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DNA Methylation May be Involved in the Analgesic Effect of Hyperbaric Oxygen via Regulating FUNDC1.

ABSTRACT: Background:Neuropathic pain (NP) is a type of chronic pain which lacks predictable, effective, and safe therapeutic options. We investigated the role of hyperbaric oxygen (HBO) in expression of FUN14 domain-containing 1 (FUNDC1), which is associated with DNA methylation. Methods:We randomly divided rats into four groups: sham operation (S), S?+?HBO, chronic constriction injury (CCI), and CCI?+?HBO. Lumbar (L)4 and L5 dorsal root ganglia (DRGs) were used to assess expression of DNA methyltransferase (DNMT)1, DNMT3a, and DNMT3b by western blotting and RT-PCR. Pain-related behaviors were evaluated using mechanical withdrawal threshold and thermal withdrawal latency analysis. Western blotting was also used to assess expression of FUNDC1, BCL2, and adenovirus E1B19?kDa-interacting protein 3-like (NIX) and BCL2 and adenovirus E1B19?kDa-interacting protein3 (BNIP3). And we also examined the changes of FUNDC1 with immunofluorescence. Nonnucleoside DNA methyltransferase inhibitor RG108 was administered prior to CCI. The pain-related behavior and western blotting changes were examined in all groups. Results:DNMT3a expression was higher on day 14 after CCI. HBO downregulated DNMT3a mRNA and protein expression, but not those of DNMT1 and DNMT3b. HBO increased pain-related behavior significantly, while it was down-regulated by RG108. In HBO groups, FUNDC1, NIX, and BNIP3 expression was upregulated more significantly than in the CCI group. In addition, FUNDC1 protein colocalized with NeuN and rarely with glutamine synthetase. However, expression was reduced when RG108 was administered. Immunofluorescence showed that FUNDC1 was upregulated after HBO treatment. Conclusion:Our findings suggest that DNA methylation is involved in the analgesic effect of HBO via the regulation of FUNDC1.

SUBMITTER: Liu K

PROVIDER: S-EPMC7049412 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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DNA Methylation May be Involved in the Analgesic Effect of Hyperbaric Oxygen via Regulating FUNDC1.

Liu Kun K Wu Hao H Gao Rui R Han Guang G

Pain research & management 20200218

<h4>Background</h4>Neuropathic pain (NP) is a type of chronic pain which lacks predictable, effective, and safe therapeutic options. We investigated the role of hyperbaric oxygen (HBO) in expression of FUN14 domain-containing 1 (FUNDC1), which is associated with DNA methylation.<h4>Methods</h4>We randomly divided rats into four groups: sham operation (S), S + HBO, chronic constriction injury (CCI), and CCI + HBO. Lumbar (L)4 and L5 dorsal root ganglia (DRGs) were used to assess expression of DNA ...[more]

PMID: 32148597

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Project description:BACKGROUND:Poisoning with carbon monoxide (CO) remains an important cause of accidental and intentional injury worldwide. Several unblinded non-randomized trials have suggested that the use of hyperbaric oxygen (HBO) prevents the development of neurological sequelae. This has led to the widespread use of HBO in the management of patients with carbon monoxide poisoning. OBJECTIVES:To examine randomised trials of the efficacy of hyperbaric oxygen (HBO) compared to normobaric oxygen (NBO) for the prevention of neurologic sequelae in patients with acute carbon monoxide poisoning. SEARCH STRATEGY:We searched the following electronic databases; Cochrane Injuries Group Specialised Register (searched June 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 2), MEDLINE (Ovid SP) 1950 to June 2010, EMBASE (Ovid SP) 1980 to June 2010, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to June 2010, ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) 1990 to June 2010. SELECTION CRITERIA:All randomised controlled trials of HBO compared to NBO, involving non-pregnant adults who are acutely poisoned with carbon monoxide (regardless of severity). DATA COLLECTION AND ANALYSIS:Two authors independently extracted from each trial information on: the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurologic symptoms at follow-up. MAIN RESULTS:Seven randomised controlled trials of varying quality were identified; one was excluded because it did not evaluate clinical outcomes. Of the six remaining trials involving 1361 participants, two found a beneficial effect of HBO for the reduction of neurologic sequelae at one month, while four others did not. One of these is an incomplete publication (an abstract of an interim analysis). Although pooled random effects meta-analysis does not suggest a significant benefit from HBOT (OR for neurological deficits 0.78, 95%CI 0.54 to 1.12), significant methodologic and statistical heterogeneity was apparent among the trials, and this result should be interpreted cautiously. Moreover, design or analysis flaws were evident in all trials. Importantly, the conclusions of one positive trial may have been influenced by failure to adjust for multiple hypothesis testing, while interpretation of the other positive trial is hampered by a high risk of bias introduced during the analysis including an apparent change in the primary outcome. Both were also stopped early 'for benefit', which is likely to have inflated the observed effect. In contrast three negative trials had low power to detect a benefit of HBO due to exclusion of severely poisoned patients in two and very poor follow-up in the other. One trial that was said to be finished around eight years ago has not reported the final analysis in any forum. AUTHORS' CONCLUSIONS:Existing randomised trials do not establish whether the administration of HBO to patients with carbon monoxide poisoning reduces the incidence of adverse neurologic outcomes. Additional research is needed to better define the role, if any, of HBO in the treatment of patients with carbon monoxide poisoning. This research question is ideally suited to a multi-center randomised controlled trial.

