International Journal of Molecular Sciences

28 pages, 1389 KB

Open AccessReview

Charting the Future: Advanced Technologies for Sustainable Parasite Control in Aquaculture

by Jiao Yang, Subha Bhassu and Arutchelvan Rajamanikam

Int. J. Mol. Sci. 2025, 26(21), 10738; https://doi.org/10.3390/ijms262110738 (registering DOI) - 4 Nov 2025

Parasite control in aquaculture faces challenges primarily due to the drug resistance of traditional chemical treatments, as well as environmental pollution and toxicity. Aquaculture is among the fastest-growing food-producing sectors worldwide, yet parasite infections remain a significant challenge to productivity and sustainability. Emerging [...] Read more.

Parasite control in aquaculture faces challenges primarily due to the drug resistance of traditional chemical treatments, as well as environmental pollution and toxicity. Aquaculture is among the fastest-growing food-producing sectors worldwide, yet parasite infections remain a significant challenge to productivity and sustainability. Emerging methods such as natural products, gene editing, immunotherapy, and auxiliary technologies like nanotechnology and biosensors are becoming alternative strategies for sustainable parasite control. These methods show significant potential, particularly in preventing drug resistance and reducing environmental impact. However, these approaches remain at an early research stage, with issues such as unstable efficacy, limited validation in field conditions and uncertain long-term safety hindering their translation into practice. This review synthesizes current advances, highlights these knowledge and application gaps, and outlines future directions for developing more reliable and sustainable parasite management strategies in aquaculture. Full article

(This article belongs to the Section Molecular Biology)

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15 pages, 2172 KB

Open AccessArticle

Placenta-Derived Secretions Promote Liver Dysfunction, and Hepatic Serum Amyloid A Mediates Kidney Inflammatory Response in a Preeclampsia-like Mouse Model

by Ren Ozawa, Sae Suzuki, Ayaka Shirota, Shota Nomura, Takanori Komada, Masafumi Takahashi, Hisataka Iwata and Koumei Shirasuna

Int. J. Mol. Sci. 2025, 26(21), 10737; https://doi.org/10.3390/ijms262110737 (registering DOI) - 4 Nov 2025

Abstract

Preeclampsia (PE) is characterized by maternal hypertension accompanied with multi-organ dysfunction, such as maternal hepatic and renal dysfunction. Abnormal placental conditions may play a key role in regulating maternal organ function by promoting systemic inflammation. This study aimed to test the hypothesis that [...] Read more.

Preeclampsia (PE) is characterized by maternal hypertension accompanied with multi-organ dysfunction, such as maternal hepatic and renal dysfunction. Abnormal placental conditions may play a key role in regulating maternal organ function by promoting systemic inflammation. This study aimed to test the hypothesis that placenta-derived secretions contribute to hepatic and renal injury through interorgan communication using a PE-like mouse model. Pregnant mice were infused with angiotensin II (Ang II) from gestational day (GD) 12 (GD1 defined as the day of plug detection). Ang II infusion induced maternal hypertension, as well as liver injury (elevated serum amyloid A [SAA] secretion and alanine aminotransferase levels) and kidney injury (tubular damage with KIM-1 protein expression and immune cell infiltration). Treatment with placental-conditioned medium (CM) from Ang II-infused mice, but not from the control mice, stimulated SAA expression in liver cells. On the other hand, the effects of placental-CM from both the control and Ang II groups on kidney tubular cells were comparable. These findings suggest that placenta-derived secretions in the Ang II-induced PE-like phenotype specifically promote excessive SAA production in the liver. Furthermore, SAA administration in pregnant mice did not cause tubular injury but did promote renal immune cell infiltration, indicating that elevated hepatic SAA levels may contribute to maternal kidney inflammation. Taken together, these results suggest the presence of an in vivo organ network involving the placenta, liver, and kidneys during pregnancy, where dysfunction in one organ may exacerbate the pathogenesis of PE. Full article

(This article belongs to the Special Issue Molecular and Cellular Research in Pregnancy-Related Complications, 2nd Edition)

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29 pages, 1046 KB

Open AccessReview

Pharmacological and Biological Efficacy of Chitosan-Based Materials

by Anathi Dambuza, Pennie P. Mokolokolo, Mamookho E. Makhatha and Motshabi A. Sibeko

Int. J. Mol. Sci. 2025, 26(21), 10735; https://doi.org/10.3390/ijms262110735 (registering DOI) - 4 Nov 2025

Abstract

Chitosan (CS) is a biodegradable and biocompatible polysaccharide, obtained by the deacetylation of chitin. It has gained significant attention as a versatile material for biomedical applications due to its mucoadhesive properties, ease of chemical modification and intrinsic pharmacological activities. This review synthesizes two [...] Read more.

