Current Issues in Molecular Biology

19 pages, 3677 KB

Open AccessArticle

Enzymatic Degradation Behavior and Molecular Weight Regulation of Dextran: Empirical Modeling and Multi-Scale Structural Characterization

by Mei Li, Piaoran Fan, Yirui Zhang, Ranran Li, Lemin Chen, Donghui Zhang and Lei Zhong

Curr. Issues Mol. Biol. 2026, 48(7), 749; https://doi.org/10.3390/cimb48070749 - 22 Jul 2026

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Abstract

To meet the demand for controlled production of low-molecular-weight (M_w < 10 kDa) dextran with potential pharmaceutical applications, this study developed an efficient enzymatic preparation process using PC-Edex, a dextranase derived from Penicillium cyclopium CICC-4022. The effects of enzyme concentration, substrate [...] Read more.

To meet the demand for controlled production of low-molecular-weight (M_w < 10 kDa) dextran with potential pharmaceutical applications, this study developed an efficient enzymatic preparation process using PC-Edex, a dextranase derived from Penicillium cyclopium CICC-4022. The effects of enzyme concentration, substrate concentration, temperature, and pH on the degradation of high-molecular-weight dextran were systematically investigated, and the optimal process conditions were established. A staged empirical control strategy based on the Malhotra model was developed to investigate and predict the behavior of dextran molecular weight changes during enzymatic hydrolysis. Under the optimized conditions, dextran with an M_w below 10 kDa was produced within 60 min, with the mass fraction of fragments smaller than 10 kDa reaching 94.56 ± 0.32% and the degradation rate exceeding 98.96 ± 0.15%. The resulting product exhibited a narrow molecular weight distribution (M_w/M_n = 1.528 ± 0.03) and adopted a compact random-coil conformation in aqueous solution. Multi-scale characterization results indicated that enzymatic degradation altered only the molecular weight of dextran, while the backbone structure, amorphous nature, and thermal stability were preserved. These findings present a robust and reproducible laboratory-scale process, which provides a reference for the industrial production of low-molecular-weight dextran for pharmaceutical purposes. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations in Structural Biology: From Proteins to Complex Biomolecular Systems)

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19 pages, 3797 KB

Open AccessArticle

Mutational Landscape of FGFR4 Across Malignancies: A Cross-Cancer Analysis of the AACR Project GENIE Database

by Henna Ali, Tyler Gengnagel, Salem Birkholz, Gowri Vadmal, Elijah Torbenson, Beau Hsia, Abubakar Tauseef and Peter T. Silberstein

Curr. Issues Mol. Biol. 2026, 48(7), 748; https://doi.org/10.3390/cimb48070748 - 22 Jul 2026

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Abstract

Background/Aim: Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase involved in cell growth, proliferation, and angiogenesis. While FGFR1–3 are well studied in cancer, FGFR4 remains relatively understudied, and the distribution of its mutations across cancers and patient populations is not well [...] Read more.

Background/Aim: Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase involved in cell growth, proliferation, and angiogenesis. While FGFR1–3 are well studied in cancer, FGFR4 remains relatively understudied, and the distribution of its mutations across cancers and patient populations is not well defined. Materials and Methods: A retrospective pan-cancer analysis was performed using the AACR Project GENIE v12 database via cBioPortal. Tumors with somatic FGFR4 mutations were included, excluding copy number alterations and structural variants. Mutations were grouped by hotspot (amino acid 401) and major protein domains. Comparative analyses assessed cancer type distribution, demographics, mutation burden, and co-occurring genomic alterations using chi-square testing with multiple comparison correction. Results: A total of 4565 tumor samples (4283 patients) were analyzed. FGFR4 alterations were observed across diverse malignancies, most commonly non-small cell lung cancer, colorectal cancer, and melanoma. Mutations clustered primarily in the tyrosine kinase and immunoglobulin I-set domains, with no significant variation in distribution across cancer types. Sex was not associated with the mutation group, while race and ethnicity showed significant differences. The FGFR4 hotspot 401 group demonstrated a higher mutation burden, driven by a subset of hypermutated tumors, and showed enrichment for co-occurring alterations in chromatin remodeling, DNA repair, tumor suppressor, and receptor tyrosine kinase genes; however, sensitivity analyses indicated this association was largely attributable to mutation burden rather than a mutation-specific effect. Domain-based mutation groups had lower mutation burdens and fewer co-alterations. Conclusions: FGFR4 alterations occur across a broad range of cancers with consistent domain-level patterns. The hotspot 401 mutation shows a higher mutation burden and co-alteration frequency driven largely by a subset of hypermutated tumors, rather than acting as an isolated driver. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers, 3rd Edition)

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15 pages, 3434 KB

Open AccessArticle

Integrative Transcriptomic and Network Analysis of Shared Osteo-Immune Regulatory Programs in Postmenopausal Osteoporosis and Osteosarcoma Within Central Mexican Cohorts

by Rogelio Frank Jiménez-Ortega, Aldo Hugo de la Cruz-Montoya, Nelly Patiño, Rafael Velázquez-Cruz and Alberto Hidalgo-Bravo

Curr. Issues Mol. Biol. 2026, 48(7), 747; https://doi.org/10.3390/cimb48070747 - 22 Jul 2026

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Abstract

Osteoporosis (OP) and osteosarcoma (OS) are biologically distinct skeletal disorders that share dysregulated bone remodeling, inflammatory signaling, and microenvironmental interactions. This study performed an integrative transcriptomic analysis to identify shared osteoimmune regulatory programs in circulating monocytes from postmenopausal women with OP and OS [...] Read more.

Osteoporosis (OP) and osteosarcoma (OS) are biologically distinct skeletal disorders that share dysregulated bone remodeling, inflammatory signaling, and microenvironmental interactions. This study performed an integrative transcriptomic analysis to identify shared osteoimmune regulatory programs in circulating monocytes from postmenopausal women with OP and OS tumors from Central Mexican cohorts. Two independent RNA-seq cohorts were analyzed separately and then integrated: circulating monocytes from postmenopausal women with OP and controls (7 OP and 7 controls), and donor-matched OS tissues (7 tumors and 7 healthy bone samples). Differential expression, module-based filtering, pathway enrichment, cross-cohort functional integration, directional concordance, and targeted interaction network analyses were performed. The OP cohort showed 169 differentially expressed genes, whereas the OS cohort showed 2135 genes. Module-based filtering retained 82 genes in OP and 278 in OS, with only six genes directly shared. However, pathway-level integration identified convergent signals involving PI3K-Akt, HIF-1 signaling, lipid and atherosclerosis, phagosome, endoplasmic reticulum protein processing, focal adhesion, proteoglycans in cancer, and cancer-related pathways. Directional analysis of 27 shared pathway-associated genes revealed predominantly discordant regulation, with CTNNB1 emerging as a central network node. These findings suggest that OP and OS converge through specific osteoimmune pathways rather than through a uniform shared gene program. Full article

(This article belongs to the Section Molecular Medicine)

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21 pages, 9149 KB

Open AccessArticle

Content Differences of Active Ingredients in Different Flower Colors of Carthamus tinctorius L. and Their α-Glucosidase Inhibitory Effects Based on Network Pharmacology and Molecular Docking

by Fan Huang, Wenzheng Zhao, Shiqing Wang, Jun Li, Ling Zeng and Jingfang Zhu

Curr. Issues Mol. Biol. 2026, 48(7), 746; https://doi.org/10.3390/cimb48070746 - 22 Jul 2026

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Abstract

This study investigated the content differences of major active ingredients in red, yellow, and white flowers of Carthamus tinctorius L. from Yumin County, Xinjiang, and evaluated their α-glucosidase inhibitory effects using high-performance liquid chromatography (HPLC), network pharmacology, molecular docking, and in vitro enzyme [...] Read more.

This study investigated the content differences of major active ingredients in red, yellow, and white flowers of Carthamus tinctorius L. from Yumin County, Xinjiang, and evaluated their α-glucosidase inhibitory effects using high-performance liquid chromatography (HPLC), network pharmacology, molecular docking, and in vitro enzyme assays. HPLC analysis revealed that red safflower had the highest content of Hydroxysafflor yellow A (HSYA), while white safflower exhibited the highest levels of kaempferol and kaempferol-3-O-rutinoside. Network pharmacology identified 21 core targets and multiple pathways related to type 2 diabetes and insulin resistance. Molecular docking indicated that kaempferol-3-O-rutinoside had the lowest binding energy (−9.3 kcal/mol). However, in vitro assays showed that kaempferol exhibited the strongest α-glucosidase inhibition (half maximal inhibitory concentration (IC₅₀) = 0.1768 mg/mL), followed by HSYA and kaempferol-3-O-rutinoside. Among extracts, white safflower demonstrated the highest inhibitory activity (IC₅₀ = 0.5485 mg/mL). In conclusion, flower color significantly influences the chemical composition and hypoglycemic potential of safflower. White safflower extract exhibited the strongest α-glucosidase inhibitory activity among the three flower color extracts. This study identifies kaempferol as the key active ingredient for safflower’s α-glucosidase inhibitory activity, providing a scientific basis for developing Yumin safflower as hypoglycemic functional food. Full article

(This article belongs to the Section Molecular Pharmacology)

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28 pages, 2498 KB

Open AccessReview

Proteostasis Dysfunction and Heat Shock Protein Networks in Intervertebral Disc Degeneration: Molecular Mechanisms and Therapeutic Opportunities

by Zhaoxi Wang, Shijie Chen, Zhaoheng Wang, Yong Sun, Kun Wang and Xuewen Kang

Curr. Issues Mol. Biol. 2026, 48(7), 745; https://doi.org/10.3390/cimb48070745 - 21 Jul 2026

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Abstract

Intervertebral disc degeneration is a major pathological contributor to low back pain and functional impairment, yet its complex molecular mechanisms have not been fully elucidated. Heat shock proteins, as important molecular chaperones and core regulators of cellular stress responses, exhibit dual protective and [...] Read more.

