Current Issues in Molecular Biology

11 pages, 1746 KB

Open AccessBrief Report

Valproic Acid as a Histone Deacetylase Inhibitor Induces ABCB1 Overexpression and De Novo ABCB5 Expression in HeLa Cells

by Gabriela Rebeca Luna-Palencia, José Correa-Basurto and Ismael Vásquez-Moctezuma

Curr. Issues Mol. Biol. 2025, 47(9), 749; https://doi.org/10.3390/cimb47090749 - 11 Sep 2025

Abstract

Histone deacetylase inhibitors (HDACis) induce the expression of multidrug resistance (MDR) pumps and can even display the MDR phenotype in cell lines. This is the first report to include the profiles of ATP-binding cassette (ABC) transporters in intrinsically expressed HeLa cells as well [...] Read more.

Histone deacetylase inhibitors (HDACis) induce the expression of multidrug resistance (MDR) pumps and can even display the MDR phenotype in cell lines. This is the first report to include the profiles of ATP-binding cassette (ABC) transporters in intrinsically expressed HeLa cells as well as those acquired due to a 5 mM valproic acid (VPA) treatment. Expression of ABC transporters related to the MDR phenotype was analyzed by RT-PCR in untreated HeLa cells and HeLa cells treated with 5 mM VPA. The ABCB5 protein was identified in HeLa cells by immunocytochemistry. HeLa cell treatment with 5 mM VPA increased ABCB1 expression and triggered the de novo expression of ABCB5 in mRNA and protein. Despite the expression of ABCB5 and the overexpression of ABCB1, VPA reduced the growth rate by 20%, delayed doubling time by 25%, and decreased the number of living cells per well to 50% after 72 h. Pretreatment with VPA for 24 h followed by cotreatment with doxorubicin (DOX) sensitized HeLa cells to DOX. However, for the de novo expression of ABCB5, HeLa cells did not acquire the MDR phenotype from the 5 mM VPA treatment. The ABCB5 isoform induced by VPA treatment probably lacks MDR activity. Full article

(This article belongs to the Section Molecular Medicine)

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21 pages, 9510 KB

Open AccessArticle

Resina Draconis Promotes Diabetic Wound Healing by Regulating the AGE-RAGE Pathway to Modulate Macrophage Polarization

by Xin Jin, Ang Li, Zhaoyuan Dai, Yi Li, Xinchi Feng and Feng Qiu

Curr. Issues Mol. Biol. 2025, 47(9), 748; https://doi.org/10.3390/cimb47090748 - 11 Sep 2025

Abstract

Resina Draconis (RD), a traditional Chinese medicine, has been widely used in treating diabetic foot ulcers. However, its specific mechanisms of action remain incompletely understood. First, network pharmacology combined with GEO clinical sample data mining was employed to systematically analyze the therapeutic targets [...] Read more.

Resina Draconis (RD), a traditional Chinese medicine, has been widely used in treating diabetic foot ulcers. However, its specific mechanisms of action remain incompletely understood. First, network pharmacology combined with GEO clinical sample data mining was employed to systematically analyze the therapeutic targets of RD in promoting diabetic wound healing. Second, an AGEs-induced RAW264.7 cell model was utilized to investigate the regulatory effects of RD and its primary active components on the AGE-RAGE signaling pathway, along with their anti-inflammatory and antioxidant activities. Finally, a diabetic wound mouse model was established to validate the efficacy of RD and further explore its underlying molecular mechanisms. Integrated analysis of network pharmacology and GEO database mining identified 492 potential therapeutic targets of RD in diabetic wound healing, primarily involving the AGE-RAGE pathway. In vitro, RD (6.25 μg/mL) significantly suppressed AGE-induced inflammatory factors and ROS production while downregulating AGE-triggered RAGE protein overexpression. In vivo, RD hydrogel accelerated diabetic wound healing by modulating the AGE-RAGE axis and regulating macrophage polarization. RD effectively promotes diabetic wound healing through synergistic regulation of the AGE-RAGE pathway, oxidative stress suppression, and macrophage polarization modulation, providing a novel therapeutic strategy for diabetic wound management. Full article

