International Journal of Molecular Sciences

15 pages, 7318 KB

Open AccessArticle

A Rapid Active–Latent–Relapse Murine Model of Tuberculosis Based Blood Transcriptional Signature That Distinguishes Disease Stages

by Haifeng Li, Junfei Wang, Yu Wang, Fan Liu, Jun Tang, Mengmeng Sun and Lingjun Zhan

Int. J. Mol. Sci. 2026, 27(6), 2554; https://doi.org/10.3390/ijms27062554 (registering DOI) - 11 Mar 2026

Abstract

The lack of reliable diagnostic tools and relapse monitoring for latent tuberculosis infection (LTBI) constitutes a major obstacle to global tuberculosis (TB) control. This highlights an urgent need for robust animal models and predictive biomarkers. To address this, we report the successful establishment [...] Read more.

The lack of reliable diagnostic tools and relapse monitoring for latent tuberculosis infection (LTBI) constitutes a major obstacle to global tuberculosis (TB) control. This highlights an urgent need for robust animal models and predictive biomarkers. To address this, we report the successful establishment of a rapid murine model of recapitulating the active, latent, and relapse phases of TB within a compressed ten-week timeframe—hence termed the rapid multi-stage TB murine model. In this model, mice were first intravenously infected with Mycobacterium tuberculosis, followed by a four-week isoniazid (INH) regimen starting at two weeks post-infection. By week six, pulmonary bacterial loads in most mice dropped below the detection limit, signifying the establishment of latency. Reactivation was subsequently triggered by a four-week administration of anti-TNF-α (Tumor Necrosis Factor-α) monoclonal antibody. Leveraging this reproducible and time-efficient model, we performed transcriptomic profiling of peripheral blood and identified a distinct sixteen-gene signature (including Ets2, Fam111a, Fosl2, Gadd45b, Nfkbid, Rgs1, Bhlhe40, Il1r2, Clec2d, Kmo, Lynx1, Papd4, Trim34a, Wrb, Nlrp12, Spns1) that dynamically tracks disease progression. Collectively, these findings not only provide a valuable and efficient preclinical tool but also deliver transformable candidate biomarkers with immediate potential to guide the development of novel diagnostic strategies for LTBI surveillance and management. Full article

(This article belongs to the Topic Animal Models of Human Disease 3.0)

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21 pages, 1088 KB

Open AccessReview

Interplay Between Gut Microbiota and Cholesterol Metabolism in Colorectal Cancer

by Sarah Wing Lam Li, Oscar Ting Hei Au, Effie Yin Tung Lau, Riley Yanjun Lu, Adrian Leonard Zaleski and Jessie Qiaoyi Liang

Int. J. Mol. Sci. 2026, 27(6), 2553; https://doi.org/10.3390/ijms27062553 - 10 Mar 2026

Abstract

Both gut microbiota dysbiosis and disrupted cholesterol metabolism are associated with colorectal cancer (CRC). While the interactions between these two factors have been well explored in diseases such as cardiovascular disease and atherosclerosis, their interactions and underlying mechanisms in CRC pathogenesis remain insufficiently [...] Read more.

Both gut microbiota dysbiosis and disrupted cholesterol metabolism are associated with colorectal cancer (CRC). While the interactions between these two factors have been well explored in diseases such as cardiovascular disease and atherosclerosis, their interactions and underlying mechanisms in CRC pathogenesis remain insufficiently explored, constituting a critical area for further investigation. This review examines the complex relationship between gut microbiota and cholesterol metabolism in CRC development from 2 perspectives: how specific gut microbial species can increase CRC risk by modulating cholesterol metabolism, particularly through bile acids and oxysterols, and how disrupted cholesterol metabolism can exacerbate microbial dysbiosis and promote CRC. The bidirectional relationship between gut dysbiosis and cholesterol dysregulation creates a vicious cycle that drives CRC development. Moreover, the potential of targeting the gut microbiome and cholesterol metabolism to develop new strategies for preventing and treating CRC is discussed, highlighting the promise of certain bacterial strains that exert protective effects via cholesterol-lowering mechanisms. By elucidating the intricate connections between gut microbiota, cholesterol metabolism, and CRC, this review paves the way for innovative approaches in CRC prevention and therapy. Full article

(This article belongs to the Collection Latest Review Papers in Endocrinology and Metabolism)

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19 pages, 858 KB

Open AccessReview

Association Between Myocardial Dysfunction and Septic Shock

by Vlad Pădureanu, Daniel Cosmin Caragea, Denisa Floriana Vasilica Pîrșcoveanu, Dalia Dop, Alexandru Claudiu Munteanu, Dumitru Rădulescu, Dragoș George Popa, Dragoș Forțofoiu, Alice Nicoleta Drăgoescu and Rodica Pădureanu

Int. J. Mol. Sci. 2026, 27(6), 2552; https://doi.org/10.3390/ijms27062552 - 10 Mar 2026

Abstract

There is a substantial correlation between cardiac dysfunction and elevated mortality in sepsis. Impaired myocardial perfusion, direct myocardial injury, and mitochondrial dysfunction are all part of the complex pathophysiology of sepsis-induced myocardial dysfunction. Recent evidence has shown the critical role mitochondrial dysfunction plays [...] Read more.

There is a substantial correlation between cardiac dysfunction and elevated mortality in sepsis. Impaired myocardial perfusion, direct myocardial injury, and mitochondrial dysfunction are all part of the complex pathophysiology of sepsis-induced myocardial dysfunction. Recent evidence has shown the critical role mitochondrial dysfunction plays in the development of sepsis-induced myocardial dysfunction. In order to prevent and treat sepsis-induced myocardial dysfunction, a variety of drugs have been proposed. However, patient outcomes have not been appreciably enhanced by this therapy. This underscores the need for novel treatment approaches that target the specific pathways underlying cardiac dysfunction in sepsis. The prognosis is greatly impacted by sepsis-induced cardiac dysfunction, monitoring it is crucial. Clinicians employ a mix of clinical evaluations, hemodynamic monitoring, echocardiography, and bSICiomarkers to efficiently monitor this illness. The combined application of these techniques provides a comprehensive evaluation of cardiac function, thereby supporting timely optimization of treatment strategies. Treatments for septic shock and established sepsis will be beneficial for patients with this condition. However, there is little information and evidence about more targeted therapy, except than general management with vasopressors, inotropes, and fluid resuscitation. This study provides an outline of current knowledge on the pathophysiological mechanisms underlying sepsis-induced cardiac dysfunction, as well as the effects of monitoring and current treatments on sepsis-induced myocardial dysfunction. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Sepsis (2nd Edition))

16 pages, 10276 KB

Open AccessArticle

Far Infrared Radiation Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice via Modulation of the p53/TGF-β Signaling Pathway

by Jicheng Li, Jingxu Chang, Wenhan Chu, Yu Jiang, Shaodi Sun, Xiaodi Ding, Liying Zhang and Lihong Shi

Int. J. Mol. Sci. 2026, 27(6), 2551; https://doi.org/10.3390/ijms27062551 - 10 Mar 2026

Abstract

Currently, there is no curative medication for idiopathic pulmonary fibrosis (IPF), and therapeutic interventions for IPF are hindered by limited efficacy and severe adverse side effects. Far Infrared Radiation (FIR), an invisible form of electromagnetic energy, has garnered increasing attention for its multiple [...] Read more.

Currently, there is no curative medication for idiopathic pulmonary fibrosis (IPF), and therapeutic interventions for IPF are hindered by limited efficacy and severe adverse side effects. Far Infrared Radiation (FIR), an invisible form of electromagnetic energy, has garnered increasing attention for its multiple biological effects. However, its therapeutic benefits and the underlying mechanisms of IPF have not been investigated. In the present study, we established a mouse model of bleomycin-induced pulmonary fibrosis (BIPF) to assess the efficacy of FIR in attenuating BIPF. The results showed that FIR therapy significantly improved the general condition of the mice and protected pulmonary function by ameliorating lung fibrosis, collagen deposition and excessive inflammation. Moreover, FIR could alleviate fibroblast-to-myofibroblast differentiation (FMD), the epithelial–mesenchymal transition (EMT) and angiogenesis in BIPF mice. These beneficial effects were notable both in the pro-fibrotic inflammatory stage and the following fibrotic stage. Mechanistically, FIR exerted anti-inflammatory and anti-fibrotic effects through modulating the p53/TGF-β signaling pathway. Overall, this study elucidates the anti-fibrotic activity and the potential molecular mechanisms of FIR in treating BIPF, providing a therapeutic strategy of convenient, non-invasive physical therapy for alleviating IPF. Of greater significance, the findings of this study display the promising future applications of FIR in managing the physiopathology of various chronic diseases. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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31 pages, 959 KB

Open AccessReview

Neuronal Calcium Signaling and Cytoskeletal Dynamics in Neurodegeneration

by Anastasiya Rakovskaya, Ekaterina Volkova and Ekaterina Pchitskaya

Int. J. Mol. Sci. 2026, 27(6), 2550; https://doi.org/10.3390/ijms27062550 - 10 Mar 2026

Abstract

Neuronal function relies on the precise coordination between intracellular calcium (Ca²⁺) signaling and the cytoskeletal architecture that underpins synaptic transmission, plasticity, and structural stability. Disruption of this calcium–cytoskeleton interplay has been noted in numerous neurodegenerative diseases. We discuss how Ca²⁺ [...] Read more.

