Biomedicines

21 pages, 2390 KB

Open AccessArticle

Mandibular Advancement Device Therapy in 182 DISE-Selected Adults with Moderate-to-Severe Obstructive Sleep Apnea: A Multicenter Real-World Study

by Marc J. Braem, Muriel Lins, Annelies Van Den Bergh, Frans Verhelst, Leslee Willes and Ellen Collier

Biomedicines 2026, 14(7), 1652; https://doi.org/10.3390/biomedicines14071652 - 22 Jul 2026

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Abstract

Background/Objectives: The study evaluates the effectiveness of mandibular advancement device (MAD) treatment in drug-induced sleep endoscopy (DISE) preselected adults with moderate-to-severe obstructive sleep apnea (OSA). Methods: It is a retrospective observational cohort study without a control arm/treatment, including 182 patients with [...] Read more.

Background/Objectives: The study evaluates the effectiveness of mandibular advancement device (MAD) treatment in drug-induced sleep endoscopy (DISE) preselected adults with moderate-to-severe obstructive sleep apnea (OSA). Methods: It is a retrospective observational cohort study without a control arm/treatment, including 182 patients with an apnea–hypopnea index (AHI) ≥ 15 events/h of sleep (Level-1 polysomnography) from six Belgian hospitals. After DISE preselection, a custom-made MAD (EVO, ProSomnus, Pleasanton, CA, USA) was titrated to symptom relief or physiological limits. Level-3 home polygraphy with MAD was performed within five months. The primary outcome was change in AHI from baseline. Secondary outcomes included percentage change in AHI, change in OSA severity category, snoring loudness and Epworth Sleepiness Scale (ESS) scores. Analysis of covariance methods adjusting for baseline AHI were employed. Exploratory analyses compared outcome measures by OSA severity at baseline. ‘Success’ equaled AHI < 10 with ≥50% improvement. Results: Mean AHI significantly decreased from 24.4 to 7.1 (p < 0.0001) with a significant mean percent decrease by 68.6% (p < 0.0001), improving more (p < 0.0001) in severe cases. Mean change in snoring loudness improved significantly from a mean of 7.1 to 1.7 (p < 0.0001), improving more (p = 0.049) in moderate cases. Mean change from baseline in overall ESS score was −1.7 (p < 0.0001). Greater improvements were observed in participants with elevated baseline ESS scores. MAD significantly (p = 0.03) improved OSA category: moderate OSA cases improved by a mean of 1.4 levels, severe cases by a mean of 2.1 levels (p < 0.0001). A total of 75.8% of participants achieved ‘Success’. Conclusions: In this retrospective multicenter cohort, MAD therapy was associated with significant reductions in AHI, snoring loudness, and ESS scores among DISE-preselected adults with moderate-to-severe OSA. Because treatment outcomes were assessed using Level-3 home polygraphy, the findings should be interpreted as real-world effectiveness outcomes obtained within the Belgian clinical care pathway. Full article

(This article belongs to the Special Issue Obstructive Sleep Apnea: Mechanisms, Comorbidities, and Optimization of Emerging and Established Therapies)

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16 pages, 3248 KB

Open AccessArticle

Discovery of a Novel 4,5-Dihydro-1H-pyrazole-1-carbothioamide Derivative with Cytotoxic, Apoptotic, and ABL1 Inhibitory Activities Against Chronic Myeloid Leukemia

by Ayben Erkan, Ayca Irgit Calayir, Halilibrahim Ciftci and Belgin Sever

Biomedicines 2026, 14(7), 1651; https://doi.org/10.3390/biomedicines14071651 - 22 Jul 2026

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Abstract

Background/Objectives: Chronic myeloid leukemia (CML) is a hematological malignancy driven by the constitutively active BCR-ABL1 fusion protein. Although current ABL1 tyrosine kinase inhibitors (TKIs) have improved CML management, resistance remains a major challenge, highlighting the need for novel therapeutic strategies. Methods: [...] Read more.

Background/Objectives: Chronic myeloid leukemia (CML) is a hematological malignancy driven by the constitutively active BCR-ABL1 fusion protein. Although current ABL1 tyrosine kinase inhibitors (TKIs) have improved CML management, resistance remains a major challenge, highlighting the need for novel therapeutic strategies. Methods: A chalcone derivative containing naphthalene and toluene moieties (A) was synthesized from 2-acetonaphthone and p-tolualdehyde and subsequently converted into a novel 4,5-dihydro-1H-pyrazole-1-carbothioamide derivative (B) through reaction with thiosemicarbazide. The cytotoxicity of compounds A and B against K562 CML cells was evaluated using the MTT assay. The active compound was further investigated for cytotoxic selectivity using HL-60 acute myeloid leukemia (AML) cells and healthy PBMCs. Apoptotic effects in K562 cells were analyzed using Annexin V/ethidium homodimer staining, whereas ABL1 inhibitory activity was determined using the ADP-Glo kinase assay. The potential interaction between the active compound and ABL1 was assessed by molecular docking analysis. Results: Compound B displayed potent cytotoxic activity against K562 cells with an IC₅₀ value of 6.92 ± 1.14 µM and demonstrated selectivity toward leukemic cells over PBMCs (SI = 5.4). Treatment with compound B markedly induced apoptosis in K562 cells. In addition, compound B inhibited ABL1 activity in a concentration-dependent manner. Molecular docking studies revealed a favorable binding orientation within the ATP-binding pocket of ABL1. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) analysis predicted favorable pharmacokinetic properties for compound B. Conclusions: These findings demonstrate that compound B possesses cytotoxic, pro-apoptotic, and ABL1 inhibitory activities against CML cells and may serve as a promising lead structure for the development of novel therapeutic agents targeting CML. Full article

(This article belongs to the Special Issue Bioactive Compounds as Therapeutic Leads: From Natural Sources to Mechanisms and Translation)

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17 pages, 821 KB

Open AccessArticle

Occult Parathyroid Lesions on ^99mTc-Sestamibi Scintigraphy: Morphometric, Histopathological and Anatomical Determinants of Detection

by Oriana-Eliana Pelineagră, Ioana Golu, Melania Balaș, Daniela Georgiana Amzăr, Iulia Plotuna, Oana Popa, Diana Aruncutean, Dan Cristian Roşu, Ion Icma, Agneta Maria Pusztai, Mărioara Cornianu, Mihaela Iacob, Nicu Olariu and Mihaela Vlad

Biomedicines 2026, 14(7), 1650; https://doi.org/10.3390/biomedicines14071650 - 22 Jul 2026

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Abstract

Background: Accurate preoperative localization of hyperfunctioning parathyroid glands remains challenging, particularly in secondary hyperparathyroidism where multiglandular disease may compromise scintigraphic performance. Methods: Our study evaluated biochemical, morphometric, and histopathological predictors of ^99mTc-sestamibi scintigraphy detectability in both primary and secondary hyperparathyroidism. [...] Read more.

Background: Accurate preoperative localization of hyperfunctioning parathyroid glands remains challenging, particularly in secondary hyperparathyroidism where multiglandular disease may compromise scintigraphic performance. Methods: Our study evaluated biochemical, morphometric, and histopathological predictors of ^99mTc-sestamibi scintigraphy detectability in both primary and secondary hyperparathyroidism. The study group included a total of 162 patients with primary and secondary hyperparathyroidism who underwent dual-phase ^99mTc-sestamibi scintigraphy followed by parathyroidectomy. Demographics, biochemical parameters, histopathological features, lesion volume and scintigraphic findings were assessed at patient and lesion level. Results: In primary hyperparathyroidism, adenomas were larger and more frequently detected than hyperplastic glands. Lesion volume and solid growth pattern were found as positive predictors of sestamibi uptake. In secondary hyperparathyroidism, nodular hyperplasia was associated with larger volume, higher cellularity, and more frequent localizing studies. Upper quadrant position and diffusely hyperplastic lesions were associated with higher lesion miss rates, while lesion volume increased the likelihood of detection. Conclusions: Our findings highlight that ^99mTc-sestamibi scintigraphy performance is strongly influenced by lesion volume, histopathological architecture and anatomical position, underscoring the needs for cautious interpretation of negative or incomplete scans, especially in secondary hyperparathyroidism. Full article

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

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16 pages, 293 KB

Open AccessReview

Sickle Cell Disease: From Ancient Origins to Modern Breakthroughs in Gene Therapy

by Bawo Ikolo, Mathew Oyelami, Odinaka Mgbeke, Kwami Jones, Shellon Thomas and Felicia Ikolo

Biomedicines 2026, 14(7), 1649; https://doi.org/10.3390/biomedicines14071649 - 22 Jul 2026

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Abstract

Sickle Cell Disease (SCD) is a hereditary hemoglobinopathy arising from a single-nucleotide transversion (GAG → GTG) at codon six of the HBB gene on chromosome 11, substituting glutamic acid with valine in the β-globin chain and producing hemoglobin S (HbS). Under hypoxic conditions, [...] Read more.

