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Keywords = plasma profiling

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24 pages, 10606 KB  
Article
Phytochemical Characterization and Immunometabolic Modulation by Mangifera indica (Mahajanaka) Pulp Extract in Diabetic and Hypertensive Rat Models
by Wachiraporn Tipsuwan, Hathairat Thananchai, Anusara Pongjanta, Suphatta Yubo, Tawat Taesothikul, Duangta Kanjanapothi, Yanping Zhong and Somdet Srichairatanakool
Int. J. Mol. Sci. 2026, 27(13), 5742; https://doi.org/10.3390/ijms27135742 (registering DOI) - 25 Jun 2026
Abstract
Mango (Mangifera indica L.) pulp contains bioactive compounds with potential therapeutic effects against metabolic and immune-related disorders. However, the integrated effects of mango pulp extract on metabolic, cardiovascular, and immunomodulatory functions remain insufficiently characterized. Therefore, this study aimed to characterize the phytochemical [...] Read more.
Mango (Mangifera indica L.) pulp contains bioactive compounds with potential therapeutic effects against metabolic and immune-related disorders. However, the integrated effects of mango pulp extract on metabolic, cardiovascular, and immunomodulatory functions remain insufficiently characterized. Therefore, this study aimed to characterize the phytochemical composition and evaluate the activity of M. indica (Mahajanaka) pulp ethanolic extract (MPEE) in rat models. Streptozotocin (STZ)-induced diabetic rats and N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats were used to assess metabolic and cardiovascular effects, while immune function was examined through neutrophil phagocytosis, splenocyte proliferation, lymphocyte subpopulation analysis, and cytokine secretion. MPEE exhibited a rich phytochemical profile, particularly phenolic compounds, along with strong antioxidant activity (339 ± 8.9 mg gallic acid equivalent/g extract). In STZ-induced diabetic rats, MPEE at 300 mg/kg significantly reduced plasma triglyceride (36.7%) and total cholesterol (45.3%) levels compared with untreated diabetic controls, although its antihyperglycemic effect was modest (6.8%). In L-NAME-induced hypertensive rats, MPEE at 400 mg/kg produced the greatest reduction in blood pressure (42.7%) and heart rate (53.5%). Furthermore, MPEE enhanced neutrophil phagocytic activity (43%), with significant increases observed at doses of 100–400 mg/kg. These findings indicate that MPEE exerts antioxidant, hypolipidemic, antihypertensive, and innate immunostimulatory activities. Full article
(This article belongs to the Special Issue Recent Advances in Bioactive Compounds in Human Health)
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26 pages, 1030 KB  
Article
Low-Pass Nanopore Sequencing of Plasma cfDNA Reveals Fragmentomic, Epigenomic, and Age-Associated Signatures Under Ultra-Low-Coverage Conditions
by Andrey Eremin, Alexander Sergeev, Tsimur Hasanau and Maria Zvereva
Int. J. Mol. Sci. 2026, 27(13), 5739; https://doi.org/10.3390/ijms27135739 (registering DOI) - 25 Jun 2026
Abstract
Circulating cell-free DNA (cfDNA) enables minimally invasive assessment of chromatin organization and DNA modifications. Whether such information can be reliably recovered under conditions of limited plasma input (below 1 mL) and ultra-low sequencing depth remains unclear. We performed low-pass whole-genome Oxford Nanopore sequencing [...] Read more.
Circulating cell-free DNA (cfDNA) enables minimally invasive assessment of chromatin organization and DNA modifications. Whether such information can be reliably recovered under conditions of limited plasma input (below 1 mL) and ultra-low sequencing depth remains unclear. We performed low-pass whole-genome Oxford Nanopore sequencing (down to 0.01× coverage) of plasma cfDNA from young and elderly donors and jointly analyzed fragment length distributions and base modifications (5mC, 5hmC, 6mA). In parallel, we analyzed an enzymatically fragmented model DNA system to assess whether controlled in vitro fragmentation can reproduce cfDNA-like nucleosomal profiles and associated modification patterns. Despite shallow coverage, cfDNA samples displayed reproducible mono-, di-, tri-, and tetra-nucleosomal peaks, indicating that major fragmentomic features can be retained under ultra-low-coverage conditions. Modification-aware basecalling enabled exploratory quantification of global modification fractions across nucleosomal size classes and nomination of candidate group-specific modification loci. Overall, these results support the feasibility of low-pass nanopore sequencing as an exploratory framework for simultaneous cfDNA fragmentomic and epigenomic profiling in low-input studies. Full article
(This article belongs to the Special Issue Advances in Next-Generation Sequencing for Aging and Cancer Research)
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23 pages, 2329 KB  
Article
Semen Quality in a Large Cohort of Males Living in Highly Polluted Areas of Campania Region in Southern Italy with a Focus on the Role of Cadmium Exposure
by Cristina de Angelis, Francesco Garifalos, Davide Menafra, Paolo Chiodini, Giacomo Galdiero, Mariangela Piscopo, Tonia Romano, Nunzia Verde, Antonella Giarra, Marco Trifuoggi, Erminio Massimo Crescenzo, Chiara Simeoli, Mariarosaria Negri, Claudia Pivonello, Annamaria Colao and Rosario Pivonello
J. Clin. Med. 2026, 15(13), 4949; https://doi.org/10.3390/jcm15134949 (registering DOI) - 25 Jun 2026
Abstract
Background/Objectives: The “Land of Fires” (LF) in the Campania Region has attracted considerable attention due to massive environmental contamination deriving from decades of illegal disposal, burial, and burning of urban, industrial, and toxic waste. Cadmium (Cd) has been repeatedly proven to affect male [...] Read more.
