Bioactivities and Action Mechanisms of Ellipticine Derivatives Reported Prior to 2023.

Currently, natural products are one of the priceless options for finding novel chemical pharmaceutical entities. Ellipticine is a naturally occurring alkaloid isolated from the leaves of Ochrosia elliptica Labill. Ellipticine and its derivatives are characterized by multiple biological activities. The purpose of this review was to provide a critical and systematic assessment of ellipticine and its derivatives as bioactive molecules over the last 60 years. Publications focused mainly on the total synthesis of alkaloids of this type without any evaluation of bioactivity have been excluded. We have reviewed papers dealing with the synthesis, bioactivity evaluation and mechanism of action of ellipticine and its derivatives. It was found that ellipticine and its derivatives showed cytotoxicity, antimicrobial ability, and anti-inflammatory activity, among which cytotoxicity toward cancer cell lines was the most investigated aspect. The inhibition of DNA topoisomerase II was the most relevant mechanism for cytotoxicity. The PI3K/AKT pathway, p53 pathway, and MAPK pathway were also closely related to the antiproliferative ability of these compounds. In addition, the structure-activity relationship was deduced, and future prospects were outlined. We are confident that these findings will lay a scientific foundation for ellipticine-based drug development, especially for anticancer agents.

Recent advances in the knowledge of the mechanism of reflux hypersensitivity.

Reflux hypersensitivity (RH) is a subtype of gastroesophageal reflux disease. The Rome IV criteria separated RH from the original nonerosive reflux disease subgroup and classified it as a new functional oesophageal disease. Recently, the pathogenesis of RH has become the focus of research. According to the latest research reports, upregulation of acid-sensitive receptors, distribution of calcitonin gene-related peptide-positive nerve fibres, and psychiatric comorbidity have key roles in the pathogenesis of RH. This work reviews the latest findings regarding RH mechanisms.

Anomalously bright single-molecule upconversion electroluminescence.

Efficient upconversion electroluminescence is highly desirable for a broad range of optoelectronic applications, yet to date, it has been reported only for ensemble systems, while the upconversion electroluminescence efficiency remains very low for single-molecule emitters. Here we report on the observation of anomalously bright single-molecule upconversion electroluminescence, with emission efficiencies improved by more than one order of magnitude over previous studies, and even stronger than normal-bias electroluminescence. Intuitively, the improvement is achieved via engineering the energy-level alignments at the molecule-substrate interface so as to activate an efficient spin-triplet mediated upconversion electroluminescence mechanism that only involves pure carrier injection steps. We further validate the intuitive picture with the construction of delicate electroluminescence diagrams for the excitation of single-molecule electroluminescence, allowing to readily identify the prerequisite conditions for producing efficient upconversion electroluminescence. These findings provide deep insights into the microscopic mechanism of single-molecule upconversion electroluminescence and organic electroluminescence in general.

Brain artery diameters and risk of dementia and stroke.

INTRODUCTION: We tested the association of brain artery diameters with dementia and stroke risk in three distinct population-based studies using conventional T2-weighted brain magnetic resonance imaging (MRI) images. METHODS: We included 8420 adults > 40 years old from three longitudinal population-based studies with brain MRI scans. We estimated and meta-analyzed the hazard ratios (HRs) of the brain and carotids and basilar diameters associated with dementia and stroke. RESULT: Overall and carotid artery diameters > 95th percentile increased the risk for dementia by 1.74 (95% confidence interval [CI], 1.13-2.68) and 1.48 (95% CI, 1.12-1.96) fold, respectively. For stroke, meta-analyses yielded HRs of 1.59 (95% CI, 1.04-2.42) for overall arteries and 2.11 (95% CI, 1.45-3.08) for basilar artery diameters > 95th percentile. DISCUSSION: Individuals with dilated brain arteries are at higher risk for dementia and stroke, across distinct populations. Our findings underline the potential value of T2-weighted brain MRI-based brain diameter assessment in estimating the risk of dementia and stroke.

miR-99b-3p/Mmp13 axis regulates NLRP3 inflammasome-dependent microglial pyroptosis and alleviates neuropathic pain via the promotion of autophagy.