Sickle Cell Disease (SCD) is a hereditary hemoglobinopathy arising from a single-nucleotide transversion (GAG → GTG) at codon six of the HBB gene on chromosome 11, substituting glutamic acid with valine in the β-globin chain and producing hemoglobin S (HbS). Under hypoxic conditions, HbS polymerizes and distorts erythrocytes into the characteristic sickle shape, initiating a cascade of vaso-occlusion, chronic hemolytic anemia, and progressive multi-organ damage that defines the clinical burden of this disease. Although SCD has ancient origins in sub-Saharan Africa, the Indian subcontinent, the Middle East, and the Mediterranean, regions where it conferred heterozygous resistance to malaria, the ease of human migration has long since made it a global health concern, affecting an estimated 300,000–400,000 newborns annually. Advances in molecular and genomic research have deepened our understanding of SCD pathophysiology, revealing the central contributions of hemoglobin polymerization, oxidative stress, endothelial inflammation, and nitric oxide depletion to disease progression. Current management rests on supportive pharmacological interventions, including hydroxyurea, chronic transfusion therapy, L-glutamine, and multimodal pain management, complemented by lifestyle modifications. Curative approaches have advanced substantially: hematopoietic stem cell transplantation (HSCT) remains the established standard of cure, while the regulatory approvals in late 2023 of the CRISPR/Cas9-based exagamglogene autotemcel (Casgevy) and the lentiviral vector-based lovotibeglogene autotemcel (Lyfgenia) represent the most transformative development in the history of SCD therapeutics. This review traces the disease from its ancient origins and molecular characterization through to its clinical manifestations, inheritance patterns, screening strategies, and the full spectrum of current and emerging therapies. Persistent challenges, prohibitive treatment costs, healthcare inequities, the ethical dimensions of genome editing, and the urgent need for long-term safety data, are examined critically, with a view to informing the research and policy agenda that must accompany these remarkable scientific advances. Full article

(This article belongs to the Special Issue Advances in Rare and Complex Multisystem Disorders: From Molecular Mechanisms to Clinical Practice)

21 pages, 2045 KB

Open AccessArticle

Reannotation of Public Transcriptomic Data Identifies Candidate lncRNAs and Putative Regulatory Networks in Rhabdomyosarcoma

by Jessica Zablocki da Luz, Leonardo Vinícius Barbosa, Thiago Rodrigues dos Santos, Aliciane de Almeida Roque, Camila Confortin, Amanda Beatriz Soares Fulan, Lúcia de Noronha, Deisy Morselli Gysi and Cleber Machado-Souza

Biomedicines 2026, 14(7), 1648; https://doi.org/10.3390/biomedicines14071648 - 22 Jul 2026

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Abstract

Background/Objectives: Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, includes two main subtypes, embryonal (eRMS) and alveolar (aRMS), each with distinct molecular and clinical characteristics. Although cellular processes underlying RMS and differences between PAX3-FOXO1 fusion-positive and fusion-negative tumors are well known, [...] Read more.

Background/Objectives: Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, includes two main subtypes, embryonal (eRMS) and alveolar (aRMS), each with distinct molecular and clinical characteristics. Although cellular processes underlying RMS and differences between PAX3-FOXO1 fusion-positive and fusion-negative tumors are well known, the contribution of long noncoding RNAs (lncRNAs) remains poorly understood. Methods: Here, we reannotated publicly available microarray datasets to comprehensively profile lncRNA expression and reconstruct lncRNA–miRNA–mRNA regulatory networks in RMS. Results: We identified several lncRNAs with subtype-specific differential expression, including HOTAIR as a potential sponge for miR-206, DSCR8 for miR-885-5p, and PRKCQ-AS1 for miR-515-5p in eRMS. Database-supported interaction analyses identified putative regulatory relationships between these lncRNAs and cancer-related miRNAs and mRNAs. Validation using the St. Jude Cloud PeCan platform confirmed distinct lncRNA expression signatures across RMS subtypes and other pediatric solid tumors, supporting subtype-specific regulation. Conclusions: Our findings provide an updated characterization of the lncRNA landscape in RMS and identify candidate lncRNA–miRNA–mRNA regulatory networks that may contribute to disease biology. The proposed regulatory interactions are hypothesis-generating and require experimental validation. Overall, our findings provide a resource for future functional studies and support the investigation of lncRNAs as potential biomarkers and therapeutic targets in RMS. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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22 pages, 2942 KB

Open AccessArticle

Apabetalone Drives a Metabolic Shift Towards Ketogenesis and Reduces Liver Steatosis in Diet-Induced Obesity Mice

by Laura M. Tsujikawa, Agostina Carestia, Sylwia Wasiak, Christopher D. Sarsons, Ravi Jahagirdar, Salman Azhar, Dean Gilham, Derek Li, Li Fu, Jan O. Johansson, Norman C. W. Wong, Michael Sweeney and Ewelina Kulikowski

Biomedicines 2026, 14(7), 1647; https://doi.org/10.3390/biomedicines14071647 - 22 Jul 2026

Viewed by 851

Abstract

Background/Objectives: Obesity can cause metabolic disorders and hepatic steatosis. Continuous hepatic influx of dietary lipids leads to adaptive metabolic changes, including increased fatty acid oxidation (FAO) and ketogenesis. However, these adaptations are not enough to counter the detrimental accumulation of lipids, resulting [...] Read more.

Background/Objectives: Obesity can cause metabolic disorders and hepatic steatosis. Continuous hepatic influx of dietary lipids leads to adaptive metabolic changes, including increased fatty acid oxidation (FAO) and ketogenesis. However, these adaptations are not enough to counter the detrimental accumulation of lipids, resulting in hepatic steatosis. Apabetalone is a clinical-stage Bromodomain and Extra-Terminal domain inhibitor (BETi) that attenuated the increase in hepatic fibrosis score (FS) and reduced the rate of ischemic major adverse cardiovascular events and hospitalizations for heart failure in a subgroup of patients having a high likelihood of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in the phase 3 clinical trial, BETonMACE. Methods: To analyze apabetalone’s effects on lipid and ketone metabolism, RNA seq, Oil Red staining and triglyceride quantification were performed in livers from a mouse model of diabetes-induced obesity and ketones were measured in plasma. Results: Mice fed a high-fat diet (HFD) were obese and demonstrated liver steatosis. Apabetalone treatment maintained the beneficial metabolic adaptation induced by HFD (increased FAO) and decreased hepatic triglycerides and lipid droplets. This inhibition of lipid anabolism redirected substrates to FAO and ketogenesis, resulting in increased plasma ketones, showing for the first time the role of BETi in ketogenesis. In the heart, apabetalone treatment reduced cardiac oxidative stress and plasma NT-proBNP levels. Conclusions: Apabetalone improves hepatic lipid handling, favoring ketogenesis. As ketones have demonstrated beneficial effects on cardiac function, increased ketones induced by apabetalone may not only contribute to the observed attenuation of FS in patients, but also a reduction in cardiac events among patients with high likelihood of MASLD, as well as in the overall trial population. Full article

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

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14 pages, 6184 KB

Open AccessArticle

Losartan Ameliorates Coronary Neointimal Thickening in a Mouse Model of Kawasaki Disease: A Pilot Study

by Eisuke Suganuma, Satoko Honda, Rina Umiguchi, Sayaka Ishikawa, Ayako Shimamura, Marina Tanaka, Masashi Kyushiki and Atsuko Nakazawa

Biomedicines 2026, 14(7), 1646; https://doi.org/10.3390/biomedicines14071646 - 22 Jul 2026

Viewed by 510

Abstract

Background: Patients with Kawasaki disease (KD) who develop coronary artery aneurysms (CAAs) are at increased risk of future fatal coronary events. Pharmacotherapeutic strategies to prevent coronary stenosis are still lacking. In this exploratory study, the therapeutic effect of the angiotensin receptor blocker (ARB) [...] Read more.

Background: Patients with Kawasaki disease (KD) who develop coronary artery aneurysms (CAAs) are at increased risk of future fatal coronary events. Pharmacotherapeutic strategies to prevent coronary stenosis are still lacking. In this exploratory study, the therapeutic effect of the angiotensin receptor blocker (ARB) losartan on coronary artery (CA) stenosis was investigated in a murine model. Methods: Five-week-old male C57BL/6J mice were intraperitoneally injected with 1000 μg of Lactobacillus casei cell wall extract (LCWE) (n = 12) to induce CA stenosis. Two weeks later, the LCWE-injected mice (n = 12) were divided into two groups: six received drinking water containing losartan (100 mg/L) (LCWE+ARB), while six received normal drinking water (LCWE group). A control group (n = 5) received phosphate-buffered saline (PBS) instead of LCWE. Sixteen weeks after LCWE administration—corresponding to the peak of CA stenosis and 14 weeks after treatment initiation—the mice were euthanized for histological evaluation of the coronary arteries. Results: Losartan treatment significantly reduced the coronary arteritis score (median [IQR (interquartile range)]: 0 [0–9.5] vs. 21.5 [15–24.3], p = 0.003). LCWE-induced neointimal formation with vascular smooth muscle cell proliferation and subsequent CA stenosis were markedly attenuated in losartan-treated mice (25% vs. 100%, p < 0.001). Losartan-associated attenuation of CA stenosis was accompanied by the preservation of medial calponin expression, a reduction in the number of proliferating cell nuclear antigen (PCNA)-positive cells in the neointima, and a decrease in serum MMP-9 (matrix metalloproteinase-9) levels. Conclusions: These findings from a murine model of KD provide preliminary evidence that losartan may attenuate coronary artery remodeling. Further mechanistic studies are warranted to clarify its potential translational relevance. Full article

(This article belongs to the Special Issue Updates on Kawasaki Disease)

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13 pages, 526 KB

Open AccessArticle

Pediatric Lower Gastrointestinal Bleeding: Endoscopic and Histopathologic Spectrum in a 16-Year Tertiary-Center Cohort

by Kamile Merve Bircan, Abdulkerim Elmas and Mustafa Akçam

Biomedicines 2026, 14(7), 1645; https://doi.org/10.3390/biomedicines14071645 - 21 Jul 2026

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Abstract

Objectives: Pediatric lower gastrointestinal bleeding encompasses a broad and age-dependent spectrum of conditions, ranging from benign anorectal disorders to inflammatory bowel disease, colorectal polyps, and less common structural or vascular lesions. Despite advances in diagnostic evaluation, contemporary pediatric data on the distribution [...] Read more.