Background/Objectives: The “Land of Fires” (LF) in the Campania Region has attracted considerable attention due to massive environmental contamination deriving from decades of illegal disposal, burial, and burning of urban, industrial, and toxic waste. Cadmium (Cd) has been repeatedly proven to affect male reproductive function by a plethora of endocrine and non-endocrine mechanisms. The scientific literature is almost devoid of large studies addressing semen quality in this area, particularly by directly correlating seminal parameters to objectively measured pollutant burden in biological samples. Therefore, the aim of the current study was to comprehensively evaluate semen quality of males of reproductive age living in the LF, by correlating seminal parameters to cumulative local male reproductive tract Cd burden objectively quantified in whole semen samples. Methods: The current single-center, observational, cross-sectional study evaluated semen quality in 493 males aged 14–50 (29.07 ± 7.17) years living in three LF municipalities. Moreover, the association of semen quality with whole semen Cd (sCd) levels measured by inductively coupled plasma mass spectrometry (ICP-MS) was addressed in a subgroup of participants; semen samples suitable for semen Cd measurements were available from 383/493 (77.7%) participants of the total cohort, and all analyses involving semen Cd were performed within the measured subset. Results: In the total cohort, seminal parameters were as follows: semen pH 8.32 ± 0.3, semen volume 3.13 ± 1.67 mL, sperm concentration 37.58 ± 30.18 × 106/mL, total count 111.2 ± 104 × 106/ejaculate, total motility 56.83 ± 16.09%, progressive motility 50.22 ± 16.63%, in situ motility 6.72 ± 3.43%, immotile spermatozoa 43.07 ± 15.88%, normal morphology 7.97 ± 4.02%, and viability 64.75 ± 15.34%. Prevalence of normozoospermia and pathological seminal parameters was as follows: normozoospermia 66.5% (328/493), pathological seminal parameters 33.5% (165/493), specifically, oligozoospermia 14% (69/493), cryptozoospermia 0.8% (4/493), azoospermia 2.2% (11/493), asthenozoospermia 3% (15/493), teratozoospermia 0.6% (3/493), oligo-astheno-teratozoospermia 6.1% (30/493), necrozoospermia 5.7% (28/493), and different combined seminal parameters alterations 7.1% (35/493). Whole semen Cd was below (undetectable) or above (detectable) the limit of detection (LoD) (0.2 μg/L) in 66.6% (255/383) and 33.4% (128/383) whole semen samples, respectively. In samples with detectable sCd, sCd level was below or above the median value (0.76 μg/L; min–max 0.1–5.95 μg/L) in 23.4% (30/128) and 76.6% (98/128) whole semen samples, respectively. Participants with detectable sCd levels had a significantly reduced sperm total count (93.28 ± 84.88 × 106/ejaculate vs. 113.2 ± 101.5 × 106/ejaculate; p = 0.037), and normal morphology (7.29 ± 3.71% vs. 8.23 ± 3.91%; p = 0.034), and a significantly lower prevalence of normozoospermia (60.2% vs. 72.2%; p = 0.02) and significantly higher prevalence of pathological seminal parameters (39.8% vs. 27.8%; p = 0.02), specifically, a significantly higher prevalence of oligozoospermia (21.1% vs. 12.6%; p = 0.036) than those with undetectable sCd levels. Whole semen Cd levels were significantly higher in participants with pathological seminal parameters (1.08 ± 0.84 μg/L vs. 0.93 ± 0.74 μg/L; p = 0.037) than those with normozoospermia. Participants with sCd levels above the median value (N = 98) had a significantly reduced sperm concentration (29.12 ± 24.84 × 106/mL vs. 43.62 ± 29.55 × 106/mL; p = 0.015) and displayed a trend towards reduced sperm normal morphology (6.92 ± 3.38% vs. 8.55 ± 4.49%; p = 0.057) than those with sCd levels below the median value (N = 30). Moreover, participants with sCd levels above the median value (N = 98) had a significantly reduced sperm concentration (29.12 ± 24.84 × 106/mL vs. 35.3 ± 26.29 × 106/mL; p = 0.03), total count (85.77 ± 80.52 × 106/ejaculate vs. 113.2 ± 101.5 × 106/ejaculate; p = 0.008) and normal morphology (6.92 ± 3.38% vs. 8.23 ± 3.91%; p = 0.006), and a significantly lower prevalence of normozoospermia (57.1% vs. 72.2%; p = 0.008) and significantly higher prevalence of pathological seminal (42.9% vs. 27.8%; p = 0.008), specifically, a significantly higher prevalence of oligozoospermia (23.5% vs. 12.6%; p = 0.014) than those with undetectable sCd levels. Conclusions: The results of the current study demonstrate an association between the environmental Cd exposure and the impairment of seminal parameters, with a significantly poorer semen quality in participants with detectable sCd, and, more markedly, in those with sCd level above the median value, compared to participants with undetectable sCd, although subgroups comparisons highlighted a homogeneous profile in major confounders including age, BMI, and smoking habits among subgroups of participants with different sCd burden. Full article
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13 pages, 4970 KB  
Article
Non-Canonical Binding of Nelfinavir in HIV-1 Protease Variants Reveals Structural Mechanisms of Antiretroviral Resistance
by Christian Cadena-Cruz, Marcio De Avila-Arias, Fabio Guzmán, Mariana Pérez, María Angelica Zuluaga, Elkin Navarro Quiroz, Alejandro Angulo, Luz Elena Prieto Garcerant, Hector Rodríguez Rojas, Dinno Alberto Fernández Chica, Guillermo Cervantes and Jose Luis Villarreal-Camacho
Viruses 2026, 18(7), 701; https://doi.org/10.3390/v18070701 (registering DOI) - 25 Jun 2026
Abstract
Background: Antiretroviral resistance-associated mutations, within the broader context of HIV-1 genetic variability, represent a growing challenge for HIV-1 control, highlighting the need for continuous molecular surveillance and mechanistic understanding of drug resistance. This study aimed to characterize mutations in the pol gene associated [...] Read more.
