Article

S‑1‑Propenylcysteine, a sulfur compound in aged garlic extract, alleviates cold‑induced reduction in peripheral blood flow in rat via activation of the AMPK/eNOS/NO pathway

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Abstract

Aged garlic extract (AGE) has been shown to improve peripheral circulatory disturbances in both clinical trials and experimental animal models. To investigate the effect of S-1-propenylcysteine (S1PC), a characteristic sulfur compound in AGE, on cold-induced reduction in tail blood flow of rat, Wistar rats were individually placed in a restraint cage and given the treatment with cold water (15˚C) after the oral administration of AGE or its constituents S1PC, S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC). After the cold-treatment the tail blood flow of rats was measured at the indicated times. The pretreatment with AGE (2 g/kg BW) and S1PC (6.5 mg/kg BW) significantly alleviated the reduction of rat tail blood flow induced by cold treatment. The effect of S1PC was dose-dependent and maximal at the dose of 6.5 mg/kg BW, whereas SAC and SAMC were ineffective. To gain insight into the mechanism of S1PC action, the concentration of nitrogen oxide metabolites (NOx) in the plasma and the levels of phosphorylated endothelial nitric oxide synthase (eNOS) and 5'-AMP-activated protein kinase (AMPK) in the aorta were measured. The pretreatment with S1PC significantly increased the plasma concentration of NOx as well as the level of phosphorylated form of AMPK and eNOS in the aorta after cold-treatment. The present findings suggest that S1PC is a major constituent responsible for the effect of AGE to alleviate the cold-induced reduction of peripheral blood flow in rat by acting on the AMPK/eNOS/NO pathway in the aorta.

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... AGE contains several water-soluble sulfur compounds such as S-1-propenylcysteine (S1PC) 42,43 . Recently, S1PC has been shown to inhibit IL-6 production through autophagy activation, improve peripheral blood circulation by increasing the NOx production, and maintain endothelial barrier function [44][45][46] . We have previously reported that AGE inhibits lipid deposition in apolipoprotein E knockout (ApoE-KO) mice, an atherosclerosis model 47,48 . ...
... While AGE contains various bioactive constituents, it is unclear which constituents are involved in the increase of M2 macrophages. Since S1PC, one of active constituents in AGE, has been reported to demonstrate various pharmacological effects, such as improving barrier function 46 , peripheral blood flow 45 and immunoregulatory function 44 , we hypothesized that it was of interest to examine whether S1PC increased M2-like macrophages induced by mIL-10. In the present study, we found that AGE and its constituent S1PC altered the balance between pro-inflammatory and anti-inflammatory macrophage populations by promoting M2-like macrophage polarization in the aorta of ApoE-KO and SAMP8 mice. ...
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Atherosclerosis is a chronic inflammatory disease that may lead to the development of serious cardiovascular diseases. Aged garlic extract (AGE) has been reported to ameliorate atherosclerosis, although its mode of action remains unclear. We found that AGE increased the mRNA or protein levels of arginase1 (Arg1), interleukin-10 (IL-10), CD206 and hypoxia-inducible factor 2α (HIF2α) and decreased that of CD68, HIF1α and inducible nitric oxide synthase in the aorta and spleen of apolipoprotein E knockout mice. We also found that S-1-propenylcysteine (S1PC), a characteristic sulfur compound in AGE, increased the level of IL-10-induced Arg1 mRNA and the extent of M2c-like macrophage polarization in vitro. In addition, S1PC increased the population of M2c-like macrophages, resulting in suppressed the population of M1-like macrophages and decreased lipopolysaccharide-induced production of pro-inflammatory cytokines. These effects were accompanied by prolonged phosphorylation of the IL-10 receptor α (IL-10Rα) and signal transducer and activator of transcription 3 (STAT3) that inhibited the interaction between IL-10Rα and Src homology-2-containing inositol 5’-phosphatase 1 (SHIP1). In addition, administration of S1PC elevated the M2c/M1 macrophage ratio in senescence-accelerated mice. These findings suggest that S1PC may help improve atherosclerosis due to its anti-inflammatory effect to promote IL-10-induced M2c macrophage polarization.
... Black garlic also contains minerals in the form of potassium (6,049 mg / 100g), sulfur (1,138 mg / 100g), magnesium (276.47 mg/100g), sodium (246.34 mg/100g), calcium (103, 91 mg/100g) [11]. Black garlic contains organosulfur components such as Sallylcysteine (SAC), S-allylmercaptocysteine (SAMC), S-1-propenylcystein (S1PC), a water-soluble component [12] and Diallyl sul fi de (DAS), Diallyl disul fi de (DADS), Diallyl trisul fi de (DATS) a fat soluble component [13]. ...
... In addition, neither black garlic nor S-1-propenylcysteine (S1PC) affected the blood flow of cold-induced rats. Black garlic can modulate the body into normalcy [12]. ...
