Biomedicines

29 pages, 1280 KB

Open AccessReview

Idiopathic Pulmonary Fibrosis: A Comprehensive Review of Risk Factors, Genetics, Diagnosis, and Therapeutic Approaches

by Lamiyae Senhaji, Nadia Senhaji, Marieme Abbassi, Meryem Karhate, Mounia Serraj, Mohammed El Biaze, Mohamed Chakib Benjelloun, Karim Ouldim, Laila Bouguenouch and Bouchra Amara

Biomedicines 2026, 14(1), 90; https://doi.org/10.3390/biomedicines14010090 (registering DOI) - 1 Jan 2026

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a severe, chronic, progressive lung disease classified within interstitial lung disorders. It predominantly affects individuals aged 50 to 70 years, with a prognosis of 3–5 years post-diagnosis. The pathophysiology of IPF is complex, involving an interplay of genetic [...] Read more.

Idiopathic Pulmonary Fibrosis (IPF) is a severe, chronic, progressive lung disease classified within interstitial lung disorders. It predominantly affects individuals aged 50 to 70 years, with a prognosis of 3–5 years post-diagnosis. The pathophysiology of IPF is complex, involving an interplay of genetic predisposition, environmental exposures, and age-related factors. A significant genetic component is evident, with key contributions from rare variants in telomere maintenance genes (e.g., TERT and TERC) and surfactant protein genes (e.g., SFTPA and SFTPC), as well as a strong association with a common promoter variant in the MUC5B gene. The diagnosis is established through high-resolution computed tomography (HRCT) and, when necessary, histopathological analysis. The search for reliable biomarkers is a key area of research, with molecules such as KL-6, SP-A, SP-D, and MMP-7 showing potential for aiding in diagnosis, prognosis, and monitoring disease activity. While antifibrotic therapies (Pirfenidone and Nintedanib) have revolutionized management by slowing the decline in lung function, the therapeutic landscape continues to evolve. Ongoing research efforts are focused on integrating clinical, radiological, genetic, and biomarker data to facilitate early diagnosis and develop personalized treatment strategies to improve patient outcomes. Full article

(This article belongs to the Special Issue New Advances in Pulmonary Fibrosis)

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17 pages, 3124 KB

Open AccessArticle

Nonthermal Atmospheric Plasma Modulates Palatal Wound Healing in Rats: A Morphometric, Histopathologic and Immunohistochemical Analysis

by Basak Kusakci Seker, Hakan Ozdemir and Suna Karadeniz Saygili

Biomedicines 2026, 14(1), 89; https://doi.org/10.3390/biomedicines14010089 (registering DOI) - 1 Jan 2026

Abstract

Background/Objectives: Non-thermal atmospheric plasma (NTAP) has recently gained attention as a promising tool for tissue regeneration due to its ability to modulate cellular signaling and enhance wound repair. However, its effects on oral mucosal healing and associated molecular pathways remain insufficiently characterized. This [...] Read more.

Background/Objectives: Non-thermal atmospheric plasma (NTAP) has recently gained attention as a promising tool for tissue regeneration due to its ability to modulate cellular signaling and enhance wound repair. However, its effects on oral mucosal healing and associated molecular pathways remain insufficiently characterized. This study aimed to investigate the histological and immunohistochemical effects of NTAP on palatal wound healing in rats and to evaluate key biomarkers involved in angiogenesis, proliferation, and extracellular matrix remodeling. Methods: Sixty rats were randomly assigned to three groups: Saline Control Group (SCG), Chlorhexidine Gluconate Group (CHG), and NTAP-Treated Group (NTAPG). Standardized full-thickness excisional wounds were created in the central palatal mucosa. Animals were sacrificed on postoperative days 7, 14, and 21. Histological assessments included vascularization, inflammatory cell infiltration, collagen fiber organization, and epithelial gap measurements. Immunohistochemical analyses were performed using antibodies targeting VEGF-A, TGF-β, FGF-2, CD34, α-SMA, and Ki67 to evaluate angiogenesis, fibroblast activity, and cellular proliferation. Results: NTAP treatment significantly elevated TGF-β levels at all time points and increased α-SMA-positive cell counts on days 7 and 14. FGF-2 expression was the highest in NTAPG, while VEGF-A and CD34 levels were significantly elevated, indicating robust angiogenic activity. NTAP also reduced inflammatory cell infiltration relative to the other groups. NTAPG exhibited enhanced fibroblast proliferation, increased collagen deposition, improved vascularization, and accelerated re-epithelialization compared with SCG and CHG. Conclusions: NTAP significantly promoted palatal wound healing by enhancing proliferative activity, stimulating growth factor expression, and accelerating tissue repair. These findings suggest that NTAP may serve as an effective therapeutic approach for improving oral mucosal wound healing. Full article

(This article belongs to the Special Issue Applications and Perspectives of Cold Electric Discharge Plasmas in Biomedicine and Bioengineering)

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22 pages, 3127 KB

Open AccessArticle

Poly(ε-caprolactone) Nanoparticle Tumor-Lysate Vaccination in Mice Generates Hybridoma-Derived Antibodies Enabling Breast Cancer Diagnosis and Chemotherapy Synergy

by Murat Ihlamur, Pelin Pelit Arayıcı and Emrah Şefik Abamor

Biomedicines 2026, 14(1), 88; https://doi.org/10.3390/biomedicines14010088 (registering DOI) - 1 Jan 2026

Abstract

Background: Tumor-lysate vaccines can capture tumor heterogeneity; however, their effectiveness may be reduced by antigen instability and short antigen presentation. Here, we aimed to improve antigen protection and prolong presentation by using a slow-degrading polymeric nanocarrier and an approved adjuvant. Methods: We encapsulated [...] Read more.

