Neurological outcome in long-chain hydroxy fatty acid oxidation disorders.

OBJECTIVE: This study aims to elucidate the long-term benefit of newborn screening (NBS) for individuals with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide. METHODS: German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long-term clinical outcomes. RESULTS: Sixty-seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved. INTERPRETATION: While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long-term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course-altering treatment.

Evaluation of earlier versus later dietary management in long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein deficiency: a systematic review.

BACKGROUND: Mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies are rare fatty acid ß-oxidation disorders. Without dietary management the conditions are life-threatening. We conducted a systematic review to investigate whether pre-symptomatic dietary management following newborn screening provides better outcomes than treatment following symptomatic detection. METHODS: We searched Web of Science, Medline, Pre-Medline, Embase and the Cochrane Library up to 23rd April 2018. Two reviewers independently screened titles, abstracts and full texts for eligibility and quality appraised the studies. Data extraction was performed by one reviewer and checked by another. RESULTS: We included 13 articles out of 7483 unique records. The 13 articles reported on 11 patient groups, including 174 people with LCHAD deficiency, 18 people with MTP deficiency and 12 people with undifferentiated LCHAD/MTP deficiency. Study quality was moderate to weak in all studies. Included studies suggested fewer heart and liver problems in screen-detected patients, but inconsistent results for mortality. Follow up analyses compared long-term outcomes of (1) pre-symptomatically versus symptomatically treated patients, (2) screened versus unscreened patients, and (3) asymptomatic screen-detected, symptomatic screen-detected, and clinically diagnosed patients in each study. For follow up analyses 1 and 2, we found few statistically significant differences in the long-term outcomes. For follow up analysis 3 we found a significant difference for only one comparison, in the incidence of cardiomyopathy between the three groups. CONCLUSIONS: There is some evidence that dietary management following screen-detection might be associated with a lower incidence of some LCHAD and MTP deficiency-related complications. However, the evidence base is limited by small study sizes, quality issues and risk of confounding. An internationally collaborative research effort is needed to fully examine the risks and the benefits to pre-emptive dietary management with particular attention paid to disease severity and treatment group.

Fatal pitfalls in newborn screening for mitochondrial trifunctional protein (MTP)/long-chain 3-Hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.

BACKGROUND: Mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency are long-chain fatty acid oxidation disorders with particularly high morbidity and mortality. Outcome can be favorable if diagnosed in time, prompting the implementation in newborn screening programs. Sporadic cases missed by the initial screening sample have been reported. However, little is known on pitfalls during confirmatory testing resulting in fatal misconception of the diagnosis. RESULTS: We report a series of three patients with MTP and LCHAD deficiency, in whom diagnosis was missed by newborn screening, resulting in life-threatening metabolic decompensations within the first half year of life. Two of the patients showed elevated concentrations of primary markers C16-OH and C18:1-OH but were missed by confirmatory testing performed by the maternity clinic. A metabolic center was not consulted. Confirmatory testing consisted of analyses of acylcarnitines in blood and organic acids in urine, the finding of normal excretion of organic acids led to rejection and underestimation of the diagnosis, respectively. The third patient, a preterm infant, was not identified in the initial screening sample due to only moderate elevations of C16-OH and C18:1-OH and normal secondary markers and analyte ratios. CONCLUSION: Our observations highlight limitations of newborn screening for MTP/LCHAD deficiency. They confirm that analyses of acylcarnitines in blood and organic acids in urine alone are not suitable for confirmatory testing and molecular or functional analysis is crucial in diagnosing MTP/LCHAD deficiency. Mild elevations of primary biomarkers in premature infants need to trigger confirmatory testing. Our report underscores the essential role of specialized centers in confirming or ruling out diagnoses in suspicious screening results.

[Regulation of pravastatin on long-chain fatty acid oxidative enzyme in pre-eclampsia-like mouse model].