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Laser Doppler velocimetry estimates tissue perfusion providing a record of microvascular blood flow. Patients with heart disease or diabetes mellitus have impaired microvascular perfusion leading to impaired wound healing. Aged garlic extract (AGE) has a positive effect on vascular elasticity. This study aimed to assess the effect of long‐term treatment with AGE on cutaneous tissue perfusion. A total of 122 patients with Framingham Risk Score ≥ 10 were randomised in a double‐blinded manner to placebo or 2400 mg AGE daily for 1 year and monitored. Cutaneous microcirculation was measured at 0 and 12 months using laser Doppler velocimetry. A repeated measures analysis of variance (ANOVA) with a Greenhouse–Geisser correction determined that mean post‐occlusive reactive hyperaemia differed significantly between time points. The mean percent change between the two time points 0 and 12 months was 102, 64 (174, 15)% change for AGE and 78, 62 (107, 92)% change for the placebo group (F[1, 120] = 5. 95, P < 0.016), 12 months of AGE increases the microcirculation in patients with an increased risk for cardiovascular events estimated using the Framingham risk score. Increased microcirculation could hypothetically facilitate wound healing.
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The present study aimed to investigate the antispasmodic effect of higenamine on cold-induced cutaneous vasoconstriction and the underlying molecular mechanisms. A cold-induced cutaneous vasoconstriction rat model was established and different doses of higenamine were delivered by intravenous injection. The changes of cutaneous regional blood flow (RBF) between groups were analyzed. In vitro, the proliferation of human dermal microvascular endothelial cells was measured by MTT. The NO concentration was detected by a nitrate reductase assay. Flow cytometry was applied to measure reactive oxygen species (ROS) levels. The protein expression levels were detected by western blotting. The results demonstrated that in the model group, RBF declined compared with the normal control group, but was reversed by treatment with higenamine. The expression of endothelial nitric oxide synthase (eNOS), phosphorylated (p)-eNOS, protein kinase B (Akt1), p-Akt1, AMP-activated protein kinase (AMPK) α1 and p-AMPKα1 was upregulated by hypothermic treatment but was reversed by higenamine treatment. Treatment with higenamine significantly reduced the level of intracellular α2C-adrenoreceptor (AR) compared with the hypothermia group (P<0.05). Furthermore, the expression of twinfilin-1 (PTK9) was downregulated in the higenamine and positive control groups compared with the hypothermia group (P<0.05). Compared with the hypothermia group, the levels of ROS and α2C-AR (intracellular & membrane) were decreased in higenamine and the positive control group (P<0.05 and P<0.01, respectively). This study, to the best of our knowledge, is the first to assess the effects of higenamine on cold-induced vasoconstriction in vivo and its molecular mechanisms on the PI3K/Akt, AMPK/eNOS/nitric oxide, ROS/α2C-AR and PTK9 signaling pathways under hypothermia conditions. Higenamine may be a good therapeutic option for Raynaud's phenomenon (RP) and cold-induced vasoconstriction.
Article
Our previous study has shown that a single dose of S-1-propenylcysteine (S1PC) exerted an antihypertensive effect in spontaneously hypertensive rats (SHR), while its mode of action remained to be further investigated. The aim of this study was to explore the potential mechanism of the antihypertensive effect of S1PC in SHR using a liquid chromatography–mass spectrometry (LC–MS)-based metabolomic approach. Blood samples were serially collected from SHR after a single oral administration of S1PC (6.5 mg/kg body weight). The metabolomics data acquired from the LC–MS analysis of plasma samples were processed using principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). In addition, the SHR were treated with S1PC or histidine (10 mg/kg body weight) with and without intravenous preinjection of thioperamide, a histamine H 3 receptor antagonist. The blood pressure of SHR was measured by the tail-cuff method at different times after administration. In the PLS-DA score plots, the clusters of the S1PC groups were clearly or partly separated from those of the control groups at 1.5 and 3 h after administration, indicating the metabolic profiles were substantially altered by the S1PC treatment at these time points. Comparative analysis based on variable importance in the projection (VIP) values obtained from PLS-DA led to the identification of 14 and 15 metabolites differing between the two groups at 1.5 and 3 h, respectively, which included various amino acids. Among the metabolites identified, the plasma histidine level in the S1PC group significantly increased at 1.5 and 3 h, and decreased to that in the control group at 6 h. Moreover, pretreatment with thioperamide inhibited the blood pressure lowering effect of S1PC as well as that of histidine. These results suggested that S1PC alters histidine metabolism and consequently exerts the antihypertensive effect via the central histamine H 3 receptor.
