Biomedicines

21 pages, 335 KB

Open AccessArticle

Pulmonary Function in Parkinson’s Disease: A Comparative Study of Spirometry and Impulse Oscillometry

by Alexandra-Cristiana Gache, Elena Danteș, Ariadna-Petronela Fildan, Andreea-Cristina Postu, Viorica Zamfir, Adina-Milena Man, Nicoleta-Larisa Șerban, Irene Rășanu and Any Axelerad

Biomedicines 2026, 14(5), 1176; https://doi.org/10.3390/biomedicines14051176 - 21 May 2026

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Abstract

Background/Objectives: Respiratory dysfunction in Parkinson’s disease (PD) is a clinically relevant but frequently underrecognized manifestation associated with functional impairment and increased risk of respiratory complications. This study compared spirometry and impulse oscillometry (IOS) in the assessment of respiratory function in PD, with particular [...] Read more.

Background/Objectives: Respiratory dysfunction in Parkinson’s disease (PD) is a clinically relevant but frequently underrecognized manifestation associated with functional impairment and increased risk of respiratory complications. This study compared spirometry and impulse oscillometry (IOS) in the assessment of respiratory function in PD, with particular focus on the detection of subtle or peripheral airway abnormalities. Methods: A prospective, single-center, cross-sectional study was conducted, including 108 participants (55 patients with PD and 53 control subjects). Pulmonary function was evaluated using standardized spirometry and IOS protocols. Group comparisons were performed using non-parametric tests, while multivariable regression analyses adjusted for potential confounding factors, including age, body mass index, smoking status, pollutant exposure, and cardiovascular comorbidities. Results: IOS identified a higher frequency of abnormal categorical findings compared with spirometry, including among subjects with normal spirometric values. Although dyspnea was more frequent in patients with PD in unadjusted analyses, multivariable regression demonstrated that PD was not an independent predictor of respiratory dysfunction. Pollutant exposure was significantly associated with abnormal IOS findings (p = 0.011). No significant differences were observed between PD and control groups regarding continuous spirometric or oscillometric parameters. Only a weak association between disease severity and FEV1 (%) was identified, whereas no significant correlations were observed for oscillometric parameters. Conclusions: IOS may provide complementary information regarding subtle or peripheral respiratory abnormalities in patients with PD. The findings suggest that respiratory alterations in this population are likely multifactorial and not independently determined by PD itself. Incorporating oscillometric assessment into respiratory evaluation may contribute to the identification of subtle respiratory mechanical alterations in patients with PD. Full article

(This article belongs to the Special Issue Advances in Parkinson’s Disease Research)

18 pages, 2281 KB

Open AccessArticle

Effects of IncobotulinumtoxinA in the Infraorbital Nerve Chronic Constriction Injury Model of Trigeminal Pain in Rats

by Wojciech Danysz, Paulina Nunez-Badinez, Andreas Gravius, Klaus Fink and Jens Nagel

Biomedicines 2026, 14(5), 1175; https://doi.org/10.3390/biomedicines14051175 - 21 May 2026

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Abstract

Background/Objectives: Trigeminal neuralgia (TN) is a debilitating neurological condition characterized by recurrent, severe pain linked to peripheral and central sensitization within trigeminal pathways. Current pharmacologic treatments are limited by inadequate efficacy or dose-limiting side effects, and botulinum neurotoxin type A (BoNT/A) has [...] Read more.

Background/Objectives: Trigeminal neuralgia (TN) is a debilitating neurological condition characterized by recurrent, severe pain linked to peripheral and central sensitization within trigeminal pathways. Current pharmacologic treatments are limited by inadequate efficacy or dose-limiting side effects, and botulinum neurotoxin type A (BoNT/A) has emerged as a viable option. However, its potential use in the management of TN is hampered by methodological limitations in existing studies and a lack of pivotal clinical trials. This study investigated the efficacy, optimal treatment site, preventive utility, and duration of effect of incobotulinumtoxinA (Inco/A), a BoNT/A, in a model of TN. Methods: An infraorbital nerve chronic constriction injury model was used to induce mechanical allodynia in male Sprague–Dawley rats, reproducing the trigeminal sensitization seen in TN. The effects of subcutaneous Inco/A (1, 2, and 4 U) were measured using the mechanical sensitivity (von Frey) test to evaluate the dose response, effect of injection location, potential preventive nature of treatment, and duration of benefit. Results: Inco/A produced a robust, dose-dependent reduction in mechanical allodynia, predominantly via a local mechanism of action. Both preventive and therapeutic administration of Inco/A was efficacious, with significant reduction in allodynia even when administered up to 28 days before nerve injury. The anti-allodynic effect persisted up to 56 days post-injection. Conclusions: Inco/A is highly effective in alleviating mechanical allodynia in a validated rat model of TN. The findings highlight Inco/A as a promising candidate for clinical translation in TN and related neuropathic pain syndromes and support systematic investigation in well-controlled human trials. Full article

(This article belongs to the Special Issue Advances in Pain Management: Exploring Molecular Mechanisms and Novel Therapies)

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16 pages, 1461 KB

Open AccessArticle

Evaluation of the Anti-Inflammatory Activity of Selected Plant Extracts in an In Vitro Model of Inflammation Using LPS-Stimulated Macrophages

by Karolina Merecz, Kinga Suska, Olga Biniszewska, Mikołaj Hirsa, Aneta Wojdyło, Aleksandra Tarasiuk-Zawadzka and Jakub Fichna

Biomedicines 2026, 14(5), 1174; https://doi.org/10.3390/biomedicines14051174 - 21 May 2026

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Abstract

Background: Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic gastrointestinal (GI) diseases with complex and multifactorial pathophysiology. The global prevalence of IBD is increasing, highlighting the need to develop new therapeutic approaches. Plant-derived extracts [...] Read more.

Background: Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic gastrointestinal (GI) diseases with complex and multifactorial pathophysiology. The global prevalence of IBD is increasing, highlighting the need to develop new therapeutic approaches. Plant-derived extracts have recently gained prominence due to their anti-inflammatory properties. Methods: This study investigated: apricot leaves (ALE), peach leaves (PLE), black chokeberry fruit (BCHE), rosehip seeds (RSE), passion fruit seeds (PSE), and linden blossom (LBE) (all at the concentration 10–200 µg/mL) in RAW 264.7 mouse macrophages. Cytotoxicity was assessed using the neutral red uptake (NRU) assay, and anti-inflammatory activity was assessed using Griess assay in the lipopolysaccharide (LPS)-induced inflammation. Additionally, the mRNA expression levels of key inflammatory genes (interferon-γ (Ifn-γ), interleukin-6 (Il-6), nitric oxide synthase (Nos2), and tumor necrosis factor-α (Tnf-α)) were analyzed. Results: ALE and PLE exhibited minimal cytotoxicity and strong anti-inflammatory activity, reducing the expression of all analyzed genes. PSE demonstrated anti-inflammatory activity in the Griess assay, but did not alter mRNA expression. Conclusions: ALE and PLE exhibit promising anti-inflammatory properties and warrant further preclinical investigation. Comprehensive in vitro and in vivo studies are necessary to confirm these results. Full article

(This article belongs to the Special Issue Inflammatory Bowel Diseases: New Diagnostic and Therapeutic Approaches—Second Edition)

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12 pages, 1741 KB

Open AccessArticle

Histological Assessment of Plasma-Induced Tissue Sublimation Using the Plasma IQ Device: An Ex Vivo Morphometric Study in a Porcine Model

by Paweł Kubik, Wojciech Gruszczyński, Aleksandra Pawłowska, Maciej Malinowski, Brygida Baran, Agnieszka Pawłowska-Kubik, Łukasz Kodłubański, Dariusz Grzanka, Paulina Antosik and Bartłomiej Łukasik

Biomedicines 2026, 14(5), 1173; https://doi.org/10.3390/biomedicines14051173 - 21 May 2026

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Abstract

Background: Minimally invasive aesthetic procedures using atmospheric plasma devices are increasingly applied to improve skin laxity and age-related loss of firmness. These systems generate a localized plasma arc at the tissue surface, enabling controlled and spatially confined tissue interaction; however, quantitative histological [...] Read more.

