International Journal of Molecular Sciences

40 pages, 850 KB

Open AccessReview

Lipidomics in Melanoma: Insights into Disease Progression and Therapeutical Targets

by Vittoria Maresca, Emanuela Bastonini, Giorgia Cardinali, Enrica Flori, Daniela Kovacs, Monica Ottaviani and Stefania Briganti

Int. J. Mol. Sci. 2026, 27(2), 1040; https://doi.org/10.3390/ijms27021040 - 20 Jan 2026

Abstract

Melanoma is the deadliest form of skin cancer, characterized by high metastatic potential and intrinsic heterogeneity. In addition to genetic mutations such as BRAF^V600E^ and NRAS, lipid metabolic reprogramming has emerged as a critical factor in tumor progression and therapy resistance. Lipid metabolism [...] Read more.

Melanoma is the deadliest form of skin cancer, characterized by high metastatic potential and intrinsic heterogeneity. In addition to genetic mutations such as BRAF^V600E^ and NRAS, lipid metabolic reprogramming has emerged as a critical factor in tumor progression and therapy resistance. Lipid metabolism supports melanoma cell survival, phenotypic switching, immune evasion, and resistance to targeted therapies and immunotherapy, while also modulating susceptibility to ferroptosis. This review summarizes current knowledge on lipid dysregulation in melanoma, highlighting alterations in fatty acid synthesis, desaturation, uptake, storage, and oxidation, as well as changes in phospholipids, sphingolipids, cholesterol, and bioactive lipid mediators. These lipid pathways are tightly regulated by oncogenic signaling networks, including MAPK and PI3K–AKT–mTOR pathways, and are influenced by tumor microenvironmental stressors such as hypoxia and nutrient limitation. Advances in lipidomics technologies, particularly mass spectrometry-based approaches, have enabled comprehensive profiling of lipid alterations at bulk, spatial, and single-cell levels, offering new opportunities for biomarker discovery and therapeutic stratification. Targeting lipid metabolic vulnerabilities represents a promising strategy to improve melanoma diagnosis, prognosis, and treatment efficacy. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer (2nd Edition))

21 pages, 2042 KB

Open AccessArticle

Zinc Supplementation Partially Reconstitutes Impaired Interferon-γ Production in the Elderly

by Krisztina Olah, Johanna Zenk, Jana Jakobs, Thea Laurentius, Leo Cornelius Bollheimer and Lothar Rink

Int. J. Mol. Sci. 2026, 27(2), 1039; https://doi.org/10.3390/ijms27021039 - 20 Jan 2026

Abstract

Aging impacts immunity, zinc status, and overall health, with these factors being closely interconnected. Zinc is known to modulate protein expression and cytokine production, with new molecular mechanisms continuing to be identified. ZIP8 facilitates IFN-γ production by increasing the intracellular zinc levels; how [...] Read more.

Aging impacts immunity, zinc status, and overall health, with these factors being closely interconnected. Zinc is known to modulate protein expression and cytokine production, with new molecular mechanisms continuing to be identified. ZIP8 facilitates IFN-γ production by increasing the intracellular zinc levels; how zinc status in humans affects ZIP8 expression remains unclear. We assessed serum zinc, dietary zinc intake, proton pump inhibitor (PPI) use, phytohemagglutinin (PHA)-stimulated IFN-γ production, and ZIP8 protein expression in elderly hospitalized patients and young healthy controls. Compared to young adults, elderly participants exhibited lower zinc status and IFN-γ levels, with PPI use among the elderly correlating with zinc deficiency. Zinc-deficient elderly participants received zinc aspartate supplementation for approximately 7 days, resulting in increased serum zinc levels, IFN-γ production, and a trend toward increased ZIP8 expression; in participants taking PPIs, this increase reached statistical significance. Although we found no clear correlation between ZIP8 expression and zinc status, the observed response to supplementation warrants further investigation. These findings reinforce the relevance of zinc supplementation in the elderly, although further studies are needed to elucidate the precise mechanisms linking zinc status to IFN-γ production, particularly regarding the role of ZIP8 expression levels. Full article

(This article belongs to the Special Issue Macro- and Micronutrients in Health and Diseases)

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28 pages, 10606 KB

Open AccessArticle

Diversity of Cardinium Endosymbiont Genomes from Plant-Parasitic Nematodes

by Sergey V. Tarlachkov, Alexander Y. Ryss, Yury Y. Ilinsky, Dmitry A. Rodionov, Lydmila I. Evtushenko and Sergei A. Subbotin

Int. J. Mol. Sci. 2026, 27(2), 1038; https://doi.org/10.3390/ijms27021038 - 20 Jan 2026

Abstract

Cardinium endosymbionts are obligate intracellular bacteria found in a wide range of invertebrate hosts. In this study, we generated ten new Cardinium genomes from plant-parasitic nematodes of the genera Amplimerlinius, Bursaphelenchus, Cactodera, Ditylenchus, Globodera, Meloidoderita, and Rotylenchus [...] Read more.