Background: Antiretroviral resistance-associated mutations, within the broader context of HIV-1 genetic variability, represent a growing challenge for HIV-1 control, highlighting the need for continuous molecular surveillance and mechanistic understanding of drug resistance. This study aimed to characterize mutations in the pol gene associated with resistance to protease inhibitors and to explore their structural implications. Methods: Viral RNA was extracted from plasma samples of HIV-positive patients, and a 266 bp fragment of the HIV-1 pol gene was amplified by RT-PCR and sequenced using the Sanger method. Sequences showing ≥98% homology were aligned and analyzed using MEGA v11 and the Stanford HIV Drug Resistance Database to identify resistance-associated mutations, while viral subtypes were determined using COMET, jpHMM-HIV, and STAR tools. Amino acid sequences were used for structural modeling with AlphaFold, followed by molecular docking with Nelfinavir using the CB-Dock2 server. Results: Four samples exhibited resistance-associated profiles, including high-level, intermediate, and low-level resistance, with one isolate showing high-level resistance to multiple protease inhibitors. Structural analyses revealed that Nelfinavir preferentially binds to alternative hydrophobic cavities rather than the canonical catalytic site, lacking direct interactions with the Asp25/Asp25′ dyad. Conclusions: These findings suggest a structural mechanism of resistance based on non-canonical ligand binding that may impair effective protease inhibition. Full article
(This article belongs to the Section General Virology)
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19 pages, 2339 KB  
Article
Identification and Expression Analysis of the Cyclin-Dependent Kinase Inhibitor ICK/KRP Gene Family in Pepper
by Tiantian Li, Qingzhi Cui, Zhuoxuan Wu, Shan Liu, Yanlong Li, Zhuqing Zhang, Wenchao Chen and Sha Yang
Genes 2026, 17(7), 733; https://doi.org/10.3390/genes17070733 (registering DOI) - 25 Jun 2026
Abstract
Background: Cell division plays a crucial role in plant growth and development. Cyclin-dependent kinase inhibitors (ICK/KRP) negatively regulate the cell cycle, thereby affecting cell elongation and organ development. This study aimed to systematically identify and characterize the ICK/ [...] Read more.
Background: Cell division plays a crucial role in plant growth and development. Cyclin-dependent kinase inhibitors (ICK/KRP) negatively regulate the cell cycle, thereby affecting cell elongation and organ development. This study aimed to systematically identify and characterize the ICK/KRP gene family in pepper, and to explore their roles in growth, development, and stress responses. Methods: Bioinformatics approaches were used for genome-wide identification, chromosomal localization, collinearity analysis, sequence characterization, promoter element prediction, and tissue-specific expression profiling of pepper ICK genes. Phylogenetic analysis was performed with homologs from Arabidopsis, tomato, maize, and rice. Quantitative real-time PCR and virus-induced gene silencing (VIGS) were applied to validate gene expression patterns and gene function, respectively. Subcellular localization assays were also conducted. Results: A total of six ICK genes were identified in pepper. They were classified into three subfamilies and distributed on different chromosomes, with one pair showing evidence of duplication. All ICK/KRPs contain the conserved Motif 1 (amino acid sequence: KIPTTREIEEFFATAEKQQQRRFIEKYNFDPVNEKPL) and were predicted to localize to the nucleus. Promoter analysis revealed cis-acting elements associated with plant development, stress responses, and hormone signaling. Expression pattern analysis indicated tissue-specific divergence and significant induction/repression under temperature stress. qRT-PCR results were consistent with transcriptome data, and expression differences were observed in materials with different stigma lengths. Subcellular localization confirmed that Caz03g38750.1 and Caz12g03790.1 proteins localize to both the nucleus and plasma membrane. Silencing of CazICK1 significantly repressed stigma elongation and altered stigma morphogenesis. Conclusions: The six pepper ICK/KRP genes display distinct diversity in distribution, structure and expression, and function in plant growth, development and stress adaptation. This work not only lays a solid basis for exploring the cell cycle regulatory network of pepper and contributes to relevant theoretical research, but it also identifies key gene resources for improving stigma traits. It has great potential for application in molecular breeding to promote high yield and efficient hybrid seed production in pepper. Full article
(This article belongs to the Special Issue Abiotic Stress in Plant: Molecular Genetics and Genomics)
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23 pages, 8418 KB  
Article
Untargeted LC–MS Plasma Metabolomics Reveals Altered Amino Acid and Carbohydrate Metabolism in Dairy Calves Supplemented with Direct-Fed Microbials
by Oludotun O. Adelusi, David P. Casper, John O. Adebayo, Ahmed E. Kholif, Ibukun M. Ogunade and Uchenna Y. Anele
Metabolites 2026, 16(7), 441; https://doi.org/10.3390/metabo16070441 (registering DOI) - 25 Jun 2026
Abstract
Background/Objectives: Direct-fed microbials (DFMs) are widely used in dairy calves to improve gut health and mitigate neonatal disorders, yet their systemic metabolic effects remain poorly defined. This study evaluated the impact of DFM supplementation on the plasma metabolome of pre-weaned dairy calves [...] Read more.