Background: Minimally invasive aesthetic procedures using atmospheric plasma devices are increasingly applied to improve skin laxity and age-related loss of firmness. These systems generate a localized plasma arc at the tissue surface, enabling controlled and spatially confined tissue interaction; however, quantitative histological data on the extent of plasma-induced tissue effects remain limited. Materials and Methods: This ex vivo study evaluated freshly collected porcine kidney, liver, and skeletal muscle tissues (n = 3 per tissue type). Tissue sublimation defects were produced using the Plasma IQ device under conditions representative of standard clinical use, applying two predefined settings (“LOW” and “HIGH”). Immediately after treatment, specimens were fixed in 10% neutral buffered formalin and processed into formalin-fixed paraffin-embedded (FFPE) blocks. Sections were stained with hematoxylin and eosin (H&E), and the diameter and depth of the sublimation zones were measured by light microscopy. Results: Plasma IQ exposure consistently produced well-demarcated superficial sublimation defects in all tissues. The HIGH setting increased the diameter of the sublimation zones compared with the LOW setting across all tissue types, whereas the depth differences were smaller and tissue-dependent. Lesions exhibited a characteristic flattened, cone-shaped morphology, with diameter exceeding depth. No histologically detectable collateral damage was observed beyond the immediate sublimation zone. Conclusions: Atmospheric plasma treatment induces controlled and spatially confined tissue sublimation with clearly defined histological boundaries and limited penetration depth. These findings provide quantitative histological support for the localized tissue effects of plasma-based devices and their rationale in aesthetic procedures. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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11 pages, 462 KB

Open AccessArticle

Women with Abdominal Aortic Aneurysms Have a Different Pattern of Genetic Variability, Compared to Men

by Jonas Wallinder, Anders Wanhainen, Helena Åkerud, Dick Wågsäter and Martin Björck

Biomedicines 2026, 14(5), 1172; https://doi.org/10.3390/biomedicines14051172 - 21 May 2026

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Abstract

Background/Objectives: The etiology behind sex differences in the prevalence of abdominal aortic aneurysm (AAA) can only partly be explained by environmental factors such as smoking. Genetic factors are also likely to be part of the explanation since family history is common. We hypothesized [...] Read more.

Background/Objectives: The etiology behind sex differences in the prevalence of abdominal aortic aneurysm (AAA) can only partly be explained by environmental factors such as smoking. Genetic factors are also likely to be part of the explanation since family history is common. We hypothesized that genetic factors on AAA prevalence might be different between the sexes. Methods: This study is designed as a case–control study with 83 female AAA patients, 101 female controls, 97 male AAA patients, and 196 male controls. Single nucleotide polymorphism (SNP) analysis was performed comparing 13 different SNPs. The selection of SNPs was based on previous SNP association studies, estrogen receptors, and SNPs important to inflammation and lipid metabolism, as these processes are modulated by estrogen. Results: A multivariable logistic regression resulted in significant differences in SNP association with AAA development between men and women in two SNPs (rs2010963 and rs8113877). Significant differences were found between cases and controls, using univariate analysis, in four SNPs: rs8113877 among women, and in rs6511720, rs2010963 and rs4988300 among men. No SNPs were significantly different compared to controls in both men and women. SNP rs8113877 is located in the promotor of the MMP-9 gene. Levels of circulating MMP-9 were measured in a subgroup of the study participants: an association between MMP-9 and AAA was found, and the association between rs8113877 and MMP-9 was sex-dependent. Conclusions: Genetic variability associated with AAA differs between men and women; these differences should be accounted for in future research. Full article

(This article belongs to the Special Issue Aortic Aneurysm: Mechanisms, Biomarkers, and Therapeutic Strategy)

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18 pages, 2123 KB

Open AccessArticle

Circulating Lymphocyte Subsets Are Associated with Diabetic Kidney Disease and Overall Survival in Patients with Type 2 Diabetes

by Guanglan Li, Jiayi Chen, Chenfeng Xu, Ganyuan He, Feng Yu, Wei Liu, Yanhua Wu, Wenke Hao and Wenxue Hu

Biomedicines 2026, 14(5), 1171; https://doi.org/10.3390/biomedicines14051171 - 21 May 2026

Cited by 1 | Viewed by 765

Abstract

Background: The immune mechanism of diabetic kidney disease (DKD) has not yet been fully elucidated. This study aimed to characterize circulating lymphocyte subsets in patients with type 2 diabetes mellitus (T2DM), with a particular focus on DKD-related immune alterations and prognosis. Methods: Circulating [...] Read more.

Background: The immune mechanism of diabetic kidney disease (DKD) has not yet been fully elucidated. This study aimed to characterize circulating lymphocyte subsets in patients with type 2 diabetes mellitus (T2DM), with a particular focus on DKD-related immune alterations and prognosis. Methods: Circulating T cells, B cells and NK cells were identified by flow cytometry. The primary endpoint was all-cause mortality, and overall survival was defined as the time from enrollment to death from any cause or last follow-up. Associations between lymphocyte subsets, inflammatory indices and renal function parameters were analyzed. Cox regression was used to identify factors associated with overall survival in patients with DKD and in the whole T2DM cohort. A prognostic nomogram was developed in the whole T2DM cohort to estimate 1-, 2-, 3-, and 5-year overall survival (OS) probabilities. Model performance was evaluated using the concordance index (C-index), calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Mendelian randomization (MR) was performed as a further exploratory analysis to assess whether immune-related traits were genetically associated with DKD susceptibility, with inverse variance weighting (IVW) as the primary analytical method. Results: In total, 74 T2DM patients were divided into DKD (stage 3–4 of chronic kidney disease) and non-DKD groups. Median follow-up duration was 34.6 months. DKD patients exhibited elevated levels of NK cells, the monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). In patients with DKD, higher PLR and serum creatinine (SCr) were associated with poorer overall survival, whereas CD4⁺CD25⁺ T cell frequency was not significant after adjustment. In the whole T2DM cohort, higher frequency of circulating CD4⁺CD25⁺ T cells were associated with improved survival (HR 0.920, 95% CI 0.858–0.986, p = 0.019), whereas elevated PLR and SCr were linked to poorer outcomes. The exploratory nomogram incorporating CD4⁺CD25⁺ T cells, PLR, and SCr, showed acceptable internal performance in this cohort. As a separate exploratory analysis, MR suggested that genetically proxied CD4 expression on activated CD4 regulatory T cells was associated with a lower risk of DKD. Conclusions: DKD was associated with higher mortality and elevated MLR-, NLR-, PLR-, and NK cell levels in patients with T2DM. In patients with DKD, PLR and SCr were associated with overall survival, supporting the prognostic relevance of systemic inflammation and renal dysfunction. Individual lymphocyte subsets were not independently associated with survival in the DKD cohort after adjustment, whereas CD4⁺CD25⁺ T cell frequency provided additional prognostic information in the whole extended T2DM cohort analysis. Further validation is warranted. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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11 pages, 362 KB

Open AccessArticle

Neutrophil–Lymphocyte–Platelet Ratio for Predicting Bacteremia in Immunosuppressed Cancer Patients: A Retrospective Diagnostic Accuracy Study

by José Manuel Martinez, Ana Espírito Santo, Pedro Leite, Ana Pinho, Ana Rita Carneiro, Ana Maria Oliveira, Diana Ramada and Rui Medeiros

Biomedicines 2026, 14(5), 1170; https://doi.org/10.3390/biomedicines14051170 - 21 May 2026

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Abstract

Background: Early identification of bacteremia in immunosuppressed cancer patients remains difficult, especially in neutropenia. This study evaluated the diagnostic accuracy of NLR, PLR, and NLPR for identifying bacteremia and sepsis in patients undergoing blood culture episode. Methods: We conducted a retrospective diagnostic accuracy [...] Read more.

Background: Early identification of bacteremia in immunosuppressed cancer patients remains difficult, especially in neutropenia. This study evaluated the diagnostic accuracy of NLR, PLR, and NLPR for identifying bacteremia and sepsis in patients undergoing blood culture episode. Methods: We conducted a retrospective diagnostic accuracy study at a tertiary oncology center between January 2023 and December 2024. All bacteremia identified were included as cases. Culture-negative episodes were subsequently sampled as controls using a frequency-matching strategy. Hematological parameters were obtained within ±24 h of first blood culture episode. Diagnostic performance was assessed using ROC curve analysis and multivariable logistic regression. Results: Of 369 screened episodes, 337 from 323 unique patients were included after excluding 31 records. NLPR showed the highest accuracy for bacteremia (AUC 0.730; 95% CI 0.671–0.788). The optimal cut-off was 0.038 (sensitivity 69.2%, specificity 72.3%) and remained consistent after excluding episodes with antibiotic therapy (AUC 0.768), corticosteroids (AUC 0.708), or growth factor use (AUC 0.718). In severe neutropenia, NLPR showed the highest accuracy (AUC 0.887; 95% CI 0.797–0.978). In multivariable analysis (n = 304), NLPR remained independently associated with bacteremia (p < 0.001), with good model discrimination (AUC 0.815; 95% CI 0.763–0.866). Diagnostic performance for sepsis was lower and not statistically significant. Conclusions: These findings suggest that NLPR may represent a simple, inexpensive, widely accessible adjunctive biomarker to support early bacteremia risk stratification in immunosuppressed cancer patients, particularly in patients with severe neutropenia. Although its overall discrimination was comparable to isolated lymphocyte count, NLPR may provide clinically relevant contextual information by integrating multiple dimensions of immune dysregulation. Further prospective multicenter validation is warranted. Full article

(This article belongs to the Special Issue Emerging Trends in Cancer: Biomarkers, Therapeutic Strategies and Future Directions)

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17 pages, 21449 KB

Open AccessArticle

Tissue microRNA Profiling Identifies Prognostic Signatures in Prostate Cancer and Highlights CPEB3 as a Candidate Biomarker

by Jae-Heon Kim, Ah-Rim Moon, Miho Song, Kwang-Woo Lee, Soo Min Suh, Hui Ji Kim, Luis Alfonso Pefianco, Kevin Andrean, Seongho Ryu and Yun-Seob Song

Biomedicines 2026, 14(5), 1169; https://doi.org/10.3390/biomedicines14051169 - 21 May 2026

Cited by 1 | Viewed by 661

Abstract

Purpose: Prostate cancer is one of the most common malignancies in men, yet current prognostic methods remain suboptimal. Emerging evidence indicates that microRNAs (miRNAs) play critical roles in prostate cancer progression. This study aimed to identify miRNAs associated with adverse clinical outcomes [...] Read more.