Background: Tumor-lysate vaccines can capture tumor heterogeneity; however, their effectiveness may be reduced by antigen instability and short antigen presentation. Here, we aimed to improve antigen protection and prolong presentation by using a slow-degrading polymeric nanocarrier and an approved adjuvant. Methods: We encapsulated breast cancer cell lysates (MCF-7 and MDA-MB-231) in poly(ε-caprolactone) (PCL) nanoparticles using a double-emulsion (w/o/w) method and co-administered them with alum. We then characterized particle size, PDI, zeta potential, morphology, and in vitro release. Next, we evaluated nitric oxide (NO), TNF-α/IL-10 responses, and cytocompatibility in J774 macrophages. Finally, we quantified serum antibody titers in Balb/c mice after six biweekly immunizations, generated hybridomas, purified IgG, and tested antibody-mediated cytotoxicity alone and together with doxorubicin. Results: PCL nanoparticles were ~220–255 nm (PDI 0.10–0.19; ζ −2 to −3 mV) and released ~90–95% of encapsulated lysate by 800 h (~33 days). Encapsulated lysate (40 μg/mL) modestly increased NO versus control and increased further with alum (p < 0.05). TNF-α increased 7.4–9.72-fold, whereas IL-10 rose 2.82–3.11-fold. Importantly, encapsulated antigen + alum produced the highest ELISA responses after the sixth dose (6.36-fold for MCF-7 and 7.00-fold for MDA-MB-231 versus control; p < 0.05). Hybridoma-derived antibody signals increased through day 42, and Protein G purification yielded up to ~395 μg and ~318 μg IgG. Purified antibodies reduced cell viability, and viability decreased further when antibodies were combined with doxorubicin (to ~31.6% in MCF-7 and ~40.3% in MDA-MB-231). Conclusions: Overall, sustained PCL-mediated antigen release combined with alum strengthened humoral responses to tumor lysate and enabled recovery of functional antibodies with diagnostic capture and in vitro cytotoxic activity. In future work, key mechanistic steps such as lymph-node trafficking and cross-presentation should be tested directly. Full article

(This article belongs to the Section Nanomedicine and Nanobiology)

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13 pages, 1488 KB

Open AccessArticle

Deciphering the Causative Role of a Novel APC Gene Variant in Attenuated Familial Adenomatous Polyposis Using Germline DNA-RNA Paired Testing

by Giovanna Forte, Candida Fasano, Matteo Iacoviello, Valentina Grossi, Martina Lepore Signorile, Katia De Marco, Paola Sanese, Antonia Lucia Buonadonna, Andrea Manghisi, Nicoletta Maria Tutino, Vittoria Disciglio and Cristiano Simone

Biomedicines 2026, 14(1), 87; https://doi.org/10.3390/biomedicines14010087 (registering DOI) - 1 Jan 2026

Abstract

Background/Objectives: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by pathogenic variants in the adenomatous polyposis coli (APC) gene. Its attenuated form (AFAP) is characterized by fewer colorectal polyps and later onset of colorectal cancer. We aimed to [...] Read more.

Background/Objectives: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by pathogenic variants in the adenomatous polyposis coli (APC) gene. Its attenuated form (AFAP) is characterized by fewer colorectal polyps and later onset of colorectal cancer. We aimed to characterize the molecular effects of a novel APC gene variant (NM_000038.6: c.1620_1624delinsT) identified in a patient with AFAP. Methods: A 56-year-old man with the AFAP phenotype underwent germline testing via a multigene NGS panel, which identified a novel APC gene variant (NM_000038.6: c.1620_1624delinsT). In silico analyses predicted disruption of the canonical donor splice site and a frameshift followed by the introduction of a premature stop codon. The transcriptional impact of the identified APC gene variant was investigated by mRNA analysis. Results: mRNA analysis revealed two distinct APC transcripts: the first transcript led to a truncated protein (p.Leu540PhefsTer8), and the second transcript lacked exon 12, resulting in an in-frame 26 amino acid deletion of APC protein (p.Ala517_Gly542del). The transcript lacking exon 12 was more abundant than the transcript with a premature stop codon, likely due to degradation through nonsense-mediated decay. Conclusions: The APC gene variant (NM_000038.6: c.1620_1624delinsT) exhibits a dual transcriptional effect, revealing its pathogenic role in AFAP. This study highlights the diagnostic value of combined DNA–RNA germline testing for improving the clinical classification of novel APC gene variants and their genotype–phenotype correlations in FAP. Full article

(This article belongs to the Special Issue Advanced Cancer Diagnosis and Treatment: Third Edition)

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24 pages, 13529 KB

Open AccessArticle

Intra-Articular N-Acetylcysteine Reduces Synovitis Without Preventing Cartilage Degeneration in Experimental Osteoarthritis

by Mustafa Dinç, Hünkar Çağdaş Bayrak, Recep Karasu, Bilal Aykaç, Ömer Cevdet Soydemir and Aysun Saricetin

Biomedicines 2026, 14(1), 86; https://doi.org/10.3390/biomedicines14010086 - 31 Dec 2025

Abstract

Background/Objectives: Osteoarthritis (OA) is a multifactorial degenerative joint disease characterized by synovial inflammation, oxidative stress, and progressive cartilage degeneration. This study investigated whether intra-articular N-acetylcysteine (NAC) attenuates synovial inflammation and oxidative stress and whether these effects translate into structural cartilage protection. Methods [...] Read more.

Background/Objectives: Osteoarthritis (OA) is a multifactorial degenerative joint disease characterized by synovial inflammation, oxidative stress, and progressive cartilage degeneration. This study investigated whether intra-articular N-acetylcysteine (NAC) attenuates synovial inflammation and oxidative stress and whether these effects translate into structural cartilage protection. Methods: OA was induced in rats by anterior cruciate ligament transection (ACLT). NAC (5 mg/50 µL) was administered intra-articularly once weekly for three weeks post-ACLT. Inflammatory cytokines (IL-1β, IL-6, TNF-α), oxidative stress markers (iNOS, TAS, TOS, OSI), and cartilage degradation markers (MMP-13, COMP, CTX-II) were quantified in synovial fluid and cartilage homogenates using ELISA. Cartilage integrity was evaluated histologically using the modified Mankin scoring system. Results: Compared with controls, NAC significantly reduced synovial IL-1β, IL-6, TNF-α, MMP-13, and iNOS levels and improved the synovial redox profile by increasing TAS and reducing TOS and OSI (all p < 0.05). In contrast, NAC did not significantly alter cartilage homogenate levels of inflammatory cytokines, oxidative stress indices, or degradation markers (COMP, CTX-II, MMP-13). Histological analysis demonstrated persistent cartilage fissuring, hypocellularity, and proteoglycan loss in both groups (p > 0.05). Conclusions: Intra-articular NAC exerts potent anti-inflammatory and antioxidative effects within the synovial compartment but fails to prevent cartilage degeneration in the ACLT model. These findings indicate a compartment-specific therapeutic profile, suggesting that NAC may function as a symptom-modifying agent in synovitis-dominant OA rather than a structure-modifying therapy. Future studies should focus on optimized delivery systems or combination strategies targeting cartilage and subchondral bone to achieve disease modification. Full article

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

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37 pages, 2862 KB

Open AccessReview

Exploring the Benefits of Cranberries in Dentistry: A Comprehensive Review

by Isabella Schönhofen Manso, Yasmim Guterres Bauer, Eduarda Blasi Magini, Gabriel Leonardo Magrin, Izabella Thais da Silva and Ariadne Cristiane Cabral Cruz

Biomedicines 2026, 14(1), 85; https://doi.org/10.3390/biomedicines14010085 - 31 Dec 2025

Abstract

Objectives: Despite the increasing scientific evidence regarding the application of Cranberries in dentistry, a comprehensive understanding of their potential benefits, active constituents, and mechanisms of action remains lacking. Consequently, this narrative review aims to meticulously analyze and consolidate the existing scientific literature on [...] Read more.