Article
Objectives: To assess gingivitis and gingival bleeding following the consumption of Aged Garlic Extract versus placebo for a period of four months. Methods: A randomized, controlled, examiner-blind, two-treatment parallel group study was conducted. Participants were stratified and randomly assigned equally to a regimen group using Aged Garlic Extract (AGE) or a control group, based on gender, age, baseline number of bleeding sites, and gingival health status. Assessment was performed at baseline and at one, two, three, and four months. Clinical assessment was conducted by three experienced calibrated examiners. Results: One hundred and fifty-one participants followed the inclusion criteria; 50.3% males, with an average age of 32.7 ± 8.2 years. Only 134 subjects completed the four-month study (11.3% attrition rate). A statistically significant decrease of the Modified Gingival Index and Gingival Bleeding Index scores was shown for the AGE compared to the placebo group, both between and within groups (p < 0.001). Conclusions: This research demonstrated that daily consumption of AGE benefits oral health by reducing gingival inflammation and gingival bleeding, as compared to a placebo control.
Article
Objectives: This study was designed to investigate the antihypertensive effect of S-1-propenylcysteine, a characteristic sulfur compound in aged garlic extract, using a hypertensive rat model. Methods: The blood pressure and tail blood flow of both spontaneously hypertensive rats and control Wistar Kyoto rats were measured by the tail-cuff method and the noncontact laser Doppler method, respectively, at various times after single oral administration of a test compound for 24 h. Key findings: Treatment with S-1-propenylcysteine (6.5 mg/kg BW) significantly decreased the systolic blood pressure of spontaneously hypertensive rat approximately 10% at 3 h after administration, and thereafter, the systolic blood pressure gradually returned to the baseline level in 24 h. The effect of S-1-propenylcysteine was dose-dependent and was maximal at the dose of 6.5 mg/kg BW at 3 h. However, the other compounds such as S-allylcysteine and S-allylmercaptocysteine in aged garlic extract were ineffective. In addition, S-1-propenylcysteine had no effect on systolic blood pressure of control Wistar Kyoto rats. Furthermore, S-1-propenylcysteine significantly increased the blood flow at 3 h after administration at the dose of 6.5 mg/kg BW. Conclusions: S-1-propenylcysteine is a key constituent of aged garlic extract responsible for its antihypertensive effect, and the effect of S-1-propenylcysteine involves the improvement in peripheral circulation.
Article
We investigated the role of nitric oxide (NO)/cGMP in the coupling of neuronal activation to regional cerebral blood flow (rCBF) in α-chloralose-anesthetized rats. Whisker deflection (60 s) increased rCBF by 18 ± 3%. NO synthase (NOS) inhibition by Nω-nitro-l-arginine (l-NNA; topically) reduced the rCBF response to 9 ± 4% and resting rCBF to 80 ± 8%. NO donors [ S-nitroso- N-acetylpenicillamine (SNAP; 50 μM), 3-morpholinosydnonimine (10 μM)] or 8-bromoguanosine 3',5'-cyclic-monophosphate (8-BrcGMP; 100 μM)] restored resting rCBF andl-NNA-induced attenuation of the whisker response in the presence ofl-NNA, whereas the NO-independent vasodilator papaverine (1 mM) had no effect on the whisker response. Basal cGMP levels were decreased to 35% byl-NNA and restored to 65% of control by subsequent SNAP superfusion. Inhibition of neuronal NOS by 7-nitroindazole (7-NI; 40 mg/kg ip) or soluble guanylyl cyclase by 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 100 μM) significantly reduced resting rCBF to 86 ± 8 and 92 ± 10% and whisker rCBF response to 7 ± 4 and 12 ± 3%, respectively. ODQ reduced tissue cGMP to 54%. 8-BrcGMP restored the whisker response in the presence of 7-NI or ODQ. We conclude that NO, produced by neuronal NOS, is a modulator in the coupling of neuronal activation and rCBF in rat somatosensory cortex and that this effect is mainly mediated by cGMP.l-NNA-induced vasomotion was significantly reduced during increased neuronal activity and after restoration of basal NO levels, but not after restoration of cGMP.
Article
Scope: Chronic inflammation plays a major role in the formation and progression of atherosclerotic plaques. To clarify the mode of action of aged garlic extract (AGE) to retard atherosclerosis, we investigated whether AGE suppresses the inflammation in apolipoprotein E-knockout (ApoE-KO) mice. Methods and results: ApoE-KO mice were fed standard diet with or without 3% AGE for 12 weeks. AGE feeding inhibited the progression of atherosclerotic lesion by 27% and reduced the level of C-reactive protein (CRP) and thromboxane B2 (TXB2 ), a marker of platelet activation, in serum by 39% and 33%, respectively, compared to ApoE-KO mice without AGE treatment. AGE treatment also decreased the level of tumor necrosis factor-α (TNF-α), a major stimulus inducing CRP production, in the liver by 35%. AGE decreased the level of interleukin-1 receptor-associated kinase 4 (IRAK4) by 60% and almost doubled the level of phospho-AMP-activated protein kinase (p-AMPK) in the liver. Conclusion: The anti-atherosclerotic effect of AGE involves the suppression of inflammation by reducing the serum level of CRP and TXB2 , and the protein level of TNF-α and IRAK4, and increasing AMPK activity in liver. This article is protected by copyright. All rights reserved.