Background/Objectives: Direct-fed microbials (DFMs) are widely used in dairy calves to improve gut health and mitigate neonatal disorders, yet their systemic metabolic effects remain poorly defined. This study evaluated the impact of DFM supplementation on the plasma metabolome of pre-weaned dairy calves using untargeted liquid chromatography–mass spectrometry (LC–MS). Methods: Eighty-six Holstein bull calves (2 to 5 days old) were assigned to one of four treatments in a 2 × 2 factorial randomized complete block design: Lactobacillus plantarum in starter (CLP), a culture mix of Bifidobacterium animalis and Lactobacillus animalis in milk replacer (BBCM), and a combination of both (CMLP), or no supplementation (CON). Blood samples collected on days 0 and 56 were subjected to metabolomic profiling, and metabolites were annotated using Human Metabolome Database and Kyoto Encyclopedia of Genes and Genomes databases. Results: A total of 231 plasma metabolites were detected. Compared with CON, 24 metabolites were differentially abundant in DFM-treated calves (fold change ≥ 1.2 or ≤ 0.83; p ≤ 0.05). Supplemented calves exhibited increased abundances of ketone functional groups, aldehydes and amino acid-related metabolites. Metabolite set enrichment analysis identified 11 significantly enriched pathways. Branched-chain amino acid degradation pathways (valine, leucine, and isoleucine) were enriched in CLP and CMLP calves, whereas carbohydrate metabolism pathways, including pentose and glucuronate interconversions, were enriched in the CLP and BBCM groups. Conclusions: These findings demonstrate that DFM supplementation modulates systemic metabolism in dairy calves, particularly pathways involved in amino acid and carbohydrate utilization, suggesting enhanced metabolic efficiency during early life. Full article
(This article belongs to the Special Issue Metabolic Research in Dairy Cattle Health)
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16 pages, 775 KB  
Article
Increased Mannosylation of Extracellular Vesicles in Long COVID Plasma as a Binding Target for Galanthus nivalis Agglutinin (GNA) Affinity Resin
by Miguel A. Pesqueira Sanchez, Rosalia de Necochea Campion, Thomas Dalhuisen, Emily A. Fehrman, Pahul S. Chhabra, J. Daniel Kelly, Jeffrey N. Martin, Steven G. Deeks, Timothy J. Henrich, Michael J. Peluso and Steven P. LaRosa
Int. J. Mol. Sci. 2026, 27(13), 5723; https://doi.org/10.3390/ijms27135723 (registering DOI) - 25 Jun 2026
Abstract
There is no proven therapy for Long COVID, a post-acute condition characterized by persistent symptoms following SARS-CoV-2 infection. Extracellular vesicles (EVs) are emerging as mediators of disease pathogenesis through their molecular cargo. We investigated whether EV glycosylation is altered in Long COVID plasma [...] Read more.
