Human skin absorption of three plasticizers: Diisononyl-1,2-cyclohexanedicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHTP), and di(2-ethylhexyl) adipate (DEHA).

Alternative plasticizers such as diisononyl-1,2-cyclohexanedicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHTP), and di(2-ethylhexyl) adipate (DEHA) are progressively replacing phthalates in many consumer and professional products because of adverse effects on reproduction associated with some phthalates. Human exposures to these phthalate substitutes can occur through ingestion, skin absorption and inhalation. Skin uptake can lead to greater concentration at the target organs compared to ingestion because the skin exposure route bypasses the first-pass effect. Skin absorption studies are almost absent for these alternative plasticizers. We therefore wanted first, to characterize skin absorption of a mixture containing DINCH, DEHA and DEHTP in vitro using a flow-through diffusion cell system with ex vivo human skin, quantifying their respective monoester metabolites (mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH), mono-2-ethylhexyl adipate (MEHA), mono-2-ethylhexyl terephthalate (MEHTP), respectively); second, to validate these results by exposing five human volunteers to this mixture on their forearm and quantifying the corresponding urinary metabolites (including the monoesters and their oxidation products). Our study showed that two of these alternative plasticizers, DEHTP and DINCH, did not permeate skin showing as quantifiable metabolite levels in vitro and only traces of DEHA were quantified as its monoester metabolite, MEHA. Permeation coefficient (Kp) 0.06 and 55.8*10-7 cm/h for neat and emulsified DEHA, respectively, while the permeation rate (J) remained low for both (0.005 and 0.001 µg/cm2/h, respectively). Participants exposed to a mixture of these three plasticizers did not have noteworthy urinary concentrations of their respective metabolites after 24 hours post-application. However, the alternative plasticizer mixture was completely absorbed after six hours post-application on the forearms of the human volunteers, and the urinary elimination curves showed a slight increase after 24 hours post-application. Further studies on skin absorption of these substances should follow the urinary elimination kinetics of these metabolites more than 24 hours post-application. We also recommend quantifying the parent compounds in the in vitro diffusion experiments.

Recent Advances in the Biosynthesis of Mid- and Long-Chain Dicarboxylic Acids Using Terminally Oxidizing Unconventional Yeasts.

As high-performance monomers for the manufacture of polyamide materials, mid- and long-chain dicarboxylic acids (DCAi, i ≥ 6) have received extensive attention from researchers. Biosynthesis is gradually replacing chemical synthesis due to its outstanding advantages in the industrial production of mid- and long-chain dicarboxylic acids, which is mostly achieved by using the strong terminal oxidation ability of nonmodel microorganisms such as Candida tropicalis to oxidize hydrophobic substrates such as alkanes. Here, we first summarize the metabolic pathways of oxidative alkane conversion into dicarboxylic acid by terminally oxidizing unconventional yeasts and the corresponding metabolic engineering strategies. Then, we summarize the research progress on new dicarboxylic acid production processes. Finally, the future development directions in the biosynthesis of mid- and long-chain dicarboxylic acids are prospected from synthetic biology and bioprocess engineering, which can also provide a reference for the synthesis of other biobased chemicals and biomaterials.

The Off-Treatment Effects of Olpasiran on Lipoprotein(a) Lowering: OCEAN(a)-DOSE Extension Period Results.