(This article belongs to the Section Molecular Pharmacology)

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17 pages, 6301 KB

Open AccessArticle

Integration of eQTL and GEO Datasets to Identify Genes Associated with Breast Ductal Carcinoma In Situ

by Cai-Qin Mo, Rui-Wang Xie, Wei-Wei Li, Min-Jie Zhong, Yu-Yang Li, Jun-Yu Lin, Juan-Si Zhang, Sheng-Kai Zheng, Wei Lin, Ling-Jun Kong, Sun-Wang Xu and Xiang-Jin Chen

Curr. Issues Mol. Biol. 2025, 47(9), 747; https://doi.org/10.3390/cimb47090747 - 11 Sep 2025

Abstract

Background: Breast ductal carcinoma in situ (DCIS), a common precursor of breast cancer, has poorly understood susceptible driver genes. This study aimed to identify genes influencing DCIS progression by integrating Mendelian randomization (MR) and Gene Expression Omnibus (GEO) datasets. Methods: The GEO database [...] Read more.

Background: Breast ductal carcinoma in situ (DCIS), a common precursor of breast cancer, has poorly understood susceptible driver genes. This study aimed to identify genes influencing DCIS progression by integrating Mendelian randomization (MR) and Gene Expression Omnibus (GEO) datasets. Methods: The GEO database was searched for DCIS-related datasets to extract differentially expressed genes (DEGs). MR was employed to find exposure single-nucleotide polymorphisms (SNPs) of expression quantitative trait locus (eQTL) gene expression from Genome-Wide Association Study database (GWAS) (IEU openGWAS project). DCIS was designated as the outcome variable. The intersection of genes was used for GO, KEGG and CIBERSORT analyses. The functional validation of selected DEGs was performed using Transwell invasion assays. Results: Four datasets (GSE7782, GSE16873, GSE21422, and GSE59246) and 19,943 eQTL exposure data were obtained from GEO and the IEU openGWAS project, respectively. By intersecting DEGs, 13 genes (LGALS8, PTPN12, YTHDC2, RNGTT, CYB5R2, KLHDC4, APOBEC3G, GPX3, RASA3, TSPAN4, MAPKAPK3, ZFP37, and RAB3IL1) were incorporated into subsequent KEGG and GO analyses. Functional assays confirmed that silencing PTPN12, YTHDC2 and MAPKAPK3, or overexpressing GPX3, RASA3 and TSPAN4, significantly suppressed DCIS cell invasion. These DEGs were linked to immune functions, such as antigen processing and presentation and the tumor microenvironment (TME), and they showed associations with dendritic cell activation differences. Conclusions: Thirteen genes were associated with DCIS progression, and six genes were validated in the cell experiments. KEGG and GO analyses highlight TME’s role in early breast cancer, enhancing understanding of DCIS occurrence and aiding identification of high-risk tumors. Full article

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

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20 pages, 1579 KB

Open AccessArticle

Serum TNF -α, IL-10 and IL-2 Trajectories and Outcomes in NSCLC and Melanoma Under Anti-PD-1 Therapy: Longitudinal Real-World Evidence from a Single Center

by Alina Miruna Grecea-Balaj, Olga Soritau, Ioana Brie, Maria Perde-Schrepler, Piroska Virag, Eva Fischer-Fodor, Nicolae Todor, Mihai Cenariu, Ioana Nedelea and Tudor Eliade Ciuleanu

Curr. Issues Mol. Biol. 2025, 47(9), 746; https://doi.org/10.3390/cimb47090746 - 11 Sep 2025

Abstract

This prospective single-center study examined associations between serum cytokines—TNF-α, IL-2, and IL-10—and outcomes in stage IV non-small cell lung cancer (NSCLC, n = 43) and melanoma (n = 15) patients treated with Nivolumab at the Oncology Institute in Cluj-Napoca, Romania. Cytokines were [...] Read more.

