International Journal of Molecular Sciences

24 pages, 1159 KB

Open AccessReview

Piperine as a Multifunctional Epigenetic Modulator: Integrative Molecular Insights into Cancer and Chronic Disease Therapy

by Andrés Alarcón, Catherine Meza, Carolina Añazco, Marcela Sepúlveda, Sebastián Alarcón and Sharin Valdivia

Int. J. Mol. Sci. 2026, 27(11), 5149; https://doi.org/10.3390/ijms27115149 - 5 Jun 2026

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Abstract

Piperine, the principal alkaloid of Piper nigrum, has gained attention as a multifunctional dietary compound with broad effects on epigenetic and transcriptional regulation in cancer and chronic diseases. Evidence shows that piperine modulates DNA methylation (↓ DNMT3B), histone acetylation (↓ HDAC activity), and [...] Read more.

Piperine, the principal alkaloid of Piper nigrum, has gained attention as a multifunctional dietary compound with broad effects on epigenetic and transcriptional regulation in cancer and chronic diseases. Evidence shows that piperine modulates DNA methylation (↓ DNMT3B), histone acetylation (↓ HDAC activity), and microRNA networks (↑ miR-29c, ↓ miR-383), thereby reshaping key oncogenic and tumor-suppressive pathways. Beyond canonical epigenetic control, it can also stabilize G-quadruplex structures in promoters such as c-MYC, adding an architecture-based mechanism of transcriptional repression. Its dual redox behavior—antioxidant at low doses and pro-oxidant at higher doses—confers context-dependent selectivity, enabling oxidative stress–mediated apoptosis in tumor cells. Compared with other nutriepigenetic agents (curcumin, resveratrol, EGCG), piperine stands out for its multi-target profile and preliminary evidence of activity against cancer stem cell–like phenotypes. Nonetheless, limited solubility, rapid metabolism, and scarce in vivo validation constrain clinical translation. Future efforts should focus on advanced formulations, multi-omics approaches, and cancer stem cell models to better define its therapeutic potential and safety. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 3rd Edition)

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25 pages, 11773 KB

Open AccessArticle

Effects of All-Trans Retinoic Acid on Ovarian Development, Lipid Metabolism, Nutritional Quality, and Gut Microbiota of Female Chinese Mitten Crab During Fattening Period

by Peng Huang, Jiancao Gao, Jinliang Du, Haojun Zhu, Liping Cao, Jun Gao, Jiayi Li, Yao Zheng, Gangchun Xu and Shunlong Meng

Int. J. Mol. Sci. 2026, 27(11), 5148; https://doi.org/10.3390/ijms27115148 - 5 Jun 2026

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Abstract

All-trans retinoic acid (atRA) is known to regulate lipid metabolism, adipocyte differentiation, and the immune system in mammals and other aquatic species. However, studies on atRA in crustaceans, especially in Eriocheir sinensis, are still scarce. The present study aimed to investigate the [...] Read more.

All-trans retinoic acid (atRA) is known to regulate lipid metabolism, adipocyte differentiation, and the immune system in mammals and other aquatic species. However, studies on atRA in crustaceans, especially in Eriocheir sinensis, are still scarce. The present study aimed to investigate the regulatory effects of dietary or injected atRA on female crabs during the fattening period. In the dietary regulation experiment, 270 female crabs were fed diets containing different doses of atRA (0, 150, 300, 600, 1200, and 2400 mg/kg) for a total of 49 days. In the in vivo injection experiment, 90 females were divided into an experimental group (injected with a 0.3 μg/g dose of atRA) and a control group (injected with the same amount of DMSO solvent). Injections were given weekly throughout the 35-day experimental period. Results: Both dietary atRA and atRA injection promoted ovarian development, as evidenced by increased GSI, elevated serum Vg levels, decreased GIH, and upregulated expression of vg, vgr, and rxr genes. In terms of mechanism, dietary atRA promoted ovarian development via the upregulation of pyrimidine nucleotides and dehydroepiandrosterone, which supplied nucleic acid precursors and hormonal support. Furthermore, RXR was identified as a potential key target of atRA in inducing ovarian development, as molecular docking revealed that atRA could spontaneously bind to RXR. Moreover, following atRA injection, the expression of rxr, along with key genes involved in ovarian development, lipid synthesis, and lipid transport, was significantly upregulated. In addition, the atRA diet created a favorable microenvironment for ovarian development by reducing pro-inflammatory lipid levels in the ovary. Transcriptomic and metabolomic analyses revealed that atRA modulates energy and lipid metabolism by activating the AMPK pathway. In terms of the bacterial community structure, the atRA diet significantly decreased Fusobacterium abundance and enriched Parabacteroides as the signature beneficial bacterium. In terms of nutritional quality, the atRA diet markedly reduced saturated and trans-fatty acids while increasing monounsaturated fatty acids and various key essential amino acids. Conclusions: This study revealed that atRA plays a key role in promoting ovarian development, improving nutritional quality, and modulating the structure of the microbiota, thereby providing theoretical support for healthy aquaculture of female crabs during the fattening period. Full article

(This article belongs to the Special Issue Advances in the Role of Retinoic Acid-Regulated Genes in Cancer Biology)

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17 pages, 548 KB

Open AccessArticle

Integrative Transcriptomic, Network, and Genomic Analysis of Peripheral Blood Mononuclear Cells Identifies Candidate Genes Associated with Dupilumab Clinical Response in Atopic Dermatitis Patients

by Martina Krušič, Mario Gorenjak, Uroš Potočnik and Maruška Marovt

Int. J. Mol. Sci. 2026, 27(11), 5147; https://doi.org/10.3390/ijms27115147 - 5 Jun 2026

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Abstract

Atopic dermatitis (AD) is among the most common chronic inflammatory diseases. Due to the heterogeneous presentation of AD, patient response to treatment may differ considerably. Therefore, there is a pressing need for biomarkers associated with response to biological therapies. Thus, we aimed to [...] Read more.

Atopic dermatitis (AD) is among the most common chronic inflammatory diseases. Due to the heterogeneous presentation of AD, patient response to treatment may differ considerably. Therefore, there is a pressing need for biomarkers associated with response to biological therapies. Thus, we aimed to identify blood-based candidate biomarkers associated with response in patients treated with dupilumab. The present study applied a multi-stage integrative analytical framework combining transcriptomic profiling, functional enrichment, co-expression network analysis, and genomic variant analysis to identify potential biomarkers. Eighteen dupilumab-naïve patients were enrolled in the transcriptomic analysis, with blood samples collected at baseline and after 16–18 weeks of therapy; five patients were identified as non-responders. Additionally, genotyping was performed in 34 patients. We identified a set of candidate genes (RPL18A, RPS28, FAU, MASTL, AURKA, TAF2, BUB1B, and RNF135) and genomic variants that may reflect underlying biological mechanisms influencing therapeutic response. However, given the limited sample size, these findings should be considered exploratory and hypothesis-generating. Finally, our study identified exploratory candidate genes potentially associated with variability in dupilumab treatment response. Moreover, our study represents an incremental contribution to existing knowledge, opening avenues for research that may ultimately lead to personalized medicine. Full article

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

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26 pages, 4590 KB

Open AccessArticle

Multi-Omics Profiling Reveals Capsaicin Suppresses EBV Lytic Reactivation in Epithelial Cancers by Targeting Viral and Host Regulatory Networks

by Nutchanat Chatchawankanpanich, Chanitchote Piyapittayanun, Chamsai Pientong and Chukkris Heawchaiyaphum

Int. J. Mol. Sci. 2026, 27(11), 5146; https://doi.org/10.3390/ijms27115146 - 5 Jun 2026

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Abstract

Epstein–Barr virus (EBV) lytic reactivation contributes to the pathogenesis of EBV-associated epithelial malignancies, including nasopharyngeal carcinoma and gastric carcinoma, highlighting the need for therapeutic strategies targeting viral reactivation. Capsaicin exhibits anticancer and antiviral activities; however, its effects on EBV lytic reactivation remain unclear. [...] Read more.

Epstein–Barr virus (EBV) lytic reactivation contributes to the pathogenesis of EBV-associated epithelial malignancies, including nasopharyngeal carcinoma and gastric carcinoma, highlighting the need for therapeutic strategies targeting viral reactivation. Capsaicin exhibits anticancer and antiviral activities; however, its effects on EBV lytic reactivation remain unclear. This study investigated the effects of capsaicin on EBV lytic reactivation in EBV-positive epithelial cancer models. Capsaicin significantly suppressed the expression of lytic genes, including BZLF1, BRLF1, BMRF1, and BLLF1, and reduced EBV virion production. Proteomic analysis revealed alterations in host cellular pathways associated with metabolism, chromatin organization, and cytoskeletal regulation, whereas metabolomic profiling demonstrated perturbations in nucleotide, amino acid, and polyamine metabolism processes involved in viral DNA replication and protein synthesis. Protein–protein interaction network analysis identified key host proteins, including HSP90AB1, MYH9, and ANXA2, implicated in metabolic reprogramming, cytoskeletal organization, and stress responses. Moreover, upstream regulators associated with EBV lytic activation, including p65, AP-1, HIF-1α, and SP1, were down-regulated following capsaicin treatment. Collectively, these findings demonstrate a multitarget inhibitory effect of capsaicin on EBV lytic reactivation and support its therapeutic potential against EBV-associated epithelial malignancies. Full article

(This article belongs to the Section Molecular Microbiology)

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12 pages, 1179 KB

Open AccessArticle

Broad-Spectrum Virucidal Activity of Polymer Cryogel-Loaded Formic Acid Against a Panel of Naked and Enveloped Viruses

by Desislava Budurova, Petar D. Petrov, Filip Ublekov, Miroslav Metodiev and Lora Simeonova

Int. J. Mol. Sci. 2026, 27(11), 5145; https://doi.org/10.3390/ijms27115145 - 5 Jun 2026

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Abstract

Viruses cause a great number of infectious diseases with medical, veterinary, agricultural, social and economic impact. Their unique mechanisms to spread, overcome and resist the existing countermeasures require innovative and smart antiviral strategies such as the effective disinfection of enclosed environments with ensured [...] Read more.

