International Journal of Molecular Sciences

28 pages, 531 KB

Open AccessReview

Drug-Induced Autoimmune Hepatitis by Varenicline and Infliximab as a Continuous Disease Spectrum with Two Different Flares: Acute Liver Injury Followed by Hepatic Autoimmunity

by Rolf Teschke

Int. J. Mol. Sci. 2025, 26(19), 9574; https://doi.org/10.3390/ijms26199574 - 30 Sep 2025

Abstract

Drug-induced autoimmune hepatitis (DIAIH) is a rare and complex disorder caused by drugs that are commonly metabolized by hepatic microsomal cytochrome P450 (CYP) pathways. Whereas DIAIH presents generally with a single clinical flare, in rare cases its clinical course shows two different, consecutively [...] Read more.

Drug-induced autoimmune hepatitis (DIAIH) is a rare and complex disorder caused by drugs that are commonly metabolized by hepatic microsomal cytochrome P450 (CYP) pathways. Whereas DIAIH presents generally with a single clinical flare, in rare cases its clinical course shows two different, consecutively emerging flares. The aim of this report was to analyze details of this rare but interesting phenomenon and to help improve appropriate causality evaluation in patients with suspected iDILI or DIAIH to provide better insight into the pathomechanistic steps leading the diseases. A clinical course with two flares was found in a DIAIH patient treated with varenicline, a smoking cessation drug, and in another patient experiencing DIAIH following intravenous application of infliximab used to treat ankylosing spondylitis. In both patients, the first flare was determined as a typical liver injury with increased serum activities of alanine aminotransferase (ALT) and normal titers of serum autoimmune parameters, classified as an acute liver injury analogous to idiosyncratic DILI (iDILI), with verified causality using a modified version of RUCAM (Roussel Uclaf Causality Assessment Method). After an interval of around two months from the cessation of varenicline use, the second flare emerged, as evidenced by increased serum ALT values now associated with newly increased serum autoimmune titers of antinuclear antibodies (ANAs), classifying this flare as hepatic autoimmune injury with verified causality for varenicline using the simplified autoimmune hepatitis (AIH) score. A similar clinical DIAIH course of a continuous disease with two flares was described for the second patient, who received infliximab and experienced an interval of one month between the first and second flare. Interestingly to note, neither varenicline nor infliximab is degraded via a CYP pathway, and the metabolic disposition of both drugs is low. In sum, DIAIH can develop with two consecutive flares caused by two drugs not metabolized by CYPs and with slow drug disposition, raising the question of whether this phenomenon of two flares can occur in additional cases of DIAIH due to other drugs metabolized by CYPs or non-CYPs, a question to be resolved by DILI experts in future cases of iDILI and DIAIH. Full article

(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 3.0)

22 pages, 1440 KB

Open AccessArticle

Unveiling Metabolic Subtypes in Endometrial Cancer Cell Lines: Insights from Metabolomic Analysis Under Standard and Stress Conditions

by Lana McCaslin, Simon Lagies, Daniel A. Mohl, Dietmar A. Plattner, Markus Jäger, Claudia Nöthling, Matthias C. Huber, Ingolf Juhasz-Böss, Bernd Kammerer and Clara Backhaus

Int. J. Mol. Sci. 2025, 26(19), 9573; https://doi.org/10.3390/ijms26199573 - 30 Sep 2025

Abstract

Endometrial carcinoma (EC) is the most common malignancy of the female reproductive tract, with increasing incidence driven by aging populations and obesity. While molecular classification has improved diagnostic precision, the identification of clinically relevant metabolic biomarkers remains incomplete, and targeted therapies are not [...] Read more.

Endometrial carcinoma (EC) is the most common malignancy of the female reproductive tract, with increasing incidence driven by aging populations and obesity. While molecular classification has improved diagnostic precision, the identification of clinically relevant metabolic biomarkers remains incomplete, and targeted therapies are not yet standardized. In this study, we investigated metabolic alterations in four EC cell lines (AN3-CA, EFE-184, HEC-1B and MFE-296) compared to non-malignant controls under normoxic and stress conditions (hypoxia and lactic acidosis) to identify metabolomic differences with potential clinical relevance. Untargeted gas chromatography–mass spectrometry (GC/MS) and targeted liquid chromatography–mass spectrometry (LC/MS) profiling revealed two distinct metabolic subtypes of EC. Cells of metabolic subtype 1 (AN3-CA and EFE-184) exhibited high biosynthetic and energy demands, enhanced cholesterol and hexosyl-ceramides synthesis and increased RNA stability, consistent with classical cancer-associated metabolic reprogramming. Cells of metabolic subtype 2 (HEC-1B and MFE-296) displayed a phospholipid-dominant metabolic profile and greater hypoxia tolerance, suggesting enhanced tumor aggressiveness and metastatic potential. Key metabolic findings were validated via real-time quantitative PCR. This study identifies and characterizes distinct metabolic subtypes of EC within the investigated cancer cell lines, thereby contributing to a better understanding of tumor heterogeneity. The results provide a basis for potential diagnostic differentiation based on specific metabolic profiles and may support the identification of novel therapeutic targets. Further validation in three-dimensional culture models and ultimately patient-derived samples is required to assess clinical relevance and integration with current molecular classifications. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Cancer Metabolism)

17 pages, 3492 KB

Open AccessArticle

Efficient Hydrolysis of Dichlorvos in Water by Stenotrophomonas acidaminiphila G1 and Methyl Parathion Hydrolase

by Quyang Mei and Rimao Hua

Int. J. Mol. Sci. 2025, 26(19), 9572; https://doi.org/10.3390/ijms26199572 - 30 Sep 2025

Abstract

Dichlorvos (DDVP) has been used in the management of agricultural pests for a long time. DDVP can cause DNA damage in mammals, and its residues in the environment and food have attracted attention. In this study, we reported a DDVP-degrading strain, Stenotrophomonas acidaminiphila [...] Read more.

Dichlorvos (DDVP) has been used in the management of agricultural pests for a long time. DDVP can cause DNA damage in mammals, and its residues in the environment and food have attracted attention. In this study, we reported a DDVP-degrading strain, Stenotrophomonas acidaminiphila G1, which could degrade DDVP to 20 mg/L with a DT₅₀ of 3.81 min at 37 °C, a pH of 7.0, and a concentration of 1.18 × 10¹⁰ colony-forming units (CFUs)/mL. Strain G1’s DDVP degradation products were determined by comparison with standard substances and UPLC-MS/MS analysis. The results showed that dimethyl phosphate (DMPP) was the main metabolite of DDVP, and its toxicity to non-target organisms was significantly lower than that of the parent compound. Furthermore, the key genes for the degradation of DDVP by strain G1 were analyzed using whole-genome sequencing. A methyl parathion hydrolase gene, mpd, was identified, and its activity was verified through prokaryotic expression and enzyme kinetics. The purified enzyme MPD could entirely degrade 20 mg/L DDVP within 1 min. These results not only provide biological resources for the rapid degradation of organophosphorus pesticides but also offer a theoretical basis for the efficient remediation of pesticide residues. Full article

(This article belongs to the Special Issue Molecular Studies on Microbial Degradation of Emerging Pollutants Toxic to Human Health)

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15 pages, 2496 KB

Open AccessArticle

Structures, Interactions, and Antimicrobial Activity of the Shortest Thanatin Peptide from Anasa tristis

by Swaleeha Jaan Abdullah, Jia Sheng Guan, Yuguang Mu and Surajit Bhattacharjya

Int. J. Mol. Sci. 2025, 26(19), 9571; https://doi.org/10.3390/ijms26199571 - 30 Sep 2025

Abstract

Antimicrobial peptides (AMPs), also referred to as host defense peptides, are promising molecules in the development of the next generation of antibiotics against drug-resistant bacterial pathogens. Thanatin comprises a family of naturally occurring cationic AMPs derived from several species of insects. The first [...] Read more.