Intervertebral disc degeneration is a major pathological contributor to low back pain and functional impairment, yet its complex molecular mechanisms have not been fully elucidated. Heat shock proteins, as important molecular chaperones and core regulators of cellular stress responses, exhibit dual protective and pathogenic roles in the process of intervertebral disc degeneration. This review summarizes the expression changes and related regulatory networks of heat shock protein family members such as HSP70, HSP90, HSP27 and GRP78 in nucleus pulposus and annulus fibrosus cells, comprehensively discussing their involvement in the molecular mechanisms of intervertebral disc degeneration by influencing key processes such as cellular homeostasis, inflammatory responses, apoptosis, autophagy, and the synthesis and degradation of the extracellular matrix. Furthermore, this review highlights HSP-centered proteostasis regulation as an emerging therapeutic framework for IVDD and discusses how HSP modulation may be integrated with biomaterials, physical stimulation, and regenerative strategies. However, direct IVDD-specific evidence for certain HSP members remains limited, and this review also highlights current knowledge gaps and future research directions for HSP-centered proteostasis regulation. Full article

(This article belongs to the Section Molecular Medicine)

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13 pages, 1584 KB

Open AccessArticle

Nitroflavone Derivatives Inhibit the Production of Actinorhodin in Streptomyces coelicolor

by Sana Slimene, Michelle David, Daniel Dauzonne, Renato Bensasson, Marie-Joelle Virolle and Fathi Moussa

Curr. Issues Mol. Biol. 2026, 48(7), 744; https://doi.org/10.3390/cimb48070744 - 21 Jul 2026

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Abstract

Streptomyces coelicolor M145 (SC) is a model strain characterised by its highly active oxidative metabolism. This results in high levels of oxidative stress and the production of actinorhodin (ACT), a blue polyketide pigment with antioxidant properties. To determine whether oxidative stress triggers ACT [...] Read more.

Streptomyces coelicolor M145 (SC) is a model strain characterised by its highly active oxidative metabolism. This results in high levels of oxidative stress and the production of actinorhodin (ACT), a blue polyketide pigment with antioxidant properties. To determine whether oxidative stress triggers ACT biosynthesis in SC, we assessed the effect of adding five nitro-flavone (NF) derivatives to the growth medium. As NF molecules are well-known antioxidants, we hypothesized that their presence in the medium would moderate ACT production. The antioxidant efficiency of NF derivatives depends on their ability to donate electrons. This ability is linked to the nature of their 4’-substituent. The Quantitative Structure–Activity Relationship (QSAR) approach and Hammett constants predict the following order: OH > OCH₃ > F > H > NO₂. The results obtained demonstrate a clear dose–response relationship between the reduction in ACT production by SC and the antioxidant efficiency of these molecules. Therefore, these results strongly suggest that oxidative stress plays a pivotal role in initiating ACT biosynthesis. Furthermore, these results suggest that the direct spectrophotometric assay of ACT production by SC is a rapid, reliable, and inexpensive method of evaluating the in vivo antioxidant activity of any molecule, as predicted by the QSAR approach. Full article

(This article belongs to the Special Issue Novel Drugs and Natural Products Discovery—2nd Edition)

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22 pages, 11617 KB

Open AccessArticle

A Three-Gene Prognostic Signature Driven by an ER Stress-Associated ceRNA Network: Integrating Single-Cell Transcriptomics and Cross-Platform Validation in Hepatocellular Carcinoma

by Qingping Shi, Shuang Gao, Beiyan Chen, Mingli Shen and Jieru Han

Curr. Issues Mol. Biol. 2026, 48(7), 743; https://doi.org/10.3390/cimb48070743 - 21 Jul 2026

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Abstract

The progression and immune escape of HCC are closely regulated by endoplasmic reticulum stress (ERS). However, the associated ceRNA regulatory networks and their prognostic value remain to be systematically elucidated. Here, we sought to establish a prognostic signature derived from an ERS-associated ceRNA [...] Read more.

The progression and immune escape of HCC are closely regulated by endoplasmic reticulum stress (ERS). However, the associated ceRNA regulatory networks and their prognostic value remain to be systematically elucidated. Here, we sought to establish a prognostic signature derived from an ERS-associated ceRNA network and to investigate its relationship with the tumor immune microenvironment. We integrated TCGA-LIHC transcriptomic data with the MSigDB ERS gene set to identify ERS-associated differentially expressed genes and construct a ceRNA regulatory network. Using a forward search strategy with 10-fold cross-validation, we screened candidate genes to select the optimal prognostic combination and constructed a multigene Cox regression signature. External validation was performed in the independent microarray cohort GSE14520. By integrating single-cell transcriptomics, CIBERSORT, ESTIMATE, TIDE, and drug sensitivity analyses, we revealed immune microenvironment characteristics associated with this signature. Based on the ceRNA network’s eight core ERS mRNAs, an optimal three-gene signature comprising STC2, CKS1B, and PSAT1 was selected via forward search. The signature demonstrated robust prognostic discrimination in the TCGA training cohort (C-index = 0.653) and was independently corroborated in the external GSE14520 dataset (C-index = 0.584, log-rank p = 0.008). The signature was confirmed as an independent prognostic indicator by multivariable Cox regression. Functional enrichment analysis demonstrated a marked accumulation of cell-cycle-related pathways in the high-risk group, notably DNA replication and the spindle assembly checkpoint. Single-cell transcriptomic profiling showed that STC2 and CKS1B were predominantly expressed by tumor epithelial cells, whereas CCL2 and ATF3 were mainly detected in macrophages and fibroblasts. Drug sensitivity analysis indicated that the high-risk group was more sensitive to drugs such as docetaxel and AZD5582, consistent with the upregulation of proliferation pathways in this group; in the low-risk group, VE-822 exhibited selective sensitivity. This study established a three-gene prognostic signature based on the ERS-associated ceRNA network. The signature demonstrated robust prognostic stratification capabilities in cross-platform validation and revealed molecular characteristics centered on uncontrolled cell-cycle progression, as well as an immunosuppressive microenvironment, in the high-risk group, providing an exploratory tool for prognostic assessment and treatment strategy selection in hepatocellular carcinoma (HCC). Full article

(This article belongs to the Special Issue Molecular Insights into Cancer Biomarkers: Identification and Practical Applications)

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18 pages, 2471 KB

Open AccessArticle

Integrative Analysis Uncovers SETD5 as an Epigenetic Regulator of Transcriptional and Immune Tumor Programs Across Human Cancers

by Ana Cristina Moura Gualberto, Brunna Letícia de Oliveira Santana, Mariana Braccialli de Loyola, Yasmim Sampaio da Costa and Fábio Pittella-Silva

Curr. Issues Mol. Biol. 2026, 48(7), 742; https://doi.org/10.3390/cimb48070742 - 21 Jul 2026

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Abstract

SETD5 (SET domain-containing 5) is a chromatin-associated regulator increasingly recognized as dysregulated in human malignancies; however, its contribution to tumor biology and tumor–immune interactions remain undefined. We performed an integrative pan-cancer multi-omics analysis to define the landscape of SETD5 dysregulation across cancer types. [...] Read more.