Chitosan (CS) is a biodegradable and biocompatible polysaccharide, obtained by the deacetylation of chitin. It has gained significant attention as a versatile material for biomedical applications due to its mucoadhesive properties, ease of chemical modification and intrinsic pharmacological activities. This review synthesizes two decades (2005–2025) of literature, focusing on chemical modifications of chitosan for pharmacological purposes and their therapeutic implications in non-communicable diseases (NCDs) and wound healing. Evidence highlights the roles of chitosan-based materials in anticancer, anti-inflammatory, antidiabetic, antihypertensive, and neuroprotective activities, alongside their integration in advanced wound healing strategies. Clinical trials have demonstrated the translational potential of chitosan-based materials. In general, chitosan-based materials exhibit promising dual functions as bioactive agents and drug carriers, necessitating additional investigation in clinical and regulatory frameworks to accelerate therapeutic adoption. In contrast to other studies, this study offers a mechanistic and integrative viewpoint that links chitosan’s chemical modification techniques with their pharmacological effects and clinical translation potential, providing novel perspectives on structure–activity correlations and therapeutic design. Full article

(This article belongs to the Special Issue Anti-Cancer, Anti-Inflammatory, and Antioxidation Active Substances: 3rd Edition)

13 pages, 4972 KB

Open AccessArticle

Mechanistic Insights into Tyrosinase-Catalyzed Metabolism of Hydroquinone: Implications for the Etiology of Exogenous Ochronosis and Cytotoxicity to Melanocytes

by Shosuke Ito, Ludger Kolbe, Tamara Rogers, Tobias Mann, Gudrun Weets, Hitomi Tanaka, Tomoko Nishimaki-Mogami, Thierry Passeron, Makoto Ojika and Kazumasa Wakamatsu

Int. J. Mol. Sci. 2025, 26(21), 10734; https://doi.org/10.3390/ijms262110734 (registering DOI) - 4 Nov 2025

Abstract

The metabolism of hydroquinone (HQ) by tyrosinase presents significant biochemical and dermatological challenges, particularly due to its association with adverse effects such as exogenous ochronosis (EO). Despite its widespread use in skin-lightening products, the detailed mechanistic pathways of HQ metabolism by tyrosinase remain [...] Read more.

The metabolism of hydroquinone (HQ) by tyrosinase presents significant biochemical and dermatological challenges, particularly due to its association with adverse effects such as exogenous ochronosis (EO). Despite its widespread use in skin-lightening products, the detailed mechanistic pathways of HQ metabolism by tyrosinase remain inadequately understood. This study aims to elucidate the mechanistic insights into the tyrosinase-catalyzed metabolism of HQ, leading to the production of HQ-eumelanin (HQ-EM) and HQ-pheomelanin (HQ-PM). We employed HPLC analysis to detect key intermediates and final metabolites. Results show that mushroom tyrosinase catalyzes the hydroxylation of HQ to 2-hydroxyhydroquinone (HHQ) via the 2-hydroxybenzoquinone (HBQ) pathway, giving rise to HQ-EM. However, in the presence of cysteine, a shift from HBQ to the benzoquinone (BQ) pathway occurs, giving rise to HQ-PM. Hydroiodic acid hydrolysis of HQ-PM and subsequent HPLC-electrochemical analysis identified 4-aminophenol (AP) as degradation product, thereby serving as a novel marker to monitor HQ oxidation in vitro. These results indicate that HQ functions both as a “pseudo” substrate for tyrosinase—undergoing redox exchange with dopaquinone to form BQ—and as a true substrate, yielding HBQ. This dual role contributes to the formation of HQ-EM and HQ-PM. It would be possible that EO is caused by a continuous oxidation of HQ mediated by tyrosinase activity in the skin. Full article

(This article belongs to the Special Issue Melanin Pigmentation: Physiology and Pathology)

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59 pages, 3216 KB

Open AccessReview

The Current State of Research in the Field of Photosensitizers and Photoactivators for Photodynamic/Photothermal Cancer Therapy: A Review

by Pavel Yudaev, Yulia Aleksandrova, Elena Chugunova and Margarita Neganova

Int. J. Mol. Sci. 2025, 26(21), 10733; https://doi.org/10.3390/ijms262110733 (registering DOI) - 4 Nov 2025

Abstract

This review is devoted to research in the field of photodynamic and photothermal therapies for malignant tumors. Special attention in the review is given to photosensitizers based on compounds with a tetrapyrrole ring system, their metal complexes, BODIPY and aza-BODIPY derivatives, squaraines, and [...] Read more.

This review is devoted to research in the field of photodynamic and photothermal therapies for malignant tumors. Special attention in the review is given to photosensitizers based on compounds with a tetrapyrrole ring system, their metal complexes, BODIPY and aza-BODIPY derivatives, squaraines, and photoactivators based on metal complexes with other ligands such as phenanthroline and its derivatives, metronidazole, pyridine, and imidazole derivatives. Additionally, the review considers nanosized carriers for photosensitizers, such as organic and inorganic nanoparticles, liposomes, and extracellular vesicles. This review also discusses the dark toxicity and phototoxicity of these compounds and the processes of free oxygen radical formation, mitochondrial dysfunction, and induction of apoptosis in cancer cells. It has been established that nanoscale delivery systems are more promising for use in photodynamic and photothermal therapy compared to molecular photosensitizers. This is due to their improved solubility in physiological environments, selective accumulation in tumors, prolonged photoactivity, and lower therapeutic dose, which allows for the minimization of the side effects of treatment. Among the molecular photosensitizers under consideration, amphiphilic tetrapyrroles appear to be the most promising. Specifically, tetrapyrrole complexes of indium (III) and iridium (III) with non-porphyrin ligands exhibit favorable photophysical and biological characteristics. The review also indicates that photosensitizers tend to localize in the mitochondria of tumor cells, contributing to oxidative stress and apoptosis activation. This review may be of interest to biochemists and oncologists. Full article

