Adverse childhood experiences (ACE) such as sexual and physical abuse or neglect are frequent in childhood and constitute a massive stressor with long-lasting adverse effects on the brain, mental and ...physical health.The aim of this qualitative review is to present a concise overview of the present literature on the impact of ACE on neurobiology, mental and somatic health in later adulthood.
The authors reviewed the existing literature on the impact of ACE on neurobiology, mental and somatic health in later adulthood and summarized the results for a concise qualitative overview.
In adulthood, the history of ACE can result in complex clinical profiles with several co-occurring mental and somatic disorders such as posttraumatic stress disorder, depression, borderline personality disorder, obesity and diabetes. Although a general stress effect in the development of the disorders and neural alterations can be assumed, the role of type and timing of ACE is of particular interest in terms of prevention and treatment of ACE-related mental and somatic conditions. It has been suggested that during certain vulnerable developmental phases the risk for subsequent ACE-related disorders is increased. Moreover, emerging evidence points to sensitive periods and specificity of ACE-subtypes in the development of neurobiological alterations, e.g., volumetric and functional changes in the amygdala and hippocampus.
Longitudinal studies are needed to investigate complex ACE-related characteristics and mechanisms relevant for mental and somatic disorders by integrating
knowledge and methods. By identifying and validating psychosocial and somatic risk factors and diagnostic markers one might improve the development of innovative somatic and psychological treatment options for individuals suffering from ACE-related disorders.
Idiopathic pulmonary fibrosis (IPF) involves the accumulation of α-smooth muscle actin-expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-β1 ...(TGF-β1) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF.
We aimed to define an association between mtDNA and fibroblast responses in IPF.
We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGF-β1 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, as well as in plasma samples from two longitudinal IPF cohorts and demographically matched control subjects.
Exposure to mtDNA augments α-smooth muscle actin expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGF-β1 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival.
These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.
Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1β (IL-1β) drives gouty flares ...that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases β-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1β in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.
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•Inflammation and joint pathology during gout flare is prevented by ketogenic diet•BHB inhibits IL-1β secretion from neutrophils•Ketogenic diet and BHB inhibit NLRP3 activation in aged neutrophils•BHB inhibits both priming and assembly steps of NLRP3 activation in neutrophils
NLRP3 inflammasome activation in macrophages and neutrophils drives painful inflammation during gout. Goldberg et al. report that ketogenic diet prevents systemic inflammation and joint damage in a rat model of gouty flare. Mechanistically, the ketone body β-hydroxybutyrate, the most abundant ketone in vivo, inhibits NLRP3/caspase-1-dependent IL-1β secretion from neutrophils.
Dysregulation of several metabolite pathways, including branched-chain amino acids (BCAAs), are associated with Non-Alcoholic Fatty Liver Disease (NAFLD) and insulin resistance in adults, while ...studies in youth reported conflicting results. We explored whether, independently of obesity and insulin resistance, obese adolescents with NAFLD display a metabolomic signature consistent with disturbances in amino acid and lipid metabolism. A total of 180 plasma metabolites were measured by a targeted metabolomic approach in 78 obese adolescents with (
= 30) or without (
= 48) NAFLD assessed by magnetic resonance imaging (MRI). All subjects underwent an oral glucose tolerance test and subsets of patients underwent a two-step hyperinsulinemic-euglycemic clamp and/or a second MRI after a 2.2 ± 0.8-year follow-up. Adolescents with NAFLD had higher plasma levels of valine (
= 0.02), isoleucine (
= 0.03), tryptophan (
= 0.02), and lysine (
= 0.02) after adjustment for confounding factors. Circulating BCAAs were negatively correlated with peripheral and hepatic insulin sensitivity. Furthermore, higher baseline valine levels predicted an increase in hepatic fat content (HFF) at follow-up (
= 0.01). These results indicate that a dysregulation of BCAA metabolism characterizes obese adolescents with NAFLD independently of obesity and insulin resistance and predict an increase in hepatic fat content over time.