Neuronal function relies on the precise coordination between intracellular calcium (Ca²⁺) signaling and the cytoskeletal architecture that underpins synaptic transmission, plasticity, and structural stability. Disruption of this calcium–cytoskeleton interplay has been noted in numerous neurodegenerative diseases. We discuss how Ca²⁺-dependent cytoskeletal remodeling governs long-term potentiation and depression, dendritic spine morphology, and presynaptic function, highlighting the functions of end-binding proteins, STIM (Stromal Interaction Molecule)/Orai-mediated store-operated calcium entry, and the spine apparatus. Disease-specific manifestations of cytoskeletal–calcium dysregulation are reviewed across Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies, and prion disorders. Finally, we evaluate emerging therapeutic strategies targeting calcium homeostasis, cytoskeletal dynamics, and their downstream effectors, including multi-target approaches. Full article

(This article belongs to the Special Issue Advances in the Role of Cytoskeletal Proteins in Diseases)

39 pages, 5452 KB

Open AccessArticle

Time-Course Evaluation of the In Vivo Resorption Process of Calcium Phosphates/Poly(lactide-co-glycolide) Composites Using Radiological Imaging and Histology

by Shunsaku Takeishi, Kazuhiro Yasukawa, Maki Hiroshima, Chie Suzuki and Yasuhiro Magata

Int. J. Mol. Sci. 2026, 27(6), 2549; https://doi.org/10.3390/ijms27062549 - 10 Mar 2026

Abstract

There has been much development of composites of calcium phosphate and polymers for use as artificial bone, with other applications still ongoing, and clarification of the in vivo absorption mechanism is considered an important perspective. In order to clarify the absorption mechanism of [...] Read more.

There has been much development of composites of calcium phosphate and polymers for use as artificial bone, with other applications still ongoing, and clarification of the in vivo absorption mechanism is considered an important perspective. In order to clarify the absorption mechanism of bioabsorbable materials used for artificial bones and bone grafts, we prepared composites of calcium phosphate and polymers and conducted in vivo experiments in experimental animals using composites as implantation samples. Two typical types of calcium phosphate, β-tricalcium phosphate (β-TCP) and unsintered hydroxyapatite (uHA), were used as calcium phosphate, and copolymers of poly-dl-lactide-co-glycolide (PDLGA) and poly-l-lactide-co-glycolide (PLGA) were used as polymers. For samples composed of PDLGA and calcium phosphates, the weight ratios of calcium phosphate were set at 40% and 10% for uHA and 40% for β-TCP (uHA(40), uHA(10) and β-TCP(40), respectively). A composite sample of PLGA and uHA was also prepared with a weight ratio of 10% uHA (uHA(10)/PLGA), intending slow degradation of the polymer matrix compared to PDLGA. The samples were implanted in the metaphysis and diaphysis region of rabbits’ femur for up to 48 weeks. In this study, positron emission tomography/X-ray computed tomography (PET/CT) was used to continuously evaluate the changes in the samples and the accumulation of cells in the animals, and histological evaluation was performed, focusing on the time of characteristic changes in the PET/CT to confirm the cell types. The results are summarized as follows: (1) the absorption mechanism of the materials used in this study was suggested to be mainly phagocytosis by macrophages; (2) the disappearance rate was faster for β-TCP(40) compared with uHA(40); and (3) uHA(10), having a lower proportion of uHA, is not prone to aggregation and exhibited a similar disappearance result to β-TCP(40). These results suggest that phagocytosis by macrophages is the dominant path in resorption of the bioresorbable materials, and the resorption period varies depending on the type of polymer. It is important to optimize the type and amount of polymers and calcium phosphate in order to achieve a degradation rate of bioresorbable materials that corresponds to the extent of damage in the healing area. Full article

(This article belongs to the Section Materials Science)

12 pages, 483 KB

Open AccessArticle

Autotaxin and Lysophosphatidic Acid Circulating Levels Correlate with Body Mass Index in Obese Subjects with MASLD

by Rossella Tatoli, Leonilde Bonfrate, Caterina Bonfiglio, Pasqua Letizia Pesole, Dolores Stabile, Rossella Donghia, Giovanni De Pergola and Gianluigi Giannelli

Int. J. Mol. Sci. 2026, 27(6), 2548; https://doi.org/10.3390/ijms27062548 - 10 Mar 2026

Abstract

Scientific evidence supports the role of the autotaxin-lysophosphatidic acid (ATX-LPA) pathway in obesity and liver damage. The present study aim is to investigate variations in serum ATX and LPA levels across different BMI categories in a subcohort of subjects with MASLD. The study [...] Read more.

Scientific evidence supports the role of the autotaxin-lysophosphatidic acid (ATX-LPA) pathway in obesity and liver damage. The present study aim is to investigate variations in serum ATX and LPA levels across different BMI categories in a subcohort of subjects with MASLD. The study sample comprises 199 patients with liver steatosis from the most recent follow-up of the MICOL study, a prospective cohort study established in 1985, based on a random sample of the population of Castellana Grotte. In adjusted model, a positive association of BMI with ATX was observed when modeled as both a continuous (β = 0.018, p < 0.001, 0.012 to 0.024 95% C.I.) and categorical variable β = 0.170, p < 0.001, 0.111 to 0.228 95% C.I.). Conversely, a negative association was observed for LPA alone (β = −0.083, p = 0.020, −0.152 to −0.013 95% C.I.) and for the BMI and LPA interaction term (β = −0.109, p = 0.002, −0.176 to −0.042 95% C.I.). A positive association between ATX levels and BMI was found, whereas LPA levels tended to decrease with increasing BMI. Within the obese subgroup, ATX concentrations were notably higher in female compared to male participants. These findings suggest that elevated ATX in MASLD may reflect obesity-related metabolic and inflammatory alterations rather than adiposity alone, possibly involving altered LPA feedback and metabolism. Full article

(This article belongs to the Section Biochemistry)

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21 pages, 14259 KB

Open AccessArticle

Clopidogrel Administration Impairs Neurovascular Unit Recovery and Exacerbates Amyloid Beta Accumulation in Aged Mice Post-Stroke

by Marina Paul, Jonathan W. Paul, Madeleine Hinwood, Rebecca J. Hood, Kristy Martin, Mahmoud Abdolhoseini, Sarah J. Johnson, Michael Pollack, Michael Nilsson and Frederick R. Walker

Int. J. Mol. Sci. 2026, 27(6), 2547; https://doi.org/10.3390/ijms27062547 - 10 Mar 2026

Abstract

Clopidogrel has been the most commonly used therapy for preventing secondary cardiovascular events since 1997 by inhibiting the purinergic receptor P2Y, G-protein coupled, 12 protein receptor (P2RY12). P2RY12 is critical for microglia function in the brain, where it facilitates repair processes following injury. [...] Read more.