Viruses cause a great number of infectious diseases with medical, veterinary, agricultural, social and economic impact. Their unique mechanisms to spread, overcome and resist the existing countermeasures require innovative and smart antiviral strategies such as the effective disinfection of enclosed environments with ensured broad-spectrum efficacy and minimized risks associated with handling liquid biocides. Formic acid (FA) is a well-established natural acaricide used in beehives with an antiviral potential; however, its application in a liquid form is hindered by severe corrosiveness and rapid, uncontrolled evaporation. This study describes a novel formulation of FA, using a cryogel carrier for achieving a vapor-phase inactivation of viruses, thus eliminating the need for direct contact between the disinfectant and the pathogen. Firstly, a poly(N-isopropylacrylamide) (PNIPAm) cryogel was synthesized by a procedure involving cryogenic treatment, photochemical crosslinking, and freeze-drying, and then the cryogel was swollen with 65% FA or _ddH₂O as a control. After an exposure of a panel of animal and human viruses to FA, evaporated by the polymer carrier for time intervals between 15 min and 12 h, they were neutralized completely as follows: Poliovirus (PV) as a surrogate for major bee viral pathogens for 60 min by 5.1 ∆lg; Feline calicivirus (FCV) for 60 min by 5.3 ∆lg; Adenovirus 5 (AdV5) for 12 h by 4.0 ∆lg; and Influenza virus A (IAV) for 15 min by 5.1 ∆lg. Results were recorded after titration, 48–72 h incubation, cytopathic effect estimation and NR uptake assay. Our results suggest that 65% FA, when delivered via the PNIPAm cryogel matrix, acts as a powerful agent for fumigation-like disinfection. This “dry” delivery strategy offers significant practical advantages: it eliminates the need for open liquid containers, prevents spill-related hazards, and provides an alternative for controlled, long-term release of active vapors. Full article

(This article belongs to the Special Issue Application of Natural Products in Biomedicine and Pharmacotherapy: 3rd Edition)

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24 pages, 3132 KB

Open AccessArticle

Beyond Glucose: Palmitic Acid Influences VEGFA-VEGFR2 Angiogenic Signaling in Müller Glial Cells

by Jesus Silvestre Albert-Garay, Alan E. Medina Arellano, Karla Hernández-Fonseca, Tania Medina-Sánchez, Matilde Ruiz-Cruz and Lenin Ochoa-de la Paz

Int. J. Mol. Sci. 2026, 27(11), 5144; https://doi.org/10.3390/ijms27115144 - 5 Jun 2026

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Abstract

Research on diabetic retinopathy (DR) usually emphasizes hyperglycemia and other causes like dyslipidemia, which are still not well understood. This study examined the effects of palmitic acid (PA) exposure, alone and combined with high glucose (G25), on Müller Glial Cell (MGC) dysfunction and [...] Read more.

Research on diabetic retinopathy (DR) usually emphasizes hyperglycemia and other causes like dyslipidemia, which are still not well understood. This study examined the effects of palmitic acid (PA) exposure, alone and combined with high glucose (G25), on Müller Glial Cell (MGC) dysfunction and angiogenic signaling. Primary MGC cultures were treated with G25 (25 mM), PA (250 µM), or PA + G25 for 24 and 48 h, followed by assessments of cell viability and analysis of the Vascular Endothelial Growth Factor (VEGFA)/VEGFA receptor 2 (VEGFR2) pathway through immunofluorescence, Western blot, and ELISA. Additionally, Gaussian mixture models (GMMs) were used to identify phenotypic subpopulations based on fluorescence intensity. The results showed that while hyperglycemia did not cause significant changes, PA and PA + G25 induced apoptosis-related cell death and significantly increased the expression of VEGFA, VEGFR2, HIF-α, and SP1. Although broad phenotypic diversity was observed at 24 h, by 48 h, a distinct shift towards an angiogenic phenotype was noted, with significantly elevated VEGFA/VEGFR2 levels. In summary, this research demonstrates that PA acts as a critical inducer of an angiogenic secretory phenotype in MGCs, indicating that lipid-mediated signaling plays a vital role in neovascularization in DR, possibly independent of glucose levels. Full article

(This article belongs to the Special Issue Glial Cells in Brain and Eye: Emerging Mechanisms and Functions in Health and Disease)

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20 pages, 519 KB

Open AccessArticle

A Multi-Locus and Machine Learning-Based Assessment of SNCA Variants in Alzheimer’s Disease

by Hatice Segmen and Mustafa Yildiz

Int. J. Mol. Sci. 2026, 27(11), 5143; https://doi.org/10.3390/ijms27115143 - 5 Jun 2026

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Abstract

This study investigates the role of single nucleotide polymorphisms (SNPs) in the SNCA gene, encoding alpha-synuclein, in Alzheimer’s disease (AD). A case–control study was conducted including 95 AD patients and 97 healthy controls. Four SNCA polymorphisms (rs2583988, rs2619363, rs2619364, rs10005233) were analyzed using [...] Read more.

This study investigates the role of single nucleotide polymorphisms (SNPs) in the SNCA gene, encoding alpha-synuclein, in Alzheimer’s disease (AD). A case–control study was conducted including 95 AD patients and 97 healthy controls. Four SNCA polymorphisms (rs2583988, rs2619363, rs2619364, rs10005233) were analyzed using logistic regression, haplotype estimation, genotype combination analysis, and Random Forest modeling. Significant associations were identified for rs2583988, rs2619364, and rs2619363, while rs10005233 showed no association. The rs2583988 C allele and rs2619364 G allele were more frequent in patients, suggesting increased disease risk. Linkage disequilibrium analysis revealed weak correlations (low r²), indicating largely independent genetic effects. Multivariate logistic regression showed that clinical parameters, rather than genetic variants, were independently associated with AD. Multi-locus genotype analysis demonstrated that specific SNP combinations were linked to increased disease risk. Firth regression confirmed associations in low-frequency genotypes. The outcomes derived from the Random Forest methodology were classified as exploratory and not as proof of clinical predictive utility, attributed to the limited sample size, the absence of external validation, and the educational imbalance. Ordinal logistic regression indicated no association between SNCA variants and cognitive severity, while education had a protective effect. The selected SNCA variants showed exploratory associations with AD in this cohort; however, they failed to maintain their validity as independent predictors in multivariate logistic regression analysis. Before drawing any conclusions regarding screening or risk stratification, these findings require independent replication, correction for multiple testing and functional validation. Full article

(This article belongs to the Special Issue Advances in Molecular Pathobiology, Diagnosis, and Treatment of Neurodegenerative Diseases)

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17 pages, 12313 KB

Open AccessArticle

Transcriptome Dynamics Reveal the Potential Roles of Long Non-Coding RNAs in Regulating Flower Color of Safflowers (Carthamus tinctorius)

by Saimire Aishan, Shuo Liu, Lu Lv, Jian Wei, Zhaojun Wei, Jiao Liu, Hong Liu and Rui Qin

Int. J. Mol. Sci. 2026, 27(11), 5142; https://doi.org/10.3390/ijms27115142 - 5 Jun 2026

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Abstract

Safflower (Carthamus tinctorius L.) is an important medicinal plant widely used as a source of natural pigments. Flower color is a key trait affecting both ornamental and commercial value; however, the roles of long non-coding RNAs (lncRNAs) in safflower flower coloration remain [...] Read more.

Safflower (Carthamus tinctorius L.) is an important medicinal plant widely used as a source of natural pigments. Flower color is a key trait affecting both ornamental and commercial value; however, the roles of long non-coding RNAs (lncRNAs) in safflower flower coloration remain largely unclear. In this study, strand-specific RNA sequencing was performed on three safflower varieties with distinct flower colors at different floral developmental stages. A total of 4851 lncRNAs were identified, including 940 natural antisense transcript (NAT) pairs. Among them, lncRNA MSTRG.28365 was identified as a natural antisense transcript paired with CtCHS.7, a chalcone synthase-like gene potentially involved in flavonoid biosynthesis. Expression analysis revealed that CtCHS.7 was highly expressed in the red-flowered variety, whereas MSTRG.28365 exhibited an opposite expression pattern, suggesting a potential regulatory association. Co-expression analysis further indicated that CtCHS.7 was associated with genes putatively involved in flavonoid modification, including UDP-glycosyltransferases and cytochrome P450 enzymes. Functional assays showed that the recombinant CtCHS.7 protein could catalyze the production of downstream flavonoid-related metabolites, although the detected product differed from canonical naringenin chalcone. These findings suggest that lncRNAs may participate in flower color variation and flavonoid biosynthesis-related processes in safflower. This study provides candidate regulatory elements for future functional validation of safflower flower coloration mechanisms. Full article

(This article belongs to the Special Issue Flowers: Molecular and Genetic Regulation of Growth and Development)

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23 pages, 2316 KB

Open AccessArticle

Proteome and miRNAs Expression in Medication-Related Osteonecrosis of the Jaw

by Alessandro Allegra, Rossana De Salvo, Antonia Marcianò, Francesca Polito, Fabio Stagno, Alfonso Carleo, Michele Costanzo, Marianna Caterino, Marco Ragusa, Laura Licitri, Selene Francesca Anna Drago, Irene Gasparo, Giuseppe Alberti, Marieme Khouyyi, Enrico Nastro Siniscalchi, Giacomo Oteri, Luca Bini, Vincenzo Macaione, Laura Bianchi and M’hammed Aguennouz

Int. J. Mol. Sci. 2026, 27(11), 5141; https://doi.org/10.3390/ijms27115141 - 5 Jun 2026

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Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a complex condition associated with the use of antiresorptive drugs, such as bisphosphonates and denosumab. The condition is characterized by the presence of exposed bone in the maxillofacial region that fails to heal. MRONJ remains highly [...] Read more.

