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19 pages, 2736 KB  
Article
Rationally Engineered D-Amino Acid Peptide DT7-3 Combats Multidrug-Resistant Helicobacter pylori via a Novel “Triple-Hit” Mechanism
by Shiying Yan, Xin Yan, Jiarui Zhao, Yue Zhou, Changyi Huang, Yiping Chen, Jia Wang, Jian Zhang, Chaoyi Han, Yu Gao, Tianlan Jiang, Hansheng Zhu, Hao Shi, Fosheng Li, Jian Zhao and Mei Cao
Microorganisms 2026, 14(4), 744; https://doi.org/10.3390/microorganisms14040744 - 26 Mar 2026
Abstract
Helicobacter pylori (H. pylori) is the primary etiological agent for chronic gastritis, peptic ulcers, and gastric adenocarcinoma. The alarming rise in multidrug-resistant (MDR) strains, particularly against clarithromycin (CLR), metronidazole (MNZ), and levofloxacin (LVX), has severely compromised standard therapies. Thus, there is [...] Read more.
Helicobacter pylori (H. pylori) is the primary etiological agent for chronic gastritis, peptic ulcers, and gastric adenocarcinoma. The alarming rise in multidrug-resistant (MDR) strains, particularly against clarithromycin (CLR), metronidazole (MNZ), and levofloxacin (LVX), has severely compromised standard therapies. Thus, there is an urgent clinical need for novel antimicrobial agents that operate through distinct mechanisms to bypass resistance pathways and mitigate gastric cancer risk. We designed and synthesized a series of antimicrobial peptides, focusing on the proteolytically stable all-D-amino acid enantiomer, DT7-3, derived from a probiotic-sourced template. Minimum inhibitory concentrations (MICs) were determined against standard strains and 11 clinical MDR isolates via the broth microdilution method. Antimicrobial mechanisms were elucidated using scanning electron microscopy (SEM) for morphology, fluorescence-based assays for anti-adhesion activity, and real-time qPCR to quantify virulence gene expression (babA, ureA, and vacA). Biocompatibility was assessed using defibrinated sheep erythrocytes, gastric epithelial cells (GES-1), and representative beneficial gut microbiota. Analysis of the clinical isolates revealed resistance rates of 63.6% for CLR/LVX and 81.8% for MNZ, with 54.5% identified as MDR. DT7-3 exhibited superior potency (MIC 1–32 µg/mL) against all strains, significantly outperforming its L-enantiomer counterparts. Mechanistic studies unveiled a “triple-hit” mechanism: (1) rapid membrane disruption; (2) potent inhibition of bacterial adhesion to host cells (~60% reduction at 0.5 × MIC); (3) significant downregulation of critical virulence factors (babA, ureA, and vacA). Furthermore, DT7-3 showed an excellent safety profile, with negligible hemolysis (<5% at 32 µg/mL) and minimal cytotoxicity toward GES-1 cells, yielding a high selectivity index (SI, MHC/MIC) > 32 relative to mammalian cells. Crucially, DT7-3 showed high selectivity for the pathogen over beneficial gut microbiota (MIC > 128 µg/mL, SI > 16). Crucially, DT7-3 maintained potent bactericidal activity (MIC ≤ 16 µg/mL) even under cholesterol-enriched conditions. The engineered D-peptide DT7-3 is a potent candidate for combating MDR H. pylori. Its multifaceted mechanism, targeting bacterial viability while suppressing core virulence factors, positions it as a robust lead compound for next-generation eradication therapies aimed at reducing the burden of H. pylori-associated diseases. Full article
(This article belongs to the Section Antimicrobial Agents and Resistance)
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16 pages, 11993 KB  
Article
25-Hydroxycholesterol Restricts Japanese Encephalitis Virus via Metabolic Suppression of the SREBP2-Mediated Signaling Axis
by Xinlei Liu, Yu Gu, Yuanyuan Yang, Xinran Li, Yu Dai, Ruiqin Zhang, Jiahui Li, Haodong Chen, Yi Zheng and Rui Wu
Microorganisms 2026, 14(4), 740; https://doi.org/10.3390/microorganisms14040740 - 26 Mar 2026
Abstract
Host lipid metabolism is a critical determinant of viral pathogenesis. Although the interferon-inducible cholesterol 25-hydroxylase (CH25H) typically acts as a broad-spectrum antiviral protein, its expression and regulatory patterns during Japanese Encephalitis Virus (JEV) infection display unique features. Here, we demonstrate that 25-hydroxycholesterol (25HC), [...] Read more.