BACKGROUND: Neuropathic pain significantly impairs quality of life, and effective interventions are limited. NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated microglial pyroptosis and the subsequent proinflammatory cytokine production are critical in exacerbating pain. Considering microglial pyroptosis as a potential target for developing specific analgesic interventions for neuropathic pain, our study investigated the pathogenesis and therapeutic targets in this condition. METHODS: In vitro experiments involved the co-culture of the immortalized BV-2 microglia cell line with lipopolysaccharide (LPS) to induce microglial pyroptosis. Differentially expressed microRNAs (miRNAs) were identified using high-throughput sequencing analysis. The downstream target genes of these miRNAs were determined through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, and the downstream target genes, combined with miRNAs, were predicted and verified through dual luciferase reporter gene assays. In vivo experiments were conducted to construct a chronic constriction injury (CCI) neuropathic pain model in rats and evaluate the analgesic effects of intrathecal injection of an adeno-associated virus vector (AAV) carrying miR-99b-3p. Gene expression was modulated through mimic or siRNA transfection. Western blot analysis assessed the expression of microglial pyroptosis and autophagy-related proteins, whereas RT-qPCR measured changes in proinflammatory cytokines expression. RESULTS: LPS-stimulated up-regulation of proinflammatory cytokines in microglia, accompanied by NLRP3-dependent pyroptosis, including increased NLRP3, GSDMD-N, Caspase1-p20, and mature-IL-1ß expression. High-throughput sequencing analysis revealed 16 upregulated and 10 downregulated miRNAs in LPS-stimulated microglia, with miR-99b-3p being the most downregulated. KEGG analysis revealed that the target genes of these miRNAs are primarily enriched in calcium, FoxO, and mitogen-activated protein kinase (MAPK) signal pathways. Furthermore, overexpression of miR-99b-3p through mimic transfection significantly inhibited the inflammatory response and NLRP3-mediated pyroptosis by promoting autophagy levels in activated microglia. In addition, we predicted that the 3' untranslated region (UTR) of matrix metalloproteinase-13 (Mmp13) could bind to miR-99b-3p, and knockdown of Mmp13 expression through siRNA transfection similarly ameliorated enhanced proinflammatory cytokines expression and microglial pyroptosis by enhancing autophagy. In vivo, Mmp13 was co-localized with spinal dorsal horn microglia and was suppressed by intrathecal injection of the AAV-miR-99b-3p vector. Moreover, overpressed miR-99b-3p alleviated CCI-induced mechanical allodynia and neuroinflammation while suppressing pyroptosis by enhancing autophagy in the spinal cord of CCI rats. CONCLUSION: miR-99b-3p exerts analgesic effects on neuropathic pain by targeting Mmp13. These antinociceptive effects are, at least in part, attributed to the promotion of autophagy, thereby inhibiting neuroinflammation and NLRP3-mediated pyroptosis in activated microglia.

The Relevance of Arterial Blood Pressure in the Management of Glaucoma Progression: A Systematic Review.

BACKGROUND: Glaucoma is one of the leading causes of global blindness and is expected to co-occur more frequently with vascular morbidities in the upcoming years, as both are aging-related diseases. Yet, the pathogenesis of glaucoma is not entirely elucidated and the interplay between intraocular pressure, arterial blood pressure (BP) and ocular perfusion pressure is poorly understood. OBJECTIVES: This systematic review aims to provide clinicians with the latest literature regarding the management of arterial BP in glaucoma patients. METHODS: A systematic search was performed in Medline, Embase, Web of Science and Cochrane Library. Articles written in English assessing the influence of arterial BP and systemic antihypertensive treatment of glaucoma and its management were eligible for inclusion. Additional studies were identified by revising references included in selected articles. RESULTS: 80 Articles were included in this systemic review. A bimodal relation between BP and glaucoma progression was found. Both high and low BP increase the risk of glaucoma. Glaucoma progression was, possibly via ocular perfusion pressure variation, strongly associated with nocturnal dipping and high variability in the BP over 24 h. CONCLUSIONS: We concluded that systemic BP level associates with glaucomatous damage and provided recommendations for the management and study of arterial BP in glaucoma. Prospective clinical trials are needed to further support these recommendations.

Bioactivities and Mechanisms of Action of Diphyllin and Its Derivatives: A Comprehensive Systematic Review.