BACKGROUND: Olpasiran, a small interfering RNA (siRNA), blocks lipoprotein(a) (Lp(a)) production by preventing translation of apolipoprotein(a) mRNA. In phase 2, higher doses of olpasiran every 12 weeks (Q12W) reduced circulating Lp(a) by >95%. OBJECTIVES: This study sought to assess the timing of return of Lp(a) to baseline after discontinuation of olpasiran, as well as longer-term safety. METHODS: OCEAN(a)-DOSE (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study) was a phase 2, dose-finding trial that enrolled 281 participants with atherosclerotic cardiovascular disease and Lp(a) >150 nmol/L to 1 of 4 active doses of olpasiran vs placebo (10 mg, 75 mg, 225 mg Q12W, or an exploratory dose of 225 mg Q24W given subcutaneously). The last dose of olpasiran was administered at week 36; after week 48, there was an extended off-treatment follow-up period for a minimum of 24 weeks. RESULTS: A total of 276 (98.2%) participants entered the off-treatment follow-up period. The median study exposure (treatment combined with off-treatment phases) was 86 weeks (Q1-Q3: 79-99 weeks). For the 75 mg Q12W dose, the off-treatment placebo-adjusted mean percent change from baseline in Lp(a) was -76.2%, -53.0%, -44.0%, and -27.9% at 60, 72, 84, and 96 weeks, respectively (all P < 0.001). The respective off-treatment changes in Lp(a) for the 225 mg Q12W dose were -84.4%, -61.6%, -52.2%, and -36.4% (all P < 0.001). During the extension follow-up phase, no new safety concerns were identified. CONCLUSIONS: Olpasiran is a potent siRNA with prolonged effects on Lp(a) lowering. Participants receiving doses ≥75 mg Q12W sustained a ∼40% to 50% reduction in Lp(a) levels close to 1 year after the last dose. (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study [OCEAN(a)-DOSE]; NCT04270760).

Dicarboxylic acids counteract the metabolic effects of a Western diet by boosting energy expenditure.

Obesity has reached pandemic proportion not only in the West but also in other countries around the world; it is now one of the leading causes of death worldwide. A Western diet is rich in saturated fats and provides more calories than necessary, contributing to the rise of the obesity rate. It also promotes the development of liver steatosis, insulin resistance, hyperglycemia, and hyperlipidemia. In this issue of the JCI, Goetzman and colleagues describe the effects of consuming dicarboxylic acids (DAs) as an alternative source of dietary fat. The 12-carbon dicarboxylic acid (DC12) was administered to mice at 20% of their daily caloric intake for nine weeks in place of triglycerides. Notably, the change in diet increased the metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. These findings highlight DAs as useful energy nutrients for combatting obesity and treating various metabolic disorders.

Comparative Cardiovascular Benefits of Bempedoic Acid and Statin Drugs.

BACKGROUND: In the CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Outcomes trial, treatment of statin-intolerant patients with bempedoic acid produced a 21% decrease in low-density lipoprotein cholesterol (LDL-C) relative to placebo and a 13% relative reduction in the risk of major adverse cardiovascular events. OBJECTIVES: This study sought to determine whether the relationship between LDL-C lowering and cardiovascular benefit achieved with bempedoic acid resembles that observed with statins when standardized per unit change in LDL-C. METHODS: To compare the treatment effect of bempedoic acid with statins, the methodology of the Cholesterol Treatment Trialists' Collaboration (CTTC) was applied to outcomes among the 13,970 patients enrolled in the CLEAR Outcomes trial. The CTTC endpoint of "major vascular event" was a composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal stroke, or coronary revascularization. HRs for CTTC-defined endpoints were normalized to 1 mmol/L differences in LDL-C levels between bempedoic acid and placebo groups. RESULTS: A first major vascular event occurred in 703 (10.1%) patients in the bempedoic acid group and 816 (11.7%) patients in the placebo group (HR: 0.85; 95% CI: 0.77-0.94). When normalized per 1 mmol/L reduction in LDL-C, the HR was 0.75 (95% CI: 0.63-0.90), comparable to the rate ratio of 0.78 reported for statins in the CTTC meta-analysis. Normalized risk reductions were similar for bempedoic acid and statins for the endpoints of major coronary events, nonfatal myocardial infarction, and coronary revascularization. CONCLUSIONS: Cardiovascular risk reduction with bempedoic acid is similar to that achieved with statins for a given absolute magnitude of LDL-C lowering. (Evaluation of Major Adverse Cardiovascular Events in Participants With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated with Bempedoic Acid [ETC-1002] or Placebo [CLEAR Outcomes]; NCT02993406).

Stability Indicating Method Development and Validation for the Estimation of Bempedoic Acid by RP-HPLC.