Host lipid metabolism is a critical determinant of viral pathogenesis. Although the interferon-inducible cholesterol 25-hydroxylase (CH25H) typically acts as a broad-spectrum antiviral protein, its expression and regulatory patterns during Japanese Encephalitis Virus (JEV) infection display unique features. Here, we demonstrate that 25-hydroxycholesterol (25HC), the product of CH25H, potently inhibits JEV proliferation by suppressing SREBP2 activation. Distinct from the majority of viral infections that induce CH25H upregulation, JEV infection elicits a transient reduction in CH25H abundance immediately after infection, coupled with a persistent elevation in SREBP2 expression. This inverse correlation suggests that JEV actively suppresses the CH25H-mediated metabolic checkpoint to maintain a cholesterol-synthetic environment favorable for replication. By pharmacologically simulating the activity of 25HC, we further verify that targeting the SREBP2 signaling axis can efficiently counteract this virally induced metabolic reprogramming. Our study identifies CH25H downregulation and concomitant SREBP2 activation as a key metabolic signature of JEV pathogenesis. Full article
(This article belongs to the Section Virology)
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11 pages, 1291 KB  
Article
Combined HDL–BMI Phenotyping Provides Incremental Prognostic Value in Idiopathic Pulmonary Fibrosis
by Qinxue Shen, Xiaoli Ouyang, Yuexin Tan, Qing Zhang, Feng Hu, Shengyang He and Hong Peng
J. Clin. Med. 2026, 15(7), 2525; https://doi.org/10.3390/jcm15072525 - 26 Mar 2026
Abstract
Background/Objectives: Risk stratification in idiopathic pulmonary fibrosis (IPF) remains primarily based on physiological indices, yet increasing evidence suggests that systemic metabolic and nutritional vulnerability may influence outcomes in chronic interstitial lung disease. Methods: In this longitudinal, single-center cohort, 211 patients with [...] Read more.
Background/Objectives: Risk stratification in idiopathic pulmonary fibrosis (IPF) remains primarily based on physiological indices, yet increasing evidence suggests that systemic metabolic and nutritional vulnerability may influence outcomes in chronic interstitial lung disease. Methods: In this longitudinal, single-center cohort, 211 patients with IPF were followed from diagnosis until death or last follow-up. Baseline lipid profiles and body mass index (BMI) were assessed. A metabolic–nutritional phenotype was constructed using high-density lipoprotein cholesterol (HDL) and BMI. Survival was analyzed using Kaplan–Meier and multivariable Cox models adjusted for GAP stage. Incremental prognostic value beyond the GAP index was evaluated using Harrell’s C-index and time-dependent ROC analysis. Results: During a median follow-up of 29 months, 134 patients (63.5%) died. Lower HDL levels were associated with increased mortality in unadjusted analysis (HR = 1.45, 95% CI 1.03–2.04) but were not independently predictive after adjustment. In contrast, the combined HDL–BMI phenotype independently stratified mortality risk. Compared with HDL ≤ 1.0 mmol/L and BMI ≤ 24 kg/m2, patients with HDL > 1.0 mmol/L and BMI > 24 kg/m2 had significantly lower mortality (adjusted HR = 0.48, 95% CI 0.29–0.80), with stronger associations among those aged ≥ 65 years (adjusted HR = 0.37, 95% CI 0.18–0.74). The addition of HDL–BMI improved discrimination beyond GAP (C-index: 0.585 vs. 0.618; 36-month AUC: 0.633 vs. 0.675; NRI: 0.243). Conclusions: The coexistence of HDL ≤ 1.0 mmol/L and BMI ≤ 24 kg/m2 identified a subgroup with poorer survival in IPF. This combined metabolic–nutritional phenotype improved mortality risk stratification beyond the GAP stage. Full article
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18 pages, 1249 KB  
Article
Effects of Passiflora edulis Leaf Extract on Lipid Accumulation in HepG2 Cells: In Vitro Evidence and Molecular Docking Analysis Involving PPARα and SREBP-1
by Johanny Aguillón Osma, Juan Sebastián León Villarreal and Nelsy Loango Chamorro
Int. J. Mol. Sci. 2026, 27(7), 3003; https://doi.org/10.3390/ijms27073003 - 26 Mar 2026
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipid accumulation and represents a major global health concern. Passiflora edulis contains numerous phytochemicals associated with diverse biological activities, including hepatoprotective and hypolipidemic effects. This study evaluated the effects of the ethanolic extract [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipid accumulation and represents a major global health concern. Passiflora edulis contains numerous phytochemicals associated with diverse biological activities, including hepatoprotective and hypolipidemic effects. This study evaluated the effects of the ethanolic extract of P. edulis leaves on lipid accumulation in a cellular model of NAFLD, as well as its potential effect on transcriptional factors involved in lipid metabolism. HepG2 cells were exposed to steatogenic conditions and treated with the extract at non-cytotoxic concentrations, quantifying intracellular and extracellular triglycerides and cholesterol levels. Additionally, molecular docking analyses were performed to evaluate the interaction of reported P. edulis phytochemicals with PPARα and SREBP-1. The results revealed a significant reduction in intracellular lipid content compared to untreated cells, while molecular docking predicted favorable binding interactions between the bioactive compounds in the extract, with higher predicted affinity for PPARα (agonist-like interaction) than for SREBP-1c (antagonist-like interaction). These findings suggest that compounds from P. edulis leaves reduce lipid accumulation in liver cells and provide preliminary evidence supporting possible interactions with lipid-regulating transcription factors. Full article
(This article belongs to the Special Issue Pharmacological Effects of Bioactive Compounds Derived from Plants)
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19 pages, 716 KB  
Article
Trends in HDL Cholesterol and Their Association with Dietary Carbohydrate Reduction Among Korean Adults: A Serial Cross-Sectional Trend Analysis Using KNHANES 2014–2023
by Myung-Gwan Kim and Hyun Wook Han
Nutrients 2026, 18(7), 1045; https://doi.org/10.3390/nu18071045 - 25 Mar 2026
Abstract
Purpose: Low HDL cholesterol (HDL-C) is a common lipid abnormality among East Asian populations, including Koreans, and is closely associated with increased cardiovascular disease risk. This has traditionally been linked to high-carbohydrate dietary patterns. Therefore, it is essential to assess how recent changes [...] Read more.