Cardinium endosymbionts are obligate intracellular bacteria found in a wide range of invertebrate hosts. In this study, we generated ten new Cardinium genomes from plant-parasitic nematodes of the genera Amplimerlinius, Bursaphelenchus, Cactodera, Ditylenchus, Globodera, Meloidoderita, and Rotylenchus, revealing their broad ecological and phylogenetic distribution. Using an expanded set of genes, we clarified the relationship between previously defined Cardinium groups B and F from nematodes, showing that they are closely related and likely share a single evolutionary origin within nematode-associated Cardinium. Among the newly assembled Cardinium genomes obtained in this study, two genomes originating from strains associated with wood-inhabiting Bursaphelenchus species exhibited remarkable genome reduction, with estimated sizes of approximately 695 kb. Functional annotation of Cardinium genomes indicated an absence of or a reduction in several central metabolic pathways, including the biotin biosynthetic pathway. A complete biotin pathway was found only in D. weischeri, and this pathway is only partially encoded in Cactodera sp. The polA gene, which encodes DNA polymerase I, showed partial loss in several Cardinium strains. Phylogenetic and comparative genomic analyses provided strong evidence that several carbohydrate, glycerophospholipid, and biotin metabolism genes in these endosymbionts have been acquired through horizontal gene transfer. Future research that integrates high-quality genome assemblies with functional analyses of host–symbiont interactions will be essential to elucidate how metabolic dependency, genome reduction, and horizontal gene transfer collectively shape the evolution and ecological diversification of Cardinium across nematode hosts. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Microbiology)

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26 pages, 3893 KB

Open AccessArticle

The Genetic and Molecular Analyses of Rare Candidate Germline BRIP1/FANCJ Variants Implicated in Hereditary Breast and Ovarian Cancers

by Wejdan M. Alenezi, Larissa Milano, Caitlin T. Fierheller, Corinne Serruya, Timothée Revil, Kathleen K. Oros, Jeffrey P. Bruce, Dan Spiegelman, Trevor Pugh, Anne-Marie Mes-Masson, Diane Provencher, William D. Foulkes, Zaki El Haffaf, Guy Rouleau, Luigi Bouchard, Celia M. T. Greenwood, Jiannis Ragoussis, Jean-Yves Masson and Patricia N. Tonin

Int. J. Mol. Sci. 2026, 27(2), 1037; https://doi.org/10.3390/ijms27021037 - 20 Jan 2026

Abstract

Five rare variants in BRIP1/FANCJ, initially identified in ovarian cancer (OC) or breast cancer (BC) cases by the adult hereditary cancer clinics, were investigated for their candidacy as clinically relevant variants. These variants were investigated genetically in a population exhibiting genetic drift [...] Read more.

Five rare variants in BRIP1/FANCJ, initially identified in ovarian cancer (OC) or breast cancer (BC) cases by the adult hereditary cancer clinics, were investigated for their candidacy as clinically relevant variants. These variants were investigated genetically in a population exhibiting genetic drift and molecularly assayed for biological impact. Using in silico tools, population-based genetic databases and other resources, three of the five reported BRIP1 variants were likely to be damaging: c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61. The carrier frequencies ranged from 0 to 0.7% in ancestry-defined cancer groups comprising 47 OC families, 49 hereditary breast and ovarian cancer syndrome families, 142 hereditary breast cancer syndrome families, 435 sporadic OC cases and 563 sporadic BC cases and 0–0.2% in 1025 population-matched controls. Multiple carriers of the these variants were identified in additional population-matched cancer cases. Of the five reported BRIP1 variants, p.Thr266Met, p.Pro696Leu and p.Thr997ArgfsTer61, which were predicted to be damaging, conferred cellular sensitivity to mitomycin C and cisplatin unlike p.Ser139Ala and p.Ala406Ser. Collectively, our investigation implicates BRIP1 c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and p.Thr997ArgfsTer61 as deleterious variants in OC and BC. Full article

(This article belongs to the Special Issue Novel Biomarkers and Emerging Therapeutic Targets for Breast and Gynecologic Cancers)

22 pages, 5937 KB

Open AccessArticle

A Novel Approach to Combating Antibiotic Resistance: A Chitosan-Based Nanocomposite with Green AgNPs and Gentamicin

by Mukil Madhusudanan, Priyanka Singh, Viney Ghai, Santosh Pandit, Roland Kádár and Ivan Mijakovic

Int. J. Mol. Sci. 2026, 27(2), 1036; https://doi.org/10.3390/ijms27021036 - 20 Jan 2026

Abstract

This study investigates the synthesis of silver nanoparticles (AgNPs) using Crassula ovata (Jade plant) leaf extract and their subsequent incorporation into chitosan-based nanocomposite films for enhanced antimicrobial activity against four pathogenic microorganisms: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Methicillin-resistant [...] Read more.