BACKGROUND: Bempedoic acid (BEM) belongs to a category of drugs known as Adenosine triphosphate-citrate Lyase (ACL) inhibitors. It is a prodrug with intracellular activation that is administered orally. Bempedoic acid is used to treat existing atherosclerotic cardiovascular diseases, mainly hypercholesterolemia. METHODS: For the stability-indicating assay, the HPLC method was employed using a Kromasil 100-5-C8 column (100 mm × 4.6 mm), a UV detector set at 230 nm, and a mobile phase comprising a 70:30 v/v mixture of acetonitrile and 0.1% Orthophosphoric Acid (OPA) buffer. The method was operated at an ambient temperature with a flow rate of 1 mL/min. The method developed has been statistically validated according to ICH guidelines. RESULTS: The stability-indicating method was executed using a Kromasil 100-5-C8 (100 mm × 4.6 mm) column at a 1.0 mL/min flow rate. A mixture of acetonitrile and 0.1% Orthophosphoric Acid (OPA) buffer in a 70:30 v/v ratio made up the mobile phase. BEM's retention times were discovered to be 1.88 minutes each. The temperature was kept at room temperature. 234 nm was the ideal wavelength for BEM. According to ICH criteria, the approach developed has undergone statistical validation. BEM's % RSD was discovered to be 0.6, respectively. For BEM, the % recovery was determined to be 100.0%. Regression models for bempedoic acid yielded LoD and LoQ values of 3.3 and 10.1 g/mL, respectively. The method showed good reproducibility and recovery with a % RSD less than 2. Studies on forced degradation confirmed the method's capacity to indicate stability in the presence of stress conditions, such as acid, basic, peroxide, UV, heat, and humidity. Both the retention times and the run time were shortened. CONCLUSION: In accordance with ICH Q2 (R1) guidelines, this method was successfully tested with HPLC to confirm the chemical structures of newly produced degradation products of bempedoic acid.

1H-Pyrrole-2,5-dicarboxylic acid, a quorum sensing inhibitor from one endophytic fungus in Areca catechu L., acts as antibiotic accelerant against Pseudomonas aeruginosa.

Pseudomonas aeruginosa has already been stipulated as a "critical" pathogen, emphasizing the urgent need for researching and developing novel antibacterial agents due to multidrug resistance. Bacterial biofilm formation facilitates cystic fibrosis development and restricts the antibacterial potential of many current antibiotics. The capacity of P. aeruginosa to form biofilms and resist antibiotics is closely correlated with quorum sensing (QS). Bacterial QS is being contemplated as a promising target for developing novel antibacterial agents. QS inhibitors are a promising strategy for treating chronic infections. This study reported that the active compound PT22 (1H-pyrrole-2,5-dicarboxylic acid) isolated from Perenniporia tephropora FF2, one endophytic fungus from Areca catechu L., presents QS inhibitory activity against P. aeruginosa. Combined with gentamycin or piperacillin, PT22 functions as a novel antibiotic accelerant against P. aeruginosa. PT22 (0.50 mg/mL, 0.75 mg/mL, and 1.00 mg/mL) reduces the production of QS-related virulence factors, such as pyocyanin and rhamnolipid, and inhibits biofilm formation of P. aeruginosa PAO1 instead of affecting its growth. The architectural disruption of the biofilms was confirmed by visualization through scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). Real-time quantitative PCR (RT-qPCR) indicated that PT22 significantly attenuated the expression of QS-related genes followed by docking analysis of molecules against QS activator proteins. PT22 dramatically increased the survival rate of Galleria mellonella. PT22 combined with gentamycin or piperacillin presents significant inhibition of biofilm formation and eradication of mature biofilm compared to monotherapy, which was also confirmed by visualization through SEM and CLSM. After being treated with PT22 combined with gentamycin or piperacillin, the survival rates of G. mellonella were significantly increased compared to those of monotherapy. PT22 significantly enhanced the susceptibility of gentamycin and piperacillin against P. aeruginosa PAO1. Our results suggest that PT22 from P. tephropora FF2 as a potent QS inhibitor is a candidate antibiotic accelerant to combat the antibiotic resistance of P. aeruginosa.

New insights into azelaic acid-induced resistance against Alternaria Solani in tomato plants.