Objectives: Pediatric lower gastrointestinal bleeding encompasses a broad and age-dependent spectrum of conditions, ranging from benign anorectal disorders to inflammatory bowel disease, colorectal polyps, and less common structural or vascular lesions. Despite advances in diagnostic evaluation, contemporary pediatric data on the distribution of underlying diagnoses, particularly according to age and sex, remain limited. This study aimed to evaluate the endoscopic and histopathologic spectrum of pediatric lower gastrointestinal bleeding and to examine age- and sex-related diagnostic patterns. Methods: This retrospective single-center study included children aged 0–18 years who presented with overt lower gastrointestinal bleeding and underwent colonoscopic evaluation at a tertiary pediatric gastroenterology center between May 2010 and May 2026. Demographic data, colonoscopic and histopathologic findings, final diagnoses, inflammatory bowel disease subtypes, and polyp histopathology were reviewed. Patients were categorized into four age groups: 0–3, 4–6, 7–12, and 13–18 years. Results: A total of 268 children were included. The mean age was 11.4 ± 4.9 years, and 130 patients were female (48.5%). The most common diagnosis was inflammatory bowel disease, identified in 79 patients (29.5%), including 62 with ulcerative colitis and 17 with Crohn’s disease. Normal colonoscopic and histopathologic findings were observed in 65 patients (24.3%), anal fissure in 63 (23.5%), and polypoid lesions in 30 (11.2%). Juvenile polyp was the most common polyp subtype. Diagnostic distribution differed significantly across age groups (p < 0.001). Inflammatory bowel disease was more frequent among adolescents, whereas polypoid lesions were most common in children aged 4–6 years. Exploratory sex-based analyses suggested a female predominance in ulcerative colitis and a male predominance in Crohn’s disease and polypoid lesions. Conclusions: In children undergoing colonoscopic evaluation for lower gastrointestinal bleeding, inflammatory bowel disease, normal findings, anal fissure, and polypoid lesions were the leading diagnostic categories. Age- and sex-related patterns may help guide clinical evaluation and interpretation of colonoscopic and histopathologic findings. Full article

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

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35 pages, 2407 KB

Open AccessReview

Unconventional Applications of Semaglutide and Tirzepatide: From Oncology to Human Reproduction

by Sandro La Vignera and Rosita A. Condorelli

Biomedicines 2026, 14(7), 1644; https://doi.org/10.3390/biomedicines14071644 - 21 Jul 2026

Viewed by 1323

Abstract

Semaglutide and tirzepatide, glucagon-like peptide-1 (GLP-1) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists, respectively, have revolutionized the management of type 2 diabetes mellitus and obesity. Beyond their established metabolic indications, emerging preclinical and clinical evidence suggests these incretin-based therapies exert pleiotropic effects [...] Read more.

Semaglutide and tirzepatide, glucagon-like peptide-1 (GLP-1) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists, respectively, have revolutionized the management of type 2 diabetes mellitus and obesity. Beyond their established metabolic indications, emerging preclinical and clinical evidence suggests these incretin-based therapies exert pleiotropic effects across multiple organ systems through mechanisms extending beyond glycemic control and weight reduction. This comprehensive review synthesizes current evidence for unconventional applications of semaglutide and tirzepatide across five distinct therapeutic domains: oncology, psychiatry and addiction medicine, orthopedics, aesthetic medicine, and human reproduction. In oncology, both agents demonstrate antitumor activity primarily through immune and metabolic reprogramming rather than direct cytotoxicity, with promising signals in pancreatic, thyroid, breast, and colorectal cancers. In psychiatry, modulation of mesolimbic dopamine reward pathways and GABAergic neurotransmission underlies robust preclinical and observational evidence for reducing alcohol use disorder, substance use, and binge-eating behaviors. Orthopedic applications include clinically meaningful improvements in knee osteoarthritis pain and function, though bone health signals remain mixed. Aesthetic medicine faces the dual challenge of managing GLP-1 receptor agonist-associated facial volume loss while exploring therapeutic potential in inflammatory dermatoses. In reproductive medicine, metabolic improvements translate to benefits in polycystic ovary syndrome and male fertility, though periconception safety concerns persist. Across all domains, evidence derives predominantly from preclinical models, observational cohorts, and pharmacoepidemiologic studies, with randomized controlled trials remaining limited. This review critically evaluates mechanisms, efficacy signals, safety considerations, and research priorities for each application domain, providing a roadmap for translating unconventional uses of semaglutide and tirzepatide into evidence-based clinical practice. Full article

(This article belongs to the Collection Feature Papers in Obesity, Type 2 Diabetes and Metabolic Syndrome)

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19 pages, 1310 KB

Open AccessReview

Pathology-Anchored Biomarker Research Progress for the Early Diagnosis of Diabetic Kidney Disease: From Pathological Association to Early Validation

by Qiu Li, Mei Yang, Yingyu Luo and Nannan Zhang

Biomedicines 2026, 14(7), 1643; https://doi.org/10.3390/biomedicines14071643 - 21 Jul 2026

Viewed by 662

Abstract

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Early diagnosis is therefore critical for improving patient outcomes.However, traditional clinical biomarkers are constrained by diagnostic latency and limited sensitivity, particularly in cases of non-albuminuric DKD. To address these limitations, [...] Read more.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Early diagnosis is therefore critical for improving patient outcomes.However, traditional clinical biomarkers are constrained by diagnostic latency and limited sensitivity, particularly in cases of non-albuminuric DKD. To address these limitations, this review systematically explores the technical framework of the pathology-anchored strategy and proposes a two-phase translational approach, consisting of Pathology Anchoring Discovery and Prospective Early Validation. This strategy employs renal biopsy as the pathological gold standard in conjunction with multi-omics technologies to correlate circulating or urinary molecules with specific renal histological lesions, ultimately identifying non-invasive biomarkers with definitive pathological relevance. While numerous biomarkers demonstrate early warning potential in high-risk populations with normal conventional indicators, the pathology-anchored framework serves as a critical bridge linking these clinical biomarkers and distinct pathological changes. This review presents potential insights for early identification, risk stratification, and prognostic assessment of DKD. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Approaches in Diabetic Microvascular Complications, 3rd Edition)

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18 pages, 1499 KB

Open AccessArticle

Lower Pain Intensity Is Associated with the Use of Recreational Edible Cannabis Products Containing Delta-9-Tetrahydrocannabinol: A Secondary Analysis in Adults Self-Managing Their Chronic Low Back Pain

by Jonathon K. Lisano, Luiza Rosa, Carillon J. Skrzynski, Angela D. Bryan and L. Cinnamon Bidwell

Biomedicines 2026, 14(7), 1642; https://doi.org/10.3390/biomedicines14071642 - 21 Jul 2026

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Abstract

Background/Objectives: Current literature regarding the efficacy of cannabis to reduce chronic pain intensity is mixed. Despite growing accessibility throughout the U.S., it is still unclear if the naturalistic use of recreational cannabis edible products is associated with decreases in pain intensity on days [...] Read more.

Background/Objectives: Current literature regarding the efficacy of cannabis to reduce chronic pain intensity is mixed. Despite growing accessibility throughout the U.S., it is still unclear if the naturalistic use of recreational cannabis edible products is associated with decreases in pain intensity on days of use or longitudinally, and if these associations are dependent on the doses of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being consumed. Methods: The trial (NCT03522324) from which these data were pulled was pre-registered in April 2018. Participants (N = 243; 56% female; mean age = 46 ± 12 years) with self-reported chronic low-back pain selected a recreational edible cannabis product to use exclusively, ad libitum, for 14 days. Labeled THC and CBD potency were used to determine product group: CBD-dominant (n = 97), THC + CBD (n = 112), or THC-dominant (n = 34). Participants completed daily surveys indicating current pain intensity (PROMIS; 0–10 scale), use or non-use of their product, and cannabinoid dose (THC and CBD). Results: Linear mixed effects showed a significant use × group interaction (p = 0.002), indicating that pain intensity was significantly lower on days of use in THC-dominant (b = −0.66, 95% CI [−0.94,−0.37]) and THC + CBD (b = −0.41, 95% CI [−0.57,−0.25]) groups compared to days when cannabis was not used. A significant group × time interaction (p = 0.02) indicated that pain intensity significantly decreased from day 1 to day 14 in those using THC + CBD products (b = −0.05, 95% CI [−0.07,−0.03]), with 36.6% of participants in the THC + CBD group experiencing ≥30% reduction in pain intensity from day 1 to day 14. Increasing doses of THC (b = −0.02, 95% CI [−0.04, −0.01]), not CBD (b = 0.003, 95% CI [−0.03, 0.01]), were associated with significantly lower pain intensity on days following product use, with increasing doses of CBD diminishing the impact of THC dose (b = 0.02, 95% CI [0.01, 0.04]). Conclusions: These findings indicate a complex relationship between THC, CBD, and pain intensity associated with the naturalistic use of recreational cannabis edible products. Lower daily pain intensity was associated with the use of products containing THC; however, dose models indicate that this association may be attenuated at higher doses of CBD. Additionally, only products containing relatively equal amounts of THC and CBD were associated with lower pain intensity after 14 days of observation. Full article

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

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21 pages, 4326 KB

Open AccessArticle

Modulation of Leptin and Serotonin by Honey and Its Glycoproteins Against High-Fat Diet-Induced Metabolic and Anxiety Phenotypes

by Atia Gohar, Richard L. Atkinson, Muhammad Shakeel, Darakhshan J. Haleem, Kaleem Ullah and Aamir Rasool

Biomedicines 2026, 14(7), 1641; https://doi.org/10.3390/biomedicines14071641 - 21 Jul 2026

Viewed by 476

Abstract

Background: Obesity-linked anxiety may involve leptin resistance, impairing serotonin (5-hydroxytryptamine; 5-HT) signaling. In addition to drugs, nutraceuticals have been explored for their potential to address this pathophysiology. Herein, natural honey and its glycoproteins were assessed for their roles in modulating the leptin–serotonin [...] Read more.

