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Current Opinion in Lipidology Aug 2023Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent progressive condition that lacks a specific pharmacological treatment. ATP-citrate lyase (ACLY) is one of... (Review)
Review
PURPOSE OF REVIEW
Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent progressive condition that lacks a specific pharmacological treatment. ATP-citrate lyase (ACLY) is one of the emergent targets for the treatment of NAFLD. This review aims to summarize the role of ACLY in NAFLD, provide evidence of the beneficial effects of the ACLY inhibitor bempedoic acid (BemA) in NAFLD and discuss the mechanisms involved.
RECENT FINDINGS
BemA is effective in reducing hepatic steatosis in several animal models that recapitulate different stages of the disease. Thus, in a dietary model of simple hepatic steatosis in female rats, BemA abrogates the accumulation of liver fat. Apart from ACLY inhibition, BemA has several functions in the liver that contribute to the antisteatotic effect: inhibition of ketohexokinase, induction of patatin-like phospholipase domain-containing protein 3 and increases in both fatty acid β-oxidation activity and hepatic H 2 S production. In models of the advanced phases of NAFLD, BemA reduces not only steatosis, but also ballooning, lobular inflammation and hepatic fibrosis, by mechanisms involving both hepatocytes and hepatic stellate cells.
SUMMARY
BemA, an ACLY inhibitor currently approved for the treatment of hypercholesterolemia, may be a useful drug to treat NAFLD through its antisteatotic, anti-inflammatory and antifibrotic effects.
Topics: Female; Animals; Rats; Non-alcoholic Fatty Liver Disease; Liver; Fatty Acids; Dicarboxylic Acids
PubMed: 36942869
DOI: 10.1097/MOL.0000000000000878 -
Carbohydrate Polymers Nov 2022A series of dicarboxylic-amylose inclusion complexes (AIC) were prepared by excess steam jet-cooking high amylose corn starch with linear C10, C12, C14, and C16...
A series of dicarboxylic-amylose inclusion complexes (AIC) were prepared by excess steam jet-cooking high amylose corn starch with linear C10, C12, C14, and C16 dicarboxylic acids to examine the influence of two polar head groups on complex formation. The C12, C14, and C16 dicarboxylic acid AIC were prepared in 48-63 % yields and contained 8.9-11.8 % diacid while the C10 AIC gave 30 % and contained 2.6 % diacid. These AIC had V6 helical amylose structures by XRD and complexation was further confirmed by DSC, FTIR, and TGA. SEM of the C12-C16 AIC revealed micron-sized toroidal spherulites while the C10 AIC was predominantly amorphous. DSC showed two AIC related transitions. This work provides a better understanding of the formation and physicochemical properties of these diacid AIC. Preparation by excess steam jet cooking demonstrates practical and commercial utility to prepare AIC as off-the-shelf materials for food and nonfood applications.
Topics: Amylose; Cooking; Dicarboxylic Acids; Starch; Steam
PubMed: 36088032
DOI: 10.1016/j.carbpol.2022.119955 -
Clinical Drug Investigation Oct 2021Statins are currently the first-line drugs for managing dyslipidemia due to their substantial clinical efficacy in reducing low-density lipoprotein cholesterol (LDL-C)... (Review)
Review
Statins are currently the first-line drugs for managing dyslipidemia due to their substantial clinical efficacy in reducing low-density lipoprotein cholesterol (LDL-C) and the risk of atherosclerotic cardiovascular disease (ASCVD). However, many patients do not reach their LDL-C target despite taking high-dose statins and some patients are intolerant of these drugs. Therefore, an additional or alternative pharmacological intervention may be required. Bempedoic acid is a novel lipid-lowering drug recently approved for the treatment of dyslipidemia. This review describes the pharmacology of bempedoic acid and its clinical role in patients with dyslipidemia. Bempedoic acid, via its active coenzyme A (CoA) form, inhibits adenosine triphosphate (ATP)-citrate lyase, and reduces hepatic cholesterol synthesis through the mevalonate pathway. The reduction in plasma LDL-C by bempedoic acid is approximately 20%. In addition, this drug is able to lower the level of high-sensitivity C-reactive protein (hs-CRP) by 20%, which suggests anti-inflammatory activity. Bempedoic acid is well tolerated by the majority of patients. Possible common adverse drug reactions include upper respiratory tract infection, urinary tract infection and arthralgia. Serum creatinine and uric acid should be monitored since increased creatinine and hyperuricemia-associated new onset of gout and gout flares have been reported in patients taking bempedoic acid. Decreased hemoglobin levels and rare tendon ruptures have also been observed. Due to its efficacy and good safety profile, bempedoic acid might serve as a potential therapeutic alternative for the management of dyslipidemia.