While large, myelinated dorsal root ganglion (DRG) neurons are capable of firing at high frequencies, small unmyelinated DRG
neurons typically display much lower maximum firing frequencies. However, ...the molecular basis for this difference has not
been delineated. Because the sodium currents in large DRG neurons exhibit rapid repriming (recovery from inactivation) kinetics
and the sodium currents in small DRG neurons exhibit predominantly slow repriming kinetics, it has been proposed that differences
in sodium channels might contribute to the determination of repetitive firing properties in DRG neurons. A recent study demonstrated
that Na v 1.7 expression is negatively correlated with conduction velocity and DRG cell size, while the Na v 1.6 voltage-gated sodium channel has been implicated as the predominant isoform present at nodes of Ranvier of myelinated
fibres. Therefore we characterized and compared the functional properties, including repriming, of recombinant Na v 1.6 and Na v 1.7 channels expressed in mouse DRG neurons. Both Na v 1.6 and Na v 1.7 channels generated fast-activating and fast-inactivating currents. However recovery from inactivation was significantly
faster (â¼5-fold at â70 mV) for Na v 1.6 currents than for Na v 1.7 currents. The recovery from inactivation of Na v 1.6 channels was also much faster than that of native tetrodotoxin-sensitive sodium currents recorded from small spinal sensory
neurons, but similar to that of tetrodotoxin-sensitive sodium currents recorded from large spinal sensory neurons. Development
of closed-state inactivation was also much faster for Na v 1.6 currents than for Na v 1.7 currents. Our results indicate that the firing properties of DRG neurons can be tuned by regulating expression of different
sodium channel isoforms that have distinct repriming and closed-state inactivation kinetics.
Mitophagy can selectively remove damaged toxic mitochondria, protecting a cell from apoptosis. The molecular spatial–temporal mechanisms governing autophagosomal selection of reactive oxygen species ...(ROS)‐damaged mitochondria, particularly in a platelet (no genomic DNA for transcriptional regulation), remain unclear. We now report that the mitochondrial matrix protein MsrB2 plays an important role in switching on mitophagy by reducing Parkin methionine oxidation (MetO), and transducing mitophagy through ubiquitination by Parkin and interacting with LC3. This biochemical signaling only occurs at damaged mitochondria where MsrB2 is released from the mitochondrial matrix. MsrB2 platelet‐specific knockout and in vivo peptide inhibition of the MsrB2/LC3 interaction lead to reduced mitophagy and increased platelet apoptosis. Pathophysiological importance is highlighted in human subjects, where increased MsrB2 expression in diabetes mellitus leads to increased platelet mitophagy, and in platelets from Parkinson's disease patients, where reduced MsrB2 expression is associated with reduced mitophagy. Moreover, Parkin mutations at Met192 are associated with Parkinson's disease, highlighting the structural sensitivity at the Met192 position. Release of the enzyme MsrB2 from damaged mitochondria, initiating autophagosome formation, represents a novel regulatory mechanism for oxidative stress‐induced mitophagy.
Synopsis
Mitophagy can be selectively switched on at sites of oxidatively damaged mitochondria: MsrB2 mediates these actions by switching on Parkin and transducing activation through LC3. This mechanism in found in diabetic platelets and may be important for Parkinson's disease.
MsrB2 removes reduces oxidized methionine back to its native state and is induced in diabetic platelets.
Parkin Met192 is oxidized in a high oxidative stress environment leading to Parkin dysfunction, aggregation and prevention of mitophagy.
MsrB2 released from damaged mitochondria reduces MetO192 restoring Parkin's function (switch), allowing ubiquitination of MsrB2 and interaction with LC3 (transducer). The process of mitophagy is restored, protecting against apoptosis.
The association of mutation of Met192 with Parkinson's disease led to studies that demonstrate a reduction in MsrB2 in patients with Parkinson's disease.
Mitophagy can be selectively switched on at sites of oxidatively damaged mitochondria: MsrB2 mediates these actions by switching on Parkin and transducing activation through LC3. This mechanism in found in diabetic platelets and may be important for Parkinson's disease.