(This article belongs to the Special Issue Anti-Cancer, Anti-Inflammatory, and Antioxidation Active Substances: 3rd Edition)

17 pages, 966 KB

Open AccessArticle

Assessing the Functional Significance of Novel and Rare Variants of the SLC26A4 Gene Found in Patients with Hearing Loss by Minigene Assay

by Valeriia Yu. Danilchenko, Ekaterina A. Panina, Marina V. Zytzar, Konstantin E. Orishchenko and Olga L. Posukh

Int. J. Mol. Sci. 2025, 26(21), 10732; https://doi.org/10.3390/ijms262110732 (registering DOI) - 4 Nov 2025

Abstract

The SLC26A4 gene is one of the key genes involved in the etiology of hearing loss. It encodes pendrin, a transmembrane transporter protein functioning as a multifunctional anion exchanger. About 600 pathogenic SLC26A4 variants are known to cause either nonsyndromic recessive hearing loss [...] Read more.

The SLC26A4 gene is one of the key genes involved in the etiology of hearing loss. It encodes pendrin, a transmembrane transporter protein functioning as a multifunctional anion exchanger. About 600 pathogenic SLC26A4 variants are known to cause either nonsyndromic recessive hearing loss (DFNB4) or Pendred syndrome (hearing loss and thyroid dysfunction). While most pathogenic variants occur in coding regions and disrupt pendrin structure or function, about 25% are thought to impair splicing. For many, pathogenicity has been assessed only in silico, with limited experimental confirmation. We identified several novel and rare SLC26A4 variants in patients with hearing loss from the Tyva and Altai Republics (Southern Siberia, Russia). Based on splicing predictions, six variants—intronic c.2034+1G>A, c.1545-168A>G, c.1708-125T>C, c.1708-18T>A, c.1804-31C>T, and exonic c.942A>G—were selected for analysis using a minigene assay. The results of in vitro analysis only partially matched in silico predictions: c.2034+1G>A caused aberrant splicing; c.1708-18T>A led to exon 16 skipping only in a small proportion of transcripts; the remaining variants showed no detectable splicing effect. These findings underscore the need for integrating in silico predictions with in vitro validation to accurately assess the functional impact of genetic variants, enabling their correct interpretation and reliable molecular diagnosis. Full article

(This article belongs to the Section Molecular Biology)

45 pages, 8431 KB

Open AccessArticle

In Silico Integrated Systems Biology Analysis of Gut-Derived Metabolites from Philippine Medicinal Plants Against Atopic Dermatitis

by Legie Mae Soriano, Kumju Youn and Mira Jun

Int. J. Mol. Sci. 2025, 26(21), 10731; https://doi.org/10.3390/ijms262110731 (registering DOI) - 4 Nov 2025

Abstract

Atopic dermatitis (AD) is a multifactorial skin disorder characterized by immune and barrier dysfunction. The gut–skin axis is a bidirectional pathway through which gut and skin influence each other via microbial metabolites. Bioactive metabolites produced by microbial transformation of phytochemicals show potential for [...] Read more.

Atopic dermatitis (AD) is a multifactorial skin disorder characterized by immune and barrier dysfunction. The gut–skin axis is a bidirectional pathway through which gut and skin influence each other via microbial metabolites. Bioactive metabolites produced by microbial transformation of phytochemicals show potential for AD prevention. This study developed a computational systems biology pipeline that prioritized gut-derived metabolites from Philippine medicinal plants by integrating metabolite prediction, pharmacokinetics, network analysis, and molecular simulations. From 2231 predicted metabolites, 31 satisfied pharmacological criteria and were mapped to 199 AD-associated targets, with ALB, CASP3, and PPARG identified as hub genes. Two metabolites, THPOC and PM38, exhibited complementary target affinities and strong binding stability. THPOC stabilized ALB and CASP3, supporting barrier integrity and apoptosis regulation, while PM38 strongly engaged PPARG, modulating lipid metabolism and anti-inflammatory transcription. They exhibited comparable or superior docking scores, stable MD interactions, and favorable binding free energies, compared to abrocitinib, an approved AD treatment. DFT analysis confirmed electronic stability and donor–acceptor properties linked to target selectivity. These findings highlight THPOC and PM38 as promising immunometabolic modulators acting on key AD-related pathways. Collectively, this study introduces a reproducible systems-based computational discovery framework, offering a novel preventive strategy for AD. Full article

(This article belongs to the Special Issue New Insights into Network Pharmacology)

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12 pages, 5310 KB

Open AccessArticle

Overexpression of miR-320-3p, miR-381-3p, and miR-27a-3p Suppresses Genes Related to Midline Facial Cleft in Mouse Cranial Neural Crest Cells

by Chihiro Iwaya, Akiko Suzuki and Junichi Iwata

Int. J. Mol. Sci. 2025, 26(21), 10730; https://doi.org/10.3390/ijms262110730 - 4 Nov 2025

Abstract

Midline facial clefts are severe craniofacial defects that occur due to an underdeveloped frontonasal process. While genetic studies in mice have identified several genes that are crucial for midfacial development, the interactions and regulatory mechanisms of these genes during development remain unclear. In [...] Read more.