There is no proven therapy for Long COVID, a post-acute condition characterized by persistent symptoms following SARS-CoV-2 infection. Extracellular vesicles (EVs) are emerging as mediators of disease pathogenesis through their molecular cargo. We investigated whether EV glycosylation is altered in Long COVID plasma and whether these vesicles can be selectively targeted using a glycan-binding affinity resin. Large (100–500 nm) and small (40–200 nm) EVs were isolated from post-acute COVID-19 plasma and analyzed by nanoparticle flow cytometry to assess surface glycosylation. Small EV capture assays were performed using Galanthus nivalis agglutinin (GNA) affinity resin. Plasma miRNA profiles before and after GNA treatment were evaluated using NanoString nCounter analysis, and potential downstream pathway effects were computationally inferred using validated miRNA–mRNA interactions and PROGENy. Mannose-positive large EVs were significantly increased in Long COVID compared to recovered controls (p < 0.05). GNA-mediated small EV capture correlated with mannose-positive EV abundance (r = 0.341, p < 0.05), and seven miRNAs were significantly reduced following treatment. Computational pathway analysis suggested modulation of key signaling pathways, including JAK-STAT, Estrogen, VEGF, and PI3K. These findings suggest a glycan-associated EV signature in Long COVID and support further investigation of lectin-based capture as a potential strategy to target vesicle-associated molecular cargo. Full article
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24 pages, 9034 KB  
Article
High-Dimensional Immunophenotyping of Plasma-Derived Small Extracellular Vesicles in Pancreatic Cancer: An Exploratory Proof-of-Principle Study
by Sabrina Sulzer, Johanna Lisa Becker, Laura Domogalla, Volker Ellenrieder, Matthias Schulz, Markus Maulhardt, Alexander Casimir Angleitner and Judith Büntzel
Biomolecules 2026, 16(7), 942; https://doi.org/10.3390/biom16070942 (registering DOI) - 24 Jun 2026
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is increasingly recognized as a systemic malignancy, characterized by profound alterations in tumor–host interactions. Small extracellular vesicles (sEVs) in peripheral blood may reflect these alterations and represent a promising minimally invasive source of biomarker information. In this proof-of-principle study, [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is increasingly recognized as a systemic malignancy, characterized by profound alterations in tumor–host interactions. Small extracellular vesicles (sEVs) in peripheral blood may reflect these alterations and represent a promising minimally invasive source of biomarker information. In this proof-of-principle study, plasma-derived sEVs from patients with PDAC, healthy controls, and a comparative cohort with neuroendocrine lung cancer (NLC) were isolated by differential ultracentrifugation and characterized by western blotting and nanoparticle tracking analysis. Surface marker profiling was performed using the MACSPlex EV Kit IO, followed by univariate, multivariate, and machine-learning-based analyses. PDAC samples exhibited a distinct sEV immunophenotype with coordinated enrichment of angiogenesis-related markers (including CD105 and CD146), immune-regulatory markers (including CD25 and CD40), the coagulation-related marker CD142 and the invasion-associated marker MCSP. Principal component analysis, hierarchical clustering, and Random Forest classification showed exploratory separation of PDAC patients from healthy controls and NLC, supporting the presence of disease-specific vesicle surface marker patterns. In a very small subset of paired samples, descriptive longitudinal analyses illustrated measurable intra-individual changes during chemotherapy. Plasma sEV immunophenotyping is a technically feasible approach for capturing systemic disease-associated alterations in PDAC and provides a foundation for future biomarker-oriented validation studies. Full article
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17 pages, 2129 KB  
Article
Exploratory LC-MS/MS-Based Proteomic and Lipidomic Profiling of Plasma Samples from Premature Coronary Artery Disease Patients: A Pilot Study in a South Asian Population
by Iftikhar Ali Ch, Zahid Hasan, Zongkai Peng, Kamrul Islam, Amit Singh, Anayat Yousuf, Mohamed S. Aborahma, Ayan S. Zubair, Ali A. Rizvi, Nouraldeen Refai, Mohammad Omer Rana, Azhar A. Chaudhry, Fazal Jalil, Yasir Ali, Waseem Iqbal, Yusra Javed, Mishal Zehra, Tayyab Adeel Afzal, Ankur Kalra, Khurram Nasir, C Michael Gibson, Zhibo Yang and Nagib Ahsanadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2026, 27(13), 5684; https://doi.org/10.3390/ijms27135684 (registering DOI) - 24 Jun 2026
Abstract
Premature coronary artery disease (PCAD) is a growing public health concern, especially in South Asia, where traditional risk factors fail to fully explain the increasing incidence of early-onset myocardial infarction. To explore its molecular underpinnings, we conducted a pilot study analyzing plasma proteins [...] Read more.
Premature coronary artery disease (PCAD) is a growing public health concern, especially in South Asia, where traditional risk factors fail to fully explain the increasing incidence of early-onset myocardial infarction. To explore its molecular underpinnings, we conducted a pilot study analyzing plasma proteins and lipids to identify potential biomarkers and dysregulated pathways associated with PCAD. Label-free quantitative proteomics revealed distinct molecular signatures separating PCAD patients from age- and sex-matched healthy controls. Key alterations included upregulation of GALE, immunoglobulin genes, and KIF20B, suggesting enhanced inflammatory responses and proliferative activity associated with post-myocardial infarction cellular repair. Similarly, down regulations of various proteins linked to multiple functions, such as myocardial infarction, hemoglobinopathy, complement and coagulation cascade, and fatty acid and lipoprotein transport in hepatocytes, were observed. Untargeted lipidomics further revealed significant elevations in several phosphatidylcholine species (PC 42:5, PC 40:3, and PC 42:7), highlighting disruption of highly unsaturated phospholipid metabolism. Overall, these findings indicate that PCAD is a multifactorial disorder involving metabolic, immune, and vascular dysfunction beyond conventional lipid abnormalities, underscoring the need for larger cohort studies to validate these biomarkers and uncover novel therapeutic targets. Full article
(This article belongs to the Special Issue Multi-Omics Platforms for Comprehensive Biological Insights)
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15 pages, 1018 KB  
Article
A Real-World Study on the Effectiveness and Safety of Elacestrant in Patients with ESR1-Mutated Metastatic Breast Cancer Progressing After CDK4/6 Inhibitors and Endocrine Therapy
by Martina Greco, Vittorio Gebbia, Rossana Berardi, Antonella Usset, Giuseppina Ricciardi, Nicla La Verde, Maria Vita Sanò, Federica Martorana, Nicoletta Staropoli, Gianfranco Pernice, Gabriella Bini, Angela Prestifilippo, Francesco Giotta, Domenico Bilancia, Calogero Cipolla, Martina De Luca and Maria Rosaria Valerio
Cancers 2026, 18(13), 2042; https://doi.org/10.3390/cancers18132042 (registering DOI) - 24 Jun 2026
Abstract
Background/Objectives: Advanced hormone receptor-positive (HR+), epidermal growth factor 2-negative (HER2−) breast carcinoma (BC) patients receive frontline therapy with cyclin-dependent tyrosine kinase 4/6 inhibitors + endocrine therapy (ET). At progression, the best management includes mutational analysis for ESR-1, allowing second-line therapy with elacestrant. [...] Read more.
