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Mitochondrial dysfunction, oxidative stress, inflammation, and metabolic reprograming are crucial contributors to hepatic injury and subsequent liver fibrosis. Poly(ADP-ribose) ...polymerases (PARP) and their interactions with sirtuins play an important role in regulating intermediary metabolism in this process. However, there is little research into whether PARP inhibition affects alcoholic and non-alcoholic steatohepatitis (ASH/NASH).
We investigated the effects of genetic deletion of PARP1 and pharmacological inhibition of PARP in models of early alcoholic steatohepatitis, as well as on Kupffer cell activation in vitro using biochemical assays, real-time PCR, and histological analyses. The effects of PARP inhibition were also evaluated in high fat or methionine and choline deficient diet-induced steatohepatitis models in mice.
PARP activity was increased in livers due to excessive alcohol intake, which was associated with decreased NAD+ content and SIRT1 activity. Pharmacological inhibition of PARP restored the hepatic NAD+ content, attenuated the decrease in SIRT1 activation and beneficially affected the metabolic-, inflammatory-, and oxidative stress-related alterations due to alcohol feeding in the liver. PARP1−/− animals were protected against alcoholic steatohepatitis and pharmacological inhibition of PARP or genetic deletion of PARP1 also attenuated Kupffer cell activation in vitro. Furthermore, PARP inhibition decreased hepatic triglyceride accumulation, metabolic dysregulation, or inflammation and/or fibrosis in models of NASH.
Our results suggests that PARP inhibition is a promising therapeutic strategy in steatohepatitis with high translational potential, considering the availability of PARP inhibitors for clinical treatment of cancer.
Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes. The PARP inhibitor olaparib (Lynparza) is a recently FDA-approved therapy for cancer. This study shows that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with 3 different PARP inhibitors, including olaparib, attenuates high fat or alcohol induced liver injury, abnormal metabolic alteration, fat accumulation, inflammation and/or fibrosis in preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver diseases.
Two-step process with H2S gas additivation to the reaction mixture for alternative jet fuel component production. Display omitted
The quality requirements for jet fuels have become stricter in the ...last few years. The reason of this is that more severe environmental regulations have been introduced and the increasing demand for performance requirements. Furthermore another requirement for jet fuels is that they should contain components of alternative origin to fulfil the requirements of the standard and to contribute to CO2 reduction. The aim of our experimental work was to study the production of jet fuel from natural triglycerides (technical grade coconut oil) with special hydrocracking (hydrogenation of olefinic double bonds, propane split, hydrodeoxygenation, decarbonylation and decarboxylation) with lower chemical and energy costs, less harmful material emission and better economy. Experiments were carried out on a sulfided NiMo/Al2O3 catalyst at different process parameters (temperature: 280–380°C, pressure: 30bar, liquid hourly space velocity: 1.0–3.0h−1, H2/feedstock volume ratio: 600Nm3/m3). Two possibilities for keeping the catalyst in sulfide-state during the special hydrocracking were investigated. These are the H2S containing hydrogen gas and the liquid sulfidation agent (dimethyl-disulfide). It was found that at the favourable process parameters (temperature 360°C, pressure 30bar, liquid hourly space velocity: 1.0h−1, H2/feedstock volume ratio 600Nm3/m3) the product yields were higher with 0.5–2.0absolute % in case of H2S containing hydrogen gas application. The jet fuel fractions were mixtures of saturated straight chain hydrocarbons; they were aromatic and olefin free, so they have excellent oxidation stability. The highest difference in the quality of jet fuel fractions obtained by the dimethyl-disulfide and H2S containing gas application was the sulfur content of the products (⩽2mg/kg with H2S, 7–9mg/kg with dimethyl-disulfide). The freezing point of jet fuel fractions obtained by special hydrocracking was high either when using dimethyl-disulfide or hydrogen-sulfide sulfidating agents (−11°C with H2S and −8°C with dimethyl-disulfide) compared to the value of the standard (maximum −47°C). Isomerisation on Pt/SAPO-11 catalyst was used to decrease the freezing point of the high n-paraffin containing jet fuel fractions resulting in products of freezing points of −45°C to −41°C (T=360°C, P=45bar, liquid hourly space velocity=1.1h−1, H2/feedstock ratio=350Nm3/m3). These values can be further decreased by using low level additivation (15mg/kg and 20mg/kg) to −49°C and −48°C respectively. These products fulfil the standard requirement.
It was concluded that H2S containing H2 gas forming as a side product during the desulfurization of jet fraction or diesel fuel in a crude oil refinery is useful to maintain the sulfide-state of the catalyst. A further advantage is that there is no need to extract the H2S from this gas stream with absorption/desorption. This means significant chemical and operation cost decreasing, less energy consumption, moreover less harmful material emission. This solution can be integrated easily in the structure of a crude oil refinery.