Purpose: Low HDL cholesterol (HDL-C) is a common lipid abnormality among East Asian populations, including Koreans, and is closely associated with increased cardiovascular disease risk. This has traditionally been linked to high-carbohydrate dietary patterns. Therefore, it is essential to assess how recent changes in dietary and lifestyle habits in Korea have influenced HDL-C levels. Methods: This study utilized data from the Korea National Health and Nutrition Examination Survey (KNHANES), conducted from 2014 to 2023. Using a complex sampling method, we analyzed annual trends in carbohydrate intake and HDL-C levels in Korean adults (aged 20–59 years), stratified by gender (male and female) and age (20–39 and 40–59 years), and identified determinants such as demographic factors, health behaviors, and dietary intake. Results: The primary factor in the increase in HDL-C levels was a reduction in carbohydrate intake. When analyzed by age and gender, this significant upward trend in HDL-C levels was consistently observed across all four groups: young men, middle-aged men, young women, and middle-aged women. However, the increase in obesity, indicated by increased BMI and waist circumference, had a negative impact on the improvement in HDL-C levels. The recent improvement in HDL-C levels in Korean adults can be attributed to the successful national dietary policy (reducing carbohydrate intake and increasing healthy fat intake). Conclusions: Public health policies should thus continue emphasizing healthy dietary practices, strengthening smoking cessation initiatives, and managing obesity. These findings suggest similar dietary and lifestyle interventions could effectively reduce cardiovascular disease risk in other Asian populations undergoing comparable dietary transitions. Full article
(This article belongs to the Special Issue Diet and Nutrition: Metabolic Diseases (2nd Edition))
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17 pages, 1131 KB  
Article
Circulating Lycopene and β-Carotene Levels Are Inversely Associated with Carotid Intima–Media Thickness: A Systematic Review and Meta-Analysis
by Iván Cavero-Redondo, Alicia Saz-Lara, Andrea Del Saz-Lara, Óscar Martínez-Cifuentes, Iris Otero-Luis, Ana González-Collado and Juan Pablo Rey-López
Nutrients 2026, 18(7), 1043; https://doi.org/10.3390/nu18071043 - 25 Mar 2026
Abstract
Background: Carotid intima-media thickness (IMT) is a well-established surrogate marker of subclinical atherosclerosis and a predictor of cardiovascular risk. Carotenoids, particularly lycopene and β-carotene, have been proposed as protective antioxidants against vascular damage, but evidence from population-based studies is inconsistent. Objective: [...] Read more.
Background: Carotid intima-media thickness (IMT) is a well-established surrogate marker of subclinical atherosclerosis and a predictor of cardiovascular risk. Carotenoids, particularly lycopene and β-carotene, have been proposed as protective antioxidants against vascular damage, but evidence from population-based studies is inconsistent. Objective: We aim to perform a systematic review and meta-analysis of the associations between circulating levels of lycopene and β-carotene and carotid IMT in the general adult population, including potential sex-specific effects. Methods: A systematic search was conducted in PubMed, Scopus, and Web of Science up to March 2025, following PRISMA guidelines (PROSPERO registration: CRD420251003810). Observational and experimental studies reporting cross-sectional associations between plasma carotenoids and IMT were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated via random effects models. Subgroup and meta-regression analyses explored potential modifiers, including sex and cardiovascular risk factors. Results: Thirteen studies (n = 9131; mean age 46.4–71.6 years) met the inclusion criteria, eight of which were eligible for meta-analysis. High circulating lycopene levels were significantly associated with low IMT (pooled OR = 0.70; 95% CI: 0.59–0.84; I2 = 65.7%). The association was stronger in men (OR = 0.62; 95% CI: 0.45–0.84) than in women (OR = 0.74; 95% CI: 0.58–0.95). In contrast, β-carotene was only marginally associated with IMT (pooled OR = 0.96; 95% CI: 0.92–0.99; I2 = 72.6%). Meta-regression suggested that systolic blood pressure modified the lycopene-IMT relationship, whereas body mass index and low-density lipoprotein cholesterol influenced the β-carotene-IMT association. No evidence of publication bias was found. Conclusions: Increased serum lycopene concentrations, and to a lesser extent β-carotene concentrations, are inversely associated with carotid IMT, suggesting a protective role of lycopene in vascular health. The effect appears more pronounced in men, highlighting potential sex-specific differences in carotenoid metabolism and cardiovascular risk modulation. Full article
(This article belongs to the Section Micronutrients and Human Health)
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17 pages, 1729 KB  
Article
Impact of Dyslipidemia on Allogeneic Transplantation Outcomes and Cardiovascular Mortality in Patients with Acute Leukemias in the Post-Transplant Cyclophosphamide Era
by Sema Seçilmiş, Burcu Aslan Candır, Uğur Hatipoğlu, Mert Seyhan, Bahar Uncu Ulu, Tuğçe Nur Yiğenoğlu, Dicle İskender, Merih Kızıl Çakar, Turgay Ulaş, Mehmet Sinan Dal and Fevzi Altuntaş
Pharmaceuticals 2026, 19(4), 529; https://doi.org/10.3390/ph19040529 - 25 Mar 2026
Abstract
Background/Objectives: Allogeneic hematopoietic stem cell transplantation is associated with increased cardiovascular risk driven by endothelial dysfunction, chronic inflammation, and treatment-related metabolic disturbances, including dyslipidemia. In the contemporary era of post-transplant cyclophosphamide-based prophylaxis, the prognostic significance of dyslipidemia—particularly as assessed by non-HDL cholesterol—remains [...] Read more.