Background/Objectives: Advanced hormone receptor-positive (HR+), epidermal growth factor 2-negative (HER2−) breast carcinoma (BC) patients receive frontline therapy with cyclin-dependent tyrosine kinase 4/6 inhibitors + endocrine therapy (ET). At progression, the best management includes mutational analysis for ESR-1, allowing second-line therapy with elacestrant. The aim of this study was to evaluate the efficacy and safety of elacestrant in an Italian real-world setting. Methods: A multicenter, observational study with a mixed retrospective and prospective design was conducted in 13 medical oncology units across Italy. The study population included adult patients with HR+/HER2− locally advanced or metastatic breast cancer with an activating ESR1 mutation documented by liquid biopsy and progressing after at least one line of endocrine therapy containing a CDK4/6 inhibitor. Mutational analysis of plasma was performed using next-generation sequencing with a multigene panel that included ESR1, PIK3CA, AKT, and PTEN. The sample size was calculated according to the two-stage Simon design. Toxicity was classified according to CTCAE version 5.0 criteria. Survival analyses were conducted using the Kaplan–Meier method. Results: At the time of analysis, 39 evaluable patients were enrolled, all female and Caucasian, with a median age of 67 years (range 41–89). The efficacy analysis documented an overall ORR of 28% and a disease control rate of 56%. The median duration of response was 6+ months (95% CL: 3.5–10.6 m). Median overall survival was not reached with a median follow-up of 10 months. The toxicity profile was overall favorable: grade ≥2 asthenia was the most frequent adverse event (23%), followed by gastrointestinal toxicity, which was generally mild. No treatment-related toxicity was reported in 64% of patients. Dose reductions were necessary in 15% of cases, while permanent treatment discontinuation due to toxicity occurred in only 4%. Conclusions: The results of this Italian multicenter observational study confirm the efficacy and tolerability of elacestrant in HR+/HER2− metastatic breast cancer with ESR1 mutation, in a real-world context consistent with the data from the pivotal EMERALD study and with real-world data present in the literature. Full article
(This article belongs to the Section Cancer Metastasis)
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31 pages, 30584 KB  
Article
Dextrin Palmitate and Disteardimonium Hectorite Construct a Gel-like EHMC Matrix: Enhanced UVB Photoprotection and Plasma Exposure Modulation
by Zhiwei Li, Yonghang Liang, Chen Liu, Weiyan Wang, Yongliang Li, Zhiyun Du, Li Lin, Junming Zhang, Ling Jiang, Lingna Xie and Meiting Li
Gels 2026, 12(7), 561; https://doi.org/10.3390/gels12070561 (registering DOI) - 23 Jun 2026
Abstract
2-Ethylhexyl-4-methoxycinnamate (EHMC) is among the most widely adopted organic UVB filters in commercial sunscreens. Nevertheless, its practical application potential is limited by unfavorable formulation compatibility and safety risks stemming from systemic exposure after topical administration. In this study, an oil-continuous structured gel matrix [...] Read more.