Purpose: Prostate cancer is one of the most common malignancies in men, yet current prognostic methods remain suboptimal. Emerging evidence indicates that microRNAs (miRNAs) play critical roles in prostate cancer progression. This study aimed to identify miRNAs associated with adverse clinical outcomes by comparing miRNA expression profiles between prostate tumors with unfavorable versus favorable prognostic features. Materials and Methods: High-throughput next-generation sequencing (NGS) was used to analyze miRNA expression in formalin-fixed, paraffin-embedded prostate cancer tissue samples. Patients were classified into favorable or unfavorable prognosis groups based on risk stratification scores, Gleason grade group, and biochemical recurrence. Differentially expressed miRNAs were identified using a fold-change threshold ≥2 and a false discovery rate (FDR) <0.05. Predicted target genes and pathway analyses were conducted to generate candidate regulatory hypotheses rather than confirm mechanistic relationships. Results: Several miRNAs were differentially expressed according to prognostic category. miR-206 was significantly downregulated in high-risk tumors compared with low-risk tumors. High-Gleason-grade tumors showed reduced expression of miR-7704 and miR-4454, while miR-25-3p and let-7f-5p were upregulated. In patients with early biochemical recurrence, miR-7704 and miR-10400-5p were downregulated relative to those with prolonged recurrence-free survival. Target prediction analysis identified CPEB3, HAND1, PTAR1, and SPRYD4 as shared candidate targets, with CPEB3 emerging as a prioritized candidate supported by consistency in external datasets rather than a confirmed molecular target. Conclusions: Distinct miRNA expression patterns correlate with prostate cancer aggressiveness and clinical outcomes. miR-206, miR-7704, miR-4454, miR-25-3p, and let-7f-5p represent candidate prognostic biomarkers. Their shared target CPEB3 should be interpreted as a prioritized candidate for future investigation. Given the very small sample size and the lack of qRT-PCR and functional validation, these findings should be considered preliminary and hypothesis-generating, requiring validation in larger independent cohorts and experimental studies. Full article

(This article belongs to the Special Issue Emerging Trends in Cancer: Biomarkers, Therapeutic Strategies and Future Directions)

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13 pages, 874 KB

Open AccessSystematic Review

Association Between SGLT2 Inhibitor Use and Hepatocellular Carcinoma Risk in Type 2 Diabetes: A Systematic Review and Meta-Analysis

by Jing-Hong Hu, Ming-Ling Chang, Tung-Jung Huang, Nai-Jen Liu and Jui-Hsiang Tang

Biomedicines 2026, 14(5), 1168; https://doi.org/10.3390/biomedicines14051168 - 21 May 2026

Cited by 1 | Viewed by 794

Abstract

Background and Aims: Type 2 diabetes mellitus is a recognized risk factor for hepatocellular carcinoma (HCC), particularly in the setting of metabolic dysfunction-associated steatotic liver disease (MASLD), chronic viral hepatitis, advanced fibrosis, and cirrhosis. Beyond hyperglycemia and insulin resistance, diabetic hepatocarcinogenesis is [...] Read more.

Background and Aims: Type 2 diabetes mellitus is a recognized risk factor for hepatocellular carcinoma (HCC), particularly in the setting of metabolic dysfunction-associated steatotic liver disease (MASLD), chronic viral hepatitis, advanced fibrosis, and cirrhosis. Beyond hyperglycemia and insulin resistance, diabetic hepatocarcinogenesis is shaped by metabolic inflammation, lipotoxicity, oxidative stress, fibrogenic remodeling, and the cirrhosis-dysplasia-HCC continuum. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) may influence several hepatometabolic pathways, but the epidemiologic evidence linking SGLT2i use to HCC risk remains heterogeneous. Methods: We conducted a systematic review and meta-analysis of observational studies evaluating SGLT2i exposure and incident HCC in adults with type 2 diabetes. PubMed, Embase, and the Cochrane Library were searched up to 15 March 2026. Adjusted time-to-event estimates were pooled using a restricted maximum likelihood (REML) random-effects model. The certainty of evidence was assessed using the GRADE framework and judged to be very low. Results: Six observational studies including 526,446 participants were included. SGLT2i exposure was associated with a lower observed risk of incident HCC (pooled HR 0.59, 95% CI 0.45–0.77), but between-study heterogeneity was substantial (I² = 75.2%, τ² = 0.074). The association remained directionally similar after exclusion of Huynh et al. (HR 0.61, 95% CI 0.45–0.81) and in a DPP-4 inhibitor-restricted active-comparator analysis (HR 0.60, 95% CI 0.39–0.92). However, the 95% prediction interval crossed the null (0.25–1.37), indicating that future comparable studies may plausibly show no protective association. Conclusions: SGLT2i exposure was associated with a lower observed risk of incident HCC across available observational studies. However, the certainty of evidence was judged to be very low, and substantial heterogeneity, comparator variation, mixed time-to-event estimands, residual confounding, and a prediction interval crossing the null preclude causal interpretation. These findings should be considered hypothesis-generating rather than practice-changing evidence and support further hepatology-oriented validation. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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20 pages, 4717 KB

Open AccessArticle

Integrative Analysis of Major Depressive Disorder and Ovarian Cancer: From Genetic Association to Single-Cell Mechanisms

by Chen Liu, Xueling Wang and Jiaqi Lu

Biomedicines 2026, 14(5), 1167; https://doi.org/10.3390/biomedicines14051167 - 21 May 2026

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Abstract

Background: Although emerging evidence indicates that major depressive disorder (MDD) raises the risk of developing ovarian cancer (OC) and worsens survival, the biological mechanisms underlying this relationship remain unclear. This study explores the MDD-OC association using single-cell transcriptomics and genetic approaches. Methods: Using [...] Read more.

Background: Although emerging evidence indicates that major depressive disorder (MDD) raises the risk of developing ovarian cancer (OC) and worsens survival, the biological mechanisms underlying this relationship remain unclear. This study explores the MDD-OC association using single-cell transcriptomics and genetic approaches. Methods: Using single-cell RNA-seq profiles of peripheral blood from MDD and OC patients, we compared shifts in immune cell subsets and selected the consistently expanded CD8⁺ effector memory (CD8_EM) T cells population for follow-up, validated using flow cytometry. We integrated expression quantitative trait loci (eQTL) data from CD8_EM T cell-specific genes with OC genome-wide association study (GWAS) summary statistics through two-sample Mendelian randomization (MR). In vitro experiments were additionally conducted to assess CLSTN3’s role in OC cell proliferation. Results: Among the 554 differentially expressed genes (DEGs) identified in CD8_EM T cells, MR showed a nominal association between CLSTN3 and ovarian cancer risk (OR 1.21, 95% CI 1.03–1.43), though this did not withstand correction for multiple comparisons. Colocalization analysis confirmed that CLSTN3 expression, regulated by the genetic variant rs3759416, shares a causal variant with the OC GWAS signal (PPH4 = 99.99%). Functionally, siRNA-mediated CLSTN3 silencing in HOC7 cells significantly reduced cell viability (CCK-8 assay). Conclusions: By focusing on CD8_EM T cells shared by MDD and ovarian cancer, we identified CLSTN3 as a candidate molecule through nominated by the convergence of genetic, transcriptomic, and functional evidence. These findings provide preliminary insights into the connection between depression and OC, though further validation is warranted. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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23 pages, 20877 KB

Open AccessArticle

Development of Type II Glucose Transporter Inhibitors: Phloretin as a GLUT-2 Screening Template from In Silico Modeling to In Vitro Assessment

by Worarat Boonpech, Pemikar Srifa, Dhassida Sooksawat, Praopim Limsakul, Jirakrit Saetang, Varomyalin Tipmanee, Krit Charupanit, Chaitong Churuangsuk and Kantida Juncheed

Biomedicines 2026, 14(5), 1166; https://doi.org/10.3390/biomedicines14051166 - 21 May 2026

Viewed by 846

Abstract

Background/Objectives: Hepatocellular carcinoma (HCC) exhibits enhanced glycolytic activity, primarily facilitated by Class I glucose transporters (GLUTs), particularly GLUT-2. Phloretin, a natural polyphenol, is known to modulate glucose transport; however, its isoform-specific interactions and functional impact on HCC metabolism remain unclear. This study compared [...] Read more.