Topics: Dicarboxylic Acids; Dyslipidemias; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pharmaceutical Preparations
PubMed: 34435333
DOI: 10.1007/s40261-021-01075-w -
Current Drug Research Reviews 2021Azelaic acid (AZA) is a white crystalline dicarboxylic acid naturally found in grains, rye, and barley. AZA has substantial biological and therapeutic abilities (viz a...
Azelaic acid (AZA) is a white crystalline dicarboxylic acid naturally found in grains, rye, and barley. AZA has substantial biological and therapeutic abilities (viz a viz) its anti-inflammatory, anti-oxidant, anti-keratinizing, anti-microbial properties, etc., which contribute to its applicability in the management of mild to harsh dermatological complications (acne, rosacea, dermatitis, hyper-pigmentation, carcinomas, etc.). AZA has shown its effectiveness against varied non-inflammatory and inflammatory lesions by normalizing hyper-keratinization state and attenuating the increased levels of microbial content. Topically AZA, either alone or in conjunction with other active moieties, has proved to effectively prevent acne and several other hyper-pigmentary conditions. Chronic applicability of AZA has been evidenced with the effects like itching, burning, stinging, redness, etc. To deal with the former issues, research is being conducted to substitute the conventional formulations with novel preparations (liposome's, niosomes, micro sponges, lipid nanocarriers, etc.), which could enhance the overall pharmaceutical and pharmacological profile of the drug. This article is an attempt to highlight the basic physiochemical properties of AZA, its physiological role (especially in dermatology), various commercial preparations and recent novel approaches that are in research with an aim to augment the therapeutic and safety profile of AZA.
Topics: Aptitude; Cosmeceuticals; Dermatologic Agents; Dicarboxylic Acids; Humans
PubMed: 34042044
DOI: 10.2174/2589977513666210526122909 -
Molecular Biology Reports Apr 2021After a local infection by the microbial pathogens, plants will produce strong resistance in distal tissues to cope with the subsequent biotic attacks. This type of the... (Review)
Review
After a local infection by the microbial pathogens, plants will produce strong resistance in distal tissues to cope with the subsequent biotic attacks. This type of the resistance in the whole plant is termed as systemic acquired resistance (SAR). The priming of SAR can confer the robust defense responses and the broad-spectrum disease resistances in plants. In general, SAR is activated by the signal substances generated at the local sites of infection, and these small signaling molecules can be rapidly transported to the systemic tissues through the phloem. In the last two decades, numerous endogenous metabolites were proved to be the potential elicitors of SAR, including methyl salicylate (MeSA), azelaic acid (AzA), glycerol-3-phosphate (G3P), free radicals (NO and ROS), pipecolic acid (Pip), N-hydroxy-pipecolic acid (NHP), dehydroabietinal (DA), monoterpenes (α-pinene and β-pinene) and NAD(P). In the meantime, the proteins associated with the transport of these signaling molecules were also identified, such as DIR1 (DEFECTIVE IN INDUCED RESISTANCE 1) and AZI1 (AZELAIC ACID INDUCED 1). This review summarizes the recent findings related to synthesis, transport and interaction of the different signal substances in SAR.
Topics: Dicarboxylic Acids; Monoterpenes; Pipecolic Acids; Plant Diseases; Plant Immunity; Plant Proteins; Signal Transduction
PubMed: 33893927
DOI: 10.1007/s11033-021-06344-7 -
JAMA Nov 2019
Topics: Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 31714973
DOI: 10.1001/jama.2019.16598 -
Biochemical and Biophysical Research... Jan 20213-methylglutaconic (3MGC) aciduria is associated with a growing number of discrete inborn errors of metabolism. Herein, an antibody-based approach to...
3-methylglutaconic (3MGC) aciduria is associated with a growing number of discrete inborn errors of metabolism. Herein, an antibody-based approach to detection/quantitation of 3MGC acid has been pursued. When trans-3MGC acid conjugated keyhole limpet hemocyanin (KLH) was inoculated into rabbits a strong immune response was elicited. Western blot analysis provided evidence that immune serum, but not pre-immune serum, recognized 3MGC-conjugated bovine serum albumin (BSA). In competition ELISAs using isolated immune IgG, the limit of detection for free trans-3MGC acid was compared to that for cis-3MGC acid and four structurally related short-chain dicarboxylic acids. Surprisingly, cis-3MGC acid yielded a much lower limit of detection (∼0.1 mg/ml) than trans-3MGC acid (∼1.0 mg/ml) while all other dicarboxylic acids tested were poor competitors. The data suggest trans-3MGC- isomerized during, or after, conjugation to KLH such that the immunogen was actually comprised of KLH harboring a mixture of cis- and trans-3MGC haptens. To investigate this unexpected isomerization reaction, trans-3MGC CoA was prepared and incubated at 37 °C in the presence of BSA. Evidence was obtained that non-enzymatic isomerization of trans-3MGC CoA to cis-3MGC CoA precedes intramolecular catalysis to form cis-3MGC anhydride plus CoASH. Anhydride-dependent acylation of BSA generated 3MGCylated BSA, as detected by anti-3MGC immunoblot. The results presented provide an explanation for the unanticipated detection of 3MGCylated proteins in a murine model of primary 3MGC aciduria. Furthermore, non-enzymatic hydrolysis of cis-3MGC anhydride represents a potential source of cis-3MGC acid found in urine of subjects with 3MGC aciduria.