This study investigates the synthesis of silver nanoparticles (AgNPs) using Crassula ovata (Jade plant) leaf extract and their subsequent incorporation into chitosan-based nanocomposite films for enhanced antimicrobial activity against four pathogenic microorganisms: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Methicillin-resistant Staphylococcus aureus. Jade AgNPs were chosen for their ease of synthesis, stability, and potent antimicrobial activity. Chitosan encapsulation improved the stability of AgNPs and enhanced their interaction with bacterial cells, leading to improved bactericidal performance. The addition of gentamicin to the nanocomposite further amplified antibacterial activity, reducing the MBC values from 10 to 4 µg/mL for E. coli, 12.5 to 6 µg/mL for P. aeruginosa, 10 to 6 µg/mL for S. epidermidis, and 15 to 8 µg/mL for MRSA, compared to AgNPs alone. Mechanical characterization using dynamic mechanical analysis revealed improved robustness, with storage modulus increasing from approximately 24 MPa for chitosan-AgNPs films to 36 MPa for gentamicin-loaded nanocomposite films, while maintaining elasticity. Overall, these multifunctional nanocomposite films demonstrate strong antimicrobial activity and improved mechanical performance, supporting further evaluation as candidate materials for wound-related antimicrobial applications and localized infection control strategies. Such localized antimicrobial platforms may also contribute to strategies aimed at mitigating antibiotic resistance. Full article

(This article belongs to the Section Molecular Pharmacology)

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24 pages, 4114 KB

Open AccessArticle

A CNS-Directed, AAV9 Gene Therapy Restores Expression and Biochemical Function of Guanidinoacetate Methyltransferase in Models of GAMT Deficiency

by Robyn Binsfeld, Troy Webster, Ilona Tkachyova, Michael Tropak, Melissa Mitchell, Tesla Peretti, Andreas Schulze and Jagdeep S. Walia

Int. J. Mol. Sci. 2026, 27(2), 1035; https://doi.org/10.3390/ijms27021035 - 20 Jan 2026

Abstract

Guanidinoacetate methyltransferase (GAMT) is an essential enzyme in the biosynthesis of creatine, an important molecule in energy recycling. GAMT loss of function leads to GAMT deficiency (GAMT-D), an autosomal recessive disorder resulting in low creatine levels and the accumulation of a toxic intermediate, [...] Read more.

Guanidinoacetate methyltransferase (GAMT) is an essential enzyme in the biosynthesis of creatine, an important molecule in energy recycling. GAMT loss of function leads to GAMT deficiency (GAMT-D), an autosomal recessive disorder resulting in low creatine levels and the accumulation of a toxic intermediate, guanidinoacetate (GAA). GAMT-D patients present with intellectual disability and epilepsy, emphasizing the detrimental consequences of disturbed creatine metabolisms in the central nervous system (CNS). Current treatments are not curative and may not restore creatine metabolism in the brain. Here, we present a proof-of concept study testing the first CNS-directed, Adeno-associated virus serotype 9 (AAV9)-based gene therapy for the treatment of GAMT-D. the delivery of GAMT construct to cellular models of GAMT-D effectively restored protein and mRNA expression of GAMT while increasing intracellular creatine content and decreasing GAA accumulation. In murine models of GAMT-D, treatment with scAAV9.hGAMT, delivered intrathecally, resulted in increased creatine content as well as significant decreases in GAA accumulation in the CNS and peripheral organs. Overall, we found that scAAV9.hGAMT represents a promising gene therapy for treating GAMT-D, warranting further investigation in animal models to determine an appropriate therapeutic window for both efficacy and safety that allows for translation into human patients in the future. Full article

(This article belongs to the Special Issue Advanced Research on Nucleic Acids: Therapeutic Potential and Applications, 2nd Edition)

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20 pages, 3962 KB

Open AccessArticle

DNA Methylation Fine-Tunes Light- and Hormone-Responsive Growth Plasticity in Arabidopsis Seedlings

by Emanuela Talarico, Eleonora Greco, Adriana Chiappetta, Fabrizio Araniti and Leonardo Bruno

Int. J. Mol. Sci. 2026, 27(2), 1034; https://doi.org/10.3390/ijms27021034 - 20 Jan 2026

Abstract

DNA methylation regulates plant growth by modulating gene expression; however, its contribution to hormone responsiveness and photomorphogenesis remains only partially understood. We examined Arabidopsis thaliana DNA methylation mutants met1 and drm1, drm2, and cmt3 (ddc) under defined light regimes and following [...] Read more.

DNA methylation regulates plant growth by modulating gene expression; however, its contribution to hormone responsiveness and photomorphogenesis remains only partially understood. We examined Arabidopsis thaliana DNA methylation mutants met1 and drm1, drm2, and cmt3 (ddc) under defined light regimes and following exogenous treatments with auxin, gibberellin, and the auxin transport inhibitor TIBA. Hypocotyl elongation and cotyledon expansion exhibited strong light dependency across all genotypes, with met1 seedlings developing a consistently reduced cotyledon area and ddc seedlings displaying impaired hypocotyl elongation under specific light qualities. Exogenous auxin inhibited growth in all genotypes, whereas GA₃ promoted elongation in hypocotyls and roots (by approximately 75–80% and 15–35%, respectively, in Col0 and met1), with ddc exhibiting delayed and non-linear dose-dependent sensitivity. Quantitative RT–PCR analysis revealed differential expression of genes involved in auxin transport (PIN1, PIN3, PIN7), auxin signalling (ARF7, IAA3, LAX3), circadian regulation (TOC1, LHY, CCA1), and light signalling (PIFs, HY5, HYH), supporting a link between DNA methylation status and coordinated regulation of hormone-, light-, and clock-controlled transcriptional networks. Together, these findings demonstrate that MET1- and DRM/CMT-dependent methylation pathways integrate epigenetic regulation with environmental and hormonal cues, modulating the intensity, timing, and organ specificity of growth responses, thereby fine-tuning growth plasticity during early Arabidopsis seedling development. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Plant Sciences)