Background: Obesity-linked anxiety may involve leptin resistance, impairing serotonin (5-hydroxytryptamine; 5-HT) signaling. In addition to drugs, nutraceuticals have been explored for their potential to address this pathophysiology. Herein, natural honey and its glycoproteins were assessed for their roles in modulating the leptin–serotonin axis to alleviate metabolic and anxiety-related disturbances. Methodology: Sixty Wistar rats were allocated to two groups (n = 30 each), one on a normal diet (ND) and the other on a high-fat diet (HFD), for four weeks to induce obesity. Each group was further divided into five sub-groups (n = 6 each) as follows: saline, low honey dose (LHD, 1 g/kg), high honey dose (HHD, 2 g/kg), low protein dose (LPD, 0.25 mg/kg), and high protein dose (HPD, 0.5 mg/kg), while continuing on the ND or HFD. The interventions were administered for four weeks. Body weight and behavioral activities were measured weekly, whereas serum leptin and triglycerides, and brain 5-HT and its primary metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured at sacrifice. Statistical analyses were performed using ANOVA, Tukey’s post hoc test, and correlation analyses. Results: The HFD induced leptin-driven metabolic dysfunction and serotonergic disruption, exacerbating anxiety-like behavior and locomotor deficits compared with the ND rats (p < 0.05). HHD produced a dual metabolic–neurochemical improvement by reducing hyperleptinemia, elevating 5-HT, and restoring locomotor activity while reducing anxiety-like behavior. In contrast, HPD increased 5-HIAA without altering 5-HT, reflecting an imbalanced serotonin turnover that yielded only partial anxiolytic effects. Overall, HHD partially reversed HFD-induced pathology through leptin–serotonin crosstalk, whereas HPD provided more targeted neurochemical modulation. Conclusions: Natural honey and its glycoproteins attenuate HFD-induced metabolic dysregulation and anxiety-like behavior by counteracting hyperleptinemia and enhancing serotonin synthesis. These findings highlight the potential of diet-personalized, honey-based interventions for metabolic–CNS comorbidities, warranting validation through clinical trials. Full article

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

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15 pages, 3501 KB

Open AccessArticle

Porphyromonas Gingivalis Outer Membrane Vesicles Disrupt Trophoblast Mitochondrial FAO and Drive Adverse Pregnancy Outcomes

by Yijia Wang, Siyan Liu, Jiebing Zhang, Ping Ma, Xiaoyuan Li and Yi Liu

Biomedicines 2026, 14(7), 1640; https://doi.org/10.3390/biomedicines14071640 - 21 Jul 2026

Viewed by 563

Abstract

Background: Periodontitis is increasingly recognised as a significant risk factor for adverse pregnancy outcomes (APOs), yet the mechanisms by which oral pathogens trigger placental dysfunction remain unclear. Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, secretes outer membrane vesicles (Pg-OMVs) [...] Read more.

Background: Periodontitis is increasingly recognised as a significant risk factor for adverse pregnancy outcomes (APOs), yet the mechanisms by which oral pathogens trigger placental dysfunction remain unclear. Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, secretes outer membrane vesicles (Pg-OMVs) that carry virulence factors and can reach distant organs. However, the impact of Pg-OMVs on placental trophoblasts and the accompanying metabolic disturbances is poorly understood. This study investigated the effects of Pg-OMVs on trophoblast function and metabolism. Methods: Pg-OMVs were isolated from Pg cultures. Pregnant mice were exposed to Pg-OMVs in vivo, and placental and uterine weights were recorded. Human trophoblast cells were treated with Pg-OMV in vitro. Untargeted metabolomic profiling of placental tissues was conducted using liquid chromatography–mass spectrometry. Fatty acid β-oxidation (FAO) activity, CD36 expression, and mitochondrial integrity were assessed via enzymatic assays, immunoblotting, transmission electron microscopy, mitochondrial membrane potential measurements, and oxygen consumption rate analysis. Results: Pg-OMVs were internalised by placental trophoblasts, and their presence was associated with significantly reduced placental and uterine weights. Metabolomics revealed a marked accumulation of long-chain acylcarnitines, particularly C20:1 carnitine, indicating impaired FAO. Pg-OMV exposure suppressed FAO activity, downregulated the fatty acid translocase CD36, and induced severe mitochondrial dysfunction, evidenced by cristae loss, decreased mitochondrial membrane potential, and diminished oxygen consumption rates. Conclusions: Pg-OMV compromise placental integrity by disrupting mitochondrial fatty acid β-oxidation, providing a novel mechanistic link between periodontal pathogen-derived vesicles and the pathogenesis of APOs. Full article

(This article belongs to the Special Issue Innovations in Bone and Craniofacial Tissue Engineering: From Biomaterials and Mechanobiology to Clinical Applications)

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4 pages, 153 KB

Open AccessEditorial

Role of Factors in Embryo Implantation and Placental Development

by Micol Massimiani

Biomedicines 2026, 14(7), 1639; https://doi.org/10.3390/biomedicines14071639 - 21 Jul 2026

Viewed by 362

Abstract

Embryo implantation and placental development are fundamental processes for the establishment and maintenance of a successful pregnancy [...] Full article

(This article belongs to the Special Issue Role of Factors in Embryo Implantation and Placental Development)

14 pages, 363 KB

Open AccessArticle

Atezolizumab Plus Bevacizumab Versus Durvalumab Plus Tremelimumab for Advanced Hepatocellular Carcinoma: A Propensity-Score-Matched Analysis

by Sarina Ailawadi, Sepideh Mehravar, Jennifer E. Murphy, Michael H. Storandt and Amit Mahipal

Biomedicines 2026, 14(7), 1638; https://doi.org/10.3390/biomedicines14071638 - 21 Jul 2026

Viewed by 818

Abstract

Background: Atezolizumab plus bevacizumab (A + B) and durvalumab plus tremelimumab (D + T) are approved first-line systemic therapy options for advanced hepatocellular carcinoma (HCC), with no head-to-head comparison. In this propensity-matched analysis, we compared the survival of patients with advanced HCC [...] Read more.

Background: Atezolizumab plus bevacizumab (A + B) and durvalumab plus tremelimumab (D + T) are approved first-line systemic therapy options for advanced hepatocellular carcinoma (HCC), with no head-to-head comparison. In this propensity-matched analysis, we compared the survival of patients with advanced HCC who received either A + B or D + T therapy. Methods: Patients with advanced HCC who received A + B or D + T treatment in the first-line setting were identified using the TriNetX platform, a health research network that provides access to electronic health record data from 112 healthcare organizations. Propensity-score-matched (PSM) analysis was conducted, and the median overall survival (OS) was estimated using the Kaplan–Meier method. Results: We identified 2819 patients with HCC who were treated with A + B or D + T: 2031 patients received A + B and 788 received D + T. Compared to patients in the A + B cohort, those who received D + T were more likely to be older (median age: 68.4 vs. 66.9 years), have lower platelet counts (186.8 vs. 201.3), higher prevalence of hypoalbuminemia with levels < 2.7 g/dL (35.2% vs. 28.4%), higher prevalence of bilirubin levels between 2.0 and 2.9 mg/dL (28.8% vs. 23.8%), and decreased INR with levels between 0.0 and 1.6 (92.1% vs. 86.3%). After PSM, 1536 patients were included in the survival analyses, with all variables adequately matched. There was no significant difference in the median OS between those receiving A + B or D + T [16.3 vs. 22.5 months, hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76–1.0]. Higher rates of immune-mediated colitis were noted in the D + T group. Conclusions: Similar survival rates were observed among patients with advanced HCC who received A + B and D + T in the first-line setting. Our study suggests that both A + B and D + T are valid treatment options, and that therapy can be tailored based on comorbidities, adverse effects, and patient preferences. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Molecular Research and Application)

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18 pages, 613 KB

Open AccessSystematic Review

BDNF Val66met Gene Polymorphism in Primary Acute and Subacute Stroke Functional Recovery: A Systematic Review

by Juliana Moura Alves Seixas, Cristina Lemos Barbosa Furia, Matheus Gomes de Castro, Larissa Sousa Silva Bonasser, Ligia Canongia de Abreu Cardoso Duarte, Calliandra Maria de Souza Silva and Izabel Cristina Rodrigues da Silva

Biomedicines 2026, 14(7), 1637; https://doi.org/10.3390/biomedicines14071637 - 20 Jul 2026

Viewed by 569

Abstract

Background/Objectives: Stroke remains a leading global cause of death and disability, resulting from acute focal injury to the central nervous system. The brain-derived neurotrophic factor (BDNF) gene has been extensively investigated for its involvement in post-stroke neuroplasticity and recovery. This systematic review [...] Read more.