Clopidogrel has been the most commonly used therapy for preventing secondary cardiovascular events since 1997 by inhibiting the purinergic receptor P2Y, G-protein coupled, 12 protein receptor (P2RY12). P2RY12 is critical for microglia function in the brain, where it facilitates repair processes following injury. Under normal conditions, the blood-brain barrier (BBB) prevents peripheral drugs like clopidogrel from entering the brain. However, stroke-induced BBB disruption may allow clopidogrel to interfere with neural recovery by impairing microglia activity. Recently, we demonstrated that clopidogrel worsened cognitive outcomes in young mice after stroke. In this study, we examined the effects of clopidogrel on aged mice, focusing on survival, body weight, neurovascular changes, immune response, and amyloid beta accumulation. Aged male mice underwent photothrombotic stroke (or sham surgery) and received daily clopidogrel or control treatment for 14 days. On day 15, brain tissue was analyzed. Clopidogrel treatment significantly reduced survival and body weight, decreased vessel density, increased vascular permeability, altered microglia activity, and increased amyloid beta levels in the peri-infarct region. Notably, some of these effects were not observed in young mice. These results suggest that BBB disruption in stroke mice enables clopidogrel to enter the central nervous system, where it impairs microglia-mediated restoration of BBB integrity and promotes amyloid accumulation, factors that may contribute to worsened cognitive recovery. This study raises the possibility that clopidogrel may similarly cross the BBB in older stroke patients, impacting microglial function, and emphasizes the need for further research into its mechanisms of action. Full article

(This article belongs to the Section Molecular Neurobiology)

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24 pages, 1220 KB

Open AccessReview

Potential Therapeutic Strategies for Steatosis, Oxidative Stress, Inflammation, and Fibrosis in Liver Disease

by Pablo Muriel, Eduardo E. Vargas-Pozada, Linda Vanessa Márquez-Quiroga and Erika Ramos-Tovar

Int. J. Mol. Sci. 2026, 27(6), 2546; https://doi.org/10.3390/ijms27062546 - 10 Mar 2026

Abstract

Liver disease encompasses a wide range of conditions, each requiring tailored therapeutic approaches. This review describes and critically discusses treatments with robust evidence for improving liver health. Ursodeoxycholic acid (UDCA) is a drug approved by the Food and Drug Administration of the USA [...] Read more.

Liver disease encompasses a wide range of conditions, each requiring tailored therapeutic approaches. This review describes and critically discusses treatments with robust evidence for improving liver health. Ursodeoxycholic acid (UDCA) is a drug approved by the Food and Drug Administration of the USA to treat primary biliary cholangitis (PBC). In addition, UDCA has been demonstrated to protect against metabolic dysfunction-associated steatohepatitis, fibrosis, and drug-induced liver injury (DILI). The mechanism of action of UDCA has been attributed not only to decreasing the effects of toxic bile acids but also to protecting mitochondrial integrity and function, as well as to antioxidant, anti-inflammatory, and anti-apoptotic activities. UDCA can scavenge reactive oxygen species (ROS) and activate the nuclear factor-E2-related factor-2 (Nrf2) pathway, thereby exerting antioxidant activity. The anti-inflammatory activity of UDCA is associated with its ability to inhibit the nuclear factor-κB pathway. Pirfenidone is a well-recognized antifibrotic drug for the treatment of idiopathic pulmonary fibrosis; its effects on liver fibrosis have also been demonstrated. Pirfenidone exerts anti-inflammatory effects by attenuating the nucleotide-binding oligomerization domain-like receptor 3 inflammasome signaling pathway. The antioxidant actions of pirfenidone are associated with its ability to upregulate the Nrf2 pathway. Both the anti-inflammatory and antioxidant properties of pirfenidone act together to attenuate lung and liver fibrosis, decreasing transforming growth factor-β levels, inhibiting profibrogenic hepatic stellate cell activation, and increasing extracellular matrix degradation. Methyltransferases utilize S-adenosyl-L-methionine (SAM) as a methyl donor for most transmethylation reactions in the body. SAM increases reduced glutathione (GSH) levels, exerting important antioxidant effects. Evidence indicates that SAM prevents fibrosis and attenuates hepatocellular carcinoma development, improving patient survival. N-acetylcysteine (NAC) is a precursor to L-cysteine and GSH and is used in clinical settings to treat cancer, nephropathy, heart disease, pulmonary fibrosis, polycystic ovary syndrome, and influenza. Regarding the liver, NAC is the most accepted treatment for DILI, especially after paracetamol overdose. Owing to its antioxidant and anti-inflammatory actions, NAC has been successfully used to treat chronic liver injuries, including hepatosteatosis and fibrosis. Therefore, ursodeoxycholic acid, pirfenidone, S-adenosyl-L-methionine, and N-acetylcysteine could represent therapeutic strategies for the treatment of liver pathologies. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

20 pages, 976 KB

Open AccessReview

The Architecture of Deep Phenotyping in Asthma: Integrating Molecular, Metabolic, and Neuro-Hormonal Endotypes

by Nicolae Demenciuc, Corina Ureche, Corina Eugenia Budin, Mircea Stoian, Teodora Nicola-Varo, Edith Simona Ianosi, Dariana-Elena Pătrîntașu, Anca Goman, Lavinia Davidescu and Diana Deleanu

Int. J. Mol. Sci. 2026, 27(6), 2545; https://doi.org/10.3390/ijms27062545 - 10 Mar 2026

Abstract

Asthma is increasingly recognized as a heterogeneous syndrome where traditional management fails, particularly given spirometry’s limitations in assessing small airway dysfunction. This review synthesizes the transition from clinical phenotyping to deep molecular endotyping, establishing a framework for precision medicine. We highlight the insufficiency [...] Read more.

Asthma is increasingly recognized as a heterogeneous syndrome where traditional management fails, particularly given spirometry’s limitations in assessing small airway dysfunction. This review synthesizes the transition from clinical phenotyping to deep molecular endotyping, establishing a framework for precision medicine. We highlight the insufficiency of absolute eosinophil counts, proposing eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) as superior activation metrics. Furthermore, we explore Type 2 drivers (IL-4/IL-13, periostin) and epithelial alarmins like TSLP. Beyond classical immunology, the text describes metabolic dysregulation, specifically asymmetric dimethylarginine (ADMA) in obese-asthma phenotypes where nitric oxide synthase uncoupling promotes oxidative stress. We also analyze YKL-40 and surfactant protein D (SP-D) as markers of remodeling and barrier permeability, alongside microRNAs—specifically miR-21—in corticosteroid resistance. We conclude that managing refractory asthma requires shifting from reactive symptom control to an integrated analysis of multi-omic biomarkers. Establishing this comprehensive molecular profile via specialized centers is fundamental for addressing current diagnostic limitations, selecting biological therapies, and modifying the disease trajectory through an endotype-driven strategy addressing inflammatory, metabolic, and structural pathologies. Full article

(This article belongs to the Special Issue Advances in Molecular Approaches to Asthma Management)

25 pages, 2774 KB

Open AccessArticle

Hydrogen Peroxide-Oxidative Signaling Enhances Biosynthesis of Specialized Metabolites in Baccharis conferta Kunth

by Norma Elizabeth Moreno-Anzúrez, Celic Sibel Sarmiento-Ramírez, Ana Silvia Gutiérrez-Román, Virginia Medina-Pérez, Luis Rafael Garibay-Castro, Elizabeth Rubio-Rodríguez and Gabriela Trejo-Tapia

Int. J. Mol. Sci. 2026, 27(6), 2544; https://doi.org/10.3390/ijms27062544 - 10 Mar 2026

Abstract

Hydrogen peroxide (H₂O₂) regulates plant metabolism. This study examined its effect on the biosynthesis of specialized metabolites in Baccharis conferta, a medicinal plant rich in phenolics and terpenes. Plants were elicited with 25 µM and 250 µM H [...] Read more.

Hydrogen peroxide (H₂O₂) regulates plant metabolism. This study examined its effect on the biosynthesis of specialized metabolites in Baccharis conferta, a medicinal plant rich in phenolics and terpenes. Plants were elicited with 25 µM and 250 µM H₂O₂. Phenolic changes were evaluated by total phenolic content (TPC), total flavonoid content (TFC), phenylalanine ammonia-lyase (PAL) activity, and LC-MS analysis of flavonoids and hydroxycinnamic acids. Meanwhile, terpene changes were evaluated by HPTLC, total terpene content (TTC), and expression of the 1-deoxy-D-xylulose-5-phosphate synthase (Bco-DXS1) gene. H₂O₂ markedly modulated both pathways. Phenolic metabolism was activated, particularly under 25 µM H₂O₂, with PAL activity increasing by 52%, TPC by 42%, and TFC by 50% relative to the control. Chemical analysis revealed that five compounds, including chlorogenic acid, differed significantly across treatments. Gene expression analysis showed that 25 µM H₂O₂ upregulated Bco-DXS1 and increased TTC, whereas 250 µM H₂O₂ repressed gene expression but still enhanced terpene accumulation. Overall, these results suggest that moderate H₂O₂ levels function as a signaling molecule in B. conferta, simultaneously boosting phenolic and terpene pathways. This highlights controlled H₂O₂ elicitation as an effective biotechnological approach to increase the production of valuable metabolites in medicinal plant cultures. Full article

(This article belongs to the Special Issue Plant Metabolism and Natural Product Biosynthesis)

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12 pages, 936 KB

Open AccessArticle

Comparative Genomics Reveals Unique Genetic Determinants of Biofilm Formation in Campylobacter

by Yiping He, Gretchen Dykes, Heather Koppenhöfer, Joseph Capobianco and Chin-Yi Chen

Int. J. Mol. Sci. 2026, 27(6), 2543; https://doi.org/10.3390/ijms27062543 - 10 Mar 2026

Abstract

A biofilm is a complex microbial community that protects bacterial cells from various stressors, including harsh environmental conditions, antimicrobial treatments, and host immune responses. This protective capability enhances Campylobacter survival during food processing and storage and facilitates transmission to humans. Despite their importance, [...] Read more.