16 pages, 1210 KB

Open AccessReview

The Renin Angiotensin System: Insights into the Role of ACE2 in Glomerular Injury Including SARS-CoV-2 Infection

by Everton Smith and James Scholey

Int. J. Mol. Sci. 2026, 27(2), 1033; https://doi.org/10.3390/ijms27021033 - 20 Jan 2026

Abstract

The circulating renin–angiotensin–aldosterone system (RAAS) plays a key role in regulating blood volume and electrolyte levels. While important for the maintenance of intravascular volume systemically, the local activation of tissue RAAS and the generation of angiotensin II contribute to inflammation and fibrosis. In [...] Read more.

The circulating renin–angiotensin–aldosterone system (RAAS) plays a key role in regulating blood volume and electrolyte levels. While important for the maintenance of intravascular volume systemically, the local activation of tissue RAAS and the generation of angiotensin II contribute to inflammation and fibrosis. In the kidney, angiotensin II plays a key role in the development and progression of glomerular injury. Angiotensin-converting enzyme 2 (ACE2), an enzyme that degrades angiotensin II, is expressed in the glomerulus, focusing attention not only on the complexity of the RAAS but also identifying a potential new determinant of glomerular injury. Accordingly, we performed a narrative review using the search terms ACE2 and glomerulus in PubMed and Google Scholar to summarize the current understanding of the role of ACE2 in glomerular injury. We also discuss the role of ACE2 as a cellular receptor for SARS-CoV-2 and the potential impact of this function on glomerular injury in the setting of COVID-19. Full article

(This article belongs to the Section Molecular Biology)

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22 pages, 748 KB

Open AccessReview

The Beneficial Effects of Marine Plant-Derived Compounds on the Musculoskeletal System

by László Szabó, Áron Gere, Zsigmond Máté Kovács, Tamás Bazsó and Beatrix Dienes

Int. J. Mol. Sci. 2026, 27(2), 1032; https://doi.org/10.3390/ijms27021032 - 20 Jan 2026

Abstract

The skeletal muscle system is particularly susceptible to degenerative and inflammatory processes that threaten mobility, quality of life, and systemic health. Marine plants, including brown, red, and green algae, are valuable yet understudied sources of bioactive compounds with therapeutic potential against skeletal muscle [...] Read more.

The skeletal muscle system is particularly susceptible to degenerative and inflammatory processes that threaten mobility, quality of life, and systemic health. Marine plants, including brown, red, and green algae, are valuable yet understudied sources of bioactive compounds with therapeutic potential against skeletal muscle inflammation and degeneration. This narrative review provides the first overview of polyphenols, polysaccharides, carotenoids, and multiminerals derived from marine plants, with a particular focus on their effects on skeletal muscle, bone, and joint tissues. It highlights both the therapeutic potential and the limitations of marine plant-derived bioactive compounds in the musculoskeletal system. The compounds discussed, such as phlorotannins, ulvan, fucoidan, carotenoids, spirulina derivatives, and Aquamin, modulate key signaling pathways, including NF-κB, JAK/STAT3, and the NLRP3 inflammasome. Among these, MAPK emerges as the most consistently affected axis across all compound classes, leading to a reduction in TNF-α, IL-1β, IL-6, and oxidative stress markers. These bioactive compounds have been shown in both in vitro and in vivo models to reduce muscle catabolism, enhance osteoblast differentiation and mineralization, and reduce cartilage inflammation. Despite favorable safety, biocompatibility, and biodegradability profiles, current evidence shows that systemic applications significantly dominate over local delivery, highlighting the untapped potential of localized delivery strategies. Overall, this narrative review underscores the growing importance of marine plant-derived bioactives as promising natural agents for maintaining musculoskeletal integrity and alleviating degenerative disorders. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

18 pages, 2995 KB

Open AccessArticle

Enhanced Retinal Ganglion Cell Survival via Autophagy Activation in a Novel Retinal Ischemia/Reperfusion Rat Model

by Si Hyung Lee, Jung Woo Han, Su-ah Yoon, Hun Soo Chang and Tae Kwann Park

Int. J. Mol. Sci. 2026, 27(2), 1031; https://doi.org/10.3390/ijms27021031 - 20 Jan 2026

Abstract

Autophagy is a fundamental catabolic process that degrades and recycles intracellular components, serving as a key survival mechanism in neurons. In glaucomatous optic neuropathy, autophagy has been linked to both protection of retinal ganglion cells (RGCs) and their accelerated loss, yet its precise [...] Read more.