BACKGROUND: The effect of azelaic acid (Aza) on the response of tomato plants to Alternaria solani was investigated in this study. After being treated with Aza, tomato plants were infected with A. solani, and their antioxidant, biochemical, and molecular responses were analyzed. RESULTS: The results demonstrated that H2O2 and MDA accumulation increased in control plants after pathogen infection. Aza-treated plants exhibited a remarkable rise in peroxidase (POD) and catalase (CAT) activities during the initial stages of A. solani infection. Gene expression analysis revealed that both Aza treatment and pathogen infection altered the expression patterns of the SlNPR1, SlERF2, SlPR1, and SlPDF1.2 genes. The expression of SlPDF1.2, a marker gene for the jasmonic acid/ethylene (JA/ET) signaling pathway, showed a remarkable increase of 4.2-fold upon pathogen infection. In contrast, for the SlNPR1, a key gene in salicylic acid (SA) pathway, this increased expression was recorded with a delay at 96 hpi. Also, the phytohormone analysis showed significantly increased SA accumulation in plant tissues with disease development. It was also revealed that tissue accumulation of JA in Aza-treated plants was increased following pathogen infection, while it was not increased in plants without pathogen inoculation. CONCLUSION: The results suggest that the resistance induced by Aza is mainly a result of modulations in both SA and JA pathways following complex antioxidant and molecular defense responses in tomato plants during A. solani infection. These findings provide novel information regarding inducing mechanisms of azelaic acid which would add to the current body of knowledge of SAR induction in plants as result of Aza application.

Novel Therapies for the Treatment of Cardiovascular Disease.

Over the last decade, randomized clinical trials of several pharmacologic agents have demonstrated a reduction in cardiovascular mortality and other important secondary outcomes. Angiotensin-Neprilysin Inhibitors and Sodium-Glucose Co-transporter 2 inhibitors have now become pillars in the treatment of heart failure. Ivabradine is a negative chronotropic agent used as an adjunctive therapy in patients with heart failure. Two new hypertension therapies, zilebresiran and aprocitentan, are currently in investigational stages. Finally, mavacamten has emerged as a pharmacologic treatment for hypertrophic obstructive cardiomyopathy. Practitioners must be familiar with the indications and side effects of newer therapies as they are now frequently prescribed.

Exploring the Role of Bempedoic Acid in Metabolic Dysfunction Associated Steatotic Liver Disease: Actual Evidence and Future Perspectives.

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves excessive lipid accumulation in hepatocytes, impacting global healthcare due to its high prevalence and risk of progression to severe liver conditions. Its pathogenesis involves genetic, metabolic, and inflammatory factors, with cardiovascular events as the leading cause of mortality. This review examines the role of lipid-lowering therapies in MASLD, with a particular focus on bempedoic acid, a recently approved cholesterol-lowering agent for hypercholesterolemia and high cardiovascular-risk patients. It explores its potential in liver disease by modulating lipid metabolism and inflammatory pathways based on the most recent studies available. Bempedoic acid inhibits ATP-citrate lyase, reducing cholesterol and fatty acid synthesis while activating AMP-activated protein kinase to suppress gluconeogenesis and lipogenesis. Animal studies indicate its efficacy in reducing hepatic steatosis, inflammation, and fibrosis. Bempedoic acid holds promise as a therapeutic for MASLD, offering dual benefits in lipid metabolism and inflammation. Further clinical trials are required to confirm its efficacy and safety in MASLD patients, potentially addressing the multifaceted nature of this disease.

Review of Recent Literature and Updates in Nonstatin Cholesterol Management.