This prospective single-center study examined associations between serum cytokines—TNF-α, IL-2, and IL-10—and outcomes in stage IV non-small cell lung cancer (NSCLC, n = 43) and melanoma (n = 15) patients treated with Nivolumab at the Oncology Institute in Cluj-Napoca, Romania. Cytokines were measured at baseline (NSCLC: n = 43; melanoma: n = 15), 3 months (NSCLC: n = 20; melanoma: n = 7), and 6 months (NSCLC: n = 10; melanoma: n = 5). Melanoma patients showed sustained IL-2 and TNF-α increases, while NSCLC patients displayed heterogeneous cytokine dynamics. In NSCLC, elevated IL-10 at 3 months correlated with shorter survival (ρ = −0.51, 95% CI −0.78 to −0.12, p = 0.022) and poorer response (ρ = −0.65, 95% CI −0.86 to −0.23, p = 0.002). TNF-α showed a borderline association with response (ρ = −0.44, 95% CI −0.74 to 0.01, p = 0.050). In melanoma, 3-month TNF-α was inversely associated with survival (ρ = −0.82, 95% CI −0.97 to −0.15, p = 0.023) and response (ρ = −0.90, 95% CI −0.99 to −0.39, p = 0.006). Strong inter-cytokine correlations were observed (NSCLC: TNF-α vs. IL-10, ρ = 0.60, 95% CI 0.19–0.82; melanoma: ρ = 0.93, 95% CI 0.44–0.99). Baseline cytokines had limited utility, particularly in melanoma due to the small sample size. The most informative finding was the association of elevated 3-month IL-10 with adverse outcomes in NSCLC. These results support the value of dynamic cytokine monitoring in immunotherapy and warrant validation in larger cohorts. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers: 2nd Edition)

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16 pages, 931 KB

Open AccessReview

Myo-Inositol Oxygenase (MIOX): A Pivotal Regulator and Therapeutic Target in Multiple Diseases

by Shaocong Han, Min Zhang, Huan Yang, Huiqiong Yang, Yanmei Tang, Weixi Li, Li Li, Jie Yu and Xingxin Yang

Curr. Issues Mol. Biol. 2025, 47(9), 745; https://doi.org/10.3390/cimb47090745 - 11 Sep 2025

Abstract

Myo-inositol oxygenase (MIOX), as the sole enzyme catalyzing myo-inositol (MI) catabolism in mammals, plays a central role in maintaining intracellular MI homeostasis. Dysregulation of MIOX activity disrupts MI metabolic balance, leading to pathological processes including oxidative stress, inflammation, and ferroptosis, which subsequently induce [...] Read more.

Myo-inositol oxygenase (MIOX), as the sole enzyme catalyzing myo-inositol (MI) catabolism in mammals, plays a central role in maintaining intracellular MI homeostasis. Dysregulation of MIOX activity disrupts MI metabolic balance, leading to pathological processes including oxidative stress, inflammation, and ferroptosis, which subsequently induce multiple diseases such as metabolic syndrome, neurological disorders, tumors, and reproductive/developmental disorders. This article systematically reviews the structure and function of MIOX as well as the pathological consequences arising from its dysregulation. Although its pathological significance is increasingly recognized, the molecular mechanisms of MIOX in many diseases have not been fully elucidated, and targeted modulators of MIOX are lacking. Future research should focus on the in-depth elucidation of the pathogenic mechanisms of MIOX disorders and the development of MIOX modulators, thereby providing precise therapeutic strategies for related diseases. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2025)

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12 pages, 814 KB

Open AccessArticle

TP53 IVS3 16 bp Variant and Breast Cancer Risk in Western Mexican Women: A Case–Control Study

by Mariana Araiza-Guzmán, Bricia M. Gutiérrez-Zepeda, Ana M. Saldaña-Cruz, Ingrid B. Montoya-Delgado, Diana Rubio-Delgado, Pablo Benítez-Villa, Diana M. Hernández-Corona, Adrian Daneri-Navarro, Alicia del Toro-Arreola, Jazmin Márquez-Pedroza, Antonio Quintero-Ramos and Betsabé Contreras-Haro

Curr. Issues Mol. Biol. 2025, 47(9), 744; https://doi.org/10.3390/cimb47090744 - 11 Sep 2025

Abstract

Background: Mutations in the TP53 gene can alter its tumor suppressor functions, thereby promoting oncogenic activity. The TP53 IVS3 16 bp genetic variant overlaps with nucleotide sequences that can alter regulatory structures, potentially affecting its function. The aim of the present study was [...] Read more.