Autophagy is a fundamental catabolic process that degrades and recycles intracellular components, serving as a key survival mechanism in neurons. In glaucomatous optic neuropathy, autophagy has been linked to both protection of retinal ganglion cells (RGCs) and their accelerated loss, yet its precise impact remains unresolved. In this study, we established and validated a straightforward rat model of retinal ischemia/reperfusion (I/R) using double circumlimbal sutures, which reliably produced RGC apoptosis, retinal thinning, and axonal degeneration compared with controls. Early after reperfusion (1–6 h), robust induction of the autophagy marker LC3B was observed, but this activation diminished within 48 h. Other autophagy-related proteins, including ATG4, ATG7, Beclin-1, and p62, followed similar temporal patterns, while components of the mammalian target of rapamycin (mTOR) pathway displayed an inverse time course. Pharmacologic suppression of mTOR with intravitreal rapamycin administered prior to ischemia provided the most significant neuroprotection, whereas post-injury treatment yielded minimal benefit. Collectively, these findings indicate that timely stimulation of autophagy before retinal ischemic injury can enhance RGC survival and may represent a therapeutic potential for glaucoma management. Full article

(This article belongs to the Special Issue New Molecular Insights into Ischemia/Reperfusion: 2nd Edition)

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15 pages, 979 KB

Open AccessCommunication

Culture Condition-Dependent Acylation Patterns of Trichothecenes in a T-2 Toxin-Producing Strain of Fusarium sporotrichioides NBRC 9955

by Kazuyuki Maeda, Yuya Tanaka, Yuichi Nakajima, Kosuke Matsui, Yoshiaki Koizumi, Shuichi Ohsato, Naoko Takahashi-Ando and Makoto Kimura

Int. J. Mol. Sci. 2026, 27(2), 1030; https://doi.org/10.3390/ijms27021030 - 20 Jan 2026

Abstract

Fusarium sporotrichioides strain M-1-1, originally deposited as Fusarium solani IFO 9955 in 1974 and later moved to NBRC, is known for producing T-2 toxin. In addition to NRRL 3299, which was used in the United States to study T-2 toxin biosynthesis, NBRC 9955 [...] Read more.

Fusarium sporotrichioides strain M-1-1, originally deposited as Fusarium solani IFO 9955 in 1974 and later moved to NBRC, is known for producing T-2 toxin. In addition to NRRL 3299, which was used in the United States to study T-2 toxin biosynthesis, NBRC 9955 has been extensively used for trichothecene research in Japan. To facilitate and accurately document studies on trichothecene biosynthesis using NBRC 9955, its phylogenetic classification and trichothecene metabolite profiles were determined. As anticipated, NBRC 9955 was classified as F. sporotrichioides, which exhibited a more distant phylogenetic relationship to other strains within the same species. Time-course TLC analyses demonstrated the accumulation of various deacetylated trichothecenes in yeast extract-rich liquid media during the late growth stages. Conversely, an increase in 3-O-acetylation of T-2 toxin was observed at late stages when cultivated in micronutrient-poor synthetic liquid medium. Northern blot analysis revealed that Tri8 expression halted in cultures with the synthetic medium, which accounts for the growth stage-dependent 3-O-acetylation observed. On a brown rice flour solid medium, the fungal strain produced mixtures of T-2 toxin, neosolaniol, HT-2 toxin, and their 3-O-acetyl derivatives. These results highlight the risk of underestimating the levels of toxic trichothecene metabolites when using the standard contamination monitoring protocols. Full article

(This article belongs to the Special Issue Molecular Biology and Chemistry of Mycotoxins and Phytotoxins, 3rd Edition)

4 pages, 303 KB

Open AccessEditorial

Advances in the Prevention and Treatment of Ischemic Diseases

by Egor Plotnikov

Int. J. Mol. Sci. 2026, 27(2), 1029; https://doi.org/10.3390/ijms27021029 - 20 Jan 2026

Abstract

Ischemic diseases represent a broad and complex group of clinical pathologies caused by acute or chronic tissue perfusion disorders [...] Full article

(This article belongs to the Special Issue Advances in the Prevention and Treatment of Ischemic Diseases)

16 pages, 632 KB

Open AccessArticle

Impact of Predischarge NT-proBNP on Treatment Optimisation in Acute Heart Failure

by Marija Polovina, Milenko Tomić, Milica Janković, Danka Civrić, Andrea Stojićević, Stefan Stanković, Teodora Pejović, Mihajlo Viduljević, Gordana Krljanac, Milika Ašanin, Sanja Stanković and Petar M. Seferović

Int. J. Mol. Sci. 2026, 27(2), 1028; https://doi.org/10.3390/ijms27021028 - 20 Jan 2026

Abstract

Residual congestion (RC) at discharge predicts adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Its impact on the implementation of guideline-directed medical therapies (GDMT) remains unclear. N-terminal pro-B-type natriuretic peptide (NT-proBNP) trajectory during hospitalisation reflects RC and may be associated with [...] Read more.