Midline facial clefts are severe craniofacial defects that occur due to an underdeveloped frontonasal process. While genetic studies in mice have identified several genes that are crucial for midfacial development, the interactions and regulatory mechanisms of these genes during development remain unclear. In this study, we conducted a systematic review and database search to curate genes associated with midline facial clefts in mice. We identified a total of 78 relevant genes, which included 69 single-gene mutant mice, nine spontaneous models, and 20 compound mutant mice. We then performed bioinformatic analyses with these genes to identify candidate microRNAs (miRNAs) that may regulate the expression of genes related to midline facial clefts. Furthermore, we experimentally evaluated the four highest-ranking candidates—miR-320-3p, miR-381-3p, miR-27a-3p, and miR-124-3p—in O9-1 cells. Our results indicated that overexpression of any of these miRNAs inhibited cell proliferation through the suppression of genes associated with midline facial clefts. Thus, our results suggest that miR-320-3p, miR-381-3p, miR-27a-3p, and miR-124-3p are involved in the cause of midline facial anomalies. Full article

(This article belongs to the Special Issue MicroRNA and Non-Coding RNA: From Basic Research to Potential Clinical Application)

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15 pages, 1912 KB

Open AccessReview

Artificial Intelligence in Histopathological Analysis for Predicting Immunotherapy Response in Cutaneous Melanoma

by Seungah Yoo and Ji Hyun Lee

Int. J. Mol. Sci. 2025, 26(21), 10729; https://doi.org/10.3390/ijms262110729 - 4 Nov 2025

Abstract

Artificial intelligence (AI) has emerged as a transformative tool in histopathology, offering new opportunities to enhance prognostic accuracy and guide immunotherapy in cutaneous melanoma. The prognostic significance of tumor-infiltrating lymphocytes (TILs) is well established, yet their manual assessment remains subjective, labor-intensive, and often [...] Read more.

Artificial intelligence (AI) has emerged as a transformative tool in histopathology, offering new opportunities to enhance prognostic accuracy and guide immunotherapy in cutaneous melanoma. The prognostic significance of tumor-infiltrating lymphocytes (TILs) is well established, yet their manual assessment remains subjective, labor-intensive, and often confined to selected tissue regions. Recent AI-based approaches enabled automated and reproducible quantification of TIL density and spatial immune profiling across whole-slide images, providing a more comprehensive view of the tumor immune microenvironment. In melanoma, these methods have demonstrated the potential to predict response to immune checkpoint blockade, with spatially resolved TIL profiling emerging as a particularly powerful prognostic and predictive biomarker. This review summarizes recent advances in AI-driven histopathologic analysis of cutaneous melanoma, focusing on automated TIL quantification and spatial immune profiling, and highlights how these innovations refine prognostic evaluation and improve the prediction of immunotherapy outcomes. Full article

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

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15 pages, 2301 KB

Open AccessArticle

Steroid Hydroxylation by Mutant Cytochrome P450 BM3-LG23 Using Two Expression Chassis

by Veronika Poshekhontseva, Vera Nikolaeva, Andrey Shutov, Alexey Kazantsev, Olesya Sazonova, Nicolai Strizhov and Marina Donova

Int. J. Mol. Sci. 2025, 26(21), 10728; https://doi.org/10.3390/ijms262110728 - 4 Nov 2025

Abstract

The unique cytochrome P450 BM3 from Priestia megaterium (syn. Bacillus megaterium) is renowned for its versatile high catalytic activity. The cyp102A1-LG23 gene encoding its CYP102A1-LG23 mutant variant was expressed in Escherichia coli and Mycolicibacterium smegmatis. The in vivo activity of the [...] Read more.

The unique cytochrome P450 BM3 from Priestia megaterium (syn. Bacillus megaterium) is renowned for its versatile high catalytic activity. The cyp102A1-LG23 gene encoding its CYP102A1-LG23 mutant variant was expressed in Escherichia coli and Mycolicibacterium smegmatis. The in vivo activity of the heterologous enzyme was assessed with respect to androstenedione (AD), androstadienedione (ADD), testosterone (TS) and dehydroepiandrosterone (DHEA). Alongside 7β-hydroxylation, the heterologous enzyme catalyzed the mono- and dihydroxylation of C19 steroids. For the first time, the formation of 7β-, 6β- and 11α-hydroxylated derivatives of ADD using a bacterial enzyme, as well as the hydroxylation of DHEA at the C7α and C7β positions, and its dihydroxylation with the formation of the 7α,15α-dihydroxylated derivative using the mutant cytochrome P450 BM3 were demonstrated. The steroid structures were confirmed using mass spectrometry and ¹H NMR spectroscopy. The advantages of using mycolicibacteria as a bacterial chassis for gene expression were also shown. The results demonstrate the unusual properties of the mutant cytochrome P450 BM3-LG23 and open up prospects for its application in the biotechnological production of valuable hydroxysteroids. Full article

(This article belongs to the Special Issue Cytochrome P450: Metabolism, Structure-Function, Evolution and Applications)

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21 pages, 1541 KB

Open AccessArticle

Comparative Analysis of Genetic Risk for Viral-Induced Axonal Loss in Genetically Diverse Mice

by Tae Wook Kang, Aracely Perez-Gomez, Koedi Lawley, Colin R. Young, C. Jane Welsh and Candice L. Brinkmeyer-Langford

Int. J. Mol. Sci. 2025, 26(21), 10727; https://doi.org/10.3390/ijms262110727 - 4 Nov 2025

Abstract

Among mouse models of neurological disease, Theiler’s murine encephalomyelitis virus (TMEV) provides a unique platform by using a naturally occurring viral trigger, paralleling the role of infections like Epstein–Barr virus in multiple sclerosis (MS). Just as not all individuals with predisposing viral infections [...] Read more.