Topics: Acylation; Animals; Coenzyme A; Dicarboxylic Acids; Glutarates; Haptens; Hemocyanins; Hot Temperature; Immune Sera; Immunoglobulin G; Isomerism; Rabbits; Serum Albumin, Bovine
PubMed: 33280817
DOI: 10.1016/j.bbrc.2020.11.100 -
American Journal of Cardiovascular... Dec 2020Despite the widespread use of statins and ezetimibe to decrease low-density lipoprotein cholesterol (LDL-C) levels and associated atherosclerotic cardiovascular disease... (Review)
Review
Despite the widespread use of statins and ezetimibe to decrease low-density lipoprotein cholesterol (LDL-C) levels and associated atherosclerotic cardiovascular disease (ASCVD), many patients do not achieve adequate LDL-C lowering as per the recommended American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines and demonstrate residual cardiovascular risk. The introduction of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in 2015 was a promising addition to hypercholesterolemia therapies, but their cost and subcutaneous administration has limited their use, and therefore, new affordable and patient friendly treatment strategies are crucial to help reduce ASCVD risk. Bempedoic acid, a drug currently under investigation, is a small molecule that has been shown to upregulate LDL receptors, decrease LDL-C, and reduce atherosclerotic plaque formation in hypercholesterolemic patients. Furthermore, bempedoic acid is a prodrug that becomes activated by an enzyme expressed primarily in the liver, allowing it to avoid the potential myotoxicity associated with statin therapy. The purpose of this review is to summarize the major clinical studies evaluating bempedoic acid and describe its potential addition to currently approved lipid-lowering therapies.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Dicarboxylic Acids; Drug Combinations; Dyslipidemias; Ezetimibe; Fatty Acids; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Randomized Controlled Trials as Topic; Receptors, LDL
PubMed: 32166726
DOI: 10.1007/s40256-020-00399-w -
Journal of Evidence-based Medicine Nov 2020The effects of topical azelaic acid, salicylic acid, nicotinamide, sulfur, zinc, and fruit acid (alpha-hydroxy acid) for acne are unclear. We aimed to assess the effects...
Evidence-based topical treatments (azelaic acid, salicylic acid, nicotinamide, sulfur, zinc, and fruit acid) for acne: an abridged version of a Cochrane systematic review.
OBJECTIVE
The effects of topical azelaic acid, salicylic acid, nicotinamide, sulfur, zinc, and fruit acid (alpha-hydroxy acid) for acne are unclear. We aimed to assess the effects of these topical treatments by collecting randomized controlled trials.
METHODS
We searched The Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS up to May 2019. We also searched five trials registers. Two review authors independently extracted data and assessed risk of bias. Meta analyses were performed by using Review Manager 5 software.
RESULTS
We included a total of 49 trials involving 3880 participants. In terms of treatment response (measured using participants' global self-assessment of acne improvement, PGA), azelaic acid was probably less effective than benzoyl peroxide (RR = 0.82, 95% CI 0.72-0.95). However, there was probably little or no difference in PGA when comparing azelaic acid to tretinoin (RR = 0.94, 95% CI 0.78-1.14). There may be little or no difference when comparing salicylic acid to tretinoin (RR = 1.00, 95% CI 0.92-1.09). There were no studies measured PGA when evaluating nicotinamide. With respect to alpha-hydroxy acid, there may be no difference in PGA when comparing glycolic acid to salicylic-mandelic acid (RR = 1.06, 95% CI 0.88-1.26). We were uncertain about the effects of sulfur and zinc. Adverse events associated with these topical treatments were always mild and transient.
CONCLUSIONS
Moderate-quality evidence was available for azelaic acid and low- to very-low-quality evidence for other topical treatments. Risk of bias and imprecision limit our confidence in the evidence.
Topics: Acne Vulgaris; Administration, Cutaneous; Dermatologic Agents; Dicarboxylic Acids; Fruit; Glycolates; Humans; Niacinamide; Salicylic Acid; Sulfur; Treatment Outcome; Zinc
PubMed: 33034949
DOI: 10.1111/jebm.12411 -
The New England Journal of Medicine Apr 2023
Topics: Humans; Dicarboxylic Acids; Fatty Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents
PubMed: 36876748
DOI: 10.1056/NEJMe2301490