionibacterium sp.

Honokiol and magnolol, two major phenolic constituents of Magnolia sp., have been known to exhibit antibacterial activities. However, until now, their antibacterial activity against Propionibacterium sp. has not been reported. To this end, the antibacterial activities of honokiol and magnolol were detected using the disk diffusion method and a two-fold serial dilution assay. Honokiol and magnolol showed strong antibacterial activities against both Propionibacterium acnes and Propionibacterium granulosum, which are acne-causing bacteria. The minimum inhibitory concentrations (MIC) of honokiol and magnolol was 3-4 microg/ml (11.3-15 microM) and 9 microg/ml (33.8 microM), respectively. In addition, the killing curve analysis showed that magnolol and honokiol killed P. acnes rapidly, with 10(5) organisms/ml eliminated within 10 min of treatment with either 45 microg (169.2 microM) of magnolol or 20 microg (75.2 microM) of honokiol per ml. The cytotoxic effect of honokiol and magnolol was determined by a colorimetric (3-(4,5-dimetyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) (MTT) assay using two animal cell lines, human normal fibroblasts and HaCaT. In this experiment, magnolol exhibited lower cytotoxic effects than honokiol at the same concentration, but they showed similar cytotoxicity when triclosan was employed as an acne-mitigating agent. In addition, they reduced secretion of interleukin-8 and tumor necrosis factor alpha (TNF-alpha) induced by P. acnes in THP-1 cells indicating the anti-inflammatory effects of them. When applied topically, neither phenolic compound induced any adverse reactions in a human skin primary irritation test. Therefore, based on these results, we suggest the possibility that magnolol and honokiol may be considered as attractive acne-mitigating candidates for topical application.

Adult↗