Background: Mutations in the TP53 gene can alter its tumor suppressor functions, thereby promoting oncogenic activity. The TP53 IVS3 16 bp genetic variant overlaps with nucleotide sequences that can alter regulatory structures, potentially affecting its function. The aim of the present study was to evaluate the association between TP53 IVS3 16 bp genetic variant and the risk of breast cancer (BC) in women from western Mexico. Methods: The study included 220 women diagnosed with BC and 198 cancer-free controls. Clinical and demographic data were collected through structured questionnaires and verified with medical records. Genotyping of the TP53 IVS3 16 bp genetic variant was performed using polymerase chain reaction (PCR) and visualized on 6% polyacrylamide gels. Results: Compared to controls, women with BC more frequently reported a family history of the disease and menopausal status (p < 0.05). Genotypic analysis revealed that carriers of the D/I genotype and the combined D/I + I/I genotypes were associated with a reduced risk of BC in codominant (OR = 0.53; 95% CI 0.32–0.88) and dominant (OR = 0.57; 95% CI 0.35–0.93) models. Conclusions: The D/I and D/I + I/I genotypes in codominant and dominant models showed a lower risk against BC. More studies are needed to confirm these findings. Full article

(This article belongs to the Special Issue Genomic Analysis of Common Disease, 2nd Edition)

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5 pages, 178 KB

Open AccessEditorial

Editorial for the Special Issue “Pharmacological Activities and Mechanisms of Action of Natural Products”

by Shining Loo, Antony Kam, Chunyue Du and Simon Ming-Yuen Lee

Curr. Issues Mol. Biol. 2025, 47(9), 743; https://doi.org/10.3390/cimb47090743 - 11 Sep 2025

Abstract

Natural products have long fascinated scientists as a vast source of structurally diverse bioactive compounds, serving as templates for many contemporary pharmaceuticals [...] Full article

(This article belongs to the Special Issue Pharmacological Activities and Mechanisms of Action of Natural Products)

22 pages, 1816 KB

Open AccessReview

Research Progress on Nutritional Components, Functional Active Components, and Pharmacological Properties of Floccularia luteovirens

by Siyuan Gou, Lihua Tang, Huange Huang, Yanqing Ni, Tongjia Shi, Wensheng Li, Yan Wan and Xu Zhao

Curr. Issues Mol. Biol. 2025, 47(9), 742; https://doi.org/10.3390/cimb47090742 - 10 Sep 2025

Abstract

Edible and medicinal fungi are a general term for large fungi with both edible and medicinal values. As a unique wild edible and medicinal fungus in the Qinghai-Tibet Plateau, the ‘Four Medical Classics’ of the Tang Dynasty has recorded Floccularia luteovirens effects of [...] Read more.

Edible and medicinal fungi are a general term for large fungi with both edible and medicinal values. As a unique wild edible and medicinal fungus in the Qinghai-Tibet Plateau, the ‘Four Medical Classics’ of the Tang Dynasty has recorded Floccularia luteovirens effects of external application and internal administration on swelling, cold disease, and neck stiffness. At present, it has not been artificially domesticated and has significant development potential. The mushroom is rich in nutrients. The crude protein content of 100 g dried product is 33~39% (up to 38.71 g, about 2.2 times that of Flammulina velutipes). It contains 19 amino acids (including 8 essential amino acids for the human body; tryptophan accounts for 21.55~22.63%). It is also rich in minerals such as selenium, zinc (0.09 g/kg), and iron (0.3 g/kg) and vitamins B1 (0.10 mg), B2 (1.10 mg), C (4.50 mg), and E (6.20 mg). Among the functional active substances, polysaccharides (containing 20.1% β-glucan and 5.7% mannan-oligosaccharide) had antioxidant and immunomodulatory effects, which could alleviate the weight loss of diabetic rats. The IC50 of DPPH free radical scavenging rate of phenolics (ferulic acid, etc.; total phenolic content of 4.21 ± 0.06 mg/g) was 43.85 μg/mL; there was also adenosine, volatile oil, and other components. Pharmacologically, the DPPH free radical scavenging rate of the extract was 65 ± 0.46%, the tumor inhibition rate of the polysaccharide on the tumor-bearing mice was 42.48%, the gastrodin was biocatalyzed (conversion rate 85.2%), and the extracellular polysaccharide could inhibit the color change in shrimp to achieve preservation. This paper reviews its related research progress and provides a reference for its development in the fields of healthy food and biomedicine. Full article