SETD5 (SET domain-containing 5) is a chromatin-associated regulator increasingly recognized as dysregulated in human malignancies; however, its contribution to tumor biology and tumor–immune interactions remain undefined. We performed an integrative pan-cancer multi-omics analysis to define the landscape of SETD5 dysregulation across cancer types. Transcriptomic, genomic, and epigenetic datasets were integrated to evaluate SETD5 alterations and molecular associations. Protein interaction and pathway enrichment analyses were conducted using STRING, GO, and KEGG, and immunogenomic profiling was used to interrogate associations between SETD5 expression, immune infiltration, and checkpoint programs. SETD5 was overexpressed across multiple malignancies, with low mutation frequency but recurrent copy-number gains. Promoter hypomethylation was detected in a subset of tumors with increased SETD5 expression, suggesting a possible association with epigenetic regulation. Pathway analyses linked SETD5 to macromolecule methylation and transcriptional regulation. SETD5 expression correlated positively with infiltration of macrophages, neutrophils, and dendritic cells, whereas associations with CD8⁺ and CD4⁺ T cells varied by tumor type. Tumor type-specific correlations were observed between SETD5 and immune checkpoints genes, including PD-L1 and TIM-3, suggesting an association with immunoregulatory tumor states. These findings identify SETD5 as a recurrently deregulated epigenetic regulator and highlight its potential role in transcriptional control and tumor immune modulation. Full article

(This article belongs to the Special Issue Molecular Impacts of DNA Methylation as Epigenetic Drivers of Disease Onset and Progression)

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19 pages, 3444 KB

Open AccessArticle

Characterization of the Complete Mitochondrial Genome of Cricula andrei (Lepidoptera: Saturniidae) and Comparison with Other Lepidoptera Species

by Xiangrong Meng, Wentao Yang, Yuan Liu, Yongqi Zhang, Die Luo, Siyu Wei, Yifan Guo and Cen Qian

Curr. Issues Mol. Biol. 2026, 48(7), 741; https://doi.org/10.3390/cimb48070741 - 21 Jul 2026

Cited by 1 | Viewed by 300

Abstract

As the second largest order of Insecta, Lepidoptera is an important component of the ecosystems. However, there are few data on the mitochondrial genomes of Saturniidae. Here, the complete mitochondrial genome of Cricula andrei was sequenced and characterized. It was 15,324 bp in [...] Read more.

As the second largest order of Insecta, Lepidoptera is an important component of the ecosystems. However, there are few data on the mitochondrial genomes of Saturniidae. Here, the complete mitochondrial genome of Cricula andrei was sequenced and characterized. It was 15,324 bp in length, containing 13 protein-coding genes (PCGs), 22 tRNAs, 2 rRNAs and a control region (AT-rich region). The control region had an AT content of 90.40%, and the conserved ATAGA sequence guided a 19 bp poly-T. Amino acid composition analysis showed that Ile, Leu, Phe and Asn were the most frequent amino acids, and codon usage analysis revealed a preference for A/U-ending codons. Phylogenetic trees constructed by Bayesian inference and Maximum likelihood methods indicated that C. andrei is grouped with C. trifenestrata and supported the current taxonomic placement of Cricula within the family. The enrichment of the mitochondrial genome database of Lepidoptera will help to better understand the genetic and evolutionary relationships of lepidopteran populations, as well as related taxonomic issues. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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22 pages, 1524 KB

Open AccessReview

Helicobacter pylori and Early Vascular Aging: Endothelial Dysfunction, Arterial Stiffness, and Conditional Cardiovascular Vulnerability

by Federica Fogacci, Giulia Fiorini, Cristina Scollo, Claudio Borghi, Dino Vaira and Arrigo Francesco Giuseppe Cicero

Curr. Issues Mol. Biol. 2026, 48(7), 740; https://doi.org/10.3390/cimb48070740 - 21 Jul 2026

Cited by 1 | Viewed by 460

Abstract

Helicobacter pylori (H. pylori) infection has been investigated as a potential contributor to extra-gastric vascular injury, although its cardiovascular relevance remains uncertain and context-dependent. This state-of-the-art narrative review synthesizes clinical, translational, and experimental evidence linking H. pylori infection to endothelial dysfunction [...] Read more.

Helicobacter pylori (H. pylori) infection has been investigated as a potential contributor to extra-gastric vascular injury, although its cardiovascular relevance remains uncertain and context-dependent. This state-of-the-art narrative review synthesizes clinical, translational, and experimental evidence linking H. pylori infection to endothelial dysfunction and arterial stiffness, two complementary phenotypes of early vascular aging. Evidence is strongest for endothelial dysfunction, particularly in the presence of active or cytotoxin-associated gene A (CagA)-positive infection, extracellular-vesicle-mediated signaling, oxidative stress, impaired endothelial repair, selective attenuation of endothelium-dependent vasodilation, and short-term improvement after eradication. Associations with arterial stiffness are less consistent and appear more evident in selected settings characterized by younger age, inflammatory or metabolic vulnerability, and severe gastric injury. Conversely, serology-based studies and studies using late structural vascular endpoints frequently report null or discordant findings. Overall, H. pylori should not be considered a universal cardiovascular risk factor, but it may amplify early vascular injury in susceptible subgroups. Prospective studies using active-infection testing, virulence profiling, gastric histology, and prespecified vascular endpoints are needed to determine whether eradication produces sustained vascular benefit. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Advances in Hypertension Management and Vascular Health)

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24 pages, 3168 KB

Open AccessEditor’s ChoiceArticle

Expression of ABCB1, ABCB5, and ABCG2 Transporters in Human Renal Cell Carcinoma and Their Underlying Signaling Pathways

by Anna Vass, József Király, Erzsébet Szabó, Gábor Kónya, Ali Shammas, Krisztián Szegedi, Balázs Dezső, Éva Juhász, Gábor Halmos and Zsuzsanna Szabó

Curr. Issues Mol. Biol. 2026, 48(7), 739; https://doi.org/10.3390/cimb48070739 - 21 Jul 2026

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Abstract

Renal cell carcinoma (RCC) is frequently resistant to tyrosine kinase inhibitors (TKIs) such as sunitinib, limiting therapeutic efficacy. ATP-binding cassette (ABC) transporters, including ABCB1, ABCB5, and ABCG2, are important transporters implicated in multidrug resistance, influencing drug efflux and tumor progression. We aimed to [...] Read more.

Renal cell carcinoma (RCC) is frequently resistant to tyrosine kinase inhibitors (TKIs) such as sunitinib, limiting therapeutic efficacy. ATP-binding cassette (ABC) transporters, including ABCB1, ABCB5, and ABCG2, are important transporters implicated in multidrug resistance, influencing drug efflux and tumor progression. We aimed to evaluate the expression of ABCB1, ABCB5, and ABCG2 in human RCC tissues and human renal cancer cell lines CAKI-2 and A-498, and to investigate their potential association with sunitinib resistance and associated signaling pathways. Twenty paired tumorous and adjacent non-tumorous human kidney tissue samples were analyzed for ABC transporter gene expression using qRT-PCR. RCC cell lines CAKI-2 and A-498, including sunitinib-resistant derivatives, were treated with 40 µM sunitinib. The levels of transporters and key signaling proteins were assessed by Western blot. ABCG2 was consistently higher in tumorous tissues, and ABCB1 and ABCB5 showed grade-dependent increases in tumors. Resistant cells exhibited elevated ABCB1 and dynamic ABCB5 and ABCG2 expression patterns compared to sensitive cells, indicating an association between altered transporter expression and the resistant phenotype. Sunitinib treatment modulated signaling pathways, with differential activation of PI3K/Akt, NF-κB, and MAPK/ERK observed in sensitive versus resistant cells. Our findings suggest that altered ABCB1 and ABCG2 expression may be associated with the development of sunitinib resistance in RCC and may be linked to changes in key survival signaling pathways. These findings provide a basis for future functional studies investigating the role of ABC transporters in sunitinib resistance and may contribute to the development of personalized therapeutic strategies in RCC. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Cancer Treatment and Anticancer Drugs)

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15 pages, 1906 KB

Open AccessArticle

Genotypic Characterization and Evaluation of Japonica Soft Rice Varieties in the Yangtze River Delta Region of China

by Fuan Niu, Yuting Dai, Can Cheng, Anpeng Zhang, Huangwei Chu, Jihua Zhou, Bin Sun, Xiao Gu, Hua Wang, Kaizhen Xie, Fengzhen Shi, Xueqing Zhang, Bilian Hu, Yue Qiu, Xinyue Zhao, Wei Tian and Liming Cao

Curr. Issues Mol. Biol. 2026, 48(7), 738; https://doi.org/10.3390/cimb48070738 - 20 Jul 2026

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Abstract

Japonica soft rice varieties possess excellent eating quality, and their cultivation area has been steadily expanding in recent years. This study aimed to analyze japonica soft rice varieties cultivated in the Yangtze River Delta region of China at the genome level and to [...] Read more.

