Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness ...the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC
values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.
Current pharmacological treatments for Parkinson’s disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible ...dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.
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•Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD•Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits•Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation
Heo et al. report that astrocytic GABA-mediated aberrant tonic inhibition of DA neurons leads to a reduction in TH expression and dopamine production, causing dormant DA neurons and motor deficits. Blocking astrocytic GABA synthesis by MAO-B inhibition or optogenetic activation of dormant DA neurons reverses PD pathology.
Abstract
RR Telescopii (RR Tel) is an interacting binary system in which a hot white dwarf (WD) accretes matter from a Mira-type variable star via gravitational capture of its stellar wind. This ...symbiotic nova shows intense Raman-scattered O
vi
1032 and 1038 features at 6825 and 7082 Å. We present high-resolution optical spectra of RR Tel taken in 2016 and 2017 with the Magellan Inamori Kyocera Echelle (MIKE) spectrograph at the Magellan-Clay telescope, Chile. We aim to study the stellar wind accretion in RR Tel from the profile analysis of Raman O
vi
features. With an asymmetric O
vi
disk model, we derive a representative Keplerian speed of >35 km s
−1
, and the corresponding scale <0.8 au. The best fit for the Raman profiles is obtained with a mass-loss rate of the Mira
M
̇
∼
2
×
10
−
6
M
⊙
yr
−
1
and a wind terminal velocity
v
∞
∼ 20 km s
−1
. We compare the MIKE data with an archival spectrum taken in 2003 with the Fiber-fed Extended Range Optical Spectrograph at the MPG/ESO 2.2 m telescope. It allows us to highlight the profile variation of the Raman O
vi
features, indicative of a change in the density distribution of the O
vi
disk in the last two decades. We also report the detection of O
vi
recombination lines at 3811 and 3834 Å, which are blended with other emission lines. Our profile decomposition suggests that the recombination of O
vii
takes place nearer to the WD than the O
vi
1032 and 1038 emission region.
Diethylnitrosamine (DEN) is a potent toxic material that can cause necrosis and subsequent fibrosis in the liver. Based on the previously reported hepatoprotective effect of Limonium tetragonum ...against the proliferation of hepatic stellate cells, we tested the EtOAc soluble fraction of L. tetragonum extract (EALT) in a DEN-induced hepatotoxic rat model. The development of hepatotoxicity including mononuclear cell infiltration and fibrosis induced by intraperitoneal injections of DEN (70 mg/2 mL/kg body weight (b.w.) per week) was observed at 4, 6 and 8 weeks after the first DEN treatment. Administration of EALT (200 mg/kg body weight, per os (p.o.)) induced significant reductions in serum alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and triglycerides (TG) in DEN-injected rats. Increased oxidative stress in DEN-induced liver fibrosis rats was diminished by EALT treatment through a decrease in malondialdehyde (MDA) and increase in superoxide dismutase (SOD). Histologic findings that included markedly attenuated mononuclear cell infiltration and fibrosis could be observed in liver samples from the EALT-treated groups. An extract of Hovenia dulcis fruit and Sylimarin were used as positive controls. The present study provides direct experimental evidence for EALT attenuated hepatic injury and fibrosis in DEN-treated mice. The L. tetragonum EtOAc fraction might be useful in treating fibrotic liver diseases.
Sarcopenia is defined as the involuntary loss of skeletal muscle mass and function with aging and is associated with several adverse health outcomes. Recently, the disruption of regular circadian ...rhythms, due to shift work or nocturnal lifestyle, is emerging as a novel deleterious factor for the development of sarcopenia. The underlying mechanisms responsible for circadian disruption-induced sarcopenia include molecular circadian clock and mitochondrial function associated with the regulation of circadian rhythms. Exercise is a potent modulator of skeletal muscle metabolism and is considered to be a crucial preventative and therapeutic intervention strategy for sarcopenia. Moreover, emerging evidence shows that exercise, acting as a zeitgeber (time cue) of the skeletal muscle clock, can be an efficacious tool for re-setting the clock in sarcopenia. In this review, we provide the evidence of the impact of circadian disruption on skeletal muscle loss resulting in sarcopenia. Furthermore, we highlight the importance of exercise timing (i.e., scheduled physical activity) as a novel therapeutic strategy to target circadian disruption in skeletal muscle.