Background/Objectives: Allogeneic hematopoietic stem cell transplantation is associated with increased cardiovascular risk driven by endothelial dysfunction, chronic inflammation, and treatment-related metabolic disturbances, including dyslipidemia. In the contemporary era of post-transplant cyclophosphamide-based prophylaxis, the prognostic significance of dyslipidemia—particularly as assessed by non-HDL cholesterol—remains unclear. In this study, we aimed to compare the engraftment days, graft-versus-host disease (GVHD) development, relapse, overall survival rates, and cardiovascular mortality in patients using myeloablative/reduced intensity conditioning regimens with post-transplant cyclophosphamide (PTCy) 50 mg/kg/day for 2 days in patients with acute leukemias. Methods: A total of 95 adult patients with acute leukemias were included in their first remission who underwent matched sibling donor transplantation with PTCy (50 mg/kg on days +3 and +4). Patients were stratified according to pre-transplant non-HDL-C levels (<160 mg/dL vs. ≥160 mg/dL). Matched related donors were selected for the patients. All patients received either myeloablative or reduced-intensity conditioning based on EBMT criteria, with fludarabine-based combinations including busulfan, treosulfan, or TBI, along with ATLG administered at a total dose of 15 mg/kg. Peripheral blood stem cells were used for all transplants, and GVHD prophylaxis consisted of cyclosporine. Results: Platelet (median 13 vs. 14 days) and neutrophil (median 14 vs. 15 days) engraftment times and veno-occlusive disease (VOD) rates were comparable across groups (all p > 0.05); cumulative incidences of grade II–IV aGVHD at +100 days, grade III–IV aGVHD at +100 days, and moderate-severe cGVHD at 1 year, relapse-free survival, and non-relapse mortality at 1 year were comparable in two cohorts (all p > 0.05). GVHD-free/relapse-free survival (GRFS) at 1 year was also comparable across groups (p = 0.15). Median GRFS was 150 (95% CI: 120–330) days and 270 (95% CI: 154-not reached) days, respectively [HR was 0.68 (0.40–1.15), p = 0.15; GRFS at 1 year was 66.6% vs. 52.0%, respectively]. The groups were also comparable in terms of overall survival (OS). Follow-up ranged from 0.5 to 108 months, and median follow-up was 60 months in two cohorts. Median OS was not reached in non-HDL-C < 160 (95% CI: 70 months–not reached) and 67 months in non-HDL-C ≥ 160 groups (95% CI: 13 months–not reached) (Log rank = 0.21). No cardiovascular death events occurred during the follow-up period. Conclusions: In this homogeneous matched sibling donor transplant cohort with extended follow-up and uniform administration of post-transplant cyclophosphamide, cyclosporine-based GVHD prophylaxis, and anti-thymocyte lymphoglobulin (ATLG), pre-existing dyslipidemia was not associated with an adverse impact on GRFS, NRM, PFS, CMV reactivation, OS or long-term cardiovascular mortality. Full article
(This article belongs to the Section Medicinal Chemistry)
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20 pages, 9217 KB  
Article
Pleuromutilins Suppress Hepatocellular Carcinoma Growth via ABCA1 Inhibition-Induced Cholesterol Accumulation
by Mingshan Zhou, Jie Cao, Junfei Chen, Bohan Zhang, Jiawen Wu, Xiaofeng Lian, Miaoxin Zhu, Peifeng Liu and Min Zhou
Cancers 2026, 18(7), 1054; https://doi.org/10.3390/cancers18071054 (registering DOI) - 24 Mar 2026
Abstract
Bcakground: Hepatocellular carcinoma (HCC) is a prevalent malignancy with limited therapeutic options. Drug repurposing offers an attractive strategy to accelerate anticancer discovery. The pleuromutilin class of antibiotics, including the human-approved agent lefamulin and the veterinary drug tiamulin, has shown preliminary anticancer potential, but [...] Read more.
