Biomolecules

19 pages, 14657 KB

Open AccessArticle

Integrated Immune–Gut Profiling Identifies an Exploratory Pediatric Inflammatory Intestinal Profile Associated with Food-Specific IgG Reactivity

by Laura-Mihaela Ion, Carmen Pavelescu, Denisa Maria Canut, Mihaela Oros, Gheorghita Jugulete and Smaranda Diaconescu

Biomolecules 2026, 16(6), 922; https://doi.org/10.3390/biom16060922 (registering DOI) - 22 Jun 2026

Abstract

The clinical relevance of food-specific IgG antibodies in pediatric gastrointestinal disorders remains controversial. Although current international guidelines discourage their use as standalone diagnostic tools, their significance within a broader immune–gut inflammatory framework has not been sufficiently explored. This study aimed to investigate associations [...] Read more.

The clinical relevance of food-specific IgG antibodies in pediatric gastrointestinal disorders remains controversial. Although current international guidelines discourage their use as standalone diagnostic tools, their significance within a broader immune–gut inflammatory framework has not been sufficiently explored. This study aimed to investigate associations between food-specific IgG reactivity, inflammatory and permeability biomarkers, microbiological findings, and abdominal ultrasound abnormalities in children with chronic gastrointestinal symptoms. Methods: (1) Children presenting chronic gastrointestinal symptoms associated with food-specific IgG polysensitization, elevated inflammatory and permeability biomarkers, and abdominal ultrasound abnormalities (number (n) = 196); (2) a symptomatic gastrointestinal group without the complete multimodal profile (n = 146); and (3) a control group with normal abdominal ultrasound findings and biomarkers within reference ranges (n = 210). All participants underwent food-specific IgG testing using a 216-antigen ELISA panel, abdominal ultrasound examination, and assessment of intestinal inflammatory and permeability biomarkers. Food-specific IgG antibodies were not interpreted as diagnostic markers of food allergy or food intolerance. Comparative analyses, correlation analyses, multivariable logistic regression, and receiver operating characteristic (ROC) analyses were performed. Results: Food-specific IgG polysensitization was significantly more frequent among children presenting the multimodal inflammatory profile compared with symptomatic and control groups (all p < 0.001). Reactivity predominantly involved gluten-containing cereals, dairy proteins, and mixed gluten–dairy patterns. Elevated fecal calprotectin, zonulin, and fecal histamine concentrations were more frequently observed in this subgroup, together with a higher prevalence of ultrasound abnormalities, including bowel wall thickening and mesenteric lymphadenopathy. Correlation analyses demonstrated significant associations between cumulative IgG burden and bowel wall thickness (r = 0.48, p < 0.001), while fecal calprotectin showed the strongest association with ultrasound abnormalities (r = 0.62, p < 0.0001). Multivariable logistic regression identified elevated calprotectin, increased zonulin, IgG polysensitization, and mixed gluten–dairy reactivity as independent predictors of pathological ultrasound findings. The integrated multimodal model demonstrated higher classification performance than isolated biomarkers. Conclusions: Children presenting chronic gastrointestinal symptoms, food-specific IgG polysensitization, inflammatory biomarker abnormalities, and ultrasound changes represented a multimodal clinical subgroup within the study population. These findings support evaluating food-specific IgG reactivity within a broader immune–gut assessment framework rather than as a standalone diagnostic biomarker. The observed associations should be considered exploratory and hypothesis-generating, requiring prospective validation and mechanistic investigation. Full article

(This article belongs to the Section Molecular Medicine)

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5 pages, 169 KB

Open AccessEditorial

Embryo Implantation: New Molecular Insights in Endometrial Receptivity, Trophoblast Invasion and Signalling—An Introduction

by Hans-Werner Denker, Evdokia Dimitriadis and Lois A. Salamonsen

Biomolecules 2026, 16(6), 921; https://doi.org/10.3390/biom16060921 (registering DOI) - 22 Jun 2026

Abstract

Embryo implantation within the uterus is critical for the establishment of pregnancy and is an important issue in infertility [...] Full article

(This article belongs to the Special Issue Embryo Implantation: New Molecular Insights in Endometrial Receptivity, Trophoblast Invasion and Signaling)

17 pages, 5935 KB

Open AccessArticle

Polyphenols Suppress Intracellular Zinc Deficiency-Induced ROS Production and NLRP3 Inflammasome Activation in Microglial and Neuronal Cells

by Ayumi Matsushita, Maki Kimura, Naoko Tajima, Tsuyoshi Yamanaka and Masato Inazu

Biomolecules 2026, 16(6), 920; https://doi.org/10.3390/biom16060920 (registering DOI) - 21 Jun 2026

Abstract

Zinc deficiency is increasingly recognized as a risk factor for neurodegenerative diseases, yet the underlying molecular mechanisms remain incompletely understood. In this study, we investigated the impact of intracellular zinc depletion on oxidative stress and inflammasome activation in microglial (SIM-A9) and neuronal (SH-SY5Y) [...] Read more.

Zinc deficiency is increasingly recognized as a risk factor for neurodegenerative diseases, yet the underlying molecular mechanisms remain incompletely understood. In this study, we investigated the impact of intracellular zinc depletion on oxidative stress and inflammasome activation in microglial (SIM-A9) and neuronal (SH-SY5Y) cell models, and evaluated the protective effects of polyphenolic compounds. Intracellular zinc chelation with the membrane-permeable chelator TPEN markedly increased reactive oxygen species (ROS) production, reduced cell viability, and upregulated the mRNA expression of NLRP3 inflammasome-related genes and pro-inflammatory cytokines. In contrast, extracellular zinc chelation had no effect, highlighting the critical role of intracellular zinc homeostasis in maintaining redox balance. Zinc supplementation significantly attenuated these responses. Among 32 polyphenols screened by DPPH radical scavenging assay, caffeic acid derivatives—chicoric acid (ChA), rosmarinic acid (RA), and caffeic acid phenethyl ester (CAPE)—exhibited the most potent antioxidant activity, surpassing that of edaravone. These compounds suppressed ROS production and differentially protected against zinc deficiency-induced cellular damage. ChA showed the strongest ROS inhibitory activity (IC50: 1.9 µM in SIM-A9), RA provided robust cytoprotection even at low concentrations, and CAPE most effectively suppressed inflammasome-related gene expression and inhibited aggregation of both Aβ1–42 and the highly neurotoxic pyroglutamate-modified variant pEAβ3–42. These findings demonstrate that intracellular zinc deficiency drives ROS-dependent upregulation of NLRP3 inflammasome-related genes, and suggest that caffeic acid derivative polyphenols may serve as complementary agents for mitigating neuroinflammatory and amyloidogenic processes relevant to Alzheimer’s disease. Full article

(This article belongs to the Special Issue The Value of Natural Compounds as Therapeutic Agents: 3rd Edition)

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22 pages, 1449 KB

Open AccessReview

Choosing the Right Extracellular Vesicle: Cross-Kingdom Immunological Functions Linking Molecular Mechanisms to Therapeutic Applications

by Boglárka Schilling-Tóth, Daiana Alymbaeva, Krisztián Németh, Dávid Sándor Kiss, István Tóth, Gábor Andócs, Ondrašovičová Silvia, Brigitta Tagscherer-Micska, Gergely Jócsák and Tibor Bartha

Biomolecules 2026, 16(6), 919; https://doi.org/10.3390/biom16060919 (registering DOI) - 20 Jun 2026

Abstract

Extracellular vesicles (EVs) are key mediators of intercellular communication across biological kingdoms, with central roles in immune regulation and disease processes. Despite shared structural features, EVs derived from bacteria, plants, and mammalian cells differ substantially in their biogenesis, molecular composition, and immunological functions. [...] Read more.