A biofilm is a complex microbial community that protects bacterial cells from various stressors, including harsh environmental conditions, antimicrobial treatments, and host immune responses. This protective capability enhances Campylobacter survival during food processing and storage and facilitates transmission to humans. Despite their importance, the molecular mechanisms underlying Campylobacter biofilm formation and its impact on pathogen persistence remain poorly understood. In this study, we characterized the biofilm-forming ability of 18 C. jejuni and C. coli strains isolated from retail meat and performed whole-genome sequencing and comparative genomic analysis to identify strain-specific genes contributing to biofilm formation and maintenance. Phenotypic analysis revealed that C. jejuni strains YH001 and YH027 exhibited the strongest biofilm-forming capacity, producing the highest biomass among all isolates. Phylogenetic analysis indicated a close genetic relationship between these two strains, while pangenome analysis identified 19 unique genes/proteins specific to these strains. Functional annotation indicated their critical roles in adhesion, extracellular matrix production, and stress response. These findings demonstrate strain-specific biofilm formation in Campylobacter and highlight genetic determinants that may serve as targets for novel therapeutic approaches and intervention strategies to disrupt biofilms, improve food safety, and reduce persistent infections. Full article

(This article belongs to the Special Issue Mechanisms in Biofilm Formation, Tolerance and Control: 3rd Edition)

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22 pages, 1102 KB

Open AccessReview

Genomic Context and Insert Orientation in the Regulation of Transgene Expression in Adenoviral Vectors

by Anna Muravyeva and Svetlana Smirnikhina

Int. J. Mol. Sci. 2026, 27(6), 2542; https://doi.org/10.3390/ijms27062542 - 10 Mar 2026

Abstract

Adenoviral vectors are among the most efficient platforms for gene delivery; however, the level and pattern of transgene expression in these vectors are largely shaped by the viral genomic context. This review discusses the mechanisms of adenoviral transcription and alternative splicing and how [...] Read more.

Adenoviral vectors are among the most efficient platforms for gene delivery; however, the level and pattern of transgene expression in these vectors are largely shaped by the viral genomic context. This review discusses the mechanisms of adenoviral transcription and alternative splicing and how they influence the expression of inserted expression cassettes. Particular attention is given to the role of insertion orientation and transgene placement within the E1 and E3 regions, as well as to the effects of viral regulatory elements, including the E1A enhancer. We analyze evidence on the use of insulating sequences to reduce nonspecific activation and improve the controllability of transgene expression. We also consider the use of endogenous adenoviral promoters—the major late promoter (MLP) and the E3 region promoter—and their contribution to enhanced transgene expression through late viral transcription. Overall, these findings support principles for the rational design of adenoviral vectors, both for high-level protein production and for building systems with regulated or tissue-specific expression. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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19 pages, 6578 KB

Open AccessArticle

Mechanisms of Programmed Cell Death in Sodium Iodate-Driven Retinal Degeneration and the Role of DJ-1

by Mala Upadhyay, Caroline Milliner and Vera L. Bonilha

Int. J. Mol. Sci. 2026, 27(6), 2541; https://doi.org/10.3390/ijms27062541 - 10 Mar 2026

Abstract

Oxidative stress-induced RPE cell death is a major cause of AMD pathogenesis. However, the exact modes of oxidative stress-driven retinal death remain elusive. To address this knowledge gap, we investigated the role of DJ-1, an antioxidant protein we previously characterized in the retina, [...] Read more.

Oxidative stress-induced RPE cell death is a major cause of AMD pathogenesis. However, the exact modes of oxidative stress-driven retinal death remain elusive. To address this knowledge gap, we investigated the role of DJ-1, an antioxidant protein we previously characterized in the retina, in cell death regulation. Specifically, we analyzed cell death pathways in the retinas of DJ-1 knockout (KO) mice, with or without sodium iodate (NaIO₃) injection. We quantified MAPK signaling protein activation by Western blot. The distribution of the cell death executioners, activated caspase 3, and pMLKL, was investigated. The effects of caspase and necroptosis inhibitors in mice previously injected with NaIO₃ were determined. Significant increases in JNK1/2 activation and FOXO1 levels were detected in RPE lysates when DJ-1 KO mice were injected with 10 mg/kg NaIO₃. The immunoreactivity of active caspase-3 and pMLKL was stronger in the retinas of DJ-1 KO compared with C57BL mice. These immunoreactivities further increased in the degenerating outer retina post NaIO₃ injection and were stronger in the retina of DJ-1 KO compared with C57BL mice at both doses of NaIO₃. ZVAD treatment rescued retinal degeneration to varying degrees in DJ-1 KO mice. However, necrostatin (Nec-1) alleviated retinal degeneration in both DJ-1 KO and C57BL mice, suggesting that apoptosis is a major cell death modality in the absence of DJ-1. Overall, oxidative stress-induced RPE and retinal cell death involve activation of both apoptosis and necroptosis in the absence of DJ-1. Full article

(This article belongs to the Special Issue Redox Homeostasis and Oxidative Stress in Human Metabolism and Disease: 3rd Edition)

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23 pages, 3783 KB

Open AccessArticle

Design and Testing of Root-Specific Synthetic Promoters by Machine Learning

by Chunhao Lu, Yuepeng Song and Deqiang Zhang

Int. J. Mol. Sci. 2026, 27(6), 2540; https://doi.org/10.3390/ijms27062540 - 10 Mar 2026

Abstract

Synthetic promoters are crucial for precise gene expression in transgenic plants, but their rational design is hindered by the difficulty in identifying functional cis-regulatory elements (CREs). In this study, we aimed to develop a systematic approach for discovering tissue-specific cis-regulatory modules (CRMs) and [...] Read more.

Synthetic promoters are crucial for precise gene expression in transgenic plants, but their rational design is hindered by the difficulty in identifying functional cis-regulatory elements (CREs). In this study, we aimed to develop a systematic approach for discovering tissue-specific cis-regulatory modules (CRMs) and generating functional synthetic promoters in poplar. We performed extensive transcriptomic analysis across various poplar tissues to obtain categorical labels and detected motifs in all gene promoters using known transcription factor binding site (TFBS) position weight matrices. Informative, tissue-specific TFBSs were predicted using a random forest model. Applying this to a root-specific gene, PopRTS1, we identified putative root-specific CRMs. These CRMs were then used to construct synthetic promoters, which were experimentally validated through rapid infiltration and GUS staining assays across different tissues. We successfully identified a root-specific synthetic promoter, PRTS1. Our findings demonstrate that machine learning can effectively decipher regulatory codes from omics data to predict functional CRMs. This work provides a feasible and systematic method for screening and designing tissue-specific synthetic promoters, offering significant potential for advancing targeted gene expression systems in plant biotechnology. Full article

(This article belongs to the Section Molecular Biology)

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39 pages, 926 KB

Open AccessReview

Resistant and Refractory Obesity: The Complexity of Anti-Obesity Therapy Failure

by Michał Nicze, Maciej Borówka, Adrianna Dec, Łukasz Bułdak, Aleksandra Bołdys and Bogusław Okopień

Int. J. Mol. Sci. 2026, 27(6), 2539; https://doi.org/10.3390/ijms27062539 - 10 Mar 2026

Abstract

Pharmacotherapy is a key component of obesity management, yet treatment failure remains a prevalent challenge in clinical practice. Such failure may present as insufficient pharmacological response, early discontinuation, or post-treatment weight regain, underscoring the discrepancy between clinical trial efficacy and real-world outcomes. The [...] Read more.

