Fatty Acid Oxidation Disorders Research Articles

The Metabolic Treatabolome and Inborn Errors of Metabolism Knowledgebase therapy tool: Do not miss the opportunity to treat!

Inborn errors of metabolism (IEMs) are rare genetic conditions with significant morbidity and mortality. Technological advances have increased therapeutic options, making it challenging to remain up to date. A centralized therapy knowledgebase is needed for early diagnosis and targeted treatment. This study aimed to identify all treatable IEMs through a scoping literature review, followed by data extraction and analysis according to the Treatabolome principles. Knowledge of treatable IEMs, therapeutic categories, efficacy, and evidence was integrated into the Inborn Errors of Metabolism Knowledgebase (IEMbase), an online database encompassing all IEMs. The study identified 275 treatable IEMs, 18% of all currently known 1564 IEMs, according to the International Classification of Inherited Metabolic Disorders. Disorders of fatty acid and ketone body metabolism had the highest treatability (67%), followed by disorders of vitamin and cofactor metabolism (60%), and disorders of lipoprotein metabolism (42%). The most common treatment strategies were pharmacological therapy (34%), nutritional therapy (34%), and vitamin and trace element supplementation (12%). Treatment effects were most commonly observed in nervous system abnormalities (34%), metabolism/homeostasis abnormalities (33%), and growth (7%). Predominant evidence sources included case reports with evidence levels 4 (48%) and 5 (12%), and individual cohort studies with evidence level 2b (12%). Our study generated the Metabolic Treatabolome 2024. IEMs are the largest group of monogenic disorders amenable to disease-modifying therapy. With drug repurposing efforts and advancements in gene therapies, this number will expand. IEMbase now provides up-to-date, comprehensive information on clinical and biochemical symptoms and therapeutic options, empowering patients, families, healthcare professionals, and researchers in improving patient outcomes.

Circulatory response to exercise relative to oxygen uptake assessed in the follow-up of patients with fatty acid beta-oxidation disorders.

Patients with fatty acid oxidation disorders (FAODs) experience muscle symptoms due to impaired ATP metabolism and the toxicity of accumulated mitochondrial FAO substrates or intermediates, especially during catabolic states. A major issue is the absence of specific and sensible biomarkers to evaluate metabolic equilibrium. The relationship between cardiac output (Q) and oxygen consumption (VO2) during incremental exercise (dQ/dVO2) provides an indirect surrogate of mitochondrial function. A high dQ/dVO2 slope indicates impaired oxidative phosphorylation in skeletal muscle during exercise. Our study aimed to evaluate dQ/dVO2 as a potential marker of the severity of FAODs. We retrospectively collected clinical, laboratory parameters and treatment data for FAOD patients over 6 years old, including a disease severity score, plasma acylcarnitines and cardiopulmonary exercise tests with Q measurement via thoracic bioelectrical impedance. FAO flux was measured in whole blood and in myoblasts when available. We included 27 FAOD patients followed from 2015 to 2022, with deficiencies in LCHAD (n = 10), CPT2 (n = 6), VLCAD (n = 7), or MADD (n = 4). CPT2 deficient patients with severe scores had the highest C18:1-, C16-, C18-acylcarnitines, and dQ/dVO2. In these patients, dQ/dVO2 was positively correlated with C18:1, C16, and C18 acylcarnitines. In a linear multivariate regression model, dQ/dVO2 was significantly associated with the severity score (B = 0.831, p = 0.008) and triheptanoin treatment (B = -0.547, p = 0.025). dQ/dVO2 and plasma long-chain acylcarnitines might be useful to monitor CPT2D, as these parameters associate with our clinical severity score and could reflect altered mitochondrial functions.

Spectrum analysis of inborn errors of metabolism for expanded newborn screening in Xinjiang, China.

