Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study

Background: Glutathione plays crucial roles in the detoxification and antioxidant systems of cells and has been used to treat acute poisoning and chronic liver diseases by intravenous injection. This is a first study examining the therapeutic effects of oral administration of glutathione in patients with nonalcoholic fatty liver disease (NAFLD). Methods: The study was an open label, single arm, multicenter, pilot trial. Thirty-four NAFLD patients diagnosed using ultrasonography were prospectively evaluated. All patients first underwent intervention to improve their lifestyle habits (diet and exercise) for 3 months, followed by treatment with glutathione (300 mg/day) for 4 months. We evaluated their clinical parameters before and after glutathione treatment. We also quantified liver fat and fibrosis using vibration-controlled transient elastography. The primary outcome of the study was the change in alanine aminotransferase (ALT) levels. Results: Twenty-nine patients finished the protocol. ALT levels significantly decreased following treatment with glutathione for 4 months. In addition, triglycerides, non-esterified fatty acids, and ferritin levels also decreased with glutathione treatment. Following dichotomization of ALT responders based on a median 12.9% decrease from baseline, we found that ALT responders were younger in age and did not have severe diabetes compared with ALT non-responders. The controlled attenuation parameter also decreased in ALT responders. Conclusions: This pilot study demonstrates the potential therapeutic effects of oral administration of glutathione in practical dose for patients with NAFLD. Large-scale clinical trials are needed to verify its efficacy. Trial registration: UMIN000011118 (date of registration: July 4, 2013)

Prospects for Detecting Gamma-Ray Bursts at Very High Energies with the Cherenkov Telescope Array

We discuss the prospects for the detection of gamma-ray bursts (GRBs) by the Cherenkov Telescope Array (CTA), the next generation, ground-based facility of imaging atmospheric Cherenkov telescopes (IACTs) operating above a few tens of GeV. By virtue of its fast slewing capabilities, the lower energy threshold compared to current IACTs, and the much larger effective area compared to satellite instruments, CTA can measure the spectra and variability of GRBs with excellent photon statistics at multi-GeV energies. Employing a model of the GRB population whose properties are broadly consistent with observations by the Gamma-ray Burst Monitor (GBM) and Large Area Telescope (LAT) onboard Fermi, we simulate follow-up observations of GRBs with the Large Size Telescopes (LSTs), the component of CTA with the fastest slew speed and the best sensitivity at energies below a few hundred GeV. For our fiducial assumptions, we foresee that the LSTs can detect ~0.1 GRBs per year during the prompt phase and ~0.5 per year in the afterglow phase, considering only one array site and both GBM and the Space-based multi-band astronomical Variable Object Monitor (SVOM) as the alert instruments. The detection rates can be enhanced by a factor of about 5 and 6 for the prompt emission and the afterglow, respectively, assuming two array sites with the same sensitivity and that the GBM localization error can be reduced to less than 1 deg. The expected distribution of redshift and photon counts are presented, showing that despite the modest event rate, hundreds or more multi-GeV photons can be anticipated from a single burst once they are detected. We also study how the detection rate depends on the intrinsic GRB properties and the delay time between the burst trigger and the follow-up observation.Comment: 15 pages, 9 figures, accepted for publication in MNRA

An up-scattered cocoon emission model of Gamma-Ray Burst high-energy lags

The Fermi Gamma-ray Space Telescope recently detected the most energetic gamma-ray burst so far, GRB 080916C, and reported its detailed temporal properties in an extremely broad spectral range: (i) the time-resolved spectra are well described by broken power-law forms over the energy range of $10 {\rm keV}-10$ GeV, (ii) the high-energy emission (at $\epsilon > 100$ MeV) is delayed by $\approx 5$s with respect to the $\epsilon \lesssim 1$ MeV emission, and (iii) the emission onset times shift towards later times in the higher energy bands. We show that this behavior of the high-energy emission can be explained by a model in which the prompt emission consists of two components: one is the emission component peaking at $\epsilon \sim 1$ MeV due to the synchrotron-self-Compton radiation of electrons accelerated in the internal shock of the jet and the other is the component peaking at $\epsilon \sim 100$ MeV due to up-scattering of the photospheric X-ray emission of the expanding cocoon (i.e., the hot bubble produced by dissipation of the jet energy inside the progenitor star) off the same electrons in the jet. Based on this model, we derive some constraints on the radius of the progenitor star and the total energy and mass of the cocoon of this GRB, which may provide information on the structure of the progenitor star and the physical conditions of the jet propagating in the star. The up-scattered cocoon emission could be important for other Fermi-GRBs as well. We discuss some predictions of this model, including a prompt bright optical emission and a soft X-ray excess.Comment: emulateapj 16 pages, 5 figures, accepted version uploaded (no changes from v2). From v1, introduction and summary expanded, discussion on photospheric emission of jet (section 5.3) modified, discussion on other long and short GRBs (section 6) adde