Pharmacotherapy is a key component of obesity management, yet treatment failure remains a prevalent challenge in clinical practice. Such failure may present as insufficient pharmacological response, early discontinuation, or post-treatment weight regain, underscoring the discrepancy between clinical trial efficacy and real-world outcomes. The effectiveness of anti-obesity medications (AOMs) is influenced by psychiatric comorbidities, including depression, anxiety, and disordered eating patterns, as well as environmental and socioeconomic factors such as limited healthcare access, weight-related stigma, and high medication costs. Individual characteristics, including physical activity, body composition, visceral adiposity, and microbiome profile, further modulate treatment outcomes. Pharmacokinetic and pharmacotherapeutic limitations such as drug-phenotype mismatch, route of administration, suboptimal formulations, and exposure to counterfeit products also compromise efficacy. No less important are genetic and immunological factors, comprising pharmacogenomic variants of both incretin and melanocortin receptors along with antidrug antibodies (ADAs), which may constitute therapy resistance. Concomitant medications and comorbid endocrine disorders can additionally attenuate weight-loss effects. The objective of this review is to characterize the multifactorial nature of resistance and refractoriness to anti-obesity therapy, and the importance of identifying pretreatment predictive factors for recognizing individuals at risk of inadequate or lack of response, thereby enabling personalized management strategies and improving long-term clinical outcomes, particularly in “difficult-to-treat” patients. Full article

(This article belongs to the Special Issue Recent Developments in Obesity: Metabolism, Pathophysiology and Treatment)

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39 pages, 3108 KB

Open AccessReview

Across the Social Network of the Gut: Bacterial, Fungal, and Viral Determinants of Checkpoint Inhibitor Efficacy and Toxicity

by Andreea Laura Antohi, Andreea Daria Gheorghiță, Octavian Andronic, Gratiela Gradisteanu Pircalabioru and Andreea-Ramona Treteanu

Int. J. Mol. Sci. 2026, 27(6), 2538; https://doi.org/10.3390/ijms27062538 - 10 Mar 2026

Abstract

Recent findings suggest that the gut microbiome significantly influences cancer outcomes, including responses to immune checkpoint inhibitor (ICI) treatments. Although early research focused on gut bacteria, it is now understood that the microbiome includes a bacteriome, virome, and mycobiome, all of which can [...] Read more.

Recent findings suggest that the gut microbiome significantly influences cancer outcomes, including responses to immune checkpoint inhibitor (ICI) treatments. Although early research focused on gut bacteria, it is now understood that the microbiome includes a bacteriome, virome, and mycobiome, all of which can modulate host immunity. Some commensal bacteria enhance anti-tumor immune responses and improve ICI efficacy, as demonstrated in both mice and patients. Fecal microbiota transplants (FMT) from patients responding to ICI have successfully reversed resistance in certain non-responders. In addition to bacteria, gut fungi and viruses are gaining attention as further factors influencing ICI effectiveness and toxicity. Recent multi-omics studies across cancer cohorts show that fungal and viral populations in the gut vary between ICI responders and non-responders. Commensal fungi may shape anti-cancer immunity by inducing inflammatory or tolerogenic pathways, while viral components can stimulate innate immune sensors that promote tumor surveillance. On the other hand, gut dysbiosis marked by expansion of pathobionts (including opportunistic fungi) and reduction in beneficial microbes is linked to serious immune-related adverse events (irAEs) such as ICI-induced colitis. This review discusses the multi-kingdom gut microbiome–bacteria, fungi, and viruses–and their interactions with the immune system in cancer therapy. We emphasize known mechanisms linking these microbes to anti-tumor immunity, overview human studies associating gut microbiome profiles with ICI outcomes and explore strategies to modulate the microbiome to enhance ICI efficacy while reducing toxicity. Understanding and utilizing the gut mycobiome and virome in conjunction with the bacteriome could pave the way for new biomarkers and therapeutic adjuvants in cancer immunotherapy. Full article

(This article belongs to the Special Issue Current Advances in Immuno-Oncology)

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11 pages, 1758 KB

Open AccessArticle

A Comparative Study for the Incorporation of 8-oxo-dATP in DNA by Human DNA Polymerases

by Alexander A. Kruchinin, Polina N. Kamzeeva, Mikhail S. Baranov, Yana G. Belova, Elizaveta O. Boldinova, Andrey G. Baranovskiy, Tahir H. Tahirov, Andrey V. Aralov and Alena V. Makarova

Int. J. Mol. Sci. 2026, 27(6), 2537; https://doi.org/10.3390/ijms27062537 - 10 Mar 2026

Abstract

In this work, we analyzed the ability to incorporate 8-oxo-dATP by several human DNA polymerases: replicative Pol ε (exo-) from Family B; base excision repair (BER) enzymes Pol β and Pol λ from Family X; and translesion Pol η, Pol ι, and Pol [...] Read more.

In this work, we analyzed the ability to incorporate 8-oxo-dATP by several human DNA polymerases: replicative Pol ε (exo-) from Family B; base excision repair (BER) enzymes Pol β and Pol λ from Family X; and translesion Pol η, Pol ι, and Pol κ from Family Y. We demonstrated that human DNA polymerases differ in their abilities to discriminate against 8-oxo-dATP. Among the tested DNA polymerases, Pol λ exhibited the worst ability to discriminate against 8-oxo-dATP opposite template T on DNA substrates with a protruding single-stranded 5′-end and a double-stranded DNA with a 1 nt gap. Pol β and DNA polymerases of Family Y showed relatively high accuracy. Pol η demonstrated the most effective discrimination against 8-oxo-dATP on templates T and G. Pol ι exclusively incorporated 8-oxo-dATP opposite template G but not T. Unexpectedly, the catalytic subunit of high-fidelity Pol ε (exo-) incorporated 8-oxo-dATP opposite templates T and G with higher efficiency compared with the error-prone polymerases of Family Y and Pol β. While the structures of human polymerases with incoming 8-oxo-dATP are not available, we speculate on a possible mechanism of 8-oxo-dATP discrimination. Full article

(This article belongs to the Section Biochemistry)

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45 pages, 49169 KB

Open AccessReview

Addressing the Challenges of Solid-State Nanopores: Strategies for Performance Enhancement

by Xi Chen, Jiayi Liu, Zhiyou Xiao, Guowei Wang, Yu Li, Hongwen Wu and Derong Xu

Int. J. Mol. Sci. 2026, 27(6), 2536; https://doi.org/10.3390/ijms27062536 - 10 Mar 2026

Abstract

Solid-state nanopore sequencing, a key third-generation sequencing technology, offers considerable potential for genomics and diagnostics due to its long read lengths, real-time detection, and amplification-free operation. The technology identifies DNA sequences by measuring characteristic changes in ionic current as single-stranded DNA translocates through [...] Read more.

Solid-state nanopore sequencing, a key third-generation sequencing technology, offers considerable potential for genomics and diagnostics due to its long read lengths, real-time detection, and amplification-free operation. The technology identifies DNA sequences by measuring characteristic changes in ionic current as single-stranded DNA translocates through a nanoscale pore. However, its practical development faces challenges including limited spatiotemporal resolution, pore clogging from nonspecific adsorption, and significant electrical noise. This review systematically examines strategies developed to address these limitations. We discuss the use of ultrathin two-dimensional materials such as graphene and molybdenum disulfide to improve spatial resolution, and methods to modulate DNA translocation through optimized solution conditions, pore geometry, surface charge engineering, and bio-solid hybrid pore designs. Furthermore, we detail noise suppression strategies targeting key sources like thermal noise, 1/f noise, and dielectric noise. These approaches encompass careful material selection, surface coatings, innovations in chip and amplifier design, and machine learning–based signal processing. The review also outlines surface functionalization techniques that reduce clogging and enhance analytical specificity. While challenges remain, continued convergence of materials science, nanofabrication, and data science is advancing solid-state nanopore technology toward reliable, high-precision sequencing platforms, promising to significantly impact personalized medicine and biological research. Full article

(This article belongs to the Special Issue Advanced Research on Nanosensors for Molecular Sensing Applications)

