Procyanidins and sensory nutrition; do procyanidins modulate homeostasis via astringent taste receptors?

Long-term intake of procyanidins has been suggested to reduce the risk of cardiovascular disease, dementia, and sensory function decline associated with aging. However, most of the ingested procyanidins are not absorbed and are excreted in the feces, so the mechanism of their beneficial impact is unknown. Procyanidins are the components of astringency in plant foods and their stimulation appears to be directly transmitted to the central nervous system via sensory nerves. Recent attention has been focused on the taste receptors expressed in the extra-oral gastrointestinal tract may regulate homeostasis via the neuroendocrine system. In this paper, we have reviewed recent findings on the relationship between the astringency of procyanidins and their bioregulatory effects.

Impact of cyanidin 3-O-glucoside on rat micro-and systemic circulation, possibly thorough angiogenesis.

Cyanidin 3-O-glucoside (C3G), an antioxidant, is one of the most abundant anthocyanin in plant foods. Intervention trials and subsequent meta-analyses have suggested that anthocyanins could reduce the risks of cardiovascular diseases. This study investigated hemodynamic alterations following a single intragastric dose of C3G by measuring blood flow in rat cremaster muscle arteriole for 60 min. Next, in excised aortas, we performed western blotting to measure the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). A single oral dose of C3G significantly increased blood flow soon after ingestion, and it was maintained throughout the experimental period. In addition, aortic Akt phosphorylation increased. Then, we examined the impact of repeated oral administrations of C3G for 14 days. The mean blood pressure was significantly reduced at 7 and 14 days after treatment, with a slight increase in aortic eNOS expression. Immunohistochemical analyses of the soleus showed that the level of CD31, an angiogenesis-marker protein, was significantly increased with C3G. These results suggested that an oral dose of C3G increased blood flow, which promoted angiogenesis within skeletal muscle, and consequently, blood pressure was reduced.

Cinnamtannin A2, (-)-epicatechin tetramer, attenuates skeletal muscle wasting in disuse atrophy model mice induced by hindlimb suspension.

The impact of repeated administration of cinntamtannin A2 (A2, 25 µg/kg) on skeletal muscle disuse atrophy model mice induced by hindlimb suspension for 14 days was examined. In soleus, weight loss and a reduction in the average myofibre size with shifting to the smaller side of the peak were observed in the suspension-vehicle group, but A2 reduced these changes. Average myofibre size significantly increased in ground-A2 compared to ground-vehicle. A marked increase in the dephosphorylation of forkhead box O (FoxO) 3a by the suspension was reduced by A2. The phosphorylation of protein kinase B (Akt) and eukaryotic translation initiation factor 4E-binding protein (4EBP)-1 were significantly increased by the treatment of A2. In addition, a single dose of A2 increased dramatically in the 24-h excretion of catecholamines in urine. These results suggest that A2 administration results in sympathetic nerve activation and promotes hypertrophy while inhibiting the progress of disuse muscle atrophy.

Polyphenols in Inner Ear Neurobiology, Health and Disease: From Bench to Clinics.

There is substantial experimental and clinical interest in providing effective ways to both prevent and slow the onset of hearing loss. Auditory hair cells, which occur along the basilar membrane of the cochlea, often lose functionality due to age-related biological alterations, as well as from exposure to high decibel sounds affecting a diminished/damaged auditory sensitivity. Hearing loss is also seen to take place due to neuronal degeneration before or following hair cell destruction/loss. A strategy is necessary to protect hair cells and XIII cranial/auditory nerve cells prior to injury and throughout aging. Within this context, it was proposed that cochlea neural stem cells may be protected from such aging and environmental/noise insults via the ingestion of protective dietary supplements. Of particular importance is that these studies typically display a hormetic-like biphasic dose-response pattern that prevents the occurrence of auditory cell damage induced by various model chemical toxins, such as cisplatin. Likewise, the hormetic dose-response also enhances the occurrence of cochlear neural cell viability, proliferation, and differentiation. These findings are particularly important since they confirmed a strong dose dependency of the significant beneficial effects (which is biphasic), whilst having a low-dose beneficial response, whereas extensive exposures may become ineffective and/or potentially harmful. According to hormesis, phytochemicals including polyphenols exhibit biphasic dose-response effects activating low-dose antioxidant signaling pathways, resulting in the upregulation of vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Modulation of the vitagene network through polyphenols increases cellular resilience mechanisms, thus impacting neurological disorder pathophysiology. Here, we aimed to explore polyphenols targeting the NF-E2-related factor 2 (Nrf2) pathway to neuroprotective and therapeutic strategies that can potentially reduce oxidative stress and inflammation, thus preventing auditory hair cell and XIII cranial/auditory nerve cell degeneration. Furthermore, we explored techniques to enhance their bioavailability and efficacy.