Medication-related osteonecrosis of the jaw (MRONJ) is a complex condition associated with the use of antiresorptive drugs, such as bisphosphonates and denosumab. The condition is characterized by the presence of exposed bone in the maxillofacial region that fails to heal. MRONJ remains highly intractable, as its pathogenic mechanisms are not yet fully understood. It is therefore essential to elucidate the molecular mechanisms underlying the disease. MiRNA expression analysis and proteomic studies were performed on a selected cohort of patients with MRONJ on jawbone tissue, using qRT-PCR and 2D electrophoresis followed by mass spectrometry. MiRNAs and proteomics data validation was carried out by Western blot analysis of differentially expressed proteins highlighted by a proteome study and predicted targets of differentially expressed miRNAs. Nineteen miRNAs were overexpressed and two downregulated in jawbone tissue from all MRONJ patients. Notably, five of these dysregulated miRNAs are involved in the regulation of angiogenesis and desmosome functions, suggesting a potential link to the molecular alterations observed at the protein level. Proteomic analysis revealed decreased concentrations of the pigment epithelium-derived factor, and of desmoglein-1, a desmosomal cadherin. Validation analysis confirmed the dysregulation of pathways involved in bone remodeling and necroptosis. The pathophysiology of MRONJ arises from a complex interplay of factors, including impaired bone remodeling, affected angiogenesis, and altered cell adhesion and differentiation mechanisms, ultimately leading to necroptosis. Through proteomic analysis and validation of miRNA expression, our study proposes specific molecular alteration in MRONJ-compromised bone tissue, involving desmosomal component imbalance and angiogenesis inhibition. Full article

(This article belongs to the Section Molecular Biology)

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19 pages, 26075 KB

Open AccessArticle

Integrated Transcriptomic Analysis Suggests a C1Q-Related Macrophage–Fibroblast Signaling Axis in Keloids

by Yutong Yuan, Yuanbo Liu, Ningbei Yin, Shan Zhu and Nuo Si

Int. J. Mol. Sci. 2026, 27(11), 5140; https://doi.org/10.3390/ijms27115140 - 5 Jun 2026

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Abstract

Keloids are fibroproliferative scars characterized by immune dysregulation, persistent fibroblast activation, and excessive extracellular matrix deposition. The mechanisms by which macrophage functional states regulate pathological fibroblast activation remain incompletely understood. Bulk RNA-seq and single-cell RNA-seq datasets were integrated to characterize the immune–fibrotic microenvironment [...] Read more.

Keloids are fibroproliferative scars characterized by immune dysregulation, persistent fibroblast activation, and excessive extracellular matrix deposition. The mechanisms by which macrophage functional states regulate pathological fibroblast activation remain incompletely understood. Bulk RNA-seq and single-cell RNA-seq datasets were integrated to characterize the immune–fibrotic microenvironment of keloids and infer candidate macrophage–fibroblast communication axes. Candidate findings were further assessed by tissue immunofluorescence and preliminary in vitro phenotypic evaluation using C1Q stimulation and RAP intervention in keloid fibroblasts. Bulk transcriptomic analysis revealed coordinated activation of immune-related and fibrotic remodeling programs in keloids. Single-cell analysis identified activated profibrotic fibroblast states and a macrophage population with M2-like features. Ligand–target inference nominated C1QB as a candidate macrophage-associated ligand transcript potentially involved in fibroblast activation, while low-density lipoprotein receptor-related protein 1 (LRP1), a biologically plausible receptor candidate, was enriched in activated fibroblast states. Tissue immunofluorescence showed the coexistence of C1QB⁺ macrophages and LRP1⁺ fibroblasts in keloid lesions. In vitro phenotypic assessment using the intact C1Q complex showed that C1Q increased ACTA2 expression in primary keloid fibroblasts, whereas RAP attenuated this effect; COL1A1 and POSTN showed no consistent induction. Together, these findings support a candidate C1Q-related macrophage–fibroblast communication model and provide a preliminary framework for understanding immune-driven fibroblast activation during keloid progression, with implications for future exploration of potential intervention strategies. Full article

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

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44 pages, 27142 KB

Open AccessArticle

Identifying Conserved Regions in HIV-1 Proteins by Entropy Analysis of Sequence Variability

by Alexandr N. Shchemelev, Elena N. Serikova, Yulia V. Ostankova, Vladimir S. Davydenko, Edward S. Ramsay and Areg A. Totolian

Int. J. Mol. Sci. 2026, 27(11), 5139; https://doi.org/10.3390/ijms27115139 - 5 Jun 2026

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Abstract

The extraordinary genetic diversity of human immunodeficiency virus type 1 (HIV-1), driven by high mutation and recombination rates, poses significant challenges for diagnostics, therapy, and vaccine development. While variable regions enable immune escape, hyperconserved regions are critical for viral function and represent promising [...] Read more.

The extraordinary genetic diversity of human immunodeficiency virus type 1 (HIV-1), driven by high mutation and recombination rates, poses significant challenges for diagnostics, therapy, and vaccine development. While variable regions enable immune escape, hyperconserved regions are critical for viral function and represent promising targets for novel therapeutic interventions. This study aimed to develop and validate a bioinformatic algorithm for quantitative assessment of sequence conservation and automated identification of functionally significant conserved regions across all major HIV-1 proteins. A total of 1119 full-length HIV-1 genome sequences representing major subtypes (A1, A2, A6, B, C, D, F1, F2, G, H, J, K) were analyzed. Normalized Shannon entropy (S-index) was calculated for each alignment column. Statistical thresholds for conserved regions were established using 95% confidence intervals derived from bootstrap resampling. Two complementary algorithms, clustering and local maxima detection, were applied to identify conserved regions, which were subsequently mapped to known functional domains based on literature data. Protein conservation varied markedly, with S_m values ranging from 0.784 (Vpu) to 0.920 (Pol). Gag, Pol, and Vpr demonstrated the highest overall conservation, while Env, Rev, Tat, and Vpu exhibited pronounced variability interspersed with conserved domains. In total, 25 conserved regions in Gag, 49 in Pol, 28 in Env, and 6–4 regions in accessory proteins (Vif, Vpr, Rev, Tat, Nef, Vpu) were identified. These regions corresponded to critical functional elements including enzyme catalytic centers, zinc fingers, receptor-binding sites, protein interaction interfaces, and membrane-anchoring domains. The developed computational framework enables statistically grounded identification of evolutionarily constrained regions across analyzed HIV-1 subtypes. The identified conserved regions represent candidate sites for further investigation and may inform downstream studies focused on antiviral target prioritization, immunogen design, and diagnostic assay development. However, their translational applicability requires additional analytical, structural, and experimental validation. Full article

(This article belongs to the Special Issue Viral Infections and Viral Pathogenesis)

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31 pages, 41472 KB

Open AccessArticle

Novel Disease-Specific Panel of Salivary microRNAs for the Detection of Oral Squamous Cell Carcinoma from Early Invasion to Stage IV Disease

by Iphigenia Gintoni, Stavros Vassiliou, Myrto Kardara Bellou, Athanasios Balakas, Nikolaos Lefantzis, Veronica Papakosta, Dimitrios Vlachakis, George P. Chrousos and Christos Yapijakis

Int. J. Mol. Sci. 2026, 27(11), 5138; https://doi.org/10.3390/ijms27115138 - 5 Jun 2026

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Abstract

Oral squamous cell carcinoma (OSCC) is characterized by consistently high mortality rates (≤60%) despite therapeutic advances. This is attributable to diagnostic delays arising from the asymptomatic early stages and time-consuming protocols. Hence, the establishment of reliable biomarkers for the routine assessment of the [...] Read more.