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4 pages, 152 KB

Open AccessCorrection

Correction: Ziranu et al. Navigating the Landscape of Liquid Biopsy in Colorectal Cancer: Current Insights and Future Directions. Int. J. Mol. Sci. 2025, 26, 7619

by Pina Ziranu, Andrea Pretta, Giorgio Saba, Dario Spanu, Clelia Donisi, Paolo Albino Ferrari, Flaviana Cau, Alessandra Pia D’Agata, Monica Piras, Stefano Mariani, Marco Puzzoni, Valeria Pusceddu, Ferdinando Coghe, Gavino Faa and Mario Scartozzi

Int. J. Mol. Sci. 2026, 27(6), 2535; https://doi.org/10.3390/ijms27062535 - 10 Mar 2026

Abstract

Error in Table and Legend [...] Full article

(This article belongs to the Special Issue Cancer Biology and Epigenetic Modifications)

23 pages, 5966 KB

Open AccessArticle

Drug Repurposing of Verapamil for H1N1 Influenza Virus Infection: A Multi-Target Strategy Revealed by Network Pharmacology and Experimental Validation

by Yan Cao, Jiajing Wu, Xuena Li, Feifan Qiu, Shuo Wang, Bingshuo Qian, Lingjun Fan, Yueqi Wang, Kun Xue, Junkui Zhang, Beilei Shen and Yuwei Gao

Int. J. Mol. Sci. 2026, 27(6), 2534; https://doi.org/10.3390/ijms27062534 - 10 Mar 2026

Abstract

Influenza A virus (IAV) infection constitutes a major public health threat. Severe influenza virus infection can induce intense inflammatory responses and lung injury, leading to serious clinical symptoms or even death. The utility of current anti-influenza drugs is often limited by side effects [...] Read more.

Influenza A virus (IAV) infection constitutes a major public health threat. Severe influenza virus infection can induce intense inflammatory responses and lung injury, leading to serious clinical symptoms or even death. The utility of current anti-influenza drugs is often limited by side effects and the emergence of drug-resistant strains. Based on the critical role of L-type voltage-gated calcium channels (L-VGCCs) in influenza virus replication, this study investigates the antiviral activity and mechanism of verapamil, a classic L-type calcium channel antagonist, against H1N1-UI182 virus. Verapamil, an L-type calcium channel blocker, is widely used in the treatment of cardiovascular diseases and has a well-established safety profile. Through molecular dynamics (MD) simulation and network pharmacology analysis, we predicted the stable binding mode of verapamil to the target protein (PDB id: 6JPA) and its potential multi-target network. In vitro, verapamil exhibited antiviral activity against H1N1-UI182 in MDCK cells, enhancing the survival rate of infected cells and reducing viral nucleoprotein (NP) expression. In a lethal H1N1-UI182 infection mouse model, verapamil treatment markedly improved survival rates, alleviated weight loss and lung pathological damage, exhibiting a dose-dependent protective effect. Lung tissue analysis showed that verapamil effectively reduced the lung index and viral load, suppressed the activation of the Nuclear factor kappa B (NF-κB) signaling pathway, and decreased the expression of key inflammatory factors, thereby mitigating the cytokine storm. A comparison of administration regimens indicated that pre-treatment yielded optimal efficacy, suggesting verapamil acts primarily during the early stage of the viral life cycle. This study systematically elucidates that verapamil exerts antiviral and immunomodulatory effects by regulating the NF-κB pathway. Network pharmacology analysis suggested the potential involvement of multiple targets and pathways, including EGFR, SRC, and phospholipase D signaling, providing hypotheses for future mechanistic investigation. This paper supports a drug repurposing strategy against drug-resistant influenza viruses and highlights its significant potential for clinical translation. Full article

(This article belongs to the Special Issue Network Pharmacology: An Emerging Field in Drug Discovery (2nd Edition))

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14 pages, 919 KB

Open AccessArticle

Genome-Wide Association Study of Vertical Jump Performance Among Elite Badminton Players

by Fevzi Coşkun Sökmen, Anıl Kasakolu, Celal Bulgay, Naoki Kikuchi, Hasan Hüseyin Kazan, Seyrani Koncagul, Yeliz Ay Yildiz, Attila Szabo, Nicola Luigi Bragazzi and Mehmet Ali Ergün

Int. J. Mol. Sci. 2026, 27(6), 2533; https://doi.org/10.3390/ijms27062533 - 10 Mar 2026

Abstract

Vertical jump performance is known to be a moderately heritable trait. However, previous studies on sport genetics have largely relied on candidate-gene approaches, which do not adequately reflect the polygenic nature of explosive performance, particularly among elite badminton players. Therefore, the aim of [...] Read more.

Vertical jump performance is known to be a moderately heritable trait. However, previous studies on sport genetics have largely relied on candidate-gene approaches, which do not adequately reflect the polygenic nature of explosive performance, particularly among elite badminton players. Therefore, the aim of the present study was to identify genetic variants associated with lower-limb explosive performance, assessed via vertical jump measures, among elite Turkish badminton players using a genome-wide association study (GWAS) approach. The present study included 90 elite male (n = 47) and female (n = 43) badminton players, and 557 non-athletic controls sourced from a public database. Performance-related traits were evaluated through countermovement jump (CMJ), squat jump (SJ), and their differential. Genome-wide genotyping was performed using DNA microarrays, and associations were examined using linear mixed models fixed for sex/gender, body mass index, and sport experience. Although no variants reached genome-wide significance (p < 1.00 × 10⁻⁷), 13 single-nucleotide polymorphisms (SNPs) exceeded the suggestive threshold (p < 1.00 × 10⁻⁵). CMJ-associated variants were rs4905767, rs2911702, rs10246591, and rs9842454; SJ-associated variants were rs55817650, rs62318127, rs115197840, rs78317172, and rs35930589; and CMJ–SJ-associated variants were rs34638064, rs6679342, rs4931233, and rs9442615. The present study provides preliminary evidence that lower-limb explosive performance among elite badminton players is polygenic, involving regulatory and signaling pathways rather than single performance genes. Full article

(This article belongs to the Special Issue Molecular Mechanisms Associated with Exercise for Health and Performance)

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31 pages, 1320 KB

Open AccessReview

Vitamin D and Metabolic Dysfunction-Associated Steatotic Liver Disease: Molecular Mechanisms and Clinical Implications—A Narrative Review

by Héctor Fuentes-Barría, Raúl Aguilera-Eguía, Miguel Alarcón-Rivera, Lisse Angarita-Davila and Cherie Flores-Fernández

Int. J. Mol. Sci. 2026, 27(6), 2532; https://doi.org/10.3390/ijms27062532 - 10 Mar 2026

Abstract

Vitamin D has been extensively investigated for its role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), a chronic condition characterized by hepatic steatosis, insulin resistance, inflammation, and metabolic dysregulation. This review examines the molecular mechanisms through which vitamin D influences liver metabolism, insulin [...] Read more.

Vitamin D has been extensively investigated for its role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), a chronic condition characterized by hepatic steatosis, insulin resistance, inflammation, and metabolic dysregulation. This review examines the molecular mechanisms through which vitamin D influences liver metabolism, insulin signaling, lipid accumulation, and inflammatory pathways while evaluating its potential clinical applications in MASLD management. In its active form, 1,25-dihydroxyvitamin D3, vitamin D modulates hepatocyte function by reducing proinflammatory cytokines, enhancing insulin sensitivity, activating AMPK signaling, inhibiting mTOR pathways, and regulating lipid homeostasis. These effects contribute to decreased hepatic fat deposition and improved metabolic profiles, which are key in MASLD progression. Evidence also suggests that vitamin D supplementation may improve liver enzymes, insulin resistance, and lipid parameters in patients with MASLD, although responses vary depending on dosage, baseline vitamin D status, and patient characteristics. Despite promising findings, inconsistencies in study design, measurement methods, and population differences underscore the need for standardized approaches and personalized strategies. In conclusion, vitamin D demonstrates complementary therapeutic potential in MASLD, highlighting research gaps related to optimal dosing, duration, and long-term outcomes. Future studies should integrate mechanistic insights with clinical trials to optimize vitamin D’s role in improving liver and metabolic health. Full article

(This article belongs to the Special Issue Vitamin D Signaling in Human Health and Diseases)

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20 pages, 3093 KB

Open AccessArticle

Predominantly Independent Genetic Control Between Growth and Visceral White Nodules Disease Resistance Revealed by High-Density Linkage Map and QTL Mapping in Larimichthys crocea

by Ting Ye, Dandan Guo, Yilian Zhou, Bao Lou and Feng Liu

Int. J. Mol. Sci. 2026, 27(6), 2531; https://doi.org/10.3390/ijms27062531 - 10 Mar 2026

Abstract

The large yellow croaker (Larimichthys crocea) is a key mariculture species in China, however, its industry is threatened by visceral white nodules disease (VWND) caused by the bacterium Pseudomonas plecoglossicida. A significant challenge in breeding is the potential genetic trade-off [...] Read more.