Previously, the presence of a blood-myenteric plexus barrier and its disruption was reported in experimentally induced colitis via a macrophage-dependent process. The aim of this study is to reveal ...how myenteric barrier disruption and subsequent neuronal injury affects gut motility in vivo in a murine colitis model. We induced colitis with dextran sulfate sodium (DSS), with the co-administration of liposome-encapsulated clodronate (L-clodronate) to simultaneously deplete blood monocytes contributing to macrophage infiltration in the inflamed muscularis of experimental mice. DSS-treated animals receiving concurrent L-clodronate injection showed significantly decreased blood monocyte numbers and colon muscularis macrophage (MM) density compared to DSS-treated control (DSS-vehicle). DSS-clodronate-treated mice exhibited significantly slower whole gut transit time than DSS-vehicle-treated animals and comparable to that of controls. Experiments with oral gavage-fed Evans-blue dye showed similar whole gut transit times in DSS-clodronate-treated mice as in control animals. Furthermore, qPCR-analysis and immunofluorescence on colon muscularis samples revealed that factors associated with neuroinflammation and neurodegeneration, including Bax1, Hdac4, IL-18, Casp8 and Hif1a are overexpressed after DSS-treatment, but not in the case of concurrent L-clodronate administration. Our findings highlight that MM-infiltration in the muscularis layer is responsible for colitis-associated dysmotility and enteric neuronal dysfunction along with the release of mediators associated with neurodegeneration in a murine experimental model.
Ischemic heart disease including myocardial infarction develops on the basis of several risk-factors and comorbidities such as obesity, diabetes, hypertension, and hypercholesterolemia. Ischemic ...heart disease is the leading cause of mortality worldwide, therefore, identification of novel drug targets for cardioprotection is of great importance. Ischemic preconditioning, postconditioning, and remote conditioning trigger endogenous cardioprotective mechanisms that render the heart more resistant to lethal ischemic-reperfusion injury. However, major cardiovascular co-morbidities such as hyperlipidemia, diabetes, and their co-medications interfere with these cardioprotective mechanisms thereby limiting the efficacy of cardioprotective ischemic conditioning maneuvers. Ischemia reperfusion injury and cardioprotection by conditioning have been shown to affect global myocardial gene expression profile at the transcript level. Further understanding and the comprehensive analysis of the cardioprotective gene expression fingerprint in normal, protected, and in comorbid conditions may lead to identification of novel molecular targets for cardioprotection.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are drugs with analgesic, anti-inflammatory, and antipyretic activity. Their effect is achieved by the reduction in synthesis of prostanoids. Inhibition ...of prostanoids is responsible for a substantial risk of adverse effects. The risk of side effects affecting the gastrointestinal tract and kidneys has long been known. The possibilities of blood pressure elevation and the development of congestive heart failure are also widely recognized. Increased incidence of acute myocardial infarction in clinical trials with rofecoxib drew attention to the potential cardiotoxicity of selective cyclooxygenase-2 inhibitors, and similarly, concerns have been raised regarding the cardiovascular safety of non-selective NSAIDs. The safety of NSAIDs with regards to cardiovascular events has been studied in recent years in a large number of retrospective and prospective clinical studies and meta-analyses. The results indicate that cardiotoxicity is a class effect, but the magnitude of the risk is widely variable between individual NSAID drugs. This article aims to summarize the available data on the risk of adverse cardiovascular events with NSAIDs, the clinical impact of these events and possible underlying mechanisms.
The available pharmacological options in the management of cardiovascular diseases such as ischaemic heart disease and subsequent heart failure are effective in slowing the progression of this ...condition. However, the long‐term prognosis is still poor, raising the demand for new therapeutic strategies. Drug repurposing is a time‐ and cost‐effective drug development strategy that offers approved and abandoned drugs a new chance for new indications. Recently, drugs used for the management of gout‐related inflammation such as canakinumab or colchicine have been considered for drug repurposing in cardiovascular indications. The old uricosuric drug, probenecid, has been identified as a novel therapeutic option in the management of specific cardiac diseases as well. Probenecid can modulate myocardial contractility and vascular tone and exerts anti‐inflammatory properties. The mechanisms behind these beneficial effects might be related inhibition of inflammasomes, and to modulation purinergic–pannexin‐1 signalling and TRPV2 channels, which are recently identified molecular targets of probenecid. In this review, we provide an overview on repurposing probenecid for ischaemic heart disease and subsequent heart failure by summarizing the related experimental and clinical data and propose its potential repurposing to treat cardiovascular diseases.