Objective: To investigate the modulation of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) expression by pravastatin in pre-eclampsia-like mouse model. Methods: C57BL/6J mice were randomly injected with N-nitro-L-arginine methyl ester (L-NAME) as pre-eclampsia-like model group (PE) or saline as normal pregnancy control group (Con) respectively, from gestational the 7th to 18th day. For each group, pravastatin (PE+Pra, Con+Pra group) or saline (PE+N, Con+N Group) was given from the 8th to 18th day of gestation, respectively. Liver and placenta of pregnant mice were collected on gestational day 18. The LCHAD protein expression and mRNA levels of liver and placenta were detected through western blot, immunohistochemistry and real-time quantitative PCR. Results: (1) The average arterial pressure of pregnant mice increased gradually from the 8th to 18th day in PE+N group, but decreased in PE+Pra group from gestational 10th day, 24 hour urinary protein levels in PE+N group [(1 494 ± 201) µg] were significantly higher than that in Con+N group [(935±128) µg, P<0.01], and also higher than that in PE+Pra group [(981±116) µg, P<0.01].(2) The results of western blot: the expression of LCHAD was significantly lower in PE+N group (liver: 0.64±0.11, placenta: 0.48±0.06) than that in Con+N group (liver: 1.06±0.10, placenta: 0.60±0.10), and lower than that in PE+Pra group (liver: 0.99±0.04, placenta: 0.60±0.08; all P<0.01).(3)The results of real-time quantitative PCR: the levels of LCHAD mRNA in liver and placenta in PE+N group (liver: 0.621±0.128, placenta: 0.646±0.129) were significantly decreased compared with Con+N group (liver: 1.007±0.130, placenta: 1.004±0.103; all P<0.01), but there was no significant difference between PE+Pra group (liver: 0.693±0.678, placenta: 0.662±0.183; P>0.05). (4) LCHAD protein was expressed widely and evenly in liver. The expression in placental cytotrophoblast and syncytial trophoblast cells located in outer layer of villous in labyrinth layer was the most. The expression of LCHAD was significantly lower in PE+N group (liver: 0.062±0.016, placenta: 0.147±0.018) than that in Con+N group (liver: 0.126±0.013, placenta: 0.183±0.024), and lower than that in PE+Pra group (liver: 0.111±0.017, placenta: 0.174±0.027; all P<0.05). Conclusion: Pravastatin could upregulate the LCHAD protein expression of liver and placenta in the pre-eclampsia-like mouse, which may be a mechanism to improve the clinical manifestations of pre-eclampsia.

Two Fungicides Alter Reproduction of the Small Brown Planthopper Laodelphax striatellus by Influencing Gene and Protein Expression.

Aside from their intended actions, fungicides can drive pest insect outbreaks due to virtually continuous use and pest evolution. Small brown planthopper (SBPH), Laodelphax striatellus, outbreaks occurred recently in many provinces in China, with devastating rice losses. Because exposure to the fungicide jinggangmycin (JGM) increased reproduction of the brown plant hopper, Nilaparvata lugens, via its influence on fatty acid synthase, we posed the hypothesis that JGM and carbendazim (CBM) influence SBPH reproduction via their influence on enzymes involved in other aspects of lipid metabolism. Exposure to the fungicide CBM stimulated SBPH reproduction (egg-laying up by 78%) and to another fungicide, JGM, led to decreased egg-laying (down by 47.3%). These inverse effects are mediated by down-regulated expression of l-3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) in JGM-treated females and up-regulated expression of hydroxysteroid dehydrogenase-like protein 2-like (HSD) in CBM-treated females. RNAi knockdown of, separately, LCHAD and HSD led to reduced egg-laying (down by 52% for dsLCHAD and by 73% for dsHSD). dsLCHAD, dsHSD, and JGM treatments also led to severely reduced ovarian development in experimental SBPH, with shorted and thinned valvula and lack of egg cells in ovaries. Valvula of CBM-treated females enlarged, with banana-shaped eggs in ovaries. These data strongly support our hypothesis.

Oligo(cis-1,4-isoprene) aldehyde-oxidizing dehydrogenases of the rubber-degrading bacterium Gordonia polyisoprenivorans VH2.

The actinomycete Gordonia polyisoprenivorans strain VH2 is well-known for its ability to efficiently degrade and catabolize natural rubber [poly(cis-1,4-isoprene)]. Recently, a pathway for the catabolism of rubber by strain VH2 was postulated based on genomic data and the analysis of mutants (Hiessl et al. in Appl Environ Microbiol 78:2874-2887, 2012). To further elucidate the degradation pathway of poly(cis-1,4-isoprene), 2-dimensional-polyacrylamide gel electrophoresis was performed. The analysis of the identified protein spots by matrix-assisted laser desorption/ionization-time of flight tandem mass spectrometry confirmed the postulated intracellular pathway suggesting a degradation of rubber via ß-oxidation. In addition, other valuable information on rubber catabolism of G. polyisoprenivorans strain VH2 (e.g. oxidative stress response) was provided. Identified proteins, which were more abundant in cells grown with rubber than in cells grown with propionate, implied a putative long-chain acyl-CoA-dehydrogenase, a 3-ketoacyl-CoA-thiolase, and an aldehyde dehydrogenase. The amino acid sequence of the latter showed a high similarity towards geranial dehydrogenases. The expression of the corresponding gene was upregulated > 10-fold under poly(cis-1,4-isoprene)-degrading conditions. The putative geranial dehydrogenase and a homolog were purified and used for enzyme assays. Deletion mutants for five aldehyde dehydrogenases were generated, and growth with poly(cis-1,4-isoprene) was investigated. While none of the mutants had an altered phenotype regarding growth with poly(cis-1,4-isoprene) as sole carbon and energy source, purified aldehyde dehydrogenases were able to catalyze the oxidation of oligoisoprene aldehydes indicating an involvement in rubber degradation.

