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PloS One 2024Bempedoic acid, an innovative oral medication, has garnered significant interest in recent times due to its potential as a therapeutic intervention for... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Bempedoic acid, an innovative oral medication, has garnered significant interest in recent times due to its potential as a therapeutic intervention for hypercholesterolemia. Nonetheless, the outcomes of the initial investigations might have been more definitive and coherent. Our objective was to perform a quantitative meta-analysis in order to evaluate bempedoic acid's safety and effectiveness.
METHODS
A search was conducted on ClinicalTrials.gov, and PubMed from the time of inception until September 28, 2023. Randomized controlled trials comparing the safety and efficacy of bempedoic acid among patients with statin intolerance and those without were included in our analysis. The trial outcomes were summarized using a random effects model and were provided as mean differences or odds ratios (ORs) with a confidence interval of 95%. Additionally, trial heterogeneity and the possibility of bias were evaluated and investigated.
RESULTS
Bempedoic acid treatment reduced low-density lipoprotein cholesterol levels more than placebo (mean difference -2.97%, 95% CI -5.89% to -0.05%), according to a pooled analysis of 16 eligible trials. The risk of death (OR 1.18, 95% CI 0.70 to 1.98) and muscle-associated occurrences (OR 1.00, 95% CI 0.77 to 1.31) was not impacted by bempedoic acid. In contrast, discontinuation of treatment was more frequently caused by adverse events in the bempedoic acid group (OR 1.13, 95% CI 1.01 to 1.27).
CONCLUSIONS
In patients with statin intolerance as well as those without, bempedoic acid is a safe and efficacious lipid-lowering agent, according to findings from randomized controlled trials.
Topics: Humans; Dicarboxylic Acids; Fatty Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Randomized Controlled Trials as Topic
PubMed: 38277431
DOI: 10.1371/journal.pone.0297854 -
The Journal of Clinical Investigation Apr 2024Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an...
Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an alternative source of dietary fat have not been explored. Here, we fed dodecanedioic acid, a 12-carbon dicarboxylic (DC12), to mice at 20% of daily caloric intake for nine weeks. DC12 increased metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escaped first-pass liver metabolism and was utilized by many tissues. In tissues expressing the "a" isoform of acyl-CoA oxidase-1 (ACOX1), a key peroxisomal fatty acid oxidation enzyme, DC12 was chain shortened to the TCA cycle intermediate succinyl-CoA. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. In vitro, DC12 was catabolized even by adipose tissue and was not stored intracellularly. We conclude that DC12 and other dicarboxylic acids may be useful for combatting obesity and for treating metabolic disorders.
PubMed: 38687608
DOI: 10.1172/JCI174186 -
Applied Microbiology and Biotechnology Oct 2023Acyl-CoA-thioesterases, which hydrolyze acyl-CoA-esters and thereby release the respective acid, have essential functions in cellular metabolism and have also been used...
Acyl-CoA-thioesterases, which hydrolyze acyl-CoA-esters and thereby release the respective acid, have essential functions in cellular metabolism and have also been used to produce valuable compounds in biotechnological processes. Thioesterase YciA originating from Haemophilus influenzae has been previously used to produce specific dicarboxylic acids from CoA-bound intermediates of the ethylmalonyl CoA pathway (EMCP) in Methylorubrum extorquens. In order to identify variants of the YciA enzyme with the capability to hydrolyze so far inaccessible CoA-esters of the EMCP or with improved productivity, we engineered the substrate-binding region of the enzyme. Screening a small semi-rational mutant library directly in M. extorquens yielded the F35L variant which showed a drastic product level increase for mesaconic acid (6.4-fold) and 2-methylsuccinic acid (4.4-fold) compared to the unaltered YciA enzyme. Unexpectedly, in vitro enzyme assays using respective M. extorquens cell extracts or recombinantly produced thioesterases could not deliver congruent data, as the F35L variant showed strongly reduced activity in these experiments. However, applied in an Escherichia coli production strain, the protein variant again outperformed the wild-type enzyme by allowing threefold increased 3-hydroxybutyric acid product titers. Saturation mutagenesis of the codon for position 35 led to the identification of another highly efficient YciA variant and enabled structure-function interpretations. Our work describes an important module for dicarboxylic acid production with M. extorquens and can guide future thioesterase improvement approaches. KEY POINTS: • Substitutions at position F35 of YciAHI changed the productivity of YciA-based release of carboxylic acid products in M. extorquens AM1 and E. coli. • YciAHI F35N and F35L are improved variants for dicarboxylic production of 2-methylsuccinic acid and mesaconic acid with M. extorquens AM1. • In vitro enzyme assays did not reveal superior properties of the optimized protein variants.