Halophyte Limonium tetragonum has recently been of interest in Korea for its nutritional value and salty taste which made it an ideal vegetable. In this study, the potential of L. tetragonum ...preventing excess weight gain, obesity and the related health problem has been evaluated in vitro and in vivo. The treatment with 100 mg/kg of L. tetragonum EtOAc soluble fraction (EALT) apparently prevented the body weight gain, adipose tissue weight gain, and the increase of triglyceride and total cholesterol level in mice fed a high-fat diet for 8 weeks. In addition, both glucose tolerance and insulin resistance in dietary obese mice were improved by EALT administration. A marked decrease in adipocyte differentiation was observed in the EALT (50 µg/mL)-treated 3T3-L1 cells, which was mediated by the suppression of adipogenesis-related transcription factors including peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer binding protein (C/EBP)α, and Sterol regulatory element binding protein-1 (SREBP-1) and adipocyte-specific proteins such as fatty acid synthase (FAS), lipoprotein lipase (LPL), and adipocyte fatty acid-binding protein (aP2). The major components contained in EALT were identified as (−)-epigallocatechin-3-(3″-O-methyl) gallate, (−)-epigallocatechin-3-gallate, and myricetin-3-O-β-D-galactopyranoside based on its phytochemical analysis. Results suggested that EALT might be available as functional crop and bioactive diet supplement for the prevention and/or treatment of obesity.
Emodin, an active constituent of oriental herbs, is widely used to treat allergy, inflammation, and other symptoms. This study provides the scientific basis for the anti-inflammasome effects of ...emodin on both in vitro and in vivo experimental models. Bone marrow-derived macrophages were used to study the effects of emodin on inflammasome activation by using inflammasome inducers such as ATP, nigericin, and silica crystals. The lipopolysaccharide (LPS)-induced endotoxin shock model was employed to study the effect of emodin on in vivo efficacy. Emodin treatment attenuated interleukin (IL)-1β secretion via the inhibition of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation induced by ATP, nigericin, and silica crystals. Further, emodin ameliorated the severity of NLRP3 inflammasome-mediated symptoms in LPS-induced endotoxin mouse models. This study is the first to reveal mechanism-based evidence, especially with respect to regulation of inflammasome activation, substantiating traditional claims of emodin in the treatment of inflammation-related disorders.
ABSTRACT We present a detailed modeling of the two broad bands observed at 6825 and 7082 in Sanduleak's star, a controversial object in the Large Magellanic Cloud. These bands are known to originate ...from Raman scattering of O vi λλ 1032 and 1038 photons with atomic hydrogen and are only observed in bona fide symbiotic stars. Our high-resolution spectrum obtained with the Magellan Inamori Kyocera Echelle spectrograph at the Magellan-Clay Telescope reveals, quite surprisingly, that the profiles of the two bands look very different: while the Raman 6825 band shows a single broad profile with a redward extended bump, the Raman 7082 band exhibits a distinct triple-peak profile. Our model suggests that the O vi emission nebula can be decomposed into a red, blue, and central emission region from an accretion disk, a bipolar outflow, and a further compact, optically thick region. We also perform Monte Carlo simulations with the aim of fitting the observed flux ratio F(6825)/F(7082) ∼ 4.5, which indicates that the neutral region in Sanduleak's star is characterized by the column density NH i ∼ 1 × 1023 cm−2.
•16 PFAAs in 397 samples of 66 food types and 34 tap water samples were analyzed.•Dietary exposure to PFAAs was estimated by using the PFAAs measured concentrations.•The major contributors of PFAAs ...dietary exposure were confirmed.
We measured concentrations of PFAAs in 397 foods, of 66 types, in Korea, and determined the daily human dietary PFAAs intake and the contribution of each foodstuff to that intake. The PFAAs concentration in the 66 different food types ranged from below the detection limit to 48.3ng/g. Perfluorooctane sulfonate (PFOS) and long-chain perfluorocarboxylic acids (PFCAs) were the dominant PFAAs in fish, shellfish, and processed foods, while perfluorooctanoic acid (PFOA) and short-chain PFCAs dominated dairy foodstuffs and beverages. The Korean adult dietary intake ranges, estimated for a range of scenarios, were 0.60–3.03 and 0.17–1.68ngkg−1bwd−1 for PFOS and PFOA, respectively, which were lower than the total daily intake limits suggested by European Food Safety Authority (PFOS: 150ngkg−1bwd−1; PFOA: 1500ngkg−1bwd−1). The major contributors to PFAAs dietary exposure varied with subject age and PFAAs. For example, fish was a major contributor of PFOS but dairy foods were major contributors of PFOA. However, tap water was a major contributor to PFOA intake when it was the main source of drinking water (rather than bottled water).
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