Among mouse models of neurological disease, Theiler’s murine encephalomyelitis virus (TMEV) provides a unique platform by using a naturally occurring viral trigger, paralleling the role of infections like Epstein–Barr virus in multiple sclerosis (MS). Just as not all individuals with predisposing viral infections develop the same neurological disease, not all mouse strains develop the same diseases following TMEV infection, so susceptibility is dictated by genetic background. For example, certain sets of alleles, called haplotypes, of the major histocompatibility complex (MHC) region have been associated with susceptibility to TMEV-induced demyelination (TVID) and MS. However, our previous work revealed that these MHC susceptibility haplotypes are not the sole contributors to TMEV-induced diseases in all mice. We infected mice from the genetically diverse Collaborative Cross (CC), a resource designed to reflect human population-level genetic variation. All 15 CC strains tested exhibited some form of neurological phenotype or CNS lesion following TMEV infection. However, chronic radiculoneuropathy characterized by axonal degeneration with myelin loss was observed in the CNS of only two strains, CC002 and CC023, which had markedly different immune responses and clinical profiles throughout the course of infection. Moreover, the pathology seen in CC002 and CC023 was not the same as what is typically seen in TVID. We used previous results from RNA sequencing of the hippocampus and spinal cord to test our hypothesis that myelin loss in these strains resulted from the convergent biological effects of multiple genetic risk variants, many previously unassociated with TMEV-induced diseases. These findings identify novel genetic targets and demonstrate the utility of genetically diverse models for uncovering complex neuroimmune interactions. Full article

(This article belongs to the Special Issue Latest Advances in Comparative Genomics)

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14 pages, 2333 KB

Open AccessArticle

Identification of Small Molecules as Zika Virus Entry Inhibitors

by Abhijeet Roy, Hansam Cho, Kristin V. Lyles, Wen Lu, Ming Luo, Asim K. Debnath and Lanying Du

Int. J. Mol. Sci. 2025, 26(21), 10726; https://doi.org/10.3390/ijms262110726 - 4 Nov 2025

Abstract

Zika virus (ZIKV) caused Zika outbreaks and continues to post threats to public health. ZIKV infection may cause congenital abnormalities during pregnancy and neurological manifestations in adults. The recurrent public health threat of Zika in various geographical areas demonstrates a need for the [...] Read more.

Zika virus (ZIKV) caused Zika outbreaks and continues to post threats to public health. ZIKV infection may cause congenital abnormalities during pregnancy and neurological manifestations in adults. The recurrent public health threat of Zika in various geographical areas demonstrates a need for the development of effective therapeutics. Currently, there are no approved therapies for Zika. ZIKV is a single-stranded, positive-sense RNA virus, whose genome encodes three structural proteins and seven non-structural proteins. The surface envelope (E) protein is essential for host–cell recognition and viral entry; therefore, inhibition of E-mediated viral entry is a key strategy underlying antiviral treatments. Here, molecular docking-based virtual screening was used to screen small-molecule compound libraries to identify potential ZIKV entry inhibitors. Among the compounds identified, Pyrimidine-Der1 exhibited efficient inhibition of reporter ZIKV infection. The microscale thermophoresis assay confirmed its binding with the ZIKV E protein. This compound has effective inhibition of authentic ZIKV infection in a plaque inhibition assay against R103451, PAN2016, and FLR human strains (IC₅₀: ~3–5 μM). Additionally, it efficiently inhibited ZIKV infection at viral entry and fusion steps of the virus life cycle in a time-of-addition assay. Overall, Pyrimidine-Der1 is a promising ZIKV entry inhibitor, warranting further optimization and evaluation. Full article

(This article belongs to the Special Issue Small Molecule Drug Design and Research: 3rd Edition)

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25 pages, 7207 KB

Open AccessArticle

Feeding for Well-Being: Porcine Blood Hydrolysate Supplementation Improves Metabolic and Welfare-Related Traits in Farmed Gilthead Sea Bream (Sparus aurata)

by Cristina Moreno-Mariscal, Paul Holhorea, Federico Moroni, Leticia Mora, Fidel Toldrá and Jaume Pérez-Sánchez

Int. J. Mol. Sci. 2025, 26(21), 10725; https://doi.org/10.3390/ijms262110725 - 4 Nov 2025

Abstract

The revalorization of animal by-products, such as porcine blood, is a key strategy for sustainable aquaculture and circular economy practices. This study aimed to fill the existing knowledge gap on the effects of spray-dried porcine blood hydrolysate (PBSH), assessing its potential as a [...] Read more.