Bcakground: Hepatocellular carcinoma (HCC) is a prevalent malignancy with limited therapeutic options. Drug repurposing offers an attractive strategy to accelerate anticancer discovery. The pleuromutilin class of antibiotics, including the human-approved agent lefamulin and the veterinary drug tiamulin, has shown preliminary anticancer potential, but its efficacy and mechanism in HCC remain unexplored. Methods: The anti-tumor effects of lefamulin and tiamulin were evaluated in HCC cell lines, patient-derived organoids, and a C57BL/6 mouse subcutaneous tumor model. Safety was assessed in a human normal hepatocyte cell line and by histopathological examination of major organs in treated mice. Mechanistic investigations were performed using RNA-sequencing, RT-qPCR, immunohistochemistry (IHC), filipin staining, pharmacological rescue assays, and shRNA-mediated gene silencing. Results: In this study, we found that both lefamulin and tiamulin markedly inhibited HCC cell proliferation in vitro and significantly suppressed tumor growth in vivo (lefamulin vs. control, p = 0.014; tiamulin vs. control, p = 0.021), without causing significant toxicity. RNA-sequencing analysis revealed consistent downregulation of the cholesterol transporter Abca1 (ATP-binding cassette transporter A1) and alterations in cell adhesion molecule pathways. Functional studies confirmed that treatment reduced ABCA1 protein levels, leading to intracellular cholesterol accumulation and aberrant distribution. Furthermore, treated tumors exhibited a significant increase in CD8+ T-cell infiltration, with CD4+ T cells and macrophage infiltration remained unchanged, indicating a specific modulation of the tumor immune microenvironment. Conclusions: These findings suggest that lefamulin and tiamulin are promising therapeutic candidates for HCC. Full article
(This article belongs to the Special Issue Research and Treatment of Hepatocellular Carcinoma)
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18 pages, 825 KB  
Article
Changes in Cardiometabolic Risk Factors and Ischaemic Heart Disease Mortality Between 2000 and 2015: A Global Ecological Analysis
by Hyemi Lee, Jang-Hun Jeong, Sang-Chul Kim, Yong-Dae Kim and Sang-Yong Eom
Medicina 2026, 62(4), 617; https://doi.org/10.3390/medicina62040617 (registering DOI) - 24 Mar 2026
Abstract
Background and Objectives: To assess whether country-level changes in major cardiometabolic risk factors were associated with concurrent changes in age-standardized death rates (ASDR) from ischaemic heart disease (IHD) and stroke between 2000 and 2015. Materials and Methods: We conducted a multinational [...] Read more.
Background and Objectives: To assess whether country-level changes in major cardiometabolic risk factors were associated with concurrent changes in age-standardized death rates (ASDR) from ischaemic heart disease (IHD) and stroke between 2000 and 2015. Materials and Methods: We conducted a multinational ecological analysis using harmonized data from WHO, NCD-RisC, and the World Bank across 157 countries (n = 157). Absolute changes in systolic blood pressure, obesity, diabetes, and total cholesterol were standardized to z-scores. Linear regression models examined change–change associations, adjusting for income group and behavioral factors. Income-stratified and quartile-based analyses were performed. Results: Between 2000 and 2015, IHD and stroke mortality declined, while obesity and diabetes increased. In adjusted models, change in total cholesterol showed the most consistent association with change in IHD ASDR (β = 13.09, 95% CIs = 4.58–21.60, p = 0.003), whereas the other risk factors did not show consistent independent associations. Significant associations were confined to high- and upper middle-income countries, where change in total cholesterol was associated with IHD mortality. Conclusions: Changes in total cholesterol showed the most consistent correspondence with concurrent changes in IHD mortality at the country level, whereas other cardiometabolic risk factors showed less consistent patterns. These patterns were observed mainly in high- and upper–middle-income countries, suggesting heterogeneity by socioeconomic context. Full article
(This article belongs to the Section Epidemiology & Public Health)
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24 pages, 1043 KB  
Article
Rationale, Design, and Participant Baseline Characteristics of a Parallel Randomized Trial of the Effect of Replacing SSBs with Cow’s Milk Versus Soymilk on Intrahepatocellular Lipid and Other Cardiometabolic Risk Factors in Adults with Obesity Who Consume Sugar-Sweetened Beverages: The Soy Treatment Evaluation for Metabolic health (STEM) Trial
by Madeline N. Erlich, Diana Ghidanac, Sonia Blanco Mejia, Sabrina Ayoub-Charette, Claudia Vittes Combe, Tauseef A. Khan, Devina Ramdath, Heather Crewson, Amanda Beck, Constança Silva, D. Dan Ramdath, Adam H. Metherel, Lawrence A. Leiter, Richard P. Bazinet, Cyril W. C. Kendall, David J. A. Jenkins, Laura Chiavaroli and John L. Sievenpiper
Nutrients 2026, 18(7), 1026; https://doi.org/10.3390/nu18071026 - 24 Mar 2026
Abstract
Background/Objectives: Liver fat represents an early metabolic lesion in the development of diabetes and its cardiometabolic complications. Diets high in free sugars, particularly from sugar-sweetened beverages (SSBs), are associated with abdominal obesity and increased cardiometabolic risk, prompting global guidelines to limit SSBs [...] Read more.