Oral squamous cell carcinoma (OSCC) is characterized by consistently high mortality rates (≤60%) despite therapeutic advances. This is attributable to diagnostic delays arising from the asymptomatic early stages and time-consuming protocols. Hence, the establishment of reliable biomarkers for the routine assessment of the oral mucosa is imperative. MicroRNAs (miRNAs), key epigenetic regulators of gene expression, represent ideal candidates given their characteristic dysregulation across different pathologies. Here, we aimed to identify novel OSCC-specific miRNAs for the saliva-based detection of OSCC from the presymptomatic stage of early invasion. Through a multistep bioinformatic workflow, four miRNAs (miR-20b-5p, miR-484, miR-185-5p and miR-181d-5p) were identified as disease-specific since they simultaneously regulated >65% of a panel encompassing the 15 primarily overexpressed oncogenes in OSCC and a stage-specific panel including the six upregulated genes that genetically define the malignant stages of sequential oral carcinogenesis. The salivary expression of the identified miRNAs was studied in 31 OSCC patients and 31 healthy controls, using quantitative real-time PCR, followed by statistical analysis and an evaluation of the diagnostic accuracy. All studied miRNAs were significantly downregulated in the saliva of OSCC patients compared to controls (miR-484, p < 0.001; miR-181d-5p, p < 0.001; miR-185, p = 0.008; miR-20b, p = 0.026) and exhibited combinatory diagnostic performance of 95.4% (p < 0.001) for OSCC detection. Their expression remained uninfluenced by lifestyle and clinicopathological parameters, including smoking/alcohol, tumor site, grade and disease stage. The proposed 4-miRNA panel exhibits high diagnostic performance for the early, saliva-based detection of OSCC, irrespective of histopathological and lifestyle confounders, highlighting its potential as a robust non-invasive screening tool. Full article

(This article belongs to the Section Molecular Oncology)

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19 pages, 4262 KB

Open AccessArticle

Immune Dysregulation After COVID-19: Longitudinal Analysis up to 9 Months

by Paweł Mitkowski, Monika Leśniak, Dagmara Kobza, Karolina Aleksandrowicz, Aleksander Chodowiec, Krzysztof Piwowarek, Wojciech Włodarczyk, Klaudia Porębska, Katarzyna Plewka-Barcik, Agata Borkowska, Renata Rożyńska, Ewa Pietruszka-Wałęka, Andrzej Wojtyszek, Karina Jahnz-Różyk, Marcin Pękalski, Andrzej Chciałowski, Robert Zdanowski and Krzysztof Kłos

Int. J. Mol. Sci. 2026, 27(11), 5137; https://doi.org/10.3390/ijms27115137 - 5 Jun 2026

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Abstract

SARS-CoV-2 infection triggers a strong inflammatory response, and persistent symptoms after recovery are thought to reflect prolonged systemic dysregulation. However, mechanisms underlying long COVID remain unclear. This study evaluated longitudinal changes in cytokine hematological and biochemical parameters up to nine months after hospitalization [...] Read more.

SARS-CoV-2 infection triggers a strong inflammatory response, and persistent symptoms after recovery are thought to reflect prolonged systemic dysregulation. However, mechanisms underlying long COVID remain unclear. This study evaluated longitudinal changes in cytokine hematological and biochemical parameters up to nine months after hospitalization for COVID-19 and examined their relationship with persistent symptoms, vaccination status, and the occurrence of comorbidities. Long COVID patients showed sustained elevations in IL-2, IL-6, IL-10, IL-17A, CXCL9, TNF-α, and IFN-γ compared with healthy controls, exhibiting heterogeneous temporal trajectories. Specifically, levels of IL-2, IL-10, TNF-α, and creatinine continued to increase over time, whereas IFN-γ, LDH, CCL2, CXCL9, and CXCL10 declined. Other parameters exhibited greater variability without a uniform longitudinal pattern. IL-6 demonstrated consistently high diagnostic performance in distinguishing individuals after COVID-19 from healthy controls (AUC > 0.82). Aging substantially affects cytokine profiles and systemic inflammatory status; therefore, residual age-related confounding cannot be fully excluded despite statistical adjustment. Although symptoms such as fatigue, cough, and dyspnea were still reported at nine months, no stable associations were identified between cytokine concentrations and clinical manifestations. These findings indicate that while immune alterations persist long after acute infection, systemic cytokine measurements alone may be insufficient to explain the presence or persistence of symptoms. The results suggest that long COVID reflects multifactorial processes extending beyond systemic inflammation and highlight the need for further research into mechanisms driving long-term long COVID sequelae. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology (6th Edition))

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17 pages, 3090 KB

Open AccessArticle

Exploring the Role of Macrophage Marker CD68 in Pediatric Acute Myeloid Leukemia

by Laurens Van Camp, Jolien Vanhooren, Barbara Depreter, Mattias Hofmans, Inge D’Hont, Christophe Chantrain, Laurence Dedeken, An Van Damme, Anne Uyttebroeck, Tim Lammens and Barbara De Moerloose

Int. J. Mol. Sci. 2026, 27(11), 5136; https://doi.org/10.3390/ijms27115136 - 5 Jun 2026

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Abstract

Pediatric acute myeloid leukemia (pedAML) is a childhood malignancy with relapse rates of approximately 30%. CD68, a macrophage marker involved in phagocytosis and macrophage recruitment, may contribute to AML biology. We analyzed CD68 expression using the TARGET database and performed survival analyses, mRNA/protein [...] Read more.

Pediatric acute myeloid leukemia (pedAML) is a childhood malignancy with relapse rates of approximately 30%. CD68, a macrophage marker involved in phagocytosis and macrophage recruitment, may contribute to AML biology. We analyzed CD68 expression using the TARGET database and performed survival analyses, mRNA/protein profiling, and functional assays in AML cell lines, pedAML samples, and cord blood samples. High CD68 transcript levels correlated with KMT2A-rearrangements and inversion 16. Survival analysis showed that high CD68 predicted worse event-free survival, though not independently in a multivariate analysis. Flow cytometry confirmed higher CD68 expression in 7/8 pedAML samples compared to cord blood samples. Functionally, CD68 knockdown reduced proliferation and increased drug sensitivity, while overexpression promoted growth and resistance. Gene set enrichment analysis (GSEA) indicated enrichment of MAPK signaling, AP-1–mediated stress response, and epithelial–mesenchymal transition (EMT)/migration-associated pathways in CD68-high models. Together, these findings suggest that CD68 contributes to a pro-tumorigenic and stress-adaptive phenotype in pedAML and may represent a biologically relevant therapeutic target. Full article

(This article belongs to the Special Issue Molecular Research in Hematologic Malignancies)

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17 pages, 11450 KB

Open AccessArticle

Control of Schwann Cell Myelination by DDR1 Receptor Tyrosine Kinase

by Mengyuan Fan, Yuchen Sun, Ruyi Mei, Wenwen Lu, Xiaofeng Zhao, Aifen Yang and Mengsheng Qiu

Int. J. Mol. Sci. 2026, 27(11), 5135; https://doi.org/10.3390/ijms27115135 - 5 Jun 2026

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Abstract

In peripheral nervous system (PNS), immature Schwann cells differentiate into two functionally distinct types of mature Schwann cells: myelinating Schwann cells, which establish a one-to-one relationship with large-diameter axons and initiate the complex myelination program that enables the rapid saltatory conduction of nerve [...] Read more.

In peripheral nervous system (PNS), immature Schwann cells differentiate into two functionally distinct types of mature Schwann cells: myelinating Schwann cells, which establish a one-to-one relationship with large-diameter axons and initiate the complex myelination program that enables the rapid saltatory conduction of nerve impulses, and non-myelinating Schwann cells, which envelop multiple small-diameter axons without forming myelin, but support axon survival and maintain microenvironment homeostasis. Here, we demonstrate that discoidin domain receptor 1 (DDR1) signaling plays a pivotal role in Schwann cell maturation and peripheral nerve myelination. Ddr1^−/− mice of both sexes exhibited fewer myelinating Schwann cells and profound hypomyelination, reduced nerve conduction velocity, and apparent motor dysfunction. Expression of myelin markers was markedly reduced in the mutants accompanied by the formation of abnormal myelin ultrastructure resembling “onion bulbs”. Mechanistically, Ddr1 deficiency impaired Schwann cell myelination through the marked hyperactivation of the MAPK/ERK signaling pathway. These findings establish DDR1 as a novel regulator of Schwann cell myelination and highlight its potential as a therapeutic target for demyelinating neuropathies. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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44 pages, 45387 KB

Open AccessArticle

Development of an H₂S-Associated Matrix Based on Rhizostoma pulmo Jellyfish Collagen: A Pilot Evaluation of Neuroprotective Effects and Cx43/p53 Regulation in Penetrating Traumatic Brain Injury

by Stanislav Rodkin, Maria Kaplya, Sergey Golovin, Evgeniya Kirichenko, Chizaram Nwosu, Aleksandr Logvinov, Alina Sereda, Yulia Gordeeva, Aleksandr Romanov and Stanislav Bachurin

Int. J. Mol. Sci. 2026, 27(11), 5134; https://doi.org/10.3390/ijms27115134 - 5 Jun 2026

Viewed by 538

Abstract

Severe traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide. To date, there are no clinically effective neuroprotective agents. Biomaterials that combine structural support for damaged tissue with a depot for therapeutic agents may represent a key [...] Read more.