(This article belongs to the Section Molecular Microbiology)

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28 pages, 2063 KB

Open AccessReview

JUNB and JUND in Urological Cancers: A Literature Review

by Georgios Kalampounias, Theodosia Androutsopoulou and Panagiotis Katsoris

Curr. Issues Mol. Biol. 2025, 47(9), 741; https://doi.org/10.3390/cimb47090741 - 10 Sep 2025

Abstract

JUNB and JUND are two transcriptional factors (TFs) of increased interest in cancer, regulating the expression of genes associated with survival, proliferation, differentiation, migration, invasion, angiogenesis, adhesion, apoptosis, and cell cycle regulation. Together with c-JUN, they constitute the JUN family of TFs, acting [...] Read more.

JUNB and JUND are two transcriptional factors (TFs) of increased interest in cancer, regulating the expression of genes associated with survival, proliferation, differentiation, migration, invasion, angiogenesis, adhesion, apoptosis, and cell cycle regulation. Together with c-JUN, they constitute the JUN family of TFs, acting as downstream effectors of the MAPKs, with established roles in carcinogenesis, disease progression, metastasis, and therapy resistance. Their phosphorylation leads to the formation of dimeric complexes with other TFs (from the JUN, FOS, or ATF families), thereby assembling the AP-1 complex, which exerts multifaceted influences on both normal and cancerous cells. JUNB and JUND are credited with both tumor-suppressing and oncogenic roles, since the outcome of their activation relies on the specific cancer type, disease stage, intracellular localization, and the expression of interacting cofactors. This narrative review explores the current understanding of JUNB and JUND roles within urological cancers (prostate, bladder, renal, and testicular cancer) as these malignancies, while distinct, share common genetic and/or environmental risk factors and varying degrees of androgen receptor (AR) dependency. The study discusses commonalities and differences in the expression patterns, mechanisms, and clinical implications of JUNB and JUND across urological cancers, thus highlighting their potential as prevention, diagnosis, prognosis, and treatment targets. Full article

(This article belongs to the Special Issue Molecular Research of Urological Diseases)

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9 pages, 1118 KB

Open AccessArticle

Inflammatory Molecule Elaboration in Secondhand Smoke (SHS)-Induced or Conditional RAGE Transgenic Modeling of Chronic Rhinosinusitis (CRS)

by Logan Ponder, Ryan Kinney, Ankita Chatterjee, Kristina Vu, Harishma Sidhu, Neha Patel, Tejus Desai, Daniel L. Orr II, Juan A. Arroyo and Paul R. Reynolds

Curr. Issues Mol. Biol. 2025, 47(9), 740; https://doi.org/10.3390/cimb47090740 - 10 Sep 2025

Abstract

Chronic rhinosinusitis (CRS) is characterized by sinonasal inflammation, mucus overproduction, and edematous mucosal tissue. This inflammatory condition is characterized by mucosal thickening, nasal obstruction, facial pain or pressure, hyposmia, and nasal discharge. The aim of this research was to clarify a potential role [...] Read more.