Natural products are treasure houses for modern drug discovery. Diphyllin is a natural arylnaphthalene lignan lactone isolated from the leaf of Astilboides tabularis. Studies have found that it possesses plenty of bioactivity characteristics. In this paper, we reviewed the structure, bioactivity, and mechanism of action of diphyllin and its derivatives. The references were obtained from PubMed, Web of Science, and Science Direct databases up to August 2023. Papers without a bio-evaluation were excluded. Diphyllin and its derivatives have demonstrated V-ATPase inhibition, anti-tumor, anti-virus, anti-biofilm, anti-inflammatory, and anti-oxidant activities. The most studied activities of diphyllin and its derivatives are V-ATPase inhibition, anti-tumor activities, and anti-virus activities. Furthermore, V-ATPase inhibition activity is the mechanism of many bioactivities, including anti-tumor, anti-virus, and anti-inflammatory activities. We also found that the galactosylated modification of diphyllin is a common phenomenon in plants, and therefore, galactosylated modification is applied by researchers in the laboratory to obtain more excellent diphyllin derivatives. This review will provide useful information for the development of diphyllin-based anti-tumor and anti-virus compounds.

Recent Research Progress in Fluorescent Probes for Detection of Amyloid-ß In Vivo.

Alzheimer's disease (AD) is a neurodegenerative disease. Due to its complex pathological mechanism, its etiology is not yet clear. As one of the main pathological markers of AD, amyloid-ß (Aß) plays an important role in the development of AD. The deposition of Aß is not only related to the degeneration of neurons, but also can activate a series of pathological events, including the activation of astrocytes and microglia, the breakdown of the blood-brain barrier, and the change in microcirculation, which is the main cause of brain lesions and death in AD patients. Therefore, the development of efficient and reliable Aß-specific probes is crucial for the early diagnosis and treatment of AD. This paper focuses on reviewing the application of small-molecule fluorescent probes in Aß imaging in vivo in recent years. These probes efficiently map the presence of Aß in vivo, providing a pathway for the early diagnosis of AD and providing enlightenment for the design of Aß-specific probes in the future.

Comparison of vonoprazan-based with rabeprazole-based dual therapy for treatment-naive patients of Helicobacter pylori infection: a prospective, multi-center, randomized controlled study.

BACKGROUND: The application of vonoprazan significantly improved the eradication rate of Helicobacter pylori (H. pylori). This study aimed to compare efficacy and safety of the 10-day vonoprazan-amoxicillin (VA) and 14-day rabeprazole-amoxicillin (RA) dual therapy, and to provide a more efficient, safer, and convenient dual regimen for H. pylori infection. METHODS: This was a prospective, open-label, multi-center, randomized controlled study of treatment-naive patients with H. pylori infection. The participants were randomly assigned to the 10-day VA group with vonoprazan 20 mg Bid plus amoxicillin 1 g Tid or the 14-day RA group with rabeprazole 10 mg Tid plus amoxicillin 1 g Tid. The effectiveness, the adverse events, and the patient compliance of the two groups were compared. RESULTS: A total of 690 patients were enrolled. The eradication rates of 10-day VA and 14-day RA dual therapy were 89.3% and 84.9% in intention-to-treat (ITT) analysis (P = 0.088); 90.6% and 85.9% by modified intention-to-treat (mITT) analysis (P = 0.059); 91.4% and 86.6% by per-protocol (PP) analysis (P = 0.047). Non-inferiority was confirmed between the two groups (all P < 0.001). No discernible differences were observed in adverse effects and compliance between groups. Poor compliance reduced the eradication efficacy (P < 0.05). CONCLUSIONS: The 10-day VA dual therapy was non-inferior to the 14-day RA dual therapy for H. pylori treatment-naive patients, which should be given priority in the first-line treatment. The application of vonoprazan reduced treatment course and antibiotic use. Patients' adherence was crucial for the success of eradication.

Synthesis towards Phainanoid F: Photo-induced 6π-Electrocyclization for Constructing Contiguous All-Carbon Quaternary Centers.

In this paper, we report an efficient strategy for synthesizing the DEFGH rings of phainanoid F. The key to the construction of the 13,30-cyclodammarane skeleton of the molecule was a photo-induced 6π-electrocyclization and a homoallylic elimination. Notably, this is a rare example of using electrocyclization reaction to simultaneously construct two vicinal quaternary carbons in total synthesis. The strategy outlined here forms the basis of our total synthesis of Phainanoid F, and it could also serve as a generally applicable approach for synthesizing other natural products containing similar 13,30-cyclodammarane skeletons.