Japonica soft rice varieties possess excellent eating quality, and their cultivation area has been steadily expanding in recent years. This study aimed to analyze japonica soft rice varieties cultivated in the Yangtze River Delta region of China at the genome level and to provide a theoretical basis for optimizing disease resistance and other important traits. Genotypic characterization and evaluation of ten major japonica soft rice varieties from the Yangtze River Delta region were conducted using a genome-wide single nucleotide polymorphism (SNP) chip. The experimental results indicated that the soft rice varieties in the Yangtze River Delta region had a relatively high japonica component and were all classified as typical japonica rice varieties. Specifically, the highest (95.6%) and lowest (91.5%) proportions of japonica genomic segments were detected in Tai’an 1 and Zhehexiang 2, respectively. Japonica soft rice varieties from Shanghai exhibited a closer genetic distance to those from Jiangsu Province than to those from Zhejiang Province. Genomic identity was highest between Tai’an 1 and Nanjing 46 (87.9%) and lowest between Tai’an 1 and Jia 67 (74.4%). Based on the results of the chip assay, a total of twenty-six functional genes controlling key traits, such as yield, quality, and resistance to biotic and abiotic stresses, were identified in the ten analyzed varieties. Among them, Zhehexiang 2 carried the broad-spectrum blast resistance genes Pi2 and Pita, which is useful for improving the blast resistance of japonica soft rice varieties. The findings of this study provide genetic resources and carrier materials for the efficient molecular improvement of japonica soft rice varieties. Full article

(This article belongs to the Special Issue Advances in Molecular Plant Physiology and Genomic Breeding of Cereals)

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22 pages, 7650 KB

Open AccessArticle

The Oncogenic Role of Prostate Stem Cell Antigen (PSCA) in Colorectal Cancer: Implications for Targeted Therapy

by Jinyue Duan, Yi Wang, Qisen Li, Yujue Wang, Jinrui Liu, Yi Qi, Yichi Zhang, Changhao Fu, Zhongyi Cong, Can Wang and Manman Su

Curr. Issues Mol. Biol. 2026, 48(7), 737; https://doi.org/10.3390/cimb48070737 - 20 Jul 2026

Viewed by 665

Abstract

Prostate stem cell antigen (PSCA), a pivotal member of the lymphocyte antigen-6 (Ly6) protein family, has been implicated in the tumorigenesis and neoplastic progression of diverse cancer types. In this study, we conducted a thorough investigation into the role of PSCA in the [...] Read more.

Prostate stem cell antigen (PSCA), a pivotal member of the lymphocyte antigen-6 (Ly6) protein family, has been implicated in the tumorigenesis and neoplastic progression of diverse cancer types. In this study, we conducted a thorough investigation into the role of PSCA in the development of colorectal cancer (CRC). Survival analysis based on The Cancer Genome Atlas (TCGA) dataset demonstrated that elevated expression of PSCA was tightly correlated with unfavorable overall survival, inferior relapse-free survival, and worse post-progression survival among CRC patients. Additionally, PSCA exhibited significantly higher expression levels in colorectal cancer stem cell (CRC-SCs) relative to CRC cell lines. Loss-of-function assays using small interfering RNA (siRNA)-mediated silencing were performed to evaluate the effects of PSCA downregulation on the stemness properties of CRC-SCs, including proliferative capacity, invasive potential, and apoptotic rate, which were assessed by MTS assay, transwell invasion assay, and flow cytometry analysis, respectively. The results showed that silencing PSCA markedly suppressed the proliferation and invasion of CRC-SCs, while significantly promoting cellular apoptosis. RNA sequencing was performed to identify differentially expressed genes (DEGs) in the PSCA knockdown group compared to the negative control group. Follow-up analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) indicated that these DEGs were significantly enriched in the cell-substrate adherens junction term and the mitogen-activated protein kinase 9MAPK signaling pathway. Moreover, PSCA silencing substantially reduced the phosphorylation levels of the core MAPK signaling constituents, pBRAF and pERK1/2; conversely, PSCA overexpression prominently upregulated the expression of pBRAF and pERK1/2. In nude mice with CRC-SCs cancer xenograft tumors, treatment with PSCA siRNA significantly decreased tumor volume and weight, while also notably extending the survival time of the tumor-bearing mice compared to the control group. Collectively, these findings confirm that PSCA plays a critical oncogenic role in CRC cancer growth and malignant progression, suggesting its potential as a novel and promising therapeutic target for CRC. Full article

(This article belongs to the Special Issue Cancer-Associated Remodeling of Functional Molecular Pathways)

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14 pages, 2675 KB

Open AccessArticle

Carnosic Acid Attenuates TNF-α-Induced Insulin Resistance by Regulating Mitochondrial Function in 3T3-L1 Adipocytes

by Chia-Yuan Lin, Lok-I Chan, Yu-Hsuan Chang, Meng-Chun Lu and Chia-Wen Tsai

Curr. Issues Mol. Biol. 2026, 48(7), 736; https://doi.org/10.3390/cimb48070736 - 20 Jul 2026

Viewed by 387

Abstract

The disruption of mitochondrial homeostasis is a trigger for insulin resistance. The loss of N-acetyltransferase 1 (Nat1) function, an insulin-sensitivity gene, contributes to mitochondrial dysfunction and insulin resistance. Carnosic acid (CA), a diterpene derived from rosemary, has demonstrated an anti-insulin-resistance effect. This study [...] Read more.

The disruption of mitochondrial homeostasis is a trigger for insulin resistance. The loss of N-acetyltransferase 1 (Nat1) function, an insulin-sensitivity gene, contributes to mitochondrial dysfunction and insulin resistance. Carnosic acid (CA), a diterpene derived from rosemary, has demonstrated an anti-insulin-resistance effect. This study hypothesized that CA protects against TNF-α-induced insulin resistance in 3T3-L1 adipocytes by regulating mitochondrial dynamics, biogenesis, and function via Nat1. 3T3-L1 adipocytes were pretreated with CA for 12 h, followed by co-treatment with TNF-α for an additional indicated duration. Results showed that treatment of 3T3-L1 adipocytes with TNF-α decreases mitochondrial membrane potential (MMP) and PGC-1α protein levels and alters mitochondrial fission/fusion dynamics. Pretreatment with CA improved these effects. In parallel, CA prevented the TNF-α-induced reduction in Nat1 protein and improved insulin signaling by suppressing the phosphorylation of insulin receptor substrate-1 (IRS-1) at serine³⁰⁷, while restoring the phosphorylation of IRS-1 at tyrosine⁶²⁸ and Akt. Moreover, transfection with Nat1 siRNA inhibited the protective effect of CA against TNF-α-induced reductions in MMP, PGC-1α, and insulin signaling. In conclusion, CA ameliorated TNF-α-induced insulin resistance by reducing mitochondrial dysregulation by Nat1. Full article

(This article belongs to the Special Issue Molecular Insights into Multifactorial Causes of Insulin Resistance in Obesity, 2nd Edition)

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17 pages, 2597 KB

Open AccessArticle

Comprehensive Characterization and Antioxidant Function Prediction of Endogenous and Exogenous Peptides from Polygonatum kingianum

by Jieyao Ma, Huiling Liu, Yalan Wu, Tingsheng Ma, Huaming Xiao and Wei Cai

Curr. Issues Mol. Biol. 2026, 48(7), 735; https://doi.org/10.3390/cimb48070735 - 19 Jul 2026

Viewed by 419

Abstract

Background/Objectives: Polygonatum kingianum Collett & Hemsl. (PK) is an edible medicinal herb with tonic effects. Its natural antioxidant peptides are valuable for functional food development, while their characteristics and mechanisms are unclear. This study aimed to identify PK antioxidant peptides and explore [...] Read more.

Background/Objectives: Polygonatum kingianum Collett & Hemsl. (PK) is an edible medicinal herb with tonic effects. Its natural antioxidant peptides are valuable for functional food development, while their characteristics and mechanisms are unclear. This study aimed to identify PK antioxidant peptides and explore their antioxidant molecular mechanisms to support the utilization of PK active ingredients. Methods: Three peptide fractions (P1, P2, P3) were prepared from PK via defatting, alkali–acid precipitation and enzymatic hydrolysis. Nano-liquid chromatography coupled with Q Exactive mass spectrometry was used for peptide identification. Bioinformatic tools predicted peptide antioxidant activity, and molecular docking targeting the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) pathway verified peptide–target-binding affinity. Results: A total of 747, 1850 and 2537 peptides were identified from P1, P2 and P3, respectively, among which 119 peptides were screened out as potential antioxidant candidates. Docking analysis revealed 10 peptides with strong binding affinity to Keap1. These active peptides were short sequences of 3–5 residues enriched in hydrophobic and aromatic amino acids, which stably bound key residues within the Keap1 binding pocket. Conclusions: This study fills the research gap in PK peptidome profiling, clarifies structural signatures of candidate antioxidant peptides, and identifies high-affinity short peptides targeting the Keap1-Nrf2 antioxidant pathway. The established screening pipeline provides technical support for bioactive peptide mining and deep processing of PK resources. Full article

(This article belongs to the Special Issue The Efficacy and Applications of Synthetic and Natural Plant Compounds)

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26 pages, 477 KB

Open AccessReview

Pipettes and Pipelines: The Weapons of Omics Sciences for a New Age of Clinical Studies

by Ícaro S. Lopes, Eduardo R. Fukutani, Tiago F. Mota, Bruno B. Andrade, Mariana Araújo-Pereira and Artur T. L. Queiroz

Curr. Issues Mol. Biol. 2026, 48(7), 734; https://doi.org/10.3390/cimb48070734 - 18 Jul 2026

Viewed by 380

Abstract

The omics sciences represent a revolution for clinical studies, offering integrative approaches to analyzing biological data with unprecedented depth. From the discovery of the double-helix structure of DNA to the CRISPR-Cas9 gene editing tool, passing through the evolution of sequencing platforms and the [...] Read more.

