Reduction in hypoxia-reoxygenation-induced myocardial mitochondrial damage with exogenous methane.

Albeit previous experiments suggest potential anti-inflammatory effect of exogenous methane (CH4 ) in various organs, the mechanism of its bioactivity is not entirely understood. We aimed to investigate the potential mitochondrial effects and the underlying mechanisms of CH4 in rat cardiomyocytes and mitochondria under simulated ischaemia/reperfusion (sI/R) conditions. Three-day-old cultured cardiomyocytes were treated with 2.2% CH4 -artificial air mixture during 2-hour-long reoxygenation following 4-hour-long anoxia (sI/R and sI/R + CH4 , n = 6-6), with normoxic groups serving as controls (SH and SH + CH4 ; n = 6-6). Mitochondrial functions were investigated with high-resolution respirometry, and mitochondrial membrane injury was detected by cytochrome c release and apoptotic characteristics by using TUNEL staining. CH4 admixture had no effect on complex II (CII)-linked respiration under normoxia but significantly decreased the complex I (CI)-linked oxygen consumption. Nevertheless, addition of CH4 in the sI/R + CH4 group significantly reduced the respiratory activity of CII in contrast to CI and the CH4 treatment diminished mitochondrial H2 O2 production. Substrate-induced changes to membrane potential were partially preserved by CH4 , and additionally, cytochrome c release and apoptosis of cardiomyocytes were reduced in the CH4 -treated group. In conclusion, the addition of CH4 decreases mitochondrial ROS generation via blockade of electron transport at CI and reduces anoxia-reoxygenation-induced mitochondrial dysfunction and cardiomyocyte injury in vitro.

Methane supplementation improves graft function in experimental heart transplantation.

BACKGROUND: Maintenance of cell viability during cold storage is a key issue in organ transplantation. Methane (CH4) bioactivity has recently been recognized in ischemia/reperfusion conditions; we therefore hypothesized that cold storage in CH4-enriched preservation solution can provide an increased defense against organ dysfunction during experimental heart transplantation (HTX). METHODS: The hearts of donor Lewis rats were stored for 60 minutes in cold histidine-tryptophan-ketoglutarate (Custodiol [CS]) or CH4-saturated CS solution (CS-CH4) (n = 12 each). Standard heterotopic HTX was performed, and 60 minutes later, the left ventricular (LV) pressure-volume relationships LV systolic pressure (LVSP), systolic pressure increment (dP/dtmax), diastolic pressure decrement, and coronary blood flow (CBF) were measured. Tissue samples were taken to detect proinflammatory parameters, structural damage (by light microscopy), endoplasmic reticulum (ER) stress, and apoptosis markers (CCAAT/enhancer binding protein [C/EBP] homologous protein, GRP78, glycogen synthase kinase-3ß, very low-density lipoprotein receptor, caspase 3 and 9, B-cell lymphoma 2, and bcl-2-like protein 4), whereas mitochondrial functional changes were analyzed by high-resolution respirometry. RESULTS: LVSP and dP/dtmax increased significantly at the largest pre-load volumes in CS-CH4 grafts as compared with the CS group (114.5 ± 16.6 mm Hg vs 82.8 ± 4.6 mm Hg and 3,133 ± 430 mm Hg/s vs 1,739 ± 169 mm Hg/s, respectively); the diastolic function and CBF (2.4 ± 0.4 ml/min/g vs 1.3 ± 0.3 ml/min/g) also improved. Mitochondrial oxidative phosphorylation capacity was more preserved (58.5 ± 9.4 pmol/s/ml vs 27.7 ± 6.6 pmol/s/ml), and cytochrome c release was reduced in CS-CH4 storage. Signs of HTX-caused myocardial damage, level of ER stress, and the transcription of proapoptotic proteins were significantly lower in CS-CH4 grafts. CONCLUSION: The addition of CH4 during 1 hour of cold storage improved early in vitro graft function and reduced mitochondrial dysfunction and activation of inflammation. Evidence shows that CH4 reduced ER stress-linked proapoptotic signaling.