Background/Objectives: Liver fat represents an early metabolic lesion in the development of diabetes and its cardiometabolic complications. Diets high in free sugars, particularly from sugar-sweetened beverages (SSBs), are associated with abdominal obesity and increased cardiometabolic risk, prompting global guidelines to limit SSBs as a major public health strategy. Low-fat cow’s milk is promoted as the preferred caloric replacement strategy for SSBs due to its high nutritional value and cardiometabolic advantages. Fortified soymilk is a plant-based alternative with approved health claims for cholesterol and coronary heart disease risk reduction that offers an equivalent nutritional value to cow’s milk. However, given concerns about its classification as an ultra-processed food (UPF), it is unclear whether soymilk offers comparable metabolic health benefits to milk as part of clinical and public health strategies to reduce SSB intake. The Soy Treatment Evaluation for Metabolic (STEM) health trial seeks to evaluate the impact of replacing SSBs with either 2% soymilk or 2% cow’s milk on liver fat and other cardiometabolic risk factors in habitual adult consumers of SSBs with obesity. Methods: The STEM trial is a 24-week, pragmatic, 3-arm, parallel, randomized trial. We recruited adults with obesity (high BMI plus high waist circumference based on ethnic specific cut-offs) consuming ≥1 SSB/day. Participants were randomized to one of three groups based on their usual SSB intake at baseline (servings/day): continued SSB (355 mL can) intake; replacement with fortified, sweetened 2% soymilk (250 mL); or replacement with 2% cow’s milk (250 mL). The primary outcome is the change in intrahepatocellular lipid (IHCL) measured by 1H-MRS at 24 weeks. Hierarchical testing will be done to reduce the familywise error rate. The superiority of cow’s milk to SSBs will be assessed first to establish assay sensitivity. If superiority is established, then the non-inferiority of soymilk to cow’s milk will be assessed using a pre-specified non-inferiority margin of 1.5% IHCL units (assessed by difference of means using a 90% confidence interval [CI]). Analyses will be conducted according to the intention-to-treat (ITT) principle using inverse probability weighting (IPW) for superiority testing and per-protocol analyses for non-inferiority testing, using ANCOVA adjusted for age, sex, metabolic dysfunction-associated steatotic liver disease (MASLD) status, medication use, intervention dose, and baseline levels. We hypothesize that soymilk will be non-inferior to cow’s milk (Clinicaltrials.gov NCT05191160). Results: Recruitment began in November 2021. A total of 3050 individuals were screened. We randomized 186 participants (62 per group) between 19 April 2022 and 16 April 2024. Participants are 57% male; with a mean [SD] age of 39.9 [11.8] years; BMI of 34.6 [6.1] kg/m2, waist circumference of 112.6 [13.8] cm; IHCL of 10.0 [8.2] % with 64.1% meeting the criteria for MASLD; and SSBs intake of 2.3 [1.3] servings/day. Conclusions: Baseline characteristics were balanced across the study arms, with participants representing adults with a high-risk metabolic phenotype, and 64.1% meeting the criteria for MASLD. Findings will contribute to evidence on the cardiometabolic benefits of soymilk, informing clinical practice guidelines and public health policy. Full article
(This article belongs to the Special Issue Dietary Patterns, Lipid Metabolism and Fatty Liver Disease)
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20 pages, 4550 KB  
Article
AS1411-Bivalent-Cholesterol-Anchor Equipped with Zinc Phthalocya-Nine Enables NK Cells Derived Exosomes to Realize Effective Tumor-Tropism Photodynamic Therapy
by Yuchen Qi, Haoran Jiang, Yuying Zhang, Zhe Wang, Qianqian Wu, Hua Yu, Boning Xia and Jianjun Li
Pharmaceutics 2026, 18(4), 401; https://doi.org/10.3390/pharmaceutics18040401 - 24 Mar 2026
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Abstract
Background/Objectives: Benefiting from their outstanding tumor-penetrating ability and cytotoxic proteins and cytokines, natural-killer-cell-derived exosomes (NEX) show great potential for cell-free tumor immunotherapy. To meet the clinical tumor therapeutic need, engineered NEX are highly required to further enhance their tumor-tropism and antitumor abilities. [...] Read more.
Background/Objectives: Benefiting from their outstanding tumor-penetrating ability and cytotoxic proteins and cytokines, natural-killer-cell-derived exosomes (NEX) show great potential for cell-free tumor immunotherapy. To meet the clinical tumor therapeutic need, engineered NEX are highly required to further enhance their tumor-tropism and antitumor abilities. Methods: We proposed a NEX engineering strategy, using a structure of AS1411-bivalent-cholesterol (B-Chol) anchor equipped with photosensitizer zinc phthalocyanine (ZnPc) attached on the membrane of NEX to form A-P-NEX. It not only preferably maintains the spatial structure of the AS1411 aptamer via a B-Chol anchor contributing to the tumor-tropism and stability of NEX but also significantly improves the photodynamic therapy (PDT) effect by firmly binding ZnPc in the unique G-quadruplex structure in the AS1411 aptamer. Results: The results showed that A-P-NEX could promote the precise uptake of NEX and ZnPc by tumor cells and produce obvious synergistic NEX-based immunotherapy and PDT upon laser irradiation, demonstrating excellent targeted antitumor effects both in vitro and in vivo. Conclusions: This study demonstrates a reliable NEX engineering strategy and paves the way for developing a useful tumor-tropism PDT method. Full article
(This article belongs to the Section Drug Targeting and Design)
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19 pages, 1511 KB  
Article
Inflammatory, Nutritional, and Atherogenic Profiles Associated with Histologic Activity in Inflammatory Bowel Disease
by Dilek Ayvaz and Muammer Bilici
Biomedicines 2026, 14(4), 740; https://doi.org/10.3390/biomedicines14040740 (registering DOI) - 24 Mar 2026
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Abstract
Background/Objectives: Histologic remission has emerged as a key treatment target in inflammatory bowel disease (IBD), but routine assessment requires repeated endoscopy and biopsies. Blood-based indices reflecting inflammation, nutritional status and atherogenic risk are inexpensive and widely available, yet their integrated contribution to [...] Read more.