Effect of 24-h blood pressure dysregulations and reduced ocular perfusion pressure in open-angle glaucoma progression.

BACKGROUND: Low ocular perfusion pressure (OPP), which depends on the mean arterial pressure (MAP) and intraocular pressure (IOP), is associated with glaucoma. We studied 24-h MAP dysregulations and OPP in relation to the progression of glaucoma damage. METHODS: We retrospectively analyzed 155 normal-tension glaucoma (NTG) and 110 primary open-angle glaucoma (POAG) patients aged 18 years old followed at the University Hospital Leuven with repeated visual field tests ( n  = 7000 measures, including both eyes) who underwent 24-h ambulatory blood pressure monitoring. Twenty-four-hour MAP dysregulations were variability independent of the mean (VIM), and the five lowest dips in MAP readings over 24 h. OPP was the difference between 2/3 of the MAP and IOP. Glaucoma progression was the deterioration of the visual field, expressed as decibel (dB) changes in mean deviation analyzed by applying multivariable linear mixed regression models. RESULTS: The mean age was 68 years (53% were women). High 24-h VIMmap was associated with glaucoma progression in POAG ( P  < 0.001) independently of the 24-h MAP level. The estimated changes in mean deviation in relation to dip MAP measures ranged from -2.84 dB [95% confidence interval (CI) -4.12 to -1.57] to -2.16 dB (95% CI -3.46 to -0.85) in POAG. Reduced OPP along with high variability and dips in MAP resulted in worse mean deviation deterioration. CONCLUSION: The progression of glaucoma damage associates with repetitive and extreme dips in MAP caused by high variability in MAP throughout 24 h. This progression exacerbates if 24-h MAP dysregulations occur along with reduced OPP.

Citric acid-modified pH-sensitive bone-targeted delivery of estrogen for the treatment of postmenopausal osteoporosis.

Bone targeted delivery of estrogen offers great promise for the clinical application of estrogen in the treatment of postmenopausal osteoporosis (PMOP). However, the current bone-targeted drug delivery system still has several issues that need to be solved, such as the side effects of bone-targeted modifier molecules and the failure of the delivery system to release rapidly in the bone tissue. It is important to aggressively search for new bone-targeted modifier molecules and bone microenvironment-responsive delivery vehicles. Inspired by the distribution of citric acid (CA) mainly in bone tissue and the acidic bone resorption microenvironment, we constructed a CA-modified diblock copolymer poly(2-ethyl-2-oxazoline)-poly(ε-caprolactone) (CA-PEOz) drug delivery system. In our study, we found that the CA modification significantly increased the bone targeting of this drug delivery system, and the delivery system was able to achieve rapid drug release under bone acidic conditions. The delivery system significantly reduced bone loss in postmenopausal osteoporotic mice with a significant reduction in estrogenic side effects on the uterus. In summary, our study shows that CA can act as an effective bone targeting modifier molecule and provides a new option for bone targeting modifications. Our study also provides a new approach for bone-targeted delivery of estrogen for the treatment of PMOP.

The Addition of an Ultra-Small Amount of Black Phosphorous Quantum Dots Endow Self-Healing Polyurethane with a Biomimetic Intelligent Response.

This study explores new applications of black phosphorus quantum dots (BPQDs) by adding them to self-healing material systems for the first time. Self-healing polyurethane with an ultra-small amount of BPQDs has biomimetic intelligent responsiveness and achieves balance between its mechanical and self-healing properties. By adding 0.0001 wt% BPQDs to self-healing polyurethane, the fracture strength of the material increases from 3.0 to 12.3 MPa, and the elongation at break also increases from 750% to 860%. Meanwhile, the self-healing efficiency remains at 98%. The addition of BPQDs significantly improves the deformation recovery ability of the composite materials and transforms the surface of self-healing polyurethane from hydrophilic to hydrophobic, making it suitable for applications in fields such as electronic skin and flexible wearable devices. This study provides a simple and feasible strategy for endowing self-healing materials with biomimetic intelligent responsiveness using a small amount of BPQDs.

Recent Progress of Activity-Based Fluorescent Probes for Imaging Leucine Aminopeptidase.