The effects of TNF-alpha inhibitor therapy on the incidence of infection in JIA children: a meta-analysis.

BACKGROUND: Juvenile Idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. The diagnosis is based on the underlying symptoms of arthritis with an exclusion of other diseases Biologic agents are increasingly used on the side of disease-modifying anti-rheumatic drugs (DMARD) in JIA treatment. MAIN BODY: The aim of this meta-analysis was to investigate the observed infections in JIA children during tumor necrosis factor (TNF)-alpha inhibitor therapy. A systematic search of three databases (Medline via PubMed, Embase, Cochrane Library) was carried out up to May 2018. Published trials that evaluated the infectious adverse events in patients receiving TNF-alpha inhibitor vs. a control group were included in the analysis. Full-text data extraction was carried out independently by the investigators from ten relevant publications. 1434 patients received TNF-alpha inhibitor therapy; the control group consisted of 696 subjects. The analysis presented the risk of infection in the active treatment group (OR = 1.13; 95% CI: 0.76-1.69; p = 0.543). The majority of infections were upper respiratory tract infections (URTIs). Furthermore, the subgroup analysis demonstrated a higher infection rate in the observed localization. CONCLUSION: Anti-TNF therapy slightly but not significantly increases the incidence of infection in JIA children compared to other therapies (GRADE: moderate evidence). The most common infections reported were mild URTIs. Further studies with larger patients number with a strong evidence level are crucially needed to finalize the answer whether anti-TNF therapy elevates and if yes on what extent the incidence of infection in JIA children. TRIAL REGISTRATION: Prospero: CRD42017067873 .

Theory of mind disturbances in borderline personality disorder: A meta-analysis.

Impairments of theory of mind (ToM) are widely accepted underlying factors of disturbed relatedness in borderline personality disorder (BPD). The aim of this meta-analysis a was to assess the weighted mean effect sizes of ToM performances in BPD compared to healthy controls (HC), and to investigate the effect of demographic variables and comorbidities on the variability of effect sizes across the studies. Seventeen studies involving 585 BPD patients and 501 HC were selected after literature search. Effect sizes for overall ToM, mental state decoding and reasoning, cognitive and affective ToM, and for task types were calculated. BPD patients significantly underperformed HC in overall ToM, mental state reasoning, and cognitive ToM, but had no deficits in mental state decoding. Affective ToM performance was largely task dependent in BPD. Comorbid anxiety disorders had a positive moderating effect on overall and affective ToM in BPD. Our results support the notion that BPD patients' have specific ToM impairments. Further research is necessary to evaluate the role of confounding factors, especially those of clinical comorbidities, neurocognitive functions, and adverse childhood life events. Complex ToM tasks with high contextual demands seem to be the most appropriate tests to assess ToM in patients with BPD.

Electroporation-enhanced transdermal diclofenac sodium delivery into the knee joint in a rat model of acute arthritis.

PURPOSE: Since electroporation (EP) can increase the permeability of biological membranes, we hypothesized that it offers an opportunity to enhance the transdermal delivery of drugs for intra-articular indications. Our aim was to compare the anti-inflammatory and analgesic efficacy of EP-combined topical administration of diclofenac sodium hydrogel (50 mg mL-1 in 230 µL volume) with that of an equivalent dose of oral (75 mg kg-1) and simple topical administration. METHODS: Arthritis was induced with the injection of 2% λ-carrageenan and 4% kaolin into the right knee joints of male Sprague Dawley rats. EP was applied for 8 min with 900 V high-voltage pulses for 5 ms followed by a 20 ms break. Drug penetration into the synovial fluid and plasma was detected by high-performance liquid chromatography. Leukocyte-endothelial interactions were visualized by intravital videomicroscopy on the internal surface of the synovium. Inflammation-induced thermal and mechanical hyperalgesia reactions, knee joint edema, and inflammatory enzyme activities were assessed at 24 and 48 h after arthritis induction. RESULTS: EP significantly increased the plasma level of diclofenac as compared with the topical controls 10 min after the 2% λ-carrageenan and 4% kaolin injection. Increased leukocyte-endothelial interactions were accompanied by joint inflammation, which was significantly reduced by oral and EP diclofenac (by 45% and by 30%, respectively) and only slightly ameliorated by simple topical diclofenac treatment (by 18%). The arthritis-related secondary hyperalgesic reactions were significantly ameliorated by oral and EP-enhanced topical diclofenac treatments. The knee cross-section area (which increased by 35%) was also reduced with both approaches. However, simple topical application did not influence the development of joint edema and secondary hyperalgesia. CONCLUSION: The study provides evidence for the first time of the potent anti-inflammatory and analgesic effects of EP-enhanced topical diclofenac during arthritis. The therapeutic benefit provided by EP is comparable with that of oral diclofenac; EP is a useful alternative to conventional routes of administration.

