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This commentary provides a novel synthesis of how biological systems adapt to a broad spectrum of environmental and age-related stresses that are underlying causes of numerous degenerative diseases and debilitating effects of aging. It proposes that the most fundamental, evolutionary-based integrative strategy to sustain and protect health is based on the concept of hormesis. This concept integrates anti-oxidant, anti-inflammatory and cellular repair responses at all levels of biological organization (i.e., cell, organ and organism) within the framework of biphasic dose responses that describe the quantitative limits of biological plasticity in all cells and organisms from bacteria and plants to humans. A major feature of the hormetic concept is that low levels of biological, chemical, physical and psychological stress upregulate adaptive responses that not only precondition, repair and restore normal functions to damaged tissues/organs but modestly overcompensate, reducing ongoing background damage, thereby enhancing health beyond that in control groups, lacking the low level "beneficial" stress. Higher doses of such stress often become counterproductive and eventually harmful. Hormesis is active throughout the life-cycle and can be diminished by aging processes affecting the onset and severity of debilitating conditions/diseases, especially in elderly subjects. The most significant feature of the hormetic dose response is that the limits of biological plasticity for adaptive processes are less than twice that of control group responses, with most, at maximum, being 30-60 % greater than control group values. Yet, these modest increases can make the difference between health or disease and living or dying. The quantitative features of these adaptive hormetic dose responses are also independent of mechanism. These features of the hormetic dose response determine the capacity to which systems can adapt/be protected, the extent to which biological performance (e.g., memory, resistance to injury/disease, wound healing, hair growth or lifespan) can be enhanced/extended and the extent to which synergistic interactions may occur. Hormesis defines the quantitative rules within which adaptive processes operate and is central to evolution and biology and should become transformational for experimental concepts and study design strategies, public health practices and a vast range of therapeutic strategies and interventions., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Intervention trials confirmed that blood flow-mediated dilatation increases significantly after intake of astringent (-)-epicatechin (EC) oligomers (procyanidins)-rich foods, but the mechanism remains unclear. We have previously found that procyanidins can activate the sympathetic nervous and subsequently increase blood flow. Here, we examined whether procyanidin-derived reactive oxygen species (ROS) activate transient receptor potential (TRP) channels in gastrointestinal sensory nerves and consequently induce sympathoexcitation. We evaluated the redox properties of EC and its tetramer cinntamtannin A2 (A2) at pH 5 or 7, mimicking plant vacuole or oral cavity/small intestine using a luminescent probe. At pH 5, A2 or EC showed O 2 ·- generation at pH 7. We observed blood flow in rat cremaster arterioles using laser Doppler, a single oral dose of 10 µg/kg A2 markedly increased blood flow, while EC showed little activity. This change with A2 was significantly dampened by co-administration of adrenaline blocker, ROS scavenger N-acetyl-L-cysteine (NAC), TRP vanilloid 1, or ankyrin 1 antagonist. We also performed a docking simulation of EC or A2 with the binding site of a typical ligand for each TRP channel and calculated the respective binding affinities. The binding energies were notably higher for A2 than typical ligands, suggesting that A2 is less likely to bind to these sites. ROS produced at neutral pH following the orally administered A2 to the gastrointestinal tract could activate TRP channels, triggering sympathetic hyperactivation and causing hemodynamic changes.2 ·- generation at pH 7. We observed blood flow in rat cremaster arterioles using laser Doppler, a single oral dose of 10 µg/kg A2 markedly increased blood flow, while EC showed little activity. This change with A2 was significantly dampened by co-administration of adrenaline blocker, ROS scavenger N-acetyl-L-cysteine (NAC), TRP vanilloid 1, or ankyrin 1 antagonist. We also performed a docking simulation of EC or A2 with the binding site of a typical ligand for each TRP channel and calculated the respective binding affinities. The binding energies were notably higher for A2 than typical ligands, suggesting that A2 is less likely to bind to these sites. ROS produced at neutral pH following the orally administered A2 to the gastrointestinal tract could activate TRP channels, triggering sympathetic hyperactivation and causing hemodynamic changes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Periods of skeletal muscle disuse, for example due to a sedentary lifestyle or bed rest, are associated with aging and can lead to muscle atrophy. We previously found that the flavan 3-ol fraction derived from cocoa (FL) enhanced energy expenditure with metabolic changes in skeletal muscle. In the present study, we examined the effect of FL on disuse muscle atrophy induced by hindlimb suspension in mice. Male C57BL/6J mice were assigned to four groups as follows: unsuspended-vehicle, unsuspended-FL, suspended-vehicle, and suspended-FL. Mice in the vehicle treatment groups were administered distilled water and those in the FL treatment groups were dosed with FL (50mg/kg/day) for 2weeks. The weights of the gastrocnemius (GC), tibialis anterior (TA), and soleus (SOL), but not the extensor digitorum longus (EDL), decreased significantly in mice with hindlimb suspension (-11.8%, -16.5%, and -41.0%, respectively). This reduction in GC, TA, and SOL mass was inhibited by FL (-5.3%, +2.0%, and -16.6%, respectively). The FL increased the EDL weight >20% with or without hindlimb suspension. The protein level of the ubiquitin ligase, muscle ring finger-1, in the SOL was significantly increased by hindlimb suspension, but inhibited by treatment with FL. Protein expression of p70S6 kinase in the SOL was significantly decreased by hindlimb suspension, and FL treatment inhibited this change. These results suggested that FL delayed disuse muscle atrophy by metabolic alteration., (Copyright © 2017. Published by Elsevier Inc.)