Extracellular vesicles (EVs) are key mediators of intercellular communication across biological kingdoms, with central roles in immune regulation and disease processes. Despite shared structural features, EVs derived from bacteria, plants, and mammalian cells differ substantially in their biogenesis, molecular composition, and immunological functions. EV formation pathways generate vesicles with distinct cargo profiles, including pathogen-associated molecular patterns (PAMPs) in bacterial EVs, regulatory small RNAs in plant-derived vesicles, and cytokines, microRNAs, and antigen-presenting complexes in mammalian EVs. Differences in cargo result in divergent immune outcomes. Bacterial EVs predominantly activate innate immunity via pattern recognition receptors such as Toll-like receptors, whereas plant-derived EVs exhibit low immunogenicity and mediate cross-kingdom RNA interference. In contrast, mammalian EVs primarily regulate immune responses by modulating antigen presentation and cytokine signaling. These findings support a framework in which EV origin determines immunological function and therapeutic applicability. This perspective highlights the importance of selecting appropriate EV sources for vaccine development, regenerative medicine, and targeted delivery strategies, while addressing current challenges related to heterogeneity, standardization, and safety. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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19 pages, 1799 KB

Open AccessArticle

Bacterial Community Composition and Functional Potential of the Kleptoplastic Sea Slug Elysia papillosa

by Jada L. Brown, Padmanabhan Mahadevan and Michael Middlebrooks

Biomolecules 2026, 16(6), 918; https://doi.org/10.3390/biom16060918 (registering DOI) - 20 Jun 2026

Abstract

Certain sacoglossan sea slugs, often known as “solar-powered sea slugs”, are a group of marine gastropods that have the unique ability to photosynthesize by stealing functional chloroplasts from algae. The sacoglossan Elysia papillosa can maintain functional chloroplasts for up to two weeks after [...] Read more.

Certain sacoglossan sea slugs, often known as “solar-powered sea slugs”, are a group of marine gastropods that have the unique ability to photosynthesize by stealing functional chloroplasts from algae. The sacoglossan Elysia papillosa can maintain functional chloroplasts for up to two weeks after feeding. The microbiome of these slugs may play a crucial role in their metabolism, immunity, development, but more importantly their photosynthesis. Shotgun metagenomic sequencing was conducted on four samples of E. papillosa in order to characterize their microbiome. Sequences were classified and relative abundance was quantified with Centrifuger and functional data was examined using SqueezeMeta. Bacteria were analyzed by taxonomic groups and hypothesized function to the sea slug was determined with literature analysis. All samples were dominated by phyla Actinomycetota, Bacillota, Patescibacteriota, and Pseudomonadota. The presence of the phyla Bacteroidota and Bacillota was notable in all samples, which contain species known to produce enzymes that break down polysaccharides. It is possible that these bacteria could assist in degradation of the polysaccharide xylan found in the cell walls of Penicillus, the algal food source of E. papillosa. One species that was found in all samples was Cutibacterium acnes which has been shown to be an important component of the gut microbiota in other marine invertebrates and may provide the host with vitamin B12 and other beneficial nutrients. Many of these bacteria may be opportunistic rather than commensal. As a result, more research is required to describe the interactions between the slug and its microbiome, but this preliminary report provides a valuable starting point for identifying the microbiome make-up to further understanding of these relationships. Full article

(This article belongs to the Special Issue Metagenomics and Genomics of Marine Organisms)

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18 pages, 22421 KB

Open AccessArticle

Alginate Oligosaccharide Alleviates Severe Acute Pancreatitis in Mice via Suppression of Oxidative Stress, Inflammation and Modulation of Intestinal Epithelial Barrier Integrity

by Xianglong Ou, Yi Dai, Xiangyue Hu, Yuan Liu, Shibin Yuan, Le Wang, Bangyuan Wu and Tingting Fang

Biomolecules 2026, 16(6), 917; https://doi.org/10.3390/biom16060917 (registering DOI) - 20 Jun 2026

Abstract

Severe acute pancreatitis (SAP) is a life-threatening inflammatory disorder characterized by high mortality and limited therapeutic options. Alginate oligosaccharide (AOS), a marine-derived bioactive polysaccharide, exhibits prebiotic, anti-inflammatory and antioxidant properties that are effective against various inflammatory diseases. In this study, a mouse model [...] Read more.

Severe acute pancreatitis (SAP) is a life-threatening inflammatory disorder characterized by high mortality and limited therapeutic options. Alginate oligosaccharide (AOS), a marine-derived bioactive polysaccharide, exhibits prebiotic, anti-inflammatory and antioxidant properties that are effective against various inflammatory diseases. In this study, a mouse model of SAP was established by intraperitoneal injection of cerulein (100 μg/kg) and lipopolysaccharide (5 mg/kg), and the mice were pretreated with AOS (200 mg/kg) by gavage for 4 consecutive weeks to explore the potential protective efficacy and underlying mechanisms. The results shown that AOS attenuated the severity of SAP, as evidenced by reduced serum amylase and lipase levels, as well as alleviated histopathological injury in both pancreatic and ileal tissues. AOS suppressed the overproduction of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in serum, pancreas, and ileum at protein or mRNA levels. Moreover, AOS effectively diminished pancreatic and ileal inflammatory infiltration and oxidative stress in SAP mice, accompanied by inhibited the TLR4/MyD88/NF-κB pathway and activated the Nrf2/HO-1 antioxidant axis. Furthermore, AOS restored intestinal barrier integrity, as manifested by upregulated expression of tight junction proteins (claudin-1, occludin, ZO-1), reduced serum diamine oxidase, and decreased bacterial translocation from the gut to the pancreas. It was revealed by 16S rRNA sequencing that AOS ameliorated SAP-induced gut dysbiosis by restoring microbial diversity, normalizing the Firmicutes/Bacteroidetes ratio, enriching beneficial genera (Lactobacillus, Blautia), and enhancing cecal short-chain fatty acid (acetic, propionic, butyric acid) production. Collectively, our findings demonstrate that AOS exerts comprehensive protective effects against SAP through suppression of inflammatory signaling and oxidative stress, as well as restoring gut homeostasis. These results suggest that AOS may serve as a promising prebiotic-based nutritional strategy for the management of SAP. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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18 pages, 964 KB

Open AccessReview

PRMT5 as a Key Driver of Stemness and Metastatic Potential in Triple-Negative Breast Cancer

by Jae Jin Jeong, Mauli Maniar, Shahrzad Ghane, Sakshi Deshpande, Claire Ellis and Ashakumary Lakshmikuttyamma

Biomolecules 2026, 16(6), 916; https://doi.org/10.3390/biom16060916 (registering DOI) - 20 Jun 2026

Abstract

Protein arginine methyltransferase 5 (PRMT5) mediates arginine methylation of a wide range of proteins and plays context-dependent oncogenic or tumor-suppressive roles. In cancer, PRMT5 represses several tumor suppressor genes, including E-cadherin, TP53BP1, ST7, PTEN, and RB (retinoblastoma). Elevated PRMT5 expression has been reported [...] Read more.

Protein arginine methyltransferase 5 (PRMT5) mediates arginine methylation of a wide range of proteins and plays context-dependent oncogenic or tumor-suppressive roles. In cancer, PRMT5 represses several tumor suppressor genes, including E-cadherin, TP53BP1, ST7, PTEN, and RB (retinoblastoma). Elevated PRMT5 expression has been reported across multiple cancer types, notably triple-negative breast cancer (TNBC). In TNBC, high PRMT5 levels are associated with enhanced cancer stem cell self-renewal, increased tumor growth and metastasis, and reduced patient survival. Mechanistically, PRMT5 promotes breast cancer stem cell maintenance and proliferation through stabilization of the transcription factors KLF4 and KLF5. Disruption of the PRMT5–KLF4 axis results in significant tumor reduction in TNBC models. Moreover, increased PRMT5 expression has been linked to resistance to chemotherapy and immunotherapy in TNBC. Notably, PRMT5 inhibitors demonstrate synergistic anticancer activity when combined with inhibitors of key oncogenic signaling pathways, including EGFR, PARP, and AKT. While several PRMT5 inhibitors are currently being evaluated in clinical trials for other malignancies, no clinical trials have yet been initiated specifically for TNBC. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Breast Cancer)

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17 pages, 1398 KB

Open AccessReview

Biochemical Changes and Molecular Mechanisms Mediated by Sulfur Dioxide in Healthy Skin and Dermatological Disorders

by Mircea Tampa, Ilinca Nicolae, Madalina Irina Mitran, Cristina Iulia Mitran, Clara Matei, Milena Tocut, Simona Roxana Georgescu, Cosmin Ene, Cristina Capusa and Corina Daniela Ene

Biomolecules 2026, 16(6), 915; https://doi.org/10.3390/biom16060915 (registering DOI) - 19 Jun 2026

Viewed by 151

Abstract

The skin serves as the body’s first line of defense against environmental threats, acting as a barrier between external aggressors and internal systems. Current evidence regarding the roles of sulfur dioxide (SO₂) in biology and medicine is limited. Environmental pollutants, including [...] Read more.