JASMINE: Near-infrared astrometry and time-series photometry science

The Japan Astrometry Satellite Mission for INfrared Exploration (JASMINE) is a planned M-class science space mission by the Institute of Space and Astronautical Science, the Japan Aerospace Exploration Agency. JASMINE has two main science goals. One is Galactic archaeology with a Galactic Center survey, which aims to reveal the Milky Way’s central core structure and formation history from Gaia-level (∼25 ${\mu}$as) astrometry in the near-infrared (NIR) Hw band (1.0–1.6 ${\mu}$m). The other is an exoplanet survey, which aims to discover transiting Earth-like exoplanets in the habitable zone from NIR time-series photometry of M dwarfs when the Galactic Center is not accessible. We introduce the mission, review many science objectives, and present the instrument concept. JASMINE will be the first dedicated NIR astrometry space mission and provide precise astrometric information on the stars in the Galactic Center, taking advantage of the significantly lower extinction in the NIR. The precise astrometry is obtained by taking many short-exposure images. Hence, the JASMINE Galactic Center survey data will be valuable for studies of exoplanet transits, asteroseismology, variable stars, and microlensing studies, including discovery of (intermediate-mass) black holes. We highlight a swath of such potential science, and also describe synergies with other missions

Glutathione supplementation suppresses muscle fatigue induced by prolonged exercise via improved aerobic metabolism

Backgrounds: Glutathione is an endogenous redox couple in animal cells and plays important roles in antioxidant defense and detoxification, although it is unknown if oral glutathione supplementation affects exercise-induced physiological changes. The present study investigated the effect of glutathione intake on exercise-induced muscle metabolism and fatigue in mice and humans. Methods: ICR mice were divided into 4 groups: sedentary control, sedentary supplemented with glutathione (2.0%, 5μL/g body weight), exercise control, and exercise supplemented with glutathione. After 2weeks, the exercise groups ran on a treadmill at 25m/min for 30min. Immediately post-exercise, intermuscular pH was measured, and hind limb muscle and blood samples were collected to measure biochemical parameters. In a double-blind, cross-over study, 8 healthy men (35.9 ± 2.0 y) were administered either glutathione (1g/d) or placebo for 2weeks. Then, they exercised on a cycle ergometer at 40% maximal heart rate for 60min. Psychological state and blood biochemical parameters were examined after exercise. Results: In the mouse experiment, post-exercise plasma non-esterified fatty acids were significantly lower in the exercise supplemented with glutathione group (820 ± 44mEq/L) compared with the exercise control group (1152 ± 61mEq/L). Intermuscular pH decreased with exercise (7.17 ± 0.01); however, this reduction was prevented by glutathione supplementation (7.23 ± 0.02). The peroxisome proliferator-activated receptor-γ coactivator-1α protein and mitochondrial DNA levels were significantly higher in the sedentary supplemented with glutathione group compared with the sedentary control group (25% and 53% higher, respectively). In the human study, the elevation of blood lactate was suppressed by glutathione intake (placebo, 3.4 ± 1.1mM; glutathione, 2.9 ± 0.6mM). Fatigue-related psychological factors were significantly decreased in the glutathione trial compared with the placebo trial. Conclusions: These results suggest that glutathione supplementation improved lipid metabolism and acidification in skeletal muscles during exercise, leading to less muscle fatigue

The effect of Katsura-uri (Japanese pickling melon, Cucumis melo var. conomon) and its derived ingredient methylthioacetic acid on energy metabolism during aerobic exercise