Background/Objectives: Histologic remission has emerged as a key treatment target in inflammatory bowel disease (IBD), but routine assessment requires repeated endoscopy and biopsies. Blood-based indices reflecting inflammation, nutritional status and atherogenic risk are inexpensive and widely available, yet their integrated contribution to histologic activity remains unclear. This study addresses this gap by simultaneously analyzing a broad panel of 44 variables—including nutritional status indicators, CBC-derived inflammation indices, and atherogenic lipid indices—in IBD patients. Methods: In this retrospective study, 100 patients with IBD (50 Crohn’s disease [CD], 50 ulcerative colitis [UC]) without additional comorbidities and with concomitant histologic assessment were analyzed. Histologic activity was coded as active vs. remission. At the time of biopsy, the complete blood count, biochemistry and lipid profile were used to calculate immuno-nutritional indices (CONUT score, prognostic nutritional index), inflammatory indices (neutrophil-to-platelet ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio [LMR], systemic immune-inflammation index, systemic immune-inflammation index, systemic inflammation response index [SIRI], aggregate index of systemic inflammation, C-reactive protein to albumin ratio) and atherogenic indices (atherogenic index of plasma [AIP], triglyceride-to-HDL cholesterol ratio). Variable selection was performed separately for CD and UC using least absolute shrinkage and selection operator (LASSO) regression and sparse partial least squares discriminant analysis (sPLS-DA). Independently associated predictors were then entered into multivariable logistic regression models, and their discriminative performance was evaluated using ROC analysis with bootstrap-derived 95% confidence intervals. Results: LASSO analysis identified a broadly similar systemic profile associated with histologic activity in CD and UC, dominated by the CONUT score, SIRI, AIP, LMR and red blood cell parameters, whereas demographic features and most routine biochemical markers were shrunk towards zero. Cross-validated AUCs for the LASSO models were 0.93 in CD and 0.87 in UC. sPLS-DA confirmed this pattern: CONUT, SIRI and AIP consistently showed the highest variable importance in projection scores and loadings on the first latent component. In multivariable regression, the CONUT score, SIRI and AIP remained independent predictors of histologic activity in CD, while hematocrit, CONUT score, SIRI and AIP were independently associated with histologic activity in UC. In ROC analysis, AUCs for CONUT, SIRI and AIP were 0.81, 0.89 and 0.87 in UC, and 0.72, 0.82 and 0.83 in CD, respectively. Conclusions: Histologic activity in IBD is characterized by a coupled systemic profile in which immuno-nutritional compromise (captured by CONUT) forms the core signal, supplemented by systemic inflammation (SIRI) and atherogenic dyslipidemia (AIP). These readily available blood-based indices may help to approximate histologic disease activity in clinical practice. However, considering that comorbid diseases may affect these indices, the strict exclusion criteria applied in this study may limit the generalizability of the findings among patients with IBD. Consequently, further validation in larger prospective cohorts is warranted. Full article
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18 pages, 872 KB  
Article
Valorization of Kinmen Peanut Skin, an Agro-Industrial By-Product: A Polyphenol- and Phytosterol-Rich Extract with Antioxidant and Hypolipidemic Effects in Hamsters
by Cheng-Pei Chung, Shu-Hsien Tsai, Ying-Jang Lai, Ching-Yun Hsu, Chia-Hsin Chang, Bao-Hong Shi and Ming-Yi Lee
Appl. Sci. 2026, 16(7), 3116; https://doi.org/10.3390/app16073116 - 24 Mar 2026
Viewed by 74
Abstract
Kinmen peanut (Arachis hypogaea L. cultivar Kinmen No. 1) is a unique crop used to produce local specialty “peanut candy”; however, the peanut skins (PSs) are treated as waste owing to the bitter taste. To support the valorization of this agro-industrial by-product, [...] Read more.
Kinmen peanut (Arachis hypogaea L. cultivar Kinmen No. 1) is a unique crop used to produce local specialty “peanut candy”; however, the peanut skins (PSs) are treated as waste owing to the bitter taste. To support the valorization of this agro-industrial by-product, peanut skin ethanolic extract (PSE) was prepared and evaluated for its hypolipidemic potential in a cholesterol/fat-fed hamster model, together with its antioxidant capacity and chemical composition. Hamsters were fed a cholesterol/fat-enriched diet supplemented with PSE at 0.1%, 0.2%, or 0.4% (w/w) for 8 weeks. Serum lipid profiles were determined, and derived atherogenic indices were calculated. In parallel, antioxidant activity was assessed using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and reducing power assays, while chemical characterization included total phenolics, crude phytosterols, and HPLC profiling of representative phenolic compounds. PSE significantly reduced serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) compared with the cholesterol/fat-enriched control, whereas triglycerides were not significantly altered. The LDL-C/HDL-C ratio was also reduced in PSE-treated groups, with the greatest reduction observed in the 0.1% PSE group (0.33 ± 0.04 vs. 0.56 ± 0.12 in the negative control). In addition, PSE exhibited marked antioxidant activity, with IC50 values of 141.3 and 76.2 μg/mL in the DPPH and ABTS assays, respectively. Chemical analyses showed that PS contained 1098 ± 189 µg β-sitosterol equivalents/g PS and 199.3 ± 4.6 mg gallic acid equivalent (GAE)/g PS, and HPLC identified p-coumaric acid, ferulic acid, gallic acid, chlorogenic acid, daidzein, catechin, and resveratrol as representative phenolic constituents. Collectively, these findings support Kinmen peanut skin as a promising value-added source of bioactives for functional ingredient development targeting cholesterol dysregulation and oxidative processes. Full article
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26 pages, 871 KB  
Review
Physiological Regulation of Nutritional and Metabolic Biomarkers in Obesity: Implications for Precision Nutrition
by Girolamo Di Maio, Maria Giovanna Tafuri, Maria Casillo, Antonietta Messina, Salvatore Allocca, Ines Villano, Fiorenzo Moscatelli, Antonietta Monda, Marco La Marra and Vincenzo Monda
Nutrients 2026, 18(6), 1014; https://doi.org/10.3390/nu18061014 - 23 Mar 2026
Viewed by 123
Abstract
Obesity represents a heterogeneous metabolic disorder characterized by substantial interindividual variation in inflammatory status, insulin sensitivity, and cardiometabolic risk. Traditional anthropometric measures fail to capture this metabolic diversity, limiting risk stratification and personalized intervention strategies. This review critically examines nutritional and metabolic biomarkers [...] Read more.
