A stress sensor, IRE1α, is required for bacterial-exotoxin-induced interleukin-1ß production in tissue-resident macrophages.

Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1ß (IL-1ß), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarify the roles of inositol-requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1ß production in RPMs. In RPMs, CTB is incorporated into the ER and induces ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1α-deficient RPMs show a significant impairment of CT- or CTB-induced IL-1ß production, indicating that IRE1α is required for CT- or CTB-induced IL-1ß production in RPMs. This study demonstrates the critical roles of IRE1α in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages.

Identification and Characterization of Synaptic Vesicle Membrane Protein VAT-1 Homolog as a New Catechin-Binding Protein.

(-)-Epigallocatechin-3-gallate (EGCg), a major constituent of green tea extract, is well-known to exhibit many beneficial actions for human health by interacting with numerous proteins. In this study we identified synaptic vesicle membrane protein VAT-1 homolog (VAT1) as a novel EGCg-binding protein in human neuroglioma cell extracts using a magnetic pull-down assay and LC-tandem mass spectrometry. We prepared recombinant human VAT1 and analyzed its direct binding to EGCg and its alkylated derivatives using surface plasmon resonance. For EGCg and the derivative NUP-15, we measured an association constant of 0.02-0.85 ×103 M-1s-1 and a dissociation constant of nearly 8 × 10-4 s-1. The affinity Km(affinity) of their binding to VAT1 was in the 10-20 µM range and comparable with that of other EGCg-binding proteins reported previously. Based on the common structure of the compounds, VAT1 appeared to recognize a catechol or pyrogallol moiety around the B-, C- and G-rings of EGCg. Next, we examined whether VAT1 mediates the effects of EGCg and NUP-15 on expression of neprilysin (NEP). Treatments of mock cells with these compounds upregulated NEP, as observed previously, whereas no effect was observed in the VAT1-overexpressing cells, indicating that VAT1 prevented the effects of EGCg or NUP-15 by binding to and inactivating them in the cells overexpressing VAT1. Further investigation is required to determine the biological significance of the VAT1-EGCg interaction.

[Dynamic Chemistry of Tannins].

Tannins are a group of polyphenols that possess the ability to precipitate proteins, causing an undesirable astringent taste by interacting with salivary peptides. This interaction deactivates the digestive enzymes; therefore, tannins are considered as plant defense substances. The health benefits of tannins and related polyphenols in foods and beverages have been demonstrated by biological and epidemiological studies; however, their metabolism in living plants and the chemical changes observed during processing of foods and medicinal herbs raises some questions. This review summarizes our studies concerning dynamic changes observed in tannins. Ellagitannins present in the young leaves of Camellia japonica and Quercus glauca undergo oxidative degradation as the leaves mature. Similar oxidative degradation is also observed in whiskey when it is kept for aging in oak barrels, and in decaying wood caused by fungi in natural forests. In contrast, ellagitannins have been observed to undergo reduction in the leaves of Carpinus, Castanopsis, and Triadica species as the leaves mature. This phenomenon of reductive metabolism in leaves enabled us to propose a new biosynthetic pathway for the most fundamental ellagitannin acyl groups, which was also supported by biomimetic synthetic studies. Polyphenols undergo dynamic changes during the process of food processing. Catechin in tea leaves undergo oxidation upon mechanical crushing to generate black tea polyphenols. Though detailed production mechanisms of catechin dimers have been elucidated, structures of thearubigins (TRs), which are complex mixtures of oligomers, remain ambiguous. Our recent studies suggested that catechin B-ring quinones couple with catechin A-rings during the process of oligomerization.