Objectives: Despite the increasing scientific evidence regarding the application of Cranberries in dentistry, a comprehensive understanding of their potential benefits, active constituents, and mechanisms of action remains lacking. Consequently, this narrative review aims to meticulously analyze and consolidate the existing scientific literature on the utilization of Cranberries for the prevention and treatment of oral diseases. Materials and Methods: Electronic databases (PubMed, Scopus, and Web of Science) were searched up to October 2025. This review included in vitro, in vivo, and clinical research studies. A two-phase selection process was carried out. In phase 1, two reviewers independently screened titles and abstracts to identify potentially eligible studies. In phase 2, the same reviewers performed the full-text assessments of the eligible articles. Results: Among the 93 eligible articles, most assessed Cranberry use in Cariology (n = 28) and Periodontics (n = 26). Biofilm and microbial virulence factors (n = 46) were the most frequently studied topics. Cranberry extract (n = 32) and high-molecular-weight non-dialyzable material (NDM) (n = 23) were the most evaluated Cranberry fractions. Overall, Cranberry-derived compounds were identified as non-toxic and demonstrated promising antimicrobial activity against dental caries-related microorganisms in preclinical studies (n = 20). Regarding periodontal and peri-implant diseases, Cranberry demonstrated host immune modulator effects, counteracting the inflammatory and destructive mechanisms (n = 8). Additionally, Cranberries presented benefits in reducing the inflammation associated with periodontal disease and temporal mandibular joint lesions (n = 1). Regarding dental erosion, Cranberry inhibited dentin erosion (n = 4); however, no effect was observed on enamel lesions (n = 2). As an antioxidant agent, Cranberry showed effectiveness in preventing dental erosion (n = 18). Beyond that, Cranberry neutralized reactive oxygen species generated immediately after dental bleaching, enhancing bond strength (n = 2) and counteracting the oxygen ions formed on the tooth surface following bleaching procedures (n = 3). In osteoclastogenesis assays, A-type proanthocyanidins inhibited bone resorption (n = 1). In osteogenic analysis, preservation of hydroxycarbonate apatite deposition and an increase in early and late osteogenic markers were observed (n = 2). Conclusions: Cranberry bioactive compounds, both individually and synergistically, exhibit substantial potential for diverse applications within dentistry, particularly in the prevention and management of oral and maxillofacial diseases. This review provides insights into the plausible incorporation of Cranberries in contemporary dentistry, offering readers an informed perspective on their potential role. Full article

(This article belongs to the Special Issue Poly-Pharmacological Effects and Mechanisms of Phytochemicals)

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16 pages, 1959 KB

Open AccessArticle

Serum Bile Acid Profiling Across the Full Spectrum of HBV-Related Liver Diseases in Chinese Population: Implications for Diagnosis and Treatment Assessment

by Jiahua Mu, Deliang Huang, Lingyun Chen, Guilan Zhu, Guixue Hou, Liang Lin, Jiuxin Qu, Siqi Liu and Jun Chen

Biomedicines 2026, 14(1), 84; https://doi.org/10.3390/biomedicines14010084 - 31 Dec 2025

Abstract

Background/Objectives: Conventional serum biomarkers such as ALT and AST exhibit limited sensitivity and specificity in distinguishing the spectrum of HBV-related liver diseases, especially chronic hepatitis (CHB), cirrhosis (LC), and hepatocellular carcinoma (HCC). This study aimed to investigate the diagnostic potential of serum bile [...] Read more.

Background/Objectives: Conventional serum biomarkers such as ALT and AST exhibit limited sensitivity and specificity in distinguishing the spectrum of HBV-related liver diseases, especially chronic hepatitis (CHB), cirrhosis (LC), and hepatocellular carcinoma (HCC). This study aimed to investigate the diagnostic potential of serum bile acid profiles as novel metabolic discriminators to differentiate among healthy individuals, CHB, LC, HCC, and liver failure, thereby addressing a key unmet need in clinical practice. Methods: A total of 625 participants were recruited and serum concentrations of 15 bile acids were determined by LC-MS/MS using targeted absolute quantification. Machine learning was employed to establish the diagnostic panels for classifying the distinct stages of HBV-related diseases. Results: The combinations of taurolithocholic acid (TLCA) and taurochenodeoxycholic acid (TDCA) effectively differentiated healthy individuals from the patients with liver diseases (AUCs = 0.880–1.000 across subgroups), and the specific panel of four bile acids achieved discriminative AUCs of 0.874 between CHB and LC, and 0.825 between CHB and HCC, which outperformed conventional biomarkers. Bile acid profiles also demonstrated significant responsiveness to antiviral therapy, some bile acid concentrations consistently decreasing during the post-treatment periods. Conclusion: Serum bile acid panels thus offer a sensitive and reliable diagnostic performance that could significantly enhance clinical decision-making and patient management. Full article

(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches—4th Edition)

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15 pages, 1402 KB

Open AccessArticle

Persistent Low-Grade Inflammation and Post-COVID Condition: Evidence from the ORCHESTRA Cohort

by Elisa Gentilotti, Carolina Alvarez Garavito, Anna Górska, Roy Gusinow, Lorenzo Maria Canziani, Pasquale De Nardo, Alessandro Visentin, Maria Giulia Caponcello, Michela Di Chiara, Aline-Marie Florence, Gerolf de Boer, Salvatore Cataudella, the ORCHESTRA Study Group, Gabriel Levy Hara, Adriana Tami, Maddalena Giannella, Cédric Laouénan, Jan Hasenauer, Jesús Rodríguez-Baño and Evelina Tacconelli

Biomedicines 2026, 14(1), 83; https://doi.org/10.3390/biomedicines14010083 - 31 Dec 2025

Abstract

Background: Persistent low-grade inflammation has been proposed as part of the biological mechanisms underlying post-COVID condition (PCC), which can result in laboratory tests abnormalities. However, the accuracy of routine laboratory tests for the diagnosis and follow-up of PCC is still under discussion. Methods: [...] Read more.