Background/Objectives: Stroke remains a leading global cause of death and disability, resulting from acute focal injury to the central nervous system. The brain-derived neurotrophic factor (BDNF) gene has been extensively investigated for its involvement in post-stroke neuroplasticity and recovery. This systematic review examines the influence of the BDNF Val66Met (rs6265) variant on functional recovery during the acute and early subacute phases of primary stroke. Methods: The review followed PRISMA guidelines and was registered in PROSPERO (CRD42024549967). Comprehensive literature searches were performed in PubMed, Web of Science, and the Virtual Health Library in December 2024 to identify observational and interventional studies involving adults with acute or subacute primary stroke that evaluated this polymorphism. Results: Of 475 records identified, 11 studies met the inclusion criteria. Sample sizes ranged from 14 to 829 participants, with follow-up intervals ranging from 2 days to 3 months post-stroke. All studies included ischemic stroke, and seven also included hemorrhagic stroke cases. Outcomes assessed were motor recovery, cortical excitability, swallowing, and language function. Overall, most studies reported poorer recovery among Met allele carriers (Val/Met or Met/Met), particularly in motor outcomes. Evidence for cortical excitability and swallowing also suggested unfavorable effects, while language outcomes were inconclusive. Methodological heterogeneity contributed to inconsistent findings. Conclusions: The Met carriers were the most prevalent and frequently associated with poorer post-stroke outcomes, though results varied. These findings underscore the complex interplay between genetics and post-stroke recovery and indicate the need for more robust, standardized research across diverse populations. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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13 pages, 20275 KB

Open AccessArticle

Somatic Cancer Driver Mutation Analysis in Endometriosis with Tumor-like Presentations: A Case Series Study

by Lucy Chen, Elizabeth Severino, Dao-Sian Wu, Bhuchitra Singh, James Segars and Ie-Ming Shih

Biomedicines 2026, 14(7), 1636; https://doi.org/10.3390/biomedicines14071636 - 20 Jul 2026

Viewed by 655

Abstract

Background/Objectives: Endometriosis manifests as ectopic endometrial tissue outside the uterine cavity. This lesion can sometimes appear at unusual anatomical sites or within the intestinal tract, growing and mimicking cancer. Such tumor-like endometriosis lesions are relatively uncommon and biologically intriguing. Methods: This study is [...] Read more.

Background/Objectives: Endometriosis manifests as ectopic endometrial tissue outside the uterine cavity. This lesion can sometimes appear at unusual anatomical sites or within the intestinal tract, growing and mimicking cancer. Such tumor-like endometriosis lesions are relatively uncommon and biologically intriguing. Methods: This study is a retrospective case series of 14 patients presenting with tumor-like endometriosis at a single institution between 2007 and 2023. Laser capture microdissection was used to isolate epithelial cells from endometriotic glands in tissue sections from formalin-fixed, paraffin-embedded blocks, and the microdissected epithelium was analyzed for cancer driver mutations. Results: Unlike conventional endometriosis, these tumor-like lesions were generally sizable and clinically presented in the groin area, aortic wall, omentum, bowel wall, or lymph nodes, all of which raised suspicion for malignancy, despite 11 (78.6%) of the 14 cases having a history of or clinical signs of endometriosis. A total of 11 cancer-driver mutations were identified in 6 of the 14 patients, with four patients harboring multiple mutations. Recurrent mutations included KRAS-activating mutations in four cases and ARID1A-inactivating mutations in two cases. Additional mutations involved PIK3CA, CTNNB1, CHD4, MYD88, and STAG2. Conclusions: This study detected mutations in KRAS, ARID1A, PIK3CA, CTNNB1, and MYD88 in endometriotic lesions, consistent with previous literature, and identified newly reported mutations in CHD4 and STAG2. Not every tumor-like lesion harbored cancer driver mutations. Full article

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

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15 pages, 1340 KB

Open AccessArticle

Hexosylceramide Species in the Blood Decline in Both COVID-19 and Non-COVID-19 Sepsis

by Vlad Pavel, Patricia Mester, Stephan Schmid, Sabrina Krautbauer, Marcus Höring, Gerhard Liebisch, Martina Müller and Christa Buechler

Biomedicines 2026, 14(7), 1635; https://doi.org/10.3390/biomedicines14071635 - 20 Jul 2026

Viewed by 456

Abstract

Background/Objectives: Hexosylceramides (HexCers) are bioactive lipids whose circulating levels have been associated with severe illness. Blood lipid profiles differ between COVID-19 and non-COVID-19 sepsis and are also affected by liver cirrhosis. To evaluate the impact of SARS-CoV-2 infection and investigate associations with disease [...] Read more.

Background/Objectives: Hexosylceramides (HexCers) are bioactive lipids whose circulating levels have been associated with severe illness. Blood lipid profiles differ between COVID-19 and non-COVID-19 sepsis and are also affected by liver cirrhosis. To evaluate the impact of SARS-CoV-2 infection and investigate associations with disease severity and underlying liver cirrhosis among circulating HexCer species, we analyzed plasma samples from patients with systemic inflammatory response syndrome (SIRS), sepsis, or septic shock. Methods: Plasma levels of five HexCer species were quantified by flow injection analysis tandem mass spectrometry (FIA-MS/MS) in 159 patients with SIRS, sepsis, or septic shock. Among these patients, 24 had COVID-19, and 31 liver cirrhosis. In addition, serum HexCer levels were analyzed in 41 patients with moderate and 61 patients with severe COVID-19. Results: Patients with SIRS, sepsis or septic shock exhibited largely comparable plasma HexCer18:1;O2/22:0, 23:0, and 24:0 concentrations, all of which were significantly lower than those observed in healthy controls. These species and in addition HexCer18:1;O2/16:0 and 24:1 levels were modestly lower in patients with septic shock compared to those with SIRS. No significant differences in any of the five HexCer species were observed between patients with COVID-19 and non-COVID-19 septic shock or between ventilated patients with and without COVID-19, indicating that circulating HexCer levels are associated with disease severity rather than SARS-CoV-2 infection. HexCer18:1;O2/24:1 levels were increased in patients with cirrhosis. No significant differences in HexCer levels were observed between survivors and non-survivors. Conclusions: In COVID-19 and non-COVID-19 patients circulating levels of HexCer18:1;O2/22:0, HexCer18:1;O2/23:0, and HexCer18:1;O2/24:0 decline early during systemic inflammation, whereas reductions in HexCer18:1;O2/16:0 and 24:1 levels become apparent in septic shock. These findings indicate that alterations in circulating HexCer species reflect sepsis severity rather than being specific to COVID-19. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Health and Diseases: 2nd Edition)

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20 pages, 2290 KB

Open AccessArticle

BRAF V600E/TERT Promoter Co-Mutation Is Associated with Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Translational Molecular Biomarker Study

by Madina A. Mussulmanova, Laura A. Pak, Aidana M. Rakhmankulova, Arailym Baurzhan, Lyudmila M. Pivina, Diana A. Pak, Zhandos K. Burkitbayev, Andrey Yu. Orekhov, Azhar S. Baktiyar, Saltanat O. Bolsynbekova and Masahiro Nakashima

Biomedicines 2026, 14(7), 1634; https://doi.org/10.3390/biomedicines14071634 - 20 Jul 2026

Viewed by 615

Abstract

Background/Objectives: Radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC) is associated with limited treatment options and a less favorable clinical course. Combining molecular alterations with clinicopathological characteristics may improve the early identification of patients at risk of radioiodine refractoriness. This study aimed to evaluate the association [...] Read more.

Background/Objectives: Radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC) is associated with limited treatment options and a less favorable clinical course. Combining molecular alterations with clinicopathological characteristics may improve the early identification of patients at risk of radioiodine refractoriness. This study aimed to evaluate the association between molecular genetic alterations, particularly BRAF and TERT promoter mutations, and RAIR-DTC. Methods: This retrospective single-center study conducted in Kazakhstan included 167 patients with differentiated thyroid carcinoma treated between 2021 and 2023. Patients were classified into radioiodine-sensitive (n = 130) and radioiodine-refractory (n = 37) groups. Clinical, histopathological, and molecular genetic characteristics were analyzed. Results: Radioiodine refractoriness was observed in all 13 patients (100.0%) with concurrent BRAF and TERT promoter mutations, compared with 24 of 154 patients (15.6%) without this co-mutation (OR = 163.46, 95% CI 9.31–2870.79; p < 0.001). The BRAF + TERT co-mutation was also associated with less differentiated histological architecture and a higher T category. In contrast, the BRAF mutation alone showed a substantially weaker association with radioiodine refractoriness, highlighting the incremental value of the combined BRAF + TERT molecular status. Conclusions: The concurrent presence of BRAF and TERT promoter mutations, rather than the BRAF mutation alone, may improve the identification of patients at increased risk of radioiodine refractoriness. Integrating molecular profiling with clinicopathological characteristics may support individualized risk stratification and treatment planning. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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20 pages, 16110 KB

Open AccessArticle

Sex-Dependent Cardiac Responses to β3-Adrenergic Receptor Activation in a Murine Model of Heart Failure with Preserved Ejection Fraction

by Sara-Ève Thibodeau, Élisabeth Walsh-Wilkinson, Emylie-Ann Labbé, Diwaba Carmel Teou, Marie-Lune Legros and Jacques Couet

Biomedicines 2026, 14(7), 1633; https://doi.org/10.3390/biomedicines14071633 - 20 Jul 2026

Viewed by 571

Abstract

Background: Brown adipose tissue (BAT) is increasingly recognized as an endocrine organ that releases bioactive factors (batokines) with cardioprotective properties. Activation of BAT is primarily mediated by the β3-adrenergic receptor (β3-AR). Here, we investigated whether pharmacological activation of β3-AR using mirabegron modulates cardiac [...] Read more.

