José María Castellano

Aims: Chronic kidney disease (CKD) is a major complication of type 2 diabetes mellitus (T2DM), driven in part by oxidative stress and the accumulation of advanced glycation end products (AGEs). Oleanolic acid (OA), a natural triterpene present in olive‐derived matrices, may modulate AGE metabolism. In this prespecified, exploratory secondary analysis of the OLTRAD trial, we evaluated whether long‐term intake of OA‐enriched olive oil attenuates kidney function decline in patients with T2DM. Methods: In the OLTRAD randomised controlled trial, 97 patients with T2DM were assigned to consume OA‐enriched olive oil (600 mg OA/kg) or control olive oil for 12 months, alongside standard therapy. Kidney outcomes included estimated glomerular filtration rate (eGFR) and urinary albumin‐to‐creatinine ratio (uACR). Circulating AGEs (methylglyoxal [MG], carboxymethyllysine [CML]), enzymes involved in AGE metabolism (aldose reductase [AR], glyoxalase‐I [GloxI]), and oxidative stress markers (ROS and MDA) were assessed. Results: OA‐enriched olive oil attenuated eGFR decline relative to control, an effect restricted to participants with mildly impaired eGFR at baseline (60–90 mL/min/1.73 m ² ; time × group interaction p = 0.010), with no significant interaction among participants with normal baseline eGFR. OA‐enriched oil also prevented the rise in uACR observed with control oil. Mechanistically, OA reduced AR concentration and increased GloxI activity, resulting in lower circulating MG, whereas CML remained unchanged. OA‐enriched oil further reduced ROS and MDA levels, while MDA increased with control oil. Conclusions: In this exploratory, hypothesis‐generating secondary analysis, long‐term consumption of OA‐enriched olive oil was associated with attenuated kidney function decline in patients with T2DM, an effect limited to those with baseline mildly impaired eGFR. These changes were associated with modulation of AGE‐related pathways and reduced oxidative stress. As the trial was powered for glycemic control rather than renal outcomes, larger, adequately powered studies are needed to confirm these findings before their clinical relevance can be established. Trial Registration: Clinicaltrials.gov identifier: NCT06030544; https://clinicaltrials.gov/study/NCT06030544

Background and objectives: Since postprandial lipid metabolism has emerged as a risk factor for cardiovascular disease, the quality of dietary fat may have a crucial role in atherogenesis and metabolic inflammation. In this study, we propose that the quality of dietary fats and the metabolic status of individuals modulate postprandial triglyceride-rich lipoprotein (TRL) composition and the response of macrophages to TRL. Methods: Randomized controlled crossover trial in the postprandial phase in 12 normal-weight adults and 12 adults with obesity. Each participant consumed both a Western-style (WB) and a Mediterranean-style (MB) breakfast in separate sessions, containing butter or olive oil as the fat source, respectively. Blood samples were collected at baseline (0 h), 2 h, and 4 h postprandially, and TRL were isolated and used to treat THP-1 macrophages. Results: The intake of the WB led to higher concentrations of inflammatory-related markers, particularly in individuals with obesity, and resulted in a higher content of saturated fatty acids and lower of monounsaturated fatty acids in TRL compared to the MB. Staining TRL-treated macrophages with Oil Red O revealed substantial lipid accumulation, which was more pronounced in cells cultured with 4 h TRL from individuals with obesity. This was also evidenced by upregulation of gene expression of lipoprotein uptake receptors following the consumption of the WB. Conclusions: Consumption of a WB led to a more pro-inflammatory postprandial profile and promoted greater lipid accumulation in macrophages, particularly in individuals with obesity, compared to a MB. These findings highlight the importance of fat quality in meals for cardiovascular risk management, especially in populations with obesity.

Numerous hypotheses have been proposed to explain the origin of Alzheimer’s disease (AD), a chronic neurodegenerative disorder that currently has no curative treatment. These hypotheses include the abnormal accumulation of β-amyloid and hyperphosphorylated Tau, degeneration of cholinergic neurons associated with chronic neuroinflammation and oxidative stress, and dysregulation of lipid and carbohydrate metabolism. oleanolic acid (OA), a pentacyclic triterpenoid widely distributed across plant species, has demonstrated anti-inflammatory and antioxidant activities, anti-aggregation properties, together with regulatory effects on carbohydrate and lipid metabolism. Given the diversity of hypotheses proposed for AD and its multifactorial nature, the pleiotropic actions of OA positions it as a promising candidate for preventive and therapeutic strategies. This review compiles evidence on OA and selected synthetic derivatives, analyzing their impact across the major mechanistic hypotheses of AD pathogenesis. Collectively, these findings support OA as a promising candidate to address protein aggregation, metabolic imbalance, and neuroinflammation in AD.

In the context of the alarming rise of infant obesity and its health implications, the present research aims to uncover disruptions in postprandial lipid metabolism and the composition of triglyceride-rich lipoproteins in obese adolescents. A double-blind, controlled clinical trial in the postprandial phase on 23 adolescents aged 12 to 16 years was carried out. Twelve participants were categorized as obese (BMI > 30 kg/m² and percentile > 95) and 11 as normal-weight (BMI = 20–25 kg/m², percentile 5–85). Blood samples were collected after a 12-h overnight fast and postprandially after consumption of a standardized breakfast containing olive oil, tomato, bread, orange juice, and skimmed milk. Obese adolescents exhibited elevated triglyceride concentrations in both fasting and postprandial states and higher TG/apo-B48 ratios, indicating larger postprandial triglyceride-rich lipoprotein (TRL) particle size, which suggests impaired clearance. Obese subjects also exhibited higher n-6 PUFA concentrations, potentially linked to increased TRL hydrolysis and the release of pro-inflammatory adipokines. In contrast, TRL from normal-weight individuals showed higher concentrations of oleic acid and DHA (n-3 PUFA), with possible anti-inflammatory effects. The results indicate an interplay involving postprandial TRL metabolism and adipokines within the context of adolescent obesity, pointing to potential cardiovascular implications in the future.