PubMed: 37572123
DOI: 10.1007/s00253-023-12691-1 -
Ultrasonics Sonochemistry Oct 2023In this study, the effects of organic acid-soaking (malic, citric, tartaric, and succinic acid) and sonication on the formation of flavor and α-dicarbonyl compounds in...
In this study, the effects of organic acid-soaking (malic, citric, tartaric, and succinic acid) and sonication on the formation of flavor and α-dicarbonyl compounds in Robusta (C. canephora syn. Coffea robusta) green beans were investigated. A total of 20 volatile compounds were identified in Robusta coffee. Furfural and 5-methyl furfural, two dominant volatile compounds in Arabica coffee, increased after organic acid pretreatment. In Robusta coffee processed from 3% malic acid-soaked coffee beans, furfural and 5-methyl furfural increased by 90.99% and 24.92%, respectively, compared to the control. In Robusta coffee processed from 3% malic acid-sonicated (280 W, 1 h) coffee beans, furfural and 5-methyl furfural increased by 236.03% and 114.77%, respectively. α-Dicarbonyls (glyoxal, methylglyoxal, and diacetyl) were significantly (p < 0.05) decreased in all Robusta coffees after organic acid pretreatment. In Robusta coffee processed from coffee beans soaked and sonicated in tartaric acid solution, the α-dicarbonyls decreased by up to 44% and 58%, respectively, compared to the control. This study suggested the pretreatment methods to enhance the flavor substances and reduce the α-DCs in Robusta coffee.
Topics: Coffea; Sonication; Furaldehyde; Malates; Organic Chemicals
PubMed: 37673014
DOI: 10.1016/j.ultsonch.2023.106580 -
The Journal of Hand Surgery, European... Dec 2023Madelung deformity remains a fascinating yet unresolved challenge. There is an increasing awareness for early diagnosis by healthcare providers with improvement in... (Review)
Review
Madelung deformity remains a fascinating yet unresolved challenge. There is an increasing awareness for early diagnosis by healthcare providers with improvement in diagnostic modalities, however, the exact mechanisms for the development of the deformity have still to be clarified. While some corrective procedures have been described to effectively address an established deformity, the existing literature lacks clear and evidence-based treatment guidelines on how to proceed in daily practice. This review article aims to summarize the current best evidence on this topic, including particular areas of controversy and areas with need for future research.
Topics: Humans; Growth Disorders; Osteochondrodysplasias; Osteotomy; Dioctyl Sulfosuccinic Acid; Radius
PubMed: 37572317
DOI: 10.1177/17531934231191208 -
ACS Applied Materials & Interfaces Dec 2023We synthesized a series of [(l-Ala)--(l-Thr succinate)] (PATs), which are analogous to natural antifreezing glycoprotein with the structure of [l-Ala-l-Ala-l-Thr...
We synthesized a series of [(l-Ala)--(l-Thr succinate)] (PATs), which are analogous to natural antifreezing glycoprotein with the structure of [l-Ala-l-Ala-l-Thr disaccharide], by varying the composition and degree of succinylation while fixing their molecular weight () and Ala/Thr ratio at approximately 10-12 kDa and 2:1, respectively. We investigated their ice recrystallization inhibition (IRI), ice nucleation inhibition (INI), dynamic ice shaping (DIS), thermal hysteresis (TH), and protein cryopreservation activities. Both IRI and INI activities were greater for PATs with higher l-Ala content (PATs-3 and PATs-4) than those with lower l-Ala content (PATs-1 and PATs-2). DIS activity with faceted crystal growth was clearly observed in PATs-2 and PATs-4 with a high degree of succinylation. TH was small with <0.1 °C for all PATs and slightly greater for PATs with a high l-Ala content. Except for PATs-1, the protein (lactate dehydrogenase, LDH) stabilization activity was excellent for all PATs studied, maintaining LDH activity as high as that of fresh LDH even after 15 freeze-thaw cycles. To conclude, the cryo-active biomimetic PATs were synthesized by controlling the l-Ala content and degree of succinylation. Our results showed that PATs with an l-Ala content of 65-70% and degree of succinylation of 12-19% exhibited the cryo-activities of IRI, INI, and DIS, and particularly promising properties for the cryoprotection of LDH protein.