Several morphological and mitochondrial lineages of the alpine ringlet butterfly species Erebia pronoe have been described, indicating a complex phylogenetic structure. However, the existing data ...were insufficient and allow neither a reconstruction of the biogeographic history, nor an assessment of the genetic lineages. Therefore, we analysed mitochondrial (COI, NDI) and nuclear (EF1α, RPS5) gene sequences and compared them with sequences from the sister species Erebia melas. Additionally, we combined this information with morphometric data of the male genitalia and the infection patterns with Wolbachia strains, based on a WSP analysis. We obtained a distinct phylogeographic structure within the E. pronoe-melas complex with eight well-distinguishable geographic groups, but also a remarkable mito-nuclear discordance. The mito-nuclear discordance in E. melas and E. pronoe glottis can be explained by different ages of Wolbachia infections with different Wolbachia strains, associated selective sweeps, and hybridisation inhibition. Additionally, we found indications for incipient speciation of E. pronoe glottis in the Pyrenees and a pronounced range dynamic within and among the other high mountain systems of Europe. Our results emphasize the importance of combined approaches in reconstructing biogeographic patterns and evaluating phylogeographic splits.
The Eurasian Steppe belt is one of the largest biomes in the Northern Hemisphere. We provide here a range-wide phylogeography of the flightless steppe beetle Lethrus apterus that inhabits the western ...part of the Steppe belt through the study of population-level variance of mitochondrial cytochrome oxidase I sequences and nuclear microsatellites. We detected a concordant geographic structure of genetic data with a significant isolation-by-distance pattern. We found more genetic variation in the western part of the area and identified Northern Bulgaria and the Pannonian Basin as possible refugia. Genetic clusters were separated by main rivers in the eastern part of the area. This implies west-to-east colonisation and argues for an evolutionarily recent arrival of this species to its current main distribution area, the Pontic Steppes. This contradicts the classical biogeographical wisdom that assumed an east-to-west colonisation pattern.
Little is known about the molecular mechanism including microRNAs (miRNA) in hypercholesterolemia-induced cardiac dysfunction. We aimed to explore novel hypercholesterolemia-induced pathway ...alterations in the heart by an unbiased approach based on miRNA omics, target prediction and validation. With miRNA microarray we identified forty-seven upregulated and ten downregulated miRNAs in hypercholesterolemic rat hearts compared to the normocholesterolemic group. Eleven mRNAs with at least 4 interacting upregulated miRNAs were selected by a network theoretical approach, out of which 3 mRNAs (beta-2 adrenergic receptor Adrb2, calcineurin B type 1 Ppp3r1 and calcium/calmodulin-dependent serine protein kinase Cask) were validated with qRT-PCR and Western blot. In hypercholesterolemic hearts, the expression of Adrb2 mRNA was significantly decreased. ADRB2 and PPP3R1 protein were significantly downregulated in hypercholesterolemic hearts. The direct interaction of Adrb2 with upregulated miRNAs was demonstrated by luciferase reporter assay. Gene ontology analysis revealed that the majority of the predicted mRNA changes may contribute to the hypercholesterolemia-induced cardiac dysfunction. In summary, the present unbiased target prediction approach based on global cardiac miRNA expression profiling revealed for the first time in the literature that both the mRNA and protein product of Adrb2 and PPP3R1 protein are decreased in the hypercholesterolemic heart.
Cardioprotective value of ischemic post- (IPostC), remote (RIC) conditioning in acute myocardial infarction (AMI) is unclear in clinical trials. To evaluate cardioprotection, most translational ...animal studies and clinical trials utilize necrotic tissue referred to the area at risk (AAR) by magnetic resonance imaging (MRI). However, determination of AAR by MRI' may not be accurate, since MRI-indices of microvascular damage, i.e., myocardial edema and microvascular obstruction (MVO), may be affected by cardioprotection independently from myocardial necrosis. Therefore, we assessed the effect of IPostC, RIC conditioning and ischemic preconditioning (IPreC; positive control) on myocardial necrosis, edema and MVO in a clinically relevant, closed-chest pig model of AMI.
Acute myocardial infarction was induced by a 90-min balloon occlusion of the left anterior descending coronary artery (LAD) in domestic juvenile female pigs. IPostC (6 × 30 s ischemia/reperfusion after 90-min occlusion) and RIC (4 × 5 min hind limb ischemia/reperfusion during 90-min LAD occlusion) did not reduce myocardial necrosis as assessed by late gadolinium enhancement 3 days after reperfusion and by ex vivo triphenyltetrazolium chloride staining 3 h after reperfusion, however, the positive control, IPreC (3 × 5 min ischemia/reperfusion before 90-min LAD occlusion) did. IPostC and RIC attenuated myocardial edema as measured by cardiac T2-weighted MRI 3 days after reperfusion, however, AAR measured by Evans blue staining was not different among groups, which confirms that myocardial edema is not a measure of AAR, IPostC and IPreC but not RIC decreased MVO.
We conclude that IPostC and RIC interventions may protect the coronary microvasculature even without reducing myocardial necrosis.
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