[Purpose] We investigated the effect of Katsura-uri (Japanese pickling melon; Cucumis melo var. conomon) on energy metabolism during exercise in human and animal studies. Methods Eight healthy men (mean age, 21.4 ± 0.7 years) participated in a single-blind, crossover study. Thirty minutes after ingesting the Katsura-uri drink or placebo drink, they exercised on a cycle ergometer at 40% maximal heart rate for 30 min. Respiratory gas analysis was performed during exercise to examine oxygen consumption and substrate utilization. Blood biochemical parameters were evaluated during exercise. In the animal study, the effect of methylthioacetic acid (MTA), a Katsura-uri derived component was examined in mice. Immediately after running at 25 m/min for 30 min, biochemical parameters in the hind limb muscle and blood of mice were measured. [Results] Oxygen consumption during exercise was higher in the Katsura-uri condition (19.8 ± 3.5 mL/kg/min) than the placebo condition (18.6 ± 3.0 mL/kg/min) (P < 0.05). The elevation of blood lactate was lower in the Katsura-uri condition (1.7 ± 0.4 mM) than the placebo condition (2.2 ± 0.6 mM) 15 min after beginning exercise (P < 0.05). There was a higher positive correlation between lactate concentration and carbohydrate oxidation during exercise in the Katsura-uri condition (R2 = 0.86) compared to the placebo condition (R2 = 0.47). The decrease in intermuscular pH and the increase in blood lactate following exercise were prevented by MTA supplementation (250 ppm) with significant differences in the MTA-supplemented group compared to the control group. [Conclusions] These results suggest that the ingestion of Katsura-uri and/or MTA improves glucose metabolism and acidification in skeletal muscles during exercise in human and animal studies

Statuses of food-derived glutathione in intestine, blood, and liver of rat

Oral administration of glutathione has been demonstrated to reduce exercise-induced fatigue and improve liver function, although glutathione can be synthesized in the liver. However, little is known about the underlying mechanism of this effect. To address this, the status of food-derived glutathione in the intestine, blood, and liver was examined. Glutathione-1-13C or N-acetyl-cysteine-1-13C (NAC) was orally administered to rats (50 mg/kg). Food-derived glutathione contents within tissues were estimated by subtracting endogenous glutathione-1-13C from the total glutathione-1-13C. Food-derived glutathione was present in rat intestines and livers (approximately 60 and 300 μmol/kg, respectively, 120 min after ingestion) in electrochemically reduced form, while all food-derived glutathione in the blood plasma was conjugated with proteins and low-molecular-weight thiol compounds. However, no significant amounts of NAC-derived glutathione were detected in the blood plasma. These findings indicate that food-derived glutathione is directly absorbed in its electrochemically reduced form in the intestine, is then transported in the blood in bound forms, and is finally deposited into the liver in reduced form. Therefore, upon entering the bloodstream, food-derived glutathione binds to thiol compounds and releases hydrogen atom; subsequently, it does the reverse upon incorporation into the liver, which might impact the physiological redox condition. With respect to food-derived glutathione and cysteine-containing peptides, this study provides new insights on their modes of transportation and mechanisms of action

Induction of Cancer Stem Cell Properties in Colon Cancer Cells by Defined Factors

Cancer stem cells (CSCs) are considered to be responsible for the dismal prognosis of cancer patients. However, little is known about the molecular mechanisms underlying the acquisition and maintenance of CSC properties in cancer cells because of their rarity in clinical samples. We herein induced CSC properties in cancer cells using defined factors. We retrovirally introduced a set of defined factors (OCT3/4, SOX2 and KLF4) into human colon cancer cells, followed by culture with conventional serum-containing medium, not human embryonic stem cell medium. We then evaluated the CSC properties in the cells. The colon cancer cells transduced with the three factors showed significantly enhanced CSC properties in terms of the marker gene expression, sphere formation, chemoresistance and tumorigenicity. We designated the cells with CSC properties induced by the factors, a subset of the transduced cells, as induced CSCs (iCSCs). Moreover, we established a novel technology to isolate and collect the iCSCs based on the differences in the degree of the dye-effluxing activity enhancement. The xenografts derived from our iCSCs were not teratomas. Notably, in contrast to the tumors from the parental cancer cells, the iCSC-based tumors mimicked actual human colon cancer tissues in terms of their immunohistological findings, which showed colonic lineage differentiation. In addition, we confirmed that the phenotypes of our iCSCs were reproducible in serial transplantation experiments. By introducing defined factors, we generated iCSCs with lineage specificity directly from cancer cells, not via an induced pluripotent stem cell state. The novel method enables us to obtain abundant materials of CSCs that not only have enhanced tumorigenicity, but also the ability to differentiate to recapitulate a specific type of cancer tissues. Our method can be of great value to fully understand CSCs and develop new therapies targeting CSCs