To determine the disease spectrum and genetic characteristics of inborn errors of metabolism (IEM) in Xinjiang province in the northwest of China, 41,690 newborn babies were screening by tandem mass spectrometry from November 2018 to December 2021. Of these, 57 newborn babies were referred for genetic analysis by next-generation sequencing, which was validated by Sanger sequencing. A total of 36 newborn babies and one relative were diagnosed with IEM, and the overall positive predictive value was 29.03%. The overall incidence of IEM in Xinjiang was 1:1,158 (36/41,690). The incidence of amino acidemias, organic acidemias, and fatty acid oxidation disorder were 1:1,668 (25/41,690), 1:4,632 (9/41,690), and 1:20,845 (2/41,690), respectively. Phenylketonuria and methylmalonic acidemia were the two most common inborn errors of metabolism (IEM), accounting for 83% (30/36) of all confirmed cases. Some hotspot mutations were observed for several IEMs, including PAH gene c.158G > A (p.Arg53His) and c.688G > A (p.Val230Ile) for hyperphenylalaninemia. Four mutation types of the MMACHC gene (e.g., c.609G > A (p.Trp203Ter), c.567dupT (p.Ile190fs)) and six mutation types of the MMUT gene (e.g., c.729_730insT (p.Asp244fs)) were found for methylmalonic acidemia. We also found 11 mutations in six genes: PCCB, IVD, GCDH, MCCC1, SLC22A5, and ACADS in this region. This study combined tandem mass spectrometry and next-generation sequencing technology for the screening and diagnosis of IEM. The study provides effective clinical guidance, and the data provide a basis for expanding newborn screening, genetic screening, and IEM gene consultation in Xinjiang, China.

Homozygous slc25a20 zebrafish mutant reveals insights into carnitine-acylcarnitine translocase deficiency pathogenesis

The SLC25A20 gene encodes carnitine-acylcarnitine translocase (CACT), facilitating the transport of long-chain acylcarnitine required for energy production via β-oxidation into the mitochondria. Loss-of-function mutations in this gene lead to CACT deficiency, a rare autosomal recessive disorder of fatty acid metabolism characterized by severe symptoms including cardiomyopathy, hepatic dysfunction, rhabdomyolysis, hypoketotic hypoglycemia, and hyperammonemia, often resulting in neonatal mortality. Here, we utilized CRISPR/Cas9 gene editing to isolate slc25a20 mutant zebrafish. Homozygous mutants displayed significant lethality, with the majority succumbing before reaching maturity. However, we identified a notably rare homozygous individual that survived into adulthood, prompting a histological examination. Firstly, we observed adipose tissue accumulation at various sites in the homozygous mutant. The mutant heart exhibited hypertrophy, along with degenerated myocardial and muscle cells containing numerous eosinophilic nuclei. Additionally, we found no large oil droplet vacuoles in the mutant liver; however, the hepatocytes displayed numerous small vacuoles resembling lipid droplets. Iron deposition was evident in the spleen and parts of the liver. Overall, our slc25a20 zebrafish mutant displayed tissue pathologies analogous to human CACT deficiency, suggesting its potential as a pathological model contributing to the elucidation of pathogenesis and the improvement/development of therapies for CACT deficiency.

Loss-of-function SLC25A20 mutation causes carnitine-acylcarnitine translocase deficiency by reducing SLC25A20 protein stability.

Autosomal-recessive carnitine-acylcarnitine translocase deficiency (CACTD) is a rare disorder of long-chain fatty acid oxidation caused by variants in the SLC25A20 gene. Under fasting conditions, most newborns with severe CACTD experience sudden cardiac arrest and hypotonia, often leading to premature death due to rapid disease progression. Understanding of genetic factors and pathogenic mechanisms in CACTD is essential for its diagnosis, treatment, and prevention. Whole-exome sequencing was carried out on the CACTD patients. Bioinformatics analysis predicted the pathogenicity and three-dimensional structure of SLC25A20. Quantitative PCR was employed to detect changes in SLC25A20, CPT1A and CPT2 mRNA levels. The expression and stability of the mutant protein were assessed via Western blot. Additionally, the subcellular localization of the mutant protein was observed using immunofluorescence. We identified novel pathogenic compound heterozygous variants of SLC25A20 (c.476 T > C and c.199-10 T > G) in CACTD families, with patients exhibiting an abnormal carnitine spectrum. In vitro functional studies demonstrated that the c.476 T > C and c.199-10 T > G variants decreased the protein stability of SLC25A20, reduced CPT1A and CPT2 mRNA expression, and caused protein aggregation of SLC25A20. We propose that the decreased stability of the SLC25A20 variants c.476 T > C and c.199-10 T > G has the potential to lead to the development of CACTD by affecting the mitochondrial shuttle of acylcarnitine and carnitine, thereby inhibiting the β-oxidation pathway. Therefore, we believe this novel combination of variants (c.199-10 T > G and c.476 T > C) are loss-of-function variants. Our findings provide valuable data on CACTD pathogenesis and genotype-phenotype correlations.