Can a Short-term Daily Oral Administration of Propolis Improve Muscle Fatigue and Recovery?

This study investigated the effect of 1-week oral administration of propolis on muscle fatigue and recovery after performing a fatigue task (total 100 maximal voluntary concentric knee extension repetitions). In this placebo-controlled, double-blind study, 18 young men consumed a formulation with high Brazilian green propolis dose (H-BGP), a formulation with low Brazilian green propolis dose, or a placebo, for 1 week before performing the fatigue task (an interval between each intervention: 1-2 weeks). Maximal voluntary contraction torque, central fatigue (voluntary activation and root mean square values of the surface electromyography amplitude), and peripheral fatigue (potentiated triplet torque) were assessed before, immediately after, and 2 minutes after the fatigue task. Maximal voluntary contraction torque decreased immediately after the fatigue task in all conditions (P<0.001); however, it recovered from immediately after to 2 minutes after the fatigue task only in the H-BGP condition (P<0.001). Furthermore, there was a significant decrease in voluntary activation (P<0.001) and root mean square values of the surface electromyography amplitude (P≤0.035) only in the placebo condition. No significant difference was observed in the time-course change in potentiated triplet torque between the conditions. These results suggest that oral administration of propolis promotes muscle fatigue recovery by reducing central fatigue.

Impact of short-term oral dose of cinnamtannin A2, an (-)-epicatechin tetramer, on spatial memory and adult hippocampal neurogenesis in mouse.

Recent epidemiological and intervention studies have suggested that polyphenol-rich plant food consumption reduced the risk of cognitive decline. However, the findings were tentative and by no means definitive. In the present study, we examined the impact of short-term oral administration of cinnamtannin A2 (A2), an (-)-epicatechin tetramer, on adult hippocampal neurogenesis and cognitive function in mice. Mice received supplementation with vehicle (20% glycerol) or 100 µg/kg A2 for 10 days. Then, we conducted the open field test, the object location test, and the novel object test. In the open field test, the A2-treated group tended to spend more time in the center of the arena, compared to the vehicle-treated group. The A2-treated group spent significantly more time exploring objects placed in different locations, compared to the vehicle-treated group. There were no significant differences between groups in the object preference index or in the novel object test. In addition, A2 administration significantly increased the number of hippocampal bromodeoxyuridine-labeled cells in the dentate gyrus, but not in the CA1 or CA3 regions. These results suggested that short-term administration of A2 may impact spatial memory by enhancing neurogenesis in the dentate gyrus of adult mice.

Theaflavins decrease skeletal muscle wasting in disuse atrophy induced by hindlimb suspension in mice.

We previously found that a single dose of theaflavins induced skeletal muscle metabolic changes. In this study, we examined the effect of theaflavins on disuse muscle atrophy model mice by hindlimb suspension. Mice were assigned to 4 groups; ground-vehicle, ground-theaflavins, suspension-vehicle, and suspension-theaflavins, dosed with theaflavins (250 mg/kg/day) for 2 weeks. The peak of myotube size of cross sectional area was significantly moved to the smaller side in the suspension-vehicle group compared with the ground-vehicle group, and these shifts were significantly reduced by the treatment with theaflavins in both soleus and extensor digitorum longus. The level of phosphorylated eukaryotic translation initiation factor 4E-binding protein (4EBP)-1, located downstream of the Akt/mTOR pathway, was significantly different between suspension-vehicle and suspension-theaflavins in soleus. The ratio of forkhead box O (FoxO) 3a to phosphorylated FoxO3a significantly increased in soleus or tended to rise in extensor digitorum longus of suspension-vehicle group compared with ground-vehicle. In contrast, these changes were not observed in suspension-theaflavins group. These results suggested that theaflavins inhibited the progress of disuse muscle atrophy through modulation of protein metabolism.

Dual real-time in vivo monitoring system of the brain-gut axis.