Article
Aged garlic extract (AGE) has been shown to improve hypertension in both clinical trials and experimental animal models. However, the active ingredient of AGE remains unknown. In the present study, we investigated the antihypertensive effects of AGE and its major constituents including S-1-propenylcysteine (S1PC) and S-allylcysteine (SAC) using spontaneously hypertensive rats (SHR) and found that S1PC is an active substance to lower blood pressure in SHR. In addition, the metabolomics approach was used to investigate the potential mechanism of the antihypertensive action of S1PC in SHR. Treatment with AGE (2 g/kg body weight) or S1PC (6.5 mg/kg body weight; equivalent to AGE 2 g/kg body weight) significantly decreased the systolic blood pressure (SBP) of SHR after the repeated administration for 10 weeks, whereas treatment with SAC (7.9 mg/kg body weight; equivalent to AGE 2 g/kg body weight) did not decrease the SBP. After the treatment for 10 weeks, the plasma samples obtained from Wistar Kyoto (WKY) rats and SHR were analyzed by means of ultra high performance liquid chromatography coupled with high-resolution quadrupole-Orbitrap mass spectrometry. Multivariate statistical analysis of LC–MS data showed a clear difference in the metabolite profiles between WKY rats and SHR. The results indicated that 30 endogenous metabolites significantly contributed to the difference and 7 of 30 metabolites were changed by the S1PC treatment. Furthermore, regression analysis showed correlation between SBP and the plasma levels of betaine, tryptophan and 3 LysoPCs. This metabolomics approach suggested that S1PC could exert its antihypertensive effect by affecting glycine, serine and threonine metabolism, tryptophan metabolism and glycerophospholipid metabolism.
Article
Background: Clinical trials have shown that aged garlic extract (AGE) is effective in reducing blood pressure of hypertensive patients. However, the mechanisms involved remain to be elucidated. Purpose: The aim of the present study was to investigate the vasorelaxant effect of AGE on the aorta and its mechanism of action in order to clarify the blood pressure-lowering action of AGE. Methods: The vasorelaxant effect was evaluated in isolated rat aortic rings. After aortic rings were contracted by 3 × 10(-6)M norepinephrine (NE) for 30min, AGE and other test drugs were added to the aortic rings. All results were expressed as percentages of the maximal NE-induced contraction. Results: AGE induced the concentration-dependent vasorelaxation of isolated rat aortic rings that had been precontracted with norepinephrine. The effect of AGE was severely impaired in aortic rings lacking endothelium. In addition, the effect of AGE was inhibited by a nitric oxide synthase (NOS) inhibitor and a nitric oxide (NO) scavenger. Moreover, AGE treatment of aorta significantly increased the NO production. When various constituents of AGE were tested, the vasorelaxation of aorta was observed only in the presence of L-arginine, a substrate of NOS. Conclusion: AGE causes endothelium-dependent vasorelaxation of aorta via stimulation of NO production and that L-arginine in AGE serves as a key agent for NOS-mediated NO production.
Article
Objectives: S-Allylcysteine (SAC) and S-1-propenylcysteine (S1PC) are the characteristic sulfur-containing amino acids in aged garlic extract. In this study, we investigated the effect of SAC and S1PC on intestinal immunoglobulin (Ig)A production to gain insight into the immunomodulatory effect of aged garlic extract. Methods: In vitro study: Mouse splenic lymphocytes were treated with S1PC (0.1 and 0.3 mM) or SAC (0.1 and 0.3 mM) for 3 d, and IgA concentration in the culture medium was examined. In vivo study: Mice were orally administrated S1PC (7.5, 15, and 30 mg/kg) for 5 d and the IgA level in the intestinal lavage fluids as well as the population of IgA-producing cells in Peyer's patches were measured using mouse IgA enzyme-linked immunosorbent assay quantification set and flow cytometer, respectively. Results: S1PC enhanced IgA production in mouse splenic lymphocytes in culture. However, SAC was ineffective. In addition, oral administration of S1PC to mice increased the IgA level and number of IgA-producing cells in Peyer's Patches. Furthermore, S1PC induced the expression of X-box binding protein 1 (Xbp1) mRNA, an inducer of plasma cell differentiation, in Peyer's patches. This induction was accompanied by the degradation of paired box protein 5 and the activation of mitogen activated protein/extracellular signal-regulated kinase signaling pathway. Conclusion: These results suggest that S1PC increases IgA-producing cells via the enhancement of Erk1/2-mediated Xbp1 expression in the intestine.
