Biomedicines

50 pages, 4933 KB

Open AccessReview

Multifunctional Nano-Contrast Agent Carriers: From Traditional Platforms to Next-Generation Theranostic Applications in Molecular Imaging

by Danial Mirzaee, Marzieh Ramezani Farani, Maryam Ghasemzaei, Amir Gholami, Mohammad Seyedhamzeh, Iraj Alipourfard, Majid Farsadrooh, Mostafa Saffari, Mehdi Mirzaei, Omid Akhavan, Seyed Majid Ghoreishian, Yun Suk Huh, H. Bryan Riley and Mehdi Shafiee Ardestani

Biomedicines 2026, 14(7), 1552; https://doi.org/10.3390/biomedicines14071552 - 10 Jul 2026

Abstract

Multifunctional nano-contrast agent carriers are redefining molecular imaging by combining high-fidelity visualization with targeted delivery, controlled release, and, increasingly, therapeutic action. This review encompasses the development of nano-contrast platforms from conventional dendrimer, liposome, chitosan, and silica systems to modular nano-contrast platforms for multimodal, [...] Read more.

Multifunctional nano-contrast agent carriers are redefining molecular imaging by combining high-fidelity visualization with targeted delivery, controlled release, and, increasingly, therapeutic action. This review encompasses the development of nano-contrast platforms from conventional dendrimer, liposome, chitosan, and silica systems to modular nano-contrast platforms for multimodal, multi-parametric, and activatable imaging in clinically relevant environments. We dissect engineering strategies that govern surface chemistry, ligand organization, stimulus responsiveness, and microenvironmental sensing, and relate them to theranostic performance, immune system engagement, and quantitative image readouts. Biodistribution, pharmacokinetics, and safety are discussed from both classical and model-informed perspectives, with design principles that favor predictable behavior, manufacturability, and regulatory acceptance. Current clinical translation, regulatory pathway evolution, and market dynamics are critically reviewed to elucidate that a few nano-contrast agents have reached patients despite a widespread experimental landscape. Finally, we discuss emerging trends, including biomimetic and ultrasmall carriers, metal–organic and hybrid frameworks, AI-assisted design, digital twins, and precision medicine workflows, which are likely to shape the next-generation nano-contrast theranostics. By systematically relating material selection and carrier architecture to imaging function and translational limitations, this review suggests concrete research priorities for taking nano-contrast agents from sophisticated prototypes to robust, patient-tailored tools. Full article

(This article belongs to the Special Issue Emerging Trends and Applications in Nanomedicine and Targeted Therapies)

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Graphical abstract

30 pages, 8927 KB

Open AccessArticle

Preliminary Assessment of Anticancer Activity of Aqueous Meadowsweet (Filipendula ulmaria (L.) Maxim.) Extract in LoVo Colorectal Cancer Cells

by Łukasz Sobczak, Agata Wszołek, Wojciech Żwierełło, Kinga Rybak, Anna Nowakowska, Edyta Stępień-Zawal, Marcin Wilhelm, Magdalena Rutkowska, Dominika Ciosek, Katarzyna Marzoch, Izabela Gutowska and Agnieszka Maruszewska

Biomedicines 2026, 14(7), 1551; https://doi.org/10.3390/biomedicines14071551 - 10 Jul 2026

Abstract

Background/Objectives: Filipendula ulmaria (L.) Maxim. (meadowsweet) is a medicinal plant traditionally used for its antioxidant and anti-inflammatory effects. There is also some data indicating its anticancer potential; however, its impact on colorectal cancer cells remains poorly understood. Here we investigated the cytotoxic [...] Read more.

Background/Objectives: Filipendula ulmaria (L.) Maxim. (meadowsweet) is a medicinal plant traditionally used for its antioxidant and anti-inflammatory effects. There is also some data indicating its anticancer potential; however, its impact on colorectal cancer cells remains poorly understood. Here we investigated the cytotoxic and pro-apoptotic effects of an aqueous F. ulmaria extract on human LoVo colorectal cancer cells and analyzed some of the mechanisms underlying it. Methods: LoVo colorectal cancer cells were treated with the aqueous extract and analyzed for intracellular reactive oxygen species (ROS), mitochondrial membrane potential, DNA damage, lysosomal alterations, apoptosis-related mechanisms, and antioxidant activity. Phytochemical profiling was performed by HPLC-TOF/MS. Results: The extract elevated intracellular ROS levels, disrupted mitochondrial membrane potential, and induced DNA damage in LoVo cells. Activation of crucial caspases, along with increased p53 levels, confirmed engagement of both extrinsic and intrinsic apoptotic pathways. Changes in lysosomal fluorescence were also observed, indicating alterations in lysosomal properties. In chemical assays (FRAP, TAC, DPPH, ABTS, and superoxide scavenging), the extract demonstrated robust antioxidant capacity comparable to or exceeding that of ascorbic acid. Phytochemical profiling by HPLC-TOF/MS revealed a rich presence of bioactive flavonoids, phenolic acids, and coumarins. Altogether, our findings indicate that the extract’s cytotoxicity against colon cancer cells arises from a multifaceted mechanism involving oxidative stress, organelle dysfunction, and apoptosis induction. Conclusions: These results highlight F. ulmaria aqueous extract as a promising candidate for colorectal cancer phytotherapy as a form of supportive treatment and warrant further preclinical validation. Full article

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

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17 pages, 10638 KB

Open AccessArticle

Multi-Layer Omics Analysis Identifies Anxa3 and Coro1a as Candidate Targets of Pien Tze Huang in a Mouse Model of Liver Fibrosis

by Hao Wu, Longhui Gao, Xianglong Zhao, Xiangyi Li, Yunxiao Lin, Luan Chen, Lixing Li, Lu Shen, Wei Bao, Jinhang Zhu, Cong Huai, Zhiliang Chen, Yichao Zhuang and Shengying Qin

Biomedicines 2026, 14(7), 1550; https://doi.org/10.3390/biomedicines14071550 - 10 Jul 2026

Abstract

Background/Objectives: Liver fibrosis, a wound-healing response to chronic liver injury characterized by excessive extracellular matrix (ECM) accumulation, represents a major global health burden with no approved anti-fibrotic therapies. Pien Tze Huang (PZH), an officially approved traditional Chinese medicine (NMPA Drug Approval No. Z35020243), [...] Read more.