Leucine aminopeptidase (LAP) is an important protease that can specifically hydrolyze Leucine residues. LAP occurs in microorganisms, plants, animals, and humans and is involved in a variety of physiological processes in the human body. In the physiological system, abnormal levels of LAP are associated with a variety of diseases and pathological processes, such as cancer and drug-induced liver injury; thus, LAP was chosen as the early biochemical marker for many physiological processes, including cancer. Considering the importance of LAP in physiological and pathological processes, it is critical that high-efficiency and dependable technology be developed to monitor LAP levels. Herein, we summarize the organic small molecule fluorescence/chemiluminescence probes used for LAP detection in recent years, which can image LAP in cancer, drug-induced liver injury (DILI), and bacteria. It can also reveal the role of LAP in tumors and differentiate the serum of cirrhotic, drug-induced liver injury and normal models.

Pharmacological activity and mechanism of pyrazines.

Heterocycles are common in the structure of drugs used clinically to deal with diseases. Such drugs usually contain nitrogen, oxygen and sulfur, which possess electron-accepting capacity and can form hydrogen bonds. These properties often bring enhanced target binding ability to these compounds when compared to alkanes. Pyrazine is a nitrogen-containing six-membered heterocyclic ring and many of its derivatives are identified as bioactive molecules. We review here the most active pyrazine compounds in terms of their structure, activity in vitro and in vivo (mainly antitumor activity) and the reported mechanisms of action. References have been downloaded through Web of Science, PubMed, Science Direct, Google Scholar and SciFinder Scholar. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. We found that compounds in which a pyrazine ring was fused into other heterocycles especially pyrrole or imidazole were the highly studied pyrazine derivatives, whose antineoplastic activity had been widely investigated. To the best of our knowledge, this is the first review of pyrazine derivatives and their bioactivity, especially their antitumor activity. This review should be useful for those engaged in development of medications based on heterocyclic compounds especially those based on pyrazine.

Statistical approaches applicable in managing OMICS data: Urinary proteomics as exemplary case.

With urinary proteomics profiling (UPP) as exemplary omics technology, this review describes a workflow for the analysis of omics data in large study populations. The proposed workflow includes: (i) planning omics studies and sample size considerations; (ii) preparing the data for analysis; (iii) preprocessing the UPP data; (iv) the basic statistical steps required for data curation; (v) the selection of covariables; (vi) relating continuously distributed or categorical outcomes to a series of single markers (e.g., sequenced urinary peptide fragments identifying the parental proteins); (vii) showing the added diagnostic or prognostic value of the UPP markers over and beyond classical risk factors, and (viii) pathway analysis to identify targets for personalized intervention in disease prevention or treatment. Additionally, two short sections respectively address multiomics studies and machine learning. In conclusion, the analysis of adverse health outcomes in relation to omics biomarkers rests on the same statistical principle as any other data collected in large population or patient cohorts. The large number of biomarkers, which have to be considered simultaneously requires planning ahead how the study database will be structured and curated, imported in statistical software packages, analysis results will be triaged for clinical relevance, and presented.

Efficacy and Safety of Keverprazan Compared With Lansoprazole in the Treatment of Duodenal Ulcer: A Phase III, Randomized, Double-Blind, Multicenter Trial.

INTRODUCTION: Keverprazan is a novel potassium-competitive acid blocker for the treatment of acid-related disorders requiring potent acid inhibition. This study aimed to establish the noninferiority of keverprazan to lansoprazole in the treatment of patients with duodenal ulcer (DU). METHODS: In this phase III, double-blind, multicenter study, 360 Chinese patients with endoscopically confirmed active DU were randomized 1:1 to take either keverprazan (20 mg) or lansoprazole (30 mg) treatment for up to 6 weeks. The primary end point was DU healing rate at week 6. The secondary end point was DU healing rate at week 4. Symptom improvement and safety were also assessed. RESULTS: Based on the full analysis set, the cumulative healing rates at week 6 were 94.4% (170/180) and 93.3% (166/178) for keverprazan and lansoprazole, respectively (difference: 1.2%; 95% confidence intervel: -4.0%-6.5%). At week 4, the respective healing rates were 83.9% (151/180) and 80.3% (143/178). In the per protocol set, the 6-week healing rates in keverprazan and lansoprazole groups were 98.2% (163/166) and 97.6% (163/167), respectively (difference: 0.6%; 95% confidence intervel: -3.1%-4.4%); the 4-week healing rates were respectively 86.8% (144/166) and 85.6% (143/167). Keverprazan was noninferior to lansoprazole in DU healing after the treatment for 4 and 6 weeks. The incidence of treatment-emergent adverse events was comparable among groups. DISCUSSION: Keverprazan 20 mg had a good safety profile and was noninferior to lansoprazole 30 mg once daily for DU healing.