A high bioavailability formulation for oleanolic acid (OA) suggests its potential therapeutic application in humans.

Triglyceride-rich lipoproteins obtained from pomace olive oil consumed by healthy women reduce microglial inflammation in BV-2 cells stimulated with LPS compared to high-oleic sunflower oil.

Oleanolic acid (OA) is a natural triterpene widely found in olive leaves that possesses antioxidant, anti-inflammatory, and insulin-sensitizing properties, among others. These OA characteristics could be of special interest in the treatment and prevention of insulin resistance (IR), but greater in-depth knowledge on the pathways involved in these properties is still needed. We aimed to systematically review the effects of OA on the molecular mechanisms and signaling pathways involved in the development of IR and underlying oxidative stress in insulin-resistant animal models or cell lines. The bibliographic search was carried out on PubMed, Web of Science, Scopus, Cochrane, and CINHAL databases between January 2001 and May 2022. The electronic search produced 5034 articles but, after applying the inclusion criteria, 13 animal studies and 3 cell experiments were identified, using SYRCLE’s Risk of Bias for assessing the risk of bias of the animal studies. OA was found to enhance insulin sensitivity and glucose uptake, and was found to suppress the hepatic glucose production, probably by modulating the IRS/PI3K/Akt/FoxO1 signaling pathway and by mitigating oxidative stress through regulating MAPK pathways. Future randomized controlled clinical trials to assess the potential benefit of OA as new therapeutic and preventive strategies for IR are warranted.

Microglial cells can contribute to Alzheimer’s disease by triggering an inflammatory response that leads to neuronal death. In addition, the presence of amyloid-β in the brain is consistent with alterations in the blood–brain barrier integrity and triglyceride-rich lipoproteins (TRL) permeation. In the present work, we used lab-made TRL as carriers of lipophilic bioactive compounds that are commonly present in dietary oils, namely oleanolic acid (OA), α-tocopherol (AT) and β-sitosterol (BS), to assess their ability to modulate the inflammatory response of microglial BV-2 cells. We show that treatment with lab-made TRL increases the release and gene-expression of IL-1β, IL-6, and TNF-α, as well as NO and iNOS in microglia. On the other hand, TRL revealed bioactive compounds α-tocopherol and β-sitosterol as suitable carriers for oleanolic acid. The inclusion of these biomolecules in TRL reduced the release of proinflammatory cytokines. The inclusion of these biomolecules in TRL reduced the release of proinflammatory cytokines. AT reduced IL-6 release by 72%, OA reduced TNF-α release by approximately 50%, and all three biomolecules together (M) reduced IL-1β release by 35% and TNF-α release by more than 70%. In addition, NO generation was reduced, with the inclusion of OA by 45%, BS by 80% and the presence of M by 88%. Finally, a recovery of the basal glutathione content was observed with the inclusion of OA and M in the TRL. Our results open the way to exploiting the neuro-pharmacological potential of these lipophilic bioactive compounds through their delivery to the brain as part of TRL.

Oleanolic acid, a pentacyclic triterpenoid ubiquitously present in the plant kingdom, is receiving outstanding attention from the scientific community due to its biological activity against multiple diseases. Oleanolic acid is endowed with a wide range of biological activities with therapeutic potential by means of complex and multifactorial mechanisms. There is evidence suggesting that oleanolic acid might be effective against dyslipidemia, diabetes and metabolic syndrome, through enhancing insulin response, preserving the functionality and survival of β-cells and protecting against diabetes complications. In addition, several other functions have been proposed, including antiviral, anti-HIV, antibacterial, antifungal, anticarcinogenic, anti-inflammatory, hepatoprotective, gastroprotective, hypolipidemic and anti-atherosclerotic activities, as well as interfering in several stages of the development of different types of cancer; however, due to its hydrophobic nature, oleanolic acid is almost insoluble in water, which has led to a number of approaches to enhance its biopharmaceutical properties. In this scenario, the present review aimed to summarize the current knowledge and the research progress made in the last years on the extraction and characterization of oleanolic acid and its biological activities and the underlying mechanisms of action.

Oleanolic acid (OA), a triterpene that is highly present in olive leaves, has been proposed as a component of functional foods for the prevention of metabolic syndrome, due to its anti-inflammatory activity. We analyzed the effects of OA on inflammatory parameters and signaling proteins in LPS-stimulated THP-1 macrophages. Thus, THP-1 macrophages were incubated with LPS for 48 h after pretreatment with OA at different concentrations. Pretreatment with OA was significantly effective in attenuating IL-6 and TNF-α overproduction induced by LPS in macrophages, and also improved the levels of AMPK-α. We also evaluated the effects of human triglyceride-rich lipoproteins (TRLs) derived from individuals consuming an OA-enriched functional olive oil. For this purpose, TRLs were isolated from healthy adolescents before, 2 and 5 h postprandially after the intake of a meal containing the functional olive oil or common olive oil, and were incubated with THP-1 macrophages. THP-1 macrophages incubated with TRLs isolated at 2 h after the consumption of the OA-enriched olive oil showed significant lower levels of IL-6 compared to the TRLs derived from olive oil. Our results suggest that OA might have potential to be used as a lipid-based formulation in functional olive oils to prevent inflammatory processes underlying metabolic syndrome in adolescents.