Antimicrobial peptides (AMPs), also referred to as host defense peptides, are promising molecules in the development of the next generation of antibiotics against drug-resistant bacterial pathogens. Thanatin comprises a family of naturally occurring cationic AMPs derived from several species of insects. The first thanatin, 21 residues long, was identified from the spined soldier bug, and more thanatin peptides have been discovered in recent studies. The 16-residue thanatin from Anasa tristis, or Ana-thanatin, represents the shortest sequence in the family. However, the antimicrobial activity and mechanistic process underpinning bacterial cell killing have yet to be reported for Ana-thanatin peptide. In this work, we examined the antibacterial activity, structures, and target interactions of Ana-thanatin. Our results demonstrated that Ana-thanatin exerts potent antibiotic activity against strains of Gram-negative and Gram-positive bacteria. Biophysical studies demonstrated that Ana-thanatin interacts with LPS outer membrane and can permeabilize the OM barrier in the process. Atomic-resolution structures of the peptide in free solution and in complex with lipopolysaccharide (LPS) micelle were solved by NMR, determining canonical β-sheet structures. Notably, in complex with LPS, the β-sheet structure of the peptide was better defined in terms of the packing of amino acid residues. Further, MD simulations demonstrated rapid binding of the Ana-thanatin peptide with the LPS molecules within the lipid bilayers. These studies have revealed structural features which could be responsible for LPS-OM disruption of the Gram-negative bacteria. In addition, NMR heteronuclear single quantum coherence (HSQC) studies have demonstrated that Ana-thanatin can strongly interact with the LPS transport periplasmic protein LptA_m, potentially inhibiting OM biogenesis. Taken together, we surmise that the Ana-thanatin peptide could serve as a template for the further development of novel antibiotics. Full article

(This article belongs to the Collection Feature Papers in Molecular Biophysics)

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19 pages, 3827 KB

Open AccessArticle

Comparative Analysis of CT and MRI Combined with RNA Sequencing for Radiogenomic Staging of Bladder Cancer

by Joshua Levy, Toru Sakatani, Kaoru Murakami, Yuki Kita, Takashi Kobayashi, Susan Win, Saro Manoukian, Charles J. Rosser and Hideki Furuya

Int. J. Mol. Sci. 2025, 26(19), 9570; https://doi.org/10.3390/ijms26199570 - 30 Sep 2025

Abstract

Accurate staging of bladder cancer (BCa) is important for identifying optimal treatment. Currently, clinical tumor staging for BCa relies on computed tomography (CT) scans, but these can lead to under- or overstaging of patients. Recent research suggests that using magnetic resonance imaging (MRI) [...] Read more.

Accurate staging of bladder cancer (BCa) is important for identifying optimal treatment. Currently, clinical tumor staging for BCa relies on computed tomography (CT) scans, but these can lead to under- or overstaging of patients. Recent research suggests that using magnetic resonance imaging (MRI) along with RNA sequencing (RNASeq) gene expression analysis can provide more precise staging. In this study, 31 matched CT scans, MRI images, and formalin-fixed, paraffin-embedded (FFPE) tissues were collected. First, two radiologists reviewed the images for staging BCa. Next, radiomics features were extracted from both CT and MR images, and computational radiogenomics analyses were performed. Subsequently, RNASeq was performed using FFPE tissues of TURBT prior to cystectomy. A radiogenomic analysis was conducted to identify advanced T-stage signatures. Regarding imaging alone, MRI was found to be more accurate in staging >T2 compared to CT scans. Within a retrospective cohort, MRI radiogenomic signatures were more effective in staging patients than CT, with genomic features playing a significant role. Using canonical correlation analysis, we additionally identified radiomic features underlying genomic signatures of advanced tumor stage. When applying these signatures across a small prospective cohort, MRI radiomic data were able to stratify stage; however, the addition of the same genomic features did not improve the sensitivity and specificity of the model. These preliminary results are promising, but additional research with larger sample sizes is needed to draw definitive conclusions and explore further correlations and statistical interactions between genes and imaging features through machine learning techniques as we move radiogenomics to the clinic. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Therapeutic Targets in Bladder Cancer (Second Edition))

17 pages, 2224 KB

Open AccessArticle

Photobiomodulation at 660 nm Alleviates Alzheimer’s Disease Pathology Through Amyloid-β Reduction and SIRT1 Upregulation in the Hippocampus of 5xFAD Mice

by Tahsin Nairuz, Jin-Chul Heo, Hee-Jun Park and Jong-Ha Lee

Int. J. Mol. Sci. 2025, 26(19), 9569; https://doi.org/10.3390/ijms26199569 - 30 Sep 2025

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, synaptic dysfunction, and cognitive decline. Current pharmacological treatments provide only symptomatic relief without altering disease progression. Photobiomodulation therapy (PBMT), a light-based intervention, has shown neuroprotective potential, although its exact neurobiological [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, synaptic dysfunction, and cognitive decline. Current pharmacological treatments provide only symptomatic relief without altering disease progression. Photobiomodulation therapy (PBMT), a light-based intervention, has shown neuroprotective potential, although its exact neurobiological mechanisms in AD pathogenesis remain obscure. In this study, we investigated the effects of PBMT using a 660 nm wavelength light-emitting diode (LED) in 5xFAD transgenic mouse, a well-established model of early-onset AD. Mice were subjected to once daily PBMT sessions over a defined treatment period and outcomes were assessed through immunohistochemical analysis of hippocampal regions (CA1, CA2, CA3, and dentate gyrus) alongside behavioral testing using the Y-maze spontaneous alternation task. PBMT significantly reduced Aβ plaque load across hippocampal regions, accompanied by improved preservation of neuronal morphology. Furthermore, PBMT significantly upregulated SIRT1 expression, a critical regulator of synaptic plasticity and memory processes. Behaviorally, PBMT-treated mice displayed enhanced spatial working memory compared with controls, indicating a functional benefit linked to the observed molecular and structural changes. These findings suggest that 660 nm PBMT attenuates hallmark AD pathology, promotes neuroprotective pathways, and improves cognition, highlighting its potential as a disease-modifying therapy that warrants further preclinical and clinical investigation. Full article

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

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17 pages, 3096 KB

Open AccessArticle

Integrating Structural Bioinformatics and Functional Mechanisms of Sesquiterpene Synthases CARS and CADS in Lavandula angustifolia (Lavender)

by Dafeng Liu, Na Li, Huashui Deng, Daoqi Song and Hongjun Song

Int. J. Mol. Sci. 2025, 26(19), 9568; https://doi.org/10.3390/ijms26199568 - 30 Sep 2025

Abstract

Lavender species are economically valuable plants, widely cultivated for their essential oils (EOs), which include sesquiterpenes. The sesquiterpenes caryophyllene and cadinol are major constituents, contributing woody and balsamic notes. However, the specific enzymes catalyzing their formation in lavender have not been elucidated. This [...] Read more.

