Life

16 pages, 3977 KB

Open AccessArticle

Screening for Suspected Microplastic-like Particles in Post-Mortem Human Liver: Correlating Histopathological Alterations with Clinical Profiles

by Eugen-Toma Radu, Nastaca Alina Palade, Crina Cristina Solomon, Oana Gabriela Somcutian, Manuela Pia Pumnea, Maria Totan, Claudia Maria Mihuț, Cecilia Georgescu, Adina Frum, Carmen Maximiliana Dobrea and Felicia Gabriela Gligor

Life 2026, 16(8), 1315; https://doi.org/10.3390/life16081315 - 11 Aug 2026

Abstract

Background/Objectives: Microplastics (MPs) are emerging environmental contaminants with potential implications for human health. Experimental studies suggest that MPs accumulate in the liver and promote inflammatory and fibrotic changes, but evidence from human tissues remains limited. This study investigated the presence of suspected [...] Read more.

Background/Objectives: Microplastics (MPs) are emerging environmental contaminants with potential implications for human health. Experimental studies suggest that MPs accumulate in the liver and promote inflammatory and fibrotic changes, but evidence from human tissues remains limited. This study investigated the presence of suspected MP-like particles in post-mortem human liver tissue and their associations with clinical, biochemical, hematological and histopathological parameters. Methods: Post-mortem liver tissue samples were collected from 55 adults. Suspected MP-like particles were extracted using hydrogen peroxide digestion, filtration, Nile Red staining and image-based quantification. Histopathological evaluation assessed inflammation, fibrosis, necrosis and fatty liver degeneration. Polarized light microscopy was used as a supportive morphological assessment method. Statistical analyses included Mann–Whitney U tests, Fisher’s exact tests and Spearman correlation analysis. Results: Detectable hepatic suspected MP-like particles were identified in 9 of 55 individuals (16.4%). Individuals with detectable suspected MP-like particles had significantly lower alanine aminotransferase (ALT) levels and leukocyte counts. The hepatic suspected MP-like particle burden showed weak positive correlation with liver fibrosis and inflammation and weak inverse correlation with ALT levels and leukocyte count. Fisher’s exact test showed that liver fibrosis and liver inflammation were significantly associated with detectable hepatic suspected MP-like particles, with higher unadjusted odds observed in the corresponding 2 × 2 contingency tables. No statistically significant associations were found for liver necrosis or fatty liver degeneration. Conclusions: Detectable suspected MP-like particles were identified in post-mortem human liver tissues and were more closely associated with fibrotic and inflammatory histopathological changes than with routine biochemical abnormalities. Larger studies using standardized detection methods are needed to confirm these results. Full article

(This article belongs to the Special Issue Exploring the Mechanisms of the Effects of Microplastics and Nanomaterials on Biological Physiological Functions)

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29 pages, 4013 KB

Open AccessArticle

Integrated Chemical, Computational, and Cellular Profiling of a Dual-Oil Melanoma Formulation: An Exploratory Life-Science Study

by Katarina Dunjic, Momir Dunjic, Marina Gazdic Jankovic, Marina Miletic Kovacevic, Nikolina Kastratovic, Biljana Ljujic, Tatjana Novakovic, Milan Filipovic, Tatjana Filipovic, Zhao Jing, Marija Dunjic, Miroslav M. Sovrlić, Sandra S. Konstantinović, Jelena S. Stanojević, Milan D. Kostić and Stefano Turini

Life 2026, 16(8), 1314; https://doi.org/10.3390/life16081314 - 11 Aug 2026

Abstract

Background: Previous studies have examined bioactive constituents of Prunus dulcis oil, Pinus sylvestris essential oil, and related phytochemical matrices separately; however, their combined chemical profile, comparator-context molecular-docking landscape, and comparative cellular response in melanoma and non-malignant fibroblast models remain insufficiently characterized. Methods: The [...] Read more.

Background: Previous studies have examined bioactive constituents of Prunus dulcis oil, Pinus sylvestris essential oil, and related phytochemical matrices separately; however, their combined chemical profile, comparator-context molecular-docking landscape, and comparative cellular response in melanoma and non-malignant fibroblast models remain insufficiently characterized. Methods: The analyzed study samples were profiled by GC/MS and GC/FID-based fatty-acid methyl ester analysis. An archived molecular-docking dataset was used to summarize structurally plausible interactions of six formulation-associated markers with eight melanoma-relevant or melanoma-adjacent targets and to present representative three-dimensional complexes. Because complete protocol metadata and co-crystallized-ligand redocking records were unavailable, the computational findings were interpreted descriptively. Neutral-red uptake assays assessed the 24 h viability of B16F10 melanoma cells and MRC-5 fibroblasts after exposure to each oil, the dual-oil formulation, or cisplatin. Four-parameter logistic models provided estimated IC₅₀ values, and exact two-sided permutation tests were used for Spearman rank analyses. Results: The dual-oil formulation yielded estimated IC₅₀ values of 1.42% v/v in B16F10 cells and 4.85% v/v in MRC-5 cells, corresponding to an apparent selectivity index of 3.41. The complete eight-concentration series was non-monotonic and showed no significant rank association (B16F10: ρs = −0.4286, exact p = 0.2992; MRC-5: ρs = −0.3810, exact p = 0.3599). In a post hoc analysis of the descending branch (≥0.37% v/v), the association was perfect in B16F10 cells (ρs = −1.0000, exact p = 0.0167) but did not reach significance in MRC-5 cells (ρs = −0.9000, exact p = 0.0833). The docking matrix identified target-dependent numerical prioritization patterns; however, small score differences were not interpreted as evidence of stronger binding or cellular target engagement. Conclusions: The findings define an exploratory chemical–computational–cellular framework and a preliminary formulation-level viability phenotype. They do not establish synergy, apoptosis, pathway modulation, therapeutic efficacy, or clinical safety. Independent multi-batch chemical confirmation, a fully documented and redocking-validated computational protocol, expanded melanoma and normal-skin cell panels, orthogonal functional assays, longer exposure periods, mechanistic validation, and subsequent in vivo studies are required. Full article

(This article belongs to the Special Issue Bioactive Natural Products: From Exploration to Therapeutic Potential)

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31 pages, 3710 KB

Open AccessReview

Sugar Shockwaves: How the Fructose–Glucose–ChREBP Pathway Hijacks Liver Metabolism

by Alejandro Gugliucci

Life 2026, 16(8), 1313; https://doi.org/10.3390/life16081313 - 11 Aug 2026

Abstract

Recent research establishes carbohydrate response element-binding protein (ChREBP) as a central regulator of fructose-induced hepatic lipogenesis, underscoring its critical role in mediating the effects of excessive sugar intake on liver metabolism. Consequently, this narrative review presents a perspective of hepatic sugar metabolism and [...] Read more.