A lot of epidemiological and intervention studies support the hypotensive action resulting from ingestion of foods rich in flavan 3-ols. However, the mechanisms of this action remain unclear. We have reported previously on the alteration of the micro- and systemic circulations after administration of a flavan 3-ol fraction (FL) derived from cocoa in mammals. We also confirmed that blood catecholamine levels increase significantly after administration of FL. In the present study, we examined whether adrenaline receptors are involved in the hemodynamic changes using several adrenaline receptor (AR) blockers. First, we confirmed that mean blood pressure (MBP) decreased significantly and aortic endothelial nitric oxide synthase (eNOS) levels increased significantly following oral treatment of 10mg/kg FL for 2 weeks in normal rats compared with vehicle administration. However, these changes were not observed with treatment of 1mg/kg (-)-epicatechin (EC), which contains nearly equivalent amount of 10mg/kg FL. Secondly, we observed that a single dose of FL produced different hemodynamic changes, such as a transient elevation in heart rate (HR) after ingestion of 1-100mg/kg FL, but not with 1mg/kg EC. Furthermore, although MBP rose transiently after 1 and 10mg/kg FL, this effect was not observed with 100mg/kg or 1mg/kg EC. The increases in HR, MBP, and aortic phosphorylated eNOS (p-eNOS) induced by 10mg/kg FL were prevented completely by pretreatment with the AR blocker, carvedilol. Combination treatment with 100mg/kg FL and an α1AR blocker, prazosin, significantly reduced MBP, whereas the elevation in HR was enhanced. In addition, after pretreatment with the β2AR blocker, butoxamine, we observed no significant hemodynamic changes with or without 100mg/kg FL. Moreover, the combination of 100mg/kg FL and the α2AR blocker, yohimbine, markedly increased MBP, HR and aortic p-eNOS level. These results suggested that the postprandial hemodynamic changes after a single oral dose of FL were induced by an adrenergic effect. This adrenomimetic activity suggested the involvement of a hypotensive effect of FL., (Copyright © 2016. Published by Elsevier Inc.)