The guidelines for cholesterol management have been updated over the years from treat-to-target using any drug class to emphasis on statins without treatment targets to a hybrid of the 2 approaches. The most recent guideline updates include newer nonstatin lipid-lowering therapies (LLTs), low-density lipoprotein cholesterol (LDL-C) reduction goals, and LDL-C thresholds considering secondary prevention and cardiovascular risk. Although statins have been the mainstay of LLT for years, newer pharmacological agents such as proprotein convertase subtilisin-kexin type 9 inhibitor(s) (PCSK9i) monoclonal antibodies, small interfering RNA PCSK9i, and bempedoic acid to optimize LDL-C levels may be underutilized in clinical practice. To provide an updated review for clinicians, we performed a literature search in PubMed for articles published from January 1, 2000, to August 31, 2023, that included the terms cholesterol, LLT, bempedoic acid, inclisiran, or PCSK9 inhibitor. Studies were selected for inclusion according to relatedness to cholesterol management and outcomes with novel LLT agents. Optimization of statins can improve the lipid profile and contribute to primary and secondary atherosclerotic cardiovascular disease (ASCVD) prevention. The newest guidance combines anticipated LDL-C reduction from statins and LDL-C thresholds for primary and secondary prevention. Nonstatin agents such as PCSK9i monoclonal antibodies, small interfering RNA PCSK9i, and bempedoic acid are safe and effective LLTs that can be used in addition to statin therapy for additional LDL-C lowering and prevention of ASCVD. Additionally, these nonstatin agents are reasonable to initiate in patients who have not been able to tolerate statins due to myalgias, rhabdomyolysis, or contraindications. Cost may be a barrier to initiating these agents for patients who are underinsured or uninsured. Clinicians should reference the most up-to-date guidance for LLT for primary and secondary prevention of ASCVD. Additionally, clinicians must diligently continue to optimize statin and nonstatin LLT to improve cardiovascular health outcomes.

10-hydroxy decanoic acid, trans-10-hydroxy-2-decanoic acid, and sebacic acid: Source, metabolism, and potential health functionalities and nutraceutical applications.

The popularity of royal jelly (RJ) as a functional food has attracted attention from various industries, especially nutraceuticals, due to the increasing demand from health enthusiasts. Sebacic acid, 10-hydroxy decanoic acid, and trans-10-hydroxy-2-decanoic acid are the primary medium-chain fatty acids (MCFAs) within RJ responsible for their health benefits. This review aims to consolidate information on these MCFAs' metabolic relationship and health functionalities in nutraceutical applications. We also investigated the natural characteristics mediated by these MCFAs and their metabolism in organisms. Finally, the production of these MCFAs using conventional (from castor oil) and alternative (from RJ) pathways was also discussed. This review can be a reference for using them as functional ingredients in nutraceutical industries.

Rosacea: Common Questions and Answers.

Rosacea is a chronic inflammatory skin disease of the central face, affecting 5% of the population. The exact etiology is unknown. A diagnosis is made based on the updated 2017 National Rosacea Society Expert Committee guidelines, including fixed erythema, phymatous changes of skin thickening due to sebaceous gland hyperplasia and fibrosis, papules, pustules, telangiectasia, and flushing. Delays in an accurate diagnosis and treatment may occur in skin of color due to difficulty visualizing erythema and telangiectasia. The daily use of sunscreen, moisturizers, and mild skin cleansers and avoidance of triggers are essential aspects of maintenance treatment. Effective topical treatment options include alpha-adrenergic receptor agonists for flushing and ivermectin, metronidazole, and azelaic acid for papules and pustules. Systemic treatments include nonselective beta blockers for flushing, low-dose doxycycline, and isotretinoin for papules and pustules. Rosacea can significantly affect a patient's emotional health and quality of life. A referral for care is recommended for fixed phymatous changes and ocular rosacea. (Am Fam Physician. 2024;109(6):533-542.

Two-year carcinogenicity study of a novel plasticizer, bis(2-ethylhexyl) cyclohexane-1,4-dicarboxylate (Eco-DEHCH), by oral diet in Han Wistar rats.

Plasticizers are necessary for the usability of various products, including food contact materials. Exposure to plasticizers is most commonly made through the oral route. Several plasticizers have been reported to have adverse effects on humans and the environment. Thus, the present study aimed to determine the long-term toxicity and carcinogenicity of a novel plasticizer called bis(2-ethylhexyl) cyclohexane-1,4-dicarboxylate (Eco-DEHCH), which is an ecofriendly and biologically less harmful replacer. Groups of 50 male and 50 female Han Wistar rats were fed Eco-DEHCH at daily doses of 1,600, 5,000, or 16,000 ppm in their diet for at least 104 weeks. The rats were regularly monitored for mortality, clinical signs, body weight, food consumption, food efficiency, and perceivable mass. All animals were subjected to complete necropsy and histopathological examination. The results indicate that the rats well tolerated chronic exposure to Eco-DEHCH at highest daily doses of 16,000 ppm, with was equivalent to 805.1 mg/kg/day in males and 1060.6 mg/kg/day in females and did not show signs of toxicity or carcinogenicity. In conclusion, Eco-DEHCH could be a safe and promising alternative plasticizer.