Background/Objectives: Hepatocellular carcinoma (HCC) exhibits enhanced glycolytic activity, primarily facilitated by Class I glucose transporters (GLUTs), particularly GLUT-2. Phloretin, a natural polyphenol, is known to modulate glucose transport; however, its isoform-specific interactions and functional impact on HCC metabolism remain unclear. This study compared phloretin’s inhibitory effects on glucose uptake in HCC cells versus normal liver cell models and assessed its binding affinity across Class I GLUTs using molecular docking. Methods: Cytotoxicity was evaluated in HepG2 (HCC) and THLE-2 (normal hepatocyte) cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays to determine biologically relevant concentrations. Glucose uptake at sub-cytotoxic levels was quantified using the fluorescent analog 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose. To elucidate the molecular mechanism, in silico docking simulations were performed to compare the binding affinities of phloretin, glucose, and reference inhibitors (glutor and cytochalasin B) with the outward-facing conformations of GLUT-1 through GLUT-4. Results: Phloretin induced dose- and time-dependent cytotoxicity, with HepG2 cells exhibiting significantly higher sensitivity than THLE-2 cells. Functionally, phloretin markedly reduced glucose uptake in HepG2 cells, whereas THLE-2 cells showed minimal inhibition. Molecular docking revealed that phloretin occupies the central substrate-binding cavity of Class I GLUTs, forming its most stable interaction network with GLUT-2. Conclusions: These results demonstrate that phloretin selectively inhibits glucose uptake in liver cancer cells, likely through its high-affinity interaction with GLUT-2. Collectively, these findings highlight phloretin’s potential as a metabolic therapeutic agent and support GLUT-2 as a viable target for HCC intervention. Full article

(This article belongs to the Special Issue Advanced Research in Anticancer Inhibitors and Targeted Therapy)

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16 pages, 1073 KB

Open AccessArticle

NSAID Use Attenuates the Protective Effect of Physical Activity on Chronic Low Back Pain: A Cross-Sectional Analysis of NHANES 2009–2010

by William Sosa, Lucas Camargo and Felipe Fregni

Biomedicines 2026, 14(5), 1165; https://doi.org/10.3390/biomedicines14051165 - 21 May 2026

Viewed by 687

Abstract

Background: Chronic low back pain (CLBP) is a leading cause of disability worldwide, with exercise endorsed as first-line treatment and non-steroidal anti-inflammatory drugs (NSAIDs) among the most used pharmacologic options. These interventions are frequently combined in clinical practice, yet their synergistic effects [...] Read more.

Background: Chronic low back pain (CLBP) is a leading cause of disability worldwide, with exercise endorsed as first-line treatment and non-steroidal anti-inflammatory drugs (NSAIDs) among the most used pharmacologic options. These interventions are frequently combined in clinical practice, yet their synergistic effects remain unclear. To evaluate whether NSAID use modifies the association between physical activity (PA) and CLBP using nationally representative data from NHANES 2009–2010. Methods: We analyzed 988 adults aged ≥20 years with complete data on chronic low back pain, physical activity, medication use, and modeled covariates. Results: Among participants not using NSAIDs, moderate recreational physical activity was associated with lower odds of CLBP (adjusted OR = 0.47, 95% CI 0.25–0.91; p = 0.029). Active transport showed a similar direction but was not statistically significant (OR = 0.38, 95% CI 0.13–1.12; p = 0.074). In interaction models, active transport x aspirin was associated with higher odds of CLBP (OR = 2.24, 95% CI 1.02–4.90; p = 0.044), and moderate recreational PA x any NSAID use was also associated with higher odds of CLBP (OR = 2.26, 95% CI 1.01–5.06; p = 0.047). Subgroup analyses were exploratory and heterogeneous, including a significant potential protective interaction (OR ≈ 0.19, 95% CI 0.06–0.69; p = 0.015). Conclusions: In a nationally representative sample, NSAID use appeared to modify the association between physical activity and chronic low back pain. These findings are exploratory and hypothesis-generating. Therefore, longitudinal studies are needed to clarify the temporal and causal relationships and the potential influence of NSAIDs. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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15 pages, 558 KB

Open AccessArticle

Association Between Clinical Signs and CBCT-Confirmed TMJ Involvement in Juvenile Idiopathic Arthritis: The Diagnostic Value of Facial Asymmetry and Mandibular Mobility

by Tamara Pawlaczyk-Kamieńska and Tomasz Kulczyk

Biomedicines 2026, 14(5), 1164; https://doi.org/10.3390/biomedicines14051164 - 21 May 2026

Cited by 1 | Viewed by 655

Abstract

Juvenile idiopathic arthritis (JIA) is the most common systemic chronic inflammatory connective tissue disease in children, characterized by joint inflammation lasting at least six months. Temporomandibular joint (TMJ) involvement can occur in conjunction with other joints and may often be asymptomatic in its [...] Read more.

Juvenile idiopathic arthritis (JIA) is the most common systemic chronic inflammatory connective tissue disease in children, characterized by joint inflammation lasting at least six months. Temporomandibular joint (TMJ) involvement can occur in conjunction with other joints and may often be asymptomatic in its early stages. Objective: This study aims to evaluate the relationship between clinical symptoms of the stomatognathic system and radiologically confirmed cone beam computed tomography (CBCT)-detected structural TMJ changes in children with JIA. The research hypothesis posits that specific clinical symptoms are more prevalent in patients with CBCT-confirmed structural TMJ changes. Methods: A cohort of children diagnosed with JIA was examined. Clinical symptoms, including facial asymmetry, limited mandibular movement, and joint and masticatory muscle pain upon palpation, were assessed. CBCT imaging was performed to assess osseous TMJ structural changes. Results: The frequency of orofacial clinical symptoms was assessed and compared between patients with and without radiological evidence of TMJ involvement. Children with CBCT-confirmed TMJ changes demonstrated significantly higher rates of facial asymmetry, reduced maximum mouth opening, mandibular deviation during opening, and limitations in lateral or protrusive movements compared with those without TMJ involvement. Pain-related symptoms (TMJ pain, muscle tenderness, and pain during movement) and joint sounds occurred at similar frequencies in both groups. Conclusions: Facial asymmetry, mandibular deviation during opening and reduced mandibular mobility are the clinical signs most strongly associated with structural TMJ involvement in JIA and should prompt targeted imaging. Pain-related symptoms show limited diagnostic value, highlighting the need for focused clinical assessment and future studies integrating CBCT and MRI to refine early screening protocols. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Diagnostic Techniques in Juvenile Idiopathic Arthritis—Second Edition)

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15 pages, 957 KB

Open AccessSystematic Review

Cannabidiol in Periodontal Therapy—Is There Hope or Just a Bias? A Systematic Review

by Ruxandra Ștefănescu, Amelia Tero-Vescan, Camil-Eugen Vari, Dragoș Sita and Bianca-Eugenia Ősz

Biomedicines 2026, 14(5), 1163; https://doi.org/10.3390/biomedicines14051163 - 20 May 2026

Viewed by 1036

Abstract

Background: Periodontitis is a chronic inflammatory disease characterized by dysbiotic biofilm formation, progressive destruction of periodontal tissues, and alveolar bone resorption. Conventional periodontal therapy primarily focuses on mechanical biofilm removal; however, adjunctive therapeutic approaches targeting host inflammatory responses and microbial activity have gained [...] Read more.

Background: Periodontitis is a chronic inflammatory disease characterized by dysbiotic biofilm formation, progressive destruction of periodontal tissues, and alveolar bone resorption. Conventional periodontal therapy primarily focuses on mechanical biofilm removal; however, adjunctive therapeutic approaches targeting host inflammatory responses and microbial activity have gained increasing attention. Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has demonstrated anti-inflammatory, antimicrobial, and immunomodulatory properties that may be relevant in periodontal disease management. Objective: This systematic review aimed to evaluate the available evidence regarding the potential role of CBD in modulating periodontal inflammation, microbial biofilms, and bone resorption processes. Methods: A systematic literature search was conducted in Web of Science, Cochrane, PubMed, Scopus, and Google Scholar. The review was conducted in accordance with PRISMA guidelines. Studies investigating the effects of CBD on periodontal inflammation, oral biofilms, or bone remodeling were included. Both preclinical (in vitro and animal) and clinical studies were considered. Results: Evidence from experimental studies consistently demonstrated that CBD modulates inflammatory signaling pathways, including inhibition of the TLR4/NF-κB pathway and a reduction in pro-inflammatory cytokine expression, but some results are contradictory. Animal studies reported reduced alveolar bone loss and decreased osteoclast activity following CBD administration. Several studies also demonstrated antimicrobial and antibiofilm effects of CBD against oral microorganisms. Conclusions: While preclinical evidence is promising, the current body of clinical data remains limited. Further well-designed randomized clinical trials are required to determine the efficacy, type of formulation, optimal dosing, and long-term safety of CBD as an adjunctive therapy in periodontal treatment. Full article

(This article belongs to the Section Drug Discovery, Development and Delivery)

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48 pages, 1144 KB

Open AccessReview

Strategies for Optimizing Genetic Mouse Models to Enhance the Understanding of Parkinson’s Disease

by Zhiqiang Shen, Linlin Ma and George D. Mellick

Biomedicines 2026, 14(5), 1162; https://doi.org/10.3390/biomedicines14051162 - 20 May 2026

Viewed by 877

Abstract

Background: Parkinson’s disease (PD) has become the fastest-growing neurodegenerative disorder worldwide. A valuable approach for unraveling the disease’s mechanisms and new therapeutic targets involves investigating the PD-causing genes identified in families exhibiting the Mendelian inheritance of parkinsonism. Methods: In this article, [...] Read more.