Recent research establishes carbohydrate response element-binding protein (ChREBP) as a central regulator of fructose-induced hepatic lipogenesis, underscoring its critical role in mediating the effects of excessive sugar intake on liver metabolism. Consequently, this narrative review presents a perspective of hepatic sugar metabolism and ChREBP signaling, highlighting areas for further exploration to better understand and address the metabolic consequences of fructose-driven activation of ChREBP. The discussion encompasses five principal domains: (1) fructose metabolism; (2) the structure and function of ChREBP; (3) interactions between glucose and fructose metabolism with ChREBP activity; (4) mechanisms that intensify fructose’s influence on ChREBP pathways; and (5) future research opportunities. Under physiological conditions, ChREBP mitigates accumulation of glycolytic intermediates; however, excessive sugar consumption overwhelms these capacities, thereby increasing lipogenesis. Fructose demonstrates notably stronger activation of ChREBP in vivo relative to glucose. Given ChREBP’s dual role in maintaining metabolic homeostasis and promoting insulin resistance under high fructose intake, therapeutic targeting poses considerable challenges. We propose the testable hypothesis that the MG generated from excessive fructose metabolism may bind to ChREBP’s lysine residues, stabilizing the protein and reducing degradation by impeding ubiquitination. This stabilization of ChREBP would prolong its activity, thereby further promoting sustained hepatic lipogenesis and exacerbating the risk of MASLD. Experimental and clinical research is needed to confirm its validity and define the molecular pathways involved. Future studies should aim to identify glucose metabolites involved in ChREBP regulation and clarify its beneficial versus adverse effects. The specific functions and regulation of ChREBPβ vs. ChREBPα remain to be elucidated. Full article

(This article belongs to the Section Physiology and Pathology)

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36 pages, 657 KB

Open AccessArticle

Proto-Biosignatures and Planetary Geochemical Metabolism: A Thermodynamic Screening Model of Prebiotic Geochemical Organization

by Sebastiano Ettore Spoto

Life 2026, 16(8), 1312; https://doi.org/10.3390/life16081312 - 10 Aug 2026

Abstract

Astrobiological observations usually return atmospheric, mineralogical, molecular, isotopic, or textural states rather than organisms. The interval between environmental habitability and confirmed life detection is therefore an evidential problem. This article develops planetary geochemical metabolism (PGM) as a scale-explicit description of abiotic water–rock–fluid reactions, [...] Read more.

Astrobiological observations usually return atmospheric, mineralogical, molecular, isotopic, or textural states rather than organisms. The interval between environmental habitability and confirmed life detection is therefore an evidential problem. This article develops planetary geochemical metabolism (PGM) as a scale-explicit description of abiotic water–rock–fluid reactions, including atmospheric or ice-shell boundary conditions where relevant, that sustain redox disequilibria, catalytic mineral interfaces, prebiotic molecular fluxes, and preservable mineral products. Proto-biosignatures are defined as contextual, non-diagnostic signatures of this interval: signals that do not demonstrate life, but increase the plausibility of prebiotic network organization relative to low-organization abiotic chemistry. A nondimensional Geochemical Metabolic Potential,

Φ_{PGM}

, is formalized as a target-specific screening index describing redox exergy, catalytic-interface density, reaction-network closure, environmental cycling efficacy, and preservation potential. The index is not calibrated as a probability of life. A reproducible Latin-hypercube experiment across

M_{sim} = 5000

synthetic environments examines internal model behavior rather than ranking planets. Higher

Φ_{PGM}

values mark hypotheses to be tested under declared scale, uncertainty, and observability constraints. Applications to early Earth, Noachian Mars, ocean worlds, and terrestrial exoplanets illustrate that habitability, prebiotic organization, biological inference, and preservation are distinct quantities. Full article

(This article belongs to the Section Origins of Life)

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20 pages, 1636 KB

Open AccessReview

Antidiabetic Properties of Ficus deltoidea Jack: A Review of In Vitro, In Vivo, and Clinical Evidence

by Siti Hajar Adam, Nor Syaza Syahirah Amat Junaidi, Shariff Halim and Mohd Helmy Mokhtar

Life 2026, 16(8), 1311; https://doi.org/10.3390/life16081311 - 10 Aug 2026

Abstract

Ficus deltoidea Jack (Moraceae), locally known as Mas Cotek, is a medicinal plant traditionally used throughout Southeast Asia for the management of diabetes mellitus. This review summarises the available evidence on the antidiabetic properties of F. deltoidea based on eleven in vitro, nine [...] Read more.