Lavender species are economically valuable plants, widely cultivated for their essential oils (EOs), which include sesquiterpenes. The sesquiterpenes caryophyllene and cadinol are major constituents, contributing woody and balsamic notes. However, the specific enzymes catalyzing their formation in lavender have not been elucidated. This study reports the comprehensive functional and structural characterization of two pivotal sesquiterpene synthases from Lavandula angustifolia (lavender): caryophyllene synthase (CARS) and cadinol synthase (CADS). Mutation experiments were performed based on molecular docking predictions, revealing that negatively charged residues interact electrostatically with magnesium ions (Mg²⁺). Both deletion of 1–226 and 1–228 (∆1–226 and ∆1–228) display activity levels equivalent to their corresponding wild-type proteins, while deletions at positions 522–548 and 529–555 significantly enhanced enzyme activity. Additionally, the highest expression levels of CARS were in the flowers under white light for 8 h, while CADS exhibited peak expression in the leaves under white light for 12 h. These findings deepen our understanding of the regulatory mechanisms involved in sesquiterpene biosynthesis in lavender and provide insights for genetic engineering strategies aimed at enhancing EO production. Such advances could also inform the development of cosmetic, personal care, and medicinal products. Full article

(This article belongs to the Section Molecular Plant Sciences)

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22 pages, 2332 KB

Open AccessArticle

Genetic Diversity and Infection Prevalence of Biomphalaria pfeifferi (Krauss, 1848), the Intermediate Snail Host of Schistosoma mansoni in Gezira State, Sudan

by Arwa Osman, Peter S. Andrus, Yuan Fang, Ibrahim Elhassan, Xiaonong Zhou, Bakri Y. M. Nour and Liming Zhao

Int. J. Mol. Sci. 2025, 26(19), 9567; https://doi.org/10.3390/ijms26199567 - 30 Sep 2025

Abstract

Biomphalaria pfeifferi snails serve as the major intermediate host for intestinal schistosomiasis in Sudan. The genetic structure and infection status of 163 B. pfeifferi collected from six localities in Gezira State, Sudan (East Gezira, Greater Wadmedani, Hasahisa, North Umelgura, South Gezira, and Managil) [...] Read more.

Biomphalaria pfeifferi snails serve as the major intermediate host for intestinal schistosomiasis in Sudan. The genetic structure and infection status of 163 B. pfeifferi collected from six localities in Gezira State, Sudan (East Gezira, Greater Wadmedani, Hasahisa, North Umelgura, South Gezira, and Managil) were characterized. Cytochrome oxidase subunit I (COI) and 16S ribosomal RNA (16S rRNA) mitochondrial genes were used for B. pfeifferi molecular identification and genetic diversity investigation. Schistosoma mansoni infection was detected using the traditional cercarial shedding and molecular methods (Sm^F/R primers). Five COI haplotypes and ten 16S haplotypes were identified, with haplotype diversity of 0.50 for COI and 0.11 for 16S. High evolutionary divergence was observed between groups (Fst = 0.94) for the COI, and low genetic divergence (Fst = 0.04) for the 16S, indicating genetic divergence among Sudanese B. pfeifferi, with the 16S showing lower divergence than the COI, consistent with a post-bottleneck population expansion. Cercarial shedding detected an overall infection prevalence of 3.6% (8/219), with only two snails from Hasahisa shedding S. mansoni cercariae. The Sm^F/R primers revealed a higher infection prevalence of 7.4% (12/163), with all S. mansoni positive samples found at the Hasahisa site. Findings highlight the value of molecular diagnostic tools for accurate surveillance and emphasize the need for site-specific control strategies. Full article

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

20 pages, 1156 KB

Open AccessArticle

Developing Up-Scale Allogeneic Chondrocyte Therapies Using Juvenile Donor Cartilage

by Charlotte H. Hulme, Jade Perry, Helen S. McCarthy, Tian Lan, Thavisha Ranasinghe, Nigel Kiely, Robert Freeman, Jonathan Wright and Karina T. Wright

Int. J. Mol. Sci. 2025, 26(19), 9566; https://doi.org/10.3390/ijms26199566 - 30 Sep 2025

Abstract

Allogeneic chondrocyte therapies present an attractive alternative to existing autologous therapies for the repair of cartilage defects, enabling the selection of optimal donor cells and streamlined manufacturing processes. This study investigates the potential of juvenile chondrocytes derived from human infantile (aged 0–4 y) [...] Read more.

Allogeneic chondrocyte therapies present an attractive alternative to existing autologous therapies for the repair of cartilage defects, enabling the selection of optimal donor cells and streamlined manufacturing processes. This study investigates the potential of juvenile chondrocytes derived from human infantile (aged 0–4 y) polydactyly digits and the iliac apophysis for cartilage repair using Good Manufacturing Practice bioreactor expansion. Iliac apophysis (n = 4) and polydactyly tissues (n = 4) were assessed histologically. Chondrocytes were isolated enzymatically and cultured using standard tissue culture plastic (TCP) methodology. Upon sufficient cell expansion, chondrocytes were seeded into the Quantum^® bioreactor system or onto TCP (±vitronectin coating). The manufactured chondrocytes growth rates, total cell yields, chondrogenic pellet forming capacity (GAG/DNA, histology), immunoprofiles (flow cytometry) and gene expression (RT-qPCR) were assessed. Equivalent chondrocyte numbers were isolated from polydactyly and iliac apophysis donors per wet weight of tissue. Quantum^®-expanded chondrocytes from both sources yielded comparable cell numbers; however, growth was slowed in the Quantum^® compared to TCP. Polydactyly and iliac apophysis-derived chondrocytes expressed chondrocyte cell surface markers (CD166, CD44, CD151, SOX9) and formed chondrogenic pellets. Quantum^® bioreactor expansion did not alter, gene expression or capacity to form glycosaminoglycans (GAGs (normalised to DNA content)) compared to matched TCP expansion. Juvenile cartilage donors are a promising chondrocyte source for the development of an allogeneic therapy. This novel study expanding juvenile chondrocytes in the Quantum^® GMP-compliant bioreactor suggests that culture conditions may need modification to improve growth, whilst retaining cartilage forming capacity. Full article

(This article belongs to the Special Issue Ligament/Tendon and Cartilage Tissue Engineering and Reconstruction)

50 pages, 2929 KB

Open AccessReview

Mechanosensing of Shear Stress and Uterine Spiral Artery Remodeling by Invasive Trophoblasts in Early Pregnancy

by Dariusz Szukiewicz, Seweryn Trojanowski, Edyta Wróbel, Piotr Wojdasiewicz and Grzegorz Szewczyk

Int. J. Mol. Sci. 2025, 26(19), 9565; https://doi.org/10.3390/ijms26199565 - 30 Sep 2025

Abstract

The development of low-resistance blood flow within the developing placenta in the early weeks of pregnancy requires trophoblast invasion of the uterine spiral arteries. Therefore, understanding the migration and differentiation of trophoblasts is necessary. Recently, researchers have focused increasingly on the regulation of [...] Read more.