Background: Parkinson’s disease (PD) has become the fastest-growing neurodegenerative disorder worldwide. A valuable approach for unraveling the disease’s mechanisms and new therapeutic targets involves investigating the PD-causing genes identified in families exhibiting the Mendelian inheritance of parkinsonism. Methods: In this article, we review how genetically modified mouse models can be employed to decipher the genetic architecture of PD. Results: We first discuss how well the human motor and non-motor symptoms of PD are currently evaluated in these PD mouse models, highlighting limitations. The pathogenic roles of five inherited PARK genes in PD are then extensively examined through their respective genetic mouse models in terms of phenotypic and cellular impacts. Furthermore, we discuss the strengths and weaknesses of existing transgenic mouse models and highlight significant accomplishments and advancements in this field from 2018 to the present. Conclusions: Building upon the current understanding of PD, we propose potential directions for enhancing genetic mouse models to further unveil the underlying mechanisms of PD and advance therapeutic research. Full article

(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements (4th Edition))

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47 pages, 1607 KB

Open AccessReview

From Metabolically Healthy to Unhealthy Obesity Through Low-Grade Inflammation

by Anastasia Voznesenskaya, Alyona Sorokina, Marina Shestakova, Ekaterina Shestakova, Ildar Minniakhmetov, Anna Ivanova, Sergey Rumyantsev, Natalia Mokrysheva, Vladimir Chekhonin and Marina Loguinova

Biomedicines 2026, 14(5), 1161; https://doi.org/10.3390/biomedicines14051161 - 20 May 2026

Cited by 2 | Viewed by 1165

Abstract

Of the many clinical phenotypes of obesity, the most prevalent are metabolically “healthy” (MHO) and metabolically “unhealthy” (MUO) obesities, the latter being associated with a range of comorbidities, including type 2 diabetes mellitus (T2DM). The underlying causes of different obesity phenotypes and the [...] Read more.

Of the many clinical phenotypes of obesity, the most prevalent are metabolically “healthy” (MHO) and metabolically “unhealthy” (MUO) obesities, the latter being associated with a range of comorbidities, including type 2 diabetes mellitus (T2DM). The underlying causes of different obesity phenotypes and the mechanisms of conversion of one phenotype into another have yet to be fully elucidated. However, increasing evidence suggests the key role of low-grade metabolic inflammation (metaflammation) in the pathogenesis of obesity and metabolic dysfunction. The review presents a comprehensive description of changes in immune cell populations and pro-inflammatory mediators, as well as a detailed comparative mapping of the adipose tissue immune landscape during MHO/MUO transition. Based upon a conceptual model for the intensification of metaflammation during MHO progression and conversion to MUO, a pattern of dynamical changes that accompany MHO/MUO transition is described. Though many parameters demonstrate significant differences in multiple cross-sectional and some longitudinal studies, only a few of them (CRP, IL-6, IL-17A, absolute counts of leukocytes and neutrophils) meet the criteria of a validated biomarker in clinical setting. A lack of standardization in MHO definition and heterogeneity in the severity of MUO make the search for predictive biomarkers a challenge. The review also discusses the mechanisms underlying metabolic memory and the incomplete reversibility of metabolic disturbances after bariatric surgery. Full article

(This article belongs to the Special Issue Obesity and Obesity-Related Pathology)

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17 pages, 575 KB

Open AccessArticle

Sex and Atrial Fibrillation Independently Stratify Cardiac Remodeling and Outcomes in Heart Failure with Preserved Ejection Fraction

by Diana-Ruxandra Hădăreanu, Flavia-Mihaela Stoiculescu, Călin-Dinu Hădăreanu, Maria-Livia Iovănescu, Anca Mihu-Marinescu, Georgică-Costinel Târtea, Ionuț Donoiu, Oana Munteanu-Mirea, Răzvan-Ilie Radu, Eugen-Nicolae Țieranu, Octavian Istrătoaie and Cristina Florescu

Biomedicines 2026, 14(5), 1160; https://doi.org/10.3390/biomedicines14051160 - 20 May 2026

Viewed by 499

Abstract

Background/Objectives: Atrial fibrillation (AF) is common in heart failure with preserved ejection fraction (HFpEF) and is associated with worse symptoms and prognosis. Emerging evidence suggests that sex modifies the AF–HFpEF relationship through differences in atrial remodeling, comorbidity burden, and hemodynamic vulnerability. This [...] Read more.

Background/Objectives: Atrial fibrillation (AF) is common in heart failure with preserved ejection fraction (HFpEF) and is associated with worse symptoms and prognosis. Emerging evidence suggests that sex modifies the AF–HFpEF relationship through differences in atrial remodeling, comorbidity burden, and hemodynamic vulnerability. This study aimed to evaluate how sex and AF jointly relate to differences in cardiac structure, clinical characteristics, and outcomes in HFpEF. Methods: We retrospectively analyzed 622 patients with HFpEF admitted between January 2019 and May 2023. Patients were categorized into four predefined clinical subgroups: women without AF, women with AF, men without AF, and men with AF. The primary endpoint was first rehospitalization for HF decompensation. Results: Over a mean follow-up of 48.6 ± 16.4 months, 181 patients (29.1%) were rehospitalized for worsening HF, with the highest event burden observed in men with AF. Sex and AF were each associated with distinct clinical and remodeling profiles, without significant sex-by-AF interaction effects. AF was independently associated with a higher risk of HF rehospitalization (HR 1.45, 95% CI 1.06–1.99, p = 0.021), whereas female sex was protective (HR 0.71, 95% CI 0.53–0.97, p = 0.032). Men with AF exhibited the most adverse remodeling profile, characterized by the largest unindexed left atrial and left ventricular dimensions, the highest prevalence of significant tricuspid regurgitation, and the lowest event-free survival (HR 1.92, 95% CI 1.23–2.99, p = 0.004). In contrast, women with AF more frequently displayed concentric remodeling and significant mitral regurgitation. Independent predictors of rehospitalization included higher NYHA functional class and lower left ventricular EF within the preserved EF range. Conclusions: Sex and AF were independently associated with substantial differences in cardiac structure, clinical characteristics and prognosis in HFpEF. Men with AF represent the highest-risk subgroup, driven by more advanced structural remodeling and valvular dysfunction. These findings suggest that simple sex- and rhythm-based classification may provide complementary information for risk stratification and management in HFpEF. Further validation in independent cohorts is warranted. Full article

(This article belongs to the Special Issue Arrhythmia: Mechanisms, Biomarkers, and Emerging Therapies)

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3 pages, 564 KB

Open AccessCorrection

Correction: Di Crosta et al. Valemetostat–SAHA-Driven Acetylation of p53 via SET/TAF-Iβ Displacement and p300 Activation Modulates Cell Cycle Regulators in Pancreatic Cancer Cells. Biomedicines 2025, 13, 2279

by Michele Di Crosta, Francesca Chiara Ragone, Rossella Benedetti, Gabriella D’Orazi, Roberta Santarelli, Maria Saveria Gilardini Montani and Mara Cirone

Biomedicines 2026, 14(5), 1159; https://doi.org/10.3390/biomedicines14051159 - 20 May 2026

Viewed by 487

Abstract

In the original publication [...] Full article

(This article belongs to the Section Cell Biology and Pathology)

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20 pages, 4449 KB

Open AccessArticle

Multimodal Factor Analysis Reveals Five Robust Phenotypes of Healthy Aging in a Russian Population Cohort

by Lyubov V. Machekhina, Alexandra A. Melnitskaya, Mikhail S. Arbatskiy, Anna V. Permyakova, Alexey V. Churov, Irina D. Strazhesko and Olga N. Tkacheva

Biomedicines 2026, 14(5), 1158; https://doi.org/10.3390/biomedicines14051158 - 20 May 2026

Viewed by 706

Abstract

Background/Objectives: Population aging necessitates a shift from disease-focused paradigms to a holistic characterization of biological aging processes. While chronological age remains the primary metric, it poorly captures inter-individual variability in physiological resilience and health trajectories. This study aimed to identify robust, multidimensional aging [...] Read more.