The revalorization of animal by-products, such as porcine blood, is a key strategy for sustainable aquaculture and circular economy practices. This study aimed to fill the existing knowledge gap on the effects of spray-dried porcine blood hydrolysate (PBSH), assessing its potential as a functional feed ingredient for gilthead sea bream. Two practical diets were formulated: a control diet containing 5% blood meal, and a PBSH diet including 5% PBSH previously characterized in vitro. The results indicated that the PBSH diet promoted lower hepatosomatic index, a down-regulation of key hepatic lipogenic enzymes (scd1b, hl, lpl), and a better stress condition with lower circulating levels of glucose and cortisol and a reduction in aggressive attacks. Positive findings were also achieved in energy management, obtaining lower metabolic rates along with an enhanced swimming performance (20% increase in the critical speed) and a quicker weigh recovery after a fasting period. The PBSH diet also shaped the intestinal bacterial composition, determining a redistribution of abundant genera including Aureimonas and Halomonas. Ultimately, this study demonstrated that PBSH would act as a functional ingredient capable of enhancing fish energy management and resilience in the face of stressful events, exhibiting a transient transcriptional modulation, yet persistent physiological and welfare benefits. Full article

(This article belongs to the Special Issue Fish Nutrition, Biochemical Pathways, and Physiological Adaptations)

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15 pages, 2409 KB

Open AccessArticle

Over-Represented Senescent Keratinocytes in Hyperpigmented Spots Promote Melanocyte Activation via IGFBP3 and NGF

by Tomohiro Hakozaki, Holly Rovito, Bradley B. Jarrold, John Snowball, Jiazhen Wang, Wenzhu Zhao and Timothy Laughlin

Int. J. Mol. Sci. 2025, 26(21), 10724; https://doi.org/10.3390/ijms262110724 - 4 Nov 2025

Abstract

The occurrence and impact of cellular senescence on skin aging and hyperpigmentation is an ongoing area of exploration, encompassing both intrinsic and extrinsic stressors. Traditionally, research has focused on melanocyte and fibroblast senescence due to their slower turnover compared to keratinocytes. In this [...] Read more.

The occurrence and impact of cellular senescence on skin aging and hyperpigmentation is an ongoing area of exploration, encompassing both intrinsic and extrinsic stressors. Traditionally, research has focused on melanocyte and fibroblast senescence due to their slower turnover compared to keratinocytes. In this study, we identified the accumulation of p16, a senescence marker, in keratinocytes from biopsies of multiple spot types. We explored their impact using doxorubicin-induced senescent keratinocytes in vitro. Conditioned media from these senescent keratinocytes stimulated melanocyte dendricity, a hallmark of hyperpigmented spots. Transcriptomic analysis of senescent keratinocytes identified two key senescence-induced factors: Insulin-like Growth Factor-Binding Protein 3 (IGFBP3) and Nerve Growth Factor (NGF). IGFBP3 and NGF ligand treatment enhanced dendricity by 33% and 17%, and melanin synthesis by 23% and 14%, respectively, in human melanocyte cultures. These findings suggest that keratinocyte senescence contributes to spot formation by mediating melanocyte activation through IGFBP3 and NGF. Furthermore, we evaluated skincare ingredients such as sucrose dilaurate, glabridin, and niacinamide in neutral and low pH solutions, demonstrating their efficacy in reducing the secretion of these ligands, thereby offering potential cosmetic benefits. This study provides insights into the mechanisms of spot formation and highlights promising strategies for managing pigmentation disorders. Full article

(This article belongs to the Special Issue Melanin Pigmentation: Physiology and Pathology)

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28 pages, 4327 KB

Open AccessReview

Optimizing rhBMP-2 Therapy for Bone Regeneration: From Safety Concerns to Biomaterial-Guided Delivery Systems

by Maria Chernysheva, Evgenii Ruchko and Artem Eremeev

Int. J. Mol. Sci. 2025, 26(21), 10723; https://doi.org/10.3390/ijms262110723 - 4 Nov 2025

Abstract

Reconstruction of large and complex hard tissue defects remains a major clinical challenge, as conventional autografts and allografts are often limited in availability, biological compatibility, and long-term efficacy, particularly for extensive defects or poor bone quality. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is [...] Read more.

Reconstruction of large and complex hard tissue defects remains a major clinical challenge, as conventional autografts and allografts are often limited in availability, biological compatibility, and long-term efficacy, particularly for extensive defects or poor bone quality. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a potent osteoinductive factor capable of initiating the complete cascade of bone formation. However, its clinical use is restricted by dose-dependent complications such as inflammation, ectopic ossification, and osteolysis. This review synthesizes current evidence on the safety profile of rhBMP-2 and examines strategies to enhance its therapeutic index. Preclinical and clinical data indicate that conventional collagen-based carriers frequently cause rapid burst release and uncontrolled diffusion, aggravating adverse outcomes. It is noteworthy that low doses of rhBMP-2 (0.5–0.7 mg/level in anterior cervical discectomy and fusion (ACDF) or 0.5–1.0 mg/level in transforaminal lumbar interbody fusion (TLIF)) provide the optimal balance of efficacy and safety. Advanced biomaterial-based platforms, such as bioceramic–polymer composites, injectable hydrogels, and 3D-printed scaffolds, enable spatially and temporally controlled release while maintaining osteogenic efficacy. Molecular delivery approaches, including chemically modified messenger RNA (cmRNA) and regional gene therapy, provide transient, site-specific rhBMP-2 expression with reduced dosing and minimal systemic exposure. By integrating mechanistic insights with translational advances, this review outlines a framework for optimizing rhBMP-2-based regenerative protocols, emphasizing their potential role in multidisciplinary strategies for reconstructing complex hard tissue defects. Full article

(This article belongs to the Special Issue Biomaterials for Tissue Regeneration: Current Progress and Future Directions)