The development of low-resistance blood flow within the developing placenta in the early weeks of pregnancy requires trophoblast invasion of the uterine spiral arteries. Therefore, understanding the migration and differentiation of trophoblasts is necessary. Recently, researchers have focused increasingly on the regulation of the response of endovascular extravillous trophoblasts (enEVTs) to mechanical stimuli associated with shear stress. The starting point for these studies is that enEVTs, which adopt a pseudoendothelial phenotype, functionally resemble endothelial cells in terms of ability to promote angiogenesis, vascular remodeling and cell–cell communication. The complex process of mechanotransduction requires the coordinated participation of many types of mechanoreceptors, whose activated signaling pathways are translated into whole-cell mechanosensing involving components of the cytoskeleton and extracellular matrix. The aim of this review is to comprehensively present the current knowledge on the importance of mechanical stimuli associated with shear stress in the development of local changes in the vascular system at the site of blastocyst implantation. The characteristics of individual mechanoreceptors are determined, and the most important factors influencing mechanotransduction are discussed. Understanding the importance of mechanosensing disorders in trophoblasts in the pathogenesis of unexplained recurrent abortions or preeclampsia may be helpful in the development of new therapeutic strategies based on the regulation of mechanotransduction in response to shear stress. Full article

(This article belongs to the Section Molecular Biology)

4 pages, 323 KB

Open AccessEditorial

Special Issue: “New Challenges of Parkinson’s Disease”

by Cristina Agliardi and Franca Rosa Guerini

Int. J. Mol. Sci. 2025, 26(19), 9564; https://doi.org/10.3390/ijms26199564 - 30 Sep 2025

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting more than 10 million people worldwide [...] Full article

(This article belongs to the Special Issue New Challenges of Parkinson’s Disease)

16 pages, 4153 KB

Open AccessArticle

Transcriptomic Analysis Reveals Glycolysis and Gluconeogenesis Pathway Activation Underlying Growth Enhancement by Duck-Blood Protein Hydrolysate in Flowerhorn Cichlid Fish

by Pimpisut Manassila, Papungkorn Sangsawad, Surintorn Boonanuntanasarn, Jirawadee Kaewda, Pakpoom Boonchuen, Sirawich Limkul and Chatsirin Nakharuthai

Int. J. Mol. Sci. 2025, 26(19), 9563; https://doi.org/10.3390/ijms26199563 - 30 Sep 2025

Abstract

Protein hydrolysates have potential as sustainable functional feed ingredients or additives for the aquaculture industry. This study examined the growth-promoting effects of duck-blood protein hydrolysate (DBPH, <10 kDa) on the flowerhorn cichlid (Amphilophus citrinellus × Cichlasoma trimaculatum). Fish with an average [...] Read more.

Protein hydrolysates have potential as sustainable functional feed ingredients or additives for the aquaculture industry. This study examined the growth-promoting effects of duck-blood protein hydrolysate (DBPH, <10 kDa) on the flowerhorn cichlid (Amphilophus citrinellus × Cichlasoma trimaculatum). Fish with an average weight of 3.24 ± 0.22 g were randomly assigned to four dietary treatments: a negative control (basal diet) and basal diets supplemented with 0.5%, 1%, and 2% DBPH. After 90 days of the feeding trial, growth parameters indicated that supplementation with 1% and 2% DBPH enhanced growth. However, the muscle composition and skin coloration did not differ significantly. Transcriptome sequencing of the liver tissue yielded 39.83 GB of high-quality clean data. De novo transcriptome assembly identified 32,824 unigenes, of which 21,385 were successfully annotated based on public databases. Differential expression analysis identified 269 upregulated and 232 downregulated genes. To clarify the growth-promoting effects of DBPH, five glycolysis/gluconeogenesis-related genes (tpi, gapdh, pck1, ldh, and adh) were validated by liver qRT-PCR, and the results were consistent with those of the transcriptomic analysis. These findings provide new insights into the mechanisms by which DBPH supplementation could enhance growth, as evidenced by alterations in glycolysis and gluconeogenesis pathways, indicating potential as a novel feed additive in aquaculture. Full article

(This article belongs to the Section Molecular Biology)

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16 pages, 2581 KB

Open AccessArticle

Candidate Transcript Panel in Semen Extracellular Vesicles Can Improve Prediction of Aggressiveness of Prostate Cancer

by Adriana Ferre-Giraldo, Manel Castells, Alicia Madurga, Ariadna Arbiol-Roca, Maurizio de Rocco-Ponce, Lluís Bassas, Francesc Vigués and Sara Larriba

Int. J. Mol. Sci. 2025, 26(19), 9562; https://doi.org/10.3390/ijms26199562 - 30 Sep 2025

Abstract

The need for prostate cancer (PCa)-specific biomarkers that enable more accurate detection of the disease and better prediction of tumor aggressiveness remains ongoing due to the low cancer specificity of PSA screening. Several potential mRNA markers for diagnosing PCa, in tissue and urine, [...] Read more.

The need for prostate cancer (PCa)-specific biomarkers that enable more accurate detection of the disease and better prediction of tumor aggressiveness remains ongoing due to the low cancer specificity of PSA screening. Several potential mRNA markers for diagnosing PCa, in tissue and urine, have been reported in the literature. In this study, we aim to explore the potential of selected prostate-specific molecules and transcripts contained in small extracellular vesicles (sEVs) in semen to predict PCa risk reclassification for patients with moderately elevated PSA levels—a clinical scenario where identifying truly non-invasive biomarkers is especially critical. RT-qPCR analysis in semen sEVs successfully showed differential expression of KLK3 and PCA3 genes between PCa and healthy controls, whereas CREB3L4, CCNQ and DUSP23 levels were related to the severity or degree of PCa affectation. Our findings also present strong evidence that classifiers based on combined long transcript levels in semen sEVs serve as effective biomarkers. They can be used alone or in combination with blood PSA and/or semen citric acid levels to improve the diagnosis of PCa and assess its severity and disease progression with high accuracy. This strategy would allow a more comprehensive assessment, increase prognostic accuracy, and facilitate accurate clinical decision-making in the management of PCa. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancers: Advances and Challenges, 2nd Edition)

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19 pages, 3594 KB

Open AccessArticle

Chloroplast Genome Diversity and Marker Potentials of Diverse Ensete ventricosum Accessions

by Manosh Kumar Biswas, Bulbul Ahmed, Mohamed Hijri, Trude Schwarzacher and J. S. (Pat) Heslop-Harrison

Int. J. Mol. Sci. 2025, 26(19), 9561; https://doi.org/10.3390/ijms26199561 - 30 Sep 2025

Abstract

Ensete ventricosum is a morphologically gigantic, monocot, diploid sister to the banana plant species. It is commercially cultivated as a starch source, only in Ethiopia, where it feeds twenty million people. Here, the complete chloroplast (CP) genomes of 15 diverse landraces of E. [...] Read more.