The skin serves as the body’s first line of defense against environmental threats, acting as a barrier between external aggressors and internal systems. Current evidence regarding the roles of sulfur dioxide (SO₂) in biology and medicine is limited. Environmental pollutants, including SO₂, can increase the production of reactive oxygen species in the skin, leading to oxidative damage that may worsen various dermatological conditions. Endogenous SO₂, proposed as the fourth member of the gasotransmitter family, functions as a biological signaling molecule. It is generated in various human skin cells, including vascular smooth muscle cells, endothelial cells, mast cells, keratinocytes, macrophages, adipocytes, fibroblasts, dermal immune cell population, etc, where it performs multiple functions at physiologically relevant concentrations. Endogenous SO₂ plays a crucial role in regulating cell signaling and maintaining skin homeostasis through its antioxidant, anti-inflammatory, and cytoprotective effects. Abnormal generation and metabolism of SO₂ are linked to several critical processes in the skin, including vascular biology, immune response, cell proliferation, pigmentation, malignancy, protective barriers, senescence, and resistance to stress. This paper provides a narrative review of the significant roles of SO₂ in skin health and disease. A comprehensive understanding of the complex molecular effects and mechanisms mediated by SO₂ in human skin, along with the development of gas therapy, will be essential for translating fundamental research into clinical applications. Full article

(This article belongs to the Special Issue Skin Diseases: Molecular Pathogenesis and Therapeutic Approaches)

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15 pages, 1494 KB

Open AccessArticle

L-Arginine and Its Metabolites in Age-Related Cerebral Small Vessel Disease with Cognitive Impairment

by Larisa Dobrynina, Alexandra Byrochkina, Kamila Shamtieva, Elena Kremneva, Maryam Zabitova and Alla Shabalina

Biomolecules 2026, 16(6), 914; https://doi.org/10.3390/biom16060914 (registering DOI) - 19 Jun 2026

Viewed by 76

Abstract

A key mechanism in the pathogenesis of cerebral small vessel disease (CSVD) is endothelial dysfunction associated with impaired metabolism of nitric oxide (NO) and its main substrate, L-arginine. The aim of the study was to assess parameters of L-arginine metabolism and their association [...] Read more.

A key mechanism in the pathogenesis of cerebral small vessel disease (CSVD) is endothelial dysfunction associated with impaired metabolism of nitric oxide (NO) and its main substrate, L-arginine. The aim of the study was to assess parameters of L-arginine metabolism and their association with MRI-defined brain damage in CSVD patients. A total of 100 CSVD patients (according to MRI STRIVE standards) and cognitive impairment (CI) of varying severity, as well as 20 healthy volunteers, were analyzed. Levels of L-arginine and its metabolites—L-ornithine, L-citrulline, and asymmetric dimethylarginine (ADMA)—were measured; diffusion tensor MRI, MRI volumetry, and morphometry were performed. A threshold level of L-arginine (51.25 μmol/L) was identified, above which an association with CI was observed. Patients with L-arginine ≥ 51.25 μmol/L demonstrated poorer performance on cognitive tests (Stroop test, trail-making test (TMT)-B, TMT B–A, 10-word test) and more severe brain damage, reflected by greater severity of MRI markers (white matter hyperintensities, microbleeds), changes in brain component volumes, cortical atrophy in specific regions, and impairment of white matter microstructural integrity. The obtained data indicate a pathogenetic link between disturbances in L-arginine homeostasis and the development of CSVD with CI and support the need for further studies aimed at refining approaches to their correction. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment (2nd Edition))

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22 pages, 16217 KB

Open AccessArticle

Revitalizing Muscle Repair: Hyaluronan Preserves Mitochondrial Architecture and Promotes Myogenesis Under Pro-Inflammatory Conditions

by Fabio Ferrini, Giosuè Annibalini, Michela Battistelli, Seyedeh Mahboobeh Moosavi, Osman Riham, Fabiana Fanelli, Italo Capparucci, Piero Sestili and Elena Barbieri

Biomolecules 2026, 16(6), 913; https://doi.org/10.3390/biom16060913 (registering DOI) - 19 Jun 2026

Viewed by 130

Abstract

Hyaluronic acid (HA), a major component of the glycome and a non-sulfated glycosaminoglycan, plays a crucial role in regulating stem cell behavior and function, thereby supporting skeletal muscle repair under inflammatory conditions. In this study, we investigated the effects of a mixture of [...] Read more.

Hyaluronic acid (HA), a major component of the glycome and a non-sulfated glycosaminoglycan, plays a crucial role in regulating stem cell behavior and function, thereby supporting skeletal muscle repair under inflammatory conditions. In this study, we investigated the effects of a mixture of HA fractions with different molecular weights (M-HA; 2–1000 kDa) on the repair capacity and myogenic potential of C2C12 murine myoblasts exposed to inflammatory stimuli. C2C12 cells were cultured, induced to differentiate, and treated with M-HA (1 mg/mL) under either physiological or inflammatory conditions (LPS, 10 µg/mL; IL-1β, 20 ng/mL). M-HA exhibited no cytotoxic effects, even at the highest concentration tested (1.0 mg/mL), and significantly enhanced scratch wound closure. Moreover, M-HA improved the myogenic index at day 5 of differentiation, promoted the expression of myogenic markers, preserved myosin heavy chain (MHC) levels under inflammatory stress, and reduced the expression of autophagy-related genes. Ultrastructural analyses revealed that untreated myotubes displayed swollen mitochondria, disrupted cristae architecture, and numerous autophagic vacuoles, whereas M-HA-treated cells exhibited well-preserved mitochondrial morphology, intact cristae organization, reduced cytoplasmic damage, and maintained myofibrillar structure. Taken together, the functional, molecular, and ultrastructural findings demonstrate that M-HA protects myoblasts from inflammation-induced cellular damage and supports their regenerative capacity. These results underscore the potential of glycomics-based strategies to enhance myogenic differentiation and promote skeletal muscle regeneration in inflammatory microenvironments. Full article

(This article belongs to the Special Issue Glycomics in Health, Aging and Disease)

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21 pages, 900 KB

Open AccessReview

The Gut-Bone Axis and Skeletal Health: Regulatory Mechanisms and Therapeutic Applications of Plant-Derived Bioactive Compounds

by Tianzhu Zhang, Yufei Li, Jiahui Pei, Qingxia Zhang, Fengyun Lin and Shuzhen Li

Biomolecules 2026, 16(6), 912; https://doi.org/10.3390/biom16060912 (registering DOI) - 19 Jun 2026

Viewed by 73

Abstract

The gut microbiota and its metabolites, as components of the gut–bone axis, play a pivotal role in regulating skeletal homeostasis through the bidirectional communication network. In this systematic review, evidence was collected from mainstream databases following standardized inclusion/exclusion criteria for screening, to comprehensively [...] Read more.

The gut microbiota and its metabolites, as components of the gut–bone axis, play a pivotal role in regulating skeletal homeostasis through the bidirectional communication network. In this systematic review, evidence was collected from mainstream databases following standardized inclusion/exclusion criteria for screening, to comprehensively retrieve and screen eligible studies from multiple mainstream databases according to standardized inclusion and exclusion criteria, and systematically summarize current research progress on plant-derived bioactive compounds targeting the gut–bone axis for skeletal health regulation. This review systematically explores the underlying mechanisms of the gut–bone axis and critically evaluates the regulatory effects and therapeutic potential of plant-derived bioactive compounds. Particular attention is given to targeted interventions involving prebiotics, probiotics, synbiotics, and plant-rich diets or functional foods. Among these interventions, synbiotics represent the most successful strategy and show the most prominent therapeutic possibilities in bone-related disorders. Different from single prebiotics (only nourish endogenous intestinal microbes), individual probiotics (easy to be degraded in gastrointestinal tract with poor colonization) and ordinary plant-rich diets (unfixed effective dosage and weak targeting property), synbiotics combine prebiotic carriers and viable probiotic strains to produce complementary advantages, which is the core reason for its outstanding therapeutic prospect against bone diseases. Synbiotics exert synergistic effects on gut microecology, mineral absorption, and immune regulation, leading to more robust and consistent improvements in bone health than single prebiotics, probiotics, or general plant-rich diets. They have been verified in preclinical and clinical studies to ameliorate osteoporosis and related skeletal diseases via the gut–bone axis. These strategies offer novel insights into the prevention and treatment of bone metabolic disorders, such as osteoporosis, by targeting the gut–bone axis with phytochemicals. Key outcomes of this review include that synbiotics, soy isoflavones, naringin, curcumin, and resveratrol effectively improve bone mineral density, restore gut microbiota balance, and inhibit pathological bone resorption via the gut–bone axis. Collectively, the above bioactive substances realize bone protection mainly by reshaping gut flora, elevating mineral uptake and suppressing excessive osteoclast activity. Representative cases include soy isoflavones mitigating estrogen-deficient bone loss in OVX models, naringin improving the trabecular microarchitecture, and probiotic BL-11 promoting longitudinal bone growth in children. Future directions will focus on clarifying dose–response relationships, developing standardized synbiotic formulations, constructing microbiome-guided precision diets, and conducting large-sample randomized controlled trials to translate plant-derived compounds into clinical therapies. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

