Thiolane-type sulfides from garlic, onion, and Welsh onion.

In this paper, we review our work in the last 10 years wherein we examined the sulfides in the acetone extracts of garlic (Allium sativum), onion (A. cepa), and Welsh onion (A. fistulosum), obtained and characterized the structures of new sulfides, three 3,4-dimethylthiolane-type sulfides from onion and Welsh onion, respectively, and four acyclic-type, nine 3,4-dimethyl- thiolane-type, four 2-methylthiolane (and thiane)-type, two 1,2-dithiolane-type, and two 2-oxothiolane-type sulfides, together with (E)-ajoene and one kujounin-type sulfide from garlic. During this process, structural corrections were made in onionin A group, garlicnin A, and garlicnin B group in some 3,4-dimethylthiolane-type sulfides. Next, hypothetical pathways for the production of the aforementioned sulfides were proposed. Furthermore, it was revealed that a typical 3,4-dimethylthiolane-type sulfide, onionin A1 obtained from onion, having the isomeric structure of garlicnin B1 obtained from garlic, decreased tumor proliferation and controlled tumor metastasis. These results showed that onionin A1 is an effective agent for controlling tumors, and that the antitumor effects observed in vivo are likely caused by reversing the antitumor immune system. Activation of the antitumor immune system by onionin A1 might be an effective adjuvant therapy for patients with osteosarcoma, ovarian cancer and other malignant tumors.

Alginates as food ingredients absorb extra salt in sodium chloride-treated mice.

Many patients with impaired renal function undergoing dialysis are subject to severe dietary restrictions. Especially overdose of salt is related to crisis of their life, so their meals are basically salt-free or low salt. Therefore, their quality of life is declined due to their yearning for salty taste. In the present study, we searched new salt-adsorbing food materials in dietary fibers to develop food ingredients preventing salt-sensitive hypertension and kidney dysfunction. As a result, calcium alginate and ammonium alginate possessed sodium-binding capacity without releasing potassium which causes a problem in chronic kidney injury. Furthermore, the administration of those fibers inhibited blood NaCl concentration and induced NaCl excretion in mice model. Therefore, calcium alginate and ammonium alginate are new candidate materials as salt-adsorbing materials, thus indicating that the health foods and/or health supplements containing those fibers may be a potentially new tool for prevention of salt-sensitive hypertension and kidney dysfunction.

New cyclic sulfides extracted from Allium sativum: garlicnins P, J2, and Q.

Two atypical cyclic-type sulfides, garlicnin P (1) and garlicnin J2 (2), and one thiabicyclic-type sulfide, garlicnin Q (3), were isolated from the acetone extracts of garlic, Allium sativum, bulbs cultivated in the Kumamoto city area, and their structures characterized. Their production pathways are also discussed.

New cyclic sulfides, garlicnins I2, M, N, and O, from Allium sativum.

One atypical thiolane-type sulfide, garlicnin I2 (1), two 3,4-dimethylthiolane-type sulfides, garlicnins M (2) and N (3), and one thiabicyclic-type sulfide, garlicnin O (4), were isolated from the acetone extracts of Chinese garlic bulbs, Allium sativum and their structures were characterized. Hypothetical pathways for the production of the respective sulfides were discussed.

Antitumor Allium Sulfides.

We examined the sulfides in onion (Allium cepa L.), Welsh onion (A. fistulosum L.), and garlic (A. sativum L.), and obtained three new thiolane-type sulfides (onionins A1-A3) from onion; two new thiabicyclic-type sulfides (welsonins A1, A2), together with onionins A1-A3, from Welsh onion; and six new acyclic-type sulfides (garlicnins L-1-L-4, E, and F), ten new thiolane-type sulfides (garlicnins A, B1-B4, C1-C3, K1, and K2), and three new atypical cyclic-type sulfides (garlicnins G, I, and J) from garlic. Acetone extracts showed the potential of these sulfides in inhibiting the polarization of M2 activated macrophages that are capable of suppressing tumor-cell proliferation. The effect of the thiolane-type sulfide of a major component, onionin A1, on tumor progression and metastasis in both osteosarcoma and ovarian cancer-bearing mouse models was then examined. Tumor proliferation was depressed, and tumor metastasis was controlled by regulating macrophage activation. These results showed that onionin A1 is an effective agent for controlling tumors in both in vitro and in vivo models, and that the antitumor effects observed in vivo are likely caused by reversing the antitumor immune system. Activation of the antitumor immune system by onionin A1 might be an effective adjuvant therapy for patients with osteosarcoma, ovarian cancer and other malignant tumors. Based on these findings, pharmacological investigations will be conducted in the future to develop natural and healthy foods and anti-cancer agents that can prevent or combat disease.