Background/Objectives: Liver fibrosis, a wound-healing response to chronic liver injury characterized by excessive extracellular matrix (ECM) accumulation, represents a major global health burden with no approved anti-fibrotic therapies. Pien Tze Huang (PZH), an officially approved traditional Chinese medicine (NMPA Drug Approval No. Z35020243), has demonstrated hepatoprotective effects, yet its epigenetic mechanisms in fibrosis treatment remain unexplored. Methods: We performed the first integrated methylome–transcriptome–proteome analysis to investigate PZH’s anti-fibrotic mechanisms in a CCl₄-induced mouse model using reduced representation bisulfite sequencing (RRBS), RNA-seq, and TMT-labeled LC-MS/MS. Results: We identified 10,974 differentially methylated loci (DMLs) and 773 differentially expressed genes (DEGs) modulated by PZH treatment. Integration analysis revealed ANXA3 and CORO1A as candidate therapeutic targets exhibiting significant inverse methylation-expression correlations validated at both transcriptomic and proteomic levels. Notably, PZH treatment modulated the CRLF-CLCF1 cytokine complex and the EGR-3 transcription factor network (42/44 genes enriched), suggesting broad transcriptional reprogramming in fibrotic liver. Protein–protein interaction (PPI) analysis highlighted key gene pairs such as Dnmt1-Uhrf1, Cbfb-Runx1, and Col4a1-Col4a2, implicating PZH in epigenetic maintenance, transcription factor regulation, and ECM remodeling. Conclusions: These findings suggest mechanistic insights into PZH’s multi-target anti-fibrotic effects and offer a rationale for developing potential therapeutic targets for liver fibrosis. Full article

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

16 pages, 3795 KB

Open AccessArticle

Colostrum Extracellular Vesicle Isolation, Characterization, and Function

by Samia Akter, Nada Fayez, Mohit Kumar, Susmita Sil and Howard E. Gendelman

Biomedicines 2026, 14(7), 1549; https://doi.org/10.3390/biomedicines14071549 - 10 Jul 2026

Abstract

Background: Colostrum extracellular vesicles (C-EVs) are nanoscale, bioactive vesicles with therapeutic potential. The mechanisms of action include the control of cellular and tissue homeostasis. These make C-EVs a novel means to control inflammatory and cellular dysfunctions. However, a limitation for their broad [...] Read more.

Background: Colostrum extracellular vesicles (C-EVs) are nanoscale, bioactive vesicles with therapeutic potential. The mechanisms of action include the control of cellular and tissue homeostasis. These make C-EVs a novel means to control inflammatory and cellular dysfunctions. However, a limitation for their broad use is the ease of C-EV isolation and in ensuring their stability. Methods: Standard ultracentrifugation and gradient techniques used for EV recovery were employed, which included ultracentrifugation. Exodus dual-frequency ultrasonic nanofiltration (UNF) was a comparator used to overcome standard limitations by recovering pure vesicles at high concentrations. Both systems were evaluated for their abilities to recover clinical-grade C-EVs with optimal vesicle structural integrity and intact biological functions. Results: This study affirms UNF C-EV recovery by demonstrating intact Alix, CD63, Tsg101, and Flotillin antigens. The EVs maintained an intact bilayer structure with sizes ranging from to 50–200 nm. Functional tests showed preservation of their anti-inflammatory activities by suppression of pro-inflammatory cytokines and the NLRP3 inflammasome, caspase 1, interleukin-1, and 18 and maintaining cellular homeostasis. Processing time, high yield, and functional responses controlled cellular function. Conclusions: These data support the notion that UNF C-EVs can be recovered safely, at high yields, and reproducibly for future clinical applications. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Exosomes as Therapeutic Agents—2nd Edition)

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36 pages, 30919 KB

Open AccessReview

Benign Biliary Tumors and Precursor Neoplasms: An Updated Clinicopathological and Molecular Review Based on the 2026 WHO Classification

by Joon Hyuk Choi

Biomedicines 2026, 14(7), 1548; https://doi.org/10.3390/biomedicines14071548 - 10 Jul 2026

Abstract

Benign biliary tumors and precursor neoplasms of the biliary tract are a heterogeneous group of uncommon neoplasms with significant clinical and diagnostic implications. Their importance lies in their variable malignant potential and morphological and molecular similarities to pancreatic neoplasms. The sixth edition of [...] Read more.