CO171 Major Clinical Manifestation Events and Healthcare Resource Use Among Patients With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Pre- and Post-Triheptanoin Initiation: A Retrospective Claims Database Analysis in the US

CO171 Major Clinical Manifestation Events and Healthcare Resource Use Among Patients With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Pre- and Post-Triheptanoin Initiation: A Retrospective Claims Database Analysis in the US

Maternal odd-chain fatty acid-rich algal oil supplementation during pregnancy improves litter characteristics of intrauterine growth restricted pregnant mice via regulating placental function

Intrauterine growth restriction (IUGR) severely impairs fetal development and offspring health. Odd-chain fatty acid (OCFA) possess beneficial biological activities in regulating insulin resistance, inflammation and oxidative stress. However, the effects of OCFA on improving IUGR through regulating placental function and maternal health remain unclear. Herein, maternal OCFA-rich algal oil supplementation improved variable coefficient of fetal weight and fetal oxidative stress in low protein diet (LPD)-induced IUGR mice model. OCFA-rich algal oil also improved placental dysfunction, placental fatty acid metabolism disorder, maternal insulin resistance, oxidative stress and intestinal injury, suggesting an improved maternal health. OCFA-rich algal oil reshaped the intestinal microbiome of dams, decreasing unclassified Bacteroidales and Parvibacter, and increasing Weissella, which positively impacted insulin resistance and intestinal injury. Overall, OCFA-rich algal oil supplementation during pregnancy ameliorated oxidative stress, insulin resistance and intestinal injury in LPD-induced IUGR pregnant mice, improved placental functions and litter characteristics, and further enhanced fetal antioxidant capacity.

Common biological processes and mutual crosstalk mechanisms between cardiovascular disease and cancer.

Cancer and cardiovascular disease (CVD) are leading causes of mortality and thus represent major health challenges worldwide. Clinical data suggest that cancer patients have an increased likelihood of developing cardiovascular disease, while epidemiologic studies have shown that patients with cardiovascular disease are also more likely to develop cancer. These observations underscore the increasing importance of studies exploring the mechanisms underlying the interaction between the two diseases. We review their common physiological processes and potential pathophysiological links. We explore the effects of chronic inflammation, oxidative stress, and disorders of fatty acid metabolism in CVD and cancer, and also provide insights into how cancer and its treatments affect heart health, as well as present recent advances in reverse cardio-oncology using a new classification approach.

Berberine Mediates Exosomes Regulating the Lipid Metabolism Pathways to Promote Apoptosis of RA-FLS Cells.

Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint damage and commonly linked to symptoms such as inflammation, swelling, and pain. Traditional Chinese Medicine offers complementary and integrative approaches in the management of rheumatoid arthritis, potentially providing additional options that may help address treatment challenges and enhance overall patient care. This paper explores the mechanism of action of berberine from the perspective of cellular exosomes by mediating exosomal contents and thus treating RA. Methods: With the help of flow cytometry and confocal laser scanning microscope, it was determined that berberine promotes apoptosis in RA-FLS cells, and then lipid metabolomics technology was applied to screen and characterize the exosomes of RA-FLS cells to identify lipid core biomarkers closely related to RA, which were then projected into various databases for comprehensive analysis. Results: The data analysis showed that berberine could call back 11 lipid core biomarkers closely associated with RA, and interactive visualization of the database revealed that these markers were mainly focused on lipid metabolism aspects such as fatty acid elongation, degradation, and biosynthesis, as well as the biosynthesis of unsaturated fatty acids or PPARA activation of gene expression, PPARα's role in lipid metabolism regulation, glycerophospholipid metabolism, mitochondrial fatty acid oxidation disorders, and organelle biogenesis and maintenance. Conclusions: Berberine exerts its therapeutic effect on RA by mediating exosomal contents and thus regulating multiple lipid-related biological pathways, affecting the PPARγ-NF-κB complex binding rate, CREB and EGR-1 expression, cellular phagocytosis, and other aspects needed to inhibit proliferation and inflammatory responses in RA-FLS. This study offers a research foundation for exploring the mechanism of action of berberine in the treatment of RA.