Residual congestion (RC) at discharge predicts adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Its impact on the implementation of guideline-directed medical therapies (GDMT) remains unclear. N-terminal pro-B-type natriuretic peptide (NT-proBNP) trajectory during hospitalisation reflects RC and may be associated with GDMT implementation. The aim was to assess whether discharge NT-proBNP and a fall in NT-proBNP < 30% during hospitalisation (ΔNT-proBNP < 30%) predict GDMT underuse in acute HFrEF. In this prospective observational study, NT-proBNP was measured at hospital admission and 48–72 h before discharge. Provision of individual GDMT drug classes was assessed and GDMT underuse was defined as prescription of <3 key GDMT drug classes at discharge. 391 HFrEF patients (mean age, 69.9 ± 13.1years, 67.3% male) were included. ΔNT-proBNP < 30% was identified in 108 (27.6%). Higher discharge NT-proBNP was independently associated with lower likelihood of prescribing ACE-inhibitors, sacubitril/valsartan, eplerenone/spironolactone, or empagliflozin/dapagliflozin. ΔNT-proBNP < 30% was associated with 17% higher odds of GDMT underuse (95% confidence interval, 1.10–1.31, p < 0.001), regardless of clinical characteristics or in-hospital management. Patients with ΔNT-proBNP < 30% were discharged on lower doses of titratable GDMT medications. In-hospital NT-proBNP burden and trajectory, as markers of RC, are associated with GDMT underutilisation at discharge in acute HFrEF. Addressing RC may impact treatment quality in acute HFrEF. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Interventions in Cardiovascular Disease: 2nd Edition)

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22 pages, 6486 KB

Open AccessArticle

Regenerative Skin Remodeling by a Dual Hyaluronic Acid Hybrid Complex in Multimodal Preclinical Models

by Hyojin Roh, Ngoc Ha Nguyen, Jinyoung Jung, Jewan Kaiser Hwang, Young In Lee, Inhee Jung and Ju Hee Lee

Int. J. Mol. Sci. 2026, 27(2), 1027; https://doi.org/10.3390/ijms27021027 - 20 Jan 2026

Abstract

Skin aging arises from extracellular matrix degradation, inflammation, and pigmentation dysregulation, yet most existing rejuvenation strategies target only a subset of these processes. This study investigated the multimodal rejuvenation potential of a dual hyaluronic acid compound (DHC), composed of low- and high-molecular-weight HA [...] Read more.

Skin aging arises from extracellular matrix degradation, inflammation, and pigmentation dysregulation, yet most existing rejuvenation strategies target only a subset of these processes. This study investigated the multimodal rejuvenation potential of a dual hyaluronic acid compound (DHC), composed of low- and high-molecular-weight HA integrated within a minimally cross-linked hybrid complex. In vitro assays using dermal fibroblasts, melanoma cells, and macrophages demonstrated that DHC enhanced fibroblast viability, collagen I/III and elastin production, antioxidant enzyme activity, and wound-healing capacity while reducing senescence markers. DHC markedly suppressed melanogenesis by downregulating the gene expression of MITF, TYR, and TRP1, and exerted strong anti-inflammatory activity by decreasing nitric oxide (NO) production and key cytokines, including TNF-α, IL-1β, IL-6, and CCL1. In a UVB-induced photoaging rat model, DHC reduced wrinkle depth, epidermal thickening, and melanin accumulation while improving elasticity, collagen density, hydration, and barrier integrity. Across these outcomes, DHC demonstrated biological effects that were comparable to, and in selected endpoints greater than, those of commonly used biostimulators and HA fillers in preclinical models. Collectively, these laboratory findings suggest that DHC exhibits broad preclinical bioactivity through combined biostimulatory, antioxidant, anti-inflammatory, and pigmentation-modulating effects. Further mechanistic and clinical studies are required to determine its translational relevance. Full article

(This article belongs to the Collection Advances in Cell and Molecular Biology)

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68 pages, 4947 KB

Open AccessReview

Antithrombotic Polymers: A Narrative Review on Current and Future Strategies for Their Design, Synthesis, and Application

by Anna Smola-Dmochowska, Natalia Śmigiel-Gac, Katarzyna Jelonek, Kamila Lewicka-Brzoza, Jakub Bojdol and Piotr Dobrzyński

Int. J. Mol. Sci. 2026, 27(2), 1026; https://doi.org/10.3390/ijms27021026 - 20 Jan 2026

Abstract

Bleeding and thromboembolism are among the leading causes of mortality worldwide. Thrombosis encompasses both arterial forms—primarily associated with atherosclerosis and leading to heart attacks or strokes—and venous forms. Microvascular thrombosis typically arises in the context of sepsis or systemic inflammation, and it became [...] Read more.