Benign biliary tumors and precursor neoplasms of the biliary tract are a heterogeneous group of uncommon neoplasms with significant clinical and diagnostic implications. Their importance lies in their variable malignant potential and morphological and molecular similarities to pancreatic neoplasms. The sixth edition of the World Health Organization Classification of Digestive System Tumours (WHO DST6), published online in 2026, introduced major revisions to the classification of these entities. According to WHO DST6, benign tumors and precursor neoplasms of the liver and intrahepatic bile ducts include bile duct adenoma, biliary adenofibroma, and mucinous cystic neoplasm, whereas those of the gallbladder and extrahepatic bile ducts include biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile ducts, intraductal tubulopapillary neoplasm of the bile ducts, intraductal oncocytic papillary neoplasm of the bile ducts, and mass-forming intracholecystic neoplasm. Despite these advances, their histological and molecular heterogeneity continues to pose significant diagnostic challenges, particularly in distinguishing them from malignant biliary tumors on limited biopsy specimens and in recognizing early invasive lesions. This review summarizes the clinicopathological and molecular features of benign biliary tumors and precursor neoplasms, emphasizing differential diagnosis and key updates introduced in WHO DST6. Full article

(This article belongs to the Special Issue Liver Cancer: Molecular and Translational Insights of Carcinogenesis and Treatments)

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16 pages, 2606 KB

Open AccessArticle

Clinical Determinants and Bone Metabolic Correlates of 24-h Urinary PGE2 and PGEM Excretion in Chinese Adults: A Multicenter Cross-Sectional Study

by Qi Lu, Li Shen, Yang Xu and Zhenlin Zhang

Biomedicines 2026, 14(7), 1547; https://doi.org/10.3390/biomedicines14071547 - 10 Jul 2026

Abstract

Background: Prostaglandin E₂ (PGE₂) is a key lipid mediator involved in inflammation and bone homeostasis. Its systemic production is reliably reflected by 24 h urinary excretion of PGE₂ (U-PGE₂) and its major metabolite (U-PGEM). However, the [...] Read more.

Background: Prostaglandin E₂ (PGE₂) is a key lipid mediator involved in inflammation and bone homeostasis. Its systemic production is reliably reflected by 24 h urinary excretion of PGE₂ (U-PGE₂) and its major metabolite (U-PGEM). However, the physiological association between systemic PGE₂ production, calcium-phosphorus homeostasis and bone turnover markers remains unclear. This study aims to elucidate these relationships in a general Chinese adult population. Methods: In this multicenter, cross-sectional study, 737 Chinese adults underwent standardized 24 h urine collection. Multivariable linear regression was used to assess independent associations with bone metabolism markers. Restricted cubic spline models were further employed to examine nonlinear relationships. Results: The median 24 h U-PGE₂ and U-PGEM excretion levels were 133.87 and 246.76 pg/mmol creatinine, respectively, with no significant sex differences (both p > 0.05). Multivariable regression analyses revealed that both 24 h U-PGE₂ and U-PGEM were independently and positively associated with advancing age. Notably, both 24 h U-PGE₂ and U-PGEM maintained a significant inverse association with serum calcium (Overall p < 0.05). Restricted cubic spline analyses further demonstrated a significant non-linear association between both 24 h U-PGE₂ and U-PGEM and total procollagen type 1 N-propeptide (P1NP; both Overall p < 0.05). This relationship was characterized by a steep decline in U-PGE₂ and U-PGEM excretion at lower P1NP concentrations, which subsequently plateaued at higher concentrations (Overall p < 0.05). Additionally, U-PGEM exhibited a significant inverse linear association with intact parathyroid hormone (PTH; Overall p < 0.05). Conclusions: This study provided valuable insights into the clinical determinants of 24 h U-PGE₂ and U-PGEM in Chinese adults and their independent associations with calcium-phosphorus homeostasis and bone turnover markers. Full article

(This article belongs to the Special Issue Recent Advances in Osteoporosis)

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14 pages, 3108 KB

Open AccessArticle

Association Between Geriatric Assessment Scores and Corneal Biomechanical Parameters in Patients with Glaucoma

by Yuto Yoshida, Yuri Fujino, Yuya Kato, Mayumi Furue, Hinako Ohtani, Chisako Ida, Kana Murakami, Mizuki Koike, Keigo Takagi, Kazunobu Sugihara and Masaki Tanito

Biomedicines 2026, 14(7), 1546; https://doi.org/10.3390/biomedicines14071546 - 10 Jul 2026

Abstract

Background/Objectives: Multiple age-related systemic conditions, including frailty, cognitive impairment, and comorbid diseases, have been suggested to be associated with glaucoma. However, their relationship with corneal biomechanical properties in patients with glaucoma remains unclear. Methods: This retrospective cross-sectional study included patients with [...] Read more.

Background/Objectives: Multiple age-related systemic conditions, including frailty, cognitive impairment, and comorbid diseases, have been suggested to be associated with glaucoma. However, their relationship with corneal biomechanical properties in patients with glaucoma remains unclear. Methods: This retrospective cross-sectional study included patients with glaucoma who attended the Department of Ophthalmology at Shimane University Hospital between May 2019 and August 2024. Corneal biomechanical parameters, including corneal hysteresis (CH), corneal resistance factor (CRF), corneal-compensated intraocular pressure (IOPcc), and Goldmann-correlated intraocular pressure (IOPg), were measured using the Ocular Response Analyzer (ORA; Reichert Technologies, Depew, NY, USA). Geriatric assessments, including the Geriatric 8 (G8), Mini-Cog, and Charlson Comorbidity Index (CCI), were also evaluated. Associations between geriatric assessment measures and ocular parameters were examined using multivariable linear mixed-effects models adjusted for age, sex, medication score, and glaucoma subtype. Results: A total of 280 patients (456 eyes) were included. The mean age was 70.2 ± 11.1 years, and 126 patients (45.0%) were women. In multivariable linear mixed-effects models, lower G8 scores were significantly associated with lower CRF (β = 0.18, 95% CI: 0.05 to 0.30), lower IOPcc (β = 0.55, 95% CI: 0.18 to 0.92), and lower IOPg (β = 0.62, 95% CI: 0.25 to 1.00). In contrast, no significant association was observed between G8 scores and CH (β = −0.02, 95% CI: −0.12 to 0.09). Neither Mini-Cog nor CCI was significantly associated with any ocular parameters. Conclusions: In patients with glaucoma, frailty may be associated with corneal biomechanical properties, particularly CRF and intraocular pressure-related parameters. Full article

(This article belongs to the Special Issue Glaucoma: New Diagnostic and Therapeutic Approaches, 3rd Edition)

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9 pages, 258 KB

Open AccessArticle

Community-Based SERPINA1 Genotyping in an Isolated Alpine Town Reveals Heterozygous Pi*Mheerlen Carriers: Implications for Targeted Screening

by Beatrice Ragnoli, Carlotta Bertelegni, Xheni Veselagu, Fausto Chiazza and Mario Malerba

Biomedicines 2026, 14(7), 1545; https://doi.org/10.3390/biomedicines14071545 - 10 Jul 2026

Abstract

Background/Objectives: Alpha-1 antitrypsin deficiency (AATD) is an underdiagnosed hereditary disorder that predisposes individuals to lung and liver disease. While its prevalence is higher in Northern Europe, data from specific, isolated populations in other regions are scarce. This study assessed the prevalence of pathogenic [...] Read more.

