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Inserting a sulfur atom into the 1,2-dithiolane ring of lipoic acid (LA racemate) is a promising approach for improving the diversity of lipoic acid (LA racemate). For this purpose, we prepared 1,2,3-trisulfur–lipoic acid derivatives (trisulfur lipoic acid (R-enantiomer, TR-LA, trisulfur lipoamide, racemate TLPA)) by the reaction of R-LA (lipoic acid R-enantiomer) or lipoamide (LPA) and H2S and performed precise stereochemical studies. As a result, the 6-membered-1,2,3-trisulfur ring (TR-LA and TLPA) showed a completely different profile from that of the five-membered dithiolane compounds (R-LA and LPA) in 1H- and 13C-NMR spectroscopy. Raman spectroscopy of TR-LA and TLPA showed a different profile to that of LA and LPA, which also indicates the uniqueness of the 6-membered 1,2,3-trisulfur ring chromophore. The regeneration of lipoic acid from 1,2,3-trisulfur lipoic acid (TR-LA) was achieved using a phosphine derivative and sodium cyanide while maintaining the stereochemistry of the chirality center, with an almost quantitative yield.

Pyrrole-2-carboxaldehyde (Py-2-C) derivatives have been isolated from many natural sources, including fungi, plants (roots, leaves, and seeds), and microorganisms. The well-known diabetes molecular marker, pyrraline, which is produced after sequential reactions in vivo, has a Py-2-C skeleton. Py-2-Cs can be chemically produced by the strong acid-catalyzed condensation of glucose and amino acid derivatives in vitro. These observations indicate the importance of the Py-2-C skeleton in vivo and suggest that molecules containing this skeleton have various biological functions. In this review, we have summarized Py-2-C derivatives based on their origins. We also discuss the structural characteristics, natural sources, and physiological activities of isolated compounds containing the Py-2-C group.

Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that causes skeletal muscle insulin resistance. The circulating levels of LECT2 are a possible biomarker that can predict weight cycling because they reflect liver fat and precede the onset of weight loss or gain. Herein, to clarify the dynamics of this rapid change in serum LECT2 levels, we investigated the in vivo kinetics of LECT2, including its plasma half-life and tissue distribution, by injecting 125 I-labelled LECT2 into ICR mice and radioactivity tracing. The injected LECT2 was eliminated from the bloodstream within 10 min (approximate half-life, 5 min). In the kidneys, the radioactivity accumulated within 10 min after injection and declined thereafter. Conversely, the radioactivity in urine increased after 30 min of injection, indicating that LECT2 is mainly excreted by the kidneys into the urine. Finally, LECT2 accumulated in the skeletal muscle and liver until 30 min and 2 min after injection, respectively. LECT2 accumulation was not observed in the adipose tissue. These findings are in agreement with LECT2 action on the skeletal muscle. The present study indicates that LECT2 is a rapid-turnover protein, which renders the circulating level of LECT2 a useful rapid-response biomarker to predict body weight alterations.

Astaxanthin is a coloring agent which is used as a feed additive in aquaculture nutrition. Recently, potential health benefits of astaxanthin have been discussed which may be partly related to its free radical scavenging and antioxidant properties. Our electron spin resonance (ESR) and spin trapping data suggest that synthetic astaxanthin is a potent free radical scavenger in terms of diphenylpicryl-hydrazyl (DPPH) and galvinoxyl free radicals. Furthermore, astaxanthin dose-dependently quenched singlet oxygen as determined by photon counting. In addition to free radical scavenging and singlet oxygen quenching properties, astaxanthin induced the antioxidant enzyme paroxoanase-1, enhanced glutathione concentrations and prevented lipid peroxidation in cultured hepatocytes. Present results suggest that, beyond its coloring properties, synthetic astaxanthin exhibits free radical scavenging, singlet oxygen quenching, and antioxidant activities which could probably positively affect animal and human health.

Selenoprotein P is released from the liver and acts through LRP1 in the muscle to contribute to exercise resistance in mouse and man by inhibiting ROS levels via inhibition of AMPK and PGC-1α. Exercise has numerous health-promoting effects in humans 1 ; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly 2 , 3 , 4 . This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) 5 , 6 , 7 causes exercise resistance through its muscle receptor low-density lipoprotein receptor–related protein 1 (LRP1) 8 . SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation 9 and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a ) 10 expression in skeletal muscle. Supplementation with the anti-oxidant N -acetylcysteine (NAC) reduced ROS production and the endurance capacity in SeP-deficient mice. SeP treatment impaired hydrogen-peroxide-induced adaptations through LRP1 in cultured myotubes and suppressed exercise-induced AMPK phosphorylation and Ppargc1a gene expression in mouse skeletal muscle—effects which were blunted in mice with a muscle-specific LRP1 deficiency. Furthermore, we found that increased amounts of circulating SeP predicted the ineffectiveness of training on endurance capacity in humans. Our study suggests that inhibitors of the SeP–LRP1 axis may function as exercise-enhancing drugs to treat diseases associated with a sedentary lifestyle.

Three pyrrole alkaloid derivatives were isolated from the edible mushroom Basidiomycetes-X (Echigoshirayukidake) by water extraction followed by ethyl acetate fractionation. The chemical structures determined by MS and NMR were 4-[2-formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl] butanoic acid (compound I), 4-[2-formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl] butanamide (compound II), and 5-(hydroxymethyl)-1H-pyrrole-2-carboxaldehyde (compound III). Compound I was found to be the major component, followed by compound II, and compound III was the minor component. The dry powder of Basidiomycetes-X contained approximately 825 μg g−1 compound I and 484 μg g−1 compound II. Compound II was found to be a novel pyrrole aldehyde homologue not previously reported and thus is a specific component of this mushroom.