The omics sciences represent a revolution for clinical studies, offering integrative approaches to analyzing biological data with unprecedented depth. From the discovery of the double-helix structure of DNA to the CRISPR-Cas9 gene editing tool, passing through the evolution of sequencing platforms and the exponential advance of computing power and in silico tools, omics has progressed in its role of leading innovative solutions for old challenges in health sciences. In this review, we describe different omics, the history of their techniques and technologies, data analysis and up-to-date visualization tools used for clinical data in research and health systems. We also discuss how omics are currently being applied in diagnosis, precision and personalized medicine. For the future, omics vow to underpin the majority of decisions made by health professionals, allowing individualized treatments based on Big Data and personal biological information. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

20 pages, 41026 KB

Open AccessArticle

Targeted Degradation of MCL-1 by PROTAC Mcl-1 Degrader-1 Exhibits Antiproliferative and Antimigratory Effects and Triggers Mitochondria-Mediated Apoptosis in Colorectal Cancer

by Seher Saruhan, Deniz Özdemir and Can Ali Ağca

Curr. Issues Mol. Biol. 2026, 48(7), 733; https://doi.org/10.3390/cimb48070733 - 17 Jul 2026

Viewed by 639

Abstract

Myeloid cell leukemia-1 (MCL-1) is a cellular survival protein belonging to the Bcl-2 protein family and is overexpressed in human colorectal cancer (CRC). Background: This study aimed to reduce cancer progression by suppressing the MCL-1 protein using PROTAC MCL-1 Degrader-1 and Trametinib, with [...] Read more.

Myeloid cell leukemia-1 (MCL-1) is a cellular survival protein belonging to the Bcl-2 protein family and is overexpressed in human colorectal cancer (CRC). Background: This study aimed to reduce cancer progression by suppressing the MCL-1 protein using PROTAC MCL-1 Degrader-1 and Trametinib, with the aim of overcoming the apoptosis resistance caused by high MCL-1 expression levels in colorectal cancer cells. Methods: Therefore, we tested the cell viability, proliferation, mitochondrial membrane potential, cell cycle progression, and cell death potential of MCL1-specific PROTAC Mcl-1 Degrader-1 and the combination of PROTAC Mcl-1 Degrader-1 and Trametinib in colorectal cancer cell lines using different methods such as WST-8 assays, real-time cell analysis, MMP/JC-1 staining assays, flow cytometry, and Western blot analysis. Results: The results suggest that PROTAC Mcl-1 Degrader-1 is associated with dose- and time-dependent reductions in cell proliferation in colorectal cancer cells. Under the experimental conditions used in this study, PROTAC MCL-1 Degrader-1 showed limited effects on the migratory potential of colorectal cancer cells but was associated with changes in cell cycle distribution, including an increased proportion of HT-29 cells in the G2/M phase. In addition, combination treatment with PROTAC MCL-1 Degrader-1 and trametinib was associated with greater reductions in cell viability and proliferation than either monotherapy. The combination treatment was also accompanied by changes in mitochondrial membrane potential and increased apoptotic cell populations, with a higher proportion of early apoptotic cells observed in HT-29 and COLO-205 colorectal cancer cell lines. Conclusion: Our findings suggest that the reduction in MCL-1 protein levels observed following PROTAC Mcl-1 Degrader-1 treatment may contribute to its potential therapeutic relevance in colorectal cancer. Full article

(This article belongs to the Special Issue Gastrointestinal Cancers: From Pathogenesis to Treatment)

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48 pages, 5353 KB

Open AccessReview

Dietary Polyphenols as Modulators of Redox Signalling: From the Antioxidant-Pro-Oxidant Continuum to Clinical Translation (2015–2025)

by José Manuel Pérez de la Lastra, Celia María Curieses Andrés, Elena Bustamante Munguira, Celia Andrés Juan and Eduardo Pérez Lebeña

Curr. Issues Mol. Biol. 2026, 48(7), 732; https://doi.org/10.3390/cimb48070732 - 17 Jul 2026

Cited by 1 | Viewed by 609

Abstract

Polyphenols often oscillate between antioxidant and pro-oxidant behaviours depending on structural motifs and context, yet the field still relies heavily on test-tube antioxidant assays that poorly predict cellular and clinical outcomes. This review (2015-2025) integrates chemistry, enzymology, and human data to frame polyphenols [...] Read more.

Polyphenols often oscillate between antioxidant and pro-oxidant behaviours depending on structural motifs and context, yet the field still relies heavily on test-tube antioxidant assays that poorly predict cellular and clinical outcomes. This review (2015-2025) integrates chemistry, enzymology, and human data to frame polyphenols as modulators of redox signalling rather than mere radical scavengers. We first formalize the catechol/o-quinone-hydroquinone/p-quinone cycle and the role of NQO1 and Keap1/NRF2 thresholds. We then examine bioavailability, conjugation, and microbiota-derived metabolites (metabotypes), highlighting when the “active” species is a conjugate or a microbial derivative. We discuss safety through quinone speciation and adduct chemistry, and connect food processing (e.g., PPO-driven browning) with shifts in quinone pools. Contextual “levers” (pH, O₂, Fe/Cu, oxidases) can flip antioxidant to pro-oxidant outputs, sometimes beneficial via hormesis and redox preconditioning. In humans, randomised trials and prospective cohorts point in a broadly consistent direction, although primary composite endpoints have often proved null, and observational associations should not be read as equivalent to trial evidence. Heterogeneous results across studies are largely explained by dose, adherence, metabotypes, matrix, and endpoint selection. We propose a practical dose-response framework and a reporting checklist to improve interpretation and translation. Recasting polyphenols as tuneable redox-signalling agents clarifies apparent contradictions across models and suggests precision-nutrition strategies (metabotype-aware) and food design approaches (PPO and quinone speciation) with potential in healthy ageing, muscle, and brain. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Natural Products and Their Antioxidant Roles in Health and Disease)

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21 pages, 8428 KB

Open AccessArticle

p53 and p21 Status Influences Cellular Response to Metformin in KRAS-Mutant HCT116 Colorectal Cancer Cells

by Asma Saeed, Jamila Hijazi, Zainab Bashir, Pierre Khoueiry, Assaad A. Eid, Nadine Darwiche, Maria Teresa Bengoechea-Alonso, Johan Ericsson, Borbala I. Mifsud and Georges Nemer

Curr. Issues Mol. Biol. 2026, 48(7), 731; https://doi.org/10.3390/cimb48070731 - 17 Jul 2026

Viewed by 599

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer morbidity worldwide, highlighting the need for improved therapies. Metformin, a widely used antihyperglycemic agent, has gained attention for its potential antitumor properties. In this study, we evaluated the effects of the tumor suppressor genes [...] Read more.

Colorectal cancer (CRC) remains a leading cause of cancer morbidity worldwide, highlighting the need for improved therapies. Metformin, a widely used antihyperglycemic agent, has gained attention for its potential antitumor properties. In this study, we evaluated the effects of the tumor suppressor genes TP53 and CDKN1A on metformin responsiveness in a KRAS-mutant CRC in vitro model using HCT116 cells harboring a G13D mutation in KRAS. Using parental (p53^+/+, p21^+/+) and isogenic knockout cell lines, we assessed cell-cycle distribution and transcriptomic responses following metformin treatment. In parental wild-type cells, metformin exposure was associated with a dose- and time-dependent reduction in cell viability and an increased proportion of cells in the G0/G1 phase, with significance levels across treatment conditions ranging from p = 0.03 to p < 0.0001. Loss of p53 or p21 was associated with attenuated cellular responses to metformin, with p21-deficient cells responding primarily at higher doses and prolonged exposure (72 h). Transcriptomic profiling revealed extensive differential gene expression in parental cells (1399 DEGs), compared with more limited responses in p53^−/− (270 DEGs) and p21^−/− cells (32 DEGs). Differentially expressed genes associated with MAPK signaling (DUSP5) and inflammatory regulation (TNFAIP3) were observed across genotypes, whereas pathway enrichment of DNA replication and chromatin organization was specific to p53-deficient cells. These findings provide a transcriptomic and phenotypic characterization of genotype-dependent cellular responses to metformin and establish a basis for future mechanistic and functional validation studies. Full article

(This article belongs to the Special Issue Gastrointestinal Cancers: From Pathogenesis to Treatment)

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17 pages, 2384 KB

Open AccessArticle

Plerixafor Engages β-Arrestin-Dependent CXCR4 Signaling to Promote Melanogenesis via β-Catenin-MITF Activation

by Tsong-Min Chang, Ting-Ya Yang and Huey-Chun Huang

Curr. Issues Mol. Biol. 2026, 48(7), 730; https://doi.org/10.3390/cimb48070730 - 17 Jul 2026

Viewed by 386

Abstract

Plerixafor is a clinically approved CXCR4 antagonist that mobilizes hematopoietic stem cells by disrupting CXCL12/CXCR4 retention signaling. However, its biochemical effects on melanocytes and pigmentation remain unexplored. We investigated how Plerixafor modulates CXCR4 signaling in melanocytes and evaluated its potential as a pro-melanogenic [...] Read more.