Neurological Outcomes of Chemotherapy-Induced Peripheral Neuropathy in Patients With Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: This systematic review and meta-analysis aimed to determine whether chemotherapy-induced peripheral neuropathy (CIPN) affects the risk of falls and physical function in patients with cancer. METHODS: A literature search was conducted in the CINAHL, Scopus, and PubMed databases for articles published from January 1950 to April 2022. Seven review authors retrieved studies using predetermined eligibility criteria, extracted the data, and evaluated the quality. RESULTS: Nine studies were included in the analysis. Patients with CIPN had a significantly higher risk of falls than those without CIPN (risk ratio = 1.38, 95% confidence interval [CI] =1.18-1.62). Patients with CIPN had lower grip strength (standardized mean difference [SMD] =-0.42, 95% CIs = -0.70 to -0.14, P = .003), longer chair stand time (SMD = 0.56, 95% CIs = -0.01 to 1.17, P = .05), worse timed up and go test time (SMD = 0.79, 95% CIs = 0.41 to 1.17, P < .0001), and lower mean Fullerton Advanced Balance scale score (SMD = -0.81, 95% CIs = -1.27 to -0.36, P = .005) than patients without CIPN. There were no significant differences in gait speed (P = .38) or Activities-specific Balance Confidence Scale score (P = .09) between patients with and without CIPN. CONCLUSIONS: This systematic review and meta-analysis demonstrated that patients with CIPN are prone to falls and impaired balance function and muscle strength.

Oligomerization Mechanisms of Tea Catechins Involved in the Production of Black Tea Thearubigins.

Thearubigins (TRs) are chemically ill-defined black tea pigments composed of numerous catechin oxidation products. TRs contain oligomeric components; however, the oligomerization mechanisms are poorly understood. The comparison of the 13C nuclear magnetic resonance (NMR) spectra of TRs with different molecular sizes suggested the participation of A-ring methine carbons in the oligomerization. Crushing fresh tea leaves with phloroglucinol, a mimic of the catechin A-rings, yielded the phloroglucinol adducts of the B-ring quinones of pyrogallol-type catechins and dehydrotheasinensins, indicating that intermolecular oxidative couplings between pyrogallol-type B-rings and A-rings are involved in the oligomerization. This is supported by the comparison of the 13C NMR spectra of the oligomers generated from the dehydrotheasinensins and epicatechin. Furthermore, the presence of the quinones or related structures in the catechin oligomers is shown by condensation with 1,2-phenylenediamine. The pyrogallol-type catechins account for approximately 70% of tea catechins; therefore, the B-A ring couplings of the pyrogallol-type catechins are important in the catechin oligomerization involved in TR production.

ATF6ß Deficiency Elicits Anxiety-like Behavior and Hyperactivity Under Stress Conditions.

Activating transcription factor 6 (ATF6) is an endoplasmic reticulum (ER) stress-regulated transcription factor that induces expression of major molecular chaperones in the ER. We recently reported that ATF6ß, a subtype of ATF6, promoted survival of hippocampal neurons exposed to ER stress and excitotoxicity, at least in part by inducing expression of calreticulin, an ER molecular chaperone with high Ca2+-binding capacity. In the present study, we demonstrate that ATF6ß deficiency in mice also decreases calreticulin expression and increases expression of glucose-regulated protein 78, another ER molecular chaperone, in emotional brain regions such as the prefrontal cortex (PFC), hypothalamus, hippocampus, and amygdala. Comprehensive behavioral analyses revealed that Atf6b-/- mice exhibit anxiety-like behavior in the light/dark transition test and hyperactivity in the forced swim test. Consistent with these results, PFC and hypothalamic corticotropin-releasing hormone (CRH) expression was increased in Atf6b-/- mice, as was circulating corticosterone. Moreover, CRH receptor 1 antagonism alleviated anxiety-like behavior in Atf6b-/- mice. These findings suggest that ATF6ß deficiency produces anxiety-like behavior and hyperactivity via a CRH receptor 1-dependent mechanism. ATF6ß could play a role in psychiatric conditions in the emotional centers of the brain.

New degradation mechanism of black tea pigment theaflavin involving condensation with epigallocatechin-3-O-gallate.