Déficit de 3-hidroxiacil-CoA-deshidrogenasa de cadena larga: a propósito de un caso / Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: A case report

CASO CLÍNICO: Paciente de 5 años de edad remitido para valoración oftalmológica con el diagnóstico de déficit de 3-hidroxiacil-CoA deshidrogenasa de cadena larga. Presentaba como antecedente la aparición de crisis metabólicas agudas precipitadas por infecciones banales y rabdomiólisis. El examen oftalmoscópico reveló una atrofia coriorretiniana peripapilar y una maculopatía granular difusa. La agudeza visual era de 6/6 en ambos ojos y las pruebas electrofisiológicas normales. DISCUSIÓN: Se realiza una revisión de la bibliografía y los conocimientos recientes de esta enfermedad mediante la descripción de un caso clínico documentando los hallazgos obtenidos mediante autofluorescencia y tomografía de coherencia óptica para mejorar el conocimiento existente sobre ella

CLINICAL CASE: A five-year-old patient, with a diagnosis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, was referred for an ophthalmological examination. He had a history of acute metabolic crises precipitated by intercurrent infections,as well as rhabdomyolysis. The fundoscopic examination revealed a peripapillary chorioretinal atrophy and a diffuse granular appearance of the macular retinal pigment epithelium. Best corrected visual acuity was 6/6 in both eyes, and he had a normal electroretinography test. DISCUSSION: We perform a review of the literature and recent findings in relation to this disease through the description of a clinical case in order to improve the knowledge of this uncommon disorder

[Variation of long-chain 3-hydroxyacyl CoA dehydrogenase DNA methylated modification and correlation with gene mRNA expression of early-onset preeclampsia, HELLP syndrome and antiphospholipid syndrome in trophoblast cells of placenta].

OBJECTIVE: By detecting the DNA methylation and gene expression of long-chain 3-hydroxyacyl CoA dehydrogenase(LCHAD)in trophoblast cells, analyze the correlation of DNA methylation and gene expression in early-onset preeclampsia(EPE), hemolysis, elevated liver enzymes, and low platelets(HELLP)syndrome and antiphospholipid syndrome(APS), to investigate the molecular basis of long-chain fatty acid oxidation changes in different preeclampsia and pathological pregnancy. METHODS: Primary human cytotrophoblast cells and HTR8/Svneo cells were treated with serum from patients with EPE(14 cases), HELLP(12 cases), APS(14 cases), and normal pregnant women(NP, 14 cases). The methylation level of LCHAD gene promoter region through the MassARRAY platform and mRNA expression level by real-time fluorescent quantitative PCR technique were conducted. RESULTS: (1)Cytosine-phosphate-guanine(CpG)sites in human LCHAD DNA promoter region: CpG sites were detected in the range of 558 bp before LCHAD gene transcription start site, the detected CpG sites were 11 sites including 8 single sites and 3 complex sites. The position of these sites were at-984,-960,-899,-853,-811,-796,-774,-727,-615,-595,-579 respectively.(2)The sites of-899,-853,-615 and-595 showed increased methylation level in EPE and HELLP groups. The methylation level at-899,-853 and-615 sites in EPE and HELLP groups were significantly higher than those in NP group(P<0.01). The methylation level at-853 site was higher in EPE group than that in HELLP group(P<0.05). The-595 site showed the unmethylated in EPE, HELLP and APS groups. There were significantly difference between the 3 groups and EPE group(P<0.01).(3)The gene expression of LCHAD mRNA in EPE(0.048±0.005), HELLP(0.045±0.006)and APS(0.044±0.004)groups were significantly lower than NP group(0.076±0.009; P<0.01).(4)The correlation of methylation level and gene expression in all groups: the methylation level at-899,-853,-727,-615 and-579 sites were negatively correlated with gene mRNA expression in EPE group(P<0.05). The methylation level at-899,-853 and-615 sites were negatively correlated with gene mRNA expression in HELLP group(P< 0.05). CONCLUSIONS: The variation of LCHAD DNA methylation of trophoblast cells are found among EPE, HELLP syndrome and APS. The different correlation of LCHAD DNA methylation and gene expression are different in pathological groups. LCHAD DNA methylation of EPE and HELLP syndrome were significantly increased and negatively correlated with LCHAD gene mRNA expression. These results further revealed the molecular basis of long-chain fatty acid oxidation in different preeclampsia and pathological pregnancy.