Ficus deltoidea Jack (Moraceae), locally known as Mas Cotek, is a medicinal plant traditionally used throughout Southeast Asia for the management of diabetes mellitus. This review summarises the available evidence on the antidiabetic properties of F. deltoidea based on eleven in vitro, nine in vivo and one clinical study identified through a structured literature search. In vitro investigations show that F. deltoidea inhibits α-glucosidase and α-amylase, stimulates insulin secretion in pancreatic β-cells via both K⁺-ATP channel-dependent and -independent pathways, enhances glucose uptake in hepatocytes and adipocytes, promotes adiponectin secretion and inhibits protein tyrosine phosphatase 1B (PTP1B). Vitexin and isovitexin, the predominant C-glycosyl flavonoids in F. deltoidea leaves, appear to be the main bioactive compounds responsible for these effects. Meanwhile, in vivo studies in streptozotocin-induced diabetic rodents report dose-dependent reductions in fasting blood glucose, improved glucose tolerance, restoration of pancreatic islet architecture, modulation of hepatic gluconeogenic and glucose-metabolic genes, and protection against diabetic nephropathy and bone loss. Inter-varietal differences in chemical composition and biological activity were observed, with var. trengganuensis and var. intermedia reported as the most active. The only available clinical trial in adults with prediabetes (1000 mg/day for 8 weeks) showed a reduction in LDL and total cholesterol but no significant change in fasting blood glucose or insulin. The discrepancy between preclinical and clinical findings highlights the need for standardised extracts, pharmacokinetic studies and adequately powered clinical trials in patients with established type 2 diabetes mellitus. Full article

(This article belongs to the Special Issue Therapeutic Effects of Natural Products on Human Diseases—3rd Edition)

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23 pages, 1629 KB

Open AccessReview

Generative AI and Large Language Models in Rehabilitation: A Scoping Review

by Su-Min Cha

Life 2026, 16(8), 1310; https://doi.org/10.3390/life16081310 - 10 Aug 2026

Abstract

Generative artificial intelligence (AI) and large language models (LLMs) are increasingly evaluated in rehabilitation, yet their clinical validity, reproducibility, and safety remain uncertain. This scoping review mapped peer-reviewed studies of generative AI/LLMs across rehabilitation assessment, clinical reasoning, decision support, planning, education, and functional [...] Read more.

Generative artificial intelligence (AI) and large language models (LLMs) are increasingly evaluated in rehabilitation, yet their clinical validity, reproducibility, and safety remain uncertain. This scoping review mapped peer-reviewed studies of generative AI/LLMs across rehabilitation assessment, clinical reasoning, decision support, planning, education, and functional classification. Following JBI methodology and PRISMA-ScR, five databases were searched for English-language studies published from 1 January 2015 to 24 July 2026. Two reviewers independently conducted study selection, data extraction, methodological appraisal, and application-domain coding. Of 2126 records, 43 publications representing 42 unique studies were included, predominantly from 2025–2026 and involving GPT/ChatGPT/OpenAI-family systems. At the unique-study level, six application domains were identified: clinical reasoning and decision support (n = 13), rehabilitation education, simulation, and feedback (n = 10), rehabilitation planning and prescription (n = 9), guideline adherence and clinical-question support (n = 6), adaptive feedback and rehabilitation support (n = 2), and assessment and functional classification (n = 2). Evidence was concentrated in benchmark, scenario-based, and educational evaluations, with limited patient-level outcomes. Heterogeneous methods, incomplete reporting of reproducibility, inconsistent safety assessment, and possible selective publication limited comparability and clinical generalizability. Generative AI/LLMs should therefore be used primarily as clinician-supervised assistive tools, with prospective validation, standardized reporting, and active safety evaluation prioritized. Full article

(This article belongs to the Section Medical Research)

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21 pages, 7856 KB

Open AccessArticle

Attention-Enhanced ResNet–U–Net for Automated Colorectal Tumor Segmentation in CT Scans

by Lucian Mihai Florescu, Cosmin Vasile Obleagă, Mădălin Mămuleanu, Ioana Andreea Cîrlig, Alesandra Florescu, Mihai Alexandru Ene, Aurelia Ștefania Domenco, Alexandru Marian Olaru, Alexandra Gabriela Cosmina Țâru, Raluca Elena Nica, Rossy Vlăduț Teică and Ioana Andreea Gheonea

Life 2026, 16(8), 1309; https://doi.org/10.3390/life16081309 - 10 Aug 2026

Abstract

Automated colorectal tumor segmentation on routine computed tomography (CT) remains technically challenging because of limited soft-tissue contrast, heterogeneous tumor morphology, complex bowel anatomy, and marked imbalance between tumor and background pixels. This retrospective technical feasibility study aimed to develop and evaluate an attention-enhanced [...] Read more.

Automated colorectal tumor segmentation on routine computed tomography (CT) remains technically challenging because of limited soft-tissue contrast, heterogeneous tumor morphology, complex bowel anatomy, and marked imbalance between tumor and background pixels. This retrospective technical feasibility study aimed to develop and evaluate an attention-enhanced ResNet50–U-Net architecture for automated segmentation of primary colorectal tumors on contrast-enhanced abdominopelvic CT images. The dataset comprised 493 axial CT image–mask pairs containing visible colorectal tumors, including 70 institutional images obtained from 25 patients and 423 images from publicly available colorectal cancer imaging resources. Reference masks were generated by manual tumor delineation performed by an experienced radiologist and reviewed by a second abdominal radiologist, with uncertain contours resolved by consensus. The proposed model combined an ImageNet-pretrained ResNet50 encoder with an attention-guided U-Net decoder and was trained using a composite Binary Cross-Entropy and Focal Tversky loss function to address foreground–background class imbalance. Performance was assessed using five-fold image-level cross-validation. Predicted probability maps were binarized using a threshold of 0.5, and segmentation metrics were calculated through global micro-averaging within each validation fold. The model achieved a mean Intersection over Union of 0.7406 ± 0.0276, a Dice similarity coefficient of 0.8507 ± 0.0182, a pixel-level sensitivity of 0.9559 ± 0.0266, and a pixel-level background specificity of 0.9956 ± 0.0003. Qualitative assessment demonstrated substantial spatial agreement between predicted masks and expert annotations, although minor boundary discrepancies and small false-positive components were observed. These findings support the technical feasibility of attention-enhanced encoder–decoder architectures for colorectal tumor segmentation on routine CT images. However, because validation was performed at the image level, entirely tumor-negative images were not included (preventing the evaluation of clinical specificity and false-positive rates), and no independent external test cohort was available, further patient-level, multicenter, and DICOM-based validation is required before clinical implementation. While the model demonstrated robust internal performance, future studies must prioritize large-scale external validation and patient-level cross-validation to rigorously assess generalizability and specificity. Full article

