Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to ...metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in β-oxidation following suppression of transactivation by PPARα. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPARα to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPARα activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPARα activation upon fasting by promoting degradation of NCoR1 and thus regulates β-oxidation and ketone bodies production.
We present Mass Spectrometry-Data Independent Analysis software version 4 (MS-DIAL 4), a comprehensive lipidome atlas with retention time, collision cross-section and tandem mass spectrometry ...information. We formulated mass spectral fragmentations of lipids across 117 lipid subclasses and included ion mobility tandem mass spectrometry. Using human, murine, algal and plant biological samples, we annotated and semiquantified 8,051 lipids using MS-DIAL 4 with a 1-2% estimated false discovery rate. MS-DIAL 4 helps standardize lipidomics data and discover lipid pathways.
Fast ionic conductors have considerable potential to enable technological development for energy storage and conversion. Hydride (H
) ions are a unique species because of their natural abundance, ...light mass, and large polarizability. Herein, we investigate characteristic H
conduction, i.e., fast ionic conduction controlled by a pre-exponential factor. Oxygen-doped LaH
(LaH
O
) has an optimum ionic conductivity of 2.6 × 10
S cm
, which to the best of our knowledge is the highest H
conductivity reported to date at intermediate temperatures. With increasing oxygen content, the relatively high activation energy remains unchanged, whereas the pre-exponential factor decreases dramatically. This extraordinarily large pre-exponential factor is explained by introducing temperature-dependent enthalpy, derived from H
trapped by lanthanum ions bonded to oxygen ions. Consequently, light mass and large polarizability of H
, and the framework comprising densely packed H
in LaH
O
are crucial factors that impose significant temperature dependence on the potential energy and implement characteristic fast H
conduction.
Oxidized phospholipids (OxPLs) are widely held to be associated with various diseases, such as arteriosclerosis, diabetes, and cancer. To characterize the structure-specific behavior of OxPLs and ...their physiological relevance, we developed a comprehensive analytical method by establishing a measured MS/MS spectra library of OxPLs. Biogenic OxPLs were prepared by the addition of specific oxidized fatty acids to cultured cells, where they were incorporated into cellular phospholipids, and untargeted lipidomics by LC-quadrupole/TOF-MS was applied to collect MS/MS spectra for the OxPLs. Based on the measured MS/MS spectra for about 400 molecular species of the biogenic OxPLs, we developed a broad-targeted lipidomics system using triple quadrupole MS. Separation precision of structural isomers was optimized by multiple reaction monitoring analysis and this system enabled us to detect OxPLs at levels as low as 10 fmol. When applied to biological samples, i.e., mouse peritoneal macrophages, this system enabled us to monitor a series of OxPLs endogenously produced in a 12/15-lipoxygenase-dependent manner. This advanced analytical method will be useful to elucidate the structure-specific behavior of OxPLs and their physiological relevance in vivo.
Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, ...we identified glutaminase 1 (
) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.
The prevalence of cancer‐related pain is 64% among patients with metastatic, advanced, or terminal cancer, 59% among patients undergoing anticancer treatment, and 33% among patients who completed ...curative treatment. According to the World Health Organization cancer pain relief guidelines, opioid analgesics are the mainstay analgesic therapy in addition to conventional first‐step analgesics, such as non‐steroidal anti‐inflammatory drugs and acetaminophen. The indications for strong opioids have recently been expanded to include mild‐to‐moderate pain in addition to moderate‐to‐severe pain. The U.S. Centers for Disease Control and Prevention guidelines emphasize that realistic expectations should be weighed against potential serious harm from opioids, rather than relying on the unrealized long‐term benefits of these drugs. Therefore, treatment strategies for both cancer‐related chronic or acute pain have been unfortunately deviated from opioid analgesics. The barriers hindering adequate cancer‐related pain management with opioid analgesics are related to the inadequate knowledge of opioid analgesics (e.g., effective dose, adverse effects, and likelihood of addiction or tolerance). To achieve adequate opioid availability, these barriers should be overcome in a clinically suitable manner. Genetic assessments could play an important role in overcoming challenges in opioid management. To balance the improvement in opioid availability and the prevention of opioid misuse and addiction, the following two considerations concerning opioids and genetic polymorphisms warrant attention: (A) pain severity, opioid sensitivity, and opioid tolerance; and (B) vulnerability to opioid dependence and addiction.