Article
Background: Garlic and its processed preparations contain numerous sulfur compounds that are difficult to analyze in a single run using HPLC. Objective: The aim of this study was to develop a rapid and convenient sulfur-specific HPLC method to analyze sulfur compounds in aged garlic extract (AGE). Methods: We modified a conventional postcolumn HPLC method by employing a hexaiodoplatinate reagent. Identification and structural analysis of sulfur compounds were conducted by LC-mass spectrometry (LC-MS) and nuclear magnetic resonance. The production mechanisms of cis-S-1-propenylcysteine (cis-S1PC) and S-allylmercaptocysteine (SAMC) were examined by model reactions. Results: Our method has the following advantages: less interference from nonsulfur compounds, high sensitivity, good correlation coefficients (r > 0.98), and high resolution that can separate >20 sulfur compounds, including several isomers, in garlic preparations in a single run. This method was adapted for LC-MS analysis. We identified cis-S1PC and γ-glutamyl-S-allyl-mercaptocysteine in AGE. The results of model reactions suggest that cis-S1PC is produced from trans-S1PC through an isomerization reaction and that SAMC is produced by a reaction involving S-allylcysteine/S1PC and diallyldisulfide during the aging period. Conclusion: We developed a rapid postcolumn HPLC method for both qualitative and quantitative analyses of sulfur compounds, and this method helped elucidate a potential mechanism of cis-S1PC and SAMC action in AGE.
Article
Background: Although several previous studies have demonstrated that aged garlic extract (AGE) inhibits the progression of coronary artery calcification, its effect on noncalcified plaque (NCP) has been unclear. Objective: This study investigated whether AGE reduces coronary plaque volume measured by cardiac computed tomography angiography (CCTA) in patients with metabolic syndrome (MetS). Methods: Fifty-five patients with MetS (mean ± SD age: 58.7 ± 6.7 y; 71% men) were prospectively assigned to consume 2400 mg AGE/d (27 patients) or placebo (28 patients) orally. Both groups underwent CCTA at baseline and follow-up 354 ± 41 d apart. Coronary plaque volume, including total plaque volume (TPV), dense calcium (DC), NCP, and low-attenuation plaque (LAP), were measured based upon predefined intensity cutoff values. Multivariable linear regression analysis, adjusted for age, gender, number of risk factors, hyperlipidemia medications, history of coronary artery disease, scan interval time, and baseline %TPV, was performed to examine whether AGE affected each plaque change. Results: The %LAP change was significantly reduced in the AGE group compared with the placebo group (-1.5% ± 2.3% compared with 0.2% ± 2.0%, P = 0.0049). In contrast, no difference was observed in %TPV change (0.3% ± 3.3% compared with 1.6% ± 3.0%, P = 0.13), %NCP change (0.2% ± 3.3% compared with 1.4% ± 2.9%, P = 0.14), and %DC change (0.2% ± 1.4%, compared with 0.2% ± 1.7%, P = 0.99). Multivariable linear regression analysis found a beneficial effect of AGE on %LAP regression (β: -1.61; 95% CI: -2.79, -0.43; P = 0.008). Conclusions: This study indicates that the %LAP change was significantly greater in the AGE group than in the placebo group. Further studies are needed to evaluate whether AGE has the ability to stabilize vulnerable plaque and decrease adverse cardiovascular events. This trial was registered at clinicaltrials.gov as NCT01534910.
Article
We newly produced an aged garlic extract preparation combined with ginseng, oriental bezoar, antler velvet, cuscuta seed and epimedium herb (LEOPINROYAL; LER), and examined whether it would improve peripheral blood circulation, as determined by the cooling-rewarming test in mice, or by a four-week trial in humans. In the mouse cooling-rewarming test, LER accelerated recovery from a fall in rectal temperature induced by cooling treatment (15°C for 10 min), and LER was especially superior in controlling the rate of increase in rectal temperature at 30 min after administration and beyond (p<0.01). In the four-week human trial, LER (1 ml) was taken twice a day after meals in the morning and evening. The condition of the peripheral blood circulation was estimated 0, 2 and 4 weeks after taking LER using two instruments: a BC-Checker for measuring the peripheral blood circulation index, and a ASTRIM SU for measurement or visualization of the width of small veins. In consequence, LER was found to improve the peripheral blood circulation index and the width of small veins. We tried to analyze in detail the extent of change among different groups (sex, blood circulation index at initial point, change of condition by interview, etc.), and it was noteworthy that women, a group who claimed they felt good upon interview after LER treatment, and a group showing lowering of the blood circulation index at initial point were highly responsive. In conclusion, the present results indicate that LER improves the condition of the peripheral blood circulation, suggesting that it acts as a preventive or care agent to resolve various kinds of problems, such as a stiff shoulders or lower back pain, caused by disorders of the peripheral blood circulation.