[Variation of long-chain 3-hydroxyacyl-CoA dehydrogenase DNA methylation in placenta of different preeclampsia-like mouse models].

OBJECTIVE: By detecting the variation of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) DNA methylation in preeclampsia-like mouse models generated by different ways, to explore the roles of multifactor and multiple pathways in preeclampsia pathogenesis on molecular basis. METHODS: Established preeclampsia-like mouse models in different ways and divided into groups as follows: (1) Nw-nitro-L-arginine-methyl ester (L-NAME) group: wild-type pregnant mouse received subcutaneous injection of L-NAME; (2) lipopolysaccharide (LPS) group: wild-type pregnant mouse received intraperitoneal injection of LPS; (3) apolipoprotein C-III (ApoC3) group: ApoC3 transgenic pregnant mouse with dysregulated lipid metabolism received subcutaneous injection of L-NAME; (4) ß2 glycoprotein I (ß-2GPI) group: wild-type pregnant mouse received subcutaneous injection of ß-2GPI. According to the first injection time (on day 3, 11, 16 respectively), the L-NAME, LPS and ApoC3 groups were further subdivided into: pre-implantation (PI) experimental stage, early gestation (EG) experimental stage, and late gestation (LG) experimental stage. ß-2GPI group was only injected before implantation. LCHAD gene methylation levels in placental were detected in different experimental stage. Normal saline control groups were set within wild-type and ApoC3 transgenic pregnant mice simultaneously. RESULTS: (1) CG sites in LCHAD DNA: 45 CG sites were detected in the range of 728 bp before LCHAD gene transcription start site, the 5, 12, 13, 14, 15, 16, 19, 24, 25, 27, 28, 29, 30, 31, 32, 34, 35, 43 CG sites were complex sites which contained two or more CG sequences, others were single site which contained one CG sequence. The 3, 5, 6, 11, 13, 14, 18, 28 sites in L-NAME, LPS, ApoC3 and ß-2GPI groups showed different high levels of methylation; the 16, 25, 31, 42, 44 sites showed different low levels of methylation; other 32 sites were unmethylated. (2) Comparison of LCHAD gene methylation between different groups: the methylation levels of LCAHD gene at 3, 11, 13, 14, 18 sites in L-NAME, LPS, ApoC3 and ß-2GPI groups were significantly higher than those in the normal saline control group (P < 0.05); and the methylation levels of 42, 44 sites in these groups were significantly lower than those in the normal saline control group (P < 0.05). (3) Methylation of LCHAD gene at the same site between different experimental stages: ① The 3, 11, 18 sites of EG experimental stage was significantly lower than PI and LG experimental stage in L-NAME group (P < 0.05); the 3, 11, 18 sites of PI experimental stage was significantly lower than EG and LG experimental stage in LPS group (P < 0.05); these sites of PI experimental stage was significantly higher than EG and LG experimental stages in ApoC3 group (P < 0.05). ② The methylation of site 5 in L-NAME and LPS groups were significantly higher than that of the normal saline control group (P < 0.05), and the LG experimental stages were significantly higher than other stages, but in ApoC3 group, only PI and EG stages were significantly higher than the normal saline control group (P < 0.05). ③ At site 6 in L-NAME group which showed high methylation level was significantly higher than the same site in other groups which showed low methylation level (P < 0.05). ④ At 13, 14 sites, earlier preeclampsia onset caused a lower methylation level in L-NAME group, but PI experimental stage was significantly higher than EG and LG experimental stages in LPS group (P < 0.05), EG experimental stage was significantly higher than PI and LG experimental stages in ApoC3 group (P < 0.05). ⑤ At site 28, earlier preeclampsia onset caused a higher methylation level in L-NAME group, but PI experimental stage was significantly lower than EG and LG experimental stages in LPS group (P < 0.05), EG experimental stage was significantly higher than PI and LG experimental stages in ApoC3 group (P < 0.05). ⑥ The 16, 25, 31 sites in ApoC3 group were significantly higher than other groups (P < 0.05). ⑦ At site 42 in ß-2GPI group was unmethylated, but it in other groups showed low methylation level, the methylation level of site 42 in ß-2GPI group was significantly lower than that in other groups (P < 0.05). CONCLUSIONS: The methylation of 6 and 42 CG sites may be related to LCHAD gene expression in placenta of L-NAME and ß-2GPI induced preeclampsia-like models respectively; LCHAD gene expression and DNA methylation may not have obvious correlation in LPS and ApoC3 induced preeclampsia-like models. Differences exist in LCHAD DNA methylation in preeclampsia-like models generated by different ways, revealed a molecular basis to expand our understanding of the multi-factorial pathogenesis of preeclampsia.