(This article belongs to the Section Artificial Intelligence in the Life Sciences)

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15 pages, 4033 KB

Open AccessArticle

Predicting Abdominal Aortic Aneurysm Progression: The Role of 18F-Fluorodeoxyglucose Aortic Wall Uptake and Flow Dynamics

by Marta Ferrer-Cornet, Marvin Garcia-Reyes, Mireia Bragulat-Arévalo, Andrea Guala, Juan Garrido-Oliver, Alba Catala-Santarrufina, Pere Lopez-Gutierrez, Ruperto Oliveró-Soldevila, Gisela Teixidó-Turà, Ignacio Ferreira-Gonzalez, Jose Rodriguez-Palomares, Sergi Bellmunt-Montoya and Lydia Dux-Santoy

Life 2026, 16(8), 1308; https://doi.org/10.3390/life16081308 - 10 Aug 2026

Abstract

As abdominal aortic aneurysms (AAA) rupture results in a high mortality rate, early detection and risk stratification are critical for timely elective intervention. Although the maximum diameter is the sole imaging metric used to assess risk, other factors may provide complementary information. This [...] Read more.

As abdominal aortic aneurysms (AAA) rupture results in a high mortality rate, early detection and risk stratification are critical for timely elective intervention. Although the maximum diameter is the sole imaging metric used to assess risk, other factors may provide complementary information. This study investigated the role of inflammation and hemodynamics in AAA progression. Methods: Patients with AAA underwent hybrid 18F-fluorodeoxyglucose ([18F]FDG) PET/CMR imaging, including a four-dimensional flow sequence and contrast-enhanced magnetic resonance angiography, and were followed to assess AAA diameter growth rate. Abdominal aorta hemodynamics and [18F]FDG PET target-to-background (TBR) were quantified at 28 standardized regions. Correlations between AAA diameter, hemodynamics, PET and growth rate were assessed. Results: Thirty-two AAA patients (84.4% men) with a median age of 73 and an interquartile range of [68; 77] years were prospectively recruited. The AAA maximum diameter was 48.1 [44.8; 55.0] mm, and the growth rate was 2.7 [1.3; 4.0] mm/year during a follow-up of 2 [1.1; 3.5] years. The AAA maximum diameter (R = 0.443, p = 0.011) and flow vorticity (R = 0.453, p = 0.009) showed significant bivariate correlation with the growth rate. When correcting for the aneurysm diameter, the helicity density was significantly correlated with the growth rate (p = 0.045), while the AAA thrombus volume was inversely associated with it (p = 0.042). Aneurysms with negative helicity density (counterclockwise rotation) grew significantly faster (p = 0.042) than those with positive helicity. In multivariable analysis, beyond the AAA diameter, the thrombus volume, helicity density and TBR were inversely related to the growth rate. Conclusions: Integrating flow, inflammatory and thrombus information may improve AAA growth rate prediction beyond the maximum aneurysm diameter. Full article

(This article belongs to the Special Issue Advances in Vascular Medicine: From Endovascular Innovations to Pathophysiological Insights)

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30 pages, 3924 KB

Open AccessArticle

Comparative Genomic and Transcriptomic Analyses of ⁶⁰Co-Mutagenized Scheffersomyces stipitis Strains: Identification of Candidate Genes Associated with High-Ethanol-Producing Xylose-to-Ethanol Fermentation

by Hao Zou, Yuanjie Zhou, Suiyin Lin, Tingting Pang, Linxi Zhang, Jing Zhou and Renzhi Wu

Life 2026, 16(8), 1307; https://doi.org/10.3390/life16081307 - 10 Aug 2026

Abstract

Sugarcane bagasse is an important renewable lignocellulosic resource, yet its bioconversion efficiency remains low, primarily because wild-type Saccharomyces cerevisiae cannot utilize xylose, which limits the industrial production of cellulosic ethanol. In this study, a high-ethanol-yielding strain 31.1 was obtained from Scheffersomyces stipitis (formerly [...] Read more.

Sugarcane bagasse is an important renewable lignocellulosic resource, yet its bioconversion efficiency remains low, primarily because wild-type Saccharomyces cerevisiae cannot utilize xylose, which limits the industrial production of cellulosic ethanol. In this study, a high-ethanol-yielding strain 31.1 was obtained from Scheffersomyces stipitis (formerly known as Pichia stipitis) 1960 through ⁶⁰Co mutagenesis and long-term domestication. Strain 31.1 exhibited an ethanol productivity of 0.78 g/(L·h), a sugar-to-ethanol conversion rate of 0.38 g/g, and a fermentation efficiency of 82.61%. Using the wild-type strain 1960 and a low-yielding strain 12.1 as controls, comparative genomics and transcriptomics were employed to elucidate the mechanism underlying the high ethanol production. Our findings are as follows: at the genomic level, there were 271 genomic structural variations. At the transcriptomic level, most genes involved in secondary metabolite synthesis, antibiotic synthesis, ribosomal pathways, amino acid biosynthesis, and oxidative phosphorylation pathways were down-regulated. Additionally, two key genes—XYL1 (xylose reductase gene) and XUT4 (high-affinity xylose transporter gene)—were significantly up-regulated. Through comprehensive integration of phenotypic comparison (e.g., fermentation performance of the high-yield strain 31.1 in yeast propagation and ethanol fermentation), comparative genomics, transcriptomics, and bioinformatics analyses of pathways involved in oxidative phosphorylation and the cell cycle (related to yeast cell growth), we identified 60 candidate key genes associated with high xylose-to-ethanol yield in S. stipitis. These genes are predominantly involved in the cell cycle pathway, including CDC15 and PHO81. In conclusion, our study preliminarily reveals the mechanisms underlying the high xylose ethanol production of the high-yield strain at the genomic and transcriptomic levels. Full article

(This article belongs to the Special Issue Microbial Biotechnology and Biomanufacturing)