Background: Brown adipose tissue (BAT) is increasingly recognized as an endocrine organ that releases bioactive factors (batokines) with cardioprotective properties. Activation of BAT is primarily mediated by the β3-adrenergic receptor (β3-AR). Here, we investigated whether pharmacological activation of β3-AR using mirabegron modulates cardiac remodelling in a murine model of heart failure with preserved ejection fraction (HFpEF) induced by metabolic and hypertensive stress (MHS). Methods: Male and female C57BL/6J mice were exposed to MHS (angiotensin II + high-fat diet) for 28 days, with or without mirabegron treatment (2 mg/kg/day). Cardiac structure and function were assessed by echocardiography, and molecular and histological analyses were performed on cardiac and BATs. Results: Mirabegron attenuated several features of cardiac remodelling in males, including cardiac hypertrophy, left atrial enlargement, and left ventricular dilation. These effects were associated with reduced expression of genes related to hypertrophy and fibrosis. In contrast, it was shown that females exhibited a less pronounced response pattern. BAT mass and thermogenic gene expression (Ucp1) increased more markedly in males than in females, suggesting differential BAT responsiveness between sexes. Conclusions: β3-AR activation is associated with sex-dependent cardiac responses in this HFpEF model, with more pronounced protective effects in males. These findings are consistent with a potential contribution of BAT activation to cardiac remodelling, although causality was not directly demonstrated in the present study. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—5th Edition)

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15 pages, 3541 KB

Open AccessArticle

Human Umbilical Cord Mesenchymal Stem Cells Alleviate LPS-Induced Acute Lung Injury in Mice: Association with TLR4/MyD88/NF-κB Pathway Suppression

by Mingyou Yu, Ziyi Zhang, Ying Hu, Jinhui Zhang, Panpan Lu, Jingyu Luo and Jianwei Xu

Biomedicines 2026, 14(7), 1632; https://doi.org/10.3390/biomedicines14071632 - 20 Jul 2026

Viewed by 595

Abstract

Objective: In a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model, the present study sought to assess the therapeutic efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and characterize their anti-inflammatory mechanistic basis. Methods: Forty mice were randomly divided into four groups: [...] Read more.

Objective: In a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model, the present study sought to assess the therapeutic efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and characterize their anti-inflammatory mechanistic basis. Methods: Forty mice were randomly divided into four groups: control, LPS model, LPS + DEX (positive control), and LPS + hUC-MSCs. Except for the control group, mice received intratracheal instillation of LPS to establish ALI. One hour after LPS administration, animals in the hUC-MSC group were intravenously infused with hUC-MSCs. The positive control group was given an intraperitoneal injection of DEX for 3 consecutive days, starting at 24 h after modeling. On day 4 after cell transplantation or at 24 h after the completion of DEX injection, lung function indicators were detected. Bronchoalveolar lavage fluid (BALF), serum, and lung tissues were subsequently obtained for evaluation of inflammatory cell infiltration, histopathological injury, lung wet-to-dry (W/D) ratio, and cytokine levels. Additionally, the localization of transplanted hUC-MSCs in lungs was examined, and the mRNA and protein expression levels of TLR4, MyD88, and NF-κB p65 were quantified. Results: LPS exposure markedly impaired pulmonary function and induced robust inflammatory responses, evidenced by elevated levels of pro-inflammatory cytokines, increased inflammatory cell counts in BALF and serum, and extensive histological lung damage. Moreover, hUC-MSC injection improved lung function, decreased inflammatory cytokine production and alleviated pulmonary edema, while inhibiting the TLR4/MyD88/NF-κB pathway at transcriptional and protein levels. Conclusions: Intravenous hUC-MSC administration alleviates LPS-induced ALI in mice, an effect associated with suppression of the TLR4/MyD88/NF-κB cascade. These results indicate that this signaling cascade partially mediates the observed anti-inflammatory effects. Full article

(This article belongs to the Special Issue Human Stem Cells in Disease Modelling and Treatment (2nd Edition))

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16 pages, 5689 KB

Open AccessArticle

Phosphoproteomic Profiling Identifies PAK4 S474 Phosphorylation Affects Docetaxel Chemosensitivity via Modulation of Microtubule Stabilization in Breast Cancer

by Shiyang Liu, Shuyu Li, Zonghong Lu, Xiaofei Tong, Zhengwei Gui, Meina Sun and Lin Zhang

Biomedicines 2026, 14(7), 1631; https://doi.org/10.3390/biomedicines14071631 - 20 Jul 2026

Viewed by 531

Abstract

Background/Objectives: Docetaxel is a frontline chemotherapeutic agent for breast cancer; however, therapeutic resistance remains a major clinical challenge. Emerging evidence suggests that chemotherapy-induced adaptive phosphorylation events can promote survival signaling and contribute to drug resistance. However, the phosphoproteomic mechanisms underlying docetaxel-induced adaptive [...] Read more.

Background/Objectives: Docetaxel is a frontline chemotherapeutic agent for breast cancer; however, therapeutic resistance remains a major clinical challenge. Emerging evidence suggests that chemotherapy-induced adaptive phosphorylation events can promote survival signaling and contribute to drug resistance. However, the phosphoproteomic mechanisms underlying docetaxel-induced adaptive responses remain poorly characterized. Methods: We performed integrated quantitative proteomic and phosphoproteomic profiling in breast cancer cells following docetaxel exposure. Candidate kinases associated with phosphorylation remodeling were identified and validated using TCGA-BRCA and CPTAC clinical datasets. The functional significance of PAK4 phosphorylation was validated using phosphomimetic and phospho-deficient mutants, pharmacological inhibition, and assessment of microtubule stabilization. Results: Integrated phosphoproteomic analysis revealed extensive phosphorylation remodeling following docetaxel treatment and identified PAK4 as a candidate kinase associated with the adaptive response. Analysis of the CPTAC phosphoproteomic dataset showed that phosphorylation of PAK4 at S474 was elevated in breast cancer tissues, increased with tumor stage, and was associated with poorer overall survival. In breast cancer cells, docetaxel induced phosphorylation of PAK4 at S474 without altering total PAK4 expression. Functionally, phosphomimetic PAK4 (S474D) reduced docetaxel sensitivity, whereas phospho-deficient PAK4 (S474A) enhanced drug sensitivity. Pharmacological inhibition of PAK4 using LCH-7749944 significantly enhanced the inhibitory effect of docetaxel on cell viability and increased apoptosis in breast cancer cells. Mechanistically, PAK4 inhibition enhanced docetaxel-induced microtubule stabilization, as evidenced by increased α-tubulin acetylation and accumulation of stabilized microtubule structures. Conclusions: Our study demonstrates that docetaxel induces global phosphorylation network reprogramming in breast cancer cells and identifies PAK4 S474 phosphorylation as a key determinant of docetaxel sensitivity. Inhibition of PAK4 enhances microtubule stabilization and improves the efficacy of docetaxel, providing a potential combinatorial strategy to overcome taxane resistance. Full article

(This article belongs to the Special Issue The Brain–Body Interplay in Pain, Anesthesia, and Oncology)

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19 pages, 1470 KB

Open AccessReview

The Framework of Host Innate and Adaptive Immunological Pathways

by Wan-Chung Hu

Biomedicines 2026, 14(7), 1630; https://doi.org/10.3390/biomedicines14071630 - 20 Jul 2026

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Abstract

Background: Host immune responses can be broadly divided into innate and adaptive immunity. Numerous adaptive immune responses have been identified, including TH1, TH2, TH3, TH9, TH17, and TH22 immunity. Within innate immunity, Vγ9-chain γδ T cells are among the most extensively studied [...] Read more.

Background: Host immune responses can be broadly divided into innate and adaptive immunity. Numerous adaptive immune responses have been identified, including TH1, TH2, TH3, TH9, TH17, and TH22 immunity. Within innate immunity, Vγ9-chain γδ T cells are among the most extensively studied immune-cell populations. Knowledge Gap: However, the precise functional classification of these innate and adaptive immunological pathways in responses to different types of pathogens remains incompletely understood. Purpose of the Review: This review proposes an integrated framework for the detailed functional classification of host innate and adaptive immunological pathways. Proposed Framework: Within innate immunity, γδ T cells can be categorized into several functional groups. The clonal anergy and tolerance pathway is associated with Vγ2-chain γδ T cells. The host innate immunological pathway against viruses is associated with Vγ8-chain γδ T cells, whereas the pathway against intracellular microorganisms is associated with Vγ9-chain γδ T cells. The pathway against extracellular microorganisms is associated with Vγ4-chain γδ T cells, the pathway against helminths with Vγ5-chain γδ T cells, and the pathway against insects with Vγ3-chain γδ T cells. Within adaptive immunity, five eradicable immune reactions and four tolerable immune reactions are described. Among the tolerable immune reactions, TH3 is associated with interleukin-35-producing CD4 T cells, whereas TH4 is associated with interleukin-32-producing CD4 T cells. Significance: A more precise functional classification of innate and adaptive immunological pathways may provide a useful conceptual basis for combating infections and hypersensitivity disorders. Full article

(This article belongs to the Special Issue New Insights in Immunological Pathways)

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13 pages, 324 KB

Open AccessArticle

Comparable Euploidy and Aneuploidy Patterns Between Utrogestan-Based Progesterone-Primed Ovarian Stimulation and GnRH Antagonist in PGT-M: A Retrospective Matched Cohort Study

by Xiaolan Li, Shujing He, Yajie Chang, Pan Chen, Yanfang Wang, Xiaoyan Liang, Zhiqiang Zhang and Jingjie Li

Biomedicines 2026, 14(7), 1629; https://doi.org/10.3390/biomedicines14071629 - 20 Jul 2026

Viewed by 472

Abstract

Objectives: This study compared controlled ovarian hyperstimulation (COH) outcomes and chromosomal euploidy results between the Utrogestan-based progesterone-primed ovarian stimulation (PPOS) and gonadotropin-releasing hormone antagonist (GnRH-Ant) protocols in preimplantation genetic testing for monogenic disorders (PGT-M) cycles, and assessed the efficacy and safety of the [...] Read more.