18 pages, 832 KB

Open AccessReview

Liquid Biopsy Biomarkers in Endometrial Cancer: Current Landscape and Future Perspectives

by Walter Giuseppe Giordano, Ludovica Pepe, Canio Martinelli, Valeria Zuccalà, Giuliana Ciappina, Massimiliano Berretta, Giuseppe Giuffrè, Vincenzo Fiorentino and Antonio Ieni

Biomolecules 2026, 16(6), 911; https://doi.org/10.3390/biom16060911 (registering DOI) - 19 Jun 2026

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Abstract

Endometrial cancer is the most common gynecologic malignancy in developed countries and remains challenging in terms of risk stratification, treatment monitoring, and early detection of recurrence. Liquid biopsy provides a minimally invasive approach for the dynamic assessment of tumor-derived biomarkers and may complement [...] Read more.

Endometrial cancer is the most common gynecologic malignancy in developed countries and remains challenging in terms of risk stratification, treatment monitoring, and early detection of recurrence. Liquid biopsy provides a minimally invasive approach for the dynamic assessment of tumor-derived biomarkers and may complement tissue-based diagnosis and molecular classification. This narrative review summarizes current evidence on circulating biomarkers in endometrial cancer, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), extracellular vesicles (EVs), circulating microRNAs, and tumor-educated platelets, with attention to validity, applicability, and implementation barriers. Among these biomarkers, ctDNA currently has the strongest evidence base, especially for longitudinal monitoring, prognostic stratification, molecular residual disease assessment, and early detection of relapse in high-risk or recurrent disease. However, its sensitivity remains limited in early-stage, low-volume, and low-shedding tumors. CTCs, EVs, microRNAs, and platelet-derived signatures are promising but still largely investigational. Artificial intelligence may support multimodal biomarker validation, although clinical adoption will require external validation, locked algorithms, standardized workflows, and prospective utility trials. Overall, liquid biopsy represents a promising adjunct to tissue-based diagnosis and molecular classification in endometrial cancer, particularly for monitoring and follow-up. Prospective studies are now needed to demonstrate whether liquid-biopsy-informed decisions can improve outcomes or safely reduce overtreatment. Full article

(This article belongs to the Special Issue From Target Antigens to Companion Diagnostics: Antibody-Based Therapies in Women’s Cancers)

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16 pages, 5825 KB

Open AccessArticle

Sequential Gating of Ryanodine Receptors Underlies the Development of Calcium Sparks in Frog Skeletal Muscle

by Henrietta Cserne Szappanos, László Zsolt Szabó, Ildikó Balatoni, Martin F. Schneider, László Csernoch and Péter Szentesi

Biomolecules 2026, 16(6), 910; https://doi.org/10.3390/biom16060910 (registering DOI) - 19 Jun 2026

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Abstract

Calcium sparks can arise as both voltage-dependent and voltage-independent ligand-activated release events in amphibian skeletal muscle. To assess their gating behavior, calcium sparks were recorded from intact frog skeletal muscle fibers using high-temporal-resolution confocal microscopy (line scans: 15 and 50 µs/line). Sparks were [...] Read more.

Calcium sparks can arise as both voltage-dependent and voltage-independent ligand-activated release events in amphibian skeletal muscle. To assess their gating behavior, calcium sparks were recorded from intact frog skeletal muscle fibers using high-temporal-resolution confocal microscopy (line scans: 15 and 50 µs/line). Sparks were triggered by 1 mmol/L caffeine to open ryanodine receptors (RyRs) or by subthreshold depolarization to a −65 mV membrane potential to activate dihydropyridine receptors (DHPRs). Both treatments increased the frequency of sparks and altered their morphology. The sparks were significantly greater after caffeine treatment than in depolarized cells. The signal mass of sparks (i.e., the amount of calcium released) resembled the amplitude in shape. Additionally, the calcium release flux followed a staggered function during the activation of sparks. The detailed analysis of the sparks’ time profile revealed that the events were activated in a stepwise manner. The average step size (in F/F₀; 0.071 ± 0.003) remained constant regardless of the scanning speed. The number of steps during the activation of sparks followed a linear function based on the spark’s amplitude. Our results suggest that the activation of neighboring release units may occur sequentially, and the amplitude of the sparks depends linearly on the number of activated RyR channels. Full article

(This article belongs to the Special Issue Calcium Signaling: Molecular Mechanisms and Therapeutic Targets in Cardiovascular Diseases)

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25 pages, 1545 KB

Open AccessReview

Extracellular Vesicles and Diabetes Research: Current Status and Future Promise

by Mohamed S. Gad, Samar Habib and Khaled Elmasry

Biomolecules 2026, 16(6), 909; https://doi.org/10.3390/biom16060909 (registering DOI) - 19 Jun 2026

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Abstract

Diabetes mellitus represents a major global health challenge with rapidly increasing prevalence and substantial morbidity driven by metabolic and vascular complications. Extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication and are increasingly implicated in the pathogenesis and progression of diabetes. [...] Read more.

Diabetes mellitus represents a major global health challenge with rapidly increasing prevalence and substantial morbidity driven by metabolic and vascular complications. Extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication and are increasingly implicated in the pathogenesis and progression of diabetes. This review summarizes current knowledge on EV biology, including their classification, cellular sources, biogenesis, uptake mechanisms, and molecular cargo. We discuss the contribution of EV-associated microRNAs to immune dysregulation and β-cell damage in type 1 diabetes mellitus (T1DM), as well as the role of EVs in insulin resistance, metabolic signaling, and vascular dysfunction in type 2 diabetes mellitus (T2DM). Particular emphasis is placed on EV-mediated modulation of endothelial function, angiogenesis, and tissue repair, alongside their involvement in the impairment of insulin receptor integrity. We further explore how lifestyle factors may influence EV composition and function, highlighting their potential integration into preventive strategies. Finally, we evaluate the emerging therapeutic potential of EVs as biomarkers and delivery systems, while addressing current limitations and future directions. Collectively, EVs represent a promising frontier in understanding diabetes pathophysiology and developing innovative diagnostic and therapeutic approaches. Unlike previous reviews that examine EVs separately as biomarkers or therapeutic vehicles, this review integrates emerging evidence supporting EVs as mediators of systemic communication linking pancreatic islets, adipose tissue, immune cells, vascular endothelium, kidney, heart, and retina throughout diabetes progression. We further critically evaluate translational barriers that currently limit clinical implementation of EV-based diagnostics and therapeutics. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Exosomes in Tissue Repair and Regeneration)

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26 pages, 1399 KB

Open AccessArticle

A Node-Adaptive Feature Fusion Network for Drug–Target Interaction Prediction Based on Multi-View Graphs

by Lin Xie, Hongmei Xu, Pinglu Zhang, Jianshe Xiong and Jing Li

Biomolecules 2026, 16(6), 908; https://doi.org/10.3390/biom16060908 (registering DOI) - 18 Jun 2026

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Abstract

Existing drug–target interaction (DTI) prediction methods still face challenges caused by sparse interaction data, complex multi-source relationships, and imbalanced information contributions among different nodes. In this study, we propose NAFF-DTI, a node-level adaptive feature fusion network based on multi-view graphs. The model uniformly [...] Read more.