Atypical Cyclic Sulfides, Garlicnins G, I, and J, Extracted from Allium sativum.

Newly characterized, atypical sulfides, garlicnins G (1), I (2), and J (3), were isolated from the acetone extracts of garlic bulbs, Allium sativum. Their production pathways are regarded as different from those of cyclic sulfoxides, 3,4-dimethyltetrahydrothiophene-S-oxide derivatives such as onionins A1-A3, garlicnins B1-B4 and C1-C3.

Onionin A, a sulfur-containing compound isolated from onions, impairs tumor development and lung metastasis by inhibiting the protumoral and immunosuppressive functions of myeloid cells.

SCOPE: Recent studies have demonstrated that myeloid lineage cells, such as macrophages and myeloid suppressor cells (MDSCs), are major components exhibiting protumoral functions in the setting of tumor progression. Tumor-associated macrophages polarized to the protumoral M2 phenotype promote tumor proliferation and are considered to be a therapeutic target in patients with malignant tumors. METHODS AND RESULTS: We identified a new candidate compound, called onionin A (ONA) isolated from onions, that inhibits macrophage polarization into the M2 phenotype, as well as the immunosuppressive activity of MDSCs and tumor proliferation, by suppressing signal transducer and activator of transcription-3 (Stat3) activation. Furthermore, ONA administration was found to significantly suppress subcutaneous tumor development and lung metastasis in tumor-bearing mice. ONA administration also inhibited Stat3 activation and increased the number of infiltrating lymphocytes in tumor tissues, and an ex vivo analysis showed that the immunosuppressive effect of MDSCs in tumor-bearing mice is impaired by ONA. Moreover, ONA regulated tumor proliferation by inhibiting cell-cell interactions between macrophages and tumor cells, and ONA administration enhanced the antitumor effects of cisplatin in the tumor-bearing mice. CONCLUSIONS: These findings demonstrate that ONA may be a potential new tool for antitumor therapy and also for tumor prevention.

Two new prenylflavonoids from Epimedii Herba and their inhibitory effects on advanced glycation end-products.

Because inhibitors of advanced glycation end-products (AGEs), for example pyridoxamine, significantly inhibit the development of retinopathy and neuropathy in rats with streptozotocin-induced diabetes, treatment with AGE inhibitors is believed to be a potential strategy for the prevention of lifestyle-related diseases such as diabetic complications. In the present study, the MeOH extract of Epimedii Herba (EH; aerial parts of Epimedium spp.) was found to inhibit the formation of N (ε) -(carboxymethyl)lysine (CML) and N (ω) -(carboxymethyl)arginine (CMA) during incubation of collagen-derived gelatin with ribose. Furthermore, compounds with inhibitory effects against CML and CMA formation were isolated from EH. Two new prenylflavonoids (compounds 1 and 2) and two known compounds (3 and 4) were found to significantly inhibit the formation of both CML and CMA; compound 4 (epimedokoreanin B) had the strongest inhibitory effect of the isolated compounds. These data suggest that epimedokoreanin B could prevent clinical complications of diabetes by inhibiting AGEs.

Two new bicyclic sulfoxides from Welsh onion.

Newly identified bicyclic sulfoxides, welsonins A1 (1) and A2 (2), were isolated from acetone extracts of the bulbs of the Welsh onion (Allium fistulosum). In this study, the structures of 1 and 2, which are tetrahydrothiophene-S-oxide derivatives, were characterized by spectroscopic analysis. These compounds appeared to be derived from the coupling of 1-propenyl sulfenic acid and uronic acid. Welsonin A1 (1) showed the potential to suppress tumor-cell proliferation by inhibiting the polarization of alternatively activated M2 macrophages.

Pleiotropic Effects of Levofloxacin, Fluoroquinolone Antibiotics, against Influenza Virus-Induced Lung Injury.