Compared efficacy of preservation solutions on the outcome of liver transplantation: Meta-analysis.

AIM: To compare the effects of the four most commonly used preservation solutions on the outcome of liver transplantations. METHODS: A systematic literature search was performed using MEDLINE, Scopus, EMBASE and the Cochrane Library databases up to January 31st, 2017. The inclusion criteria were comparative, randomized controlled trials (RCTs) for deceased donor liver (DDL) allografts with adult and pediatric donors using the gold standard University of Wisconsin (UW) solution or histidine-tryptophan-ketoglutarate (HTK), Celsior (CS) and Institut Georges Lopez (IGL-1) solutions. Fifteen RCTs (1830 livers) were included; the primary outcomes were primary non-function (PNF) and one-year post-transplant graft survival (OGS-1). RESULTS: All trials were homogenous with respect to donor and recipient characteristics. There was no statistical difference in the incidence of PNF with the use of UW, HTK, CS and IGL-1 (RR = 0.02, 95%CI: 0.01-0.03, P = 0.356). Comparing OGS-1 also failed to reveal any difference between UW, HTK, CS and IGL-1 (RR = 0.80, 95%CI: 0.80-0.80, P = 0.369). Two trials demonstrated higher PNF levels for UW in comparison with the HTK group, and individual studies described higher rates of biliary complications where HTK and CS were used compared to the UW and IGL-1 solutions. However, the meta-analysis of the data did not prove a statistically significant difference: the UW, CS, HTK and IGL-1 solutions were associated with nearly equivalent outcomes. CONCLUSION: Alternative solutions for UW yield the same degree of safety and effectiveness for the preservation of DDLs, but further well-designed clinical trials are warranted.

Mitochondria As Sources and Targets of Methane.

This review summarizes the current knowledge on the role of mitochondria in the context of hypoxic cell biology, while providing evidence of how these mechanisms are modulated by methane (CH4). Recent studies have unambiguously confirmed CH4 bioactivity in various in vitro and in vivo experimental models and established the possibility that CH4 can affect many aspects of mitochondrial physiology. To date, no specific binding of CH4 to any enzymes or receptors have been reported, and it is probable that many of its effects are related to physico-chemical properties of the non-polar molecule. (i) Mitochondria themselves can be sources of endogenous CH4 generation under oxido-reductive stress conditions; chemical inhibition of the mitochondrial electron transport chain with site-specific inhibitors leads to increased formation of CH4 in eukaryote cells, in plants, and in animals. (ii) Conventionally believed as physiologically inert, studies cited in this review demonstrate that exogenous CH4 modulates key events of inflammation. The anti-apoptotic effects of exogenously administered CH4 are also recognized, and these properties also suggest that CH4-mediated intracellular signaling is closely associated with mitochondria. (iii) Mitochondrial substrate oxidation is coupled with the reduction of molecular oxygen, thus providing energy for cellular metabolism. Interestingly, recent in vivo studies have shown improved basal respiration and modulated mitochondrial oxidative phosphorylation by exogenous CH4. Overall, these data suggest that CH4 liberation and effectiveness in eukaryotes are both linked to hypoxic events and redox regulation and support the notion that CH4 has therapeutic roles in mammalian pathophysiologies.