Theanaphthoquinone (TNQ) is the initial and main oxidation product of theaflavin, a representative black tea pigment. Nevertheless, TNQ is virtually undetected in the high-performance liquid chromatography analysis of black tea leaves using photodiode array detection. To elucidate the degradation mechanism of theaflavin in the black tea production process, this study investigated the reaction of TNQ with epigallocatechin-3-O-gallate (EGCg), which is the most abundant polyphenol in tea leaves. In citrate-phosphate buffer solution at pH 6 and room temperature, TNQ reacted nonenzymatically with EGCg to afford three products, whose structures were determined on the basis of spectroscopic data. The results indicated that the double bond of the ortho-naphthoquinone moiety in TNQ reacted with the autoxidation product of EGCg. This study demonstrates novel reactions occurring in the process of theaflavin degradation, which might be involved in the formation of thearubigins, the major black tea pigments composing oligomeric catechin oxidation products.

Relationship Between Physical Function and Health Utility in Patients Undergoing Surgical Treatment for Malignant Pleural Mesothelioma.

PURPOSE: Health utility, which is a measure of patient-reported outcome (PRO), has recently been used in health-related quality of life for patients with various cancers. However, the relationship between health utility and the physical function and of patients undergoing pleurectomy/decortication (P/D) as surgical treatment for malignant pleural mesothelioma (MPM) has not been reported in the perioperative and convalescent phases. This study aimed to evaluate the perioperative and postoperative health utility of patients undergoing P/D for MPM at one year postoperatively and to examine the relationship with physical function. METHODS: We included patients underwent P/D. Grip strength, knee extension strength, 6-minute walk distance (6MWD), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) were measured to assess physical function, and the Short-Form Six-Dimension (SF-6D) was completed to assess health utility. These assessments were performed preoperatively, postoperatively, and one year postoperatively. Statistical analysis was performed using one-way analysis of variance for comparison of pre and postoperative and one year mean values. RESULTS: There were 24 subjects (23 males, 65.5±8.3 year). SF-6D, 6MWD, FVC, and FEV1 values one year operatively improved significantly compared with postoperative. Additionally, SF-6D was correlated with 6MWD. CONCLUSION: Health utility were also correlated with exercise capacity.

Ellagitannin Digestion in Moth Larvae and a New Dimeric Ellagitannin from the Leaves of Platycarya strobilacea.

Ellagitannins (ETs) are plant polyphenols with various health benefits. Recent studies have indicated that the biological activities of ETs are attributable to their degradation products, including ellagic acid and its gut microflora metabolites, such as urolithins. Insect tea produced in the Guangxi region, China, is made from the frass of moth larvae that feed on the ET-rich leaves of Platycarya strobilacea. Chromatographic separation of the Guangxi insect tea showed that the major phenolic constituents are ellagic acid, brevifolin carboxylic acid, gallic acid, brevifolin, and polymeric polyphenols. Chemical investigation of the feed of the larvae, the fresh leaves of P. strobilacea, showed that the major polyphenols are ETs including pedunculagin, casuarictin, strictinin, and a new ET named platycaryanin E. The new ET was confirmed as a dimer of strictinin having a tergalloyl group. The insect tea and the leaves of P. strobilacea contained polymeric polyphenols, both of which were shown to be composed of ETs and proanthocyanidins by acid hydrolysis and thiol degradation. This study clarified that Guangxi insect tea contains ET metabolites produced in the digestive tract of moth larvae, and the metabolites probably have higher bioavailabilities than the original large-molecular ETs of the leaves of P. strobilacea.

Screening of Inhibitors Targeting Heat Shock Protein 47 Involved in the Development of Idiopathic Pulmonary Fibrosis.

Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is causally related to fibrotic diseases, including idiopathic pulmonary fibrosis. The identification of Compounds that interfere with the HSP47-collagen interaction is essential for the development of relevant therapeutics. Herein, we prepared human HSP47 as a soluble fusion protein expressed in E. coli and established an assay system for HSP47 inhibitor screening. We screened a natural and synthetic Compound library established at Nagasaki University. Among 1023 Compounds, 13 exhibited inhibitory activity against human HSP47, of which three inhibited its function in a dose-dependent manner. Epigallocatechin-3-O-gallate, one of these three Compounds, is a typical polyphenol Compound derived from tea leaves. Structurally related Compounds were synthesized and examined for their activity, revealing a hydroxyl group at A-ring position 5 as important for its activity. The present findings provide valuable insight for the development of natural product-derived therapeutics for fibrotic diseases, including idiopathic pulmonary fibrosis.