Reactive oxygen species (ROS) and nitric oxide (NO) are major pathogenic molecules produced during viral lung infections, including influenza. While fluoroquinolones are widely used as antimicrobial agents for treating a variety of bacterial infections, including secondary infections associated with the influenza virus, it has been reported that they also function as anti-oxidants against ROS and as a NO regulator. Therefore, we hypothesized that levofloxacin (LVFX), one of the most frequently used fluoroquinolone derivatives, may attenuate pulmonary injuries associated with influenza virus infections by inhibiting the production of ROS species such as hydroxyl radicals and neutrophil-derived NO that is produced during an influenza viral infection. The therapeutic impact of LVFX was examined in a PR8 (H1N1) influenza virus-induced lung injury mouse model. ESR spin-trapping experiments indicated that LVFX showed scavenging activity against neutrophil-derived hydroxyl radicals. LVFX markedly improved the survival rate of mice that were infected with the influenza virus in a dose-dependent manner. In addition, the LVFX treatment resulted in a dose-dependent decrease in the level of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative stress) and nitrotyrosine (a nitrative marker) in the lungs of virus-infected mice, and the nitrite/nitrate ratio (NO metabolites) and IFN-γ in BALF. These results indicate that LVFX may be of substantial benefit in the treatment of various acute inflammatory disorders such as influenza virus-induced pneumonia, by inhibiting inflammatory cell responses and suppressing the overproduction of NO in the lungs.

Cyclic sulfoxides-garlicnins K1, K2, and H1-extracted from Allium sativum.

Newly identified cyclic sulfoxides-garlicnins K1 (1), K2 (2), and H1 (3)-were isolated from the acetone extracts of the bulbs of garlic, Allium sativum. Garlicnin H1 (3) demonstrated potential to suppress tumor cell proliferation by regulating macrophage activation. The structures of garlicnins K1 and K2, 3,4-dimethyl-5-allyl-tetrahydrothiophen-2-one-S-oxides, and the structure of garlicnin H1, 3-carboxy-3-hydroxy-4-methyl-5-allylsulfoxide-tetrahydrothiophen-2-(ethane-1,2-diol)-S-oxide were characterized by spectroscopic analysis.

Isolation and characterization of new onionins A2 and A3 from Allium cepa, and of onionins A1, A2, and A3 from Allium fistulosum.

In this study, the new stable sulfur-containing compounds onionins A2 (1) and A3 (2) were isolated from the acetone extracts of the bulbs of Allium cepa L. and identified as the stereoisomers of onionin A1 discovered in our previous study. Their chemical structures, 3,4-dimethyl-5-(1E-propenyl)-tetrahydrothiophene-2-sulfenic acid-S-oxides, were characterized using various spectroscopic techniques. In addition, 1 and 2 together with onionin A1 were successfully isolated from the leaves of the Welsh onion, Allium fistulosum L. The onion-extracted fractions showed good potential to inhibit the polarization of M2 activated macrophages, indicating their possible ability to inhibit tumor cell proliferation.

Acyclic sulfides, garlicnins L-1-L-4, E, and F, from Allium sativum.

Six novel acyclic sulfides, named garlicnins L-1-L-4 (1-4), E (5), and F (6), were isolated from the acetone extracts, with the ability to suppress M2 macrophage activation, of the bulbs of garlic (Allium sativum L.), and their chemical structures were characterized.

Cyclic sulfoxides garlicnins B2, B3, B4, C2, and C3 from Allium sativum.

Several novel sulfides, called garlicnins B2 (1), B3 (2), B4 (3), C2 (4), and C3 (5), were isolated from acetone extracts of garlic, Allium sativum L. and characterized. These garlicnins are capable of suppressing M2 macrophage activation and they have a novel skeleton of cyclic sulfoxide. The structures of the former 3 and latter of 2 were deduced to be 2-(sulfenic acid)-5-(allyl)-3,4-dimethyltetrahydrothiophene-S-oxides and 2-(allyldithiine)-5-(propenylsulfoxide)-3,4-dimethyltetrahydrothiophene-S-oxides, respectively. The mechanism of the proposed production of these compounds is discussed. The identification of these novel sulfoxides from garlic accumulates a great deal of new chemistry in the Allium sulfide field, and future pharmacological investigations of these compounds will aid the development of natural, healthy foods and anti-cancer agents that may prevent or combat disease.

Garlicnins B(1), C(1), and D, from the fraction regulating macrophage activation of Allium sativum.

Several novel sulfides from acetone extracts of bulbs of garlic (Allium sativum L.), were identified and investigated. These were named garlicnins B(1) (1), C(1) (2), and D (3), and they were found to have the ability to control macrophage activation. Garlicnins B(1) (1) and C(1) (2) possess a new skeleton of cyclic sulfoxide and their structures of garlicnins B(1) (1) and C(1) (2) were characterized as 3,4-dimethyltetrahydrothiophene-S-oxide derivatives carrying the substitutions of a propenyl and a sulfenic acid, and an allyldithiine and a 1-propene-sulfenic acid (a), respectively. The mechanism of the proposed production of these compounds is discussed. Garlicnin D (3), dithiine-type, was estimated to be derived by addition of (a)+allyl thiosulfenic acid (b) derived from allicin. The identification of these novel sufoxides from onion and garlic accumulates a great deal of new chemistry to the Allium sulfide field, and future pharmacological investigations aid the development of natural, healthy foods and anti-cancer agents that could potentially prevent or combat disease.