Background/Objectives: Alpha-1 antitrypsin deficiency (AATD) is an underdiagnosed hereditary disorder that predisposes individuals to lung and liver disease. While its prevalence is higher in Northern Europe, data from specific, isolated populations in other regions are scarce. This study assessed the prevalence of pathogenic SERPINA1 variants in the adult population of Ponte di Legno, a secluded town in the Italian Alps, to investigate potential founder effects involving rare genotypes. Methods: A cross-sectional community-based screening was conducted. Adult residents without previously diagnosed chronic respiratory diseases were invited to undergo spirometry and provide venous blood samples for serum AAT and CRP measurement. Buccal swabs were collected for genotyping, which was performed using a validated multiplex Luminex xMAP assay detecting 14 common and rare SERPINA1 variants, with isoelectric focusing and Sanger sequencing for further characterization when required. Results: Ninety-one subjects were enrolled (median age 61 years; 37.4% male). Five individuals (5.5%) carried pathogenic SERPINA1 variants: one Pi*MS heterozygote (1.1%), two Pi*MZ heterozygotes (2.2%), and two individuals heterozygous for the rare Pi*Mheerlen variant (Pi*M/Mheerlen) (2.2%). Median serum AAT levels were significantly lower in carriers of deficient alleles compared with Pi*MM individuals (100 mg/dL vs. 125 mg/dL, p = 0.0218). Conclusions: This community-based screening revealed a notable prevalence of AATD carriers in a geographically isolated Italian community, including two cases of the rare Pi*Mheerlen variant, suggesting a possible local founder effect. These findings underscore the value of targeted screening programs using rare variant panels to uncover hidden genetic architectures in isolated populations. Full article

(This article belongs to the Section Molecular Genetics and Genetic Diseases)

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4 pages, 207 KB

Open AccessEditorial

Women’s Special Issue Series: Biomedicines (2nd Edition)

by Federica Falà, Riuko Ohashi and Letizia Polito

Biomedicines 2026, 14(7), 1544; https://doi.org/10.3390/biomedicines14071544 - 10 Jul 2026

Abstract

The second edition of the “Women’s Special Issue Series: Biomedicines” brings together a series of articles that reflect both the scientific excellence of women researchers and the growing complexity of contemporary biomedical research [...] Full article

(This article belongs to the Special Issue Women’s Special Issue Series: Biomedicines (2nd Edition))

14 pages, 1037 KB

Open AccessArticle

Evaluation of the Admission Neutrophil Percentage-to-Albumin Ratio for Predicting the Severity of Acute Pancreatitis

by Ahmet Yavuz, Berat Ebik, Ümit Karabulut, Mustafa Zanyar Akkuzu, Çiğdem Budak Ece, Ferhat Bacaksız, Muharrem Keskin, Murat Bıyık and Mehmet Asıl

Biomedicines 2026, 14(7), 1543; https://doi.org/10.3390/biomedicines14071543 - 9 Jul 2026

Abstract

Background: Early identification of disease severity in acute pancreatitis (AP) remains a major clinical challenge. The neutrophil percentage-to-albumin ratio (NPAR) is a novel inflammatory index that reflects systemic inflammation, but evidence regarding its role in predicting AP severity remains limited. This study aimed [...] Read more.

Background: Early identification of disease severity in acute pancreatitis (AP) remains a major clinical challenge. The neutrophil percentage-to-albumin ratio (NPAR) is a novel inflammatory index that reflects systemic inflammation, but evidence regarding its role in predicting AP severity remains limited. This study aimed to evaluate the association between admission NPAR and AP severity and to compare its predictive performance with other inflammatory indices. Methods: This retrospective study included 261 patients with AP. NPAR, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and the systemic immune inflammation index (SII) were calculated using laboratory parameters obtained at hospital admission. Disease severity was assessed according to the revised Atlanta classification and the Bedside Index for Severity in Acute Pancreatitis (BISAP) score. Receiver operating characteristic (ROC) curve analysis was performed to compare predictive performance, and logistic regression analyses were used to identify independent predictors of disease severity. Results: Admission NPAR values were significantly higher in patients with moderately severe/severe AP according to the revised Atlanta classification and in patients with BISAP scores ≥ 3 (both p < 0.001). Among the evaluated inflammatory indices, NPAR demonstrated the highest predictive performance for disease severity according to both the revised Atlanta classification (AUC: 0.808) and BISAP score (AUC: 0.841). In multivariate logistic regression analysis, admission NPAR remained independently associated with AP severity (OR: 1.279, 95% CI: 1.174–1.393, p < 0.001). Admission NPAR levels were also significantly higher in non-survivors than in survivors (p = 0.017). Conclusions: Admission NPAR appears to be a simple, inexpensive, and readily available inflammatory index associated with disease severity in patients with AP. These findings suggest that NPAR may serve as a useful adjunctive tool for early risk stratification. However, larger prospective multicenter studies are required to validate these findings and confirm the proposed admission cut-off value before routine clinical implementation. Full article