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19 pages, 7240 KB

Open AccessArticle

A New Approach for Achieving Earlier and More Accurate Diagnosis of Connective Tissue Disease-Related Interstitial Lung Disease: TGFB and PDGFA as Novel Promising Biomarkers

by Verónica Pulito-Cueto, Belén Atienza-Mateo, Joao C. Batista-Liz, Rebeca Nieto-Nieto, Clara Vaquera-Illescas, María Sebastián Mora-Gil, David Iturbe-Fernández, Víctor M. Mora-Cuesta, Ana Serrano-Combarro, Sheila Izquierdo-Cuervo, Carolina Aguirre Portilla, José M. Cifrián, Ricardo Blanco and Raquel López-Mejías

Int. J. Mol. Sci. 2025, 26(21), 10722; https://doi.org/10.3390/ijms262110722 - 4 Nov 2025

Abstract

An early and accurate diagnosis of connective tissue diseases-related interstitial lung disease (CTD-ILD) is crucial for delaying lung fibrosis, but its unknown etiology and the limitations of clinical tools make it challenging for clinicians. PDGF and TGFB are the main profibrotic genes. We [...] Read more.

An early and accurate diagnosis of connective tissue diseases-related interstitial lung disease (CTD-ILD) is crucial for delaying lung fibrosis, but its unknown etiology and the limitations of clinical tools make it challenging for clinicians. PDGF and TGFB are the main profibrotic genes. We evaluated PDGFA, TGFB1, TGFB2, and TGFB3 role in the diagnosis of ILD associated with rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory myopathies (IM). Blood was collected from 289 patients:33 RA-ILD, 31 SSc-ILD, 29 IM-ILD; and 22 RA-nonILD, 18 SSc-nonILD, 8 IM-nonILD; and 148 idiopathic pulmonary fibrosis (IPF). The relative expression was quantified by qPCR. Lower PDGFA, TGFB1, and TGFB2 expression differentiated RA-ILD from RA-nonILD patients, acting as ILD early diagnostic biomarkers in RA with cut-offs of <0.01153, <0.3185, and <0.001410, respectively. SSc-ILD patients revealed decreased TGFB2 expression compared to SSc-nonILD patients, with a cut-off of <0.0018 identifying ILD in SSc. PDGFA and TGFB2 expression discriminated IM-ILD from IPF acting as accurate diagnostic biomarkers with cut-offs of >0.0166 and >0.001547, respectively. PDGFA and TGFB2, as well as TGFB2 and TGFB3 expression were associated with RA-ILD and SSc-ILD prognosis, respectively. PDGFA and TGFB are promising blood biomarkers with clinical value for the early and accurate CTD-ILD diagnosis. Full article

(This article belongs to the Section Molecular Biology)

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19 pages, 927 KB

Open AccessReview

Gut Microbiota and Central Nervous System Tumors: A Comprehensive Systematic Review and Meta-Analysis of Microbiome-CNS Interactions

by Agnieszka Nowacka, Maciej Śniegocki, Dominika Bożiłow and Ewa Ziółkowska

Int. J. Mol. Sci. 2025, 26(21), 10721; https://doi.org/10.3390/ijms262110721 - 4 Nov 2025

Abstract

The gut-brain axis has emerged as a critical pathway influencing central nervous system (CNS) tumor biology through complex microbiome-mediated mechanisms. Understanding these interactions is essential for developing novel therapeutic strategies and biomarkers for CNS tumors. To systematically review and meta-analyze current evidence on [...] Read more.

The gut-brain axis has emerged as a critical pathway influencing central nervous system (CNS) tumor biology through complex microbiome-mediated mechanisms. Understanding these interactions is essential for developing novel therapeutic strategies and biomarkers for CNS tumors. To systematically review and meta-analyze current evidence on gut microbiota interactions with CNS tumors, examining mechanisms, clinical correlations, therapeutic implications, and biomarker potential. We conducted a comprehensive systematic review following PRISMA guidelines, searching PubMed, EMBASE, Google Scholar, and Cochrane Library databases for studies published from 2010–2025. A random-effects meta-analysis of reported statistical outcomes was performed to quantify microbiome alterations using standardized mean differences (Cohen’s d) and diagnostic accuracy measures. Analyses were based on published summary statistics rather than reprocessed raw sequencing data, acknowledging cross-study heterogeneity. From 161 identified records, 12 studies met inclusion criteria (6 clinical studies, n = 387 participants; 6 preclinical studies). Meta-analysis revealed significant Shannon diversity reduction in CNS tumor patients (Cohen’s d = −1.237 [95% CI: −1.614, −0.860; 95% PI: −2.48, −0.12]) with moderate heterogeneity (I² = 60.5%). Evidence demonstrated significant gut microbiome alterations with reduced microbial diversity, increased pathogenic bacteria (Akkermansia muciniphila: 2.23-fold increase, Fusobacterium spp.: 2.04-fold increase), and decreased beneficial bacteria (Bifidobacterium spp.: 47% reduction, Lachnospira spp.: 56% reduction). Diagnostic performance showed fair discrimination (pooled AUC = 0.786 [95% CI: 0.781, 0.791]). Key mechanisms include bidirectional tumor-microbiota interactions through immune system modulation, metabolic pathway alterations involving short-chain fatty acids, and inflammatory response modifications within the altered CNS immune privilege environment. Preliminary evidence suggests gut microbiota alterations in CNS tumor patients, but findings require validation in large, standardized cohorts before clinical application. Current evidence quality is low (GRADE assessment), necessitating substantial additional research. Full article