Objectives: This study compared controlled ovarian hyperstimulation (COH) outcomes and chromosomal euploidy results between the Utrogestan-based progesterone-primed ovarian stimulation (PPOS) and gonadotropin-releasing hormone antagonist (GnRH-Ant) protocols in preimplantation genetic testing for monogenic disorders (PGT-M) cycles, and assessed the efficacy and safety of the Utrogestan-based PPOS protocol. Methods: In this retrospective single-center cohort study, 176 PGT-M cycles managed with the Utrogestan-based PPOS protocol were compared with 176 GnRH-Ant cycles using 1:1 direct caliper matching without replacement. Embryos were classified as euploid, mosaic, aneuploid, or no-call according to next-generation sequencing results. The primary outcomes were euploidy rate and chromosomal aberration patterns; secondary outcomes included COH outcomes and pregnancy outcomes. Results: Baseline characteristics were comparable after matching. The total gonadotropin (Gn) dose was significantly lower in the Utrogestan-based PPOS group (2100 (1500–3000) vs. 2250 (1800–3000), p = 0.035). PGT analysis revealed comparable rates of euploidy, aneuploidy, mosaicism, and “No-call” between the Utrogestan-based PPOS (n = 586) and GnRH-Ant (n = 605) groups. The unadjusted difference in euploidy rate per MII oocyte between groups (18.98% vs. 16.36%, p = 0.045) was no longer statistically significant after multivariable adjustment (p = 0.194). In addition, patterns of aneuploidy and chromosomal involvement were similar between groups. The Utrogestan-based PPOS group showed numerically higher clinical pregnancy rate (70.67% vs. 63.22%) and live birth rate (62.67% vs. 51.72%), and a lower early abortion rate (5.66% vs. 12.73%), but none of these differences were statistically significant. Conclusions: Compared with the GnRH-Ant protocol, the Utrogestan-based PPOS protocol required a significantly lower total Gn dose while exhibiting comparable euploidy rate, analogous chromosomal abnormality spectrums, and pregnancy outcomes. The Utrogestan-based PPOS protocol may be a feasible alternative ovarian stimulation strategy in PGT-M cycles. Full article

(This article belongs to the Special Issue Genetic Research into Human Reproduction)

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14 pages, 509 KB

Open AccessArticle

Circulating Placental Growth Factor as a Prognostic Biomarker in High-Risk Glioblastoma Patients

by Filippo Gagliardi, Francesca Roncelli, Silvia Snider, Pierfrancesco De Domenico, Daniela Boselli, Simona Di Terlizzi, Chiara Villa and Pietro Mortini

Biomedicines 2026, 14(7), 1628; https://doi.org/10.3390/biomedicines14071628 - 20 Jul 2026

Viewed by 442

Abstract

Background/Objectives: Angiogenesis in glioblastoma (GBM) is a multifactorial process, and blood–brain barrier disruption enables the detection of circulating mediators. The clinical relevance of circulating placental growth factor (PlGF) in GBM remains unclear. This study aimed to investigate the role of PlGF in GBM [...] Read more.

Background/Objectives: Angiogenesis in glioblastoma (GBM) is a multifactorial process, and blood–brain barrier disruption enables the detection of circulating mediators. The clinical relevance of circulating placental growth factor (PlGF) in GBM remains unclear. This study aimed to investigate the role of PlGF in GBM and its association with disease characteristics and outcomes. Methods: We conducted a prospective observational study on 54 patients with IDH-wildtype GBM. Plasma samples collected at diagnosis and recurrence were analyzed using a multiplex panel of angiogenesis mediators. Associations with clinical, radiological, molecular, and treatment-related variables were assessed, along with survival outcomes. Statistical analysis was performed with R 4.5.0. Results: At baseline, PlGF correlated with multiple angiogenic mediators, including VEGF, IL-6, angiopoietin-1, EGF, FGF, IL-8, and TNF-α. Higher PlGF levels were associated with radiopathological features of tumor biology, including proliferation markers and the FLAIR/contrast enhancement ratio. In high-risk patients (RPA 3–4; n = 33), low baseline PlGF identified a subgroup with significantly longer overall survival (17.6 vs. 8.5 months; log-rank p = 0.031) and retained a protective association in multivariable models. In the overall cohort, this association was weaker and did not reach statistical significance. Exploratory longitudinal analyses suggested an increase in PlGF at recurrence in selected molecular and treatment-defined subgroups, while no association with bevacizumab exposure was observed. Conclusions: Circulating PlGF may reflect tumor biology in GBM and shows prognostic relevance in high-risk patients, where low baseline levels identify a subgroup with improved survival. These findings support PlGF as a candidate circulating biomarker and warrant validation in larger prospective cohorts. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Gliomas: 2nd Edition)

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11 pages, 1212 KB

Open AccessArticle

Diagnostic Contribution of SPECT/CT to Dual-Phase ^99mTc-MIBI Parathyroid Scintigraphy for Preoperative Localization in Primary Hyperparathyroidism

by Vuslat Mumcu Çimen and Ebuzer Kalender

Biomedicines 2026, 14(7), 1627; https://doi.org/10.3390/biomedicines14071627 - 20 Jul 2026

Viewed by 499

Abstract

Background: Accurate preoperative localization of hyperfunctioning parathyroid glands is essential for minimally invasive surgery in primary hyperparathyroidism (PHPT). Although dual-phase ^99mTc-MIBI planar scintigraphy is widely used, its diagnostic performance may be limited in small or ectopic lesions. Hybrid SPECT/CT imaging combines functional [...] Read more.

Background: Accurate preoperative localization of hyperfunctioning parathyroid glands is essential for minimally invasive surgery in primary hyperparathyroidism (PHPT). Although dual-phase ^99mTc-MIBI planar scintigraphy is widely used, its diagnostic performance may be limited in small or ectopic lesions. Hybrid SPECT/CT imaging combines functional and anatomical information and may improve localization accuracy. The aim of this study is to evaluate the diagnostic contribution of SPECT/CT to dual-phase ^99mTc-MIBI planar scintigraphy for preoperative localization in patients with PHPT. Methods: This retrospective study included 128 patients with biochemically confirmed PHPT who underwent dual-phase ^99mTc-MIBI planar scintigraphy followed by delayed-phase SPECT/CT imaging before parathyroidectomy between January 2020 and May 2024. Imaging findings were compared with postoperative histopathological results. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. The effects of lesion size, biochemical parameters, and ultrasonographic findings on imaging performance were also evaluated. Results: Histopathology confirmed parathyroid lesions in 122 of 128 patients (95.3%). The sensitivity, specificity, PPV, NPV, and accuracy of planar imaging were 57.4%, 66.7%, 97.2%, 7.1%, and 57.8%, respectively, whereas those of SPECT/CT were 92.6%, 66.7%, 98.3%, 30.8%, and 91.4%, respectively. SPECT/CT findings showed significant concordance with histopathology (p = 0.001), while planar imaging did not (p = 0.247). Among lesions smaller than 1 cm, sensitivities were 37.1% for planar imaging and 91.4% for SPECT/CT. SPECT/CT also provided superior anatomical localization, particularly in ectopic lesions and in patients with concomitant thyroid pathology. Conclusions: SPECT/CT demonstrated substantially higher diagnostic performance than dual-phase planar scintigraphy for preoperative localization in PHPT. Its incremental value was particularly evident in subcentimeter lesions, ectopic parathyroid adenomas, and patients with coexisting thyroid disease. Full article

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

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16 pages, 40757 KB

Open AccessArticle

Recovery Patterns After Epineuroclasis and Endoneuroclasis Stretch Injuries in the Rat Median Nerve

by Christoph A. Schroen, Damien Laudier, Philip Nasser, Paul J. Cagle and Michael R. Hausman

Biomedicines 2026, 14(7), 1626; https://doi.org/10.3390/biomedicines14071626 - 20 Jul 2026

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Abstract

Background/Objectives: This study used the neuroclasis nerve injury model to compare the long-term histomorphological, cellular, and inflammatory consequences of epineuroclasis and endoneuroclasis stretch injuries. Methods: Upon IACUC approval, 45 male Sprague-Dawley rats were allocated to 6 injury groups: an epineuroclasis and an endoneuroclasis [...] Read more.

Background/Objectives: This study used the neuroclasis nerve injury model to compare the long-term histomorphological, cellular, and inflammatory consequences of epineuroclasis and endoneuroclasis stretch injuries. Methods: Upon IACUC approval, 45 male Sprague-Dawley rats were allocated to 6 injury groups: an epineuroclasis and an endoneuroclasis group with follow-up at 2 weeks (n = 6 each), 6 weeks (n = 8 each), and 12 weeks (n = 8 and 9). Rats underwent left median nerve stretch to epineuroclasis or endoneuroclasis thresholds using load–deformation curve monitoring. Nerves were harvested at follow-up for qualitative histology and immunohistochemistry (H&E, NF200, S100, CD68, and Glut-1). Results: At 2 weeks, both injury levels demonstrated minimal NF200 staining, consistent with Wallerian degeneration. Epineuroclasis resulted in persistent epineurial rupture with exposed endoneurial tubes at 2, 6, and 12 weeks, indicating no structural restoration of the epineurium. At 12 weeks, axonal regrowth was observed primarily in regions with an intact epineurium and was limited in regions lacking epineurial coverage. Endoneuroclasis was associated with neuroma formation in 16/17 nerves (13/14 in-continuity) at 6 and 12 weeks, characterized by hypervascularity, aberrant fascicle formation, diffuse axonal sprouting, Schwann cell hypercellularity, and sustained macrophage infiltration. Conclusions: Epineurial integrity appears more important for axonal regeneration than previously thought. Persistent epineurial disruption was associated with limited axonal regrowth, whereas endoneurial disorganization was associated with neuroma formation despite macroscopic nerve continuity at time zero. Understanding the regenerative consequences of distinct degrees of connective tissue damage after stretch injury may help guide the development of tools that could diagnose these injuries early and potentially predict recovery after nerve injury. Full article

(This article belongs to the Special Issue Animal Models for Neurological Disease Research)

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33 pages, 14222 KB

Open AccessArticle

Experimental and Computational Insights into the Apoptotic Potential of New Phenanthroline-Based Copper(II) Complexes: From Spectroscopic Characterization and In Vitro Cytotoxicity to In Silico Target Identification

by Jesús Magdiel García-Díaz, Héctor Alejandro Bacilio-Beltrán, Asbiel Felipe Garibaldi-Ríos, Martha Patricia Gallegos-Arreola, Irma Idalia Rangel-Salas, Jorge Iván Delgado-Saucedo, Paola Castro-García, Moisés Martínez-Velázquez and Ana María Puebla-Pérez

Biomedicines 2026, 14(7), 1625; https://doi.org/10.3390/biomedicines14071625 - 20 Jul 2026

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Abstract

Background: Two novel copper(II) coordination complexes, PH-Cu [(1,10-phenanthroline)(malonato)copper(II)] and PC-Cu [(1,10-phenanthroline)(cyclobutane-1,1-dicarboxylato)copper(II)], were synthesized and evaluated as potential anticancer agents, aiming to characterize structural properties, explore antiproliferative activity and generate mechanistic hypotheses through experimental and computational approaches. Methods: Complexes were characterized by [...] Read more.