Bleeding and thromboembolism are among the leading causes of mortality worldwide. Thrombosis encompasses both arterial forms—primarily associated with atherosclerosis and leading to heart attacks or strokes—and venous forms. Microvascular thrombosis typically arises in the context of sepsis or systemic inflammation, and it became particularly prominent during the COVID-19 pandemic, substantially contributing to increased mortality. Given this burden, the rapid development of new therapies using advanced techniques and materials to prevent and treat these conditions is essential. This review summarizes recent advances in the design of antithrombotic polymers, discussing mechanisms of action, surface-modification strategies, and current clinical and preclinical applications. It also outlines criteria for evaluating hemocompatibility, describes in vitro and in vivo testing methods, and highlights key barriers to translating these materials into clinical practice. The review concludes by identifying promising directions for future research, including multifunctional approaches that combine antifouling properties, controlled drug release, and bioresistance strategies with the greatest potential to reduce thromboembolic complications associated with medical materials. It further evaluates the progress made to date in combating thrombotic diseases and identifies remaining gaps in the development and clinical implementation of new antithrombotic materials. Full article

(This article belongs to the Special Issue Next-Generation Therapeutic Polymers: From Molecular Design to Dual Antibacterial/Antithrombotic Action)

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32 pages, 1030 KB

Open AccessReview

Antibody–Drug Conjugates in Hematological Malignancies: Current Landscape and Future Perspectives

by Maria Chiara Montalbano, Matilde Micillo, Silvia Deaglio and Tiziana Vaisitti

Int. J. Mol. Sci. 2026, 27(2), 1025; https://doi.org/10.3390/ijms27021025 - 20 Jan 2026

Abstract

The therapeutic landscape for hematological malignancies has been fundamentally revolutionized over the last decade by the introduction of targeted antibodies. Notably, antibody–drug conjugates (ADCs) have emerged as a critical breakthrough, significantly improving the efficacy of immune-based treatment. ADCs function as highly sophisticated delivery [...] Read more.

The therapeutic landscape for hematological malignancies has been fundamentally revolutionized over the last decade by the introduction of targeted antibodies. Notably, antibody–drug conjugates (ADCs) have emerged as a critical breakthrough, significantly improving the efficacy of immune-based treatment. ADCs function as highly sophisticated delivery systems: a selective monoclonal antibody recognizes a specific cell-surface target, guiding a potent toxic payload, attached via a chemical linker, directly into the cancer cell upon internalization. Intensive research has been dedicated to optimizing these components—improving antibody selectivity, enhancing linker stability, and utilizing highly effective payloads—which has resulted in a plethora of compounds that have reached patients’ bedsides and improved the clinical course of different tumors. This review provides a crucial overview of the current landscape of approved ADCs for hematological malignancies. It critically discusses their existing limitations and details the essential structural and chemical improvements that have yielded more potent and selective next-generation tools, finally presenting future strategies to generate highly effective “bullets” capable of decisively improving long-term disease prognosis. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)

14 pages, 3504 KB

Open AccessArticle

Mechanisms of Tetramycin-Induced Resistance to Rice Blast Disease in Oryza sativa L.

by Hui Jiang, Caixia Zhao, Danting Li, Kai Sun, Yipeng Xu, Kun Pang, Xiaoping Yu and Xuping Shentu

Int. J. Mol. Sci. 2026, 27(2), 1024; https://doi.org/10.3390/ijms27021024 - 20 Jan 2026

Abstract

Rice blast, caused by the fungus Magnaporthe oryzae, is a devastating disease that threatens global food security, causing annual yield losses of 10–30%. Consequently, novel control strategies beyond conventional fungicides are urgently needed. Tetramycin, a polyene macrolide antibiotic, is known for its [...] Read more.

Rice blast, caused by the fungus Magnaporthe oryzae, is a devastating disease that threatens global food security, causing annual yield losses of 10–30%. Consequently, novel control strategies beyond conventional fungicides are urgently needed. Tetramycin, a polyene macrolide antibiotic, is known for its broad-spectrum antifungal activity. However, the specific mechanisms underlying its efficacy against rice blast remain to be fully elucidated. In this study, we demonstrate that tetramycin confers resistance through a dual mode of action. First, in vitro assays revealed that tetramycin directly inhibits M. oryzae mycelial growth. Second, and more critically, it functions as a potent immune elicitor in Oryza sativa. Transcriptome analysis coupled with physiological assays showed that tetramycin treatment triggers a rapid oxidative burst, characterized by significantly elevated activities of key defense enzymes, including superoxide dismutase, peroxidase, phenylalanine ammonia lyase, and polyphenol oxidase (PPO). This oxidative response is further orchestrated through the simultaneous activation of the jasmonic acid (JA) and salicylic acid (SA) signaling pathways, as evidenced by the distinct upregulation of their respective biosynthetic genes and hormone levels. Collectively, these findings indicate that tetramycin not only acts as a direct fungicide but also primes the rice innate immune system via a synergistic reactive oxygen species-JA-SA signaling network, offering a sustainable strategy for rice blast management. Full article

(This article belongs to the Section Molecular Plant Sciences)

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18 pages, 6891 KB

Open AccessArticle

Single-Nucleus Transcriptional Profiling Revealed Cell Diversity and Albino Mutation Mechanism in the Skin of Channa argus

by Lu Zhang, Jian Zhou, Qiang Li, Hongyu Ke, Zhipeng Huang, Zhongmeng Zhao, Han Zhao, Chengyan Mou, Wei Fan and Yuanliang Duan

Int. J. Mol. Sci. 2026, 27(2), 1023; https://doi.org/10.3390/ijms27021023 - 20 Jan 2026

Abstract

Body color is the most prominent phenotypic trait in animals. To investigate the molecular regulatory mechanisms underlying skin pigmentation and body color in Channa argus, single-nucleus RNA sequencing technology was employed to analyze cell diversity and functional changes in the skin of [...] Read more.