Background: Persistent low-grade inflammation has been proposed as part of the biological mechanisms underlying post-COVID condition (PCC), which can result in laboratory tests abnormalities. However, the accuracy of routine laboratory tests for the diagnosis and follow-up of PCC is still under discussion. Methods: Patients with SARS-CoV-2 infection enrolled in the prospective, multinational ORCHESTRA cohort study, which included both European and non-European countries, were followed up for 18 months after acute infection. Blood test results were collected at acute infection and at 6, 12, and 18 months. A multivariable analysis was performed to estimate the relationship between the alterations of biochemical markers and the presence of four distinct PCC phenotypes, identified previously through a principal component analysis—respiratory (RESc), chronic pain (CPc), chronic fatigue (CFc), and neurosensorial (NSc)—during follow-up. Furthermore, this study investigated the correlation between biochemical parameters measured during the acute phase and the subsequent development of PCC. Finally, the relationship between the severity of the acute infection and biochemical abnormalities observed during follow-up was assessed. Results: The cohort included 4587 patients, 58% male, with a mean age of 58.7 (±15.5) years. A robust multivariable analysis demonstrated that, compared to controls, patients with PCC, and in particular those in the RESc cluster, presented higher mean C-reactive protein (CRP) levels at the 12- and 18-month follow-up (p-value = 0.01). In each follow-up, CRP values in patients with PCC and RESc were above 3 mg/L, corresponding to those observed in low-grade inflammation (3–10 mg/L). The severity of COVID-19 acute infection was associated with increased levels of CRP, ferritin and LDH during follow-up (p < 0.001). Biochemistry abnormalities detected during the early stages of acute COVID-19 did not correlate with an increased risk of developing PCC and its phenotypes. Conclusions: In patients with the RESc PCC phenotype, identified through a principal component analysis, blood test abnormalities consistent with prolonged and sustained low-grade inflammation can be detected up to 18 months after acute infection, supporting its role in the pathogenesis of PCC. Based on these results, trials on anti-inflammatory drugs, together with symptom-tailored interventions for patients with RESc, should be planned to prove their effectiveness in managing PCC and improving patient outcomes. Full article

(This article belongs to the Special Issue The End of the COVID-19 Pandemic—What Is Currently Known and What Could Have Been Useful Four Years Ago? (2nd Edition))

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16 pages, 953 KB

Open AccessArticle

MASLD or MetALD? Unveiling the Role of Alcohol in Liver Disease Progression in Diabetic Patients

by Ermina Stratina, Carol Stanciu, Robert Nastasa, Sebastian Zenovia, Remus Stafie, Adrian Rotaru, Stefan Chiriac, Irina Girleanu, Cristina Muzica, Horia Minea, Laura Huiban and Anca Trifan

Biomedicines 2026, 14(1), 82; https://doi.org/10.3390/biomedicines14010082 - 31 Dec 2025

Abstract

Background: The transition from the term non-alcoholic fatty liver disease (NAFLD) to steatotic liver disease (SLD), an umbrella term for several related conditions, offers benefits, particularly in identifying cardiometabolic risk factors more effectively. However, the impact of alcohol consumption on liver disease [...] Read more.

Background: The transition from the term non-alcoholic fatty liver disease (NAFLD) to steatotic liver disease (SLD), an umbrella term for several related conditions, offers benefits, particularly in identifying cardiometabolic risk factors more effectively. However, the impact of alcohol consumption on liver disease progression remains significant, leading to the recognition of a new entity: MetALD (metabolic dysfunction-associated steatotic liver disease with moderate alcohol intake). Aim: This study aimed to compare characteristics associated with liver disease progression in diabetic patients diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD) versus those with MetALD. Materials and Methods: In this prospective study, 286 diabetic patients were followed for 12 months. All patients underwent transient elastography (TE) and ultrasound to assess hepatic steatosis. Participants were classified into MASLD and MetALD groups. The performance of fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) were also evaluated. Results: MASLD was diagnosed in 58.2% (167 patients), of whom 4.9% (7 patients) had TE values suggestive for liver cirrhosis. Among those with MetALD, 17.6% (21 patients) had TE values compatible with advanced fibrosis. MASLD subjects presented a slight decrease in liver fibrosis values from 6.58 ± 2.27 kPa to 6.03 ± 1.57 kPa in the 12 months. On the contrary, MetALD subjects had an increase of liver stiffness measurements (LSM) values from 11.83 ± 6.27 kPa to 12.24 ± 8.66 kPa. Conclusions: in diabetic patients, the coexistence of moderate alcohol intake and cardiometabolic risk factors (MetALD) is associated with more advanced liver fibrosis and impaired long-term glycemic control, compared to MASLD alone. Full article

(This article belongs to the Special Issue Gastrointestinal Diseases: From Pathophysiology to Innovative Therapeutic Approaches)

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20 pages, 613 KB

Open AccessReview

Next-Generation SGLT2 Inhibitors: Innovations and Clinical Perspectives

by Dana Movila, Daniel Duda Seiman and Simona Ruxanda Dragan

Biomedicines 2026, 14(1), 81; https://doi.org/10.3390/biomedicines14010081 - 30 Dec 2025

Abstract

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have substantially reshaped the management of type 2 diabetes mellitus (T2DM), owing not only to their glucose-lowering properties but also to their consistent cardiovascular and renal protective effects. Beyond their initial metabolic indication, these agents have emerged as [...] Read more.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have substantially reshaped the management of type 2 diabetes mellitus (T2DM), owing not only to their glucose-lowering properties but also to their consistent cardiovascular and renal protective effects. Beyond their initial metabolic indication, these agents have emerged as disease-modifying therapies across a broad spectrum of cardiometabolic and renal conditions. Building on the clinical success of first-generation SGLT2 inhibitors, such as empagliflozin and dapagliflozin, next-generation SGLT2-based therapies have been developed with the aim of refining pharmacological selectivity, optimizing pharmacokinetic profiles, and expanding therapeutic applicability beyond diabetes. These innovations include dual SGLT1/SGLT2 inhibition, alternative dosing strategies, and molecular designs tailored to specific clinical phenotypes, such as heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD). This narrative review critically evaluates the evolving landscape of next-generation SGLT2 inhibitors, with a focus on structural and pharmacokinetic innovations, transporter selectivity, glucose-independent mechanisms, and emerging clinical implications. A comprehensive literature search was conducted using PubMed/MEDLINE, Scopus, and Web of Science, encompassing publications from inception to March 2025. Eligible sources included randomized clinical trials, observational studies, meta-analyses, and authoritative reviews published in English. Available evidence indicates that, while conventional SGLT2 inhibitors confer robust and reproducible cardiorenal benefits, newer agents may further extend therapeutic potential through incretin-related effects, modulation of extra-renal pathways, and disease-specific cardiac and renal mechanisms. Nevertheless, evidence supporting incremental clinical benefit beyond established SGLT2 inhibitors remains limited and heterogeneous, particularly for recently developed compounds. Overall safety profiles appear broadly consistent within the class, although long-term data for next-generation agents are still evolving. Key limitations of the current evidence base include reliance on emerging or indirect mechanistic data, heterogeneity in study populations and clinical endpoints, and the relative scarcity of large, outcome-driven trials for newer SGLT2-based therapies. Future research should prioritize mechanism-driven clinical trials, precision-oriented patient stratification, and head-to-head comparative studies to more clearly define the role of next-generation SGLT2 inhibitors in cardiovascular, renal, and metabolic disease management. Full article