Deregulation of mitochondrial functions provoked by long-chain fatty acid accumulating in long-chain 3-hydroxyacyl-CoA dehydrogenase and mitochondrial permeability transition deficiencies in rat heart--mitochondrial permeability transition pore opening as a potential contributing pathomechanism of cardiac alterations in these disorders.

Mitochondrial trifunctional protein and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies are fatty acid oxidation disorders biochemically characterized by tissue accumulation of long-chain fatty acids and derivatives, including the monocarboxylic long-chain 3-hydroxy fatty acids (LCHFAs) 3-hydroxytetradecanoic acid (3HTA) and 3-hydroxypalmitic acid (3HPA). Patients commonly present severe cardiomyopathy for which the pathogenesis is still poorly established. We investigated the effects of 3HTA and 3HPA, the major metabolites accumulating in these disorders, on important parameters of mitochondrial homeostasis in Ca(2+) -loaded heart mitochondria. 3HTA and 3HPA significantly decreased mitochondrial membrane potential, the matrix NAD(P)H pool and Ca(2+) retention capacity, and also induced mitochondrial swelling. These fatty acids also provoked a marked decrease of ATP production reflecting severe energy dysfunction. Furthermore, 3HTA-induced mitochondrial alterations were completely prevented by the classical mitochondrial permeability transition (mPT) inhibitors cyclosporin A and ADP, as well as by ruthenium red, a Ca(2+) uptake blocker, indicating that LCHFAs induced Ca(2+)-dependent mPT pore opening. Milder effects only achieved at higher doses of LCHFAs were observed in brain mitochondria, implying a higher vulnerability of heart to these fatty acids. By contrast, 3HTA and docosanoic acids did not change mitochondrial homeostasis, indicating selective effects for monocarboxylic LCHFAs. The present data indicate that the major LCHFAs accumulating in mitochondrial trifunctional protein and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies induce mPT pore opening, compromising Ca(2+) homeostasis and oxidative phosphorylation more intensely in the heart. It is proposed that these pathomechanisms may contribute at least in part to the severe cardiac alterations characteristic of patients affected by these diseases.

Nickel inhibits mitochondrial fatty acid oxidation.

Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation-the pathway by which fatty acids are catabolized for energy-in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with l-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 h), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis.

Correlation between the different chain lengths of free fatty acid oxidation and ability of trophoblastic invasion.

BACKGROUND: Preeclampsia (PE) is associated with abnormal fatty acid beta-oxidation (FAO), especially metabolic disorders of long-chain fatty acid oxidation. The role of FAO dysfunction in inadequate invasion is unclear. The aim of this study was to explore the influence of various lengths fatty acids oxidation on invasiveness of trophoblasts. METHODS: Primary human trophoblast cells and HTR8/SVneo cells were treated with fatty acids of various lengths. Morphological changes, lipid deposition and ultrastructure changes of trophoblast cells were detected. Cells invasiveness was determined by transwell insert. CPT1, CPT2 and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) protein expression were analyzed. The correlation between intracellular lipid droplets deposition and cells invasiveness was evaluated. RESULTS: Cells treated with long-chain fatty acids showed significant increased lipid droplets deposition, severe mitochondrial damage, decreased CPT2 and LCHAD protein expression (P < 0.05) but no significant difference in CPT1 protein expression (P > 0.05). Invasiveness of the trophoblast cells of the LC-FFA group significantly decreased (P < 0.05). Intracellular lipid droplets deposition was negatively correlated with invasivenss (R = -0.745, P < 0.05). CONCLUSION: Trophoblast cells after stimulation with long chain fatty acids exist fatty acid oxidation disorders, and reduce the ability of trophoblastic invasion.