Existing drug–target interaction (DTI) prediction methods still face challenges caused by sparse interaction data, complex multi-source relationships, and imbalanced information contributions among different nodes. In this study, we propose NAFF-DTI, a node-level adaptive feature fusion network based on multi-view graphs. The model uniformly represents drug similarity, target similarity, and known drug–target interactions as multiple relational views, and learns node representations through graph encoding and cross-view representation learning. To more effectively utilize heterogeneous relational information, NAFF-DTI introduces cross-view feature discrepancy modeling and a node-level adaptive fusion mechanism to dynamically adjust the contribution of different views according to node structural characteristics. Experimental results show that NAFF-DTI achieves the best AUC and AUPR on all five benchmark datasets. Compared with the strongest baseline for each dataset and metric, NAFF-DTI achieves average relative improvements of 3.81% in AUC and 3.23% in AUPR. It can also improve the utilization of multi-source information, maintain relatively stable prediction under different data distributions, and prioritize biologically plausible candidate drug–target associations from the unannotated candidate space. These results indicate that NAFF-DTI can provide computational support for DTI candidate prioritization and repurposing-oriented hypothesis generation. Full article

(This article belongs to the Special Issue Computational Pharmacology: Advances in Computational Modeling of Drug–Receptor Interactions and Pharmacokinetics)

19 pages, 1790 KB

Open AccessReview

A3 Adenosine Receptor Agonists as Multisystem Disease Modifiers: From Molecular Signaling to Clinical Translation

by Pnina Fishman

Biomolecules 2026, 16(6), 907; https://doi.org/10.3390/biom16060907 (registering DOI) - 18 Jun 2026

Viewed by 206

Abstract

The A3 adenosine receptor (A3AR) is a stress-inducible G-protein-coupled receptor that is selectively upregulated in inflamed, hypoxic, and fibrotic tissues as well as in many malignancies, while remaining weakly expressed in most normal organs. This distinctive expression pattern provides a strong biological basis [...] Read more.

The A3 adenosine receptor (A3AR) is a stress-inducible G-protein-coupled receptor that is selectively upregulated in inflamed, hypoxic, and fibrotic tissues as well as in many malignancies, while remaining weakly expressed in most normal organs. This distinctive expression pattern provides a strong biological basis for pathology-selective pharmacology. Activation of A3AR by highly selective agonists, including piclidenoson (IB-MECA) and namodenoson (Cl-IB-MECA), initiates signaling through Gi proteins and phospholipase C (PLC), which in turn regulate a coordinated network of downstream intracellular pathways, including PI3K/Akt, NF-κB, MAPKs, and Wnt/β-catenin, resulting in suppression of inflammation, inhibition of pathological cell survival, and protection of metabolically stressed tissues. Over the three decades, extensive preclinical studies have demonstrated that A3AR agonism exerts anti-cancer, anti-fibrotic, immunomodulatory, neuroprotective, and organ-protective effects across diverse disease models, including hepatocellular carcinoma, pancreatic cancer, psoriasis, osteoarthritis, metabolic dysfunction-associated steatohepatitis, ischemic stroke, neurodegeneration, ophthalmic disorders, and inherited metabolic syndromes. Importantly, these mechanistic insights have been translated into clinical programs, with piclidenoson and namodenoson demonstrating favorable safety profiles and disease-modifying activity in inflammatory, fibrotic, and oncologic indications. This review integrates molecular, cellular, and translational evidence to highlight A3AR activation as a unifying therapeutic principle for diseases driven by inflammation, oxidative stress, hypoxia, and dysregulated cell survival, positioning selective A3AR agonists as first-in-class agents targeting the A3AR, with broad clinical applicability across multiple disease domains. Full article

(This article belongs to the Section Molecular Biology)

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31 pages, 18268 KB

Open AccessArticle

Exosomal circ_0050688 Shapes a Chemoresistant Microenvironment by Driving Spatial Resistance Spreading in Glioblastoma via the MDM2 Pathway

by Qiang Li, Jianglong Xu, Yuhao Zhang, Junbing Qian, Diana Bee-Lan Ong, Kein Seong Mun, Yiping Tang, Xiuchao Geng and Kean Chang Phang

Biomolecules 2026, 16(6), 906; https://doi.org/10.3390/biom16060906 (registering DOI) - 18 Jun 2026

Viewed by 203

Abstract

Background: Acquired tolerance to temozolomide (TMZ) remains one of the main obstacles to enduring therapeutic success in glioblastoma (GBM). While tumor-derived extracellular vesicles are known to orchestrate therapy evasion by horizontally transferring molecules across the tumor microenvironment, the precise regulatory roles of specific [...] Read more.

Background: Acquired tolerance to temozolomide (TMZ) remains one of the main obstacles to enduring therapeutic success in glioblastoma (GBM). While tumor-derived extracellular vesicles are known to orchestrate therapy evasion by horizontally transferring molecules across the tumor microenvironment, the precise regulatory roles of specific exosomal circular RNAs (circRNAs) in establishing this refractory state require further elucidation. Methods: The expression of circ_0050688 in TMZ-resistant GBM clinical tissues and cell lines was evaluated. Exosomes derived from resistant cells were isolated and confirmed via transmission electron microscopy (TEM) and marker analysis. PKH67 fluorescent tracking was utilized to visually demonstrate exosome internalization by sensitive recipient cells. Biological functions, including the expression of the multidrug resistance protein P-glycoprotein (P-gp) and the proliferation marker Ki-67, were evaluated. The competing endogenous RNA mechanism was validated using RNA FISH, dual-luciferase reporters, and functional rescue experiments. In vivo efficacy was determined using subcutaneous xenograft mouse models. Results: Clinical and in vitro analyses revealed that circ_0050688 is upregulated in TMZ-refractory GBM, predicting adverse patient survival. Through PKH67-based tracing, we confirmed that resistant cells actively secrete circ_0050688-enriched exosomes, which are subsequently engulfed by drug-sensitive bystander cells. This vesicular transfer directly instigates a chemoresistant and highly proliferative phenotype, marked by elevated P-gp and Ki-67 levels. At the molecular level, circ_0050688 operates as a molecular decoy for miR-508-5p, thereby preventing the suppression of its downstream target, MDM2. Functionally, circ_0050688 depletion eradicated these aggressive traits and restored TMZ vulnerability across both cellular and murine xenograft models. Furthermore, rescue assays confirmed that this circ_0050688-driven chemoresistance is fundamentally dependent on the miR-508-5p/MDM2 signaling axis. Conclusions: Current data uncover an intercellular signaling network driven by vesicular circ_0050688, which functions as a mobile oncogene to reshape the TMZ-refractory microenvironment. Targeting this exosomal circ_0050688/miR-508-5p/MDM2 network to suppress P-gp and Ki-67 expression represents a highly promising therapeutic strategy for refractory GBM. Full article

(This article belongs to the Section Molecular Biology)

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16 pages, 2696 KB

Open AccessArticle

Evaluation of sIgE Qualitative Conversion and Clinical Response to HDMs Sublingual Immunotherapy: Insights from Three Immunoassays

by Tarek Gheith, Sherihan M. Rohayem, Atef Taha El Bahrawy, Amira E. Mesbah, Safaa Gaber Aly Salem and Noha M. Hammad

Biomolecules 2026, 16(6), 905; https://doi.org/10.3390/biom16060905 - 18 Jun 2026

Viewed by 164

Abstract

Background: Sublingual immunotherapy (SLIT) is an effective treatment for house dust mite (HDM)-induced allergic rhinitis (AR); however, the significance of qualitative changes in specific IgE (sIgE) remains unclear. This study evaluated post-treatment changes in sIgE reactivity and compared the performance of three immunoassays. [...] Read more.