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21 pages, 3104 KB

Open AccessArticle

Heat Stress, Indoor Microclimate, and Lactation Feed Intake in Commercial Mediterranean Sows: Parity Effects and a Daily Resolution Predictive Model

by Lampros Fotos, Aris Pourlis, Eirini Valasi, Georgios I. Papakonstantinou, Konstantinos Kousenidis, Athanasios Sougias, George Tsegas, Eleftherios Chourdakis, Zisis Tsiropoulos, Alexandra V. Michailidou, Christos Vlachocostas and Vasileios G. Papatsiros

Life 2026, 16(8), 1306; https://doi.org/10.3390/life16081306 - 9 Aug 2026

Abstract

Heat stress (HS) suppresses voluntary feed intake in lactating sows, yet individual-level characterization of indoor and outdoor Temperature–Humidity Index (THI) linked to feed intake is rare in Mediterranean commercial settings. This prospective observational study enrolled 272 F1-crossbred sows (parities 1–7) farrowing from May–October [...] Read more.

Heat stress (HS) suppresses voluntary feed intake in lactating sows, yet individual-level characterization of indoor and outdoor Temperature–Humidity Index (THI) linked to feed intake is rare in Mediterranean commercial settings. This prospective observational study enrolled 272 F1-crossbred sows (parities 1–7) farrowing from May–October 2025 at a commercial Greek farm. Outdoor THI was computed from 8760 hourly records and indoor THI from calibrated dataloggers; individual daily lactation feed intake (days 1–30) was recorded via RFID transponder-feeders. Building cooling (ΔTHI = 3.7–14.3) attenuated but did not eliminate mild-to-moderate indoor stress from June–September. Only parity and stillbirth count were Bonferroni-significant correlates of feed intake (parity: β = +0.142, p = 0.002). A sow-day Gradient Boosting model, evaluated by grouped cross-validation to prevent within-sow leakage, achieved CV-R² = 0.406 ± 0.045, providing a validated, herd-tested framework for parity-stratified feeding management, pending external validation across farms, genetics, and climates. Full article

(This article belongs to the Special Issue Control of Viral Diseases and Reproductive Management in Swine)

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18 pages, 2178 KB

Open AccessArticle

Therapeutic Effect of Low-Level Laser Therapy in Patients with Temporomandibular Disorder

by Igor Djordjević, Ana Miletić, Filip Ivanjac, Danica Popović Antić, Minja Miličić Lazić and Vitomir Konstantinović

Life 2026, 16(8), 1305; https://doi.org/10.3390/life16081305 - 9 Aug 2026

Abstract

Background: Temporomandibular disorders (TMD) are associated with musculoskeletal pain affecting the masticatory muscles and temporomandibular joint (TMJ). Low-level laser therapy (LLLT) is a therapeutic modality with analgesic, anti-inflammatory, and biostimulatory effects. Protocol and laser parameter settings for TMD management have not yet been [...] Read more.

Background: Temporomandibular disorders (TMD) are associated with musculoskeletal pain affecting the masticatory muscles and temporomandibular joint (TMJ). Low-level laser therapy (LLLT) is a therapeutic modality with analgesic, anti-inflammatory, and biostimulatory effects. Protocol and laser parameter settings for TMD management have not yet been established. The aim of this prospective study was to evaluate the effectiveness of low-level laser therapy in reducing pain in TMD patients. Methods: Sixty-three participants treated at the Department of Prosthodontics, School of Dental Medicine, University of Belgrade, were sorted to the LLLT group and the control splint-medication group (SMG), which received occlusal splint therapy, with nonsteroidal anti-inflammatory drug treatment (NSAID; Ibuprofen). Results: Both therapeutic approaches resulted in significant pain reduction and improvement in patients’ quality of life. No statistically significant differences were observed between the groups, LLLT patients demonstrated a higher rate of successful treatment outcomes, reduction in pain intensity during the treatment. Conclusion: The applied LLLT was associated with significant reduction in pain intensity and improvement in oral health-related quality of life in patients with TMD. Although no statistically significant differences between the groups were demonstrated at the individual post-treatment assessment points, these findings support LLLT as a potentially useful non-invasive conservative treatment option. Full article

(This article belongs to the Special Issue New Advances in the Treatment and Assessment of Temporomandibular Joint Disorders)

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34 pages, 975 KB

Open AccessReview

SARIFA and Lipid Metabolic Reprogramming in Prostate Cancer: Fundamental Mechanisms, Tumor Microenvironment, and Novel Biomarker Prospects

by Liudmila Mikhaleva, Maria Martynova, Zarina Gioeva, Nikolay Shakhpazyan, Nikita Chizhikov, Valentina Pechnikova, Mikhail Gushchin and Alexander Ilyichev

Life 2026, 16(8), 1304; https://doi.org/10.3390/life16081304 - 9 Aug 2026

Abstract

Prostate cancer (PCa) is one of the most prevalent malignancies in men worldwide. Established clinicopathological parameters do not fully describe the biological heterogeneity of PCa or consistently predict its clinical course after radical prostatectomy, supporting the investigation of additional prognostic markers. Stroma AReactive [...] Read more.