Environmental Impact Assessment for the Use of an Orally Aerosolized Adenovirus Type-5 Vector-Based COVID-19 Vaccine in Randomized Clinical Trials.

BACKGROUND: An orally aerosolized adenovirus type-5 vector-based coronavirus disease 2019 (COVID-19) vaccine (Ad5-nCoV) has recently been authorized for boosting immunization in China. Our study aims to assess the environmental impact of the use of aerosolized Ad5-nCoV. METHODS: We collected air samples from rooms, swabs from the desks on which the vaccine nebulizer was set, mask samples from participants, and blood samples of nurses who administered the inoculation in the clinical trials. The viral load of adenovirus type-5 vector in the samples and the antibody levels against the wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain in serum were detected. RESULTS: Only one (4.00%) air sample collected before initiation of vaccination was positive and most air samples collected during and after vaccination were positive (97.96%, 100%, respectively). All nurses in trial A showed at least 4-fold increase of the neutralizing antibody against SARS-CoV-2 after initiation of the study. In trial B, the proportion of positive mask samples was 72.97% at 30 minutes after vaccination, 8.11% at day 1, and 0% at days 3, 5, and 7. CONCLUSIONS: Vaccination with the orally aerosolized Ad5-nCoV could result in some spillage of the vaccine vector viral particles in the environment and cause human exposure. Clinical Trials Registration. NCT04840992 and NCT05303584.

Cardiovascular risk of metabolically healthy obesity in two european populations: Prevention potential from a metabolomic study.

BACKGROUND: A new definition of metabolically healthy obesity (MHO) has recently been proposed to stratify the heterogeneous mortality risk of obesity. Metabolomic profiling provides clues to metabolic alterations beyond clinical definition. We aimed to evaluate the association between MHO and cardiovascular events and assess its metabolomic pattern. METHODS: This prospective study included Europeans from two population-based studies, the FLEMENGHO and the Hortega study. A total of 2339 participants with follow-up were analyzed, including 2218 with metabolomic profiling. Metabolic health was developed from the third National Health and Nutrition Examination Survey and the UK biobank cohorts and defined as systolic blood pressure < 130 mmHg, no antihypertensive drugs, waist-to-hip ratio < 0.95 for women or 1.03 for men, and the absence of diabetes. BMI categories included normal weight, overweight, and obesity (BMI < 25, 25-30, ≥ 30 kg/m2). Participants were classified into six subgroups according to BMI category and metabolic healthy status. Outcomes were fatal and nonfatal composited cardiovascular events. RESULTS: Of 2339 participants, the mean age was 51 years, 1161 (49.6%) were women, 434 (18.6%) had obesity, 117 (5.0%) were classified as MHO, and both cohorts had similar characteristics. Over a median of 9.2-year (3.7-13.0) follow-up, 245 cardiovascular events occurred. Compared to those with metabolically healthy normal weight, individuals with metabolic unhealthy status had a higher risk of cardiovascular events, regardless of BMI category (adjusted HR: 3.30 [95% CI: 1.73-6.28] for normal weight, 2.50 [95% CI: 1.34-4.66] for overweight, and 3.42 [95% CI: 1.81-6.44] for obesity), whereas those with MHO were not at increased risk of cardiovascular events (HR: 1.11 [95% CI: 0.36-3.45]). Factor analysis identified a metabolomic factor mainly associated with glucose regulation, which was associated with cardiovascular events (HR: 1.22 [95% CI: 1.10-1.36]). Individuals with MHO tended to present a higher metabolomic factor score than those with metabolically healthy normal weight (0.175 vs. -0.057, P = 0.019), and the score was comparable to metabolically unhealthy obesity (0.175 vs. -0.080, P = 0.91). CONCLUSIONS: Individuals with MHO may not present higher short-term cardiovascular risk but tend to have a metabolomic pattern associated with higher cardiovascular risk, emphasizing a need for early intervention.