The Role of Fatty Acid Metabolism, the Related Potential Biomarkers, and Targeted Therapeutic Strategies in Gastrointestinal Cancers.

Gastrointestinal cancer has emerged as a significant global health concern due to its high incidence and mortality, limited effectiveness of early detection, suboptimal treatment outcomes, and poor prognosis. Metabolic reprogramming is a prominent feature of cancer, and fatty acid metabolism assumes a pivotal role in bridging glucose metabolism and lipid metabolism. Fatty acids play important roles in cellular structural composition, energy supply, signal transduction, and other lipid-related processes. Changes in the levels of fatty acid metabolite may indicate the malignant transformation of gastrointestinal cells, which have an impact on the prognosis of patients and can be used as a marker to monitor the efficacy of anticancer therapy. Therefore, targeting key enzymes involved in fatty acid metabolism, either as monotherapy or in combination with other agents, is a promising strategy for anticancer treatment. This article reviews the potential mechanisms of fatty acid metabolism disorders in the occurrence and development of gastrointestinal tumors, and summarizes the related potential biomarkers and anticancer strategies.

ETFDH mutation involves excessive apoptosis and neurite outgrowth defect via Bcl2 pathway

The most common mutation in southern Chinese individuals with late-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD; a fatty acid metabolism disorder) is c.250G > A (p.Ala84Thr) in the electron transfer flavoprotein dehydrogenase gene (ETFDH). Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts. Our cellular models of MADD exhibit neurite growth defects and excessive apoptosis. Given that axonal degeneration and neuronal apoptosis may be regulated by B-cell lymphoma (BCL)-2 family proteins and mitochondrial outer membrane permeabilization through the activation of proapoptotic molecules, we measured the expression levels of proapoptotic BCL-2 family proteins (e.g., BCL-2-associated X protein and p53-upregulated modulator of apoptosis), cytochrome c, caspase-3, and caspase-9 in NSC-34 cells carrying the most common ETFDH mutation. The levels of these proteins were higher in the mutant cells than in the wide-type cells. Subsequent treatment of the mutant cells with coenzyme Q10 downregulated activated protein expression and mitigated neurite growth defects. These results suggest that the activation of the BCL-2/mitochondrial outer membrane permeabilization/apoptosis pathway promotes apoptosis in cellular models of MADD and that coenzyme Q10 can reverse this effect. Our findings aid the development of novel therapeutic strategies for reducing axonal degeneration and neuronal apoptosis in MADD.

Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in Italy

BackgroundLong-chain fatty acid oxidation disorders (LC-FAOD) are rare and potentially life-threatening diseases that cause deficient energy production and accumulation of toxic metabolites. Despite dietary management, adherence to maximum fasting guidelines, restricted long-chain triglyceride intake and supplementation with medium-chain triglyceride (MCT) oil (current standard of care), most patients experience recurrent decompensation episodes that can require hospitalisation. Herein, we analysed the effectiveness and safety of triheptanoin (a highly purified, synthetic medium odd-chain triglyceride) treatment in a cohort of Italian patients with LC-FAOD.MethodsThis retrospective, nationwide study included nine patients with LC-FAOD who switched from standard therapy with MCT oil to triheptanoin oral liquid. Data were collected between 2018 and 2022. Clinical outcome measures were the number and duration of intercurrent catabolic episodes and number and duration of metabolic decompensation episodes requiring hospitalisation. Creatine kinase (CK) levels and treatment-related adverse effects were also reported.ResultsPatients were provided a mean ± standard deviation (SD) triheptanoin dose of 1.5 ± 0.9 g/kg/day in four divided administrations, which accounted for 23.9 ± 8.9% of patients’ total daily caloric intake. Triheptanoin treatment was started between 2.7 and 16 years of age and was continued for 2.2 ± 0.9 years. The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014), and annualised hospitalisation rates and duration. Mean CK levels (outside metabolic decompensation episodes) were lower with triheptanoin treatment versus MCT oil for seven patients. No intensive care unit admissions were required during triheptanoin treatment. Epigastric pain and diarrhoea were recorded as adverse effects during both MCT and triheptanoin treatment.ConclusionsThe significant improvement in clinical outcome measures after the administration of triheptanoin highlights that this treatment approach can be more effective than MCT supplementation in patients with LC-FAOD. Triheptanoin was well tolerated and decreased the number of intercurrent catabolic episodes, metabolic decompensation episodes requiring hospitalisation, and the annualised rate and duration of hospitalisations.