(This article belongs to the Special Issue Pancreatic, Liver, Biliary Tract and Intestinal Diseases: Pathogenesis, Diagnostics and Therapy—2nd Edition)

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22 pages, 1079 KB

Open AccessReview

Hepatitis C in the Direct-Acting Antiviral Era: Immunopathogenesis, Dendritic Cells and Modern Clinical Management

by Klara Kurmangaliyeva, Bakhyt Kosherova, Irina Mukatova, Aida Baibusunova, Zhanna Yeshmagambetova, Karashash Askarova, Assem Kazangapova and Raikhan Shlymova

Biomedicines 2026, 14(7), 1542; https://doi.org/10.3390/biomedicines14071542 - 9 Jul 2026

Abstract

Hepatitis C virus (HCV) infection remains a major cause of chronic liver disease worldwide, with potential progression to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and extrahepatic disease. According to World Health Organization estimates, approximately 50 million people worldwide live with chronic HCV infection, and [...] Read more.

Hepatitis C virus (HCV) infection remains a major cause of chronic liver disease worldwide, with potential progression to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and extrahepatic disease. According to World Health Organization estimates, approximately 50 million people worldwide live with chronic HCV infection, and nearly 1 million new infections occur each year. In 2022, approximately 242,000 deaths were attributed to hepatitis C, mainly from cirrhosis and hepatocellular carcinoma. Chronic infection develops when antiviral immune response fails to eliminate the virus. Viral clearance requires early innate immune activation, effective antigen presentation, broad HCV-specific CD4⁺ and CD8⁺ T-cell responses and durable immune memory. Dendritic cells play a pivotal role in this process by linking innate and adaptive immunity. In chronic HCV infection, dendritic cells may be reduced in number and show impaired maturation, lower interleukin (IL)-12 production, higher IL-10 expression and weaker stimulation of HCV-specific CD4⁺ T-cell responses. This review discusses the role of dendritic cells (DCs) in HCV infection, with emphasis on DCs’ phenotype and function in acute and chronic disease. It also summarizes immune changes after direct-acting antiviral (DAA)-induced sustained virologic response (SVR), including partial recovery of innate immune responses and persistent residual immune dysregulation. When accessible and appropriately selected, modern direct-acting antiviral therapy substantially improves outcomes for patients with HCV infection. Full article

(This article belongs to the Special Issue Viral Hepatitis: From Pathophysiology to Therapeutic Approaches)

22 pages, 15869 KB

Open AccessArticle

Integrative Multi-Omics Analysis Characterizes Immune Dysregulation and Altered CD4⁺ Central Memory T-Cell Abundance in Allergic Rhinitis

by Aodeng Surita, Tianhui Kang, Chuan Chen, Hong Qiao, Wei Lv and Yang Zha

Biomedicines 2026, 14(7), 1541; https://doi.org/10.3390/biomedicines14071541 - 9 Jul 2026

Abstract

Background/Objectives: Allergic rhinitis (AR) is a highly prevalent chronic inflammatory disease of the upper airway characterized by immune dysregulation. This study aimed to systematically characterize the immunomodulatory landscape of AR and identify exploratory molecular and cellular features associated with disease-related immune remodeling. [...] Read more.

Background/Objectives: Allergic rhinitis (AR) is a highly prevalent chronic inflammatory disease of the upper airway characterized by immune dysregulation. This study aimed to systematically characterize the immunomodulatory landscape of AR and identify exploratory molecular and cellular features associated with disease-related immune remodeling. Methods: Public bulk transcriptomic datasets and single-cell RNA sequencing data were integrated to identify immunomodulatory-related differentially expressed genes (IMRDEGs), construct an immunomodulatory score (IM.Score), evaluate immune cell infiltration, and characterize cell-type composition and intercellular communication. Machine learning was used to derive an exploratory molecular signature, and L1000CDS2-based drug repositioning analysis was performed to identify in silico candidate compounds predicted to oppose AR-associated transcriptional signatures. Results: A total of 12 IMRDEGs were identified and used to construct the IM.Score, which was lower in AR samples relative to control samples. Immune infiltration analysis demonstrated that IM.Score stratification was associated with distinct immune microenvironmental profiles. Single-cell analysis revealed potential reductions in CD4⁺ central memory T cells, which represent an immune cellular alteration requiring further experimental verification, alongside attenuated intercellular communication involving this cell population. A six-gene exploratory molecular signature comprising NFKBIA, PDCD1, MYC, IFNG, FOXP3, and CD274 showed favorable performance in the training cohort (AUC = 0.992, 95% CI: 0.974–1.000) but failed to generalize in the external validation cohort (AUC = 0.500, 95% CI: 0.245–0.755), precluding clinical diagnostic interpretation at this stage. Drug repositioning analysis identified candidate compounds, including narciclasine and BRD-K91370081, with the potential to reverse AR-associated transcriptional alterations. Conclusions: This integrative multi-omics analysis identifies coordinated molecular, cellular, and communication-level immune alterations in AR. The IM.Score, altered CD4⁺ central memory T-cell abundance, and six-gene exploratory molecular signature may be regarded as hypothesis-generating candidate clues pending further experimental and clinical validation. Full article

(This article belongs to the Special Issue Allergic Rhinitis: From Pathology to Novel Therapeutic Approaches)

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28 pages, 6688 KB

Open AccessArticle

A Vortioxetine–Glycyrrhizic Acid Supramolecular Complex: Synthesis and Cellular Effects on Microglial and Blood Cells Under Inflammatory and Glucocorticoid Challenge

by Julia N. Khantakova, Elizaveta S. Meteleva, Yulia A. Ryabushkina, Nikolay E. Polyakov, Arina O. Degtyareva, Rasha Salman, Alexsander V. Dushkin and Natalya P. Bondar

Biomedicines 2026, 14(7), 1540; https://doi.org/10.3390/biomedicines14071540 - 9 Jul 2026

Abstract

Background: Depression is a severe disorder associated with hypothalamic–pituitary–adrenal (HPA) axis dysregulation and neuroinflammation, and which restrains the efficacy of conventional antidepressants. Vortioxetine is a multimodal antidepressant with potential immunomodulatory properties. Glycyrrhizic acid (GA) is a natural compound derived from licorice root [...] Read more.