Use of propofol for short duration procedures in children with long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiencies.

The medication propofol, commonly used for anesthesia, has been avoided in patients with mitochondrial fatty acid oxidation disorders (FAODs) due to concerns that it contains long-chain fatty acids (LCFAs), and because of reports of severe side effects in some critically ill patients receiving high-dose propofol infusions that mimic some of the symptoms regularly found in FAOD patients. In this secondary analysis, we examined the outcomes of 8 children with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency or trifunctional protein (TFP) deficiency who were repeatedly sedated for an electroretinogram (ERG) as part of a longitudinal study of the progression of chorioretinopathy commonly found in this population. A total of 39 sedated ERG procedures were completed using propofol for sedation. The propofol dosing, estimated total energy needs of the subject, and inpatient dietary intake recording were completed in 32 of these procedures. The LCFAs in the propofol provided approximately 1.0% of the average total daily energy needs. The sedation with propofol resulted in no adverse side effects and was safely used in this short duration procedure.

[Interaction mechanism and influence between fatty acid oxidation in trophoblast cells and p38MAPK signal transduction pathway of severe preeclampsia].

OBJECTIVE: To investigate the effects of expression of mitochondria long-chain fatty acid oxidative enzyme (long-chain 3 hyroxyacyl CoA dehydrogenase, LCHAD) and p38 mitogen activated protein kinase (p38MAPK) signal transduction pathway in severe preeclampsia. METHODS: Serum-free trophoblast cells cultured in vitro were stimulated by early onset severe preeclampsia serum (E-PE group), late onset severe preeclampsia serum (L-PE group), HELLP syndrome serum (HELLP group), and normal pregnancy serum (NP group) respectively; each group was added DMEM/F12 medium, reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor (NADPH-I) and p38MAPK inhibitor (p38-I) to stimulate cells. Expression of mRNA and protein of LCHAD in trophoblast cells were detected by real-time PCR and western blot. RESULTS: (1)The expression of mRNA of LCHAD: the level of mRNA of LCHAD in NP+DMEM, E-PE+DMEM, E-PE+NADPH-I, E-PE+p38-I, L-PE+DMEM, L-PE+NADPH-I, L-PE+p38-I and HELLP+DMEM, HELLP+NADPH-I, HELLP+p38-I groups were 1.00 ± 0.03, 0.14 ± 0.08, 0.95 ± 0.20, 1.43 ± 1.02, 0.37 ± 0.18, 1.51 ± 0.36, 1.60 ± 0.31, 0.10 ± 0.04, 0.49 ± 0.10, 0.44 ± 0.21, respectively. The relative expressions of mRNA of LCHAD were significantly reduced in E-PE+DMEM, L-PE+DMEM and HELLP+DMEM groups compared with the NP+DMEM group (P < 0.05). Compared with the NP groups, the relative expressions of mRNA of LCHAD were significantly increased in L-PE+NADPH-I and L-PE+p38-I group (P < 0.05), while reduced in HELLP groups(P < 0.05). (2) The expression of protein of LCHAD: the relative expressions of protein of LCHAD in NP+DMEM, E-PE+DMEM, E-PE+NADPH-I, E-PE+p38-I, L-PE+DMEM, L-PE+NADPH-I, L-PE+p38-I and HELLP+ DMEM, HELLP+NADPH-I, HELLP+p38-I groups were 19.4 ± 2.2, 10.7 ± 1.1, 17.9 ± 3.3, 19.1 ± 2.9, 16.4 ± 2.3, 20.3 ± 2.3, 20.9 ± 4.3, 12.4 ± 2.3, 17.6 ± 2.6, 17.7 ± 2.0 respectively. Compared with the NP groups, the protein expressions of LCHAD were significantly remarkably reduced in E-PE+DMEM, L-PE+DMEM and HELLP groups (P < 0.05). Compared with the DMEM groups, the protein expressions of LCHAD were significantly increased in NADPH-I and p38-I groups of E-PE, L-PE and HELLP groups (P < 0.05). CONCLUSIONS: These studies demonstrate that long chain fatty acid oxidation was involved in the pathogenesis and development of preeclampsia. The expressions of gene and protein of LCHAD were remarkably affected by early onset severe preeclampsia and HELLP syndrome. NADPH-I and p38-I may allay the disorder of fatty acid oxidation. p38MAPK signal transduction pathway may contributed in this process.