Periodic Paralysis in a Child With Thermosensitive Mitochondrial Trifunctional Protein Deficiency.

Mitochondrial trifunctional protein (MTP) deficiency is a fatty acid oxidation disorder associated with a spectrum of phenotypes. Patients with high residual enzyme activity tend to have milder phenotypes, and recently, fever-induced episodic myopathy was reported in association with a thermosensitive form of MTP deficiency. We report a 10-year-old male with recurrent episodes of acute flaccid paralysis involving upper and lower extremities in association with bulbar muscle weakness in the context of febrile illness, a phenotype reminiscent of recurrent periodic paralysis. The episodes started at the age of 3 years and have always been followed by full recovery within 1-2 weeks with no residual weakness. Whole exome sequencing revealed a homozygous c.2132C > T, p.(Pro711Leu) variant in HADHA. The variant leads to mildly reduced long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) and long-chain ketoacyl-CoA thiolase (LCKAT) enzyme activities and reduced MTP protein expression in patient's fibroblasts when cultured at 37°C. Enzyme activities and MTP protein expression diminished when fibroblasts were cultured at 40°C. This is the first published report of confirmed recurrent periodic paralysis as a manifestation of a thermosensitive form of MTP deficiency, and it calls for this condition to be considered when evaluating patients with recurrent periodic paralysis given therapeutic implications.

Clinical manifestations, healthcare resource utilization, and costs among patients with long-chain fatty acid oxidation disorders: a retrospective claims database analysis

Objective Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare genetic inborn errors of metabolism. Clinical manifestations may result in frequent healthcare visits, hospitalizations, and early death. This retrospective cohort study assessed manifestations, healthcare resource use (HRU), direct medical costs, and the impact of COVID-19 on HRU among patients with LC-FAOD. Methods The IQVIA PharMetrics Plus database was searched for pediatric (0–17 years) and adult (≥18 years) patients with confirmed LC-FAOD (ICD-10-CM Diagnosis Code E71.310) and ≥12 months continuous enrollment (CE) between January 2016-February 2020. A non–LC-FAOD general population cohort was randomly selected and matched using 1:20 exact matching on age, gender, payer type, and CE start year. Manifestations were identified via ICD-10 diagnosis codes (any billing position). Overall HRU and attributable costs were stratified by care setting. Pre-COVID-19 (March 2019–February 2020) and during COVID-19 (March 2020-February 2021) HRU was assessed among a subgroup of patients and the general population. Outcomes were evaluated among children and adults, respectively. Results 423 patients with LC-FAOD (47% female; 79.7% children) were included. The mean enrollment duration was 2.6 ± 1.2 years. 22.6% of children with LC-FAOD had at least one major clinical event (MCE), consisting of rhabdomyolysis (10.1%), hypoglycemia (9.8%), or cardiomyopathy (8.6%) versus 1.5% overall occurrence in the general population. Adults with LC-FAOD had a higher incidence of MCEs (37.2%) than children with LC-FAOD. Annualized all-cause HRU in all care settings and mean total annualized medical costs (children: $17,082 vs $4144; adults: $43,602 vs $3949) were higher in patients with LC-FAOD versus the general population. Patients with LC-FAOD had substantially fewer healthcare visits during COVID-19 across care settings than during the pre-COVID-19 period. Conclusions LC-FAOD impart a high burden on patients. Extended hospital stays and increased outpatient management were especially pronounced for adults and for patients with ≥1 MCE, resulting in substantially higher medical costs than the general population.

