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Darapladib, an oral inhibitor of lipoprotein-associated phospholipase A2, was compared with placebo in 15,828 patients with stable coronary heart disease. Darapladib did not significantly reduce the risk of cardiovascular death, myocardial infarction, or stroke. Atherosclerotic lesions in humans — in particular, vulnerable 1 and ruptured plaques — are characterized by inflammatory activity and a high expression of lipoprotein-associated phospholipase A 2 . 2 , 3 In atherosclerotic plaques, lipoprotein-associated phospholipase A 2 increases the production of proinflammatory and proapoptotic mediators. 4 – 8 In a meta-analysis of individual records from 79,036 participants in 32 prospective studies, there was a continuous association between lipoprotein-associated phospholipase A 2 activity and the risk of coronary heart disease, with a relative increase in risk of 1.10 (95% confidence interval [CI], 1.05 to 1.16) for each 1-SD increase in lipoprotein-associated phospholipase A 2 activity, . . .

Plantar fasciitis is the most common cause of heel pain in adults with an overall prevalence of 0.85% in the adult population of the US, affecting over 2 million adults annually. Most current treatment modalities are not supported by sufficient evidence to recommend one particular strategy over another. Topical application of analgesics for soft tissue pain is well established, however the plantar fascia presents challenges in this regard due to thick skin, fibrotic tissue, and an often thickened fat pad. Sixty-two patients with plantar fasciitis were randomized to a placebo controlled trial testing the efficacy of a topical solution of plant terpenes containing camphor, menthol, eugenol, eucalyptol, and vanillin. Skin permeation of the mixture was enhanced with 15% dimethylsulfoxide (DMSO), 1% limonene, and rosemary oil. One ml of solution was applied topically twice daily, and pain scores evaluated on Day 0, Day 1, Day 3, and Day 10. Using the validated foot function index 78.1% of patients reported an 85% or greater decrease in their total pain score by day 10 while placebo treatment was without effect (One Way ANOVA, P < 0.01). This study adapts the treatment modality of topical analgesia for soft tissue pain to a problematic area of the body and shows therapeutic promise. ClinicalTrials.gov Identifier: NCT05467631

Elevated plasma levels of lipoprotein-associated phospholipase A 2 (Lp-PLA 2) are associated with increased risk of cardiovascular (CV) events. Direct inhibition of this proinflammatory enzyme with darapladib may benefit CV patients when given as an adjunct to standard of care, including lipid-lowering and antiplatelet therapies. STABILITY is a randomized, placebo-controlled, double-blind, international, multicenter, event-driven trial. The study has randomized 15,828 patients with chronic coronary heart disease (CHD) receiving standard of care to darapladib enteric-coated (EC) tablets, 160 mg or placebo. The primary end point is the composite of major adverse cardiovascular events (MACE): CV death, nonfatal myocardial infarction, and nonfatal stroke. The key secondary end points will include major coronary events, total coronary events, individual components of MACE, and all-cause mortality. Prespecified substudies include 24-hour ambulatory blood pressure monitoring, albuminuria progression, changes in cognitive function, and pharmacokinetic and biomarker analyses. Health economic outcomes and characterization of baseline lifestyle risk factors also will be assessed. The study will continue until 1,500 primary end points have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be 2.75 years. STABILITY will assess whether direct inhibition of Lp-PLA 2 with darapladib added to the standard of care confers clinical benefit to patients with CHD.

In a trial evaluating two daily-dose levels of voxelotor, which binds to sickle hemoglobin and prevents polymerization under hypoxic conditions, hemoglobin levels increased by more than 1 g per deciliter in approximately half the patients who received the drug, and markers of hemolysis decreased. Toxic effects were mainly low grade and not different from those with placebo.