Plerixafor is a clinically approved CXCR4 antagonist that mobilizes hematopoietic stem cells by disrupting CXCL12/CXCR4 retention signaling. However, its biochemical effects on melanocytes and pigmentation remain unexplored. We investigated how Plerixafor modulates CXCR4 signaling in melanocytes and evaluated its potential as a pro-melanogenic agent using in vitro and in vivo approaches. Human PIG1 melanocytes were treated with 10 nM Plerixafor with or without hydroquinone (HQ), followed by qPCR for MITF and tyrosinase expression, flow cytometry for CXCR4/CXCR7 and integrin profiling, transwell migration assays, β-arrestin siRNA knockdown, Western blotting, subcellular fractionation, and ChIP-qPCR for β-catenin binding to MITF regulatory regions. A murine HQ-induced depigmentation model was used to test topical Plerixafor on pigmentation, hair follicles, melanogenic gene expression, and systemic safety markers. Plerixafor significantly increased MITF and tyrosinase mRNA and enhanced melanocyte migration while counteracting HQ-induced suppression of melanogenic genes. In addition, it reduced cell-surface CXCR4 (consistent with β-arrestin-mediated receptor internalization) without altering CXCR7, c-KIT, or N-cadherin. β-Arrestin knockdown abolished Plerixafor-induced ERK phosphorylation and melanogenic responses, confirming β-arrestin dependence. Plerixafor promoted β-catenin nuclear translocation and direct β-catenin occupancy at MITF promoter/enhancer TCF/LEF motifs. In vivo, topical Plerixafor restored HQ-induced depigmentation, increased hair follicle number and melanin content, and upregulated cutaneous MITF and tyrosinase without hepatic, renal, or inflammatory toxicity. Plerixafor functions as a biased CXCR4 ligand in melanocytes, influencing the β-arrestin–β-catenin–MITF signaling axis to drive melanogenesis and re-pigmentation. These findings identify β-arrestin-dependent CXCR4 signaling as a tractable pharmacologic mechanism for therapeutic re-pigmentation in pigmentary disorders. Full article

(This article belongs to the Special Issue Novel Pharmacological Strategies and Molecular Mechanisms in Nonclinical Research)

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20 pages, 4135 KB

Open AccessArticle

Metabolic and Signaling Dysregulation in a Cellular Model of Hepatic Insulin Resistance

by Hawraa Zbeeb, Chourouk Joumaa, Giulia De Negri Atanasio, Alberto Diaspro and Laura Vergani

Curr. Issues Mol. Biol. 2026, 48(7), 729; https://doi.org/10.3390/cimb48070729 - 17 Jul 2026

Viewed by 399

Abstract

Insulin resistance (IR) is the underlying pathogenic mechanism for Type 2 Diabetes Mellitus, which is interconnected with Fatty Liver Disease. To investigate the molecular mechanisms by which different metabolic triggers contribute to hepatic IR onset, we exposed human HepG₂ hepatocytes to varying [...] Read more.

Insulin resistance (IR) is the underlying pathogenic mechanism for Type 2 Diabetes Mellitus, which is interconnected with Fatty Liver Disease. To investigate the molecular mechanisms by which different metabolic triggers contribute to hepatic IR onset, we exposed human HepG₂ hepatocytes to varying glucose concentrations (25–50 mM), and/or insulin (1 nM), and a free fatty acid mixture (0.3 mM), mimicking moderate or severe hyperglycemia, hyperinsulinemia, and steatosis. Glucose consumption, glycogen and lipid droplet (LD) accumulation, gene expression, oxidative stress, and insulin signaling were assessed. Under severe hyperglycemia, both insulin and fatty acids decreased glucose consumption, whereas under moderate hyperglycemia, only insulin had this effect. Glycogen accumulation was increased across all treated conditions. Both insulin and fatty acids triggered steatosis and downregulated PPARγ and SIRT1 mRNA, with insulin increasing LD number, while FFAs increased both LD number and size. All conditions enhanced ROS production, resulting in oxidative stress, but with differences in antioxidant enzyme response. Insulin receptor expression was reduced by insulin and FFAs under moderate hyperglycemia but increased by these stimuli under severe hyperglycemia. Both stimuli enhanced AKT phosphorylation under both hyperglycemic conditions. We conclude that different triggers cooperate in promoting hepatic IR through distinct molecular and signaling mechanisms, suggesting that effective treatments may need to target multiple pathways simultaneously. Full article

(This article belongs to the Special Issue Molecular Insights into Multifactorial Causes of Insulin Resistance in Obesity, 2nd Edition)

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28 pages, 4493 KB

Open AccessReview

The Mechanism and Pathways of Formation and Modification of Salivary Metabolic Profile in Cancer

by Elena I. Dyachenko and Lyudmila V. Bel’skaya

Curr. Issues Mol. Biol. 2026, 48(7), 728; https://doi.org/10.3390/cimb48070728 - 16 Jul 2026

Viewed by 610

Abstract

Saliva is a promising diagnostic fluid for studying diseases, including cancer. Saliva composition can reflect both local processes occurring in the oral cavity and systemic changes associated with distant tumors. This review examines changes in salivary electrolyte, amino acid, lipid, and cytokine profiles, [...] Read more.

Saliva is a promising diagnostic fluid for studying diseases, including cancer. Saliva composition can reflect both local processes occurring in the oral cavity and systemic changes associated with distant tumors. This review examines changes in salivary electrolyte, amino acid, lipid, and cytokine profiles, tumor markers, and the oral microbiome in cancer. Collectively, these aspects reflect metabolic, inflammatory, immune, secretory, and tumor-associated processes. Metabolites can enter saliva via the salivary glands, systemic circulation, gingival fluid, extracellular vesicles, and oral cells, as well as directly from the site of disease during localized pathological processes. In tumors not localized in the oral cavity, changes in saliva composition are more often associated with systemic inflammation, altered oral microbiome, metabolic reprogramming, oxidative stress, and tumor-associated exosomes. Individual metabolites have limited specificity and cannot be used as independent diagnostic indicators. A comprehensive multimarker analysis of saliva is of greatest value. This approach can facilitate early diagnosis, identify the risk of disease development and progression, monitor therapy, and understand the biological changes associated with the pathological process, including tumors. Full article

(This article belongs to the Special Issue Early Molecular Diagnosis and Comprehensive Treatment of Tumors, 2nd Edition)

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17 pages, 9805 KB

Open AccessArticle

PAR2 Regulates Cardiac Pressure and Vascular Function Through Context-Dependent Signalling Mechanisms

by Joselia Carlos, Filip Konecny, Maryia Ryskina and John J. McGuire

Curr. Issues Mol. Biol. 2026, 48(7), 727; https://doi.org/10.3390/cimb48070727 - 16 Jul 2026

Cited by 1 | Viewed by 429

Abstract

Proteinase-activated receptor-2 (PAR2) regulates cardiac pressure and vascular function through context-dependent mechanisms that integrate G protein-coupled receptor signalling. We investigated the baseline cardiovascular phenotype of PAR2-deficient (PAR2^−/−) mice and the acute in vivo effects of the PAR2 agonist trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-Orn-amide (tcLIGRLO). [...] Read more.