Theaflavins are polyphenols found in black tea; their physiological activities were not well investigated. The present study in rats evaluated the influence of theaflavins on circulation. In addition, an intervention pilot study examined the influence of a theaflavin drink on postprandial hemodynamic change. In an animal study, a single oral dose of theaflavin rich fraction (TF, 10mg/kg) caused transient increase in mean blood pressure (MBP) and heart rate (HR). TF also elevated cremastric blood flow significantly, and the magnitude of this effect was in this order: theaflavin 3'-O-gallate (TF2B) >>theaflavin-3-O-gallate (TF2A) >>theaflavin (TF1)=theaflavin-3, 3'-di-O-gallate (TF3). In addition, these hemodynamic alterations in mammals totally disappeared when pretreated with carvedilol as an adrenaline blocker. We also treated 10-mg/kg/day TF to the rats for 2 weeks. At the end of the ingestion period, MBP was reduced significantly, and aortic eNOS level was elevated by the repeated ingestion of TF compared with distilled water. In the intervention trial, blood pressure of the volunteers was increased significantly 2 and 4h after ingestion of the TF drink (45mg/drink) compared with before treatment. A significant difference was observed in FMD between the placebo and theaflavin groups 4h after ingestion. These results suggested that theaflavin has potent activity to alter hemodynamics in both murine and healthy subjects. Further studies is needed to elucidate the details; however, the results of animal study suggested that the possible involvement of sympathetic nervous system in the hemodynamic changes caused by TF., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Numerous clinical studies have found that ingestion of chocolate reduces the risk of metabolic syndrome, however, the mechanisms were remain unclear. We have reported that a single dose of a flavan-3-ol fraction derived from cocoa (FL) enhanced energy expenditure (EE) and increased the mRNA expression levels of uncoupling proteins (UCPs) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), and the protein level of phosphorylated AMP-activated protein kinase (AMPK)α in tissues, along with plasma adrenaline level. In the present study, we examined whether the EE enhancing activity of FL is mediated by adrenergic effect using several adrenalin receptor (AR) blockers. In the first study, mice were butoxamine, as β2AR blocker, with vehicle or 10mg/kg FL orally. We found that pretreatment with butoxamine prevented the increases of EE, the mRNA expression of UCP-3, and phosphorylated AMPKα that were induced in the gastrocnemius muscle of mice by 10mg/kg FL. Secondly, mice were given SR52930, as β3AR blocker. Pretreatment with SR52930 prevented the increases of EE, the mRNA expression of UCP-3, and phosphorylated AMPKα that were induced in the gastrocnemius muscle of mice by 10mg/kg FL. Pretreatment with a combination of both blockers also reduced the increments in mRNA expression levels of UCPs and PGC-1α, however, phosphorylated AMPKα in skeletal muscle was rather increased. These results suggest that the ability of a single oral dose of FL to enhance metabolic activity is mediated by sympathetic nerve system (SNS)., (Copyright © 2015. Published by Elsevier Inc.)

Objective: Effective approaches should be established to prevent the onset of type 2 diabetes mellitus, which has been increasing in developed countries. The present study examined whether dietary supplementation with cacao liquor proanthocyanidins (CLPr) could prevent elevation of blood glucose levels in mice with diabetes mellitus and obesity., Methods: C57BL/KsJ-db/db (db/db) diabetic obese mice and C57BL/KsJ-db/+m (db/+m) control mice were fed a diet containing 0% w/w CLPr (0% CLPr), 0.5% w/w CLPr (0.5% CLPr), or 1.0% w/w CLPr (1.0% CLPr) from age 3 wk to age 6 wk. Levels of blood glucose were measured at 4 and 5 wk of age. The animals were sacrificed and the levels of blood glucose and fructosamine were measured at 6 wk of age., Results: The levels of blood glucose and fructosamine were higher in the db/db mice than in the db/+m mice fed a diet containing 0%, 0.5%, or 1.0% CLPr. In the db/+m mice, the levels of blood glucose or fructosamine were not significantly different across animals fed 0% CLPr, 0.5% CLPr, and 1.0% CLPr. In the db/db mice, however, a diet containing 0.5% or 1.0% CLPr decreased the levels of blood glucose and fructosamine compared with that containing 0% CLPr without significant effects on body weights or food consumption., Conclusion: Dietary supplementation with CLPr can dose-dependently prevent the development of hyperglycemia in diabetic obese mice. The dietary intake of food or drinks produced from cacao beans might be beneficial in preventing the onset of type 2 diabetes mellitus.

Densely aggregated beta-amyloid peptides are believed to play a key role in the pathogenesis of Alzheimer's disease. Amyloid plaques are a potential target for molecular imaging to determine the clinical status of Alzheimer's disease. Phase-contrast X-ray imaging combined with computed tomography is a promising technique that can be used to visualize the physical density of structures in biological tissues non-invasively, and without the use of imaging agents. Using brain tissue isolated from a mouse model of Alzheimer's disease, we show that beta-amyloid 40-positive/beta-amyloid 42-positive amyloid plaques, but not beta-amyloid 40-negative/beta-amyloid 42-positive amyloid plaques, exist as high-density aggregates that can be specifically detected by phase-contrast X-ray computed tomography. The phase-contrast X-ray computed tomography detected beta-amyloid 40-positive/beta-amyloid 42-positive amyloid plaques in three-dimensions with an extremely high sensitivity comparable to that of histological analysis, and also enabled the load of amyloid plaques to be quantified. Furthermore, the use of phase-contrast X-ray computed tomography reveals that the physical density of beta-amyloid 40-positive/beta-amyloid 42-positive amyloid plaques increases with age, and that the large volume, high-density, amyloid plaques that are specifically observed in aged Alzheimer's disease mice are closely associated with neuritic dystrophy. These results demonstrate that phase-contrast X-ray computed tomography is a highly sensitive imaging technique for analyzing dense-cored amyloid plaques in postmortem samples, and is beneficial in elucidating amyloid pathophysiology in Alzheimer's disease.