The large yellow croaker (Larimichthys crocea) is a key mariculture species in China, however, its industry is threatened by visceral white nodules disease (VWND) caused by the bacterium Pseudomonas plecoglossicida. A significant challenge in breeding is the potential genetic trade-off between growth and disease resistance. To investigate their genetic relationship, we constructed a high-density SNP-based genetic linkage map for L. crocea using a F1 full-sib family (n = 150). The map comprised 24 linkage groups with 32,429 bin markers and an average interval of 0.051 cM. Based on this map, we conducted QTL mapping for one yield trait (body weight), eight morphological traits, and three VWND-resistance traits (survival time, AT; spleen and liver pathogen loads). Phenotypic analysis revealed strong integration among growth traits and a moderate positive correlation between growth traits and AT. QTL mapping identified 53 QTLs for growth (PVE = 0.14–5.83%) and 20 for resistance (PVE = 0.78–8.93%). Notably, only two genomic intervals exhibited co-localization between a morphological trait (AL or BL) and AT, each explaining a modest phenotypic variance (0.66–5.99%). The largest-effect QTLs for growth and resistance were mapped to distinct linkage groups, and candidate genes within the co-localized intervals (Unc5d, SCN5A, HUS1) are involved in fundamental cellular processes rather than core growth or immune pathways. These results suggest that yield, morphological, and VWND-resistance traits in L. crocea are largely under independent genetic control within the studied family, indicating that simultaneous improvement of growth and disease resistance is feasible. This study provides a molecular basis for breeding strategies aimed at overcoming the trait trade-off bottleneck in this economically vital species. Full article

(This article belongs to the Special Issue Genomic, Transcriptomic, and Epigenetic Approaches in Fish Research)

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17 pages, 939 KB

Open AccessReview

Engineering MSC Migration: Roles of Nanoparticles in Activating Migratory Pathways and Functions

by Temuulen Batsaikhan, Hyun Su Lee and Young Joon Seo

Int. J. Mol. Sci. 2026, 27(6), 2530; https://doi.org/10.3390/ijms27062530 - 10 Mar 2026

Abstract

Mesenchymal stem cells (MSCs) hold strong therapeutic potential due to their regenerative, anti-inflammatory, and immunomodulatory properties. A key factor in their effectiveness is the ability to home in to injured sites. However, clinical outcomes are limited by poor homing efficiency, insufficient migration, tracking [...] Read more.

Mesenchymal stem cells (MSCs) hold strong therapeutic potential due to their regenerative, anti-inflammatory, and immunomodulatory properties. A key factor in their effectiveness is the ability to home in to injured sites. However, clinical outcomes are limited by poor homing efficiency, insufficient migration, tracking challenges, and risks of unwanted differentiation. This review explores the molecular mechanisms of MSC homing, particularly the CXCR4/SDF-1 axis and matrix remodeling. We highlight recent advances in using nanoparticles—such as magnetic, silica, and polymer-based systems—to enhance chemokine receptor expression and homing. Future directions include MSC engineering, advanced tracking, and AI-guided delivery strategies to improve therapeutic efficacy. Full article

(This article belongs to the Special Issue Molecular Research and Applications of Nanomaterials)

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22 pages, 2651 KB

Open AccessArticle

Synthesis of 2-Aryl-4-aminoquinazolines: Design, Molecular Docking, and In Vitro Assessment of Antibacterial and Cytotoxic Potential

by Felipe Verdugo, Capucine Braillon, Sana Mahjoub, Alejandro Castro-Alvarez, Régine Janel-Bintz, Pierre Fechter, Pascal Villa, Claudio A. Jiménez, Diego A. Donoso-Ruiz, Marcia Pérez-Fehrmann, Víctor Kesternich, Sergio Ortiz and Ronald Nelson

Int. J. Mol. Sci. 2026, 27(6), 2529; https://doi.org/10.3390/ijms27062529 - 10 Mar 2026

Abstract

Antimicrobial resistance (AMR) remains a major threat to modern medicine, fueled by the excessive use of antibiotics and the spread of multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). In this study, we designed and synthesized a series of 2-aryl-4-aminoquinazoline derivatives bearing an [...] Read more.

Antimicrobial resistance (AMR) remains a major threat to modern medicine, fueled by the excessive use of antibiotics and the spread of multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). In this study, we designed and synthesized a series of 2-aryl-4-aminoquinazoline derivatives bearing an aminoalkylimidazole linker, combining two pharmacophoric motifs associated with antimicrobial activity. Starting from anthranilamide, the compounds were prepared in three straightforward steps, affording good yields and high purity. Their structures were confirmed by FT-IR spectroscopy, ¹H and ¹³C nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HRMS). Biological evaluation showed that series 5 exhibited strong selectivity toward S. aureus, with compounds 5c and 5d displaying minimum inhibitory concentrations (MICs) between 2.2 and 4.4 µM. No significant activity was observed against other tested strains. Cytotoxicity assays in HepG2 cells revealed moderate to low inhibition. Molecular docking indicated preferential binding to dihydrofolate reductase (DHFR) and relevant interactions with topoisomerase IV, resembling reference inhibitors. ADME analysis predicted favourable absorption, blood–brain barrier permeability, and compliance with Lipinski’s rules. Full article

(This article belongs to the Section Molecular Microbiology)

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22 pages, 1851 KB

Open AccessReview

Invariant Natural Killer T Cells in Cancer Immunotherapy: Lipid-Based Modulation, Nanotechnology, and Translational Advances

by Abdulaziz A. Aloliqi, Abdullah M. Alnuqaydan, Mohammad Alshebremi, Arif Khan and Masood Alam Khan

Int. J. Mol. Sci. 2026, 27(6), 2528; https://doi.org/10.3390/ijms27062528 - 10 Mar 2026

Abstract

Invariant natural killer T (iNKT) cells are a unique lymphocyte subset that bridge innate and adaptive immunity through recognition of glycolipid antigens presented by CD1d. Upon activation by ligands such as α-galactosylceramide (α-GalCer), iNKT cells rapidly secrete cytokines, including IFN-γ and TNF-α, thereby [...] Read more.

Invariant natural killer T (iNKT) cells are a unique lymphocyte subset that bridge innate and adaptive immunity through recognition of glycolipid antigens presented by CD1d. Upon activation by ligands such as α-galactosylceramide (α-GalCer), iNKT cells rapidly secrete cytokines, including IFN-γ and TNF-α, thereby activating dendritic cells, natural killer (NK) cells, and cytotoxic T lymphocytes (CTLs) to promote antitumor immunity. Despite their therapeutic promise, clinical translation has been limited by rapid α-GalCer clearance, induction of iNKT cell anergy following repeated stimulation, and the immunosuppressive tumor microenvironment (TME). Recent advances in lipid-engineered nanoparticle systems offer solutions to these challenges by improving ligand stability, enhancing antigen-presenting cell targeting, and enabling controlled release that sustains Th1-biased activation while reducing anergy. Liposomal and polymer-based nano-formulations enhance bioavailability and promote more durable IFN-γ-mediated responses. In parallel, chimeric antigen receptor (CAR)-engineered iNKT cells provide antigen-specific tumor targeting while preserving intrinsic CD1d-restricted immunomodulatory functions, demonstrating encouraging safety and efficacy in early-phase studies. Combination strategies further strengthen iNKT-based immunotherapy. Integration with chemotherapy, immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4, and cytokine support enhances effector activation, counteracts TME-induced suppression, and improves therapeutic outcomes. However, challenges remain, including optimization of dosing, control of off-target immune activation, scalable manufacturing, and long-term safety evaluation. Collectively, the convergence of nanotechnology, CAR engineering, and rational combination approaches establishes iNKT cell-based therapy as a promising next-generation immunotherapeutic strategy. Continued refinement of delivery systems, genetic engineering platforms, and translational protocols may enable durable immune reprogramming and improved clinical outcomes in resistant and immunosuppressive cancers. Full article

(This article belongs to the Special Issue The Role of Lipids in Health and Diseases)

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32 pages, 3099 KB

Open AccessArticle

Metallomic Analysis of Vitreous Humor of the Human Eye—A Post-Mortem Multielemental Study

by Alicja Forma, Michał Flieger, Beata Kowalska, Jolanta Flieger, Andrzej Torbicz, Jacek Bogucki, Grzegorz Teresiński, Ryszard Maciejewski, Robert Rejdak, Joanna Dolar-Szczasny, Weronika Pająk and Jacek Baj

Int. J. Mol. Sci. 2026, 27(6), 2527; https://doi.org/10.3390/ijms27062527 - 10 Mar 2026

Abstract

The elemental composition of the vitreous humor may reflect physiological and pathological processes occurring in the eye. The objective of this study was to provide a complex multielemental analysis of human vitreous humor. Vitreous humor samples (n = 57) were collected post-mortem during [...] Read more.