Background: Two novel copper(II) coordination complexes, PH-Cu [(1,10-phenanthroline)(malonato)copper(II)] and PC-Cu [(1,10-phenanthroline)(cyclobutane-1,1-dicarboxylato)copper(II)], were synthesized and evaluated as potential anticancer agents, aiming to characterize structural properties, explore antiproliferative activity and generate mechanistic hypotheses through experimental and computational approaches. Methods: Complexes were characterized by EPR, FTIR-ATR, and ESI-MS, with preliminary SC-XRD data for PH-Cu. Antiproliferative activity was evaluated against six human cancer cell lines using the MTT assay (24 h). Subcellular effects were assessed by fluorescence microscopy and RT-qPCR. Computational studies included DFT geometry optimization, target prediction, molecular docking, and ADMET profiling. Results: Based on spectroscopic and spectrometric data and comparison with analogous Cu(II) complexes, a distorted square-pyramidal coordination geometry was proposed; this assignment was not confirmed by SC-XRD. Both complexes exhibited potent antiproliferative activity, with PH-Cu showing the highest potency in HeLa cells (IC₅₀ = 4.22 µM). Under the same conditions, cisplatin showed substantially lower activity (HepG2: 191.1 µM; Caco-2: 129.6 µM; NCI-H69: >333.3 µM; HeLa: 21.9 µM). Fluorescence microscopy at 18 h revealed pyknosis, karyorrhexis, and microtubule disorganization, consistent with regulated cell death. RT-qPCR of PH-Cu indicated intrinsic apoptotic pathway engagement (BAX +3.20-fold; BCL2 to 0.39-fold of control). DFT-optimized bond lengths were consistent with crystallographic data for analogous complexes. Molecular docking suggested PRKCG, RELA (p65), Caspase-3, and α/β-tubulin as interaction candidates, while ADMET profiling predicted favorable intestinal absorption (>92.8%) and low BBB permeability. Conclusions: These results suggest that the [Cu(phen)] unit constitutes the primary pharmacophore, with the dicarboxylate co-ligand as a modulator of the antiproliferative profile, suggesting promising anticancer pharmacological potential. Full article

(This article belongs to the Special Issue Medicinal Chemistry in Drug Design and Discovery, 2nd Edition)

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13 pages, 15955 KB

Open AccessArticle

A Self-Assembling Peptide Platform for Intratumoral Doxorubicin Delivery and Preliminary Immune-Related Modulation in B16-F10 Melanoma

by Xufang Ying, Jingjing Peng, Zhiqing Ben, Xiaoyan Bao, Linjie Wu, Xin Tan, Xiaoyan Sun, Yufan Yang, Yiqing Shen, Zhicheng Zhang, Ruolin Jiang, Yaxin Qin, Lin Zhou, Min Han and Shugang Yang

Biomedicines 2026, 14(7), 1624; https://doi.org/10.3390/biomedicines14071624 - 19 Jul 2026

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Abstract

Background: Local drug delivery can increase antitumor exposure while limiting systemic toxicity, but chemotherapy-only local treatment may not fully control residual tumor growth in immunosuppressive tumor microenvironments. This study aimed to develop and preliminarily evaluate ffky-antiCD3, a CD3-recognition peptide-functionalized self-assembling peptide platform for [...] Read more.

Background: Local drug delivery can increase antitumor exposure while limiting systemic toxicity, but chemotherapy-only local treatment may not fully control residual tumor growth in immunosuppressive tumor microenvironments. This study aimed to develop and preliminarily evaluate ffky-antiCD3, a CD3-recognition peptide-functionalized self-assembling peptide platform for intratumoral doxorubicin (DOX) delivery. Methods: The Nap aromatic group in a previous Nap-ffky scaffold was removed to improve aqueous dispersibility, and the CD3-recognition sequence AKMGEGGWGANDY was introduced to generate ffky-antiCD3. The peptide/formulation was characterized by reversed-phase high-performance liquid chromatography, mass spectrometry, TEM, circular dichroism spectroscopy, and a preliminary in vitro DOX release assay under tumor-mimicking acidic conditions. Antitumor efficacy, tumor histopathology, image-based CD3/CD8 semi-quantification, splenic IFN-γ levels, serum biochemistry, organ coefficients, and major-organ histology were assessed after repeated intratumoral treatment in B16-F10 melanoma-bearing C57BL/6 mice. Results: ffky-antiCD3 formed assemblies with a β-sheet-rich secondary structure. TEM observation further showed heterogeneous irregular/network-like supramolecular assemblies, and the preliminary release assay suggested slower apparent DOX release from ffky-antiCD3/DOX than from free DOX at pH 6.5. Among the tested groups, ffky-antiCD3/DOX produced the strongest short-term tumor-growth inhibition and the lowest endpoint tumor weight during the 10-day observation period. Ki67 staining decreased, and TUNEL signals increased after ffky-antiCD3/DOX treatment, supporting reduced proliferation and enhanced apoptosis-related damage. CD3/CD8 staining and exploratory splenic IFN-γ measurements indicated preliminary immune-related changes associated with ffky-antiCD3-containing formulations. Body weight, organ weights, serum biochemical markers, and major-organ H&E staining revealed no obvious short-term toxicity signals under the tested regimen. Conclusions: ffky-antiCD3/DOX represents a candidate local peptide-based chemo-immunomodulatory formulation. Its immune mechanism, release behavior, biodistribution, and long-term efficacy and safety require further validation before strong mechanistic or translational claims are made. Full article

(This article belongs to the Special Issue Nano-Mediated Drug Delivery)

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11 pages, 2532 KB

Open AccessArticle

Intervention with Polyvalent Bacterial Lysate Modulates T Helper Cell Subsets in Polish Children with Grass Pollen-Induced Allergic Rhinitis

by Kamil Janeczek, Wioleta Grzegorzewska, Michał Zarobkiewicz, Dorota Suszczyk, Marek Mikołajczyk, Ewa Markut-Miotła, Izabela Morawska-Michalska, Adrian Bakiera, Aleksandra Chmielewska, Andrzej Emeryk, Jacek Roliński, Marta Rachel and Krystyna Piotrowska-Weryszko

Biomedicines 2026, 14(7), 1623; https://doi.org/10.3390/biomedicines14071623 - 19 Jul 2026

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Abstract

Background: Allergic rhinitis (AR) is a chronic condition that affects children’s quality of life. Studies show that adding bacterial lysates (BLs) to treatment can improve outcomes, but their effects on the immune system are still not fully understood. Objectives: This study aimed to [...] Read more.

Background: Allergic rhinitis (AR) is a chronic condition that affects children’s quality of life. Studies show that adding bacterial lysates (BLs) to treatment can improve outcomes, but their effects on the immune system are still not fully understood. Objectives: This study aimed to evaluate the immunomodulatory impact of sublingually administered polyvalent mechanical BL (PMBL) on the expression of T helper (Th) cell-associated transcription factors and cytokines in children with grass pollen-induced AR. Methods: Immunological analyses were performed on blood samples collected during a previously conducted randomised, double-blind, placebo-controlled clinical trial (NCT04802616). Children aged 5–17 years with grass pollen-induced AR received either sublingual PMBL or placebo in three 10-day treatment cycles, each followed by a 20-day break. Peripheral blood mononuclear cells were collected at baseline before the grass pollen season (V1) and after completion of the study treatment during natural peak pollen exposure (V2) and analysed by flow cytometry to assess the expression of transcription factors and cytokines associated with Th1, Th2, Th10, Th17, and Treg-like immune responses. Results: In the PMBL group, there was a significant increase in the expression of T-bet, E4BP4, FoxP3, IFN-γ, and IL-10, along with a reduction in GATA3 and IL-4 expression (p < 0.001). The placebo group exhibited increased expression of GATA3 (p < 0.001), RORγT (p < 0.001), and IL-4 (p = 0.004) and a reduction in T-bet expression (p = 0.007). Between-group comparisons at V2 revealed significantly higher expression of Th1-, Th10-, and Treg-associated markers, and lower Th2- and Th17-associated markers in the PMBL group compared to placebo. Conclusions: Sublingual PMBL administration modulates the expression of Th cell-associated transcription factors and cytokines in children with grass pollen-induced AR, consistent with enhanced Th1-, Th10-, and Treg-like immune responses and reduced Th2-associated activity. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Poland (3rd Edition))

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Biomedicines, Volume 14, Issue 7 (July 2026) – 244 articles

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