The brain-gut axis which is an interaction between recognition and emotion and the gut sensory system for food and microbiota is important for health. However, there is no real-time monitoring system of the brain and the gut simultaneously so far. We attempted to establish a dual real-time monitoring system for the brain-gut axis by a combination of intravital Ca2+ imaging of the gut and electroencephalogram. Using a conditional Yellow Cameleon 3.60 expression mouse line, we performed intravital imaging of the gut, electrophysiological recordings of the vagus nerve, and electroencephalogram recordings of the various cortical regions simultaneously upon capsaicin stimuli as a positive control. Upon capsaicin administration into the small intestinal lumen, a simultaneous response of Ca2+ signal in the enteric nervous system and cortical local field potentials (LFPs) was successfully observed. Both of them responded immediately upon capsaicin stimuli. Capsaicin triggered a significant increase in the frequency of vagus nerve spikes and a significant decrease in the slow-wave power of cortical LFPs. Furthermore, capsaicin induced delayed and sustained Ca2+ signal in intestinal epithelial cells and then suppressed intestinal motility. The dual real-time monitoring system of the brain and the gut enables to dissect the interaction between the brain and the gut over time with precision.

Study on structure-activity relationship of vitamin K derivatives: Conversion of the naphthoquinone part into another aromatic ring and evaluation of their neuronal differentiation-inducing activity.

We synthesized novel vitamin K derivatives by converting the naphthoquinone group to benzene derivatives and benzoquinone. We evaluated their neuronal differentiation activities to investigate the effect of the quinone moiety on this process. We observed that the 1,4-quinone as well as the side chain part play important roles in neuronal differentiation. We also performed QSAR analysis to predict the compounds which would have higher differentiation activity.

Elucidation of the Interaction between Flavan-3-ols and Bovine Serum Albumin and Its Effect on Their In-Vitro Cytotoxicity.

Flavan-3-ols (FLs), specifically catechin and its oligomer B-type procyanidins, are suggested to potently bind to bovine serum albumin (BSA). We examined the interaction between BSA and FLs by fluorescence quenching and found the following order of binding activities to BSA: cinnamtannin A2 (A2; tetramer) > procyanidin C1 (C1; trimer) ≈ procyanidin B2 (B2, dimer) > (-)epicatechin (EC, monomer). Docking simulations between BSA and each compound at the binding site showed that the calculated binding energies were consistent with the results of our experimental assay. FLs exerted cytotoxicity at 1000 µg/mL in F11 cell culture with fetal bovine serum containing BSA. In culture containing serum-free medium, FLs exhibited significant cell proliferation at 10-4 µg/mL and cytotoxicity was observed at concentrations greater than 10 µg/mL. Results of this study suggest that interactions between polyphenols and BSA should be taken into account when evaluating procyanidin in an in vitro cell culture system.

Synthesis and In Vitro Evaluation of Novel Liver X Receptor Agonists Based on Naphthoquinone Derivatives.

We aimed to synthesize novel liver X receptor (LXR) agonists with potent agonist activity and subtype selectivity. Our synthetic scheme started with naphthoquinone derivatives, such as menadione and 2,3-dichloro-1,4-naphthoquinone. We introduced different substituents into the naphthoquinone structures, including aniline, piperidine, pyrrolidine, and morpholine, in one or two steps, and thus, we produced 14 target compounds. All 14 synthetic ligands were tested to determine whether they mediated LXR-mediated transcriptional activity. We investigated the transcriptional activity of each compound with two types of receptors, LXRα and LXRß. Among all 14 compounds, two showed weak LXRß-agonist activity, and two others exhibited potent LXRα-agonist activity. We also performed docking studies to obtain a better understanding of the modes of compound binding to LXR at the atomic level. In conclusion, we successfully synthesized naphthoquinone derivatives that act as LXRα/ß agonists and selective LXRα agonists.

Corticotropin-releasing hormone is significantly upregulated in the mouse paraventricular nucleus following a single oral dose of cinnamtannin A2 as an (-)-epicatechin tetramer.

Cinnamtannin A2, an (-)-epicatechin tetramer, was reported to have potent physiological activity. Cinnamtannin A2 is rarely absorbed from the gastrointestinal tract into the blood and the mechanisms of its beneficial activities are unknown. Cinnamtannin A2 reported to increase sympathetic nervous activity, which was induced by various stressors. In present study, we examined the stress response in the mouse paraventricular nucleus following a single oral dose of cinnamtannin A2 by monitoring mRNA expression of corticotropin-releasing hormone (CRH) and c-fos using in situ hybridization. Corticotropin-releasing hormone mRNA showed a tendency to increase at 15 min and significantly increased at 60 min following a single oral administration of 100 µg/kg cinnamtannin A2. After a single dose of 10 µg/kg cinnamtannin A2, there was significant upregulation of CRH mRNA at 60 min. These results suggested that cinnamtannin A2 was recognized as a stressor in central nervous system and this may lead to its beneficial effects on circulation and metabolism.

Substitution at the C-3 Position of Catechins Has an Influence on the Binding Affinities against Serum Albumin.