Although rat brain Nav1.3 voltage-gated sodium channels have been expressed and studied in Xenopus oocytes, these channels have not been studied after their expression in mammalian cells. We ...characterized the properties of the rat brain Nav1.3 sodium channels expressed in human embryonic kidney (HEK) 293 cells. Nav1.3 channels generated fast-activating and fast-inactivating currents. Recovery from inactivation was relatively rapid at negative potentials (<-80 mV) but was slow at more positive potentials. Development of closed-state inactivation was slow, and, as predicted on this basis, Nav1.3 channels generated large ramp currents in response to slow depolarizations. Coexpression of beta3 subunits had small but significant effects on the kinetic and voltage-dependent properties of Nav1.3 currents in HEK 293 cells, but coexpression of beta1 and beta2 subunits had little or no effect on Nav1.3 properties. Nav1.3 channels, mutated to be tetrodotoxin-resistant (TTX-R), were expressed in SNS-null dorsal root ganglion (DRG) neurons via biolistics and were compared with the same construct expressed in HEK 293 cells. The voltage dependence of steady-state inactivation was approximately 7 mV more depolarized in SNS-null DRG neurons, demonstrating the importance of background cell type in determining physiological properties. Moreover, consistent with the idea that cellular factors can modulate the properties of Nav1.3, the repriming kinetics were twofold faster in the neurons than in the HEK 293 cells. The rapid repriming of Nav1.3 suggests that it contributes to the acceleration of repriming of TTX-sensitive (TTX-S) sodium currents that are seen after peripheral axotomy of DRG neurons. The relatively rapid recovery from inactivation and the slow closed-state inactivation kinetics of Nav1.3 channels suggest that neurons expressing Nav1.3 may exhibit a reduced threshold and/or a relatively high frequency of firing.
Preliminary evidence suggests that the glutamate-serine-glycine (GSG) index, which combines three amino acids involved in glutathione synthesis, may be used as a potential biomarker of non-alcoholic ...fatty liver disease (NAFLD). We investigated whether the GSG index is associated with NAFLD in youth, independent of other risk factors. Intrahepatic fat content (HFF%) and abdominal fat distribution were measured by magnetic resonance imaging (MRI) in a multiethnic cohort of obese adolescents, including Caucasians, African Americans, and Hispanics. NAFLD was defined as HFF% ≥ 5.5%. Plasma amino acids were measured by mass spectrometry. The GSG index was calculated as glutamate/(serine + glycine). The GSG index was higher in NAFLD patients (
= 0.03) and positively correlated with HFF% (r = 0.26,
= 0.02), alanine aminotransferase (r = 0.39,
= 0.0006), and aspartate aminotransferase (r = 0.26,
= 0.03). Adolescents with a high GSG index had a twofold higher prevalence of NAFLD than those with a low GSG index, despite similar adiposity, abdominal fat distribution, and liver insulin resistance. NAFLD prevalence remained significantly different between groups after adjustment for age, sex, race/ethnicity, and body mass index (OR 3.07, 95% confidence interval 1.09-8.61,
= 0.03). This study demonstrates the ability of the GSG index to detect NAFLD in at-risk pediatric populations with different genetically determined susceptibilities to intrahepatic fat accumulation, independent of traditional risk factors.
Small dorsal root ganglion (DRG) neurons, which include nociceptors, express multiple voltage-gated sodium currents. In addition to a classical fast inactivating tetrodotoxin-sensitive (TTX-S) sodium ...current, many of these cells express a TTX-resistant (TTX-R) sodium current that activates near -70 mV and is persistent at negative potentials. To investigate the possible contributions of this TTX-R persistent (TTX-RP) current to neuronal excitability, we carried out computer simulations using the Neuron program with TTX-S and -RP currents, fit by the Hodgkin-Huxley model, that closely matched the currents recorded from small DRG neurons. In contrast to fast TTX-S current, which was well fit using a m(3)h model, the persistent TTX-R current was not well fit by an m(3)h model and was better fit using an mh model. The persistent TTX-R current had a strong influence on resting potential, shifting it from -70 to -49.1 mV. Inclusion of an ultra-slow inactivation gate in the persistent current model reduced the potential shift only slightly, to -56.6 mV. The persistent TTX-R current also enhanced the response to depolarizing inputs that were subthreshold for spike electrogenesis. In addition, the presence of persistent TTX-R current predisposed the cell to anode break excitation. These results suggest that, while the persistent TTX-R current is not a major contributor to the rapid depolarizing phase of the action potential, it contributes to setting the electrogenic properties of small DRG neurons by modulating their resting potentials and response to subthreshold stimuli.
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