Ensete ventricosum is a morphologically gigantic, monocot, diploid sister to the banana plant species. It is commercially cultivated as a starch source, only in Ethiopia, where it feeds twenty million people. Here, the complete chloroplast (CP) genomes of 15 diverse landraces of E. ventricosum were assembled and annotated, for comparative genomics, genetic diversity analysis, and molecular marker development. The assembled E. ventricosum CP genomes ranged between 168,388 and 168,806 bp. The sampled CP genomes were quadripartite in structure and had two single-copy regions, a large single-copy region (LSC, average length 88,657 bp), and a small single-copy region (SSC, average length 11,098 bp) separated by inverted repeat regions (IR, average length 34,437 bp). The total number of annotated genes varies between 135 and 138, including 89–92 protein-coding genes, 38 tRNA genes, and 4 rRNA genes. All CP genes, including non-functional ones and intergenic regions, were transcribed with the transcriptome, covering almost 92% of the E. ventricosum CP genome. Codon usage, amino acid frequency, GC contents, and repeat nucleotides were similar among the 15 landraces. Mono- and tetranucleotide simple sequence repeats (SSRs) were found more frequently than other SSRs. An average of 71% of these SSRs were located in the LSC region, and the majority of the SSR motifs were composed of A/T nucleotides. A phylogenetic analysis of the 15 Ensete landraces indicated a common evolutionary origin, while the China sample was positioned separately, suggesting notable genetic differences. This study presents a comparative analysis of the chloroplast genomes of 15 E. ventricosum landraces, providing valuable insights into their genetic diversity and evolution. The identified SSR markers and conserved genomic features offer essential resources for future research and an improvement in Ensete conservation and breeding. Full article

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

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14 pages, 2912 KB

Open AccessArticle

Creatinine-to-Cystatin C Ratio Combined with FIB-4 and ELF for Noninvasive Fibrosis Assessment in MASLD

by Masafumi Oyama, Tadashi Namisaki, Akihiko Shibamoto, Satoshi Iwai, Masayoshi Takami, Yuki Tsuji, Yukihisa Fujinaga, Hiroaki Takaya, Takashi Inoue, Norihisa Nishimura, Shinya Sato, Koh Kitagawa, Kosuke Kaji, Akira Mitoro, Kiyoshi Asada, Hiroyuki Masuda, Junichi Hanatani and Hitoshi Yoshiji

Int. J. Mol. Sci. 2025, 26(19), 9560; https://doi.org/10.3390/ijms26199560 - 30 Sep 2025

Abstract

The creatinine-to-cystatin C ratio (CCR), a surrogate for skeletal muscle mass, may also be associated with liver fibrosis due to the strong link between sarcopenia and liver disease progression. We aimed to evaluate the utility of CCR as a noninvasive marker of liver [...] Read more.

The creatinine-to-cystatin C ratio (CCR), a surrogate for skeletal muscle mass, may also be associated with liver fibrosis due to the strong link between sarcopenia and liver disease progression. We aimed to evaluate the utility of CCR as a noninvasive marker of liver fibrosis in metabolic-dysfunction-associated steatotic liver disease (MASLD). This retrospective study included 104 patients with biopsy-proven MASLD. CCR was calculated using serum creatinine and cystatin C levels. Liver fibrosis was staged histologically (F0–F4), and skeletal muscle mass was assessed using the skeletal muscle index (SMI) on computed tomography. Associations between CCR and liver fibrosis, SMI, and nonalcoholic fatty liver disease activity score were analyzed. ROC analysis evaluated CCR performance alone and in combination with FIB-4 and enhanced liver fibrosis (ELF) scores. CCR values were significantly lower in patients with significant fibrosis (≥F2). The AUROC of CCR for detecting ≥F2 fibrosis was 0.621 (95% CI: 0.509–0.733), with an optimal cutoff of 0.664. CCR alone yielded an AUC of 0.815 for predicting ≥F2 fibrosis. Combining CCR with FIB-4 and ELF substantially improved diagnostic accuracy, increasing the AUROC from 0.621 (CCR alone) to 0.820 for the combined model. CCR correlated positively with SMI (r = 0.451, p < 0.001). CCR is a simple, cost-effective biomarker reflecting muscle mass and liver fibrosis in MASLD. Combining CCR with established markers may enhance risk stratification and reduce the need for liver biopsy in selected cases. Full article

(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)

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23 pages, 9866 KB

Open AccessArticle

Dysferlin Protein–Protein Interaction Pathways in the Organ of Corti and Spiral Ganglion Intersect with Alzheimer’s Protein Pathways

by Marian J. Drescher, Dennis G. Drescher, Khalid M. Khan, James S. Hatfield and Darshi Hemani

Int. J. Mol. Sci. 2025, 26(19), 9559; https://doi.org/10.3390/ijms26199559 - 30 Sep 2025

Abstract

Dysferlin direct protein–protein interactions (PPI) previously have been elucidated with surface plasmon resonance (SPR) and predicted to underlie membrane repair in mechanotransducing myofibrils. In mechanotransducing inner ear hair cells, dysferlin is detected with Z-stack confocal immunofluorescence in the stereocilia and their inserts in [...] Read more.

Dysferlin direct protein–protein interactions (PPI) previously have been elucidated with surface plasmon resonance (SPR) and predicted to underlie membrane repair in mechanotransducing myofibrils. In mechanotransducing inner ear hair cells, dysferlin is detected with Z-stack confocal immunofluorescence in the stereocilia and their inserts in the tectorial membrane (TM) co-localizing with FKBP8, consistent with the SPR determination of tight, positively Ca²⁺-dependent interaction. FKBP8, a direct binding partner of mechanotransducing TMC1, when overexpressed, evokes an elevation in anti-apoptotic BCL2, inhibition of ryanodine receptor (RYR) activity, and a consequent reduction in Ca²⁺ release. RYR3 has now been immunolocalized to the tip of the TM in close association with a third-row outer hair cell (OHC) stereociliary BCL2-positive insertion. Dysferlin, annexin A2, and Alzheimer’s proteins BACE1 and amyloid precursor protein (APP) are also accumulated in these stereociliary insertions. RYR2 and RYR1 have been immunolocalized to the TM core, in position to influence TM Ca²⁺. Dysferlin PPI pathways also intersect with AD protein pathways in the spiral ganglion (SG). Dysferlin segregates with FKBP8, BACE1, and RYR3 in the interiors of SG type I cell bodies. RYR1, RYR2, PSEN1, BCL2, and caspase 3 are primarily confined to plasma membrane sites. RYR3 pathways traverse the plasma membrane to the cell body interior. Western analysis of dysferlinopathy proteins links FKBP8 and BCL2 overexpression with RYR inhibition, indicative of dysferlin targets that are ameliorative in AD. Full article

(This article belongs to the Section Molecular Neurobiology)

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15 pages, 1567 KB

Open AccessArticle

Porphyromonas gingivalis Lysate Induces TLR-2/4-Dependent NF-κB Activation and Inflammatory Damage in the Human Placental Barrier

by Sebastián Araneda-Rojas, Christian Castillo, Ana Liempi, Alejandro Fernández-Moya, Jesús Guerrero-Muñoz, Sebastián Alfaro, Christian Gallardo, Rocío Arregui, Anilei Hoare, Maria Alejandra Gleisner, Marcela Hernández and Ulrike Kemmerling

Int. J. Mol. Sci. 2025, 26(19), 9558; https://doi.org/10.3390/ijms26199558 - 30 Sep 2025

Abstract

Periodontitis has been associated with adverse pregnancy outcomes, but the effect of oral pathogens on placental tissue and local immunity remains unclear. In this study, we investigated the response of human placental explants (HPEs) to lysates of Porphyromonas (P.) gingivalis, a keystone [...] Read more.