Monocyte and macrophage profiles in patients with inherited long-chain fatty acid oxidation disorders

Patients with inherited disorders of the long-chain fatty acid oxidation (lcFAO) machinery present with a heterogeneous profile of disease manifestations and aggravation of symptoms is often triggered by inflammatory activation. Monocytes and macrophages are innate immune cells that play a major role in the onset and resolution of inflammation. These cells undergo metabolic rewiring upon activation including the regulation of the FAO rate. The rewiring of FAO and the effect of lcFAO disorders (lcFAOD) on human monocyte and macrophage phenotype and function remain largely unknown. Here, we performed extensive phenotyping of circulating monocytes and analyzed plasma cytokine levels in 11 lcFAOD patients and 11 matched control subjects. In patients with lcFAOD, we observed induced plasma levels of the inflammatory cytokines IL-1β and IL-6, and enhanced CD206 and CD62L surface marker expression in circulating monocyte subsets. To mimic the most common lcFAOD very-long-chain acyl-CoA dehydrogenase disorder (VLCADD), we used siRNA-mediated knockdown of the ACADVL gene (encoding VLCAD) in macrophages derived from healthy volunteers. Hereby, we found that siVLCAD affected IL-4-induced alternative macrophage activation while leaving LPS responses and cellular metabolism intact. In the same line, monocyte-derived macrophages from lcFAOD patients had elevated levels of the IL-4-induced alternative macrophage markers CD206 and CD200R. Still, they did not show major metabolic defects or changes in the LPS-induced inflammatory response. Our results indicate that monocytes and macrophages from lcFAOD patients present no major inflammatory or metabolic differences and show that IL-4-induced surface markers are intertwined with lcFAO in human macrophages.

IPSC-Derived LCHADD Retinal Pigment Epithelial Cells Are Susceptible to Lipid Peroxidation and Rescued by Transfection of a Wildtype AAV-HADHA Vector.

Progressive choroid and retinal pigment epithelial (RPE) degeneration causing vision loss is a unique characteristic of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), a fatty acid oxidation disorder caused by a common c.1528G>C pathogenic variant in HADHA, the α subunit of the mitochondrial trifunctional protein (TFP). We established and characterized an induced pluripotent stem cell (iPSC)-derived RPE cell model from cultured skin fibroblasts of patients with LCHADD and tested whether addition of wildtype (WT) HAHDA could rescue the phenotypes identified in LCHADD-RPE. We constructed an rAAV expression vector containing 3' 3xFLAG-tagged human HADHA cDNA under the transcriptional control of the cytomegalovirus (CMV) enhancer-chicken beta actin (CAG) promoter (CAG-HADHA-3XFLAG). LCHADD-RPE were cultured, matured, and transduced with either AAV-GFP (control) or AAV-HADHA-3XFLAG. LCHADD-RPE express TFP subunits and accumulate 3-hydroxy-acylcarnitines, cannot oxidize palmitate, and release fewer ketones than WT-RPE. When LCHADD-RPE are exposed to docosahexaenoic acid (DHA), they have increased oxidative stress, lipid peroxidation, decreased viability, and are rescued by antioxidant agents potentially explaining the pathologic mechanism of RPE loss in LCHADD. Transduced LCHADD-RPE expressing a WT copy of TFPα incorporated TFPα-FLAG into the TFP complex in the mitochondria and accumulated significantly less 3-hydroxy-acylcarnitines, released more ketones in response to palmitate, and were more resistant to oxidative stress following DHA exposure than control. iPSC-derived LCHADD-RPE are susceptible to lipid peroxidation mediated cell death and are rescued by exogenous HADHA delivered with rAAV. These results are promising for AAV-HADHA gene addition therapy as a possible treatment for chorioretinopathy in patients with LCHADD.