(This article belongs to the Special Issue Connections Between Diabetes Mellitus, Other Metabolic and Endocrine Dysfunctions and Cardiovascular Pathologies—Second Edition)

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23 pages, 3725 KB

Open AccessArticle

RXR Agonist V-125 Induces Distinct Transcriptional and Immunomodulatory Programs in Mammary Tumors of MMTV-Neu Mice Compared to Bexarotene

by Afrin Sultana Chowdhury, Lyndsey A. Reich, Karen T. Liby, Elizabeth S. Yeh and Ana S. Leal

Biomedicines 2026, 14(1), 80; https://doi.org/10.3390/biomedicines14010080 - 30 Dec 2025

Abstract

Background: The retinoid X receptor (RXR) is a ligand-activated nuclear receptor that heterodimerizes with numerous partners to regulate diverse transcriptional programs. RXR agonists, including the FDA-approved drug bexarotene, show anti-tumor activity but are limited by adverse side effects. V-125 is a next-generation RXR [...] Read more.

Background: The retinoid X receptor (RXR) is a ligand-activated nuclear receptor that heterodimerizes with numerous partners to regulate diverse transcriptional programs. RXR agonists, including the FDA-approved drug bexarotene, show anti-tumor activity but are limited by adverse side effects. V-125 is a next-generation RXR agonist engineered for improved selectivity, pharmacokinetics, and reduced lipogenic effects. This study compares the molecular and functional effects of V-125 and bexarotene in HER2⁺ breast cancer models. Methods: Female MMTV-Neu mice bearing mammary tumors were treated with control, V-125 (100 mg/kg diet), or bexarotene (100 mg/kg diet) for 10 days. RNA sequencing was used to identify differentially expressed genes and pathways. Candidate targets were validated by qPCR and immunohistochemistry (IHC). Immune modulation was evaluated by IHC staining for CD8 cells and CD206⁺ macrophages in tumors to capture the tumor microenvironment. Functional assays in JIMT-1 human HER2⁺ cells assessed RXR target activation and clonogenic potential in tumor cells. Results: V-125 induced broader transcriptional changes than bexarotene, including selective upregulation of Nrg1, Nfasc, Lrrc26, and Chi3l1 genes associated with improved patient survival. Pathway analysis revealed regulation of immune activation, cancer signaling, and lipid metabolism. Both V-125 and bexarotene suppressed colony formation in JIMT-1 cells, confirming previous observations about RXR-dependent inhibition of tumor cell growth. Moreover, V-125 in vivo had distinct capabilities to increase CD8 cell infiltration and reduced CD206⁺ macrophages, whereas bexarotene did not. Conclusions: V-125 but not bexarotene reprograms tumor transcriptional programs and the immune landscape in an anti-tumor manner in the MMTV-neu mouse model and in in vitro models of HER2⁺ breast cancer. This highlights its promise as a selective RXR agonist with anti-tumor and immunomodulatory activity in HER2⁺ breast cancer. Full article

(This article belongs to the Special Issue Breast Cancer: New Diagnostic and Therapeutic Approaches)

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12 pages, 1645 KB

Open AccessArticle

Immunohistochemical Evaluation of ALDH1 and Maspin in Oral Potentially Malignant Disorders and Oral Carcinoma

by Bianca-Andreea Onofrei, Delia Gabriela Ciobanu Apostol, Mădălina-Gabriela Tanasă, Elena-Raluca Baciu, Cristina Popa, Ana Maria Sciuca, George Alexandru Maftei and Victor-Vlad Costan

Biomedicines 2026, 14(1), 79; https://doi.org/10.3390/biomedicines14010079 - 30 Dec 2025

Abstract

Background/Objectives: Oral potentially malignant disorders (OPMDs), including oral leukoplakia (OLK), oral lichen planus (OLP), and actinic cheilitis (AC), have varying risks of progression to oral squamous cell carcinoma (OSCC). Biomarkers such as aldehyde dehydrogenase 1 (ALDH1) and mammary serine protease inhibitor (Maspin) [...] Read more.

Background/Objectives: Oral potentially malignant disorders (OPMDs), including oral leukoplakia (OLK), oral lichen planus (OLP), and actinic cheilitis (AC), have varying risks of progression to oral squamous cell carcinoma (OSCC). Biomarkers such as aldehyde dehydrogenase 1 (ALDH1) and mammary serine protease inhibitor (Maspin) have shown potential for diagnostic and prognostic use in oral cancer. The present study aimed to evaluate the immunoexpression of aldehyde dehydrogenase 1, a cancer stem cell marker associated with aggressiveness, and the mammary serine protease inhibitor, a potential tumor suppressor, in OPMD and OSCC tissues. Methods: A retrospective analysis was performed on 145 biopsy specimens collected from January 2015 to January 2023, including normal epithelium, OPMDs (OLK, OLP, AC), and OSCC. ALDH1 and Maspin expression levels were evaluated using immunohistochemistry, considering both the percentage of positive cells and staining intensity. Statistical analyses were carried out using the Statistical Package for the Social Sciences (SPSS, version 29.0; IBM Corp., Chicago, IL, USA). Results: Normal oral epithelium showed no expression of ALDH1, whereas 40.6% of OPMDs and 44.4% of OSCC samples exhibited high cytoplasmic ALDH1 expression. Nuclear ALDH1 expression was elevated in 29.7% of OPMDs and 38.9% of OSCCs (p < 0.001). Nuclear Maspin expression was high in 95.2% of normal tissues, in 67.2% of OPMDs and in 55.6% of OSCCs (p < 0.001). Maspin showed strong nuclear and cytoplasmic expression in normal tissue, but its expression decreased in OPMDs and OSCCs, with statistically significant reductions in both compartments (p < 0.001). Conclusions: The results indicate that ALDH1 upregulation and Maspin downregulation are hallmark events in oral carcinogenesis. Their combined evaluation provides a powerful tool for assessing dysplastic severity and malignant transformation risk in OPMDs. Future studies on larger cohorts are needed to confirm the prognostic utility of this dual-marker model. Full article