Periodontitis has been associated with adverse pregnancy outcomes, but the effect of oral pathogens on placental tissue and local immunity remains unclear. In this study, we investigated the response of human placental explants (HPEs) to lysates of Porphyromonas (P.) gingivalis, a keystone periodontal pathogen. Exposure to P. gingivalis induced significant histological damage and extracellular matrix degradation in placental tissue. The lysate activated the canonical NF-κB pathway, as demonstrated by increased phosphorylation of IκBα, particularly in the trophoblast. This activation was predominantly mediated by Toll-like receptor 2 (TLR-2), with partial contribution from TLR-4. Notably, TLR-2 protein levels decreased upon stimulation, while soluble (s) TLR-2 was markedly elevated in culture supernatants, suggesting receptor cleavage as a regulatory mechanism. P. gingivalis also triggered a robust proinflammatory cytokine secretion, including IL-1β, IL-6, IL-8, and TNF-α, with variable dependence on TLR-2 and TLR-4 signaling. These findings reveal that P. gingivalis components elicit a complex innate immune response in the placenta, driven by TLR-mediated NF-κB activation and modulated by sTLR-2. This study provides mechanistic insight into how periodontitis may contribute to placental inflammation and highlights potential pathways linking maternal oral health to pregnancy complications. Full article

(This article belongs to the Section Molecular Immunology)

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37 pages, 4732 KB

Open AccessArticle

Analysis of Genomic and Transcriptomic Data Revealed Key Genes and Processes in the Development of Major Depressive Disorder

by Sergey M. Ivanov, Vladislav S. Sukhachev, Olga A. Tarasova, Alexey A. Lagunin and Vladimir V. Poroikov

Int. J. Mol. Sci. 2025, 26(19), 9557; https://doi.org/10.3390/ijms26199557 - 30 Sep 2025

Abstract

Major depressive disorder (MDD) is one of the most common diseases, affecting millions of people worldwide. Existing antidepressants do not allow sustainable remission to be achieved in many cases, probably due to insufficient understanding of the etiopathogenesis of MDD. The aim of this [...] Read more.

Major depressive disorder (MDD) is one of the most common diseases, affecting millions of people worldwide. Existing antidepressants do not allow sustainable remission to be achieved in many cases, probably due to insufficient understanding of the etiopathogenesis of MDD. The aim of this study was to identify the key genes, pathways, and master regulators associated with MDD based on a combination of genomic and transcriptomic data analyses. We performed a transcriptome-wide association study (TWAS) to identify the increase and decrease in transcription of particular genes that can be associated with MDD risk, the results of which were used to perform a pathway enrichment analysis that elucidated the pathways and processes associated with MDD. Besides changes in the metabolism of neurotransmitters, the association of some other processes with MDD was revealed, including changes in phospholipid and glycan metabolism, chromatin remodeling, RNA processing and splicing, and cell–extracellular matrix interaction. The transcriptomic analysis performed for brain regions mostly confirmed genome-level findings. The gene expression changes in the brain related to MDD were mostly sex-specific, and the transcription of many genes was changed in the opposite direction in males and females. Finally, master regulators were found, which are the proteins responsible for the transcriptional regulation of the revealed genes and represent the most important proteins contributing to MDD development. Full article

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

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4 pages, 309 KB

Open AccessEditorial

Special Issue: “Pharmacological Strategies and Molecular Mechanisms Associated with the Novel Nephroprotective Treatments”

by Michele Provenzano

Int. J. Mol. Sci. 2025, 26(19), 9556; https://doi.org/10.3390/ijms26199556 - 30 Sep 2025

Abstract

In recent years, research efforts have resulted in a significant increase in the number of therapies available for kidney disease care [...] Full article

(This article belongs to the Special Issue Pharmacological Strategies and Molecular Mechanisms Associated with the Novel Nephroprotective Treatments)

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3 pages, 157 KB

Open AccessEditorial

Special Issue: Molecular Research on Mental Disorders 2.0

by Magdalena Sowa-Kućma

Int. J. Mol. Sci. 2025, 26(19), 9555; https://doi.org/10.3390/ijms26199555 - 30 Sep 2025

Abstract

Mental disorders remain one of the leading causes of disability worldwide, affecting more than 970 million people and contributing substantially to the global burden of disease [...] Full article

(This article belongs to the Special Issue Molecular Research on Mental Disorders 2.0)

31 pages, 1560 KB

Open AccessReview

Overcoming Immune Therapy Resistance in Cancer Through Innate Immune Reprogramming

by Giada Mandracci, Nardine Soliman and Nadia El Khawanky

Int. J. Mol. Sci. 2025, 26(19), 9554; https://doi.org/10.3390/ijms26199554 - 30 Sep 2025

Abstract

Overcoming immune resistance remains the critical barrier to durable immunotherapy responses. Tumors with non-inflamed, “cold” microenvironments exclude cytotoxic lymphocytes and evade checkpoint blockade. Innate nucleic acid-sensing pathways—including TLRs, RIG-I-like RNA sensors, and the cGAS–STING DNA-sensing axis—can recondition this hostile landscape by licensing dendritic [...] Read more.

Overcoming immune resistance remains the critical barrier to durable immunotherapy responses. Tumors with non-inflamed, “cold” microenvironments exclude cytotoxic lymphocytes and evade checkpoint blockade. Innate nucleic acid-sensing pathways—including TLRs, RIG-I-like RNA sensors, and the cGAS–STING DNA-sensing axis—can recondition this hostile landscape by licensing dendritic cells, restoring antigen presentation, and recruiting effector T and NK cells. In this review, we synthesize mechanistic insights into how these receptors function across tumor and immune compartments and evaluate recent translational advances spanning small-molecule and nucleic acid agonists, engineered delivery systems, and clinical trials. We highlight challenges that have limited clinical impact, including pathway silencing, systemic toxicity, and lack of predictive biomarkers, while emphasizing emerging solutions such as tumor-intrinsic targeting, CAR-T/NK engineering, and biomarker-guided patient selection. By integrating innate activation into rational combination regimens, innate immune reprogramming offers a blueprint to convert resistant disease into one susceptible to durable immune control. Full article

(This article belongs to the Special Issue Modulating the Niche: Targeting the Tumor Microenvironment for Enhanced Therapy)

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18 pages, 3941 KB

Open AccessArticle

Cerebellar Contributions to Spatial Learning and Memory: Effects of Discrete Immunotoxic Lesions

by Martina Harley Leanza, Elisa Storelli, David D’Arco, Gioacchino de Leo, Giulio Kleiner, Luciano Arancio, Giuseppe Capodieci, Rosario Gulino, Antonio Bava and Giampiero Leanza

Int. J. Mol. Sci. 2025, 26(19), 9553; https://doi.org/10.3390/ijms26199553 - 30 Sep 2025

Abstract

Evidence of possible cerebellar involvement in spatial processing, place learning and other types of higher order functions comes mainly from clinical observations, as well as from mutant mice and lesion studies. The latter, in particular, have reported deficits in spatial learning and memory [...] Read more.