Proteinase-activated receptor-2 (PAR2) regulates cardiac pressure and vascular function through context-dependent mechanisms that integrate G protein-coupled receptor signalling. We investigated the baseline cardiovascular phenotype of PAR2-deficient (PAR2^−/−) mice and the acute in vivo effects of the PAR2 agonist trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-Orn-amide (tcLIGRLO). Left ventricular pressure–volume (PV) analysis revealed that PAR2^−/− mice had elevated systolic and diastolic pressures with reduced end-diastolic volumes and increased ejection fraction while maintaining stroke volume and cardiac output. Thus, PAR2 deficiency produces a pressure-dominant cardiovascular state with increased mechanical work and preserved global function. In WT mice, tcLIGRLO dose-dependently reduced cardiac pressure generation, contractility, relaxation kinetics, and stroke work, whereas these effects were absent in PAR2^−/− mice, indicating PAR2-dependent cardiac regulation. Despite these changes, global cardiac output remained largely preserved despite modest reductions in heart rate. In contrast, tcLIGRLO elicited strain-dependent vascular responses, including altered effective aortic elastance and reduced carotid blood flow in PAR2^−/− mice. Ex vivo experiments showed that tcLIGRLO-induced contraction in PAR2^−/− arteries required Gq-dependent signalling in this experimental context. These findings identify PAR2 as a context-dependent regulator of cardiac pressure and vascular tone, in which PAR2-dependent cardiac effects and PAR2-independent, Gq-mediated vascular responses reflect distinct but interacting signalling mechanisms. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Vascular Function and Dysfunction: Roles of the Endothelium and G-Protein Coupled Receptors)

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18 pages, 6371 KB

Open AccessArticle

IGF2BP2 Promotes Esophageal Squamous-Cell Carcinoma Progression with Potential Involvement of PI3K/AKT Signaling

by Xiaohang Gao, Minghui Yang, Jing Yang, Yunpeng Zhong, Chao Ma, Guoliang Xu, Lin Zhang and Rong Zhang

Curr. Issues Mol. Biol. 2026, 48(7), 726; https://doi.org/10.3390/cimb48070726 - 16 Jul 2026

Viewed by 535

Abstract

Esophageal squamous-cell carcinoma (ESCC) remains a highly lethal malignancy, with long-term survival still unsatisfactory and an urgent need for clinically relevant molecular targets. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an RNA-binding protein with oncogenic activity in several tumor types, but [...] Read more.

Esophageal squamous-cell carcinoma (ESCC) remains a highly lethal malignancy, with long-term survival still unsatisfactory and an urgent need for clinically relevant molecular targets. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an RNA-binding protein with oncogenic activity in several tumor types, but the signaling events associated with its role in ESCC have not been fully defined. IGF2BP2 expression was examined in paired ESCC and adjacent non-tumor tissues by immunohistochemistry (10 paired samples) and qRT-PCR (16 paired samples). Associations with clinicopathological variables were evaluated in 108 TCGA ESCC cases. Stable lentiviral shRNA-mediated knockdown was established in KYSE30 and ECA109 cells. CCK-8, colony formation, Transwell, EdU, and flow cytometry assays were used to assess proliferation, clonogenic growth, migration, invasion, apoptosis, and cell-cycle distribution. EMT-associated markers were measured by Western blotting and qRT-PCR. RNA sequencing, KEGG enrichment analysis, and rescue experiments using the AKT activator SC79 were performed to explore downstream signaling. IGF2BP2 was upregulated in ESCC tissues at both the transcript and protein levels, and higher expression was associated with unfavorable clinicopathological characteristics. Silencing IGF2BP2 reduced proliferation, colony formation, migration, and invasion, promoted G0/G1 cell-cycle arrest, and increased apoptosis. EMT-associated marker analysis showed decreased Snail and increased Slug expression, indicating that these changes require cautious interpretation. RNA sequencing and KEGG analysis suggested enrichment of PI3K/AKT-related signaling after IGF2BP2 knockdown. IGF2BP2 silencing decreased PI3K and p-PI3K levels, whereas SC79 partly restored migratory and invasive capacities. IGF2BP2 contributes to malignant phenotypes in ESCC and may be associated with PI3K/AKT-related signaling. These findings indicate that IGF2BP2 is a candidate biomarker and potential therapeutic target, although further mechanistic and pharmacologic validation is required. Full article

(This article belongs to the Special Issue Cancer-Associated Remodeling of Functional Molecular Pathways)

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15 pages, 756 KB

Open AccessEditor’s ChoiceArticle

VEGF Expression in Head and Neck Squamous Cell Carcinoma: Association with TNM Staging and Tumor Progression

by Cristina Stefania Dumitru, Alina Cristina Barb, Antonia Armega Anghelescu, Dorin Novacescu, Marina Rakitovan, Cristian Silviu Suciu and Flavia Zara

Curr. Issues Mol. Biol. 2026, 48(7), 725; https://doi.org/10.3390/cimb48070725 - 16 Jul 2026

Cited by 1 | Viewed by 358

Abstract

Conventional TNM staging in head and neck squamous cell carcinoma (HNSCC) does not fully capture the molecular heterogeneity driving tumor aggressiveness. Identifying accessible biomarkers that complement staging is therefore a clinical priority. This retrospective study evaluated immunohistochemical VEGF expression in 50 histopathologically confirmed [...] Read more.

Conventional TNM staging in head and neck squamous cell carcinoma (HNSCC) does not fully capture the molecular heterogeneity driving tumor aggressiveness. Identifying accessible biomarkers that complement staging is therefore a clinical priority. This retrospective study evaluated immunohistochemical VEGF expression in 50 histopathologically confirmed HNSCC cases and examined its association with TNM staging and clinicopathological parameters. VEGF expression was assessed using a semi-quantitative immunoreactivity score (IRS; range 0–12; median 5; IQR 3–8). High VEGF expression (IRS ≥ 4) was identified in 64% of cases and was significantly associated with advanced tumor stage (III–IV; p = 0.032), higher T stage (T3–T4; p = 0.041), and regional lymph node metastasis (p = 0.018). Multivariate logistic regression confirmed nodal status as an independent predictor of high VEGF expression (OR = 2.85; 95% CI 1.12–7.24; p = 0.028). These findings indicate that VEGF expression is associated with adverse pathological features and markers of tumor progression in HNSCC. In the absence of survival data, prognostic conclusions cannot be drawn; prospective studies with survival endpoints are required to establish the clinical utility of VEGF as a prognostic biomarker. Full article

(This article belongs to the Special Issue Cancer Immunology: Molecular Tools, New Therapeutic Targets, Challenges, and Opportunities)

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19 pages, 2406 KB

Open AccessReview

Metabolic Reprogramming in Oral Cancer: A Narrative Review of Therapeutic Perspectives with Emphasis on Dichloroacetate

by Sara Senlle, Cécile Nicole, Patrícia M. A. Silva, Odília Queirós and Andrea Cunha

Curr. Issues Mol. Biol. 2026, 48(7), 724; https://doi.org/10.3390/cimb48070724 - 16 Jul 2026

Viewed by 527

Abstract

Oral squamous cell carcinoma (OSCC) represents a significant global health challenge characterized by high morbidity and mortality, frequently driven by therapeutic resistance and tumor aggressiveness. Metabolic reprogramming has emerged as a hallmark of OSCC, enabling tumor cells to sustain proliferation, survive under adverse [...] Read more.

Oral squamous cell carcinoma (OSCC) represents a significant global health challenge characterized by high morbidity and mortality, frequently driven by therapeutic resistance and tumor aggressiveness. Metabolic reprogramming has emerged as a hallmark of OSCC, enabling tumor cells to sustain proliferation, survive under adverse microenvironmental conditions, and evade therapeutic stress. Recent advances in cancer metabolism have identified metabolic plasticity as a central determinant of OSCC progression and treatment failure, highlighting the need to integrate evidence on metabolic vulnerabilities and therapeutic opportunities. This narrative review aims to provide an updated overview of metabolic reprogramming in OSCC, with particular emphasis on the interplay between glycolysis, mitochondrial metabolism, glutamine metabolism, and fatty acid oxidation, and to discuss how these interconnected pathways may be therapeutically exploited. Although OSCC cells exhibit enhanced aerobic glycolysis, mitochondria remain functionally active and play critical roles in energy production, redox homeostasis, and metabolic adaptation. The therapeutic potential of targeting tumor metabolism is discussed, highlighting dichloroacetate (DCA) as a promising metabolic modulator capable of inhibiting pyruvate dehydrogenase kinase (PDK), restoring mitochondrial glucose oxidation, and partially reversing the glycolytic phenotype. The review also examines the current translational limitations of DCA, including toxicity, pharmacokinetic constraints, and compensatory metabolic adaptations that restrict its efficacy as a standalone therapy. Furthermore, potential synergistic strategies are explored, particularly the combination of DCA with paclitaxel, which enhances therapeutic efficacy through concurrent disruption of cytoskeletal integrity and metabolic homeostasis, thereby increasing cellular susceptibility to apoptosis and overcoming chemoresistance. Full article

(This article belongs to the Special Issue Oral Cancer: Prophylaxis, Etiopathogenesis and Treatment, 2nd Edition)

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33 pages, 1729 KB

Open AccessReview

Tumoral Metabolism at the Intersection of Oncogene Signaling, Epigenetics and Immunology: Emerging Therapeutic Strategies in Cancer

by Bhoomendra A. Bhongade, Areeg Anwer Ali, Mohamed El-Tanani, Shakta Mani Satyam, Sirajunisa Talath, Adil Farooq Wali, Syed Arman Rabbani, Walaa Ibraheem, Karolina Hoffmann, Ashot Avagimyan, Ioannis Ilias, Sorina Ispas, Viviana Maggio, Anna Paczkowska and Manfredi Rizzo

Curr. Issues Mol. Biol. 2026, 48(7), 723; https://doi.org/10.3390/cimb48070723 - 15 Jul 2026

Viewed by 535

Abstract

Metabolic reprogramming is a unifying characteristic of cancer and involves orchestrated changes in glucose, amino acid, lipid, and mitochondrial metabolism that go beyond the well-known Warburg effect. Evidence is accumulating that these metabolic states are actively remodeled by oncogene signaling and tumor suppressor [...] Read more.