Tomatidine, a tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in apoE-deficient mice by inhibiting acyl-CoA:cholesterol acyl-transferase (ACAT).

It was previously revealed that esculeoside A, a new glycoalkaloid, and esculeogenin A, a new aglycon of esculeoside A, contained in ripe tomato ameliorate atherosclerosis in apoE-deficent mice. This study examined whether tomatidine, the aglycone of tomatine, which is a major tomato glycoalkaloid, also shows similar inhibitory effects on cholesterol ester (CE) accumulation in human monocyte-derived macrophages (HMDM) and atherogenesis in apoE-deficient mice. Tomatidine significantly inhibited the CE accumulation induced by acetylated LDL in HMDM in a dose-dependent manner. Tomatidine also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that tomatidine suppresses both ACAT-1 and ACAT-2 activities. Furthermore, the oral administration of tomatidine to apoE-deficient mice significantly reduced levels of serum cholesterol, LDL-cholesterol, and areas of atherosclerotic lesions. The study provides the first evidence that tomatidine significantly suppresses the activity of ACAT and leads to reduction of atherogenesis.

Garlicnin A from the fraction regulating macrophage activation of Allium sativum.

Garlicnin A (1), a new stable, sulfur-containing compound isolated from a fraction of the acetone extracts of Allium sativum L. garlic bulbs, showed the potential to suppress tumor cell proliferation by inhibiting the polarization of M2 alternatively activated macrophages, and its structure was characterized as 3,4-dimethyl-5-(4,5-dithia-1E,7-octadiene)-tetrahydrothiophene-2-sulfoxide-S-oxide, on the basis of the results of spectroscopic analysis results.

Triterpenoids isolated from Zizyphus jujuba inhibit foam cell formation in macrophages.

Because foam cell formation in macrophages is believed to play an essential role in the progression of early atherosclerotic lesions in vivo, prevention of foam cell formation is considered to be one of the major targets for the treatment of atherosclerosis. The present study examined the inhibitory effect of 50 crude plant extracts on foam cell formation. Among those crude extracts, Zizyphi Fructus (ZF) and Zizyphi Semen (ZS) extracts significantly inhibited the foam cell formation induced by acetylated LDL. Furthermore, triterpenoids such as oleanonic acid, pomolic acid, and pomonic acid were the major active compounds, and triterpenoids containing a carboxylic acid at C-28 play an important role in the inhibitory effect on foam cell formation in human macrophages. These data suggest that triterpenoids in Zizyphus jujuba , the plant source of ZF and ZS, may therefore be useful for the prevention of atherosclerosis.

Corosolic acid inhibits glioblastoma cell proliferation by suppressing the activation of signal transducer and activator of transcription-3 and nuclear factor-kappa B in tumor cells and tumor-associated macrophages.

Tumor-associated macrophages (TAM) of M2 phenotype promote tumor proliferation and are associated with a poor prognosis in patients with glioblastoma. We screened the natural compounds possessing an inhibitory effect on M2 polarization in human monocyte-derived macrophages. Among 130 purified natural compounds examined, corosolic acid significantly inhibited the expression of CD163, one of the phenotype markers of M2 macrophages, and also suppressed the secretion of IL-10, one of the anti-inflammatory cytokines preferentially produced by M2 macrophages, thus suggesting that corosolic acid suppresses M2 polarization of macrophages. Furthermore, corosolic acid inhibited the proliferation of glioblastoma cells, U373 and T98G, and the activation of signal transducer and activator of transcription-3 (STAT3) and nuclear factor-kappa B (NF-κB) in both human macrophages and glioblastoma cells. These results indicate that corosolic acid suppresses the M2 polarization of macrophages and tumor cell proliferation by inhibiting both STAT3 and NF-κB activation. Therefore, corosolic acid might be a potential new tool for tumor prevention and therapy.

Content variations of the tomato saponin esculeoside A in various processed tomatoes.

A tomato saponin, esculeoside A, may be metabolized into various steroidal hormones such as pregnane derivatives that are expected to exhibit various bioactivities in the body, such as anti-osteoporosis, anti-menopausal disorder and anti-tumor actions. Therefore, we attempted to examine the esculeoside A contents of fresh tomatoes, tomatoes boiled in water, tomatoes heated using a microwave oven, freeze-dried tomatoes, and commercially available processed tomato products contained in plastic bottles and cans, in order to develop a health food.