Epidemiological and experimental studies have suggested that diesel exhaust particles (DEP) may be involved in recent increases in lung diseases. DEP has been shown to generate reactive oxygen species. Intratracheal instillation of DEP induces lung inflammation and edema in mice. Rosmarinic acid is a naturally occurring polyphenol with antioxidative and anti-inflammatory activities. We investigated the effects of rosmarinic acid on lung injury induced by intratracheal administration of DEP (500 microg/body) in mice. Oral supplementation with administration of rosmarinic acid (2 mg/body for 3 d) inhibited DEP-induced lung injury, which was characterized by neutrophil sequestration and interstitial edema. DEP enhanced the lung expression of keratinocyte chemoattractant (KC), interleukin-1beta, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1alpha, which was inhibited by treatment with rosmarinic acid. DEP enhanced expression of iNOS mRNA and formation of nitrotyrosine and 8-OHdG in the lung, which was also inhibited by rosmarinic acid. These results suggest that rosmarinic acid inhibits DEP-induced lung injury by the reduction of proinflammatory molecule expression. Antioxidative activities of rosmarinic acid may also contribute to its protective effects.

(-)-epicatechin is one of the most potent antioxidants present in the human diet. Particularly high levels are found in black tea, apples, and chocolate. High intake of catechins has been associated with reduced risk of cardiovascular diseases. There have been several reports concerning the bioavailability of catechins, however, the chemical structure of (-)-epicatechin metabolites in blood, tissues, and urine remains unclear. In the present study, we purified and elucidated the chemical structure of (-)-epicatechin metabolites in human and rat urine after oral administration. Three metabolites were purified from human urine including (-)-epicatechin-3'-O-glucuronide, 4'-O-methyl-(-)-epicatechin-3'-O-glucuronide, and 4'-O-methyl-(-)-epicatechin-5 or 7-O-glucuronide, according to 1H- and 13C-NMR, HMBC, and LC-MS analyses. The metabolites purified from rat urine were 3'-O-methyl-(-)-epicatechin, (-)-epicatechin-7-O-glucuronide, and 3'-O-methyl-(-)-epicatechin-7-O-glucuronide. These compounds were also detected in the blood of humans and rats by LC-MS. The presence of these metabolites in blood and urine suggests that catechins are metabolized and circulated in the body after administration of catechin-containing foods.

The protective activity of rosmarinic acid from Perilla frutescens on liver injury induced by LPS in D-GalN-sensitized mice was examined. We also investigated the effects of antitumor necrosis factor-alpha antibody (anti-TNF), superoxide dismutase (SOD), and aminoguanidine (AG) on this model in order to elucidate the mechanism of rosmarinic acid protection. Perilla extract (PE) and rosmarinic acid (RA) treatments significantly reduced the elevation of plasma asparatate aminotransferase levels, as well as anti-TNF and SOD treatment, compared with controls, but this reduction was not seen in the AG group. These results were confirmed by histological examination using hematoxylin-eosin and in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. Increases in tumor necrosis factor-alpha (TNF-alpha) mRNA expression in liver and in plasma TNF-alpha levels, which were observed in control mice, were not significantly reduced by PE or RA. PE and RA treatments also did not significantly diminish iNOS mRNA expression or plasma nitrate/nitrite levels. Nitrotyrosine and N(epsilon)-(hexanonyl)lysine (HEL) production, the residue of oxidative stress, was observed in livers from controls, but not in those mice pretreated with PE or RA. These results suggest that the liver protection of RA is due to the scavenging or reducing activities-superoxide or peroxynitirite rather than to inhibition of TNF-alpha production., (Copyright 2002 Elsevier Science Inc.)

We evaluated the bioavailability and plasma antioxidative activity after administration of procyanidin B2 [epicatechin-(4beta-8)-epicatechin] in rats. After procyanidin B2 administration, procyanidin B2 is absorbed and excreted in urine, and a portion of the PB2 is degraded to (-)-epicatechin and to the metabolized conjugated and/or methylated (-)-epicatechin internally in the rat. Moreover, PB2 reduces the accumulation of lipid peroxide in plasma oxidized by copper ions.