Background: Depression is a severe disorder associated with hypothalamic–pituitary–adrenal (HPA) axis dysregulation and neuroinflammation, and which restrains the efficacy of conventional antidepressants. Vortioxetine is a multimodal antidepressant with potential immunomodulatory properties. Glycyrrhizic acid (GA) is a natural compound derived from licorice root that exhibits anti-inflammatory activity and modulates glucocorticoid signaling. We hypothesized that a supramolecular complex of vortioxetine with GA (Vort:Na₂GA) would exert synergistic effects on inflammatory and glucocorticoid pathways. Methods: Vortioxetine compositions with Na₂GA were prepared using a mechanochemical method. Cytotoxicity, anti-inflammatory property, and glucocorticoid receptor (GR) signaling pathway modulation of the complex were evaluated in vitro using SIM-A9 microglial cells. Additionally, a 7-day oral administration study in intact female C57BL/6 mice was conducted to evaluate the effects on peripheral blood cells. Results: The Vort:Na₂GA complex improves the solubility of the parent drug while increasing its stability and permeability. Furthermore, the resulting complex exhibits reduced cytotoxicity, particularly under glucocorticoid challenge. In SIM-A9 microglial cells, the Vort:Na₂GA complex upregulated expression of Nr3c1 and Nr1d1 genes without activating canonical GR target genes (Fkbp5 and Gilz) and partially reversed dexamethasone-induced glucocorticoid resistance. In vivo, the complex reduced the percentage of inflammatory Ly6C^high monocytes and preserved dexamethasone-induced Gilz expression in peripheral blood cells, indicating protection against stress-induced glucocorticoid resistance. Conclusions: The Vort:Na₂GA supramolecular complex enhances the physicochemical and pharmacological profile of vortioxetine, reduces inflammation-associated myeloid cell populations, and preserves glucocorticoid sensitivity. These findings support its further evaluation as a potential therapeutic agent for depressive disorders with inflammatory and HPA axis-related components. Full article

(This article belongs to the Special Issue Advances in Novel Drug Discovery, Synthesis, and Evaluation)

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21 pages, 8968 KB

Open AccessReview

The Expanding Therapeutic Armamentarium for Mitral Regurgitation: Surgical and Transcatheter Interventions

by Argyro Kalompatsou, Dimitris Tousoulis, Charilila-Loukia Ververeli, Ioannis Kachrimanidis, Yannis Dimitroglou, Sotirios Tsalamandris, Maria Drakopoulou, Konstantinos Aznaouridis, Kyriakos Dimitriadis, Markos Koukos, Aggelos Papanikolaou, Vasilis Lozos, Konstantinos Toutouzas, Konstantinos Tsioufis and Constantina Aggeli

Biomedicines 2026, 14(7), 1539; https://doi.org/10.3390/biomedicines14071539 - 9 Jul 2026

Abstract

Background: Mitral regurgitation (MR) is one of the most prevalent valvular heart diseases, with a rising global incidence. The 2025 European Society of Cardiology (ESC) guidelines introduced updated pathophysiological and morphological concepts for secondary MR, distinguishing ventricular and atrial mechanisms. Concurrent advances in [...] Read more.

Background: Mitral regurgitation (MR) is one of the most prevalent valvular heart diseases, with a rising global incidence. The 2025 European Society of Cardiology (ESC) guidelines introduced updated pathophysiological and morphological concepts for secondary MR, distinguishing ventricular and atrial mechanisms. Concurrent advances in cardiovascular imaging and therapeutic technologies have transformed the diagnostic and management landscape of MR. Methods: This review summarizes current evidence on the diagnosis and treatment of MR, with a focus on the updated ESC classification, multimodality cardiovascular imaging, minimally invasive surgical techniques, and contemporary transcatheter repair strategies. Recent literature was evaluated to highlight advances in anatomical assessment and individualized therapeutic approaches. Results: Multimodality imaging provides comprehensive evaluation of mitral valve anatomy, ventricular remodeling, and disease mechanisms, enabling accurate patient selection and procedural planning. Surgical management has evolved from conventional repair or replacement to minimally invasive approaches, including video-assisted right thoracotomy and robotic-assisted surgery, which have demonstrated favorable perioperative and clinical outcomes. In parallel, transcatheter interventions have expanded the therapeutic armamentarium for patients at high surgical risk or with complex anatomy. These include direct and indirect annuloplasty, transcatheter edge-to-edge repair, and emerging catheter-based repair technologies targeting specific structural abnormalities of the mitral valve apparatus. Conclusions: Contemporary management of MR requires an integrated understanding of disease pathophysiology, advanced imaging, and patient-specific anatomical characteristics. The combination of minimally invasive surgical techniques and rapidly evolving transcatheter interventions has broadened treatment options and supports a tailored, multidisciplinary approach to improve clinical outcomes and expand access to effective therapy for patients with severe MR. Full article

(This article belongs to the Special Issue Acute and Chronic Heart Failure: Pathophysiology and New Therapeutic Developments, 3rd Edition)

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19 pages, 1026 KB

Open AccessArticle

Auryon 355 nm Laser Atherectomy for Femoropopliteal In-Stent Occlusions: A Retrospective Comparative Study of Technical Success and 12-Month Outcomes

by Antonio Marzano, Federico Flora, Olga Silvestri, Maria Stella De Chiara, Danilo Barbarisi, Vito Gallicchio, Loris Flora, Luca di Marzo, Antonio Peluso and Wassim Mansour

Biomedicines 2026, 14(7), 1538; https://doi.org/10.3390/biomedicines14071538 - 9 Jul 2026

Abstract

Background: Complete femoropopliteal in-stent occlusions remain technically challenging because durable treatment requires restoration of an intraluminal channel within the pre-existing stent scaffold. This study evaluated Auryon 355 nm laser-assisted recanalization compared with conventional endovascular recanalization in symptomatic patients with femoropopliteal in-stent occlusions. [...] Read more.