Topics: Ice; Succinic Acid; Threonine; Biomimetics; Cryoprotective Agents; Succinates
PubMed: 38060278
DOI: 10.1021/acsami.3c11260 -
Kidney International Oct 2023Previous studies have indicated that succinate accumulation during kidney ischemia, and its oxidation during reperfusion, results in the production of excessive reactive...
Previous studies have indicated that succinate accumulation during kidney ischemia, and its oxidation during reperfusion, results in the production of excessive reactive oxygen species, mitochondrial dysfunction, and kidney injury. In this issue, Oh et al. have reported that pyruvate dehydrogenase kinase 4 (PDK4) inhibition in proximal tubules ameliorates kidney ischemia/reperfusion injury via suppressed succinate accumulation. This study suggests that PDK4 inhibition is a promising new treatment strategy for ischemic acute kidney injury.
Topics: Humans; Succinic Acid; Succinates; Kidney; Ischemia; Acute Kidney Injury
PubMed: 37739613
DOI: 10.1016/j.kint.2023.07.011 -
European Journal of Medicinal Chemistry Jan 2024The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway serves as a crucial regulator against oxidative stress (OS)... (Review)
Review
The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway serves as a crucial regulator against oxidative stress (OS) damage in various cells and organs. It has garnered significant attention as a potential therapeutic target for neurodegenerative diseases (NDD). Although progress has been achieved in strategies to regulate the Keap1-Nrf2 pathway, the availability of Nrf2 activators applicable to NDD is currently limited. Currently, the FDA has approved the Nrf2 activators dimethyl fumarate (DMF) and Omaveloxolone (Omav) as novel first-line oral drugs for the treatment of patients with relapsing forms of multiple sclerosis and Friedreich's ataxia. A promising alternative approach involves the direct inhibition of Keap1-Nrf2 protein-protein interactions (PPI), which offers numerous advantages over the use of electrophilic Nrf2 activators, primarily in avoiding off-target effects. This review examines the compelling evidence supporting the beneficial role of Nrf2 in NDD and explores the potential of Keap1 inhibitors and Keap1-Nrf2 PPI inhibitors as therapeutic agents, with the aim to provide further insights into the development of inhibitors targeting this pathway for the treatment of NDD.
Topics: Humans; NF-E2-Related Factor 2; Kelch-Like ECH-Associated Protein 1; Neurodegenerative Diseases; Oxidative Stress; Dimethyl Fumarate
PubMed: 38043492
DOI: 10.1016/j.ejmech.2023.115998 -
Journal of the American Chemical Society Feb 2024Dicarboxylic acids and derivatives are important building blocks in organic synthesis, biochemistry, and the polymer industry. Although catalytic dicarboxylation with CO...
Dicarboxylic acids and derivatives are important building blocks in organic synthesis, biochemistry, and the polymer industry. Although catalytic dicarboxylation with CO represents a straightforward and sustainable route to dicarboxylic acids, it is still highly challenging and limited to generation of achiral or racemic dicarboxylic acids. To date, catalytic asymmetric dicarboxylation with CO to give chiral dicarboxylic acids has not been reported. Herein, we report the first asymmetric dicarboxylation of 1,3-dienes with CO via Cu catalysis. This strategy provides an efficient and environmentally benign route to chiral dicarboxylic acids with high regio-, chemo-, and enantioselectivities. The copper self-relay catalysis, that is, Cu-catalyzed boracarboxylation of 1,3-dienes to give carboxylated allyl boronic ester intermediates and subsequent carboxylation of C-B bonds to give dicarboxylates, is key to the success of this dicarboxylation. Moreover, this protocol exhibits broad substrate scope, good functional group tolerance, easy product derivatizations, and facile synthesis of chiral liquid crystalline polyester and drug-like scaffolds.
PubMed: 38277794
DOI: 10.1021/jacs.3c14146 -
Cell Metabolism Mar 2024The Krebs-cycle-derived metabolite itaconate has been shown to be immunomodulatory, targeting multiple processes in macrophages. Ramalho et al. reveal an additional...
The Krebs-cycle-derived metabolite itaconate has been shown to be immunomodulatory, targeting multiple processes in macrophages. Ramalho et al. reveal an additional role for itaconate in malaria.Plasmodium Chabaudi induces itaconate in dendritic cells (DCs), leading to programmed death-ligand 1 (PD-L1) induction. This suppresses CD8 T cells, important for host defense against malaria, thereby promoting parasitemia.
Topics: Humans; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Dietary Supplements; Malaria; Succinates
PubMed: 38447526
DOI: 10.1016/j.cmet.2024.02.005