2-Ethylhexyl-4-methoxycinnamate (EHMC) is among the most widely adopted organic UVB filters in commercial sunscreens. Nevertheless, its practical application potential is limited by unfavorable formulation compatibility and safety risks stemming from systemic exposure after topical administration. In this study, an oil-continuous structured gel matrix consisting of EHMC, disteardimonium hectorite (DDH) and dextrin palmitate (DP) was constructed to enhance UVB photoprotection and modulate the plasma exposure profile of EHMC following topical application. Comprehensive characterizations including rheology, XRD, Raman spectroscopy, FTIR spectroscopy, TGA and SEM collectively revealed that the combined incorporation of DDH and DP facilitates matrix structural rearrangement, enables EHMC to bind within the structured network, and promotes the formation of more intact continuous surface films. In vitro SPF assays demonstrated that the finished topical formulation SC-4 delivered superior UVB blocking efficacy compared with the EHMC-only control SC-1; furthermore, SC-4 exhibited improved short-term physical stability under the preset thermal and centrifugal acceleration test conditions. Follow-up skin safety assessments, mass spectrometry imaging (MSI) and pharmacokinetic assays verified that SC-4 elicited no remarkable acute skin irritation across all experimental conditions. Relative to SC-1, the reference formulation with EHMC as the sole UV filter, SC-4 displayed weaker EHMC-related distribution signals in skin tissues, accompanied by lower early plasma EHMC concentrations and a slightly lower AUC0–48h trend. Collectively, these findings indicate that DDH/DP co-assembly serves as a viable matrix-structuring strategy to modulate EHMC-related skin distribution and early plasma exposure. Further research into UVA blocking performance, photostability, skin retention and transdermal permeation profiles, as well as long-term storage stability, is required to advance the development of broad-spectrum sunscreen formulations built on this novel matrix platform. Full article
(This article belongs to the Section Gel Processing and Engineering)
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28 pages, 6390 KB  
Article
miR-23a-3p as a Biomarker Associated with Prediabetes in People Living with HIV: An Integrative Analysis of Inflammatory, Metabolic, and Insulin Resistance Signatures
by Paula Catalina Méndez-Ríos, Yusnier Lázaro Díaz-Rodríguez, Luis F. Jave-Suarez, Luz A. González-Hernández, Jaime F. Andrade-Villanueva, Monserrat Álvarez-Zavala, Pedro Martínez-Ayala, Vida V. Ruiz-Herrera, Elsa Janneth Anaya-Ambriz and Karina Sánchez-Reyes
Int. J. Mol. Sci. 2026, 27(13), 5658; https://doi.org/10.3390/ijms27135658 (registering DOI) - 23 Jun 2026
Abstract
People living with HIV (PLWHIV) have an increased risk of developing metabolic disorders, including type 2 diabetes (T2D), partly driven by chronic low-grade inflammation and immune dysregulation. This study evaluated the potential role of circulating miR-23a-3p as a possible early biomarker of prediabetes [...] Read more.
People living with HIV (PLWHIV) have an increased risk of developing metabolic disorders, including type 2 diabetes (T2D), partly driven by chronic low-grade inflammation and immune dysregulation. This study evaluated the potential role of circulating miR-23a-3p as a possible early biomarker of prediabetes (preT2D) in PLWHIV. In this cross-sectional study, 80 adults were divided into five groups (n = 16 each): normoglycemic PLWHIV, PLWHIV with preT2D, PLWHIV with T2D, HIV-negative individuals with T2D, and controls. Clinical, anthropometric, biochemical, inflammatory, and insulin resistance (IR) markers were assessed, while plasma miR-23a-3p was quantified by digital PCR (dPCR). Bioinformatic network analysis was performed to identify potential molecular targets. PLWHIV with T2D showed the most unfavorable metabolic and inflammatory profile, including higher HbA1c, triglycerides, IL-6, TNF-α, hs-CRP, and GDF-15. In contrast, PLWHIV with preT2D exhibited significant overexpression of miR-23a-3p, whereas lower levels were observed in normoglycemic PLWHIV. miR-23a-3p correlated positively with IL-6 and GDF-15. ROC analyses showed good discriminative performance of miR-23a-3p for preT2D in PLWHIV (AUC = 0.80), and logistic regression confirmed its association with preT2D. In silico network analysis suggested potential inflammatory and metabolic targets of miR-23a-3p; however, these findings require experimental validation. These findings suggest that miR-23a-3p may represent a potential early biomarker of preT2D and immunometabolic dysfunction in PLWHIV. Full article
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40 pages, 15205 KB  
Article
CXCL13 as a Prognostic Biomarker and Immune Microenvironment-Associated Gene in Endometrial Carcinoma: A Multi-Omics Investigation
by Yiwen Sun, Xiaoyv Wang, Fangzheng Wu, Yanglin Ji and Jun Xie
Biology 2026, 15(13), 987; https://doi.org/10.3390/biology15130987 (registering DOI) - 23 Jun 2026
Abstract
Immune remodeling within the tumor microenvironment (TME) influences the progression and clinical outcome of uterine corpus endometrial carcinoma (UCEC), but the contribution of chemokine-related regulatory genes remains incompletely characterized. This study aimed to evaluate the prognostic relevance of CXCL13 and its association with [...] Read more.
Immune remodeling within the tumor microenvironment (TME) influences the progression and clinical outcome of uterine corpus endometrial carcinoma (UCEC), but the contribution of chemokine-related regulatory genes remains incompletely characterized. This study aimed to evaluate the prognostic relevance of CXCL13 and its association with immune microenvironmental features in UCEC using publicly available transcriptomic and single-cell datasets. RNA-sequencing profiles and clinical annotations from 589 UCEC cases in The Cancer Genome Atlas (TCGA) were analyzed to assess TME composition using ESTIMATE (Estimation of Stromal and Immune cells in MAlignant Tumours using Expression data) and CIBERSORT (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts), followed by survival analysis, differential gene expression analysis, protein–protein interaction network construction, Cox regression, and gene set enrichment analysis. A public single-cell RNA-sequencing dataset from the Gene Expression Omnibus (GEO; GSE173682) was further used to infer the cellular sources of CXCL13. Elevated CXCL13 expression was associated with favorable overall survival and enrichment of immune-activation pathways. CIBERSORT-based analysis indicated that high CXCL13 expression correlated with increased estimated fractions of CD8+ T cells and plasma cells, together with transcriptional features related to tertiary lymphoid structure-associated immune activation, whereas several immunosuppressive cell populations showed lower estimated abundance. Single-cell analysis suggested that CXCL13 was mainly expressed by follicular helper T cells and exhausted CD8+ T cells. These findings indicate that CXCL13 may serve as a prognostic biomarker associated with an immune-active TME in UCEC. Further histological, spatial, and functional validation is warranted to confirm its mechanistic role and translational potential. Full article
(This article belongs to the Section Immunology)
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36 pages, 3713 KB  
Article
Effects of Sodium Butyrate on Digestive Metabolism, Blood Gas Parameters and Blood Biochemical Indices in Tumbler Pigeons Based on Untargeted Metabolomics
by Kunyu Liao, Haiying Li, Xiaobin Li, Xinsheng Guo and Xiaoyu Zhao
Animals 2026, 16(13), 1941; https://doi.org/10.3390/ani16131941 (registering DOI) - 23 Jun 2026
Abstract
This study investigated the effects of dietary sodium butyrate supplementation on blood gas profiles, biochemical parameters, and untargeted plasma metabolomics in tumbler pigeons. Eighty tumbler pigeons of similar age, body weight, and training intensity were randomly allocated into four groups: a control group [...] Read more.