Production Mechanisms of Black Tea Polyphenols.

Black tea accounts for 70-80% of world tea production, and the polyphenols therein are produced by enzymatic oxidation of four tea catechins during tea fermentation. However, only limited groups of dimeric oxidation products, such as theaflavins, theasinensins, and theacitrins, have been isolated from black tea and chemically characterized. This is largely because of the complexity and heterogeneity of the oxidation products. To determine structures and production mechanisms of uncharacterized black tea polyphenols, in vitro model fermentation experiments using pure catechins and polyphenol oxidase have been applied, and basic oxidation mechanisms have been established. Contemporary methods, such as LC-MS, are also effective to identify catechin oxidation products in black tea. Despite ongoing efforts, almost 60% of the solids in black tea infusion remain uncharacterized. These compounds include the so-called thearubigins, which are a heterogeneous mixture of uncharacterized catechin oxidation products with oligomeric structures. This review summarizes the current knowledge of the production mechanisms of representative black tea polyphenols and presents recent progress in characterization of thearubigins.

Effect of Exercise on Mortality and Recurrence in Patients With Cancer: A Systematic Review and Meta-Analysis.

Purpose: Exercise could lower the risk of cancer recurrence and improve mortality, exercise capacity, physical and cardiovascular function, strength, and quality of life in patients with cancer. This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to determine the effects of exercise on mortality and recurrence in patients with cancer. Methods: We searched for articles published before May 2019 in MEDLINE, CINAHL, the Cochrane Library, Scopus, ProQuest, and PEDro. We included RCTs of exercise interventions, such as resistance exercise and aerobic exercise, in patients with cancer that evaluated the risk of mortality and recurrence. The standardized mean difference with 95% confidence intervals (CIs) was calculated for quantitative indices. The random-effect model was used as the pooling method. Results: Of 2868 retrieved articles, 8 RCTs were included in the meta-analysis, with a mean PEDro score of 4.50 (SD = 1.25). Exercise significantly reduced the risk of mortality in patients with cancer and in cancer survivors (risk ratio [RR] = 0.76, 95% CI = 0.40-0.93, I2 = 0%, P = .009). Exercise significantly reduced the risk of recurrence in cancer survivors (RR = 0.52, 95% CI = 0.29-0.92, I2 = 25%, P = .030). Conclusion: This study found that exercise has a favorable effect on mortality and recurrence in patients with cancer. However, the effect could not be fully determined due to data insufficiency.

Production of Ellagitannin Hexahydroxydiphenoyl Ester by Spontaneous Reduction of Dehydrohexa-hydroxydiphenoyl Ester.

Amariin is an ellagitannin with two dehydrohexahydroxydiphenoyl (DHHDP) moieties connecting glucose 2,4- and 3,6-hydroxy groups. This tannin is predominant in the young leaves of Triadica sebifera and Carpinus japonica. However, as the leaves grow, the 3,6-DHHDP is converted to its reduced form, the hexahydroxydiphenoyl (HHDP) group, to generate geraniin, a predominant ellagitannin of the matured leaves. The purified amariin is unstable in aqueous solution, and the 3,6-(R)-DHHDP is spontaneously degraded to give HHDP, whereas 2,4-(R)-DHHDP is stable. The driving force of the selective reduction of the 3,6-DHHDP of amariin is shown to be the conformational change of glucose from O,3B to 1C4. Heating geraniin with pyridine affords 2,4-(R)-DHHDP reduction products. Furthermore, the acid hydrolysis of geraniin yields two equivalents of ellagic acid. Although the reaction mechanism is still ambiguous, these results propose an alternative biosynthetic route of the ellagitannin HHDP groups.

Absorption and Metabolic Behavior of Hesperidin (Rutinosylated Hesperetin) after Single Oral Administration to Sprague-Dawley Rats.