(This article belongs to the Special Issue Inflammatory Mechanisms, Biomarkers and Treatment in Oral Diseases)

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22 pages, 13539 KB

Open AccessArticle

Trained Immunity in Bladder ILC3s Enhances Mucosal Defense Against Recurrent Urinary Tract Infections

by Qiaoqiao Pei, Jiaqi Liu, Ziwen Tang, Jiaqing Tan, Xu Han, Xinrong Hu, Zhou Liang, Feng Li, Changjian Zhu, Ruoni Lin, Ruilin Zheng, Jiani Shen, Qinghua Liu, Haiping Mao, Kefei Wu, Wei Chen and Yi Zhou

Biomedicines 2026, 14(1), 78; https://doi.org/10.3390/biomedicines14010078 - 30 Dec 2025

Abstract

Background: Urinary tract infections (UTIs) rank among the most prevalent infectious diseases globally, with recurrent UTIs (rUTIs) posing substantial therapeutic challenges due to the lack of durable protective immunity. While trained immunity augments innate immune responses, its induction and functional significance in [...] Read more.

Background: Urinary tract infections (UTIs) rank among the most prevalent infectious diseases globally, with recurrent UTIs (rUTIs) posing substantial therapeutic challenges due to the lack of durable protective immunity. While trained immunity augments innate immune responses, its induction and functional significance in bladder-resident group 3 innate lymphoid cells (ILC3s) remain unknown. This study investigates whether ILC3s develop trained immunity following uropathogenic Escherichia coli (UPEC) exposure and how they contribute to mucosal defense against rUTIs. Methods: The ILC3 counts were detected in bladder sections from UTI patients and health controls (HC). A recurrent UTI mouse model was established through primary and secondary urethral UPEC inoculation. Bacterial loads in tissues were assessed, and single-cell suspensions were analyzed via flow cytometry. Bladder naïve- and UPEC-trained ILC3s were adoptively transferred, with evaluations of histopathology, epithelial barrier function, inflammation, and antimicrobial peptides. The in vitro ILC3 cell line MNK-3 was detected for IL-17A and IL-22 production following primary and secondary UPEC lysate stimulation. Results: We demonstrate that primary UPEC infection triggers ILC3 expansion in both human and murine bladders. Upon secondary challenge, these ILC3s develop trained immunity, characterized by enhanced proliferation, amplified IL-17A and IL-22 production, and improved pathogen clearance. Mechanistically, trained ILC3s reinforce urothelial barrier integrity through upregulation of antimicrobial peptides (Reg3b/Reg3g) and attenuate inflammatory pathology by suppressing pro-inflammatory cytokines (IL-6, TNF-α). Conclusions: We uncover an endogenous defense mechanism wherein UPEC primes bladder ILC3s via trained immunity, enabling amplified IL-17A- and IL-22-mediated protection against recurrent infections. These findings establish ILC3-trained immunity as a novel conceptual foundation, providing a basis for developing immunotherapies against rUTIs. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Infectious Diseases)

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14 pages, 1021 KB

Open AccessArticle

Nasal Cytology Is Useful for Evaluating and Monitoring the Therapeutic Response to Biologics in Chronic Rhinosinusitis with Nasal Polyposis

by Gioia Piatti, Ludovica Battilocchi, Anna Cozzi, Lorenzo Maria Gaini, Mirko Aldè, Lorenzo Pignataro and Sara Torretta

Biomedicines 2026, 14(1), 77; https://doi.org/10.3390/biomedicines14010077 - 30 Dec 2025

Abstract

Background/Objectives: In recent years, the recognition that type 2 inflammation plays a leading role in CRSwNP has enabled the more tailored treatment of the disease through improved patient endotyping. We studied 45 patients with severe CRSwNP who were treated with dupilumab or [...] Read more.

Background/Objectives: In recent years, the recognition that type 2 inflammation plays a leading role in CRSwNP has enabled the more tailored treatment of the disease through improved patient endotyping. We studied 45 patients with severe CRSwNP who were treated with dupilumab or mepolizumab. The aim was to evaluate the efficacy of these treatments on endoscopic, clinical and patient reported parameters, and to assess whether nasal cytology could be useful for identifying responsive patients and monitoring their response to biologic drugs. Methods: Follow-up visits were scheduled at baseline (T0), and at 3 (T3), 6 (T6), 12 (T12), and 24 months (T24). At each visit, patients underwent blood analysis, nasal endoscopy, and nasal scraping for cytology. They also completed the SNOT-22 questionnaire, a visual analog scale (VAS) for nasal obstruction and smell perception, and the Asthma Control Test (ACT) test in cases of concomitant asthma. Results: Biological therapy demonstrated broad efficacy in disease management, based on both clinical and cytological findings. The Nasal Polyp Score, SNOT-22 questionnaire, VAS scores for nasal obstruction and smell, and ACT score showed progressive improvement. Blood eosinophil counts and total IgE levels also decreased over time (T0 vs. T24: p = 0.008 and p < 0.001, respectively). At nasal cytology, a reduction in eosinophil cell count and in the mixed mast cell–eosinophil pattern during treatment with both biologics were observed (T0 vs. T24: p < 0.001). Positive effects were typically recorded within six months of treatment and were sustained after two years. Conclusions: Although the histological evaluation of infiltrated tissues remains the gold standard for assessing mucosal eosinophilia, nasal cytology appears to be a simpler, non-invasive, and repeatable method for evaluating local eosinophilia. Identifying endotypes and assessing the severity of inflammation are crucial for predicting the efficacy of different treatment options. Full article

(This article belongs to the Special Issue Targeted Biologic Therapies for Allergic Conditions: From Bench to Bedside)

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18 pages, 11888 KB

Open AccessArticle

Genetic Engineering of Umbilical Cord-Derived Mesenchymal Stem Cells to Enhance BMP-2 Secretion via Signal Peptide Optimization

by Nuzli Fahdia Mazfufah, Ismail Hadisoebroto Dilogo, Retno Wahyu Nurhayati, Delvac Oceandy, Silvia Tri Widyaningtyas, Maulana Dias Pratama and Goo Jang

Biomedicines 2026, 14(1), 76; https://doi.org/10.3390/biomedicines14010076 - 30 Dec 2025

Abstract

Background/Objectives: Mesenchymal stem cells (MSCs) are recognized for their therapeutic potential due to their ability to secrete bioactive molecules. Among these secreted factors, bone morphogenetic protein-2 (BMP-2) is known as a secreted factor that plays a crucial role in bone healing and [...] Read more.