Project description:BACKGROUND:Chronic wounds are common and present a health problem with significant effect on quality of life. Various pathologies may cause tissue breakdown, including poor blood supply resulting in inadequate oxygenation of the wound bed. Hyperbaric oxygen therapy (HBOT) has been suggested to improve oxygen supply to wounds and therefore improve their healing. OBJECTIVES:To assess the benefits and harms of adjunctive HBOT for treating chronic ulcers of the lower limb. SEARCH METHODS:For this second update we searched the Cochrane Wounds Group Specialised Register (searched 18 February 2015); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 1); Ovid MEDLINE (1946 to 17 February 2015); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, 17 February 2015); Ovid EMBASE (1974 to 17 February 2015); and EBSCO CINAHL (1982 to 17 February 2015). SELECTION CRITERIA:Randomised controlled trials (RCTs) comparing the effect on chronic wound healing of therapeutic regimens which include HBOT with those that exclude HBOT (with or without sham therapy). DATA COLLECTION AND ANALYSIS:Three review authors independently evaluated the risk of bias of the relevant trials using the Cochrane methodology and extracted the data from the included trials. We resolved any disagreement by discussion. MAIN RESULTS:We included twelve trials (577 participants). Ten trials (531 participants) enrolled people with a diabetic foot ulcer: pooled data of five trials with 205 participants showed an increase in the rate of ulcer healing (risk ratio (RR) 2.35, 95% confidence interval (CI) 1.19 to 4.62; P = 0.01) with HBOT at six weeks but this benefit was not evident at longer-term follow-up at one year. There was no statistically significant difference in major amputation rate (pooled data of five trials with 312 participants, RR 0.36, 95% CI 0.11 to 1.18). One trial (16 participants) considered venous ulcers and reported data at six weeks (wound size reduction) and 18 weeks (wound size reduction and number of ulcers healed) and suggested a significant benefit of HBOT in terms of reduction in ulcer area only at six weeks (mean difference (MD) 33.00%, 95% CI 18.97 to 47.03, P < 0.00001). We identified one trial (30 participants) which enrolled patients with non-healing diabetic ulcers as well as venous ulcers ("mixed ulcers types") and patients were treated for 30 days. For this "mixed ulcers" there was a significant benefit of HBOT in terms of reduction in ulcer area at the end of treatment (30 days) (MD 61.88%, 95% CI 41.91 to 81.85, P < 0.00001). We did not identify any trials that considered arterial and pressure ulcers. AUTHORS' CONCLUSIONS:In people with foot ulcers due to diabetes, HBOT significantly improved the ulcers healed in the short term but not the long term and the trials had various flaws in design and/or reporting that means we are not confident in the results. More trials are needed to properly evaluate HBOT in people with chronic wounds; these trials must be adequately powered and designed to minimise all kinds of bias.

Project description:1. Pigeon heart mitochondria produce H(2)O(2) at a maximal rate of about 20nmol/min per mg of protein. 2. Succinate-glutamate and malate-glutamate are substrates which are able to support maximal H(2)O(2) production rates. With malate-glutamate, H(2)O(2) formation is sensitive to rotenone. Endogenous substrate, octanoate, stearoyl-CoA and palmitoyl-carnitine are by far less efficient substrates. 3. Antimycin A exerts a very pronounced effect in enhancing H(2)O(2) production in pigeon heart mitochondria; 0.26nmol of antimycin A/mg of protein and the addition of an uncoupler are required for maximal H(2)O(2) formation. 4. In the presence of endogenous substrate and of antimycin A, ATP decreases and uncoupler restores the rates of H(2)O(2) formation. 5. Reincorporation of ubiquinone-10 and ubiquinone-3 to ubiquinone-depleted pigeon heart mitochondria gives a system in which H(2)O(2) production is linearly related to the incorporated ubiquinone. 6. The generation of H(2)O(2) by pigeon heart mitochondria in the presence of succinate-glutamate and in metabolic state 4 has an optimum pH value of 7.5. In states 1 and 3u, and in the presence of antimycin A and uncoupler, the optimum pH value is shifted towards more alkaline values. 7. With increase of the partial pressure of O(2) to the hyperbaric region the formation of H(2)O(2) is markedly increased in pigeon heart mitochondria and in rat liver mitochondria. With rat liver mitochondria and succinate as substrate in state 4, an increase in the pO(2) up to 1.97MPa (19.5atm) increases H(2)O(2) formation 10-15-fold. Similar pO(2) profiles were observed when rat liver mitochondria were supplemented either with antimycin A or with antimycin A and uncoupler. No saturation of the system with O(2) was observed up to 1.97MPa (19.5atm). By increasing the pO(2) to 1.97MPa (19.5atm), H(2)O(2) formation in pigeon heart mitochondria with succinate as substrate increased fourfold in metabolic state 4, with antimycin A added the increase was threefold and with antimycin A and uncoupler it was 2.5-fold. In the last two saturation of the system with oxygen was observed, with an apparent K(m) of about 71kPa (0.7-0.8atm) and a V(max.) of 12 and 20nmol of H(2)O(2)/min per mg of protein. 8. It is postulated that in addition to the well-known flavin reaction, formation of H(2)O(2) may be due to interaction with an energy-dependent component of the respiratory chain at the cytochrome b level.

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DNA Methylation May be Involved in the Analgesic Effect of Hyperbaric Oxygen via Regulating FUNDC1.

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DNA Methylation May be Involved in the Analgesic Effect of Hyperbaric Oxygen via Regulating FUNDC1.

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