Body color is the most prominent phenotypic trait in animals. To investigate the molecular regulatory mechanisms underlying skin pigmentation and body color in Channa argus, single-nucleus RNA sequencing technology was employed to analyze cell diversity and functional changes in the skin of normal and albino C. argus. Three pigment-related cell types, seven immune-related cell types, and nine other skin-related structural and functional cell types were identified. The skin of albino C. argus, which appears white to the naked eye, contains numerous melanocytes and iridophores with reflective silver properties. Compared to normal C. argus, melanocytes in albino individuals contained fewer melanin granules, while iridophores exhibited increased chromogenic substances. Melanocyte-specific genes—kitlg, myo5a, and scarb1—were significantly downregulated in albino melanocytes (p < 0.05). Conversely, iridophore-specific genes alk, pnp, and gpnmb were significantly upregulated in albino skin, whereas mlph was significantly downregulated (p < 0.05). Weighted gene co-expression network analysis revealed that scarb1 was associated with the melanocyte module, alk was identified as a core gene, and pnp was linked to the iridophore module. Functionally, scarb1 is involved in pigment transport, pnp in purine synthesis, and alk is essential for iridophore development. Therefore, scarb1, pnp, and alk may be correlated to albinism in C. argus. Overall, this study constructed a single-cell transcriptional atlas of C. argus skin, providing valuable reference data for further research into the regulatory mechanisms governing body color formation and maintenance in this species. Full article

(This article belongs to the Topic Single-Cell Technologies: From Research to Application)

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24 pages, 8647 KB

Open AccessArticle

Mechanical Insights into the Distinct Effects of Ovariectomy Versus Adrenalectomy on Age-Related Thymic Atrophy in Female Mice

by Junan Chen, Xudong Zhou, Ling Wei, Zixuan Tian, Haozhe Zeng, Fei Yan, Junhua Zhou, Xianyin Zeng, Fengyan Meng, Xiaohan Cao, Haozhou Li and Xingfa Han

Int. J. Mol. Sci. 2026, 27(2), 1022; https://doi.org/10.3390/ijms27021022 - 20 Jan 2026

Abstract

Age-related thymic atrophy, a hallmark of immunosenescence linked to age-related diseases, involves gonadal and adrenal steroid hormones, but their distinct roles and mechanisms in this process remain unclear. Through biochemical, histological, and RNA-seq analyses, we comprehensively explored the mechanisms underpinning age-related thymic atrophy [...] Read more.

Age-related thymic atrophy, a hallmark of immunosenescence linked to age-related diseases, involves gonadal and adrenal steroid hormones, but their distinct roles and mechanisms in this process remain unclear. Through biochemical, histological, and RNA-seq analyses, we comprehensively explored the mechanisms underpinning age-related thymic atrophy in response to ovariectomy (OVX) versus adrenalectomy (ADX) in female mice. Compared to the sham controls, OVX overtly ameliorated age-related thymic atrophy, as evidenced by increased thymus mass, a larger gross thymus area, and denser cortex cellularity. In contrast, ADX evidently accelerated age-related thymic atrophy, characterized by increased adipose infiltration and decreased cortex/medulla ratio, obscure cortico-medullary junctions, and sparser thymic cortical cells. Unexpectedly, combined OVX and ADX displayed a more pronounced effect than OVX alone in ameliorating age-related thymic atrophy. Mechanistically, OVX decreased while ADX increased the circulating 17β-estradiol levels in female mice, which drove these opposing outcomes potentially by promoting Pparg-mediated thymic fat deposition and blocking Cdk1-dependent thymocyte cell cycle progression. Although OVX eliminated gonadal 17β-estradiol production, it appeared to trigger a compensatory adrenal-dependent estrogen biosynthesis, whereas combined OVX and ADX nearly eliminated all estrogen sources, thus leading to a more pronounced effect than OVX alone in ameliorating age-related thymic atrophy in female mice. Notably, OVX increased while ADX decreased serum corticosterone levels, but these alterations exerted minimal impacts on age-related thymic atrophy, highlighting a pivotal role of estrogens over glucocorticoids in accelerating age-related thymic atrophy in females. Undesirably, although OVX ameliorated age-related thymic atrophy, it appeared to simultaneously increase autoimmune susceptibility by downregulating thymic Cd74 expression. Taken together, our results indicate that OVX ameliorates while ADX accelerates age-related thymic atrophy in females. Estrogens rather than glucocorticoids act as the predominant regulator of this process, potentially via promoting Pparg-dependent fat deposition and blocking Cdk1-dependent thymocyte cycle progression. However, OVX-induced estrogen depletion also elevated autoimmune risk, emphasizing the need to balance benefits and risks in regulating thymic aging. Full article

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

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