It is known that catechins interact with the tryptophan (Trp) residue at the drug-binding site of serum albumin. In this study, we used catechin derivatives to investigate which position of the catechin structure strongly influences the binding affinity against bovine serum albumin (BSA) and human serum albumin (HSA). A docking simulation showed that (-)-epigallocatechin gallate (EGCg) interacted with both Trp residues of BSA (one at drug-binding site I and the other on the molecular surface), mainly by π-π stacking. Fluorescence analysis showed that EGCg and substituted EGCg caused a red shift of the peak wavelength of Trp similarly to warfarin (a drug-binding site I-specific compound), while 3-O-acyl-catechins caused a blue shift. To evaluate the binding affinities, the quenching constants were determined by the Stern-Volmer equation. A gallate ester at the C-3 position increased the quenching constants of the catechins. Against BSA, acyl substitution increased the quenching constant proportionally to the carbon chain lengths of the acyl group, whereas methyl substitution decreased the quenching constant. Against HSA, neither acyl nor methyl substitution affected the quenching constant. In conclusion, substitution at the C-3 position of catechins has an important influence on the binding affinity against serum albumin.

Flavan-3-ol fraction from cocoa powder promotes mitochondrial biogenesis in skeletal muscle in mice.

BACKGROUND: Numerous clinical studies have reported that ingestion of chocolate has reduced risk of metabolic syndrome. In order to elucidate the mechanism, we evaluated the influence of flavan-3-ols derived from cocoa powder on energy metabolism in mice using an indirect calorimetric method. METHOD: The mice were divided into two groups, and administered either distilled water or 50 mg/kg of flavan-3-ol fraction for 2 weeks. At the end of the experimental period, animals were sacrificed after blood pressure and the mean respiratory exchange ratio (RER) over 24 hours were measured. RESULTS: The mean respiratory exchange ratio (RER) over 24 hours was reduced significantly in the flavan-3-ols group. The mean blood pressure was significantly decreased in flavan-3-ols treatment group compared with control group. The protein level of carnitine palmitoyltransferase 2 (CPT2) was increased significantly by flavan-3-ols in skeletal muscle, but not in liver. Uncoupling protein (UCP) 1 was increased significantly in brown adipose tissue by flavan-3-ols. The mitochondria copy number in gastrocnemius and soleus muscles and brown adipose tissue were increased significantly by administration of flavan-3-ol fraction. CONCLUSION: These results suggest that flavan-3-ols enhances lipolysis and promotes mitochondrial biogenesis. We conclude that improvement of metabolic syndrome risk factors following ingestion of chocolate may be induced, in part, by the mitochondrial biogenesis-promoting effect of flavan-3-ols.

Sensory Nutrition and Bitterness and Astringency of Polyphenols.

Recent studies have demonstrated that the interaction of dietary constituents with taste and olfactory receptors and nociceptors expressed in the oral cavity, nasal cavity and gastrointestinal tract regulate homeostasis through activation of the neuroendocrine system. Polyphenols, of which 8000 have been identified to date, represent the greatest diversity of secondary metabolites in plants, most of which are bitter and some of them astringent. Epidemiological studies have shown that polyphenol intake contributes to maintaining and improving cardiovascular, cognitive and sensory health. However, because polyphenols have very low bioavailability, the mechanisms of their beneficial effects are unknown. In this review, we focused on the taste of polyphenols from the perspective of sensory nutrition, summarized the results of previous studies on their relationship with bioregulation and discussed their future potential.

Investigating hormesis, aging, and neurodegeneration: From bench to clinics.

Mitochondria-derived reactive oxygen species production at a moderate physiological level plays a fundamental role in the anti-aging signaling, due to their action as redox-active sensors for the maintenance of optimal mitochondrial balance between intracellular energy status and hormetic nutrients. Iron regulatory protein dysregulation, systematically increased iron levels, mitochondrial dysfunction, and the consequent oxidative stress are recognized to underlie the pathogenesis of multiple neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Central to their pathogenesis, Nrf2 signaling dysfunction occurs with disruption of metabolic homeostasis. We highlight the potential therapeutic importance of nutritional polyphenols as substantive regulators of the Nrf2 pathway. Here, we discuss the common mechanisms targeting the Nrf2/vitagene pathway, as novel therapeutic strategies to minimize consequences of oxidative stress and neuroinflammation, generally associated to cognitive dysfunction, and demonstrate its key neuroprotective and anti-neuroinflammatory properties, summarizing pharmacotherapeutic aspects relevant to brain pathophysiology.

Frankincense: A neuronutrient to approach Parkinson's disease treatment.