This study investigated the effects of dietary sodium butyrate supplementation on blood gas profiles, biochemical parameters, and untargeted plasma metabolomics in tumbler pigeons. Eighty tumbler pigeons of similar age, body weight, and training intensity were randomly allocated into four groups: a control group without sodium butyrate supplementation (CON) and three sodium butyrate-supplemented groups receiving 6 mg/d (T1), 12 mg/d (T2), and 18 mg/d (T3), respectively. All birds were maintained under identical husbandry conditions and fed the same basal diet throughout a 40-day experimental period consisting of a 10-day acclimation phase and a 30-day feeding trial. Results showed that dietary sodium butyrate supplementation significantly improved dry matter digestibility, with T2 and T3 exhibiting higher values than CON (p < 0.05), while metabolizable energy utilization was significantly increased in T3 compared with CON (p < 0.05). Sodium butyrate supplementation also significantly altered several blood gas parameters associated with acid–base balance and gas exchange. In addition, antioxidant enzyme activities were enhanced, with SOD, CAT, GSH-Px, and T-AOC activities significantly increased in supplemented groups compared with CON (p < 0.01). Furthermore, sodium butyrate supplementation significantly modulated inflammatory responses, increasing IL-10 concentrations (p < 0.01) while decreasing IL-6 and IL-8 levels (p < 0.01). Untargeted metabolomic analysis revealed significant alterations in pathways related to lipid metabolism, amino acid metabolism, and inflammatory regulation. In conclusion, dietary sodium butyrate supplementation influenced nutrient utilization, blood physiological parameters, antioxidant capacity, inflammatory status, and plasma metabolic profiles in tumbler pigeons. Among the tested supplementation levels, 18 mg/d sodium butyrate was associated with the most favorable overall physiological responses. These findings provide a basis for future investigations into the physiological and metabolic effects of sodium butyrate supplementation in competitive pigeons. Full article
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23 pages, 336 KB  
Review
A Literature Review of Lateral Epicondylitis: Diagnosis, Risk Factors, Management and Treatment
by Emilia Biedroń, Maciej Pitra, Jakub Chmura, Mikołaj Zieliński, Grzegorz Fibiger, Dawid Plutecki, Andrzej Dubrowski, Kamil Możdżeń, Jerzy A. Walocha, Wojciech Fibiger and Tomasz Kozioł
Life 2026, 16(7), 1043; https://doi.org/10.3390/life16071043 (registering DOI) - 23 Jun 2026
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Abstract
Lateral epicondylitis (LE), commonly referred to as tennis elbow, remains a frequent cause of lateral elbow pain, yet its optimal management and risk profile are still debated. Therefore, this review aimed to summarize current evidence on its definition, diagnosis, and treatment while addressing [...] Read more.
Lateral epicondylitis (LE), commonly referred to as tennis elbow, remains a frequent cause of lateral elbow pain, yet its optimal management and risk profile are still debated. Therefore, this review aimed to summarize current evidence on its definition, diagnosis, and treatment while addressing common misconceptions. A non-systematic review of major medical databases, including PubMed, Cochrane Library, and Google Scholar, was conducted using predefined inclusion criteria to identify relevant review articles. The analyzed literature highlights that LE is primarily diagnosed clinically and managed through a spectrum of conservative and interventional approaches. Evidence suggests that structured physiotherapy and load modification remain the cornerstones of treatment, while modalities such as platelet-rich plasma and autologous blood injections may offer longer-term benefits compared with corticosteroids, which are effective mainly for short-term symptom relief. In contrast, interventions such as acupuncture and shock wave therapy show limited or inconsistent efficacy. Identified risk factors include female sex, smoking history, repetitive or forceful manual work, and higher cardiovascular risk burden. Overall, conservative management should be the first-line approach, with biologic therapies considered in refractory cases and surgery reserved as a last option; however, further high-quality randomized controlled trials are required to establish optimal treatment algorithms and clarify long-term outcomes. Full article
(This article belongs to the Special Issue Recent Advances in Physiotherapy for Musculoskeletal Disorders)
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