Oxysterols are oxygenated forms of cholesterol generated via autooxidation by free radicals and ROS, or formed enzymically by a variety of enzymes such as those involved in the synthesis of bile ...acids. Although found at very low concentrations in vivo, these metabolites play key roles in health and disease, particularly in development and regulating immune cell responses, by binding to effector proteins such as LXRα, RORγ and Insig and directly or indirectly regulating transcriptional programmes that affect cell metabolism and function. In this review, we summarise the routes by which oxysterols can be generated and subsequently modified to other oxysterol metabolites and highlight their diverse and profound biological functions and opportunities to alter their levels using pharmacological approaches.
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This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc
The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system ...leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and was positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease.
•Optogenetic excitation of nucleus accumbens dynorphin cells elicits dynorphin release•Discrete accumbens shell dynorphinergic populations drive either aversion or reward•These two nucleus accumbens subregions can be bi-directionally controlled•Both aversive and rewarding behaviors require kappa opioid receptors
Al-Hasani et al. show that dynorphin is necessary to drive opposing motivational states within subregions of the nucleus accumbens shell. Dynorphinergic neurons in the ventral shell drive aversion whereas in the dorsal shell they drive preference and reward seeking.
In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, transcatheter mitral valve repair (TMVr) ...resulted in fewer heart failure hospitalizations (HFHs) and lower mortality at 24 months in patients with heart failure (HF) with mitral regurgitation (MR) secondary to left ventricular dysfunction compared with guideline-directed medical therapy (GDMT) alone.
This study determined if these benefits persisted to 36 months and if control subjects who were allowed to cross over at 24 months derived similar benefit.
This study randomized 614 patients with HF with moderate-to-severe or severe secondary MR, who remained symptomatic despite maximally tolerated GDMT, to TMVr plus GDMT versus GDMT alone. The primary effectiveness endpoint was all HFHs through 24-month follow-up. Patients have now been followed for 36 months.
The annualized rates of HFHs per patient-year were 35.5% with TMVr and 68.8% with GDMT alone (hazard ratio HR: 0.49; 95% confidence interval CI: 0.37 to 0.63; p < 0.001; number needed to treat (NNT) = 3.0; 95% CI: 2.4 to 4.0). Mortality occurred in 42.8% of the device group versus 55.5% of control group (HR: 0.67; 95% CI: 0.52 to 0.85; p = 0.001; NNT = 7.9; 95% CI: 4.6 to 26.1). Patients who underwent TMVr also had sustained 3-year improvements in MR severity, quality-of-life measures, and functional capacity. Among 58 patients assigned to GDMT alone who crossed over and were treated with TMVr, the subsequent composite rate of mortality or HFH was reduced compared with those who continued on GDMT alone (adjusted HR: 0.43; 95% CI: 0.24 to 0.78; p = 0.006).
Among patients with HF and moderate-to-severe or severe secondary MR who remained symptomatic despite GDMT, TMVr was safe, provided a durable reduction in MR, reduced the rate of HFH, and improved survival, quality of life, and functional capacity compared with GDMT alone through 36 months. Surviving patients who crossed over to device treatment had a prognosis comparable to those originally assigned to transcatheter therapy. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation COAPT; NCT01626079).
Bisphosphonates (BP) are a class of calcium-binding drug used to prevent bone resorption in skeletal disorders such as osteoporosis and metastatic bone disease. They act by selectively targeting ...bone-resorbing osteoclasts and can be grouped into two classes depending on their intracellular mechanisms of action. Simple BPs cause osteoclast apoptosis after cytoplasmic conversion into toxic ATP analogues. In contrast, nitrogen-containing BPs potently inhibit FPP synthase, an enzyme of the mevalonate (cholesterol biosynthesis) pathway. This results in production of a toxic metabolite (ApppI) and the loss of long-chain isoprenoid lipids required for protein prenylation, a process necessary for the function of small GTPase proteins essential for the survival and activity of osteoclasts. In this review we provide a state-of-the-art overview of these mechanisms of action and a historical perspective of how they were discovered. Finally, we challenge the long-held dogma that BPs act only in the skeleton and highlight recent studies that reveal insights into hitherto unknown effects on tumour-associated and tissue-resident macrophages.
•Bisphosphonates target the skeleton and are selectively internalised by osteoclasts.•Simple bisphosphonates are metabolised intracellularly to toxic ATP analogues.•N-containing bisphosphonates inhibit the mevalonate pathway and prevent protein prenylation.•New approaches to measure prenylation reveal effects of bisphosphonates outside the skeleton.
Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear ...factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.
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•TDP-43 enters mitochondria, triggers mtDNA release via the mPTP•TDP-43-induced cytosolic mtDNA accumulation activates the cGAS/STING pathway•Evidence of cytoplasmic mtDNA was found in ALS patient cells and disease models•Blocking STING prevents inflammation and neurodegeneration in vitro and in vivo
TDP-43 causes inflammation in ALS by stimulating mitochondrial DNA release, which is subsequently sensed by the cytosolic cGAS/STING pathway, suggesting that inhibition of cGAS/STING could help alleviate inflammation-related damage in ALS.
ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in ...chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methylation patterns that could be used in the molecular diagnosis of ADNP syndrome.