Prostate cancer (PCa) is one of the most prevalent malignancies in men worldwide. Established clinicopathological parameters do not fully describe the biological heterogeneity of PCa or consistently predict its clinical course after radical prostatectomy, supporting the investigation of additional prognostic markers. Stroma AReactive Invasion Front Areas (SARIFA) is a recently described histomorphological pattern characterized by direct contact between tumor cells and adipocytes without intervening desmoplastic or inflammatory stroma at the invasion front. Limited retrospective evidence from prostatectomy specimens indicates that SARIFA positivity is associated with adverse pathological features. However, its independent prognostic value and clinical utility remain to be established. Because SARIFA can potentially be assessed on routinely prepared hematoxylin and eosin-stained sections without additional molecular assays or immunohistochemical staining, it represents a potentially accessible candidate marker, although its reproducibility, standardization, and cost-effectiveness require formal evaluation. This review summarizes current evidence concerning lipid metabolic remodeling and tumor–adipocyte interactions that may contribute to the SARIFA phenotype in PCa. Androgen receptor-regulated lipid metabolism, uptake of adipocyte-derived fatty acids, adipokine signaling, and extracellular vesicle-mediated communication provide a plausible mechanistic framework. Nevertheless, direct experimental evidence linking several of these processes specifically to SARIFA in PCa remains limited, and some proposed relationships are based on indirect evidence or findings from other tumor types. Further studies should establish standardized scoring criteria, intra- and interobserver reproducibility, external validation, and incremental prognostic value before the clinical implementation of SARIFA can be considered. Full article

(This article belongs to the Special Issue Advances and Challenges in Urothelial and Prostate Cancer: Toward Precision Urologic Oncology)

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26 pages, 6878 KB

Open AccessReview

Toward Personalized NSAID Therapy in Osteoarthritis: The Right Patient, the Right Treatment, at the Right Time

by Valerica Creanga Zarnescu, Liliana Mititelu-Tartau, Ilie Onu, Daniel Andrei Iordan and Liliana-Lăcrămioara Pavel

Life 2026, 16(8), 1303; https://doi.org/10.3390/life16081303 - 8 Aug 2026

Abstract

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) remain the cornerstone of pharmacological treatment for osteoarthritis (OA) and are recommended by international guidelines for the management of symptomatic pain. Despite their well-established efficacy, substantial interindividual variability exists in treatment response, with some patients experiencing meaningful pain [...] Read more.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) remain the cornerstone of pharmacological treatment for osteoarthritis (OA) and are recommended by international guidelines for the management of symptomatic pain. Despite their well-established efficacy, substantial interindividual variability exists in treatment response, with some patients experiencing meaningful pain relief while others derive little clinical benefit despite appropriate drug selection and dosing. This variability reflects, at least in part, the biological heterogeneity of OA pain. Objective: To review the mechanisms underlying variability in NSAID responsiveness in OA and to propose a practical framework for personalized NSAID prescribing based on pain phenotype, individual safety profile, and treatment timing. Methods: A narrative review of the contemporary scientific literature was conducted using major biomedical databases to summarize the current evidence on phenotype-guided NSAID therapy in OA. Particular attention was given to the emerging concepts of nociceptive, nociplastic, and neuropathic-like pain phenotypes and their implications for personalized anti-inflammatory therapy. Results: Current evidence indicates that OA pain is a heterogeneous and dynamic condition in which inflammatory nociceptive, nociplastic, and neuropathic-like mechanisms coexist to varying degrees. NSAIDs primarily target inflammatory nociceptive pain by inhibiting cyclooxygenase (COX)-mediated prostaglandin synthesis and reducing peripheral sensitization. Consequently, patients with predominantly inflammatory nociceptive pain are the most likely to benefit from NSAID therapy, whereas those with predominant nociplastic or neuropathic-like pain mechanisms may require alternative or multimodal treatment strategies. Beyond pain phenotype, optimal NSAID selection should integrate cardiovascular, gastrointestinal, and renal risk assessment, recognizing the important pharmacological and safety differences among individual agents. Treatment timing is also clinically relevant, as anti-inflammatory therapy appears most effective when initiated during periods of active inflammatory nociceptive pain. Based on the available evidence, we propose a conceptual clinical decision framework integrating patient selection, NSAID choice, and treatment timing. Conclusions: Personalized NSAID prescribing should move beyond a diagnosis-based approach toward a mechanism-based strategy that integrates pain phenotyping, individualized safety assessment, and appropriate treatment timing. The proposed framework is built upon three complementary principles, identifying the right patient, selecting the right treatment, and initiating therapy at the right time. It provides a practical foundation for implementing precision medicine in the pharmacological management of OA. Full article

(This article belongs to the Special Issue Global Burden of Chronic Pain: Advances and Challenges in Pain Management and Clinical Practice)

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26 pages, 6701 KB

Open AccessArticle

Comparative Effects of CuNPs, CuONPs and CuSO₄ on Biomass Quality, Culture Liquid Composition and Biostimulant Activity of Nostoc linckia

by Liliana Cepoi, Tatiana Chiriac, Ludmila Rudi, Svetlana Codreanu, Ana Valuța, Svetlana Djur, Tudor Trifan and Vera Potopová

Life 2026, 16(8), 1302; https://doi.org/10.3390/life16081302 - 8 Aug 2026

Abstract

The chemical form of copper is a key determinant of metal bioavailability and may profoundly influence cyanobacterial metabolism and the biological activity of culture-derived products. In this study, Nostoc linckia was cultivated in the presence of metallic copper nanoparticles (CuNPs), copper oxide nanoparticles [...] Read more.

The chemical form of copper is a key determinant of metal bioavailability and may profoundly influence cyanobacterial metabolism and the biological activity of culture-derived products. In this study, Nostoc linckia was cultivated in the presence of metallic copper nanoparticles (CuNPs), copper oxide nanoparticles (CuONPs), or CuSO₄·5H₂O (15 mg Cu L⁻¹). Biomass productivity, biochemical composition, and antioxidant capacity, together with the physicochemical and biochemical characteristics of the culture liquid, were determined. The culture liquid was subsequently evaluated through the seed priming of four maize (Zea mays L.) hybrids. The different copper forms induced distinct metabolic responses in Nostoc linckia. CuONPs promoted biomass accumulation while maintaining protein and photosynthetic pigment contents and inducing an adaptive oxidative response, whereas CuNPs, and particularly CuSO₄, impaired biomass production and primary metabolism. These metabolic changes were reflected in the culture liquid properties and were associated with genotype-dependent differences in maize germination dynamics, seedling vigor, and biochemical composition. Integrated correlation, hierarchical clustering, and principal component analyses revealed coordinated relationships linking cyanobacterial physiology, culture liquid profiles, and plant responses. Collectively, these findings demonstrate that the chemical form of copper drives metabolic remodeling in Nostoc linckia, thereby shaping the biochemical composition and biostimulant properties of its culture liquid. Full article

(This article belongs to the Section Microbiology)

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16 pages, 3037 KB

Open AccessReview

Zilebesiran, a Small Interfering RNA Therapeutic Targeting Angiotensinogen: Mechanism, Clinical Evidence, Safety, and Implementation Considerations

by Jawaria, Areeba Noor, Yusra Zarlashat, Muhammad Ebad Asif Khan, Enrique Mandado Loureiro and Edit Dósa

Life 2026, 16(8), 1301; https://doi.org/10.3390/life16081301 - 8 Aug 2026

Abstract

Hypertension remains a major global health burden, and control rates remain suboptimal because of poor medication adherence and limitations of existing therapies, including escape within the renin–angiotensin–aldosterone system. Zilebesiran, a first-in-class, subcutaneously administered small interfering RNA therapeutic, represents a promising advance in hypertension [...] Read more.