(This article belongs to the Special Issue The Gut-Brain Axis: Genomic and Metagenomic Involvement)

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15 pages, 507 KB

Open AccessReview

The Central Role of Th2 Immune Response in Inflammatory Dermatoses: From Pathogenesis to Targeted Therapies

by Valentina Pala, Francois Rosset, Luca Mastorino, Nadia Sciamarrelli, Sara Boskovic, Silvia Borriello, Eleonora Bongiovanni, Orsola Crespi, Simone Ribero and Pietro Quaglino

Int. J. Mol. Sci. 2025, 26(21), 10720; https://doi.org/10.3390/ijms262110720 - 4 Nov 2025

Abstract

T helper 2 (Th2)-mediated dermatoses are inflammatory skin diseases driven by CD4⁺ Th2 cells that produce interleukin (IL)-4, IL-5, IL-13, and IL-31, promoting immunoglobulin E (IgE) class switching, eosinophil recruitment, mast cell degranulation, and pruritus. We aimed to place these conditions in [...] Read more.

T helper 2 (Th2)-mediated dermatoses are inflammatory skin diseases driven by CD4⁺ Th2 cells that produce interleukin (IL)-4, IL-5, IL-13, and IL-31, promoting immunoglobulin E (IgE) class switching, eosinophil recruitment, mast cell degranulation, and pruritus. We aimed to place these conditions in context and clarify how Th2 biology informs diagnosis and therapy. We conducted a narrative synthesis of mechanistic, translational, and clinical evidence on Th2 pathways in atopic dermatitis (AD), prurigo nodularis, bullous pemphigoid, chronic spontaneous urticaria, and selected type I/IVb hypersensitivity reactions, with focused appraisal of trials targeting IL-4Rα, IL-13, and IL-31R. Persistent Th2 activation is associated with epidermal barrier dysfunction, immune dysregulation, and pruritogenic neural signaling; AD is the archetype, showing prominent lesional IL-4/IL-13 activity correlated with severity and itch. Across disorders, pathway-directed biologics against IL-4Rα, IL-13, and IL-31R consistently reduce disease activity and pruritus in AD and prurigo nodularis, with emerging signals of benefit in bullous pemphigoid and chronic spontaneous urticaria. The Th2 axis provides a unifying pathogenic framework and actionable therapeutic target across multiple dermatoses. Integrating cytokine profiling with clinical phenotypes may refine patient stratification and optimize the deployment of existing and next-generation Th2-targeting therapies. Full article

(This article belongs to the Special Issue Th2-Mediated Inflammation in Dermatology: Mechanistic and Therapeutic Perspectives)

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10 pages, 595 KB

Open AccessArticle

Antibodies to Periodontal Bacteria Are Associated with Systemic Lupus Erythematosus and Autoantibody Positivity

by Laura Massarenti, Henrik Christian Bidstrup Leffers, Thorsten Brodersen, Peter Riis Hansen, Christian Damgaard, Ole Birger Pedersen, Søren Jacobsen and Claus Henrik Nielsen

Int. J. Mol. Sci. 2025, 26(21), 10719; https://doi.org/10.3390/ijms262110719 - 4 Nov 2025

Abstract

Periodontitis has been suggested to play a role in the etiology of systemic lupus erythematosus (SLE). However, evidence remains limited, and the underlying mechanisms are unclear. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans are strongly linked to periodontitis. Here, we evaluate the levels of circulating [...] Read more.

Periodontitis has been suggested to play a role in the etiology of systemic lupus erythematosus (SLE). However, evidence remains limited, and the underlying mechanisms are unclear. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans are strongly linked to periodontitis. Here, we evaluate the levels of circulating antibodies against these bacteria in patients with SLE and healthy controls and analyze their association with SLE-related autoantibodies. Serum IgG antibodies against P. gingivalis, A. actinomycetemcomitans leukotoxin A (LtxA), and two control bacteria (Capnocytophaga ochracea and Escherichia coli) were quantified in 223 patients with SLE and 301 healthy controls. Data was analyzed with ANCOVA and logistic regressions adjusting for age, sex, and smoking status. Exposure to P. gingivalis and A. actinomycetemcomitans, as estimated from antibody levels, was associated with SLE (Odds Ratios (ORs) = 3.0, p = 0.0002 and OR = 2.61, p = 0.0007, respectively). An additive interaction on SLE susceptibility was observed for exposure to P. gingivalis and smoking, with an attributable proportion due to interaction (AP) = 0.72 (95% CI = 0.41–1.02). Anti-A. actinomycetemcomitans LtxA antibodies were elevated in patients positive for anti-dsDNA antibodies (p = 0.02) and nominally increased in those positive for anti-cardiolipin antibodies (p = 0.06). Elevated levels of antibodies against P. gingivalis and A. actinomycetemcomitans in patients with SLE suggest a role for these bacteria, or periodontitis, in the immunopathogenesis of SLE. An additive interaction with smoking was observed for P. gingivalis, and A. actinomycetemcomitans exposure was associated with anti–DSNA antibody positivity, supporting a link between these bacteria and SLE. Full article

(This article belongs to the Special Issue Periodontal Disease, Association with Systemic Conditions and Periodontal Pathogens: 2nd Edition)

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