Subjects with peripheral artery disease (PAD) are at increased risk of cardiovascular morbidity and mortality, perhaps in part, related to increased levels of inflammation, platelet activity, and lipids. We therefore sought to investigate the relationship between PAD and levels of inflammatory, platelet, and lipid biomarkers and the treatment effect of darapladib, a novel lipoprotein-associated phospholipase A 2 (Lp-PLA 2) inhibitor. This is a post hoc analysis of the 959 patients with coronary disease or their risk equivalent receiving atorvastatin who were randomized to receive darapladib or placebo to examine the effects of an Lp-PLA 2 inhibitor on the biomarkers of cardiovascular risk. We conducted an exploratory analysis evaluating the levels of biomarkers in subjects with PAD (n = 172) compared with those without PAD (n = 787). After adjustment for age, sex, smoking, body mass index, and diabetes, subjects with PAD had greater levels of matrix metalloproteinase-9 (between group comparisons 22%, 95% confidence interval [10-31], P < .01), myeloperoxidase (12% [2-20], P = .01), interleukin-6 (13% [4-21], P = .01), adiponectin (17% [7-26], P < .01), intercellular adhesion molecule-1 (7% [2-11], P < .01), osteoprotegrin (6% [1-10], P = .02), CD40 ligand (15% [1-28], P = .04), high-sensitivity C-reactive protein (17% [1-31], P = .04), and triglycerides (11% [0.2-21], P = .05). No significant difference was detected for Lp-PLA 2 activity, P-selectin, urinary 11-dehydrothroboxane B2, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol between subjects with and without PAD. Darapladib produced highly significant inhibition of Lp-PLA 2 activity when compared with placebo at weeks 4 and 12 ( P < .01) in patients with and without PAD. Subjects with PAD had elevated levels of matrix metalloproteinase-9, myeloperoxidase, interleukin-6, adiponectin, intercellular adhesion molecule-1, osteoprotegrin, CD40 ligand, high-sensitivity C-reactive protein, and triglycerides compared with those without PAD. Darapladib, a novel Lp-PLA 2 inhibitor, was equally effective in reducing Lp-PLA 2 activity levels in subjects with and without PAD.

Treating infected wounds is a major clinical challenge, and concerns about bacterial resistance have driven the shift toward natural antimicrobials over antibiotics. Herein, a 3D printed scaffold wound dressing consisting of alginate (Alg) and fucoidan (F) was prepared, and Soluplus (Sol) nanomicelles (NMs) were used to load vanillin (Vn) as a lipophilic antibacterial agent into the 3D printed scaffold. Characterization analyses revealed that the fabricated scaffold exhibited a peak swelling capacity of 294.3 ± 24.1% and underwent a weight loss of 38.0 ± 2.25% following a seven-day immersion in PBS. The Vn release from the Alg-F-VnNMs scaffold reached 80.6 ± 5.3% after seven days of immersion in PBS. The controlled release of Vn from the scaffold resulted in inhibition zones of 21.4 ± 1.15 mm against S. aureus and 23.2 ± 0.9 mm against E. coli within 24 h, while further analysis displayed a potent bactericidal effect, eradicating more than 80% of the bacterial population. In vivo studies on a full-thickness rat wound model showed that the Alg-F-VnNMs scaffold reduced inflammation, enhanced collagen deposition, and accelerated regeneration, leading to complete wound healing in 14 days, confirming its efficacy in wound management and skin repair.

RationaleFlavors can alter the orosensory properties of tobacco products. Specifically, flavors can serve as an oral cue for smokeless tobacco products.ObjectivesWe aimed to investigate the impact of oral vanillin, the principal chemical of vanilla flavor in tobacco products, on nicotine’s taste, and nicotine choice, intake, and seeking behaviors.MethodsExperiments were performed in young adult Sprague Dawley rats. We employed a two-bottle free-choice test (2BC) to measure the preference for different concentrations of vanillin and its effect on nicotine preference. To explore the long-term effects of early exposure to sweetened vanillin, we utilized a combined 2BC and intraoral self-administration (IOSA) model. We assessed the nicotine taking and seeking behaviors in the presence or absence of vanillin. We performed a taste reactivity test (TRT) to quantify liking (ingestive) and disliking (aversive) taste responses to oral nicotine with or without vanillin.ResultsIn 2BC, female rats preferred vanillin containing solutions more than their male counterparts. In IOSA, vanillin alone and in combination with nicotine led to greater IOSA compared to water. Female rats self-administered vanillin plus nicotine more than male rats. Vanillin increased motivation to nicotine taking, but only in females. In TRT, vanillin increased nicotine’s ingestive responses but blocked aversive responses in both sexes.ConclusionsThese results indicate that vanilla flavor can increase oral nicotine intake. It can also increase liking and decrease disliking of nicotine’s taste. Furthermore, the impact of vanilla flavor on nicotine taste and nicotine choice, intake, and seeking behaviors is concentration and sex dependent.