Article
The effect of several kinds of garlic preparations such as raw garlic juice (RGJ), heated garlic juice (HGJ), processed garlic powder (PGP) and aged garlic extract (AGE) on both physiological and psychological stress were investigated using four stress models in mice: forced swimming test, mechanical treadmill running, immobilization stress test, and a cooling rewarming test. RGJ was shown to be effective only at a low dose in the forced swimming test, whereas the effect was reduced at a high dosage. HGJ and PGP demonstrated no antistress effects. In contrast, AGE was shown to be effective in all of the stress tests. © 1997 by John Wiley & Sons, Ltd.
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Article
The hepato-protective effects of aged garlic extract (GE), S-allyl cysteine (SAC) and S-allylmercapto cysteine (SAMC) were evaluated, using mice with acute hepatitis, induced by hepatotoxins. These substances reduced the rise of serum enzyme levels and liver necrosis caused by paracetamol or carbon tetrachloride. It was found that the protective effect of SAMC upon the liver cells were far superior than that of SAC and the other chemicals tested.
Article
Reduced plasma adiponectin (APN) in diabetic patients is associated with endothelial dysfunction. However, APN knockout animals manifest modest systemic dysfunction unless metabolically challenged. The protein family CTRPs (C1q/TNF-related proteins) has recently been identified as APN paralogs and some CTRP members share APN's metabolic regulatory function. However, the vasoactive properties of CTRPs remain completely unknown. The vasoactivity of currently identified murine CTRP members was assessed in aortic vascular rings and underlying molecular mechanisms was elucidated in human umbilical vein endothelial cells. Of 8 CTRPs, CTRPs 3, 5, and 9 caused significant vasorelaxation. The vasoactive potency of CTRP9 exceeded that of APN (3-fold) and is endothelium-dependent and nitric oxide (NO)-mediated. Mechanistically, CTRP9 increased AMPK/Akt/eNOS phosphorylation and increased NO production. AMPK knockdown completely blocked CTRP9-induced Akt/eNOS phosphorylation and NO production. Akt knockdown had no significant effect on CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1, but not receptor 2, knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, preincubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasorelaxative effects. We have provided the first evidence that CTRP9 is a novel vasorelaxative adipocytokine that may exert vasculoprotective effects via the adiponectin receptor 1/AMPK/eNOS dependent/NO mediated signaling pathway.
Article
Endothelial nitric oxide synthase (eNOS) is the primary enzyme that produces nitric oxide (NO), which plays an important role in blood vessel relaxation. eNOS activation is stimulated by various mechanical forces, such as shear stress. Several studies have shown that local cooling of the human finger causes strong vasoconstriction, followed after several minutes by cold-induced vasodilation (CIVD). However, the role played by endothelial cells (ECs) in blood vessel regulation in respond to cold temperatures is not fully understood. In this study, we found that low temperature alone does not significantly increase or decrease eNOS activation in ECs. We further found that the combination of shear stress with temperature change leads to a significant increase in eNOS activation at 37°C and 28°C, and a decrease at 4°C. These results show that ECs play an important role in blood vessel regulation under shear stress and low temperature.
Article
To assess the effect, tolerability and acceptability of aged garlic extract as an adjunct treatment to existing antihypertensive medication in patients with treated, but uncontrolled, hypertension. A double-blind parallel randomised placebo-controlled trial involving 50 patients whose routine clinical records in general practice documented treated but uncontrolled hypertension. The active treatment group received four capsules of aged garlic extract (960 mg containing 2.4 mg S-allylcysteine) daily for 12 weeks, and the control group received matching placebos. The primary outcome measures were systolic and diastolic blood pressure at baseline, 4, 8 and 12 weeks, and change over time. We also assessed tolerability during the trial and acceptability at 12 weeks. In patients with uncontrolled hypertension (SBP ≥ 140 mmHg at baseline), systolic blood pressure was on average 10.2 ± 4.3 mmHg (p=0.03) lower in the garlic group compared with controls over the 12-week treatment period. Changes in blood pressure between the groups were not significant in patients with SBP<140 mmHg at baseline. Aged garlic extract was generally well tolerated and acceptability of trial treatment was high (92%). Our trial suggests that aged garlic extract is superior to placebo in lowering systolic blood pressure similarly to current first line medications in patients with treated but uncontrolled hypertension.