Background: Complete femoropopliteal in-stent occlusions remain technically challenging because durable treatment requires restoration of an intraluminal channel within the pre-existing stent scaffold. This study evaluated Auryon 355 nm laser-assisted recanalization compared with conventional endovascular recanalization in symptomatic patients with femoropopliteal in-stent occlusions. Methods: This retrospective single-center comparative study included patients treated with Auryon laser-assisted recanalization between May 2023 and June 2024 and a historical control group treated with conventional recanalization between January 2020 and April 2022. The prespecified primary endpoint was a conditional endpoint of 12-month primary patency among primary-strategy technically successful procedures. An exploratory full-cohort strategy-level analysis of 12-month durable technical success was also performed to account for initial technical failures. Results: Forty-four patients were analyzed: 18 in the Auryon group and 26 in the control group. Baseline clinical characteristics were broadly comparable, although selected anatomical and clinical imbalances were present. Post hoc sensitivity analyses were considered hypothesis-generating because of sparse events and wide confidence intervals. Primary-strategy technical success was significantly higher with Auryon-assisted recanalization than with conventional recanalization (94.4% vs. 65.4%, p = 0.031). In the conventional group, six of nine primary-strategy failures were subsequently recanalized after distal retrograde bailout puncture, yielding a descriptive final assisted recanalization rate of 88.5% (23/26). In the full-cohort strategy-level analysis, 12-month durable technical success was achieved in 83.3% of patients in the Auryon group and 50.0% in the control group (p = 0.030). Among primary-strategy technically successful procedures, 12-month primary patency was numerically higher after Auryon-assisted treatment (88.2% vs. 76.5%; log-rank p = 0.37), without statistically significant differences in patency-related secondary outcomes. No distal embolization or procedure-related complication occurred in the Auryon group. Conclusions: In this retrospective comparative experience, Auryon 355 nm laser atherectomy was associated with significantly higher primary-strategy technical success than conventional endovascular recanalization. Among successfully recanalized patients, 12-month patency-related outcomes were numerically favorable but not statistically significant. Larger prospective studies are warranted. Full article

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

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6 pages, 167 KB

Open AccessEditorial

Editorial: Advancements in Lung Cancer Precision Oncology Research and Treatments

by Panagiotis Paliogiannis, Francesca Colonese and Giuseppe Palmieri

Biomedicines 2026, 14(7), 1537; https://doi.org/10.3390/biomedicines14071537 - 9 Jul 2026

Abstract

Lung cancer is one of the most common malignancies and the primary cause of cancer death worldwide [...] Full article

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

18 pages, 342 KB

Open AccessReview

Safety Profile of Intranasal Corticosteroids in Allergic Rhinitis: A Comprehensive Review

by Mirko Maglica, Franko Batinović, Marin Gudelj, Braco Bošković, Ivan Mizdrak, Stjepan Radić, Marta Knežević and Ivan Paladin

Biomedicines 2026, 14(7), 1536; https://doi.org/10.3390/biomedicines14071536 - 9 Jul 2026

Abstract

Intranasal corticosteroids (INCS) remain the cornerstone of pharmacologic treatment for allergic rhinitis (AR) because of their well-established anti-inflammatory efficacy and generally favorable benefit–risk profile. Nevertheless, concerns regarding local and systemic corticosteroid-related adverse events (AEs) continue to influence patient adherence, prescribing practices, and long-term [...] Read more.

Intranasal corticosteroids (INCS) remain the cornerstone of pharmacologic treatment for allergic rhinitis (AR) because of their well-established anti-inflammatory efficacy and generally favorable benefit–risk profile. Nevertheless, concerns regarding local and systemic corticosteroid-related adverse events (AEs) continue to influence patient adherence, prescribing practices, and long-term treatment acceptance. In routine clinical practice, safety perception and corticosteroid-related concerns frequently influence adherence and formulation selection to a greater extent than differences in clinical efficacy, particularly in pediatric populations and in patients requiring prolonged continuous therapy. Differences in pharmacokinetic and pharmacodynamic properties, including systemic bioavailability, glucocorticoid receptor affinity, lipophilicity, protein binding, and extent of first-pass metabolism, are considered important safety profile determinants of currently available INCS formulations. Available evidence indicates that local AEs, particularly epistaxis, nasal irritation, dryness, and sensory discomfort, represent the most frequently reported treatment-related AEs across INCS formulations, although these events are generally mild, self-limiting, and infrequently treatment-limiting. Clinically significant structural nasal complications, including septal perforation or progressive mucosal injury, appear uncommon in currently available studies. Systemic AEs, including hypothalamic–pituitary–adrenal (HPA) axis suppression, ocular toxicity, growth impairment, or clinically meaningful effects on bone metabolism, have not been consistently demonstrated with currently used low-systemic-exposure formulations administered at recommended therapeutic doses. Although systemic glucocorticoid exposure has been associated with alterations in lipid metabolism, adipose tissue function, and metabolic homeostasis, currently available intranasal corticosteroids demonstrate minimal systemic exposure, making clinically relevant metabolic effects unlikely under recommended therapeutic conditions. Formulations such as mometasone furoate, fluticasone propionate, fluticasone furoate, and ciclesonide exhibit pharmacokinetic characteristics associated with minimal systemic exposure because of extensive first-pass metabolism and low oral bioavailability. Although substantial pharmacokinetic differences exist between currently available INCS formulations, direct comparative evidence demonstrating clinically meaningful superiority in systemic safety outcomes remains limited. Current evidence suggests that formulation-dependent differences are clinically more relevant with respect to local tolerability, sensory characteristics, patient preference, and long-term adherence than major systemic safety outcomes. Pediatric evidence is generally reassuring, although historical concerns regarding growth suppression associated with earlier corticosteroid formulations continue to influence clinical practice. Currently available evidence supports the use of modern INCS as effective and generally well-tolerated therapeutic options across adult and pediatric populations. Full article