We investigated the absorption and metabolic behavior of hesperidin (hesperetin-7-O-rutinoside) in the blood system of Sprague-Dawley rats by liquid chromatography- and matrix-assisted laser desorption ionization mass spectrometries (LC-MS and MALDI-MS). After a single oral administration of hesperidin (10 mg/kg), which was expected to be absorbed in its degraded hesperetin form, we detected intact hesperidin in the portal vein blood (tmax, 2 h) for the first time. We successfully detected glucuronized hesperidin in the circulating bloodstream, while intact hesperidin had disappeared. Further MS analyses revealed that homoeriodictyol and eriodictyol conjugates were detected in both portal and circulating blood systems. This indicated that hesperidin and/or hesperetin are susceptible to methylation and demethylation during the intestinal membrane transport process. Sulfated and glucuronized metabolites were also detected in both blood systems. In conclusion, hesperidin can enter into the circulating bloodstream in its conjugated forms, together with the conjugated forms of hesperetin, homoeriodictyol, and/or eriodictyol.

Oligomerization mechanism of tea catechins during tea roasting.

Roasting of green tea causes oligomerization of tea catechins, which decreases the astringency. The aim of this study was to elucidate the oligomerization mechanism. The 13C NMR spectrum of the oligomer fraction showed signals arising from catechin and sugar residues. Heating of epigallocatechin-3-O-gallate with 13C-labeled glucose (150 °C for 2 h) suggested that condensation of sugars with catechin A-rings caused the oligomerization. The dimeric product obtained by heating for a shorter period (30 min) suggested cross-linking occurred between sugars and catechin A-rings. Furthermore, heating of phloroglucinol, a catechin A-ring mimic, with glucose, methylglyoxal, and dihydroxyacetone, confirmed that the basic mechanism included reaction of the catechin A-ring methine carbons with carbonyl carbons of glucose and their pyrolysis products.

Solubility of Tannins and Preparation of Oil-Soluble Derivatives.

Tannins are plant defense substances that exhibit a strong astringent taste and precipitate proteins, leading to the inhibition of protein functions; however, owing to their relatively low toxicity, tannins must be accumulated in high concentrations in cell vacuoles. Therefore, the solubility of tannins is crucial for their functions. In this review, the structure and reactions of tannins related to solubility; insolubilization of persimmon proanthocyanidins on fruit ripening; pigment formation from cinnamon procyanidins by reaction with cinnamaldehyde in case of wounding; and insolubilization of ellagitannins in chestnut wood is discussed. In addition, the development of functional polyphenols including oil-soluble tea catechins is introduced.

Utilization of Flavonoid Compounds from Bark and Wood. III. Application in Health Foods.

Dietary supplements ACAPOLIA® and ACAPOLIA PLUS have been sold in Japan under the classification "Foods in General" for a number of years. In April 2015, the classification of "Foods with Function Claims" was introduced in Japan to make more products available to the public that were clearly labeled with functional claims based on scientific evidence. In order to obtain recognition of ACAPOLIA PLUS under this new classification, the following information needed to be established. The safety of the bark extract of Acacia mearnsii was shown from the history of the long-term safe consumption of the extract as a health supplement, together with several additional clinical safety tests. Robinetinidol-(4α,8)-catechin was detected by high performance liquid chromatography (HPLC) in the supplement and was suitable for use as the basis of the quantitative analysis. In clinical tests, the amount of change in the plasma glucose concentration in the initial 60 min after rice consumption by a test group who had been given the Acadia extract was significantly lower than the glucose concentration in the group that was given a placebo. The blood glucose incremental areas under the curve (IAUC) in the first 60 min after rice consumption were also significantly lower in the Acacia group. The functional mechanisms were explained in terms of the inhibition of the absorption of glucose in the small intestine and the reduction in the activity of the digestive enzymes caused by proanthocyanidins derived from A. mearnsii bark. As a result, ACAPOLIA PLUS was accepted as a "Food with Function Claims" in August 2016. ACAPOLIA PLUS is now sold under this new classification. The growth of a typical intestinal bacterium is inhibited by an extract containing flavonoid compounds from A. mearnsii bark; thus, one of the future directions of study must be a comprehensive investigation of the effect that flavonoid compounds, proanthocyanidins, have on intestinal bacteria.