Unveiling the multitargeted potential of deprodone and control comparison with linezolid against hydrolase and transferase enzymes of methicillin-resistant Staphylococcus aureus

Staphylococcus aureus (S. aureus), commonly found on the skin and nose, causes minor skin conditions to life-threatening diseases, including boils or impetigo, pneumonia, and bloodstream infections. MRSA (Methicillin-Resistant S. aureus) is a strain resistant to many antibiotics and poses a significant challenge in clinical settings. Nowadays, the alternative drug Linezolid is used, and it is not clear when MRSA starts resistance to it, necessitating the need for more alternative drugs with the least chance of developing resistance. This study aims to identify a multitargeted drug candidate with better efficacy than Linezolid. We have taken three hydrolase and transferase proteins from S. aureus, performed the multitargeted docking studies with human-approved drugs, and compared them with the control drug Linezolid. The docking and MM\\GBSA scores ranging from −6.79 to −5.78 Kcal/mol and − 37.47 to 30.16 Kcal/mol, respectively, that revealed Deprodone (used for inflammatory skin disorders, bowel disease, and fatty acid metabolism disorders) can be a far better and multitargeted drug candidate than Linezolid. We extended our studies to include extensive pharmacokinetics and molecular interaction fingerprints for interaction pattern studies. Also, the DFT computations optimised the drug, and we extended our studies for MD Simulation in water for 100 ns, which showed the complexes among the identified drug with proteins are entirely stable with acceptable deviation, fluctuations and many intermolecular interactions that make them stable. We also performed the MM\\GBSA studies on MD simulation's all 1000 frames to understand the complex energy level. All the results reveal promising interactions between Deprodone and the targeted enzymes, suggesting its potential as a multitargeted therapeutic agent—however, experimental studies need to validate Deprodone against MRSA.

Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS.

Stimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for subsequent release of pro-inflammatory cytokines. This has become particularly clear for enzymes of tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (SDH). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS-induced formation of IL-1β. If enzymes involved in beta-oxidation of fatty acids are important for sufficient responses to LPS is currently not clear. Using cells from various patients with inborn long-chain fatty acid oxidation disorders (lcFAOD), we report that disease-causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) and of Very Long Chain Acyl-CoA Dehydrogenase (ACADVL), both cause insufficient inflammatory responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6. The insufficient responses to LPS were reproduced in cells from healthy controls by targeted loss-of-function of either ETFDH or ACADVL, supporting that the deleterious ETFDH and ACADVL variants cause the attenuated responses to LPS. ETFDH and ACADVL encode two distinct enzymes both involved in fatty acid beta-oxidation, and patients with these deficiencies cannot sufficiently metabolize long-chain fatty acids. We report that genes important for beta-oxidation of long-chain fatty acids are also important for inflammatory responses to an acute immunogen trigger like LPS, which may have important implications for understanding infection and other metabolic stress induced disease pathology in lcFAODs.

Prediction of inherited metabolic disorders using tandem mass spectrometry data with the help of artificial neural networks.

Tandem mass spectrometry is helpful in diagnosing amino acid metabolism disorders, organic acidemias, and fatty acid oxidation disorders and can provide rapid and accurate diagnosis for inborn errors of metabolism. The aim of this study was to predict inborn errors of metabolism in children with the help of artificial neural networks using tandem mass spectrometry data. Forty-seven and 13 parameters of tandem mass spectrometry datasets obtained from 2938 different patients were respectively taken into account to train and test the artificial neural networks. Different artificial neural network models were established to obtain better prediction performances. The obtained results were compared with each other for fair comparisons. The best results were obtained by using the rectified linear unit activation function. One, two, and three hidden layers were considered for artificial neural network models established with both 47 and 13 parameters. The sensitivity of model B2 for definitive inherited metabolic disorders was found to be 80%. The accuracy rates of model A3 and model B2 are 99.3% and 99.2%, respectively. The area under the curve value of model A3 was 0.87, while that of model B2 was 0.90. The results showed that the proposed artificial neural networks are capable of predicting inborn errors of metabolism very accurately. Therefore, developing new technologies to identify and predict inborn errors of metabolism will be very useful.

Nutritional Management of Patients with Fatty Acid Oxidation Disorders.

Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible. Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake. In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 ratio), with medium-chain triglyceride supplementation at 10-25% of total energy (total MCT+LCT ratio = 20-35%). Trihepatnoin is a new therapeutic option with a good safety and efficacy profile. Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise. In medium- and short-chain deficits, dietary modifications are not advised (except during exacerbations), with MCT contraindicated and slow sugars recommended 20 min before any significant physical exertion. Parents should be alerted to the need to increase the amount and frequency of carbohydrate intake in stressful situations. The main measure in emergency hospital treatment is the administration of IV glucose. The use of carnitine remains controversial and new therapeutic options are under investigation.