Low thermal conductivity is favorable for preserving the temperature gradient between the two ends of a thermoelectric material, in order to ensure continuous electron current generation. In ...high-performance thermoelectric materials, there are two main low thermal conductivity mechanisms: the phonon anharmonic in PbTe and SnSe, and phonon scattering resulting from the dynamic disorder in AgCrSe
and CuCrSe
, which have been successfully revealed by inelastic neutron scattering. Using neutron scattering and ab initio calculations, we report here a mechanism of static local structure distortion combined with phonon-anharmonic-induced ultralow lattice thermal conductivity in α-MgAgSb. Since the transverse acoustic phonons are almost fully scattered by the compound's intrinsic distorted rocksalt sublattice, the heat is mainly transported by the longitudinal acoustic phonons. The ultralow thermal conductivity in α-MgAgSb is attributed to its atomic dynamics being altered by the structure distortion, which presents a possible microscopic route to enhance the performance of similar thermoelectric materials.
We report a method for comprehensive structural characterization of lipids in animal tissues using a combination of differential ion mobility spectrometry (DMS) with electron-impact excitation of ...ions from organics (EIEIO) mass spectrometry. Singly charged lipid ions in protonated or sodiated forms were dissociated by an electron beam having a kinetic energy of 10 eV in a branched radio-frequency ion trap. We established a comprehensive set of diagnostics to characterize the structures of glycerophospholipids, sphingolipids, and acylglycerols, including glycosylated, plasmalogen, and ester forms. This EIEIO mass spectrometer was combined with DMS as a separation tool to analyze complex lipid extracts. Deuterated quantitative standards, which were added during extraction, allowed for the quantitative analysis of the lipid molecular species in various lipid classes. We applied this technique to the total lipids extracted from porcine brain, and we structurally characterized over 300 lipids (with the exception of cis/trans double-bond isomerism in the acyl chains). The structural dataset of the lipidomes, whose regioisomers were distinguished, exhibit a uniquely defined distribution of acyl chains within each lipid class; that is, sn-1 and sn-2 in the cases of glycerophospholipids or sn-2 and (sn-1, sn-3) in the cases of triacylglycerols.
Long‐chain acyl‐coenzyme A (CoA) synthetase 3 (ACSL3) is an androgen‐responsive gene involved in the generation of fatty acyl‐CoA esters. ACSL3 is expressed in both androgen‐sensitive and ...castration‐resistant prostate cancer (CRPC). However, its role in prostate cancer remains elusive. We overexpressed ACSL3 in androgen‐dependent LNCaP cells and examined the downstream effectors of ACSL3. Furthermore, we examined the role of ACSL3 in the androgen metabolism of prostate cancer. ACSL3 overexpression led to upregulation of several genes such as aldo‐keto reductase 1C3 (AKR1C3) involved in steroidogenesis, which utilizes adrenal androgen dehydroepiandrosterone sulfate (DHEAS) as substrate, and downregulated androgen‐inactivating enzyme UDP‐glucuronosyltransferase 2 (UGT2B). Exposure to DHEAS significantly increased testosterone levels and cell proliferative response in ACSL3‐overexpressing cells when compared to that in control cells. A public database showed that ACSL3 level was higher in CRPC than in hormone‐sensitive prostate cancer. CRPC cells showed an increased expression of ACSL3 and an expression pattern of AKR1C3 and UGT2B similar to ACSL3‐overexpressing cells. DHEAS stimulation significantly promoted the proliferation of CRPC cells when compared to that of LNCaP cells. These findings suggest that ACSL3 contributes to the growth of CRPC through intratumoral steroidogenesis (i.e. promoting androgen synthesis from DHEAS and preventing the catabolism of active androgens).
Long‐chain acyl‐coenzyme A synthetase 3 (ACSL3) expression is increased in both hormone sensitive and refractory prostate cancer. We found that ACSL3 contributes to intratumoral steroidogenesis by modulating steroidogenic genes, thereby promoting the growth of hormone refractory prostate cancer.
Abstract
Opioid addiction and the opioid overdose epidemic are becoming more serious, and the development of therapeutic agents is essential for the pharmacological treatment of substance use ...disorders. The κ-opioid receptor (KOP) is a member of the opioid receptor system that has been gaining attention as a promising molecular target for the treatment of numerous human disorders, including pain, depression, anxiety, and drug addiction. Here, we biologically and pharmacologically evaluated a novel azepane-derived ligand, NP-5497-KA, as a selective KOP agonist. NP-5497-KA had 1000-fold higher selectivity for the KOP over the μ-opioid receptor (MOP), which was higher than nalfurafine (KOP/MOP: 65-fold), and acted as a selective KOP full agonist in the 3′,5′-cyclic adenosine monophosphate assay. The oral administration of NP-5497-KA (1–10 mg/kg) dose-dependently suppressed morphine-induced conditioned place preference in C57BL/6 J mice, and its effects were comparable to an intraperitoneal injection of nalfurafine (1–10 μg/kg). Nalfurafine (10 μg/kg) significantly inhibited rotarod performance, whereas NP-5497-KA (10 mg/kg) exerted no effect on rotarod performance. These results indicate that NP-5497-KA may be a novel option for the treatment of opioid use disorder with fewer side effects.
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