Obesity represents a heterogeneous metabolic disorder characterized by substantial interindividual variation in inflammatory status, insulin sensitivity, and cardiometabolic risk. Traditional anthropometric measures fail to capture this metabolic diversity, limiting risk stratification and personalized intervention strategies. This review critically examines nutritional and metabolic biomarkers that reflect the physiological dysregulation underlying obesity, including adipokines (leptin, adiponectin, resistin), inflammatory markers (C-reactive protein, interleukin-6, TNF-α), insulin resistance indices (HOMA-IR, fasting insulin, HbA1c), and lipid metabolism indicators (LDL cholesterol, triglycerides, HDL cholesterol, and liver enzymes such as ALT and GGT). Among these, elevated CRP, reduced adiponectin, and increased HOMA-IR have demonstrated the strongest clinical utility for early metabolic risk identification. We further evaluate emerging biomarkers—including circulating microRNAs, gut microbiota-derived metabolites (short-chain fatty acids, TMAO, lipopolysaccharides), and bile acid profiles—which offer additional mechanistic insight into diet–microbiome–host interactions. We systematically assess the mechanistic basis, clinical relevance, and nutritional modulation of each biomarker class, emphasizing how dietary composition—particularly fatty acid quality, fiber intake, and overall dietary patterns such as the Mediterranean diet—influences biomarker profiles and metabolic outcomes. Furthermore, we explore how biomarker-based phenotyping enables precision nutrition approaches by identifying individuals most likely to benefit from specific dietary interventions. Integration of multi-biomarker panels with clinical and genetic data holds promise for advancing from population-based dietary guidelines toward individualized nutrition strategies that optimize metabolic health and prevent obesity-related complications. Future research should prioritize validating biomarker-guided intervention frameworks, establishing standardized thresholds across diverse populations, and developing clinically implementable tools for personalized nutritional medicine. Full article
(This article belongs to the Special Issue Nutritional and Metabolic Biomarkers in Obesity)
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26 pages, 3881 KB  
Article
Characterization and Biological Activity of Rutin Extracted from Filipendula ulmaria (L.) Maxim
by Anna Vesnina, Violeta Le, Svetlana Ivanova, Anna Frolova, Irina Milentyeva, Victor Atuchin and Alexander Prosekov
BioTech 2026, 15(1), 25; https://doi.org/10.3390/biotech15010025 - 23 Mar 2026
Viewed by 102
Abstract
In this work, Filipendula ulmaria (L.) Maxim, a perennial herbaceous plant from the Rosaceae family, was considered a novel source of obtaining rutin for pharmaceutical purposes. Rutin was extracted from the plant parts collected in the flowering summer period and dried at 40 [...] Read more.
In this work, Filipendula ulmaria (L.) Maxim, a perennial herbaceous plant from the Rosaceae family, was considered a novel source of obtaining rutin for pharmaceutical purposes. Rutin was extracted from the plant parts collected in the flowering summer period and dried at 40 ± 3 °C. The process was carried out using the ethanol extraction and fractionation of extracted compounds, and it yields the 95 wt% purity crystalline product. The phase composition of the extracted rutin was verified by the XRD analysis and NMR measurements. It was found that 2.85% of rutin could be extracted from Filipendula ulmaria, which is 1.2 times higher than the results of similar studies. The biological activity of the isolated rutin was tested on rats. It was established in vivo that the extracted rutin normalizes blood glucose levels (glucose and glycosylated hemoglobin), insulin resistance (HOMA-IR index) and reduces the severity of dystrophic changes in the liver caused by high-fat and high-carbohydrate diets. The introduction of rutin corrects lipid profile indicators (triglycerides, cholesterol, cholesterol fractions in lipoproteins and atherogenic indices), cytolysis indicators of hepatocytes, and liver steatosis (ALT, AST/ALT, triglycerides). Thus, the novel source of rutin opens the possibility for a wide use of this flavonoid in the food technology and pharmaceutical industry. Full article
(This article belongs to the Section Medical Biotechnology)
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