The elemental composition of the vitreous humor may reflect physiological and pathological processes occurring in the eye. The objective of this study was to provide a complex multielemental analysis of human vitreous humor. Vitreous humor samples (n = 57) were collected post-mortem during autopsies. Inductively coupled plasma mass spectrometry (ICP-MS) was employed to quantify micro-, trace-, ultra-trace, and toxic elements. The study showed the occurrence of elements at the ppm (Na, K, P, Ca, Mg), ppb (Al, Rb, Zn, Fe, Sr, Cu), and ppt (Ce, La, Nd, Tb) levels. Hierarchical clustering using Ward’s method and k-means analysis revealed four distinct clusters, including two major clusters representing the baseline macro- and microelement profile characteristic for the studied population. Correlations between elements revealed statistically significant (p < 0.05) positive and negative correlations between elements with (I) chemical similarity Ce-La, Cs-Rb, Rb-K, Ca-P, Zn-Cu, and Cs-K; (II) a possible common environmental origin, Cd-P, and Rb-P; (III) involvement in similar biological processes as K-P; and (iv) a common geochemical origin and similar biological functions, i.e., Se-Zn. The study identified several quantitative trends in the demographic and medical characteristics of the participants. Alcohol users had significantly higher Zn concentrations than non-alcohol users; women had significantly higher Ca concentrations than men; higher BMI correlated positively with Cs and negatively with Be and Cr levels; and Cu, Sb, Cd, Se, and Ca concentrations increased with age. The presence of several toxic and potentially toxic elements was identified in the vitreous body: Al (>10 ppb); Cd, Cr, Pb, Ni, Mn; and Ba (<10 ppb); As, Hg, Sb, Tl, Bi, Be (<1 ppb). The study showed that, within a given geographic region, the accumulation profiles of toxic metals are quite homogeneous, indicating common sources of exposure. Full article

(This article belongs to the Special Issue Molecular Insights into Ophthalmic Diseases)

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30 pages, 4440 KB

Open AccessArticle

Computational Identification of Potential Novel Allosteric IHF Inhibitors Using QSAR Modeling to Inhibit Plasmid-Mediated Antibiotic Resistance

by Oscar Saurith-Coronell, Olimpo Sierra-Hernandez, Juan David Rodríguez-Macías, José R. Mora, Noel Perez-Perez, Jackson J. Alcázar, Ricardo Olimpio de Moura, Igor José dos Santos Nascimento, Edgar A. Márquez Brazón and Yovani Marrero-Ponce

Int. J. Mol. Sci. 2026, 27(6), 2526; https://doi.org/10.3390/ijms27062526 - 10 Mar 2026

Abstract

The rapid spread of antibiotic resistance through plasmid-mediated conjugation remains a primary global health concern. Despite its critical role in horizontal gene transfer, no approved drugs currently target this process, leaving a critical therapeutic gap. Integration Host Factor (IHF), a DNA-binding protein essential [...] Read more.

The rapid spread of antibiotic resistance through plasmid-mediated conjugation remains a primary global health concern. Despite its critical role in horizontal gene transfer, no approved drugs currently target this process, leaving a critical therapeutic gap. Integration Host Factor (IHF), a DNA-binding protein essential for plasmid replication and mobilization, emerges as a promising yet underexplored target for anti-conjugation strategies. This work aimed to develop a predictive computational model and identify small molecules that disrupt IHF function, thereby reducing plasmid transfer and limiting resistance gene dissemination. A curated dataset of 65 compounds with reported anti-plasmid activity was analyzed using a 3D-QSAR model based on algebraic descriptors computed with QuBiLS-MIDAS. The model was validated through leave-one-out cross-validation (Q² = 0.82), Tropsha’s criteria, and Y-scrambling. Representative compounds were selected via pharmacophore clustering and evaluated through molecular docking at both the DNA-binding site and a predicted allosteric pocket of IHF. The most promising complexes underwent 200 ns molecular dynamics simulations to assess stability and interaction patterns. The QSAR model demonstrated strong predictive performance (R² = 0.90). Docking simulations revealed more favorable binding energies at the allosteric site (up to −12.15 kcal/mol) compared to the DNA-binding site. Molecular dynamics confirmed the stability of these interactions, with allosteric complexes showing lower RMSD fluctuations and consistent binding energy profiles. Dynamic cross-correlation analysis revealed that allosteric ligand binding induces conformational changes in key catalytic residues, including Pro65, Pro61, and Leu66. These alterations may compromise DNA recognition and disrupt the initiation of replication. To our knowledge, this is the first computational study proposing allosteric inhibition of IHF as an anti-conjugation strategy. These findings provide a foundation for experimental validation and the development of novel agents to prevent horizontal gene transfer, offering a promising approach to restoring antibiotic efficacy against multidrug-resistant pathogens. Full article

(This article belongs to the Special Issue Benchmarking of Modeling and Informatic Methods in Molecular Sciences)

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16 pages, 1634 KB

Open AccessArticle

Radiobiological Effects of Low-Dose Radiation in Normal Fibroblasts of Patients with Head and Neck Cancer Treated with Induction Chemotherapy Combined with Low-Dose Fractionated Radiation

by Gabriela Winiarska, Tomasz Rutkowski, Adam Gądek, Wojciech Fidyk, Magdalena Głowala-Kosińska, Urszula Kacorzyk, Krzysztof Składowski and Dorota Słonina

Int. J. Mol. Sci. 2026, 27(6), 2525; https://doi.org/10.3390/ijms27062525 - 10 Mar 2026

Abstract

The aim of the study was to define radiobiological effects of single and fractionated low doses in normal fibroblasts in 40 patients with squamous cell carcinoma of the head and neck (HNSCC) treated with induction chemotherapy combined with low-dose fractionated radiation (LDFR) and [...] Read more.

The aim of the study was to define radiobiological effects of single and fractionated low doses in normal fibroblasts in 40 patients with squamous cell carcinoma of the head and neck (HNSCC) treated with induction chemotherapy combined with low-dose fractionated radiation (LDFR) and to answer the question regarding the role of low-dose hyper-radiosensitivity (HRS) in these effects. HRS status was determined using flow cytometry-based clonogenic survival assay (cells were irradiated with doses 0.1–4 Gy of 6 MV X-rays). Radiobiological effects (cell kill, kinetics of DSB recognition and repair, chemopotentiation) of LDFR 4x0.5 Gy and a single dose of 2, 0.5 and 0.2 Gy were estimated by clonogenic, pATM and γH2AX foci assays. HRS response was demonstrated for normal fibroblasts in 6 of the 40 HNSCC patients. For all assessed biological parameters, significant interindividual differences were observed. The presence of HRS had no effect on the chemopotentiating effects of LDFR 4x0.5 Gy, which were similar to that after 2 Gy. There was also no association between HRS and the maximum number of pATM and γH2AX foci induced by single (0.2, 0.5, 2 Gy) or fractionated low doses 4x0.5 Gy. Significantly higher percentages of residual pATM and γH2AX foci observed after LDFR 4x0.5 Gy than after 2 Gy were independent of HRS. HRS is a rare finding (15%) in normal fibroblasts from HNSCC patients; therefore, it is of rather little importance in healthy late-reacting connective tissues. Moreover, the fibroblast response to single and fractionated low doses (alone or in combination with carboplatin and paclitaxel) appeared more dependent on individual radiosensitivity than on HRS. Full article

(This article belongs to the Section Molecular Oncology)

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Int. J. Mol. Sci., Volume 27, Issue 6 (March-2 2026) – 37 articles

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