Evidence of possible cerebellar involvement in spatial processing, place learning and other types of higher order functions comes mainly from clinical observations, as well as from mutant mice and lesion studies. The latter, in particular, have reported deficits in spatial learning and memory following surgical or neurotoxic cerebellar ablation. However, the low specificity of such manipulations has often made it difficult to precisely dissect the cognitive components of the observed behaviors. Likewise, due to conflicting data coming from lesion studies, it has not been possible so far to conclusively address whether a cerebellar dysfunction is sufficient per se to induce learning deficits, or whether concurrent damage to other regulatory structure(s) is necessary to significantly interfere with cognitive processing. In the present study, the immunotoxin 192 IgG-saporin, selectively targeting cholinergic neurons in the basal forebrain and a subpopulation of cerebellar Purkinje cells, was administered to adult rats bilaterally into the basal forebrain nuclei, the cerebellar cortices or both areas combined. Additional animals underwent injections of the toxin into the lateral ventricles. Starting from two–three weeks post-lesion, the animals were tested on paradigms of motor ability as well as spatial learning and memory and then sacrificed for post-mortem morphological analyses. All lesioned rats showed no signs of ataxia and no motor deficits that could impair their performance in the water maze task. The rats with discrete cerebellar lesions exhibited fairly normal performance and did not differ from controls in any aspect of the task. By contrast, animals with double lesions, as well as those with 192 IgG-saporin given intraventricularly did manifest severe impairments in both reference and working memory. Histo- and immunohistochemical analyses confirmed the effects of the toxin conjugate on target neurons and fairly similar patterns of Purkinje cell loss in the animals with cerebellar lesion only, basal forebrain-cerebellar double lesions and bilateral intraventricular injections of the toxin. No such loss was by contrast seen in the basal forebrain-lesioned animals, whose Purkinje cells were largely spared and exhibited a normal distribution pattern. The results suggest important functional interactions between the ascending regulatory inputs from the cerebellum and those arising in the basal forebrain nuclei that would act together to modulate the complex sensory–motor and cognitive processes required to control whole body movement in space. Full article

(This article belongs to the Section Molecular Neurobiology)

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2 pages, 205 KB

Open AccessCorrection

Correction: Chen et al. Reverse Gradient Distributions of Drug and Polymer Molecules Within Electrospun Core–Shell Nanofibers for Sustained Release. Int. J. Mol. Sci. 2024, 25, 9524

by Yaoning Chen, Wenjian Gong, Zhiyuan Zhang, Jianfeng Zhou, Deng-Guang Yu and Tao Yi

Int. J. Mol. Sci. 2025, 26(19), 9552; https://doi.org/10.3390/ijms26199552 - 30 Sep 2025

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Novel Bioactive and Biodegradable Polymeric Materials for Biomedical Applications)

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4 pages, 188 KB

Open AccessEditorial

Special Issue “Molecular Mechanisms and Pathophysiology of Sepsis”

by Vlad Pădureanu

Int. J. Mol. Sci. 2025, 26(19), 9551; https://doi.org/10.3390/ijms26199551 - 30 Sep 2025

Abstract

Sepsis was characterized for more than 20 years as a microbial infection that results in blood leukocyte alterations, tachycardia, tachypnea, and fever (or hypothermia) [...] Full article

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

13 pages, 873 KB

Open AccessArticle

Regulation of Monocyte Perilipin-2 Expression in Acuteand Chronic Coronary Syndromes: Pathogenetic Implications

by Francesco Canonico, Renzo Laborante, Chiara Pidone, Ramona Vinci, Mattia Galli, Eugenia Pisano, Alice Bonanni, Marianna Di Sario, Anna Severino, Lucia Lisi, Daniela Pedicino, Giovanna Liuzzo, Massimiliano Ruscica, Filippo Crea, Giuseppe Patti and Domenico D’Amario

Int. J. Mol. Sci. 2025, 26(19), 9550; https://doi.org/10.3390/ijms26199550 - 30 Sep 2025

Abstract

PLIN2 is involved in the lipid metabolism of macrophages resident in atherosclerotic plaques, and its upregulation leads to lipid droplets (LDs) accumulation. LDs enlargement results in the macrophage transformation into foam cells, a key step for the onset of atherosclerosis. In the present [...] Read more.

PLIN2 is involved in the lipid metabolism of macrophages resident in atherosclerotic plaques, and its upregulation leads to lipid droplets (LDs) accumulation. LDs enlargement results in the macrophage transformation into foam cells, a key step for the onset of atherosclerosis. In the present study, we investigated the role of PLIN2 and its regulation mechanisms in atherosclerosis and plaque instability in patients with a diagnosis of ST-elevation myocardial infarction (STEMI) and chronic coronary syndrome (CCS). We enrolled STEMI (n = 122) and CCS patients (n = 45). Peripheral blood mononuclear cells were isolated from whole blood samples. The PLIN2 protein level was analyzed in CD14+ monocytes by flow cytometry. Lipidomic panel and proteasome activity were evaluated. PLIN2 protein expression was significantly correlated with the age of CAD patients. We found no significant difference in monocyte lipid content between the two patient groups. The PLIN2 increased in STEMI as compared to CCS patients (p < 0.001). The proteasome activity being higher in STEMI as compared to CCS patients (p < 0.001), significant inverse correlations were evident between PLIN2 levels and proteasome activity in the CCS groups (p = 0.02). PLIN2 expression was higher in STEMI as compared to CCS patients, suggesting an involvement in plaque instability. Despite the proteasome activity being higher in STEMI patients, probably due to the elevated inflammatory burden, PLIN2 could escape proteasome degradation in a more efficient manner in STEMI as compared to CCS patients. Full article

(This article belongs to the Special Issue Molecular Pathophysiology and Treatment of Coronary Artery Disease)

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35 pages, 1689 KB

Open AccessReview

The Endocannabinoid System in the Development and Treatment of Obesity: Searching for New Ideas

by Anna Serefko, Joanna Lachowicz-Radulska, Monika Elżbieta Jach, Katarzyna Świąder and Aleksandra Szopa

Int. J. Mol. Sci. 2025, 26(19), 9549; https://doi.org/10.3390/ijms26199549 - 30 Sep 2025

Abstract

Obesity is a complex, multifactorial disease and a growing global health challenge associated with type 2 diabetes, cardiovascular disorders, cancer, and reduced quality of life. The existing pharmacological therapies are characterized by their limited number and efficacy, and safety concerns further restrict their [...] Read more.

Obesity is a complex, multifactorial disease and a growing global health challenge associated with type 2 diabetes, cardiovascular disorders, cancer, and reduced quality of life. The existing pharmacological therapies are characterized by their limited number and efficacy, and safety concerns further restrict their utilization. This review synthesizes extensive knowledge regarding the role of the endocannabinoid system (ECS) in the pathogenesis of obesity, as well as its potential as a therapeutic target. A thorough evaluation of preclinical and clinical data concerning endocannabinoid ligands, cannabinoid receptors (CB1, CB2), their genetic variants, and pharmacological interventions targeting the ECS was conducted. Literature data suggests that the overactivation of the ECS may play a role in the pathophysiology of excessive food intake, dysregulated energy balance, adiposity, and metabolic disturbances. The pharmacological modulation of ECS components, by means of CB1 receptor antagonists/inverse agonists, CB2 receptor agonists, enzyme inhibitors, and hybrid or allosteric ligands, has demonstrated promising anti-obesity effects in animal models. However, the translation of these findings into clinical practice remains challenging due to safety concerns, particularly neuropsychiatric adverse events. The development of novel strategies, including peripherally restricted compounds, hybrid dual-target agents, dietary modulation of endocannabinoid tone, and non-pharmacological interventions, promises to advance the field of obesity management. Full article

(This article belongs to the Special Issue Molecular Research and Insight into Endocannabinoid System)

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14 pages, 5315 KB

Open AccessArticle

Genome-Wide Analysis of Terpene Synthase Genes in Crocus sativus Reveals Their Regulatory Roles in Terpenoid Biosynthesis and Abiotic Stress Tolerance

by Muqaddas Bano, Xingnuo Li, Ahmad Ali, Mohsin Khan, Liang Chen and Xiujun Zhang

Int. J. Mol. Sci. 2025, 26(19), 9548; https://doi.org/10.3390/ijms26199548 - 30 Sep 2025

Abstract

Terpene synthases (TPS) facilitate terpenoid production, influencing the flavor, color, and medicinal properties of Crocus sativus (saffron), a triploid geophyte of significant commercial importance. Despite its importance, the CsTPS gene family remains poorly characterized, limiting genetic enhancements in saffron’s agronomic features. This research [...] Read more.