Background/Objectives: Population aging necessitates a shift from disease-focused paradigms to a holistic characterization of biological aging processes. While chronological age remains the primary metric, it poorly captures inter-individual variability in physiological resilience and health trajectories. This study aimed to identify robust, multidimensional aging phenotypes independent of chronological age and sex using integrative factor analysis of heterogeneous biomedical data from a Russian cohort—a population underrepresented in aging research. Methods: We analyzed data from 1201 conditionally healthy adults (aged 18–99 years) enrolled in the RUSS AGE study. A comprehensive dataset comprising 118 variables across 11 modalities—including biochemical markers, anthropometry, physical function, cognitive-emotional assessments, lifestyle factors, and psychosocial indicators—was integrated using Multi-Omics Factor Analysis v2 (MOFA2). Following the extraction of 16 latent factors and residualization for demographic confounders, consensus clustering was performed to identify distinct aging phenotypes. Phenotype stability was internally recapitulated using gradient-boosting classifiers (XGBoost, CatBoost) in a stratified five-fold cross-validation and on a held-out test set. Results: MOFA2 identified 16 stable latent factors, explaining 21.3% of the total variance and capturing coordinated variation across metabolic, inflammatory, cardiovascular, cognitive, and behavioral domains. Consensus clustering revealed five reproducible phenotypes—Anemic (n = 82), Metabolically Subcompensated (n = 99), Metabolically Decompensated (n = 304), Overloaded (n = 302), and Balanced (n = 414)—characterized by distinct multisystem profiles independent of age (p > 0.05 after FDR correction) and sex. Supervised classification achieved high discriminative performance (macro F1-score = 0.75, OvR ROC-AUC = 0.93 on the held-out test set), quantifying the internal reconstructability of the phenotype labels from the original feature space rather than external generalization to an independent cohort. Conclusions: This study demonstrates the feasibility of data-driven, biologically coherent phenotyping of healthy aging using integrative factor analysis. The identified phenotypes represent stable configurations of physiological, functional, and psychosocial characteristics that transcend chronological age, providing a foundation for the future development of risk-stratification tools, preventive interventions, and biological-age calculators, subject to subsequent validation in longitudinal and independent external cohorts. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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14 pages, 3786 KB

Open AccessArticle

Bonding Performance of Etch-and-Rinse and Universal Adhesives for Metal Bracket Fixation: An In Vitro Mechanical and SEM Study

by Cristina Iosif, Anca Labunet, Andreea Kui, Stanca Cuc, Marioara Moldovan and Sorina Sava

Biomedicines 2026, 14(5), 1157; https://doi.org/10.3390/biomedicines14051157 - 20 May 2026

Viewed by 435

Abstract

Background: Durable adhesion between orthodontic brackets and enamel is essential for successful fixed orthodontic therapy. Despite simplified adhesive systems being available, conventional etch-and-rinse adhesives remain widely used due to their reliable enamel bonding. Methods: This in vitro study evaluated the bonding performance of [...] Read more.

Background: Durable adhesion between orthodontic brackets and enamel is essential for successful fixed orthodontic therapy. Despite simplified adhesive systems being available, conventional etch-and-rinse adhesives remain widely used due to their reliable enamel bonding. Methods: This in vitro study evaluated the bonding performance of three orthodontic adhesive strategies in combination with Transbond XT composite resin for metal bracket fixation. Thirty extracted human premolars were randomly allocated to three groups according to the adhesive system applied: OptiBond Solo Plus (etch-and-rinse method), SafeBond Universal DC (selective enamel etching method) and Transbond XT primer (control method). Shear adhesion resistance, maximum force and breakout force were measured and statistically analysed. Results: No statistically significant differences were observed between the OptiBond and SafeBond groups for any of the evaluated mechanical parameters (p > 0.05), although the OptiBond group exhibited higher mean values. The Transbond XT primer group showed significantly lower adhesion resistance and debonding forces than both of the other groups (p < 0.05). SafeBond demonstrated lower variability of results compared with OptiBond. Conclusions: When used with Transbond XT composite resin, both OptiBond Solo Plus and SafeBond Universal DC provided comparable mechanical performance for metal bracket bonding. While OptiBond yielded higher mean bond strength values, SafeBond exhibited more consistent behaviour. The Transbond XT primer alone resulted in inferior bonding performance. Full article

(This article belongs to the Special Issue Biomedicine in Dental and Oral Rehabilitation)

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15 pages, 10544 KB

Open AccessBrief Report

Effects of Transcutaneous Spinal Direct Current Stimulation on Cognitive and Psychological Outcomes in Multiple Sclerosis: A Preliminary Case Series

by Carmelo Campo, Daniele Saccenti, Angelica De Sandi, Denise Mellace, Simona Mrakic-Sposta, Sara Marceglia, Maurizio Vergari, Andrea Arighi, Alberto Priori and Roberta Ferrucci

Biomedicines 2026, 14(5), 1156; https://doi.org/10.3390/biomedicines14051156 - 20 May 2026

Viewed by 629

Abstract

Introduction: Multiple Sclerosis (MS) is frequently associated with a range of neurological, cognitive and psychological issues, presenting significant challenges to patients’ Quality of Life (QoL). Among non-invasive neuromodulation techniques, transcutaneous spinal Direct Current Stimulation (tsDCS) is emerging as a potential approach for [...] Read more.

Introduction: Multiple Sclerosis (MS) is frequently associated with a range of neurological, cognitive and psychological issues, presenting significant challenges to patients’ Quality of Life (QoL). Among non-invasive neuromodulation techniques, transcutaneous spinal Direct Current Stimulation (tsDCS) is emerging as a potential approach for symptom management in neurological conditions. However, the effects of tsDCS on MS remain poorly explored. Thus, this preliminary study aimed to evaluate the effects of tsDCS on MS symptomatology, focusing on cognitive and psychological variables. Methods: Six patients with MS were recruited for a randomized, sham-controlled, double-blind crossover study, and received anodal tsDCS or sham stimulation in two separate sessions at least one month apart. Assessment outcomes included cognitive and attentional-executive functions, depressive symptoms, and several QoL components. The tests were administered at baseline (T0), immediately after treatment (T1), one week (T2) and one month (T3) post-treatment. Results: Although protocol-by-time interactions did not reach statistical significance across all measures, protocol-independent improvements over time were observed in various QoL subscales, including Physical Functioning, Role Limitations due to Physical Health, Vitality, Health Distress, and Overall QoL. Conclusions: Our findings indicate that tsDCS is a feasible and well-tolerated intervention in patients with MS, with possible implications for QoL. Given the small sample size and the exploratory nature of this study, further research is needed to clarify whether tsDCS may represent a potentially beneficial non-invasive neuromodulation approach for improving well-being in patients with MS across both physical and mental dimensions. Full article

(This article belongs to the Special Issue Non-Invasive Brain Stimulation Techniques and Their Application in the Study of Cognitive Function Physiology and Neuro-Psychiatric Rehabilitation)

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27 pages, 1134 KB

Open AccessReview

RIPK 1 in Alzheimer’s Disease: Research Progress Integrating Pathogenesis on Necroptosis-Related Neuroinflammation, and Potential Therapeutic Strategies

by Ezgi Sila Toklucu, Shiqian Shen, Changning Wang and Can Zhang

Biomedicines 2026, 14(5), 1155; https://doi.org/10.3390/biomedicines14051155 - 20 May 2026

Viewed by 1486

Abstract

Background/Objectives: Alzheimer’s disease (AD) is the most common cause of dementia worldwide; however, there is incomplete understanding of AD pathogenesis, and there are few disease-modifying treatments for AD. Research has begun to demonstrate that necroptosis, which is a regulated type of cell [...] Read more.

Background/Objectives: Alzheimer’s disease (AD) is the most common cause of dementia worldwide; however, there is incomplete understanding of AD pathogenesis, and there are few disease-modifying treatments for AD. Research has begun to demonstrate that necroptosis, which is a regulated type of cell death mediated by receptor-interacting protein kinase 1 (RIPK1), plays a significant role in neurodegeneration and neuropathology associated with AD. The purpose of this review is to summarize current research regarding the role of RIPK1 in AD and possible therapeutic uses of RIPK1 inhibitors. Methods: This study is a narrative review of the literature summarizing experimental and clinical studies on RIPK1 signaling, necroptosis, neuroinflammation, and blood–brain barrier (BBB) dysfunction in AD. Results: The cumulative evidence demonstrates that RIPK1 activation associates with common AD pathways and particularly increases the severity of amyloid-β (Aβ) and tau pathology; promotes microglial activation; decreases the integrity of the BBB; and increases neuroinflammatory signaling in AD. Preclinical studies have shown that inhibiting RIPK1 genetically or pharmacologically in preclinical models decreased the extent of neurodegeneration and the rate of cognitive decline. Conclusions: RIPK1 is a key molecular link between necroptosis and neuroinflammation in AD. While the preclinical data are encouraging, further clinical research will be necessary to investigate RIPK1 changes in the brain, which may help better understand AD and establish the safety and effectiveness of potential therapeutic RIPK1 inhibitors in AD. Full article

(This article belongs to the Special Issue New Molecular Insights into the Pathogenesis and Drug Development of Neurodegenerative Diseases: 2nd Edition)

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26 pages, 957 KB

Open AccessArticle

Machine Learning-Based Prediction of Ultrasound-Detected Hepatic Steatosis Within the Metabolic Dysfunction-Associated Steatotic Liver Disease Spectrum Using Routine Clinical and Biochemical Parameters

by Canan Akkus, Gamze Sonmez, Ali Sahin, Yigit Yazarkan, Melis Gokgoz, Feride Caglar and Sanem Kayhan

Biomedicines 2026, 14(5), 1154; https://doi.org/10.3390/biomedicines14051154 - 20 May 2026

Viewed by 884

Abstract

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the leading cause of chronic liver disease globally, mirroring the increasing prevalence of obesity, insulin resistance, and type 2 diabetes. Early detection of hepatic steatosis is vital for cardiometabolic risk assessment; however, conventional imaging [...] Read more.