Background: Sublingual immunotherapy (SLIT) is an effective treatment for house dust mite (HDM)-induced allergic rhinitis (AR); however, the significance of qualitative changes in specific IgE (sIgE) remains unclear. This study evaluated post-treatment changes in sIgE reactivity and compared the performance of three immunoassays. Methods: In this prospective study, monosensitized patients with HDM-induced AR were identified using skin prick testing and followed for 12 months after SLIT. Serum sIgE levels were assessed at baseline and after treatment using immunoblot, chemiluminescent immunoassay (CLIA), and ImmunoCAP as the reference method. Qualitative changes in sIgE reactivity were analyzed. Clinical response was assessed using the total nasal symptom score (TNSS), and total IgE (tIgE) levels were measured. Results: At baseline, HDM-sIgE reactivity was detected in 85.7%, 82.1%, and 92.9% of patients by immunoblot, CLIA, and ImmunoCAP, respectively. Following SLIT, a significant qualitative conversion to non-reactive status was observed across all assays (p < 0.001). Conversion rates were 94.0% for immunoblot, 83.3% for CLIA, and 100.0% for ImmunoCAP. Significant improvements in TNSS and reductions in tIgE were also observed. Conclusions: SLIT induces a marked qualitative reduction in HDM-sIgE reactivity, with complete serological conversion detected by ImmunoCAP. Although the immunoassays showed comparable rates of HDM-sIgE detection, their agreement in classifying individual patients differed, indicating variability in assay performance. Qualitative assessment of sIgE may provide a clinically meaningful approach for monitoring immunotherapy response. Full article

(This article belongs to the Special Issue Immune Response to Allergens)

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27 pages, 5459 KB

Open AccessReview

Molecular Determinants of O’Nyong-Nyong Virus Infection in Mammalian Hosts and Anopheles Mosquitoes

by Zhiyuan Liu, Xia Li, Hanwen Hu, Shangyu Xiao, Jianli Tao and Jing Yang

Biomolecules 2026, 16(6), 904; https://doi.org/10.3390/biom16060904 - 18 Jun 2026

Viewed by 272

Abstract

O’nyong-nyong virus (ONNV) is a mosquito-borne alphavirus responsible for large-scale epidemics in sub-Saharan Africa. As the closest evolutionary relative of Chikungunya virus (CHIKV), ONNV shares substantial genetic similarity and overlapping clinical manifestations with CHIKV. Mechanistic understanding of ONNV infection has therefore largely been [...] Read more.

O’nyong-nyong virus (ONNV) is a mosquito-borne alphavirus responsible for large-scale epidemics in sub-Saharan Africa. As the closest evolutionary relative of Chikungunya virus (CHIKV), ONNV shares substantial genetic similarity and overlapping clinical manifestations with CHIKV. Mechanistic understanding of ONNV infection has therefore largely been extrapolated from CHIKV rather than directly established. However, ONNV exhibits distinct biological features, including predominant transmission by Anopheles mosquitoes and a clinical presentation characterized by prominent lymphadenopathy with limited acute joint edema. These distinctions underscore the need for an integrated synthesis of experimentally validated determinants of ONNV infection. In this review, we summarize current evidence on molecular and immunological factors regulating ONNV infection in mammalian hosts and mosquito vectors. We first discuss species-specific viral clearance, host dependency factors, intrinsic antiviral restriction mechanisms, protective innate immunity, inflammatory pathology, and mechanism-informed therapeutic strategies in mammalian hosts. We then examine stage-specific immune regulation in Anopheles mosquitoes, emphasizing mechanisms that constrain viral replication while permitting persistent infection and transmission. Finally, we discuss nsP3-dependent vector specificity and the potential contribution of alternative mosquito species to ONNV ecology. Together, this review provides an integrated framework for understanding how host factors, immune responses, and vector-specific adaptations shape ONNV infection, pathogenesis, and transmission. Full article

(This article belongs to the Section Molecular Biology)

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19 pages, 3817 KB

Open AccessArticle

Arabidopsis HSP90C and SecA1 Have Distinct Client-Binding Modalities to the Thylakoid SEC Client Protein PsbO1

by Adheip Monikantan Nair, Leonardo Tullo, Kenneth Andrei Espinosa, Siu Lun Terrence Tong and Rongmin Zhao

Biomolecules 2026, 16(6), 903; https://doi.org/10.3390/biom16060903 - 18 Jun 2026

Viewed by 212

Abstract

The plastid stroma-localized chaperone HSP90C is essential for maintaining chloroplast proteostasis and facilitating protein translocation. Prior research has established HSP90C’s imperative role in the SEC translocase-dependent transport of the photosystem II subunit PsbO1 and its interaction with the SEC1 translocase motor protein SecA1. [...] Read more.

The plastid stroma-localized chaperone HSP90C is essential for maintaining chloroplast proteostasis and facilitating protein translocation. Prior research has established HSP90C’s imperative role in the SEC translocase-dependent transport of the photosystem II subunit PsbO1 and its interaction with the SEC1 translocase motor protein SecA1. However, the exact mechanism of this interaction remains to be explored. In this study, we delineated the interactional mode of HSP90C and SecA1 with the model client protein. Yeast two-hybrid and in vitro ATPase activity analyses with purified proteins revealed PsbO1 may bind to HSP90C at multiple sites, including the DPW motif within the C-terminal extension (CTE) region, suggesting a possible client-loading mechanism unique to plastid orthologs. We also confirmed that glycine-646 is important in mediating substrate interaction, though it conferred a much weaker binding than the CTE region, thereby elucidating a critical role for the amino acid whose mutation resulted in visible plant phenotypes. Our in vitro biochemical assays also demonstrated that the stromal intermediate form of PsbO1 with the thylakoid signal peptide (tSP) significantly enhanced SecA1 ATPase activity, suggesting a preferential binding to the motor protein. On the other hand, the mature domain of the PsbO1, excluding the tSP sequence, inhibited HSP90C ATPase activity. We also observed the HSP90C-PsbO1-SecA1 ternary complex was stabilized by the presence of the client tSP. This work therefore provides new insights into the functional mechanisms of HSP90C and its contribution to chloroplast stromal protein stabilization and thylakoid protein transport. Full article

(This article belongs to the Special Issue Dynamic Interactions Between Biomolecules: Insights from Bioinformatics and Computational Biology)

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18 pages, 30849 KB

Open AccessArticle

Multifunctional Self-Pumping Janus Dressing for Exudate Management and Diabetic Wound Healing

by Yingnan Yue, Naoyuki Chado, Rike Rachmayati, Rie Wakabayashi, Noriho Kamiya, Shinichi Aishima, Hiroyuki Ijima and Yasuhiro Ikegami

Biomolecules 2026, 16(6), 902; https://doi.org/10.3390/biom16060902 - 18 Jun 2026

Viewed by 179

Abstract

Diabetic chronic wounds are often accompanied by excessive wound exudate maceration, which prolongs the inflammatory phase and increases the risk of infection. Such a complex wound microenvironment imposes more stringent requirements on multifunctional wound dressings. A multifunctional Cur Janus nanofibrous dressing is developed [...] Read more.

Diabetic chronic wounds are often accompanied by excessive wound exudate maceration, which prolongs the inflammatory phase and increases the risk of infection. Such a complex wound microenvironment imposes more stringent requirements on multifunctional wound dressings. A multifunctional Cur Janus nanofibrous dressing is developed by integrating an electrospun poly(ε-caprolactone)/gelatin hydrophilic layer with a curcumin (Cur)-loaded PCL hydrophobic layer. Janus structure with asymmetric wettability, which exhibited unidirectional liquid transport properties both in vitro and in vivo. Its unique structure also makes it possible to carry both hydrophilic and hydrophobic drugs at the same time. The incorporation of curcumin endows the dressing with antibacterial and antioxidant functionalities, offering the potential to modulate the inflammatory microenvironment of diabetic chronic wounds. Furthermore, the wound healing ability and anti-inflammatory effects of Cur Janus nanofibers were evaluated in a diabetic mouse model. The results showed that Cur Janus nanofibers significantly reduced wound area, increased the proportion of pro-healing M2 macrophages, shortened the inflammatory phase, and ultimately accelerated diabetic wound healing. This work provides a multifunctional and scalable platform for advanced wound dressing design. Its excellent antibacterial, antioxidant (ROS scavenging) and anti-inflammatory (macrophage phenotype M1 to M2) properties, combined with the unidirectional fluid transport and dual-release potential of hydrophilic and hydrophobic drugs, demonstrate broad prospects in the management of diabetic wounds. Full article

(This article belongs to the Section Biological Factors)

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5 pages, 160 KB

Open AccessEditorial

New Discoveries in the Field of Neuropharmacology

by Beatrice Radu and Bogdan Amuzescu

Biomolecules 2026, 16(6), 901; https://doi.org/10.3390/biom16060901 - 18 Jun 2026

Viewed by 121

Abstract

Neuropharmacology has emerged in recent years as a field of active research, driven by the need to address increasing challenges posed by clinical conditions such as neurodegenerative disorders, which affect more and more elderly people worldwide as the average life expectancy extends progressively [...] Read more.