Article
Previous studies demonstrated that aged garlic extract reduces multiple cardiovascular risk factors. This study was designed to assess whether aged garlic extract therapy with supplements (AGE+S) favorably affects inflammatory and oxidation biomarkers, vascular function and progression of atherosclerosis as compared to placebo. In this placebo-controlled, double-blind, randomized trial (conducted 2005-2007), 65 intermediate risk patients (age 60+/-9 years, 79% male) were treated with a placebo capsule or a capsule containing aged garlic extract (250 mg) plus Vitamin B12 (100 microg), folic acid (300 microg), Vitamin B6 (12.5 mg) and l-arginine (100 mg) given daily for a 1 year. All patients underwent coronary artery calcium scanning (CAC), temperature rebound (TR) as an index of vascular reactivity using Digital Thermal Monitoring (DTM), and measurement of lipid profile, autoantibodies to malondialdehyde (MDA)-LDL, apoB-immune complexes, oxidized phospholipids (OxPL) on apolipoprotein B-100 (OxPL/apoB), lipoprotein (a) [Lp (a)], C-reactive protein (CRP), homocysteine were measured at baseline and 12 months. CAC progression was defined as an increase in CAC>15% per year and an increase in TR above baseline was considered a favorable response. At 1 year, CAC progression was significantly lower and TR significantly higher in the AGE+S compared to the placebo group after adjustment of cardiovascular risk factors (p<0.05). Total cholesterol, LDL-C, homocysteine, IgG and IgM autoantibodies to MDA-LDL and apoB-immune complexes were decreased, whereas HDL, OxPL/apoB, and Lp (a) were significantly increased in AGE+S to placebo. AGE+S is associated with a favorable improvement in oxidative biomarkers, vascular function, and reduced progression of atherosclerosis.
Article
Major confusion exists with regard to the definition of patients with Raynaud's phenomenon; defining the patient and the phenomenon are reasonably straightforward, but variations in the definition of its primary and secondary forms have created a situation in which the same patient might be classified as primary by one group and secondary by another. The present essay is a proposal for the strict definition of Primary Raynaud's Phenomenon (PRP) formulated as a hypothesis amenable to experimental testing. This hypothesis is tested retrospectively on a group of 240 patients with Raynaud's phenomenon. The proposed criteria permit classification in 215 of 240 cases or 89%, leaving 25 patients difficult to classify at initial evaluation. Further testing of the hypothesis is encouraged.
Article
— Some of the factors contributing to severe intravascular stasis in the blood vessels supplying the epidermis are discussed. Changes in blood viscosity result from a variety of factors which act maximally at the peak and in the venous arm of the papillary vessel. The influence of cold on blood viscosity in the papillary vessel is particularly emphasized. The importance of aggregation of blood cells in the superficial vessels and of factors such as platelet aggregation, which may be irreversible and may influence disaggregation are discussed. The presence of “preferential channels” in the capillary meshwork of the skin is illustrated and their significance as passages permitting redistribution of blood away from the epidermis is emphasized. Studies of platelet stickiness in a group of patients suffering from sensitivity to cold and studies on blood flow in one patient with acrocyanosis are presented.
Article
The effects of aged garlic extract (AGE), chronically administered in the diet, on longevity and spatial learning performances were studied using the senescence-accelerated mouse (SAM). A solid diet containing 2% AGE was given to senescence-accelerated-prone mouse 8 (SAMP8) and senescence-accelerated-resistant mouse 1 (SAMR1) from 2 months of age. The survival ratio of SAMP8, a substrain of senescence-accelerated-prone mouse, was significantly lower than that of SAMR1, a substrain of senescence-resistant mouse. In the SAMP8, administration of AGE perfectly prevented the decrease in survival ratio. Moreover, AGE markedly improved the learning deficits of SAMP8 in the Morris water maze test. These results suggest the possibility that AGE prevents physiological aging and age-related memory disorders in human.
Article
We investigated the role of nitric oxide (NO)/cGMP in the coupling of neuronal activation to regional cerebral blood flow (rCBF) in alpha-chloralose-anesthetized rats. Whisker deflection (60 s) increased rCBF by 18 +/- 3%. NO synthase (NOS) inhibition by N(omega)-nitro-L-arginine (L-NNA; topically) reduced the rCBF response to 9 +/- 4% and resting rCBF to 80 +/- 8%. NO donors [S-nitroso-N-acetylpenicillamine (SNAP; 50 microM), 3-morpholinosydnonimine (10 microM)] or 8-bromoguanosine 3', 5'-cyclic-monophosphate (8-BrcGMP; 100 microM)] restored resting rCBF and L-NNA-induced attenuation of the whisker response in the presence of L-NNA, whereas the NO-independent vasodilator papaverine (1 mM) had no effect on the whisker response. Basal cGMP levels were decreased to 35% by L-NNA and restored to 65% of control by subsequent SNAP superfusion. Inhibition of neuronal NOS by 7-nitroindazole (7-NI; 40 mg/kg ip) or soluble guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 100 microM) significantly reduced resting rCBF to 86 +/- 8 and 92 +/- 10% and whisker rCBF response to 7 +/- 4 and 12 +/- 3%, respectively. ODQ reduced tissue cGMP to 54%. 8-BrcGMP restored the whisker response in the presence of 7-NI or ODQ. We conclude that NO, produced by neuronal NOS, is a modulator in the coupling of neuronal activation and rCBF in rat somatosensory cortex and that this effect is mainly mediated by cGMP. L-NNA-induced vasomotion was significantly reduced during increased neuronal activity and after restoration of basal NO levels, but not after restoration of cGMP.