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the leading cause of chronic liver disease globally, mirroring the increasing prevalence of obesity, insulin resistance, and type 2 diabetes. Early detection of hepatic steatosis is vital for cardiometabolic risk assessment; however, conventional imaging is costly and impractical for population screening. This study aimed to develop interpretable machine-learning models to predict ultrasound-detected hepatic steatosis within the MASLD spectrum using routinely available clinical and biochemical data. Methods: We analyzed data from 644 adults, 50% of whom had ultrasound-detected hepatic steatosis. Preprocessing, imputation, and feature selection were implemented within a single scikit-learn pipeline to avoid information leakage. An Elastic Net-regularized logistic regression identified the top 20 predictors, which were subsequently used across nine supervised machine learning (ML) classifiers. Model performance was evaluated via repeated stratified 5-fold cross-validation (25 resamples) using accuracy, F1 score, sensitivity, specificity, Youden’s J, balanced accuracy, and Area Under the Receiver Operating Characteristic Curve (AUROC). Interpretability was assessed using SHapley Additive exPlanations (SHAP). Results: Participants with ultrasound-detected hepatic steatosis exhibited greater adiposity, insulin resistance, and dyslipidemia compared with controls [p < 0.05 for body mass index (BMI), waist circumference, glucose, glycated hemoglobin (HbA1c), triglycerides]. Elastic Net selection highlighted Weight, Ponderal Index, Fibrosis-4 Index (FIB-4), blood urea nitrogen (BUN)/Creatinine ratio, Aspartate Aminotransferase to Platelet Ratio Index (APRI), and Visceral Adiposity Index as the strongest predictors. Logistic Regression and Gradient Boosting achieved the best performance (accuracy = 0.65 ± 0.03; AUROC = 0.71 ± 0.04; balanced accuracy = 0.66 ± 0.06), outperforming rule-based indices such as Fatty Liver Index (FLI) and Hepatic Steatosis Index (HSI) reported in the literature. SHAP analysis confirmed clinically coherent feature effects, with higher anthropometric and hepatic injury indices increasing the predicted probability of ultrasound-detected hepatic steatosis. Conclusions: Routinely available clinical and biochemical parameters can predict hepatic steatosis with moderate accuracy using transparent, interpretable ML models. Logistic Regression and Gradient Boosting provided best discrimination and robust internal performance, offering a pragmatic, low-cost approach for early identification of ultrasound-detected hepatic steatosis within the MASLD spectrum in primary and metabolic care settings. Full article

(This article belongs to the Special Issue Emerging Trends in Liver Diseases and Cirrhosis Research)

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14 pages, 533 KB

Open AccessArticle

Associations Between Neuropathy, Nephropathy and Hearing Loss in Individuals with Type 2 Diabetes

by Joutiar Razay, Jesper Hvass Schmidt, Mette K. Andersen, Jens S. Nielsen, Michael Hecht Olsen and Thomas Bastholm Olesen

Biomedicines 2026, 14(5), 1153; https://doi.org/10.3390/biomedicines14051153 - 20 May 2026

Cited by 1 | Viewed by 768

Abstract

Aims: The aim of this study was to investigate the associations between symptomatic hearing loss (HL), neuropathy, and nephropathy in subjects with Type 2 diabetes mellitus (T2DM). Furthermore, the study evaluated whether HL was associated with chronic low-grade inflammation, assessed based on [...] Read more.

Aims: The aim of this study was to investigate the associations between symptomatic hearing loss (HL), neuropathy, and nephropathy in subjects with Type 2 diabetes mellitus (T2DM). Furthermore, the study evaluated whether HL was associated with chronic low-grade inflammation, assessed based on plasma levels of tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP), and explored potential sex-specific differences. Materials and Methods: We included 4245 subjects with T2DM from The Danish Centre for Strategic Research in Type 2 Diabetes cohort. Symptomatic HL was defined using ICD-10 codes. In 2016, a questionnaire was sent out to evaluate neuropathy using the Michigan Neuropathy Screening Instrument (MNSI ≥ 4). Nephropathy was defined as urinary albumin-to-creatinine ratio (UACR) >30 mg/g. Plasma levels of TNF-α, IL-6, and hsCRP were measured at enrolment from 2010 to 2016. Multivariable logistic regression was used, adjusting for covariates. Results: Neuropathy was significantly associated with HL (OR = 1.83, 95%CI [1.42, 2.35], p < 0.001), and the association was stronger in women (OR = 2.74 [1.81, 4.14], p < 0.001) compared to men (OR = 1.44 [1.04, 1.99], p < 0.05) (P-interaction = 0.020). No significant association was found between nephropathy and HL. Among inflammatory markers, only the highest tertile of TNF-α levels was significantly associated with HL compared to the lowest tertile (OR = 1.40 [1.07, 1.82], p < 0.05) without any sex interaction. Conclusions: In subjects with T2DM, neuropathy was associated with symptomatic HL, and the association seemed to be stronger in females. Among chronic low-grade inflammation markers, only TNF-α was significantly associated with symptomatic HL. Additionally, no significant association was found between nephropathy and HL. Full article

(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms in Diabetes and Cardiovascular Complications)

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13 pages, 1396 KB

Open AccessReview

Navigated Transcranial Magnetic Stimulation (nTMS): From Functional Brain Mapping to Clinical Applications in Neurosurgery and Neurology

by Marcin Karol Setlak, Bartłomiej Błaszczyk, Maciej Wojtacha and Adam Rudnik

Biomedicines 2026, 14(5), 1152; https://doi.org/10.3390/biomedicines14051152 - 19 May 2026

Cited by 1 | Viewed by 736

Abstract

Introduction: Navigated transcranial magnetic stimulation (nTMS) is an advanced, noninvasive method for stimulation-based functional brain mapping. Its main clinical value in neurosurgery lies in preoperative identification of eloquent cortical areas and the integration of functional information into neuronavigation-based surgical planning. State of the [...] Read more.

Introduction: Navigated transcranial magnetic stimulation (nTMS) is an advanced, noninvasive method for stimulation-based functional brain mapping. Its main clinical value in neurosurgery lies in preoperative identification of eloquent cortical areas and the integration of functional information into neuronavigation-based surgical planning. State of the Art: This narrative review with a structured literature search summarizes the historical and technical foundations of TMS/nTMS, but primarily focuses on neurosurgical applications, including motor and language mapping, comparison with functional MRI and direct cortical stimulation, safety considerations, and practical limitations. Broader neurological and therapeutic applications are discussed as contextual extensions rather than as a comprehensive disease-specific review. Clinical Implications: Current evidence is strongest for preoperative motor mapping in patients with tumors located in or near the motor–eloquent cortex. Language mapping, neurological diagnostics, and therapeutic repetitive TMS (rTMS) applications remain more heterogeneous and require careful interpretation according to the level of evidence, protocol standardization, and patient selection. Future Directions: Further multicenter studies, standardized mapping protocols, integration with advanced imaging and tractography, and health-system implementation strategies are needed to define the optimal role of nTMS in personalized neurosurgical and neurological care. Full article

(This article belongs to the Special Issue Intraoperative Neurophysiology: New Perspectives and Clinical Applications)

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26 pages, 5074 KB

Open AccessArticle

Wavelet-Enhanced CNN for Breast Ultrasound Classification Under Speckle Noise

by Ratapong Onjun, Tanakorn Sritarapipat and Sayan Kaennakham

Biomedicines 2026, 14(5), 1151; https://doi.org/10.3390/biomedicines14051151 - 19 May 2026

Viewed by 671

Abstract

Background/Objectives: Ultrasound is widely used for breast cancer screening and diagnosis, particularly in low- and middle-income settings, but its diagnostic reliability is often compromised by speckle noise that degrades lesion margins and tissue texture. This study proposes a compact convolutional neural network architecture [...] Read more.

Background/Objectives: Ultrasound is widely used for breast cancer screening and diagnosis, particularly in low- and middle-income settings, but its diagnostic reliability is often compromised by speckle noise that degrades lesion margins and tissue texture. This study proposes a compact convolutional neural network architecture that replaces standard max or average pooling layers with wavelet-based pooling using Symlet families, and optionally includes wavelet-domain preprocessing to suppress input noise. Methods: We conducted 108 experiments across six pooling configurations (avg, max, Sym2 ± preprocessing, Sym4 + preprocessing, Sym6 + preprocessing), two network depths, three batch sizes, and three simulated speckle levels (0%, 10%, 20%). Results: The proposed wavelet-based pooling framework showed consistently stronger in-domain performance than conventional pooling strategies across clean and speckle-corrupted settings, with the Sym2 + preprocessing configuration giving the best overall results. The model achieved 93.90% accuracy and 98.89% ROC AUC under clean internal test conditions and maintained stable performance under increased simulated noise levels. However, external validation on the independent BrEaST-Lesions-USG dataset revealed substantial performance degradation, with accuracy decreasing to 53.97% and ROC AUC to 0.4713, indicating limited cross-dataset generalization. Conclusions: These findings suggest that wavelet pooling is an effective architectural modification for improving in-domain robustness under controlled perturbation, although additional strategies are still required before reliable real-world deployment can be claimed. Full article

(This article belongs to the Special Issue AI/Machine Learning-Driven Multi-Omics Research in Oncology)

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13 pages, 597 KB

Open AccessArticle

Liver Fibrosis Estimated Using Noninvasive Blood Biochemical Indices Is Correlated with Visit-to-Visit Glycated Hemoglobin A1c Variability in Individuals with Type 2 Diabetes

by Yousuke Kaneko, Taiki Hori, Kohsuke Miyataka, Takahito Asai, Tomoyo Hara, Hiroki Yamagami, Toshiki Otoda, Tomoyuki Yuasa, Akio Kuroda, Shingen Nakamura, Itsuro Endo, Munehide Matsuhisa, Ken-ichi Matsuoka and Ken-ichi Aihara

Biomedicines 2026, 14(5), 1150; https://doi.org/10.3390/biomedicines14051150 - 19 May 2026

Viewed by 717

Abstract

Background/Objectives: Visit-to-visit glycated hemoglobin A1c (HbA1c) variability is associated with cardiovascular diseases (CVDs) and all-cause mortality, independent of mean HbA1c levels. Metabolic dysfunction–associated steatotic liver disease (MASLD) is associated with CVDs and mortality. We aimed to clarify the association between annual HbA1c variability [...] Read more.