Severe traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide. To date, there are no clinically effective neuroprotective agents. Biomaterials that combine structural support for damaged tissue with a depot for therapeutic agents may represent a key solution to this problem. To evaluate the neuroprotective potential of a collagen matrix derived from the jellyfish Rhizostoma pulmo (R. pulmo) and modified with sodium thiosulfate (Na₂S₂O₃) as an hydrogen sulfide (H₂S) donor in a bioengineered platform for the treatment of severe TBI. Comprehensive characterization of the collagen matrix (electrophoresis, fluorescence microscopy), its implantation in a mouse model of severe TBI, and subsequent morphological, histological, ultrastructural, and immunohistochemical analyses of connexin 43 (Cx43) and p53 protein (p53) were performed. In addition, molecular dynamics simulations of the interactions between sulfur-containing compounds and target proteins were conducted. The effects were compared with inhibition of endogenous H₂S synthesis using aminooxyacetic acid (AOAA). The collagen matrix retains the properties of type I collagen and forms a three-dimensional porous structure with high hydrophilicity and biocompatibility. Implantation ensures effective defect filling, reduces cystic degeneration, and preserves cortical structure. Modification with Na₂S₂O₃ results in a significant reduction in both nuclear and cytoplasmic accumulation of p53, prevention of Cx43 dysregulation, a decrease in the proportion of damaged neurons and inflammatory infiltration, and preservation of tissue ultrastructure. In contrast, inhibition of CBS with AOAA exacerbates pathological changes. Molecular modeling demonstrated that S₂O₃²⁻ is capable of forming stable electrostatic interactions with domains of p53 and Cx43 under conditions of acidosis and elevated Ca²⁺. A collagen matrix derived from R. pulmo and modified with Na₂S₂O₃ represents a promising biodegradable platform that combines structural support with local H₂S-dependent regulation of key mechanisms of secondary brain injury. This approach provides a multilevel neuroprotective effect and opens new opportunities for the development of therapeutic implants for severe TBI. Full article

(This article belongs to the Special Issue Cell Death in Human Diseases: Mechanisms, Biomarkers and Therapeutic Opportunities)

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21 pages, 13804 KB

Open AccessArticle

Ginsenoside Rh2 Regulates PI3K/AKT Signaling, Metabolic Pathways, and the Gut Microbiota for Coronary Heart Disease Therapy

by Zhuowen Chen, Hanye Wang, Ye Yang, Xiuming Cui, Chengxiao Wang and Yuan Liu

Int. J. Mol. Sci. 2026, 27(11), 5133; https://doi.org/10.3390/ijms27115133 - 5 Jun 2026

Viewed by 408

Abstract

This study investigated the molecular mechanisms underlying the therapeutic effects of ginsenoside Rh2 (G-Rh2) in coronary heart disease (CHD) through a network pharmacology approach, focusing on identifying key targets and pathways, including those involved in lipid metabolism, metabolism regulation and anti-apoptotic signaling. A [...] Read more.

This study investigated the molecular mechanisms underlying the therapeutic effects of ginsenoside Rh2 (G-Rh2) in coronary heart disease (CHD) through a network pharmacology approach, focusing on identifying key targets and pathways, including those involved in lipid metabolism, metabolism regulation and anti-apoptotic signaling. A multi-target network pharmacology analysis was performed to predict the pharmacoloigical targets and pathways of G-Rh2. Key molecular interactions were validated by molecular docking. In vivo experiments using CHD rat models were conducted to verify and quantify the effects of G-Rh2 on lipid profiles, myocardial pathology, and gut microbiota composition. G-Rh2 significantly ameliorated CHD in rats by reducing serum cholesterol and triglycerides levels, alleviating myocardial fibrosis, suppressing cardiomyocyte apoptosis, and mitigating tissue damage. Mechanistically, G-Rh2 activated the PI3K/AKT signaling pathway, regulated atherosclerosis-associated metabolic pathways (e.g., pentose phosphate and carbon metabolism), and modulated gut microbiota composition by reducing the abundance of harmful bacteria and increasing beneficial microbial populations, thereby enhancing lipid metabolism and energy balance. This study demonstrates that G-Rh2 alleviates CHD through the synergistic activation of the PI3K/AKT pathway, modulation of key metabolic pathways, and restructuring of gut microbiota. These findings underscore the potential of G-Rh2 as a multi-target therapeutic agent for CHD, offering mechanistic insights into its cardioprotective properties and supporting the broader application of G-Rh2 in cardiovascular drug development. Full article

(This article belongs to the Special Issue Advances in Bioactivity and Molecular Mechanisms of Natural Products)

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27 pages, 15048 KB

Open AccessArticle

Clinical Outcomes and Exploratory Longitudinal CTL/Vβ Repertoire Remodeling in Patients with Relapsed or Refractory Large B-Cell Lymphoma and Follicular Lymphoma Treated with Epcoritamab

by Tatsuro Jo, Jun Taguchi, Yasushi Sawayama, Masatoshi Matsuo, Kaho Umemoto, Kaori Yamaguchi, Kazuhiro Noguchi, Takahiro Sakai, Saori Ikegami, Rena Baba, Tomoya Inoue, Sadaharu Irie, Kuniko Abe, Kazuto Shigematsu and Yasushi Miyazaki

Int. J. Mol. Sci. 2026, 27(11), 5132; https://doi.org/10.3390/ijms27115132 - 5 Jun 2026

Viewed by 540

Abstract

Epcoritamab, a subcutaneous CD3×CD20 bispecific antibody, has shown substantial activity in relapsed or refractory (R/R) B-cell lymphomas, but the immunological correlates of durable remission and treatment discontinuation remain unclear. We retrospectively analyzed 21 consecutive patients who initiated epcoritamab at our institution between 1 [...] Read more.

Epcoritamab, a subcutaneous CD3×CD20 bispecific antibody, has shown substantial activity in relapsed or refractory (R/R) B-cell lymphomas, but the immunological correlates of durable remission and treatment discontinuation remain unclear. We retrospectively analyzed 21 consecutive patients who initiated epcoritamab at our institution between 1 December 2023 and 31 December 2025, including 17 with R/R large B-cell lymphoma (LBCL) and 4 with R/R follicular lymphoma (FL). Clinical follow-up was updated through 18 May 2026. Serial cytotoxic T lymphocyte (CTL) subset and T-cell receptor (TCR) Vβ repertoire analyses were performed in selected cases. Among response-evaluable patients, the overall response rate was 9/14 in LBCL and 4/4 in FL. Median overall survival was 431 days in LBCL and 431.5 days in FL. Progression-free survival was analyzed descriptively because of the small sample size and substantial censoring. A patient with clinically and radiologically suspected central nervous system relapse of LBCL achieved radiological complete remission after epcoritamab treatment. In two LBCL and one FL case in whom epcoritamab was electively discontinued after complete remission, Vβ-skewed CTL populations were observed, and total memory CTLs exceeded total effector CTLs at discontinuation. These exploratory findings suggest that epcoritamab treatment may be associated with longitudinal remodeling of CTL subsets and Vβ-skewed CTL populations in selected responders. The potential relevance of these immunological patterns to durable response and treatment discontinuation should be validated in larger prospective cohorts with functional and sequence-based T-cell analyses. Full article

(This article belongs to the Special Issue Molecular Immunopathogenesis and Treatment of Hematological Malignancies)

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16 pages, 10214 KB

Open AccessArticle

Deep Learning-Guided Reverse Translation Enhances Soluble Expression of Recombinant Proteins in Escherichia coli

by Dong Yu, Nan Geng, Lin Fan, Yanmei Qin, Shangshang Sun, Hao Chen, Ruoyu Wang, Xiaoping Liao and Chun You

Int. J. Mol. Sci. 2026, 27(11), 5131; https://doi.org/10.3390/ijms27115131 - 5 Jun 2026

Viewed by 410

Abstract

Enhancing the soluble expression of heterologous proteins in chassis microorganisms is critical for fundamental biological research and synthetic biology-driven industrial applications. Current methods for designing DNA sequences to ensure high soluble expression often rely excessively on high-frequency codons while overlooking optimal codon context, [...] Read more.

Enhancing the soluble expression of heterologous proteins in chassis microorganisms is critical for fundamental biological research and synthetic biology-driven industrial applications. Current methods for designing DNA sequences to ensure high soluble expression often rely excessively on high-frequency codons while overlooking optimal codon context, leading to suboptimal outcomes. To address these limitations, we developed an integrated deep learning framework combining a synonymous codon generation (SCG) model and a gene expression level prediction (GELP) model. The SCG model captures codon usage patterns in Escherichia coli using large-scale genomic data, whereas the GELP model leverages gene expression data to prioritize sequences with high soluble expression potential. We validated our approach by optimizing the DNA sequences of two industrial enzymes, α-glucan phosphorylase (αGP) and isoamylase (IA), achieving significant and reproducible improvements in soluble expression (mean 12.2–16.9-fold, n = 3 and 2.6–3.4-fold, n = 4), confirmed by one-way ANOVA and one-sample t-tests. This study provides a useful tool for designing DNA sequences that confer high soluble expression and for understanding the relationship between DNA sequence and protein expression. Notably, SCG-GELP reveals a core-avoiding codon optimization strategy that substantially enhances soluble protein yield. Full article

(This article belongs to the Special Issue Artificial Intelligence and Deep Learning in Biomedical and Molecular Research)

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24 pages, 1085 KB

Open AccessArticle

Identification and Validation of Stable Loci Underlying Productivity-Related Traits in Common Wheat

by Antonina A. Kiseleva, Irina N. Leonova, Mikhail A. Nesterov, Vyacheslav V. Piskarev and Elena A. Salina

Int. J. Mol. Sci. 2026, 27(11), 5130; https://doi.org/10.3390/ijms27115130 - 5 Jun 2026

Viewed by 369

Abstract

The genetic architecture of wheat yield-related traits is complex due to their polygenic control, relatively low heritability, and strong genotype–environment interactions. Commonly used characteristics of wheat productivity include thousand-grain weight (TGW), grain weight per ear (GWE), and grain number per ear (GNE). To [...] Read more.