Parkinson's disease (PD), characterized by tremor, slowness of movement, stiffness, and poor balance, is due to a significant loss of dopaminergic neurons in the substantia nigra pars compacta and dopaminergic nerve terminals in the striatum with deficit of dopamine. To date the mechanisms sustaining PD pathogenesis are under investigation; however, a solid body of experimental evidence involves neuroinflammation, mitochondrial dysfunction, oxidative stress, and apoptotic cell death as the crucial factors operating in the pathogenesis of PD. Nutrition is known to modulate neuroinflammatory processes implicated in the pathogenesis and progression of this neurodegenerative disorder. Consistent with this notion, the Burseraceae family, which includes the genera Boswellia and Commiphora, are attracting emerging interest in the treatment of a wide range of pathological conditions, including neuroinflammation and cognitive decline. Bioactive components present in these species have been shown to improve cognitive function and to protect neurons from degeneration in in vitro, animal, as well as clinical research. These effects are mediated through the anti-inflammatory, antiamyloidogenic, anti-apoptotic, and antioxidative properties of bioactive components. Although many studies have exploited possible therapeutic approaches, data from human studies are lacking and their neuroprotective potential makes them a promising option for preventing and treating major neurodegenerative disorders.

Transgenerational hormesis in healthy aging and antiaging medicine from bench to clinics: Role of food components.

Neurodegenerative diseases have multifactorial pathogenesis, mainly involving neuroinflammatory processes. Finding drugs able to treat these diseases, expecially because for most of these diseases there are no effective drugs, and the current drugs cause undesired side effects, represent a crucial point. Most in vivo and in vitro studies have been concentrated on various aspects related to neurons (e.g. neuroprotection), however, there has not been focus on the prevention of early stages involving glial cell activation and neuroinflammation. Recently, it has been demonstrated that nutritional phytochemicals including polyphenols, the main active constituents of the Mediterranean diet, maintain redox balance and neuroprotection through the activation of hormetic vitagene pathway. Recent lipidomics data from our laboratory indicate mushrooms as strong nutritional neuronutrients with strongly activity against neuroinflammation in Meniere' diseaseas, a model of cochleovestibular neural degeneration, as well as in animal model of traumatic brain injury, or rotenone induced parkinson's disease. Moreover, Hidrox®, an aqueous extract of olive containing hydroxytyrosol, and Boswellia, acting as Nrf2 activators, promote resilience by enhancing the redox potential, and thus, regulate through hormetic mechanisms, cellular stress response mechanisms., Thus, modulation of cellular stress pathways, in particular vitagenes system, may be an innovative approach for therapeutic intervention in neurodegenerative disorders.

Flavan 3-ols improve metabolic syndrome risk factors: evidence and mechanisms.

Flavan 3-ols, a type of polyphenolic substance, are distributed in a number of plant foods. Of these foods, chocolate is very rich in flavan 3-ols as flavan 3-ol monomers, (+)-catechin and (-)-epicatechin, and the oligomers as procyanidins. There is evidence that cacao products containing flavan 3-ols have the potential to contribute to the risk reduction of cardiometabolic disorders according to recent epidemiological or intervention studies. This review focuses on recent advances in research on the ability of flavan 3-ols to reduce the risk of cardiovascular disease as a result of improving metabolic syndrome risk factors and these mechanisms.

Difference in endocrine and behavior between short-term single- and paired-housing mice in metabolic cage.

Metabolic cage housing which is exposed to a number of environmental stressors is often used in pharmacokinetic studies. In this study, we compared the difference in stress response between single- and paired-housing in metabolic cages by evaluating the alteration of urinary stress hormones and behavior. Mice were randomly divided into single- or paired-housing groups and placed in a metabolic cage with wire mesh. Their urine was collected every 24 h for consecutive 4 days to determine excreted catecholamine and corticosterone. The change in body weight was significantly decreased at 3 and 4 days in the single-housing group compared with that before the experiment, but not paired-housing group. The level of urinary catecholamines, such as noradrenaline, adrenaline, and their metabolite vanillylmandelic acid, was significantly increased in the single-housing compared with paired housing group and urinary corticosterone increased as well. Next, for the two similarly housed groups, we observed spontaneous behavior on the fourth day and conducted an elevated plus-maze test on the fifth day. Spontaneous behavior was not different between experimental groups. In the elevated plus-maze test, the proportion of time spent in the open arms was significantly prolonged in the paired-housing group compared to that of the single-housing group. Short-term social isolation stress loading in metabolic cages was suggested to exhibit endocrinological and behavioral changes in mice. To reduce such interference due to stress exposure, it was suggested to keep two mice in a metabolic cage.