Hypertension remains a major global health burden, and control rates remain suboptimal because of poor medication adherence and limitations of existing therapies, including escape within the renin–angiotensin–aldosterone system. Zilebesiran, a first-in-class, subcutaneously administered small interfering RNA therapeutic, represents a promising advance in hypertension management. Through N-acetylgalactosamine-mediated hepatic delivery, zilebesiran selectively silences angiotensinogen (AGT) messenger RNA, the transcript encoding the common precursor of all angiotensin peptides. This upstream intervention reduces AGT production and produces durable blood pressure lowering that can persist for up to 6 months after a single dose. This review summarizes the mechanism of action of zilebesiran, its pharmacokinetic and pharmacodynamic properties, and the available phase 1 and phase 2 clinical evidence, including the KARDIA program. We also place zilebesiran within the evolving antihypertensive landscape by comparing it with aldosterone synthase inhibitors, dual endothelin receptor antagonists, and brain aminopeptidase A inhibitors. Finally, we discuss translational challenges, including reversal strategies for emergency situations, monitoring considerations, and potential roles for personalized dosing. Early-phase and phase 2 trials show dose-dependent and durable reductions in serum AGT and blood pressure with infrequent dosing; however, long-term safety, cardiovascular outcome benefit, and generalizability in diverse high-risk populations remain to be established, and zilebesiran remains investigational while phase 3 outcome testing is underway. Full article

(This article belongs to the Special Issue Clinical Updates on Cardiovascular Health: From Pathophysiology to Precision Medicine)

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28 pages, 1491 KB

Open AccessArticle

Two Faces of UV Mutagenesis: Independent and Collateral Mutagenesis in Skin Cancers

by Konstantin Gunbin, Zamart Ramazanova, Bakhyt Matkarimov, Murat Saparbaev, Sergey Nikolaev and Andrey Yurchenko

Life 2026, 16(8), 1300; https://doi.org/10.3390/life16081300 - 7 Aug 2026

Abstract

Cutaneous melanoma and basal cell carcinoma (BCC) represent the two primary malignancies driven by solar ultraviolet (UV) radiation. To map the spatial topology and distance dependence of their mutational signatures, we deployed new analytical bioinformatics workflow utilizing two convergent strategies: a data-driven read-level [...] Read more.

Cutaneous melanoma and basal cell carcinoma (BCC) represent the two primary malignancies driven by solar ultraviolet (UV) radiation. To map the spatial topology and distance dependence of their mutational signatures, we deployed new analytical bioinformatics workflow utilizing two convergent strategies: a data-driven read-level phasing framework to discriminate between collateral mutational events versus independent ones and a hypothesis-driven spatial permutational simulation model to capture density-dependent local deviations. A whole-genome analysis employing this framework unexpectedly reveals two fundamentally distinct lesion-processing landscapes, present in both BCC and melanoma. While independent mutations consistently reproduce canonical UV signatures (SBS7a–c) in both tumor types, collateral mutations tell a distinct and more varied narrative between BCC and melanoma. These collateral mutations are unusually abundant for non-UV characteristics, such as age-related SBS1 and SBS5, and display a notable 3′ to 5′ asymmetry near UV-induced lesions in pyrimidine dimers. We also demonstrated that BCC displays a pronounced enrichment of dinucleotide base substitutions flanking UV-signature sites on the 3′ side, particularly CA>TG and CG>TA changes. Ultimately, these topological patterns in both tumors indicate that a primary photoproduct seeds secondary mutagenesis within its local chromatin environment, dramatically altering our understanding of UV-induced lesion processing. Full article

(This article belongs to the Special Issue Cancer Genomics and Transcriptomics: Uncovering New Frontiers in Tumor Biology)

19 pages, 44938 KB

Open AccessReview

From Ischemic Injury to Arrhythmogenic Substrate: Molecular and Histopathological Insights into Post-Infarction Sudden Cardiac Death

by Andrea Marzullo and Cecilia Salzillo

Life 2026, 16(8), 1299; https://doi.org/10.3390/life16081299 - 7 Aug 2026

Abstract

Myocardial infarction is a major cause of cardiovascular death and a key substrate for sudden cardiac death. Traditionally, histopathological analysis of infarction has focused on the temporal sequence of morphological changes, from coagulative necrosis to inflammatory infiltrate and cicatricial fibrosis. However, recent molecular [...] Read more.