The genetic architecture of wheat yield-related traits is complex due to their polygenic control, relatively low heritability, and strong genotype–environment interactions. Commonly used characteristics of wheat productivity include thousand-grain weight (TGW), grain weight per ear (GWE), and grain number per ear (GNE). To identify stable loci associated with productivity-related traits in common wheat, we performed QTL analysis using two mapping populations derived from crosses between contrasting cultivars. The populations were phenotyped for GNE, GWE, and TGW over two years. In addition, GWAS was conducted using a cultivar panel phenotyped for yield and GWE over ten years, and for GNE, GWE, and TGW over two years. The most reproducible loci were located on chromosomes 2D, 4A, 5A, 5B, 6A, 6B, and 7A. From these regions, 16 SNPs were selected for KASP marker development. Validation in an independent panel of 296 spring common wheat varieties phenotyped over three years identified three most informative markers: wsnp_Ex_c16175_24619793 (4A), wsnp_Ex_c2171_4072995 (5A), and BS00034554_51 (6B), all consistently associated with TGW and additionally associated with GWE, GNE, or yield in individual years. These markers may be useful for marker-assisted selection of wheat productivity-related traits. Full article

(This article belongs to the Special Issue Latest Research on Plant Genomics and Genome Editing, 2nd Edition)

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13 pages, 13604 KB

Open AccessArticle

Exploratory FDG PET/CT Imaging in mCRPC Patients Treated with Sipuleucel-T ± IL-7: A Phase II Trial Subanalysis

by Sandeep Surendra Panikar, Dhruv Bansal, John Crandall, Hari Raman, Joel Picus, Joseph E. Ippolito, Daniel L. J. Thorek, Richard Wahl and Russell K. Pachynski

Int. J. Mol. Sci. 2026, 27(11), 5129; https://doi.org/10.3390/ijms27115129 - 5 Jun 2026

Viewed by 334

Abstract

Immunotherapy has shown limited efficacy in metastatic castration-resistant prostate cancer (mCRPC), highlighting the need for noninvasive tools to monitor treatment-related biological changes. This case series evaluated exploratory metabolic imaging correlates using [¹⁸F]-FDG PET/CT in mCRPC patients enrolled in a Cancer Immunotherapy [...] Read more.

Immunotherapy has shown limited efficacy in metastatic castration-resistant prostate cancer (mCRPC), highlighting the need for noninvasive tools to monitor treatment-related biological changes. This case series evaluated exploratory metabolic imaging correlates using [¹⁸F]-FDG PET/CT in mCRPC patients enrolled in a Cancer Immunotherapy Trials Network (CITN) trial of sipuleucel-T (sip-T) with or without recombinant interleukin-7 (IL-7). Among 54 enrolled patients (NCT01881867), three underwent serial [¹⁸F]-FDG PET/CT imaging at baseline and following sip-T therapy. Imaging assessed tumor metabolic activity and potential immune-related metabolic changes, based on the premise that immune processes may influence FDG uptake. Patient 1, treated with sip-T alone, demonstrated progressive sternal metastasis with stable SUV_max and marked increases in metabolic tumor volume (MTV: 10.1–34.5) and total lesion glycolysis (TLG: 43.4–145.8), consistent with poor prognosis. Patient 2 showed minimal tumor avidity but transient increases in splenic SUV_max and SUV_mean following sip-T, which may reflect treatment-related or immune-associated metabolic activity. Patient 3, treated with sip-T plus IL-7, demonstrated a 33% reduction in SUV_max, stable disease on follow-up imaging, decreased PSA levels, and metabolic changes consistent with treatment response in this individual case. These findings were observed in a single patient and are considered exploratory and hypothesis-generating only. [¹⁸F]-FDG PET/CT imaging may provide exploratory insights into metabolic changes in tumors and immune-related organs in mCRPC. Metabolic changes in tumors and immune organs may provide insights into treatment-associated biological effects. Larger studies are warranted to validate these findings. Full article

(This article belongs to the Topic New Advancements in Innate Immunity and Cancer Immunotherapy)

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16 pages, 1047 KB

Open AccessArticle

Metabolic Mechanisms of Neutrophil Phagocytic Activity in Patients with Widespread Purulent Peritonitis Bacterial Peritonitis Before and After Surgery

by Andrey A. Savchenko, Dmitry Kudlay, Ivan I. Gvozdev, Elena N. Anisimova, Dmitry V. Cherdantsev, Igor Kudryavtsev, Artem Rubinstein, Anna An. Starshinova and Alexandr Borisov

Int. J. Mol. Sci. 2026, 27(11), 5128; https://doi.org/10.3390/ijms27115128 - 5 Jun 2026

Viewed by 308

Abstract

Bacterial peritonitis (BP) remains a significant clinical challenge due to its high risk of multiple organ failure and associated mortality. Neutrophils are central effectors of innate immunity, and their functional activity and metabolism may influence the progression and outcomes of immunoinflammatory diseases. To [...] Read more.

Bacterial peritonitis (BP) remains a significant clinical challenge due to its high risk of multiple organ failure and associated mortality. Neutrophils are central effectors of innate immunity, and their functional activity and metabolism may influence the progression and outcomes of immunoinflammatory diseases. To investigate the phagocytic activity and intracellular metabolic profiles of neutrophils in patients with BP and to evaluate their relationship with postoperative clinical outcomes, 51 patients with BP (23 men, 28 women; mean age 49.6 ± 9.4 years) were examined. Blood samples were collected preoperatively and on postoperative day 7. Phagocytic activity of total, actively, and weakly phagocytic neutrophils was assessed using flow cytometry. Intracellular activity of NAD(P)- and NAD(P)H-dependent oxidoreductases and dehydrogenases was measured by bioluminescence. Patients were stratified according to postoperative outcome: favorable (n = 32) or unfavorable (n = 19). Seventy healthy individuals served as controls. Preoperatively, the proportion and phagocytic activity of neutrophils were markedly elevated in all patients. Postoperatively, the proportion of phagocytosing neutrophils remained high; however, phagocytic activity increased in patients with favorable outcomes but decreased to control levels in those with unfavorable outcomes. Neutrophil metabolism before surgery exhibited activation of both anaerobic and aerobic pathways, accompanied by reduced glucose-6-phosphate dehydrogenase activity. Postoperative metabolic adaptations differed according to outcome: patients with favorable outcomes demonstrated normalization of energy metabolism, whereas patients with unfavorable outcomes exhibited enhanced anaerobic metabolism, persistent aerobic activity, increased substrate flux towards glutamate/glutamine synthesis, and intensified lipid peroxidation. Phagocytic activity and metabolic profiles of neutrophils in BP are outcome-dependent. Effective postoperative anti-inflammatory responses, including reverse migration of activated neutrophils, are associated with favorable outcomes, whereas persistent metabolic activation and oxidative stress correlate with unfavorable prognosis. Neutrophil functional and metabolic parameters may serve as prognostic biomarkers and potential targets for therapeutic modulation in BP. Full article

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

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16 pages, 1119 KB

Open AccessArticle

Evaluating a Coenzyme Q10-Based Food for Special Medical Purpose, for Mitochondrial Diseases Management: An Open-Label, Pilot Trial

by Lucia Chico, Piervito Lopriore, Giulia Cecchi, Adriana Meli, Clara Bernardini, Linda Balestrini, Maico Polzella, Vincenzo Montano and Michelangelo Mancuso

Int. J. Mol. Sci. 2026, 27(11), 5127; https://doi.org/10.3390/ijms27115127 - 5 Jun 2026

Viewed by 338

Abstract

Primary mitochondrial diseases (PMD) are rare disorders with limited therapeutic options. Coenzyme Q10 (CoQ10) supplementation is widely used, although formulation differences can affect absorption and efficacy. This open-label pilot feasibility trial evaluated a food for special medical purposes (FSMP) containing high-dose CoQ10 (250 [...] Read more.

Primary mitochondrial diseases (PMD) are rare disorders with limited therapeutic options. Coenzyme Q10 (CoQ10) supplementation is widely used, although formulation differences can affect absorption and efficacy. This open-label pilot feasibility trial evaluated a food for special medical purposes (FSMP) containing high-dose CoQ10 (250 mg per capsule) in patients with PMD. Ten patients (mean age: 55.5 ± 8.6 years) were enrolled. Serum/plasma biomarkers, including CoQ10, fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), ferric-reducing antioxidant power (FRAP), total sulfhydryl groups (t-SH), and advanced oxidation protein products (AOPP), were assessed at baseline (T0, after ≥30 days of conventional ubidecarenone) and after 30 days of FSMP administration (T1). Fatigue severity scale (FSS) and 5-times sit-to-stand test (5xSST) were evaluated at both timepoints. FSMP was administered at 250 or 500 mg/day. Twenty sex- and age-matched healthy controls were included for CoQ10 comparison. Absolute CoQ10 concentrations remained stable overall at T1, with all patients maintaining levels above 390 ng/mL (100% vs. 60% at T0), although concentrations remained lower than in healthy controls (p < 0.01). Dose-normalized CoQ10 exposure was significantly higher with FSMP versus conventional ubidecarenone (p < 0.001, Cohen’s d = 7.31). FGF21, GDF15, AOPP, and t-SH remained unchanged, whereas FRAP increased at T1 (p < 0.01). No significant changes were observed in 5xSST and FSS. Exploratory analyses indicated inter-individual variability in functional responses. FSMP was associated with higher dose-normalized systemic CoQ10 exposure, more consistent circulating CoQ10, and increased FRAP levels. Its simplified dosing regimen may support long-term adherence. Larger studies are warranted to validate these preliminary findings. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Biological Activities of Natural and Derivatives Bioactive Compounds)

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22 pages, 4693 KB

Open AccessArticle

Physiological, Morphological, and Molecular Evaluation of Wheat Under Single (Drought, Salt, Heat) and Combined (Drought–Heat, Salt–Heat) Stress

by Conghui Li, Xiaorui Guo, Lijuan Zhao, Enyang Mei, Yu Kang, Kangqi Xiang, Yuyue Zhang, Xueyu Lin, Xinmei Li, Shuqian Qian and Haitao Liu

Int. J. Mol. Sci. 2026, 27(11), 5126; https://doi.org/10.3390/ijms27115126 - 5 Jun 2026

Viewed by 298

Abstract

Wheat (Triticum aestivum L.), a key grain food crop worldwide, faces increasing threats from combined abiotic stresses exacerbated by climate change. However, the comprehensive effects of drought, salinity, and high-temperature pressure on wheat seedlings remain poorly understood. Using the cultivar “Yannong 1212”, [...] Read more.