Neuropharmacology has emerged in recent years as a field of active research, driven by the need to address increasing challenges posed by clinical conditions such as neurodegenerative disorders, which affect more and more elderly people worldwide as the average life expectancy extends progressively [...] Full article

(This article belongs to the Special Issue New Discoveries in the Field of Neuropharmacology)

11 pages, 275 KB

Open AccessBrief Report

Oxidative Stress and Necrotizing Enterocolitis in Preterm Newborns: The Role of GSTM1 and GSTT1 Null Genotypes

by Alexandre Alberto Barros Duarte, Danielle Lopes Teixeira Ferdinando, Vânia Belintani Piatto and Heloísa Cristina Caldas

Biomolecules 2026, 16(6), 900; https://doi.org/10.3390/biom16060900 - 18 Jun 2026

Viewed by 145

Abstract

Necrotizing enterocolitis (NEC) is a multifactorial disease associated with prematurity, intestinal hypoperfusion, dysbiosis, and oxidative stress. Interindividual variability in disease occurrence suggests a role for genetic susceptibility. Null genotypes of the GSTM1 and GSTT1 genes result in absent glutathione S-transferase activity and may [...] Read more.

Necrotizing enterocolitis (NEC) is a multifactorial disease associated with prematurity, intestinal hypoperfusion, dysbiosis, and oxidative stress. Interindividual variability in disease occurrence suggests a role for genetic susceptibility. Null genotypes of the GSTM1 and GSTT1 genes result in absent glutathione S-transferase activity and may impair antioxidant defenses. This study investigated whether GSTM1 and GSTT1 null genotypes are associated with NEC development and severity in preterm newborns. This single-center case–control pilot study included 100 preterm newborns (50 NEC and 50 controls). Genotyping was performed by multiplex polymerase chain reaction. Baseline characteristics were comparable between groups (p > 0.05). Stages II-A and II-B accounted for 82% of NEC cases. A significant inverse correlation was observed between gestational age and postnatal age at NEC diagnosis (r = −0.5994; p < 0.0001). The GSTM1-null genotype was more frequent in the NEC group (60% vs. 36%) and was associated with increased disease risk in both unadjusted (OR = 2.667; 95%CI: 1.188–5.986; p = 0.027) and adjusted analyses (aOR = 3.09; 95%CI: 1.29–7.40; p = 0.011). No significant associations were observed for GSTT1, combined genotypes, or disease severity. These findings provide preliminary evidence of an association between the GSTM1-null genotype and NEC susceptibility. Given the exploratory pilot design, these results should be considered hypothesis-generating and require confirmation in larger prospective studies. Full article

(This article belongs to the Section Molecular Biology)

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13 pages, 845 KB

Open AccessReview

Infectious Agents in Multiple Sclerosis: Viral Triggers, Antibody-Mediated Autoimmunity, and Parasitic Immunomodulation

by Dafni F. T. Frohman and Stella E. Tsirka

Biomolecules 2026, 16(6), 899; https://doi.org/10.3390/biom16060899 - 18 Jun 2026

Viewed by 310

Abstract

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by demyelination, neuroinflammation, and progressive neurodegeneration. While there is a small component of genetic susceptibility to MS risk, environmental factors, including infectious exposures, are gaining increased recognition as playing [...] Read more.

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by demyelination, neuroinflammation, and progressive neurodegeneration. While there is a small component of genetic susceptibility to MS risk, environmental factors, including infectious exposures, are gaining increased recognition as playing a critical role in MS initiation and progression. Viral infections, especially by Epstein–Barr virus (EBV), have emerged as strong candidates and triggers of MS symptoms, through antibody-mediated molecular mimicry and B-cell dysregulation. In contrast, parasitic infections, including helminths and select protozoa, appear to exert neuroprotective effects by skewing immune responses toward regulation and tolerance. In this review, we examine antibody-driven mechanisms by which viral pathogens promote autoimmunity in MS and contrast these with parasite-induced immunoregulatory pathways that suppress pathogenic inflammation. We further discuss diagnostic and therapeutic implications, highlighting how insights from infectious immunology may inform novel strategies for MS treatment. Full article

(This article belongs to the Special Issue Food, Microbe, Viral and Parasite-Derived Antibodies in Autoimmune and Chronic Diseases)

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24 pages, 2555 KB

Open AccessReview

Carbon Monoxide: A Context-Dependent Regulator of the Stress Axis

by Cesare Mancuso and Rosaria Santangelo

Biomolecules 2026, 16(6), 898; https://doi.org/10.3390/biom16060898 - 18 Jun 2026

Viewed by 385

Abstract

Carbon monoxide (CO) is a gasotransmitter generated by heme oxygenase (HO) isoforms during heme catabolism. The inducible HO-1 produces CO under conditions of redox imbalance, such as oxidative stress and inflammation. On the other hand, HO-2 constitutively generates CO, primarily during the physiological [...] Read more.

Carbon monoxide (CO) is a gasotransmitter generated by heme oxygenase (HO) isoforms during heme catabolism. The inducible HO-1 produces CO under conditions of redox imbalance, such as oxidative stress and inflammation. On the other hand, HO-2 constitutively generates CO, primarily during the physiological turnover of heme. Extensive evidence indicates that CO exerts autocrine effects by targeting hemoproteins, including soluble guanylyl cyclase, cyclooxygenase, and cytochromes. Furthermore, CO regulates many biological processes within the brain, including mitochondrial biogenesis, potassium channel activity, mitogen-activated protein kinase and phosphatidylinositol-3-kinase/Akt signaling. It also controls the activity of transcription factors, such as hypoxia-inducible factor-1 and peroxisome proliferator-activated receptor-γ. Through these mechanisms, CO modulates inflammatory gene expression, promotes anti-apoptotic signaling, and contributes to local stress responses. Conversely, CO produced in the hypothalamus inhibits the stress-induced release of corticotropin-releasing hormone and arginine vasopressin under pro-inflammatory conditions, resulting in reduced adrenocorticotropin hormone release and cortisol secretion from the anterior pituitary and adrenal cortex, respectively. Moreover, hypothalamic CO acts in a paracrine manner to modulate glucocorticoid release during psychological stress, including restraint or water deprivation. Together, these findings support the view that endogenous CO is a key modulator of the stress axis, exerting pleiotropic effects that integrate neuroendocrine, immune, and metabolic responses. Full article

(This article belongs to the Special Issue The Heme Oxygenase/Biliverdin Reductase System in Human Health and Disease: New Molecular Insights and Therapeutic Targets)

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16 pages, 52294 KB

Open AccessArticle

Bone Marrow-Derived Mesenchymal Stem Cells Alleviate Cutaneous Leishmaniasis by Promoting M2 Macrophage Polarization and Skin Tissue Repair in a Murine Model

by Shirui Bai, Tao Lin, Haoxia Li, Bo Han, John P. Kastelic, Tao Zhang, Hao Shi, Gang Liu and Yipeng Jin

Biomolecules 2026, 16(6), 897; https://doi.org/10.3390/biom16060897 - 17 Jun 2026

Viewed by 183

Abstract

Cutaneous leishmaniasis (CL) is the most common clinical form of leishmaniasis, characterized by persistent skin ulcers and nodules. Standard chemotherapeutic agents have substantial toxicity and do nothing to repair the damaged tissue, an unmet need that motivates the search for adjunctive strategies. Mesenchymal [...] Read more.

Cutaneous leishmaniasis (CL) is the most common clinical form of leishmaniasis, characterized by persistent skin ulcers and nodules. Standard chemotherapeutic agents have substantial toxicity and do nothing to repair the damaged tissue, an unmet need that motivates the search for adjunctive strategies. Mesenchymal stem cells (MSCs) can modulate macrophage activity and support tissue regeneration, yet their role in CL has received limited attention. In this study, we tested whether bone marrow-derived MSCs (BM-MSCs) could attenuate Leishmania mexicana-induced inflammation and facilitate skin repair. Indirect co-culture of BM-MSCs with infected RAW264.7 macrophages shifted the macrophage phenotype from M1 toward M2, with higher IL-10 and Arg-1 expression and lower iNOS and IL-1β. In BALB/c mice with established CL, three weekly intravenous injections of BM-MSCs reduced paw swelling, improved skin histology, decreased type I collagen deposition, lowered Integrin β1 and Cytokeratin 17 expression, and reduced tissue parasite load. Immunofluorescence confirmed a predominantly M2 macrophage distribution in treated lesions. We inferred that BM-MSCs acted on both the immune and reparative aspects of the disease process, supporting their potential as an adjunct to conventional anti-leishmanial therapy. Full article

(This article belongs to the Section Molecular Medicine)

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21 pages, 11176 KB

Open AccessArticle

Protective Role of Diatomite Against Freezing Stress in Hordeum vulgare L.: Insights into Physiological Mechanisms

by Saltanat Nayekova, Vladimir Kiyan, Zhanar Tulegenova, Timur Savin, Evgeniy Ten and Zerekbay Alikulov

Biomolecules 2026, 16(6), 896; https://doi.org/10.3390/biom16060896 - 17 Jun 2026

Viewed by 186

Abstract

Freezing stress is one of the major abiotic factors limiting plant growth and productivity. This study evaluates the effects of diatomite (DTM) as a natural silicon-rich amendment on growth performance, physiological responses, and cold stress tolerance in barley (Hordeum vulgare L.). Seed [...] Read more.