Background/Objectives: Visit-to-visit glycated hemoglobin A1c (HbA1c) variability is associated with cardiovascular diseases (CVDs) and all-cause mortality, independent of mean HbA1c levels. Metabolic dysfunction–associated steatotic liver disease (MASLD) is associated with CVDs and mortality. We aimed to clarify the association between annual HbA1c variability and MASLD development in individuals with type 2 diabetes (T2D). Methods: A retrospective cohort study was conducted in 402 Japanese patients (219 men, 183 women) with T2D. The participants’ HbA1c levels were measured every 2 months, and their HbA1c coefficient of variation (HbA1c-CV) was calculated from the HbA1c in the past year. We statistically evaluated the association between HbA1c-CV and noninvasive clinical indices of MASLD, including the hepatic steatosis index (HSI), fibrosis-4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and non-alcoholic fatty liver disease fibrosis score (NFS). Results: Multiple regression analysis of clinical variables and each MASLD index showed that all liver fibrosis indices, including the FIB-4 index (p < 0.001), APRI (p = 0.005), and NFS (p < 0.001), were positively correlated with HbA1c-CV, whereas the HSI was not (p = 0.148). These associations remained even after adjusting for the medications used in the participants. Conclusions: The development of liver fibrosis, estimated using noninvasive blood biochemical indices, is independently and positively associated with annual HbA1c-CV in individuals with T2D. This result suggests that a comprehensive approach, including early MASLD risk stratification, may be beneficial for optimal diabetes management. Full article

(This article belongs to the Section Endocrinology and Metabolism Research)

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13 pages, 702 KB

Open AccessArticle

Association of Preoperative Platelet-Activating Factor and Postoperative C-Reactive Protein with Inflammatory Burden and Early Outcomes After Major Cardiac Surgery

by Adrian Stef, Gabriel Cismaru, Aurelia Georgeta Solomonean, Nadina Tintiuc, Tudor-Mihai Magdaș and Alexandru Oprea

Biomedicines 2026, 14(5), 1149; https://doi.org/10.3390/biomedicines14051149 - 19 May 2026

Viewed by 530

Abstract

Background: Major cardiac surgery with cardiopulmonary bypass (CPB) induces a systemic inflammatory response that contributes to postoperative organ dysfunction and hemodynamic instability. While C-reactive protein (CRP) is a well-established downstream marker of postoperative inflammation, the upstream determinants of interindividual variability in inflammatory burden [...] Read more.

Background: Major cardiac surgery with cardiopulmonary bypass (CPB) induces a systemic inflammatory response that contributes to postoperative organ dysfunction and hemodynamic instability. While C-reactive protein (CRP) is a well-established downstream marker of postoperative inflammation, the upstream determinants of interindividual variability in inflammatory burden are not fully understood. Platelet-activating factor (PAF) is a potent inflammatory mediator implicated in platelet activation, endothelial dysfunction, and vascular dysregulation, but its role in modulating postoperative inflammation and clinical outcomes after cardiac surgery has not been fully characterized. Methods: We conducted a retrospective observational study of 87 patients undergoing major cardiac surgery with CPB. Preoperative plasma PAF levels and postoperative CRP concentrations were measured, and patients were stratified according to postoperative CRP severity. Associations between PAF, inflammatory response, postoperative vasoactive–inotropic requirements, recovery parameters, acute kidney injury, and mortality were assessed using correlation analyses, multivariable regression models, and receiver operating characteristic curve analyses. Results: Preoperative PAF levels increased progressively across postoperative CRP strata (p < 0.001) and were strongly associated with postoperative CRP concentrations in both univariate and multivariable analyses. Specifically, each 1000 pg/mL increase in preoperative PAF was associated with an adjusted increase of 36.0 mg/L in postoperative CRP (β = 36.0; p < 0.001). Each 1000 pg/mL increase in preoperative PAF was associated with an adjusted increase of approximately 36 mg/L in postoperative CRP. Elevated PAF was also associated with increased intermediate postoperative vasoactive–inotropic requirements and a modest increase in hospital length of stay (r = 0.25, p = 0.023). However, neither PAF nor CRP independently predicted AKI or mortality after adjustment for clinical variables. Discriminative performance for mortality was modest for both biomarkers. Conclusions: Preoperative platelet-activating factor was strongly associated with postoperative inflammatory burden and early hemodynamic instability following major cardiac surgery. Although PAF and CRP were not independent predictors of adverse outcomes, they may help identify a biologically vulnerable phenotype characterized by exaggerated inflammatory and vascular responses to surgical stress. These findings support further investigation of platelet-mediated inflammatory pathways as targets for perioperative risk stratification and mechanistic research. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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1 pages, 134 KB

Open AccessRetraction

RETRACTED: Li et al. Protective Effects of Astaxanthin Supplementation Against Ultraviolet-Induced Photoaging in Hairless Mice. Biomedicines 2020, 8, 18

by Xing Li, Tomohiro Matsumoto, Miho Takuwa, Mahmood Saeed Ebrahim Shaiku Ali, Takumi Hirabashi, Hiroyo Kondo and Hidemi Fujino

Biomedicines 2026, 14(5), 1148; https://doi.org/10.3390/biomedicines14051148 - 19 May 2026

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Abstract

The journal has retracted the article “Protective Effects of Astaxanthin Supplementation against Ultraviolet-Induced Photoaging in Hairless Mice” [...] Full article

(This article belongs to the Section Drug Discovery, Development and Delivery)

14 pages, 268 KB

Open AccessReview

Metabolic Dysfunction-Associated Steatotic Liver Disease: An Update Narrative Review of the Therapeutic Potential of Combining Probiotics and Metformin

by Syifa Mustika, Sri Utami, Nur Estu Wijayanti Saputri, Levrita Nindya Poetri, Putu Ijiya Danta Awatara, Achmad Rudijanto, Hery Djagat Purnomo, Cosmas Rinaldi A. Lesmana and Ahmad Taufiq

Biomedicines 2026, 14(5), 1147; https://doi.org/10.3390/biomedicines14051147 - 19 May 2026

Viewed by 942

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has replaced older exclusion-based terminology as the preferred term for steatotic liver disease associated with cardiometabolic risk factors. MASLD is now among the most common causes of chronic liver disease and may progress from simple steatosis to [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has replaced older exclusion-based terminology as the preferred term for steatotic liver disease associated with cardiometabolic risk factors. MASLD is now among the most common causes of chronic liver disease and may progress from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. This updated rigorous narrative review synthesizes current evidence on MASLD diagnosis and management, with emphasis on the gut–liver axis and the therapeutic potential of combining probiotics with metformin. A structured narrative search was conducted in PubMed, PMC, ScienceDirect, Taylor & Francis, Cochrane Library, and Google Scholar using the keywords “MASLD”, “MAFLD”, “NAFLD”, “MASH”, “probiotics”, “synbiotics”, “metformin”, and “gut-liver axis”. The review was designed as a narrative synthesis rather than a systematic review. Current guidance supports stepwise risk stratification using serum fibrosis scores followed by elastography or advanced imaging when indicated. Ultrasonography remains accessible but has limited sensitivity for mild steatosis, is operator-dependent, and is not sufficient for comprehensive assessment of fibrosis or disease activity. Metformin is appropriate for type 2 diabetes mellitus and improves insulin resistance, but current guidelines do not recommend it as a targeted treatment for MASH because histological benefit has not been consistently demonstrated. Probiotics and synbiotics may improve aminotransferases, inflammatory markers, lipid parameters, intestinal barrier function, and gut dysbiosis; however, findings vary by strain, formulation, dose, treatment duration, population, and endpoint. The combination of probiotics and metformin is mechanistically plausible because it targets both metabolic dysfunction and intestinal dysbiosis, but human evidence remains limited. Larger, strain-specific, adequately powered trials using standardized MASLD criteria and clinically meaningful endpoints are required before routine clinical recommendations. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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Biomedicines, Volume 14, Issue 5 (May 2026) – 228 articles

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