Novel antiarthritic mechanisms of Azelaic acid against CFA-induced arthritis in rats by modulating pro- and anti-inflammatory cytokines network.

An immunologic system attacking the body's own tissues is a hallmark of autoimmune disorders, which encompass a wide range of unique conditions. Numerous essential biologic functions, including the regulation of the immune system, inflammation, cell division, and tissue repair, are carried out by cytokines. Natural compounds are an effective treatment for autoimmune illnesses by modulation of inflammatory cytokines and infiltration of leukocytes into the inflamed tissue. Here, anti-arthritic study was carried out using oral administration of Azelaic acid (AzA) for 28 days with doses (20, 40, and 80 mg/kg) in Complete Freund's Adjuvant (CFA) induced arthritis model. AzA ameliorated the adjuvant-induced arthritis by decreasing arthritic score, paw volume, improved body-weight alterations and serum levels of PGE2, 5-LOX and anti-ccp. AzA showed significant down regulation of NF-κB, COX-II, TNF-α, IL-17, IL-1ß, IL-6, and up regulation of IL4 and IL10. Hemoglobin and RBCs count remarkably increased and ESR, CRP, platelets, WBCs levels markedly reduced in post treatment. In addition, the weakened SOD (superoxide dismutase), Catalase (CAT), Glutathione (GSH) activity and the increased levels of malondialdehyde (MDA) were all reversed by AzA treatment. And showed improved radiographical and histologic alterations in the structure of the joints. Molecular docking studies targeting COX-II, iNOS, TNF-α, 5-LOX, IL4, IL10, IL-6, and IL-17 establish a correlation between theoretical and experimental results. Results showed that AzA inhibit pro-inflammatory cytokines (COX-II, TNF-α, 5-LOX, IL-17, NF-κB, IL-1ß, and IL-6) and increase anti-inflammatory cytokines, which supported the anti-arthritic and immunomodulatory potential of AzA.

Safety evaluation of bempedoic acid: A pharmacovigilance analysis using FDA adverse event reporting system data.

BACKGROUND: Bempedoic acid exhibits promising potential in hyperlipidemia therapy and preventing cardiovascular events. However, investigations into its adverse drug reactions remain scant. This study seeks to utilize data mining techniques with the FDA Adverse Event Reporting System (FAERS) database to assess adverse drug events (ADEs) linked to bempedoic acid. METHODS: Based on the drug's market release timeline, we extracted data from the FAERS database covering the fourth quarter of 2020 through the fourth quarter of 2023 for disproportionality analysis. RESULTS: This study gathered a total of 5,797,543 adverse event case reports, of which 735 were linked to bempedoic acid. These reports covered 19 System Organ Classes (SOCs) and 22 Preferred Terms (PTs). Predominantly, the musculoskeletal and nervous systems were implicated in these adverse events. By conducting PT-level screening, various signals for ADEs were detected, including myalgia (ROR 30.33, PRR 28.51, IC 4.83, EBGM 28.47), arthralgia (n = 34, ROR 6.34, PRR 6.09, IC 2.61, EBGM 6.09), tendon disorders (ROR 99.57, PRR 98.75, IC 6.62, EBGM 98.28), and dizziness (ROR 3.18, PRR 3.13, IC 1.65, EBGM 3.13). Particularly noteworthy was the hypertensive crisis (ROR 28.63, PRR 28.51, IC 4.83, EBGM 28.47), which exhibited a robust signal strength, an observation previously unreported in clinical studies and drug labeling. CONCLUSION: While our results are largely consistent with the drug's specifications, several new adverse reaction signals, such as hypertensive crisis, have not been previously documented. Therefore, further investigations are necessary to assess these unlabeled adverse reactions, offering crucial support for the clinical utilization of bempedoic acid.