Article
The effect of aged garlic extract (AGE) on stress induced hyperglycemia was investigated using the immobilization stress model in mice. After the exposure to immobilization stress for 16 hr per day for 2 consecutive days, the adrenal glands of the mice hypertrophied, and their serum glucose level and corticosterone secretion became elevated, but insulin secretion did not change. These results suggest that the elevation of serum glucose was probably due to the stimulation of the pituitary-adrenocortical axis by the stress. Pretreatment of AGE (5 and 10 ml/kg, p.o.) significantly prevented adrenal hypertrophy, hyperglycemia and elevation of corticosterone, but did not alter serum insulin level. The efficacy of AGE was the same as that of diazepam (5 mg/kg, p.o.). From these results, it is suggested that AGE may prevent stress-induced hyperglycemia, which is the risk of suffering from diabetes mellitus and its progression.
Article
Using various kinds of models, we examined the effects of aged garlic extract (AGE) on immune functions. In the immunoglobulin (Ig)E-mediated allergic mouse model, AGE significantly decreased the antigen-specific ear swelling induced by picryl chloride ointment to the ear and intravenous administration of antitrinitrophenyl antibody. In the transplanted carcinoma cell model, AGE significantly inhibited the growth of Sarcoma-180 (allogenic) and LL/2 lung carcinoma (syngenic) cells transplanted into mice. Concomitantly, increases in natural killer (NK) and killer activities of spleen cells were observed in Sarcoma-180--bearing mice administered AGE. In the psychological stress model, AGE significantly prevented the decrease in spleen weight and restored the reduction of anti-SRBC hemolytic plaque-forming cells caused by the electrical stress. These studies strongly suggest that AGE could be a promising candidate as an immune modifier, which maintains the homeostasis of immune functions; further studies are warranted to determine when it is most beneficial.
Article
Oxidative modification of DNA, proteins and lipids by reactive oxygen species (ROS) plays a role in aging and disease, including cardiovascular, neurodegenerative and inflammatory diseases and cancer. Extracts of fresh garlic that are aged over a prolonged period to produce aged garlic extract (AGE) contain antioxidant phytochemicals that prevent oxidant damage. These include unique water-soluble organosulfur compounds, lipid-soluble organosulfur components and flavonoids, notably allixin and selenium. Long-term extraction of garlic (up to 20 mo) ages the extract, creating antioxidant properties by modifying unstable molecules with antioxidant activity, such as allicin, and increasing stable and highly bioavailable water-soluble organosulfur compounds, such as S-allylcysteine and S-allylmercaptocysteine. AGE exerts antioxidant action by scavenging ROS, enhancing the cellular antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and increasing glutathione in the cells. AGE inhibits lipid peroxidation, reducing ischemic/reperfusion damage and inhibiting oxidative modification of LDL, thus protecting endothelial cells from the injury by the oxidized molecules, which contributes to atherosclerosis. AGE inhibits the activation of the oxidant-induced transcription factor, nuclear factor (NF)-kappa B, which has clinical significance in human immunodeficiency virus gene expression and atherogenesis. AGE protects DNA against free radical--mediated damage and mutations, inhibits multistep carcinogenesis and defends against ionizing radiation and UV-induced damage, including protection against some forms of UV-induced immunosuppression. AGE may have a role in protecting against loss of brain function in aging and possess other antiaging effects, as suggested by its ability to increase cognitive functions, memory and longevity in a senescence-accelerated mouse model. AGE has been shown to protect against the cardiotoxic effects of doxorubicin, an antineoplastic agent used in cancer therapy and against liver toxicity caused by carbon tetrachloride (an industrial chemical) and acetaminophen, an analgesic. Substantial experimental evidence shows the ability of AGE to protect against oxidant-induced disease, acute damage from aging, radiation and chemical exposure, and long-term toxic damage. Although additional observations are warranted in humans, compelling evidence supports the beneficial health effects attributed to AGE, i.e., reducing the risk of cardiovascular disease, stroke, cancer and aging, including the oxidant-mediated brain cell damage that is implicated in Alzheimer's disease.
Article
We determined the effect of Aged Garlic Extract (AGE) on damage caused to immune function by a psychological stress using a communication box. After four days of a psychological stress, a decrease in spleen weight and spleen cells was observed in the psychological stress-exposed mice as compared normal mice (non-stress). AGE significantly prevented the decreases in spleen weight and cells. Additionally, AGE significantly prevented the reduction of hemolytic plaque-forming-cells in spleen cells and anti-SRBC antibody titer in serum caused by this psychological stress. Moreover, a reduction in NK activities was observed in the psychological stress-exposed mice as compared with normal mice (non-stress), whereas NK activities in the AGE administered mice were almost the same as normal mice (non-stress). These results indicate that psychological stress qualitatively and quantitatively impairs immune function, and that AGE is extremely useful for preventing psychologically-induced damage.