Wheat (Triticum aestivum L.), a key grain food crop worldwide, faces increasing threats from combined abiotic stresses exacerbated by climate change. However, the comprehensive effects of drought, salinity, and high-temperature pressure on wheat seedlings remain poorly understood. Using the cultivar “Yannong 1212”, we conducted hydroponic experiments to investigate the physiological, morphological, antioxidant, osmoregulatory, membrane lipid peroxidation, and molecular responses of wheat seedlings to single and combined stresses, and then conducted multivariate statistical analyses. The results showed that drought or salt stress inhibited seed germination in a concentration-dependent manner. However, the combined stresses significantly inhibited germination and seedling growth, leading to leaf chlorosis, chlorophyll degradation, stomatal closure, and chloroplast damage. Physiologically, the combined effect of multiple stresses induced excessive ROS and MDA accumulation, promoted proline and soluble sugar synthesis, and triggered the dynamic responses of antioxidant enzymes. Drought stress increased SOD, POD, and CAT activities, whereas salt stress had the opposite effect, and combined stresses further increased SOD and POD activities, but reduced CAT activity. Additionally, stress-responsive genes were rapidly upregulated. Multivariate analyses confirmed that the combined stress of drought and heat was the most damaging. These findings explain the synergistic damage mechanisms of combined stresses, providing a theoretical basis for genetic improvement of wheat’s stress tolerance. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Plant Adaptation to Stress)

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18 pages, 18799 KB

Open AccessArticle

The Involvement of HIF-1α and BDNF in Neonatal Hypoxic–Ischemic Insult to the Cerebral Germinal Matrix

by Felipe Paes Gomes da Silva, Francys De Luca Fernandes da Silva, Nicolas Pereira Gerber, Seigo Nagashima, Eduardo Morais de Castro, Vanessa Yumie Watanabe Liberalesso, Carlos Frederico Oldenburg Neto, Gustavo David dos Santos, Fernanda Gimenez de Souza, Ana Paula Camargo Martins, Lucia de Noronha and Caroline Busatta Vaz de Paula

Int. J. Mol. Sci. 2026, 27(11), 5125; https://doi.org/10.3390/ijms27115125 - 5 Jun 2026

Viewed by 359

Abstract

Perinatal asphyxia is a major contributor to neonatal morbidity and mortality, particularly among preterm infants, whose brains are highly vulnerable to hypoxic–ischemic injury. The germinal matrix (GM), owing to its vascular fragility and high metabolic demand, is especially susceptible in this context. This [...] Read more.

Perinatal asphyxia is a major contributor to neonatal morbidity and mortality, particularly among preterm infants, whose brains are highly vulnerable to hypoxic–ischemic injury. The germinal matrix (GM), owing to its vascular fragility and high metabolic demand, is especially susceptible in this context. This study analyzed 118 germinal matrix samples from neonates, stratified into three groups according to gestational age—Extremely Preterm (EP), Late Preterm (LP), and Term (T)—to investigate the immunopositivity of hypoxia-inducible factor 1-alpha (HIF-1α) and brain-derived neurotrophic factor (BDNF), correlating these findings with gestational age, the presence of asphyxia, neuronal injury, and survival time. BDNF expression showed a positive association with postnatal survival in neonates without neuronal injury (ρ = 0.309; p = 0.012). Linear regression analysis further demonstrated that BDNF immunopositivity was a significant predictor of survival time, with each 11.82% increase in positive staining corresponding to an additional predicted hour of survival (p < 0.001). HIF-1α expression was positively associated with survival in asphyxiated extremely preterm neonates (ρ = 0.492; p = 0.024) and demonstrated a strong correlation that approached, but did not reach, conventional statistical significance in late preterm neonates with neuronal injury (ρ = 0.949; p = 0.051). Collectively, these findings suggest a complementary role for BDNF and HIF-1α in neonatal neuroprotective responses, with BDNF showing potential as a prognostic biomarker in neonates without neuronal injury and HIF-1α reflecting adaptive responses to hypoxic–ischemic stress in a gestational age-dependent manner. However, additional studies are required to validate these associations and further clarify their prognostic and therapeutic relevance in neonatal hypoxic–ischemic conditions. Full article

(This article belongs to the Special Issue Molecular Physiopathological Role of Hypoxia)

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28 pages, 1192 KB

Open AccessReview

From Molecules to Biomarkers: Nogo Proteins and Receptors in the Early Detection of Type 2 Diabetes Complications: A Systematic Review

by Jelena M. Bogdanović, Ivana Babić, Jelena Stanarčić Gajović, Sandra Singh Lukač, Dragana Mijač, Dušan Popović, Ivan Ranković, Ljiljana Popović, Iva Rasulić and Katarina Lalić

Int. J. Mol. Sci. 2026, 27(11), 5124; https://doi.org/10.3390/ijms27115124 - 5 Jun 2026

Cited by 1 | Viewed by 369

Abstract

Nogo (RTN4) proteins and their receptors have emerged as candidate mediators of metabolic regulation and vascular pathology relevant to type 2 diabetes (T2D). The primary objective of this PRISMA-guided systematic review was to evaluate the clinical and cohort evidence for RTN4/RTN4R as potential [...] Read more.

Nogo (RTN4) proteins and their receptors have emerged as candidate mediators of metabolic regulation and vascular pathology relevant to type 2 diabetes (T2D). The primary objective of this PRISMA-guided systematic review was to evaluate the clinical and cohort evidence for RTN4/RTN4R as potential biomarkers of T2D progression and vascular complications. A secondary objective was to synthesize preclinical mechanistic evidence on the effects of Nogo axis modulation on pathways relevant to the pathogenesis of T2D. We performed a PRISMA-guided systematic review. The protocol was not prospectively registered in PROSPERO. To ensure reproducibility, we provide complete search keywords, the screening log and the full-text exclusion table. PubMed/MEDLINE, EMBASE and Web of Science were searched for studies published 2000–2025; full search keywords are provided in the main text. The search strategy combined and free-text terms with Boolean operators. We included original preclinical and clinical studies, cohort/proteomic analyses, meta-analyses, and mechanistic papers reporting expression, function, signaling, or clinical associations of Nogo proteins/receptors in metabolic or vascular outcomes. Exclusion criteria: non-English articles, unclear methods, studies outside 2000–2025, and studies lacking primary data. Two reviewers independently screened records; conflicts were resolved by consensus. Study quality was appraised using established tools (SYRCLE for animal studies, Newcastle–Ottawa Scale for cohort/case-control studies). Preclinical evidence supports tissue-specific roles for RTN4 isoforms and receptors in the regulation of insulin secretion, proGCG → GLP-1 processing, ER homeostasis, and vascular permeability through the Src/PI3K/Akt and RhoA/ROCK axes. Cohort and proteomic analyses report associations between RTN4/RTN4R or serum NogoB and faster progression of T2D or vascular complications, but genetic assessment of causality (Mendelian randomization) has so far provided limited support in available data sets. Findings are heterogeneous with respect to directionality and tissue localization. RTN4 signaling exhibits tissue-specific mechanisms relevant to glucose regulation and vascular biology and warrants further translational study. However, heterogeneity across studies and limited genetic support for causality indicate that isoform-specific quantitative validation, longitudinal cohorts and integrated genetic–functional analyses are required before RTN4/RTN4R can be considered as clinical biomarkers. Full article

(This article belongs to the Special Issue Biomarkers in Diabetes Mellitus: From Discovery to Clinical Application)

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25 pages, 25310 KB

Open AccessArticle

Resveratrol Alleviates Arsenic-Induced Liver Fibrosis in Rats by Correcting SIRT1-Mediated Disorder of Hepatic Bile Acid Metabolism

by Qi Wang, Hualin Chen, Qiming Ran, Fang Hu, Qiwen Fu and Lu Ma

Int. J. Mol. Sci. 2026, 27(11), 5123; https://doi.org/10.3390/ijms27115123 - 5 Jun 2026

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Abstract

Liver fibrosis is a reversible phase of arsenic-induced chronic liver injury, with bile acid metabolic alterations closely associated with this pathological process. SIRT1 is a key metabolic regulator and promising therapeutic candidate, while its role in bile acid metabolism during arsenic-induced liver fibrosis [...] Read more.