Electrospun phospholipid (asolectin) microfibers were investigated as antioxidants and encapsulation matrices for curcumin and vanillin. These phospholipid microfibers exhibited antioxidant properties which increased after the encapsulation of both curcumin and vanillin. The total antioxidant capacity (TAC) and the total phenolic content (TPC) of curcumin/phospholipid and vanillin/phospholipid microfibers remained stable over time at different temperatures (refrigerated, ambient) and pressures (vacuum, ambient). 1H-NMR confirmed the chemical stability of both encapsulated curcumin and vanillin within phospholipid fibers. Release studies in aqueous media revealed that the phenolic bioactives were released mainly due to swelling of the phospholipid fiber matrix over time. The above studies confirm the efficacy of electrospun phospholipid microfibers as encapsulation and antioxidant systems.

In this study, we investigated the anti-allergic effects of 3,4-dihydroxybenzaldehyde (DHB) isolated from the marine red alga, Polysiphonia morrowii, in mouse bone-marrow-derived cultured mast cells (BMCMCs) and passive cutaneous anaphylaxis (PCA) in anti-dinitrophenyl (DNP) immunoglobulin E (IgE)-sensitized mice. DHB inhibited IgE/bovine serum albumin (BSA)-induced BMCMCs degranulation by reducing the release of β-hexosaminidase without inducing cytotoxicity. Further, DHB dose-dependently decreased the IgE binding and high-affinity IgE receptor (FcεRI) expression and FcεRI-IgE binding on the surface of BMCMCs. Moreover, DHB suppressed the secretion and/or the expression of the allergic cytokines, interleukin (IL)-4, IL-5, IL-6, IL-13, and tumor necrosis factor (TNF)-α, and the chemokine, thymus activation-regulated chemokine (TARC), by regulating the phosphorylation of IκBα and the translocation of cytoplasmic NF-κB into the nucleus. Furthermore, DHB attenuated the passive cutaneous anaphylactic (PCA) reaction reducing the exuded Evans blue amount in the mouse ear stimulated by IgE/BSA. These results suggest that DHB is a potential therapeutic candidate for the prevention and treatment of type I allergic disorders.

Angiostrongylus cantonensis is a zoonotic nematode that causes eosinophilic meningitis and central nervous system injury in humans; 3-hydroxybenzaldehyde (3-HBA) is a benzaldehyde compound that exhibits antioxidant and anti-inflammatory activities. Brain injury promotes Ca²⁺ influx and mitochondrial Ca²⁺ loading via voltage-dependent anion channel 1 (VDAC1) and the mitochondrial Ca²⁺ uniporter (MCU), leading to mitochondrial dysfunction and cytochrome c-mediated apoptosis. This study aimed to evaluate the therapeutic effects of 3-HBA combined with albendazole on brain injury and the expression of mitochondria-related molecules in A. cantonensis-infected mice. In BALB/c mice infected with A. cantonensis, the infection significantly increased glial fibrillary acidic protein expression in five regions: the cerebral cortex, hippocampus, subcortical areas, cerebellum, and brainstem and elevated the expression of MCU and cytochrome c in the cerebral cortex and hippocampus. Hematoxylin and eosin staining revealed pathological changes, such as meningitis, hemorrhage, and vascular congestion. However, combined treatment with 3-HBA and albendazole reduced these pathological changes and the expression of mitochondria-related molecules, including glial fibrillary acidic protein, VDAC1, MCU, and cytochrome c. In cultured mouse astrocytes, soluble antigens from fifth-stage larval-activated astrocytes induced mitochondria-related molecule expression, but 3-HBA suppressed these effects. These results suggest that the combination of 3-HBA and albendazole downregulates astrocyte activation and VDAC1/MCU-associated mitochondrial pathways following A. cantonensis infection. These findings support the use of 3-HBA as a promising adjuvant to albendazole in the treatment of angiostrongyliasis.