Myocardial infarction is a major cause of cardiovascular death and a key substrate for sudden cardiac death. Traditionally, histopathological analysis of infarction has focused on the temporal sequence of morphological changes, from coagulative necrosis to inflammatory infiltrate and cicatricial fibrosis. However, recent molecular studies have highlighted how these processes are tightly regulated by cell death pathways, including apoptosis, autophagy, and ferroptosis, and by electrical and microvascular remodeling mechanisms that contribute to cardiac instability. This review integrates histopathological and molecular evidence relating to post-infarction evolution, with particular attention to the infarct border zone, the privileged substrate for arrhythmogenesis. Key molecular markers and cells involved in the inflammatory response and wound healing are discussed, as well as implications for ventricular reentry circuit formation and sudden cardiac death risk. An integrated understanding of these mechanisms offers innovative perspectives for the identification of predictive biomarkers and the development of therapeutic strategies aimed at reducing post-infarction arrhythmic outcomes. Full article

(This article belongs to the Special Issue Common and Novel Markers of Inflammation and Tissue Damage in Various Pathological Conditions—2nd Edition)

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20 pages, 717 KB

Open AccessReview

Postprandial Inflammatory Stress: A Hypothesis-Generating Framework Linking Metabolic, Immune and Vascular Responses

by Roko Šantić, Marko Kumrić, Lovre Martinović, Nikola Pavlović, Azer Rizikalo, Marino Vilović, Josip Vrdoljak and Joško Božić

Life 2026, 16(8), 1298; https://doi.org/10.3390/life16081298 - 7 Aug 2026

Abstract

Chronic low-grade inflammation accompanies cardiometabolic disease, while routine risk assessment is based mainly on fasting measurements. This structured narrative review summarises human evidence for discrete postprandial changes in triglyceride-rich lipoproteins and remnants, glucose and insulin, endotoxin-related markers, innate immune cells and endothelial function. [...] Read more.

Chronic low-grade inflammation accompanies cardiometabolic disease, while routine risk assessment is based mainly on fasting measurements. This structured narrative review summarises human evidence for discrete postprandial changes in triglyceride-rich lipoproteins and remnants, glucose and insulin, endotoxin-related markers, innate immune cells and endothelial function. The evidence is comparatively consistent for postprandial lipaemia, glycaemic excursions and acute flow-mediated dilation responses, whereas endotoxin, cytokine and cellular findings are smaller, assay-sensitive and less consistently replicated. Based on this evidence, we introduce PRISM-CM (Postprandial Inflammatory Stress Modules in CardioMetabolic disease) as an author-developed, hypothesis-generating evidence map. It comprises five candidate biological domains—lipid–remnant burden, glucose–insulin stress, endotoxin handling, innate immune-cell activation and endothelial response—with recovery kinetics treated as a cross-domain analytic dimension. The framework was not derived by clustering, consensus methods or predictive modelling; its illustrative response patterns are not validated endotypes. A composite score is not proposed because the independence, reproducibility and incremental predictive value of the candidate measurements have not been established. Potential future diagnostic and prognostic applications require prospective validation. Reference ranges, age- and sex-specific norms, within-person reproducibility, reproducible response patterns and outcome-linked thresholds remain unknown. PRISM-CM is therefore not a clinical algorithm, risk score or treatment-selection tool. Full article

(This article belongs to the Special Issue Mechanisms and Novel Biomarkers in Chronic Inflammatory Diseases)

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27 pages, 7684 KB

Open AccessArticle

Predicting ACI Outcomes with GMP In-Process Control Kinetic Metrics: Initial Chondrocyte Yield and Population Doubling Time as Prognostic Clinical Biomarkers

by Virginie Philippe, Alexis E. Laurent, André Berchtold, Nathalie Hirt-Burri, Lee Ann Applegate and Robin Martin

Life 2026, 16(8), 1297; https://doi.org/10.3390/life16081297 - 6 Aug 2026

Abstract

Purpose: To determine whether specific in vitro biologic characteristics and manufacturing kinetics of cultured human articular chondrocytes (HACs) can serve as predictive biomarkers for patient-reported and structural outcomes following second-generation autologous chondrocyte implantation (ACI) in the knee. Materials and Methods: This prospective cohort [...] Read more.

Purpose: To determine whether specific in vitro biologic characteristics and manufacturing kinetics of cultured human articular chondrocytes (HACs) can serve as predictive biomarkers for patient-reported and structural outcomes following second-generation autologous chondrocyte implantation (ACI) in the knee. Materials and Methods: This prospective cohort study evaluated 67 patients (mean age 25.1 ± 8.3 years) treated with second-generation ACI for large focal cartilage defects (mean size 5.4 ± 2.5 cm²) between 2017 and 2024. HACs were expanded under Good Manufacturing Practice (GMP) conditions using human platelet lysate-supplemented media. Four biological determinants were analyzed: (1) initial chondrocyte yield (ICY) isolated from the cartilage biopsy; (2) chondrogenic activity (relative ACAN and COL2A1 expression); (3) final culture confluence level; and (4) HAC population doubling time (PDT) pre- and post-cryopreservation. Clinical outcomes (KOOS and IKDC) and MRI outcomes (MOCART) were assessed at 2 years (T1) and at a mean final follow-up of 4.2 ± 1.7 years (T2) via univariate and multiple regression analyses. Results: Static biosynthetic markers (ACAN/COL2A1 expression) and final culture confluence did not significantly correlate with longitudinal clinical (KOOS/IKDC) or structural (MOCART) outcomes. Conversely, the retained kinetic parameters served as strong prognostic indicators. Multiple regression revealed that higher ICY values significantly predicted improvements across most KOOS subscales from baseline to T2, including KOOS Symptoms (β = 63.56; p < 0.01), KOOS Pain (β = 88.83; p < 0.001), KOOS ADL (β = 107.84; p < 0.001), and KOOS Sport and Recreation Function (β = 92.3; p < 0.05). Furthermore, a prolonged PDT, indicative of diminished in vitro proliferative vigor, inversely correlated with functional recovery in IKDC (β = −26.12; p < 0.01), KOOS Pain (β = −23.09; p < 0.05), and KOOS ADL (β = −21.71; p < 0.05) scores. Conclusions: The intrinsic proliferative vigor of the HAC cellular payload (shorter PDT) and higher initial cell yields are robust kinetic biomarkers associated with markedly superior mid-term clinical outcomes following second-generation ACI for large focal chondral defects in the knee. In contrast, standard morphological and gene expression metrics failed to predict in vivo functional success. These findings advocate for a risk-based paradigm shift in GMP quality control methodologies, emphasizing dynamic HAC growth kinetics over static cellular features to optimize patient-specific regenerative potential. Full article

(This article belongs to the Section Physiology and Pathology)

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