Liver fibrosis is a reversible phase of arsenic-induced chronic liver injury, with bile acid metabolic alterations closely associated with this pathological process. SIRT1 is a key metabolic regulator and promising therapeutic candidate, while its role in bile acid metabolism during arsenic-induced liver fibrosis remains poorly defined. This study established time-dependent rat models of arsenic-induced liver fibrosis with resveratrol intervention to investigate the potential association between SIRT1, bile acid metabolic disturbance, and liver fibrosis, as well as resveratrol’s hepatoprotective effects. Arsenic exposure induces progressive accumulation of hydrophobic bile acids in the liver, inflammation, hepatic stellate cell activation, and fibrosis, accompanied by suppressed expression of bile acid phase II detoxification genes (Baat, Ugt1a1, Sult2a1) and the bile acid efflux transporter gene Abcb11 (BSEP). Arsenic exposure reduces SIRT1 expression and increases C/EBPα acetylation, which may relate to impaired transcription of the aforementioned bile acid metabolic genes. Resveratrol may restore SIRT1 expression, normalize C/EBPα acetylation and bile acid homeostasis, and reduce hepatic arsenic accumulation, thereby alleviating liver fibrosis. Collectively, the SIRT1/C/EBPα axis and bile acid metabolism may be linked to the progression of arsenic-induced liver fibrosis. Resveratrol may exert protective effects via multiple mechanisms, including regulating these molecular targets and reducing hepatic arsenic accumulation. Full article

(This article belongs to the Section Molecular Toxicology)

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24 pages, 5915 KB

Open AccessArticle

Study of Artemisia ordosica Krasch. Against Allergic Rhinitis Based on the P815 Mast Cell Degranulation Model, Network Pharmacology, Molecular Docking, and Molecular Dynamics

by Mengmeng Wang, Jingming Zou, Qi Zhang, Xianxiang Bai, Si Wu, Yawei Hu, Xiaoyan Han, Na Han and Bin Xiao

Int. J. Mol. Sci. 2026, 27(11), 5122; https://doi.org/10.3390/ijms27115122 - 5 Jun 2026

Viewed by 342

Abstract

Allergic rhinitis (AR) is one of the most prevalent allergic disorders worldwide. Current pharmacological treatments are often limited by suboptimal efficacy and notable adverse effects. Herbal medicines, with their multi-component and multi-target therapeutic characteristics, have attracted increasing attention. Artemisia ordosica Krasch. (AOK), a [...] Read more.

Allergic rhinitis (AR) is one of the most prevalent allergic disorders worldwide. Current pharmacological treatments are often limited by suboptimal efficacy and notable adverse effects. Herbal medicines, with their multi-component and multi-target therapeutic characteristics, have attracted increasing attention. Artemisia ordosica Krasch. (AOK), a traditional Chinese/Mongolian medicine has demonstrated immunomodulatory, antioxidant, and anti-inflammatory activities. The anti-AR potential of AOK extract fractions was evaluated using in vitro mast cell degranulation inhibition assays, network pharmacology analysis, molecular docking, and molecular dynamics simulations to elucidate underlying pharmacological mechanisms. The P815 mast cell model induced by compound 48/80 was employed to assess the inhibitory activity and cytotoxicity of different extract fractions. Among the tested fractions, the ethyl acetate fraction exhibited the most potent inhibitory effect on mast cell degranulation without significant cytotoxicity. Network pharmacology analysis identified 254 potential AR-related targets of AOK, with Signal Transducer and Activator of Transcription 3(STAT3), Src protein(SRC), Tumor protein 53(TP53), AKT Serine/Threonine Kinase 1(AKT1), Heat Shock Protein 90 Alpha Family Class A Member 1(HSP90AA1), Estrogen Receptor 1(ESR1), and Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA) identified as key hub proteins. Gene Ontology and KEGG pathway enrichment analyses indicated that AOK primarily modulated inflammatory and oxidative stress-related processes through the lipid and atherosclerosis, hypoxia-inducible factor-1, and AGE-RAGE signaling pathways. Molecular docking and dynamics simulations demonstrated strong binding affinities and stable interactions between major active constituents, particularly hydroxygenkwanin, and key targets such as SRC. The ethyl acetate fraction of AOK extract exhibited significant mast cell degranulation inhibitory activity, likely mediated via a synergistic multi-component, multi-target mechanism involving regulation of inflammatory and immune-related signaling pathways. These findings provide a pharmacological basis for the potential application of AOK in AR treatment. Full article

(This article belongs to the Section Molecular Pharmacology)

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26 pages, 480 KB

Open AccessArticle

A Systemic Immune State Axis Distinguishes Psoriatic Arthritis from Psoriasis

by Yoon Kyeong Lee and Hyun-A. Seong

Int. J. Mol. Sci. 2026, 27(11), 5121; https://doi.org/10.3390/ijms27115121 - 5 Jun 2026

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Abstract

Psoriasis and psoriatic arthritis (PsA) are systemic immune-mediated diseases, but the features that distinguish cutaneous-dominant psoriasis from musculoskeletal involvement remain unclear. We analyzed four core public cross-sectional datasets spanning whole-blood methylation, PBMC single-cell RNA sequencing summarized at the subject level, skin RNA sequencing, [...] Read more.

Psoriasis and psoriatic arthritis (PsA) are systemic immune-mediated diseases, but the features that distinguish cutaneous-dominant psoriasis from musculoskeletal involvement remain unclear. We analyzed four core public cross-sectional datasets spanning whole-blood methylation, PBMC single-cell RNA sequencing summarized at the subject level, skin RNA sequencing, and purified CD4⁺ T-cell methylation, and used two additional public skin cohorts for external contextual checks to define a disease inflammatory response axis (DIR) and a contrast-resolved systemic state coordinate (CRS) representing systemic immune state variation associated with PsA. In whole-blood methylation, DIR primarily separated healthy controls from psoriasis, whereas CRS separated psoriasis from PsA with minimal correlation to DIR. In untreated-only PBMC single-cell reanalysis, CRS separated PsA from PsO; the source-defined PSX subgroup (joint pain without CASPAR-classified PsA) showed heterogeneous subject-level positioning, with above-band enrichment concentrated at the cell-type level. Cell-type-resolved analyses localized CRS-related shifts to T-cell, monocyte, B-cell, and regulatory compartments and identified multicompartment pathway state remodeling along the CRS continuum. In contrast, skin RNA sequencing mainly captured lesional inflammatory burden and showed only limited additional PsA-related separation within the same tissue state. These findings support a model in which PsA is distinguished from psoriasis by an additional systemic immune state axis rather than by skin inflammatory burden alone. Full article

(This article belongs to the Special Issue Psoriasis and Associated Complications: Pathogenic Mechanisms, Gene Biomarkers and Treatments)

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15 pages, 26757 KB

Open AccessArticle

Multiple Myeloma Concomitant with AL Amyloidosis: Histopathological Aspects of the Common Plasma Cell Spectrum

by Zarina Gioeva, Liudmila Mikhaleva, Aslan Tsutsaev, Anna Tebenkova, Nikita Gutyrchik, Nikolay Shakhpazyan, Alexander Ilyichev and Lev Kakturskij

Int. J. Mol. Sci. 2026, 27(11), 5120; https://doi.org/10.3390/ijms27115120 - 5 Jun 2026

Viewed by 309

Abstract

Concurrent multiple myeloma (MM) and AL amyloidosis is associated with the poorest outcomes among plasma cell dyscrasias and has dramatically reduced median overall survival. Despite their clinical significance, comprehensive systematic histopathological studies, characterizing multiorgan involvement and lesion severity are remarkably scarce. This study [...] Read more.

Concurrent multiple myeloma (MM) and AL amyloidosis is associated with the poorest outcomes among plasma cell dyscrasias and has dramatically reduced median overall survival. Despite their clinical significance, comprehensive systematic histopathological studies, characterizing multiorgan involvement and lesion severity are remarkably scarce. This study includes 24 autopsies (of 18 women and six men; median age—68 years) with MM-AL. Immunohistochemical (IHC) typing was performed with an expanded antibody panel targeting the amyloid precursor protein; anti-human CD138 antibody was used to identify plasma cells in bone marrow sections. Clinical diagnosis of MM with monoclonal G-lambda secretion, Durie–Salmon Stages II–III, was established in 17 (71%) patients; MM with monoclonal G-kappa secretion, Stage III, in five (21%); and non-secreting MM in two (8%). Systemic amyloidosis was revealed during life in only 15 (62.5%) patients. In all cases, extensive amyloid deposits were observed in the myocardium, lungs and kidneys, establishing the morphological basis for multiorgan failure. IHC typing of amyloids confirmed 18 (75%) cases of AL-lambda amyloidosis and six (25%) of AL-kappa amyloidosis. Our results clarify MM-AL morphogenesis and underscore that AL is frequently underdiagnosed in MM patients. Comprehensive histopathological studies with IHC typing are necessary to confirm the diagnosis, refine the prognosis, and optimize the therapeutic strategies. Full article

(This article belongs to the Special Issue Advancements in Hematology: Molecular Biology and Targeted Therapies)

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Int. J. Mol. Sci., Volume 27, Issue 11 (June-1 2026) – 498 articles

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