Characterization of Proanthocyanidin Oligomers of Ephedra sinica.

Ephedra sinica, an important plant in Chinese traditional medicine, contains a complex mixture of proanthocyanidin oligomers as major constituents; however, only the minor components have been chemically characterized. In this study, oligomers with relatively large molecular weights, which form the main body of the proanthocyanidin fractions, were separated by adsorption and size-exclusion chromatography. Acid-catalyzed degradation in the presence of mercaptoethanol or phloroglucinol led to the isolation of 18 fragments, the structures of which were elucidated from their experimental and TDDFT-calculated ECD spectra. The results indicated that (-)-epigallocatechin was the main extension unit, while catechin, the A-type epigallocatechin-gallocatechin dimer, and the A-type epigallocatechin homodimer, were identified as the terminal units. Among the degradation products, thioethers of gallocatechin with 3,4-cis configurations, a B-type prodelphinidin dimer, a prodelphinidin trimer with both A- and B-type linkages, and a prodelphinidin dimer with an α-substituted A-type linkage were new compounds. In addition, a phloroglucinol adduct of an A-type prodelphinidin dimer, a doubly-linked phloroglucinol adduct of epigallocatechin, and a unique product with a flavan-3-ol skeleton generated by the rearrangement of the aromatic rings were also isolated.

Potential anti-cholinesterase and ß-site amyloid precursor protein cleaving enzyme 1 inhibitory activities of cornuside and gallotannins from Cornus officinalis fruits.

Cholinesterase (ChE) and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors are promising agents for the treatment of Alzheimer's disease (AD). In the present study, we examined the inhibitory activity of seven compounds isolated from the fruits of Cornus officinalis, cornuside, polymeric proanthocyanidins, 1,2,3-tri-O-galloyl-ß-D-glucose, 1,2,3,6-tetra-O-galloyl-ß-D-glucose, tellimagrandin I, tellimagrandin II, and isoterchebin, against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE1. All of the compounds displayed concentration-dependent in vitro inhibitory activity toward the ChEs and BACE1. Among them, tellimagrandin II exhibited the best inhibitory activity toward ChEs, whereas the best BACE1 inhibitor was 1,2,3,6-tetra-O-galloyl-ß-D-glucose. Isoterchebin and polymeric proanthocyanidins were also significant ChE inhibitors. The kinetic and docking studies demonstrated that all compounds interacted with both the catalytic active sites and the peripheral anionic sites of the ChEs and BACE1. Tellimagrandin II, isoterchebin, and the polymeric proanthocyanidins exhibited concentration-dependent inhibition of peroxynitrite-mediated protein tyrosine nitration. In conclusion, we identified significant ChE and BACE1 inhibitors from Corni Fructus that could have value as new multi-targeted compounds for anti-AD agents.

Phenolic Compounds from the Leaves of Castanopsis fargesii.

In the course of a phytochemical and chemotaxonomical investigation of Castanopsis species (Fagaceae), three new phenolic compounds, (3R,1'S)-[1'-(6″-O-galloyl-ß-d-gluco-pyranosyl)oxyethyl]-3-hydroxy-dihydrofuran-2(3H)-one (1), (2R,3S)-2-[2'-(galloyl)oxyethyl]-dihydroxybutanoic acid (2), and (3S,4S)-3-hydroxymethyl-3,4-dihydro-5,6,7-trihydroxy-4-(4'-hydroxy-3'-methoxyphenyl)-1H-[2]-benzopyran-1-one (3) were isolated from the fresh leaves of Castanopsis fargesii. In addition, a known phenolic glycoside, gentisic acid 5-O-α-l-rhamnopyranosyl-(1→2)-ß-d-glucopyranoside (4) was also isolated and identified. Their structures were elucidated by means of spectroscopic methods including one- and two-dimensional NMR techniques.