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

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25 pages, 999 KB

Open AccessArticle

Neurotrophins and Matrix Metalloproteinases in Treatment-Resistant Schizophrenia: Effects of Electroconvulsive Therapy on Serum Biomarkers and Clinical Outcomes: A Preliminary Study

by Anna Maria Szota, Małgorzata Ćwiklińska-Jurkowska, Izabela Radajewska, Kinga Lis, Przemysław Grudzka and Wiktor Dróżdż

Biomedicines 2026, 14(7), 1535; https://doi.org/10.3390/biomedicines14071535 - 8 Jul 2026

Abstract

Background: Available data indicate that the development of refractory schizophrenia may result from neuroinflammation, dysregulation of neurotrophins and metalloproteinases (MMPs), oxidative stress (OS), and hormonal imbalance. Electroconvulsive therapy (ECT) is an effective therapeutic option for drug resistance, but its impact on brain-derived neurotrophic [...] Read more.

Background: Available data indicate that the development of refractory schizophrenia may result from neuroinflammation, dysregulation of neurotrophins and metalloproteinases (MMPs), oxidative stress (OS), and hormonal imbalance. Electroconvulsive therapy (ECT) is an effective therapeutic option for drug resistance, but its impact on brain-derived neurotrophic factor (BDNF) and MMPs remains underinvestigated. This study evaluates the influence of ECT on serum BDNF, MMPs (MMP-7, MMP-9, MMP-14), and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3) in patients with treatment-resistant schizophrenia (TRS). Another goal of this study is an assessment of the relationships between these biomarkers and the intensity of schizophrenia symptoms. Methods: Serum concentrations of the aforementioned biomarkers were measured prior to and after ECT in eight patients and 13 healthy controls. The severity of schizophrenia symptoms was evaluated with the Positive and Negative Syndrome Scale (PANSS). Results: Bayesian analysis comparing pre-ECT serum concentrations of BDNF, MMPs, and their inhibitors in TRS patients with a control group showed a significant difference only for MMP-9. Furthermore, convincing evidence of a correlation between MMP-9 and MMP-14 was found in TRS patients. Although the ECT therapy did not result in changes in the serum concentrations of the studied biomarkers, substantial improvement in schizophrenia symptoms on the PANSS was observed. Conclusions: No significant biomarker changes (post- versus pre-treatment) were detected in this small exploratory cohort. Whether these biomarkers are involved in neuroinflammation (as possible contributors to the development of TRS) remains an open question, and therefore, further research on biomarkers in cerebrospinal fluid (CSF) may be suggested. Full article

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

12 pages, 2204 KB

Open AccessArticle

Significance of Tuft Cells Expressing Hematopoietic Prostaglandin D Synthase During the Pathogenesis of Eosinophilic Chronic Rhinosinusitis

by Kenta Hosomi, Mitsuaki Ishida, Kensuke Nakanishi, Akinori Sasaki, Takaki Inui, Tetsuya Terada, Shin-ichi Haginomori, Ko Fujimori and Yoshinobu Hirose

Biomedicines 2026, 14(7), 1534; https://doi.org/10.3390/biomedicines14071534 - 8 Jul 2026

Abstract

Background/Objective: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis with nasal polyps that is characterized by abundant eosinophilic infiltration within nasal polyps. Tuft cells are epithelial chemosensory cells that are present in the normal respiratory tract and activate group-2 innate lymphoid [...] Read more.

Background/Objective: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis with nasal polyps that is characterized by abundant eosinophilic infiltration within nasal polyps. Tuft cells are epithelial chemosensory cells that are present in the normal respiratory tract and activate group-2 innate lymphoid cells through their secretion of interleukin-25 and prostaglandin (PG) D₂. ECRS is also characterized by the activation of group-2 innate lymphoid cells; however, the involvement of tuft cell-derived PGD₂ in this process remains unclear. Methods: We selected consecutive patients with and without ECRS who underwent biopsy or surgical resection. Dual immunohistochemical analyses were performed to determine the presence of tuft cells producing PGD₂, using POU class 2 transcription factor (POU2F3), a specific tuft cell marker, and hematopoietic prostaglandin D synthase (H-PGDS). Results: The cohort included 52 and 14 patients with and without ECRS, respectively. The number of total POU2F3-positive tuft cells (POU2F3⁺/H-PGDS⁺ and POU2F3⁺/H-PGDS⁻) was significantly higher in the ECRS group vs. the non-ECRS one (p < 0.0001). Moreover, the ratio of POU2F3-positive tuft cells expressing H-PGDS [POU2F3⁺/H-PGDS⁺/(POU2F3⁺/H-PGDS⁺ + POU2F3⁺/H-PGDS⁻)] was also significantly higher in the ECRS group vs. the non-ECRS one (p = 0.0084). Conclusions: These results suggest that tuft cells present in the context of ECRS may serve as a potential source of PGD₂, thus involving to the amplification of type 2 inflammation. Full article

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

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