Metabolic reprogramming is a unifying characteristic of cancer and involves orchestrated changes in glucose, amino acid, lipid, and mitochondrial metabolism that go beyond the well-known Warburg effect. Evidence is accumulating that these metabolic states are actively remodeled by oncogene signaling and tumor suppressor loss, allowing cancer cells to sustain anabolic growth, redox homeostasis, and therapeutic stress. This review provides an overview of new findings on tumor metabolism, mechanisms, and the molecular networks governing this reprogramming. We discuss how the major oncogenic pathways, such as MYC, mTOR, HIF, and AMPK, reprogram metabolism using transcriptional, epigenetic, and post-translational control of metabolic flux. A focus is placed on mitochondrial bioenergetics, dynamics, and metabolite signaling such as cancer cell fitness and stress tolerance-defining factors. We also discussed metabolic crosstalk in the tumor ecosystem, including nutrient competition, metabolite coupling, and immunometabolic reprogramming to coordinate metabolism-mediated effects on tumorigenesis and therapeutic response. The review further considers the mechanistic basis for metabolism-targeted therapies, including pathway dependencies, adaptive responses, and micro-environmental context that constrain clinical benefit. Recent innovations such as spatial metabolomics, single-cell metabolic profiling, and systems-level models have unveiled significant intratumoral heterogeneity of metabolism, and they have provided important information about diverse vulnerabilities to therapeutic intervention. Accordingly, understanding the complex crosstalk between these metabolic networks is crucial to rationally designing combination strategies that selectively leverage cancer-specific metabolic liabilities with minimal toxicities against normal tissues. Full article

(This article belongs to the Special Issue Tumor Immunology: From Molecular Mechanisms to Treatment)

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23 pages, 2296 KB

Open AccessArticle

Evolutionary Divergence, Predicted Interaction Interface, and Regulatory Specialization of MTB as a Non-Catalytic Scaffold in the Plant m6A Writer Complex

by Hariharan Balasubramaniam, Susiharan Govindasamy Srinivasan and A. Santhana Krishna Kumar

Curr. Issues Mol. Biol. 2026, 48(7), 722; https://doi.org/10.3390/cimb48070722 - 15 Jul 2026

Viewed by 366

Abstract

N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic mRNA and a central regulator of plant development and stress adaptation. The plant m6A writer complex requires two MT-A70 family proteins, the catalytic subunit MTA70 and its non-catalytic partner MTB, yet the evolutionary [...] Read more.

N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic mRNA and a central regulator of plant development and stress adaptation. The plant m6A writer complex requires two MT-A70 family proteins, the catalytic subunit MTA70 and its non-catalytic partner MTB, yet the evolutionary basis and structural logic underlying this functional division remain unresolved across land plant lineages. Here, we present an integrative computational analysis of MTA70 and MTB across 15 phylogenetically representative species spanning bryophytes, lycophytes, charophyte algae, monocots, and dicots. Phylogenomic reconstruction resolved three strongly supported clades, namely MTA70, MTB, and an intermediate MTA70-like group, demonstrating that catalytic-to-regulatory divergence predates the separation of major land plant lineages. MTA70 proteins exhibited strict conservation of gene structure, catalytic motifs, and domain architecture, reflecting selective constraint at functionally critical residues, whereas MTB showed extensive divergence in exon–intron organization and surface-exposed residues, consistent with relaxed structural constraints. AlphaFold2-based structural modeling and data-driven protein–protein docking predicted a stable MTA70–MTB heterodimer with a buried surface area of 1435 Å² and a binding free energy of −8.1 kcal/mol, with Lys746 and Lys637 of MTB identified as primary interface hotspots by computational alanine scanning. Expression profiling across six species revealed preferential MTB accumulation in reproductive tissues, while promoter analysis identified statistically significant enrichment of jasmonate-responsive elements (TGACG-motif) in MTB promoters (Mann–Whitney U, p = 0.025) and a 3.4-fold higher abundance of ABA-responsive elements (ABRE) in MTB relative to MTA70, suggesting potential responsiveness to multiple phytohormone signals. Together, these findings establish an evolutionary and regulatory framework for MTB as a conserved scaffold coupling m6A deposition to developmental and environmental signaling in land plants. Full article

(This article belongs to the Section Molecular Plant Sciences)

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22 pages, 3499 KB

Open AccessReview

Next-Generation Sequencing in Pulmonary Fibrosis: Translational Promise and Current Clinical Limitations

by Raffaella Pagliaro, Fabio Perrotta, Stefano Sanduzzi Zamparelli, Valerio Maria Carrozzo, Alfredo Cipriano, Michele Mondoni, Giulia Maria Stella, Andrea Bianco and Filippo Scialò

Curr. Issues Mol. Biol. 2026, 48(7), 721; https://doi.org/10.3390/cimb48070721 - 15 Jul 2026

Viewed by 504

Abstract

Pulmonary fibrosis (PF), particularly idiopathic pulmonary fibrosis (IPF), is a progressive and often fatal interstitial lung disease characterised by complex genetic and molecular heterogeneity. Traditional diagnostic approaches, which rely on clinical, radiological and histopathological assessment, are frequently insufficient to capture the underlying biological [...] Read more.

Pulmonary fibrosis (PF), particularly idiopathic pulmonary fibrosis (IPF), is a progressive and often fatal interstitial lung disease characterised by complex genetic and molecular heterogeneity. Traditional diagnostic approaches, which rely on clinical, radiological and histopathological assessment, are frequently insufficient to capture the underlying biological diversity of the disease. The advent of next-generation sequencing (NGS) has substantially advanced the understanding of PF by enabling comprehensive genomic and transcriptomic profiling. NGS technologies, including whole-exome sequencing (WES), whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and targeted gene panels, have uncovered key genetic determinants. These include mutations in telomere-related genes (TERT, TERC, RTEL1) and surfactant-related genes (SFTPC, SFTPA2), as well as common variants like the MUC5B promoter polymorphism. These discoveries have clarified disease pathogenesis, revealed polygenic risk models, and may improve diagnostic accuracy, particularly in distinguishing overlapping interstitial lung disease (ILD) phenotypes. Beyond genetics, transcriptomic analyses have identified dysregulated pathways, including TGF-β, Wnt/β-catenin, and PI3K/Akt signalling, and have enabled the discovery of novel biomarkers for prognosis and therapeutic response. In selected clinical settings, NGS is beginning to support patient stratification and inform management decisions. Emerging applications, including liquid biopsy and integration with artificial intelligence, further expand the potential clinical utility of NGS. Despite challenges related to cost, data interpretation and standardisation, NGS represents a powerful research tool in PF. Full article

(This article belongs to the Special Issue Technological Advances Around Next-Generation Sequencing Application, 2nd Edition)

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Open AccessArticle

Development of Wedelia (Sphagneticola trilobata) and Sembung Rambat (Mikania micrantha) Extracts as Herbal Medicine for Chronic Obstructive Pulmonary Disease (COPD)

by Dyah Iswantini, Min Rahminiwati, Trivadila Trivadila, Novriyandi Hanif, Siti Sadiah, Rut Novalia Rahmawati Sianipar, Riska Amelia Candra, Rani Melati Sukma, Susi Indariani, Raisa Zahra and Muthia Khansa

Curr. Issues Mol. Biol. 2026, 48(7), 720; https://doi.org/10.3390/cimb48070720 - 15 Jul 2026

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Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory condition characterized by progressive deterioration in lung function and persistent symptoms, particularly dyspnea, which can lead to death. Inflammation is important in COPD pathogenesis because it causes persistent inflammatory responses in the respiratory tract. [...] Read more.

Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory condition characterized by progressive deterioration in lung function and persistent symptoms, particularly dyspnea, which can lead to death. Inflammation is important in COPD pathogenesis because it causes persistent inflammatory responses in the respiratory tract. Therefore, this study aimed to investigate H₂O extracts derived from Wedelia (Sphagneticola trilobata) and Sembung Rambat (Mikania micrantha), respectively, as anti-inflammatory agents and to analyze the metabolite profiles contained in the extracts. The results showed that Sembung Rambat H₂O extract demonstrated significant inhibition of IL-2 (100 ± 0.00%), while Wedelia extract inhibited 74.68 ± 7.13% release of pro-inflammatory cytokine IL-6. Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) analysis mainly identified the presence of amino acids, phenolic acids, organic acids, and terpenoids in both extracts. These results suggest the promising potential of Wedelia and Sembung Rambat extracts as herbal therapy for COPD. Full article

(This article belongs to the Special Issue The Role of Bioactives in Inflammation, 2nd Edition)

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Curr. Issues Mol. Biol., Volume 48, Issue 7 (July 2026) – 106 articles

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