Background/Objectives: Mesenchymal stem cells (MSCs) are recognized for their therapeutic potential due to their ability to secrete bioactive molecules. Among these secreted factors, bone morphogenetic protein-2 (BMP-2) is known as a secreted factor that plays a crucial role in bone healing and regeneration. However, MSCs naturally secrete only small amounts of BMP-2. To improve the bone healing capacity of MSCs, it is essential to enhance the secretion of BMP-2 in MSCs. One approach that can be used to achieve this goal is by genetically engineering MSCs. Incorporating signal peptides (SPs) into the inserted gene sequence can significantly improve protein secretion efficiency. In this proof-of-concept study, we explored the role of SPs in optimizing BMP-2 secretion in umbilical cord-derived MSCs; Methods: Three human-derived SPs, namely glial-derived neurotrophic factor (GDNF), chemotactic antibacterial glycoprotein 7 (CAP7), and platelet-derived growth factor subunit B (PDGFB), were selected. Transfection of MSCs was performed using polyethylenimine, Lipofectamine 2000^®, and Lipofectamine 3000^®. Transfection efficiency confirmed based on Green Fluorescence Protein expression. BMP-2 secretion levels were quantified using an ELISA assay; Results: Lipofectamine 3000^® achieved the highest transfection efficiency, reaching approximately 10%. BMP-2 secretion levels varied significantly depending on the SPs used, with PDGFB yielding the highest BMP-2 concentration (279.21 ± 6.91 pg/mL), followed by GDNF (265.65 ± 11.49 pg/mL) and CAP7 (233.72 ± 32.33 pg/mL); Conclusions: These findings demonstrate that SP selection critically influences BMP-2 secretion efficiency in genetically engineered MSCs and underscore its potential to enhance the therapeutic applicability of MSC-based strategies for bone healing. Full article

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

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16 pages, 871 KB

Open AccessArticle

Long-Term Prognosis and Impact Factors of Metoprolol Treatment in Children with Vasovagal Syncope

by Jing Wang, Ping Liu, Yuli Wang, Junbao Du, Ying Liao and Hongfang Jin

Biomedicines 2026, 14(1), 75; https://doi.org/10.3390/biomedicines14010075 - 30 Dec 2025

Abstract

Objective: To investigate long-term prognosis and impact factors in children with vasovagal syncope (VVS) receiving metoprolol therapy. Method: This retrospective study included children with VVS who underwent metoprolol therapy at the Pediatric Syncope Unit of Peking University First Hospital between January 2012 and [...] Read more.

Objective: To investigate long-term prognosis and impact factors in children with vasovagal syncope (VVS) receiving metoprolol therapy. Method: This retrospective study included children with VVS who underwent metoprolol therapy at the Pediatric Syncope Unit of Peking University First Hospital between January 2012 and November 2023. Baseline demographic data, pre-treatment indices, including head-up tilt test (HUTT) and 24 h Holter monitoring, were collected. All participants received standardized metoprolol therapy for a minimum duration of one month. Follow-up was conducted between June and July 2025, with syncope recurrence as the primary endpoint. Multivariable Cox proportional hazards regression analysis was performed to identify independent impact factors of prognosis and to construct a Prognostic Risk Score (PRS) model. The model’s performance was rigorously validated through receiver operating characteristic (ROC) curve analysis, decision curve analysis (DCA), and Bootstrap resampling (1000 iterations). Furthermore, children were stratified into high- and low-risk groups based on median PRS values. Kaplan–Meier survival analysis was then performed to assess the model’s discriminative efficacy. Result: This study included 97 children diagnosed with VVS. The median duration of metoprolol therapy was 2.5 months (interquartile range [IQR]: 2.0–3.0 months), with a median follow-up period of 59 months (IQR: 25.5–72 months). During follow-up, syncope recurrence was observed in 37 patients, while 60 patients remained symptom-free. COX regression analysis showed that time-domain indices of heart rate variability (HRV), including the standard deviation of all NN intervals (SDNN) and the triangular index (TR), as well as the frequency-domain index of HRV very low frequency (VLF), were relative factors of the long-term prognosis in children with VVS treated with metoprolol. Based on the above three identified factors, the PRS model was calculated as: PRS = 0.03 × SDNN − 0.02 × VLF − 0.1 × TR. ROC showed that the area under the curve (AUC) for discriminative power related to long-term prognosis was 0.808 (p < 0.01). The cumulative recurrence rate of symptoms in the high-risk score group was significantly higher than that in the low-risk score group (p < 0.01). The DCA curve demonstrated the clinical applicability of the model. Bootstrap internal verification indicated high stability, with the bias-corrected and accelerated (Bca) confidence interval (CI) of the C index ranging from 0.71 to 0.89. Conclusions: After metoprolol treatment, 38.1% of children with VVS experienced syncope recurrence during a median follow-up period of 59 months. Baseline HRV index, SDNN, TR, and VLF were identified as factors associated with the long-term prognosis of children with VVS treated with metoprolol. The PRS model based on the above indices demonstrated good value in linking to the individual long-term prognosis. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: From Pathophysiology to Novel Therapeutic Approaches)

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Graphical abstract

15 pages, 717 KB

Open AccessSystematic Review

Enhanced Monovision Intraocular Lenses: Current Status and Future Perspectives—Systematic Review

by Zofia Honorata Trusiak, Aleksandra Leoniuk, Aleksandra Tomaszuk, Michał Sawicki and Joanna Konopińska

Biomedicines 2026, 14(1), 74; https://doi.org/10.3390/biomedicines14010074 - 29 Dec 2025

Abstract

Background/Objectives: Cataract is the most common cause of blindness in the world. Enhanced monovision intraocular lenses (EMV IOLs) have been recently made available on the market. In this study, we aimed to further the understanding of EMV IOLs and their potential benefits [...] Read more.