Freezing stress is one of the major abiotic factors limiting plant growth and productivity. This study evaluates the effects of diatomite (DTM) as a natural silicon-rich amendment on growth performance, physiological responses, and cold stress tolerance in barley (Hordeum vulgare L.). Seed priming and substrate application of DTM at different concentrations (5–20%) were used to assess morphological, biochemical, and ultrastructural changes under normal and low-temperature conditions. Results showed that DTM significantly enhanced root growth and biomass accumulation, with the most pronounced effect at 10% concentration. Treated plants exhibited improved survival under freezing stress, along with better preservation of leaf cellular structure and photosynthetic pigments. Biochemical analyses revealed reduced proline accumulation and decreased activity of key antioxidant enzymes, indicating alleviation of oxidative stress and improved redox balance. Electron microscopy confirmed the integration of diatomite particles into seed and tissue structures, providing physical reinforcement and thermal protection. Overall, diatomite acts as a multifunctional, environmentally safe soil amendment that enhances plant growth and improves tolerance to cold stress through combined physical and physiological mechanisms. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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23 pages, 3054 KB

Open AccessReview

Peroxisomes in Liver Diseases: From Metabolite Quality Control to Inter-Organelle and Inter-Organ Signaling

by Carolina Hogerty, Yantao Zhao, Weiran Wang, Steven A. Weinman and Wei Zhong

Biomolecules 2026, 16(6), 895; https://doi.org/10.3390/biom16060895 - 17 Jun 2026

Viewed by 262

Abstract

Peroxisomes are essential metabolic organelles that support core aspects of cellular homeostasis. In the hepatocytes, peroxisomes govern key aspects of cellular homeostasis, including processing lipid substrates that are inadequately handled by mitochondria, controlling hydrogen peroxide metabolism, and regulating bile acid synthesis. Increasing evidence [...] Read more.

Peroxisomes are essential metabolic organelles that support core aspects of cellular homeostasis. In the hepatocytes, peroxisomes govern key aspects of cellular homeostasis, including processing lipid substrates that are inadequately handled by mitochondria, controlling hydrogen peroxide metabolism, and regulating bile acid synthesis. Increasing evidence indicates that these organelles are not merely auxiliary metabolic compartments but active contributors to the development and progression of liver disease. Dynamic alterations in peroxisomal proteins and function are being noted. Across metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic disorders, fibrosis, and hepatocellular carcinoma, peroxisomes undergo remodeling that shows a change from adaptive reactions to maladaptive states. These changes perturb signaling pathways that regulate inflammation, stress responses, and cell fate. In addition, because peroxisomes operate within an interconnected organelle network, their dysfunction propagates to mitochondria, endoplasmic reticulum, and other cellular systems, amplifying metabolic and cellular stress. This review summarizes current understanding of how peroxisomal pathways contribute to liver disease, highlighting mechanisms involving lipid accumulation, oxidative stress, and disrupted organelle crosstalk. How peroxisome-dependent control of circulating metabolites links hepatic injury to extrahepatic organ systems is further discussed. At the end, emerging therapeutic strategies for liver disease targeting peroxisomal pathways are discussed. Together, the emerging understanding of peroxisomal remodeling, metabolic regulation, organelle crosstalk, and inter-organ communication positions peroxisomes as active and dynamic regulators of liver disease and potential targets for therapeutic intervention. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases: 2nd Edition)

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15 pages, 1453 KB

Open AccessReview

Beyond Genetic Conservation: The Baton Pass Model of Essential Biological Functions

by Takayuki Miyazawa

Biomolecules 2026, 16(6), 894; https://doi.org/10.3390/biom16060894 - 17 Jun 2026

Viewed by 588

Abstract

Essential host functions are often maintained by conserved molecular systems, but in biological contexts shaped by evolutionary conflict, the genes that execute such functions may be unstable, replaceable, or repeatedly recruited from different evolutionary sources. Mammalian placentation provides a striking example of this [...] Read more.

Essential host functions are often maintained by conserved molecular systems, but in biological contexts shaped by evolutionary conflict, the genes that execute such functions may be unstable, replaceable, or repeatedly recruited from different evolutionary sources. Mammalian placentation provides a striking example of this principle. Trophoblast cell fusion is essential for placental development, yet this function is mediated in different mammalian lineages by distinct endogenous retrovirus-derived envelope proteins, including syncytin-1, syncytin-2, and other lineage-specific Env-derived fusogens. Here, I propose the Baton Pass model as a conceptual framework for explaining how host-level biological functions can be maintained despite turnover of the molecular agents that execute them. This model differs from conventional examples of antagonistic coevolution, which often emphasize recurrent mutations within the same interacting genes, and from non-orthologous gene displacement, which generally concerns replacement among cellular genes. In the syncytin paradigm, the molecular executors are repeatedly supplied by exogenous retroviral env genes that become endogenized, domesticated, and incorporated into host developmental programs. I further discuss how receptor compatibility, placental expression control, and host–virus evolutionary conflict may together destabilize individual Env–receptor systems while allowing the host-level function of trophoblast fusion to persist. Analogous functional reassignment is also observed in primate lentiviruses, where antagonism of BST-2 shifts among distinct viral genes. The Baton Pass model therefore describes a testable evolutionary principle: essential host functions can be preserved not only through conservation of specific genes, but also through dynamic succession of genes of distinct evolutionary origins. Full article

(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond 2025)

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20 pages, 1517 KB

Open AccessReview

Extracellular Pgk1 or Its Derived Short Peptide Interacted with Membrane-Associated Enolase 2 Receptor: A Potential Therapy for ALS Motor Neuron Degeneration

by Bing-Chang Lee, Juey-Jen Hwang and Huai-Jen Tsai

Biomolecules 2026, 16(6), 893; https://doi.org/10.3390/biom16060893 - 17 Jun 2026

Viewed by 225

Abstract

Amyotrophic lateral sclerosis (ALS) remains an intractable motor neuron (MN) disease with a growing patient population and few effective treatments. Here, we review how extracellular phosphoglycerate kinase 1 (ePgk1) improves neurite outgrowth of MNs (NOMN) and axonal growth, both in vitro and in [...] Read more.

Amyotrophic lateral sclerosis (ALS) remains an intractable motor neuron (MN) disease with a growing patient population and few effective treatments. Here, we review how extracellular phosphoglycerate kinase 1 (ePgk1) improves neurite outgrowth of MNs (NOMN) and axonal growth, both in vitro and in vivo. Our group first elucidated a novel non-canonical function of ePgk1 as a cross-tissue mediator between nerve and muscle tissues. We then discovered that neural membranous Enolase 2 (Eno2) serves as a receptor of ligand ePgk1 and that ePgk1-Eno2 interaction suppresses the Rac1-GTP/p-Pak1-T423/p-P38-T180/pMK2-T334/p-Limk1-S323 axis, reducing p-Cofilin and promoting NOMN and axonal growth, finally suggesting that the 419th aspartic acid residue of Eno2 mediates this interaction. In a crucial preclinical step, we truncated two short 16-amino-acid derivatives from Pgk1, FD-1/-2, each mediating neuroprotection comparable to that of full-length 417-amino-acid Pgk1 in ALS animal models, in terms of improvements of innervated neuromuscular junction, MN cell bodies, motor performance, and endpoint prolongation. In this context, we also discuss the opposite function driven by Eno1-plasminogen interaction and by Eno2-ePgk1 interaction; the latter results in unfavorable for tumorigenesis. Unlike intracellular Pgk1 roles, ePgk1 is an extracellular factor with anti-angiogenic properties, further positioning ePgk1 and its FD-1/-2 as promising protein/peptide drugs for ALS treatment. Full article

(This article belongs to the Special Issue Key Mechanisms in the Pathogenesis of ALS)

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Biomolecules, Volume 16, Issue 6 (June 2026) – 166 articles

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