Terpene synthases (TPS) facilitate terpenoid production, influencing the flavor, color, and medicinal properties of Crocus sativus (saffron), a triploid geophyte of significant commercial importance. Despite its importance, the CsTPS gene family remains poorly characterized, limiting genetic enhancements in saffron’s agronomic features. This research performed a comprehensive genome-wide analysis of CsTPS genes using genomic, transcriptomic, and in silico approaches. BLASTP and PfamScan discovered thirty CsTPS genes, demonstrating conserved TPS domains, varied exon–intron architectures, and chromosomal clustering indicative of tandem duplications. Phylogenetic research categorized these genes into five subfamilies (TPS-a to TPS-e), with the prevalence of TPS-a suggesting a role in sesquiterpene biosynthesis. RNA-seq data (PRJNA976833, PRJNA400472) revealed tissue-specific expression, with CsTPS1 and CsTPS5 expressed in reproductive tissues and CsTPS2 in vegetative tissues. Stress-responsive genes (CsTPS1, CsTPS4) exhibited upregulation in response to cold and pathogen stress, with cis-regulatory elements (e.g., ARE, ABRE) indicating hormone control. The in-silico validation of CsTPS1, chosen for its elevated GMQE score (0.89), included primer design, ePCR, and vector optimization for expression in Arabidopsis thaliana. This study elucidates the contribution of the CsTPS family to saffron terpenoid diversity, providing a foundation for enhancing flavor, yield, and stress tolerance through genetic engineering. Full article

(This article belongs to the Special Issue Plant Molecular Regulatory Networks and Stress Responses)

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30 pages, 3330 KB

Open AccessReview

Translational Insights into NK Immunophenotyping: Comparative Surface Marker Analysis and Circulating Immune Cell Profiling in Cancer Immunotherapy

by Kirill K. Tsyplenkov, Arina A. Belousova, Marina V. Zinovyeva, Irina V. Alekseenko and Victor V. Pleshkan

Int. J. Mol. Sci. 2025, 26(19), 9547; https://doi.org/10.3390/ijms26199547 - 30 Sep 2025

Abstract

Cells of the innate immune system, particularly natural killer (NK) cells, serve as the first line of defense against tumor development and play a critical role in antitumor immunity. Characterizing the immune cell pool and its functional state is essential for understanding immunotherapy [...] Read more.

Cells of the innate immune system, particularly natural killer (NK) cells, serve as the first line of defense against tumor development and play a critical role in antitumor immunity. Characterizing the immune cell pool and its functional state is essential for understanding immunotherapy mechanisms and identifying key cellular players. However, defining NK cell populations in mice, the primary model for cancer immunotherapy, is challenging due to strain-specific marker variability and the absence of a universal NK cell marker, such as human CD56. This study evaluates surface markers of NK and other peripheral blood immune cells in both humans and mice, associating these markers with specific functional profiles. Bioinformatic approaches are employed to visualize these markers, enabling rapid immunoprofiling. We explore the translational relevance of these markers in assessing immunotherapy efficacy, including their gene associations, ligand interactions, and interspecies variations. Markers compatible with rapid flow-cytometry-based detection are prioritized to streamline experimental workflows. We propose a standardized immunoprofiling strategy for monitoring systemic immune status and evaluating the effectiveness of immunotherapy in preclinical and clinical settings. This approach facilitates the design of preclinical studies that aim to identify predictive biomarkers for immunotherapy outcomes by monitoring immune status. Full article

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

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17 pages, 399 KB

Open AccessReview

A Comprehensive Review of Robinetin: Distribution, Biological Activity and Pharmacokinetic Parameters

by Katarzyna Jakimiuk

Int. J. Mol. Sci. 2025, 26(19), 9546; https://doi.org/10.3390/ijms26199546 - 30 Sep 2025

Abstract

Robinetin, a naturally occurring polyhydroxylated flavonol, has gained attention due to its broad spectrum of biological activities and potential therapeutic applications. This review presents a comprehensive summary of the current knowledge concerning the natural occurrence, extraction, spectroscopic characterization, and pharmacological properties of robinetin. [...] Read more.

Robinetin, a naturally occurring polyhydroxylated flavonol, has gained attention due to its broad spectrum of biological activities and potential therapeutic applications. This review presents a comprehensive summary of the current knowledge concerning the natural occurrence, extraction, spectroscopic characterization, and pharmacological properties of robinetin. Ethnobotanical evidence highlights its presence in various medicinal plants, particularly within the Fabaceae family, where it contributes to traditional treatments of infections, inflammation, and metabolic disorders. Robinetin exhibits diverse bioactivities, including antiviral, antibacterial, antiparasitic, antioxidant, anti-mutagenic, and enzyme-inhibitory effects. Notably, it inhibits HIV-1 integrase and acetylcholinesterase and demonstrates moderate antiproliferative activity in cancer cell lines. Despite limited water solubility, its redox behavior and metal-chelating capabilities support its antioxidant potential. Recent in vivo studies indicate its hepatoprotective and metabolic regulatory effects. Additionally, computational models reveal promising interactions with molecular targets such as CDK1. Collectively, these findings underscore the multifaceted therapeutic potential of robinetin and advocate for further pharmacokinetic and clinical investigations to validate its efficacy as a lead compound for the development of phytochemically derived pharmaceuticals. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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20 pages, 1191 KB

Open AccessReview

Emerging Paradigms in Cholesteatoma: From a Traditional Approach to Personalized Therapy

by Adina Zamfir-Chiru-Anton, Dana Manda and Dan-Cristian Gheorghe

Int. J. Mol. Sci. 2025, 26(19), 9545; https://doi.org/10.3390/ijms26199545 - 30 Sep 2025

Abstract

Cholesteatoma is a prevalent disease affecting both children and adults. In this review, we present the recent findings related to the molecular mechanisms involved in cholesteatoma and discuss how researchers can target new molecules to treat this disease. These new approaches illustrate the [...] Read more.

Cholesteatoma is a prevalent disease affecting both children and adults. In this review, we present the recent findings related to the molecular mechanisms involved in cholesteatoma and discuss how researchers can target new molecules to treat this disease. These new approaches illustrate the paradigm shift from a primarily surgical solution to a biological “control and prevent” strategy. Full article

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

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