Oxidative stress induced by the accumulation of reactive oxygen species (ROS) has a causal role in the development of insulin resistance, whereas ROS themselves function as intracellular second messengers that promote insulin signal transduction. ROS can act both positively and negatively on insulin signaling, but the molecular mechanisms controlling these dual actions of ROS are not fully understood. Here, we directly treated H4IIEC hepatocytes with hydrogen peroxide (H2O2), a representative membrane-permeable oxidant and the most abundant ROS in cells, to identify the key factors determining whether ROS impair or enhance intracellular insulin signaling. Treatment with high concentrations of H2O2 (25-50 µM) for 3 h reduced insulin-stimulated Akt phosphorylation, and increased the phosphorylation of both JNK and its substrate c-Jun. In contrast, lower concentrations of H2O2 (5-10 µM) enhanced insulin-stimulated phosphorylation of Akt. Moreover, lower concentrations suppressed PTP1B activity, suggesting that JNK and phosphatases such as PTP1B may play roles in determining the thresholds for the diametrical effects of H2O2 on cellular insulin signaling. Pretreatment with antioxidant N-acetyl-L-cysteine (10 mM) canceled the signal-promoting action of low H2O2 (5 µM), and it canceled out further impairment of insulin of insulin signaling induced by high H₂O₂ (25 µM). Our results demonstrate that depending on its concentration, H2O2 can have the positive or negative effect on insulin signal transduction in H4IIEC hepatocytes, suggesting that the concentration of intracellular ROS may be a major factor in determining whether ROS impair or enhance insulin signaling.

α-Lipoic acid (LA) has the specific absorption band at 330 nm and is quite vulnerable to UV irradiation, affording a variety of compounds including polymeric materials and hydrogen sulfide. A better understanding of the photochemical reaction of LA has already been carried out focusing mainly on the reaction product analysis derived from LA. We re-investigated the photochemical reaction of LA focusing our attention on the fate of hydrogen sulfide (H2S) produced in the photochemical reaction procedure. The photoirradiation of LA in the presence of oxidized glutathione (GSSG) formed glutathione trisulfide (GSSSG) and a reduced form of glutathione (GSH). Similar results were obtained in the co-presence of cystine and dimethyl disulfide. The concentration of H2S was reaching the maximum concentration, which was gradually decreasing within 10 min after photoirradiation, while the concentration of GSSSG was increasing with the decrease of H2S concentration. The structural confirmation of GSSSG and the plausible mechanism for the formation of GSSSG are proposed based on the time-dependent and pH-dependent profile of the photoirradiation.

Secondary plant metabolites, e.g., polyphenols, are widely known as health-improving compounds that occur in natural functional foods such as pomegranates. While extracts generated from these fruits inhibit oxidative stress, the allocation of these effects to the different subgroups of substances, e.g., anthocyanins, “copigments” (polyphenols without anthocyanins), or polymeric compounds, is still unknown. Therefore, in the present study, polyphenols from pomegranate juice were extracted and separated into an anthocyanin and copigment fraction using adsorptive membrane chromatography. Phenolic compounds were determined by high performance liquid chromatography with photodiode array (HPLC–PDA) detection and HPLC-PDA electrospray ionization tandem mass spectrometry (HPLC–PDA–ESI–MS/MS), while the free radical scavenging activity of the pomegranate XAD‑7 extract and its fractions was evaluated by the Trolox equivalent antioxidant capacity (TEAC) assay and electron spin resonance (ESR) spectroscopy. Compared to juice, the total phenolic content and free radical scavenging potential was significantly higher in the pomegranate XAD-7 extract and its fractions. In comparison to the anthocyanin and copigment fraction, pomegranate XAD-7 extract showed the highest radical scavenging activity against galvinoxyl and DPPH radicals. Moreover, the enriched XAD-7 extract and its fractions were able to protect human hepatocellular HepG2 cells against oxidative stress induced by hydrogen peroxide. Overall, these results indicated that anthocyanins and copigments act together in reducing oxidative stress.

Lingonberries contain high contents of bioactive compounds such as chlorogenic acids and anthocyanins. In addition to radical scavenging and antioxidant activities, these compounds can protect cells from DNA damage. For this reason, lingonberries might be well suited for nutraceuticals or natural biomedicines. To assess these applications, the present study characterized and identified the most effective extract, only consisting of anthocyanins, copigments or a mixture of both, obtained from a lingonberry juice concentrate. An extract was generated by using a XAD-7 column followed by fractionation into anthocyanins and copigments using adsorptive membrane chromatography. After identification of main polyphenols by HPLC–photodiode array–electrospray ionization–tandem mass spectrometry, free radical scavenging activity was analyzed by electron spin resonance spectroscopy using 2,2-diphenyl-1-picrylhydrazyl and galvinoxyl radicals. Furthermore, cyclic voltammetry analyses and the Trolox equivalent antioxidant capacity (TEAC) assay were applied. Finally, the reactive oxygen species (ROS) reducing effects of the lingonberry extract and its fractions were evaluated in HepG2 cells. While the combination of anthocyanins and copigments possessed the highest antioxidant activities, all samples (XAD-7 extract, anthocyanin and copigment fraction) protected cells from oxidative stress. Thus, synergistic effects between phenolic compounds may be responsible for the high antioxidant potential of lingonberries, enabling their use as nutraceuticals.