We identified two distinct and partially opposing genomic DNA methylation episignatures in the peripheral blood samples from 22 patients with ADNP syndrome. The "epi-ADNP-1" episignature included ~ 6000 mostly hypomethylated CpGs, and the "epi-ADNP-2" episignature included ~ 1000 predominantly hypermethylated CpGs. The two signatures correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N- and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. The episignatures were enriched for genes involved in neuronal system development and function. A classifier trained on these profiles yielded full sensitivity and specificity in detecting patients with either of the two episignatures. Applying this model to seven patients with uncertain clinical diagnosis enabled reclassification of genetic variants of uncertain significance and assigned new diagnosis when the primary clinical suspicion was not correct. When applied to a large cohort of unresolved patients with developmental delay (N = 1150), the model predicted three additional previously undiagnosed patients to have ADNP syndrome. DNA sequencing of these subjects, wherever available, identified pathogenic mutations within the gene domains predicted by the model.
We describe the first Mendelian condition with two distinct episignatures caused by mutations in a single gene. These highly sensitive and specific DNA methylation episignatures enable diagnosis, screening, and genetic variant classifications in ADNP syndrome.
Mixed lineage kinase domain-like (MLKL) is the terminal protein in the pro-inflammatory necroptotic cell death program. RIPK3-mediated phosphorylation is thought to initiate MLKL oligomerization, ...membrane translocation and membrane disruption, although the precise choreography of events is incompletely understood. Here, we use single-cell imaging approaches to map the chronology of endogenous human MLKL activation during necroptosis. During the effector phase of necroptosis, we observe that phosphorylated MLKL assembles into higher order species on presumed cytoplasmic necrosomes. Subsequently, MLKL co-traffics with tight junction proteins to the cell periphery via Golgi-microtubule-actin-dependent mechanisms. MLKL and tight junction proteins then steadily co-accumulate at the plasma membrane as heterogeneous micron-sized hotspots. Our studies identify MLKL trafficking and plasma membrane accumulation as crucial necroptosis checkpoints. Furthermore, the accumulation of phosphorylated MLKL at intercellular junctions accelerates necroptosis between neighbouring cells, which may be relevant to inflammatory bowel disease and other necroptosis-mediated enteropathies.
The mechanisms that determine patterns of species dispersal are important factors in the production and maintenance of biodiversity. Understanding these mechanisms helps to forecast the responses of ...species to environmental change. Here, we used a comparative framework and genomewide data obtained through RAD‐Seq to compare the patterns of connectivity among breeding colonies for five penguin species with shared ancestry, overlapping distributions and differing ecological niches, allowing an examination of the intrinsic and extrinsic barriers governing dispersal patterns. Our findings show that at‐sea range and oceanography underlie patterns of dispersal in these penguins. The pelagic niche of emperor (Aptenodytes forsteri), king (A. patagonicus), Adélie (Pygoscelis adeliae) and chinstrap (P. antarctica) penguins facilitates gene flow over thousands of kilometres. In contrast, the coastal niche of gentoo penguins (P. papua) limits dispersal, resulting in population divergences. Oceanographic fronts also act as dispersal barriers to some extent. We recommend that forecasts of extinction risk incorporate dispersal and that management units are defined by at‐sea range and oceanography in species lacking genetic data.
•COVID-19 psychological factors may be risk factors for substance use initiation.•COVID-19-related worry is specifically related to using substances to cope during the pandemic.•COVID-19-related ...psychological factors may require specific clinical attention.
The 2019 outbreak of the novel coronavirus (COVID-19) has had a devastating impact. Given the on-going nature of the outbreak, the deleterious toll on mental health, including substance use, is unknown. Negative reinforcement models of substance use posit that elevations in stress from the COVID-19 pandemic will elicit a corresponding motivation to downregulate COVID-19-related stress reactivity via substance use for a subset of the population. The current study sought to evaluate: (1) if COVID-19-related worry and fear were associated with substance use coping motives; and (2) how levels of COVID-19-related worry and fear differ between pre-COVID-19 substance users, COVID-19 substance initiators, and abstainers. Participants were 160 adults recruited nationally between April-May 2020 for an online study. Results indicated that COVID-19-related worry was associated with substance use coping motives. Additionally, compared to abstainers, pre-COVID-19 substance users and COVID-19 substance initiators demonstrated the highest levels of worry and fear. Examination of differences suggested that the COVID-19 substance initiators had the highest COVID-19-related worry and fear for all substances except for opioids, with effect size estimates ranging from small to medium. The results of this study suggest that COVID-19-specific psychological factors appear to be involved in substance use behavior.
Countermeasures to prevent and treat coronavirus disease 2019 (COVID-19) are a global health priority. We enrolled a cohort of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-recovered ...participants, developed neutralization assays to investigate antibody responses, adapted our high-throughput antibody generation pipeline to rapidly screen more than 1800 antibodies, and established an animal model to test protection. We isolated potent neutralizing antibodies (nAbs) to two epitopes on the receptor binding domain (RBD) and to distinct non-RBD epitopes on the spike (S) protein. As indicated by maintained weight and low lung viral titers in treated animals, the passive transfer of a nAb provides protection against disease in high-dose SARS-CoV-2 challenge in Syrian hamsters. The study suggests a role for nAbs in prophylaxis, and potentially therapy, of COVID-19. The nAbs also define protective epitopes to guide vaccine design.
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