Background/Objectives: Cataract is the most common cause of blindness in the world. Enhanced monovision intraocular lenses (EMV IOLs) have been recently made available on the market. In this study, we aimed to further the understanding of EMV IOLs and their potential benefits in cataract surgery, while also identifying areas for future research. Methods: In this review, we discuss the findings of a few previously published comparative studies concerning different types of EMV IOLs. We conducted a systematic review of comparative studies (randomized controlled trials, prospective and retrospective observational studies) describing binocular uncorrected intermediate vision acuity (UIVA) in patients after cataract surgery and implantation of monofocal plus IOLs based on emmetropia and monovision. Results: The secondary outcomes measured were uncorrected distance visual acuity, uncorrected near visual acuity (UNVA; described in eight studies), spectacle independence and patients’ satisfaction. A total of 199 patients (average age 68.11 years) were analyzed in the included studies; of these patients, 169 achieved UNVA reaching an average of 0.188 logMAR. Conclusions: The monovision approach may provide enhanced intermediate and near vision without significantly compromising distance vision or patient satisfaction, though results varied across studies. Future randomized trials with standardized outcome measures and conducted over a longer follow-up period are warranted to confirm these findings. Full article

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

33 pages, 1431 KB

Open AccessReview

Microbiota-Driven Immune Dysregulation Along the Gut–Lung–Vascular Axis in Asthma and Atherosclerosis

by Elena-Larisa Zimbru, Răzvan-Ionuț Zimbru, Florina-Maria Bojin, Sorin Dan Chiriac, Laura Haidar, Minodora Andor, Gabriela Tănasie, Carmen Tatu, Marius Georgescu, Cristina Uța, Camelia-Felicia Bănărescu, Sabine Groza and Carmen Panaitescu

Biomedicines 2026, 14(1), 73; https://doi.org/10.3390/biomedicines14010073 - 29 Dec 2025

Abstract

Background: Asthma and atherosclerosis frequently coexist in clinical populations and share convergent immunometabolic pathways amplified by gut microbial dysbiosis. We propose the gut–lung–vascular axis as a unifying mechanistic framework connecting epithelial and endothelial inflammation providing a foundation for understanding shared inflammatory mechanisms beyond [...] Read more.

Background: Asthma and atherosclerosis frequently coexist in clinical populations and share convergent immunometabolic pathways amplified by gut microbial dysbiosis. We propose the gut–lung–vascular axis as a unifying mechanistic framework connecting epithelial and endothelial inflammation providing a foundation for understanding shared inflammatory mechanisms beyond tissue-specific disease boundaries. Methods: A targeted narrative review systematically appraised clinical, experimental and multi-omics studies published over the last five years to delineate microbiota-driven pathways relevant to asthma and atherosclerosis. Particular emphasis was placed on specific microbial taxa, metabolite profiles and immunometabolic networks that connect gut dysbiosis with respiratory and cardiovascular dysfunction. Results: Across human and experimental cohorts, dysbiosis marked by depletion of short-chain fatty acids (SCFAs) producing taxa (Faecalibacterium, Roseburia, Bacteroides) and enrichment of pathobionts (Proteobacteria, Haemophilus, Moraxella, Streptococcus) promotes epithelial and endothelial barrier dysfunction, amplifying Th2/Th17-skewed inflammation and endothelial injury. Key metabolites, including SCFAs, trimethylamine N-oxide (TMAO), secondary bile acids (BA), indole/tryptophan derivatives and lipopolysaccharides (LPS), serve as molecular connectors linking gut, airway and vascular inflammation. Microbial signatures and metabolomic patterns hold emerging diagnostic and therapeutic potential, and several drug classes (e.g., statins, corticosteroids, proton-pump inhibitors (PPIs)) further modulate host–microbiota interactions. Conclusions: Shared microbial taxa and metabolite signatures in asthma and atherosclerosis support microbiota-mediated immune dysregulation along the gut–lung–vascular axis as a common pathogenic framework. Microbial and metabolite profiling may enable improved risk stratification and precise, microbiota-targeted therapies. Integrating microbiome-informed diagnostics and personalized interventions could help reduce systemic inflammation and the burden of these overlapping inflammatory diseases. Full article

(This article belongs to the Special Issue Omics Approaches on Immune-Mediated Inflammatory Diseases: Towards Novel Biomarkers and Potential Therapeutic Targets, 3rd Edition)

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30 pages, 1460 KB

Open AccessReview

Neuron–Glioma Synapses in Tumor Progression

by Cristina Cueto-Ureña, María Jesús Ramírez-Expósito and José Manuel Martínez-Martos

Biomedicines 2026, 14(1), 72; https://doi.org/10.3390/biomedicines14010072 - 29 Dec 2025

Abstract

Gliomas are the most common malignant primary brain tumors in adults. The treatment of high-grade gliomas is very limited due to their diffuse infiltration, high plasticity, and resistance to conventional therapies. Although they were long considered passive massive lesions, they are now regarded [...] Read more.

Gliomas are the most common malignant primary brain tumors in adults. The treatment of high-grade gliomas is very limited due to their diffuse infiltration, high plasticity, and resistance to conventional therapies. Although they were long considered passive massive lesions, they are now regarded as functionally integrated components of neural circuits, as they form authentic electrochemical synapses with neurons. This allows them to mimic neuronal activity to drive tumor growth and invasion. Ultrastructural studies show presynaptic vesicles in neurons and postsynaptic densities in glioma cell membranes, while electrophysiological recordings detect postsynaptic currents in tumor cells. Tumor microtubules (TMs), dynamic cytoplasmic protrusions enriched in AMPA receptors, are the structures responsible for glioma–glioma and glioma–neuron connectivity, also contributing to treatment resistance and tumor network integration. In these connections, neurons release glutamate that mainly activates their AMPA receptors in glioma cells, while gliomas release excess glutamate, causing excitotoxicity, altering the local excitatory-inhibitory balance, and promoting a hyperexcitable and pro-tumorigenic microenvironment. In addition, certain gliomas, such as diffuse midline gliomas, have altered chloride homeostasis, which makes GABAergic signaling depolarizing and growth promoting. Synaptogenic factors, such as neuroligin-3 and BDNF, further enhance glioma proliferation and synapse formation. These synaptic and paracrine interactions contribute to cognitive impairment, epileptogenesis, and resistance to surgical and pharmacological interventions. High functional connectivity within gliomas correlates with shorter patient survival. Therapies such as AMPA receptor antagonists (perampanel), glutamate release modulators (riluzole or sulfasalazine), and chloride cotransporter inhibitors (NKCC1 blockers) aim to improve outcomes for patients. Full article

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

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