Chronic rhinosinusitis (CRS) is characterized by sinonasal inflammation, mucus overproduction, and edematous mucosal tissue. This inflammatory condition is characterized by mucosal thickening, nasal obstruction, facial pain or pressure, hyposmia, and nasal discharge. The aim of this research was to clarify a potential role for the receptor for advanced glycation end-products (RAGE) in mouse nasoantral epithelium in perpetuating pro-inflammatory cytokine elaboration similarly expressed by CRS patients. Specifically, wild-type (WT) mice and transgenic (TG) mice overexpressing RAGE in sinonasal epithelium (RAGE TG mice) were maintained in room air or subjected to secondhand smoke exposure using a nose-only delivery system (Scireq Scientific, Montreal, QC, Canada) for five days per week over a 30-day period. Histological analysis was performed using staining for RAGE. Tissue lysates were analyzed for pro-inflammatory cytokines. We observed increased RAGE expression in sinus tissue following SHS exposure and in sinuses from RAGE TG mice in the absence of SHS. We also discovered elevated T helper (Th)1 products (TNF-α, IL-1β, IFN-γ) and Th2/Th17 (IL-5, IL-13, IL-17A) cytokine abundance in SHS-exposed WT and SHS-exposed RTG tissues compared to room air controls. These findings highlight the pivotal role of RAGE signaling in the exacerbation of inflammatory processes, particularly in the context of chronic inflammation induced by smoke exposure. The study expands our understanding of the RAGE signaling axis as a key contributor to the progression of smoke-related lung and sinonasal pathologies. Targeting RAGE-mediated pathways could represent a novel therapeutic strategy to mitigate the progression of chronic sinusitis associated with smoke exposure. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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14 pages, 4874 KB

Open AccessArticle

The Influence of Short Peptides on Cell Senescence and Neuronal Differentiation

by Elena Sakhenberg, Natalia Linkova, Nina Kraskovskaya, Daria Krieger, Victoria Polyakova, Dmitrii Medvedev, Alexander Krasichkov, Mikhail Khotin and Galina Ryzhak

Curr. Issues Mol. Biol. 2025, 47(9), 739; https://doi.org/10.3390/cimb47090739 - 10 Sep 2025

Abstract

It has been previously shown that some short peptides are involved in various cellular processes, such as transcription modulation and regulation of differentiation mechanisms. In particular, the effect of peptides on the neuronal differentiation of human periodontal ligament stem cells has been demonstrated. [...] Read more.

It has been previously shown that some short peptides are involved in various cellular processes, such as transcription modulation and regulation of differentiation mechanisms. In particular, the effect of peptides on the neuronal differentiation of human periodontal ligament stem cells has been demonstrated. The goal of this study was to assess the effect of KED, EDR, and AEDG short peptides in stimulating the transdifferentiation of fetal MSCs into induced neuronal cells and prevention of their senescence. We applied a novel in vitro technique for neuronal cell generation, which combines the use of microRNAs, transcription factors, and small molecules to transdifferentiate fetal mesenchymal stem cells into induced cortical neurons. It was shown that the application of AEDG and KED short peptides at the end of the transdifferentiation process decreases the expression of the cell cycle marker p21 by 15% and beta-galactosidase activity by 1.51–2.4 times. However, short peptides did not affect the expression levels of TUj-1 and LaminB1, whose expression also changes during neuronal differentiation. The experiments indicate the potential of AEDG and KED short peptides as modulators of neurogenesis and geroprotectors and suggest that they can be used as stimulators of neuronal differentiation. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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20 pages, 937 KB

Open AccessReview

Multi-Biofluid Approaches for cftDNA and cftRNA Biomarker Detection: Advances in Early Cancer Detection and Monitoring

by Douglas M. Ruden

Curr. Issues Mol. Biol. 2025, 47(9), 738; https://doi.org/10.3390/cimb47090738 - 10 Sep 2025

Abstract

Cell-free tumor DNA (cftDNA) and cell-free tumor RNA (cftRNA) are emerging as powerful biomarkers for cancer detection, monitoring, and prognosis. These nucleic acids, released into the bloodstream by tumor cells, carry cancer-specific genetic and epigenetic alterations and can be detected non-invasively. Detection before [...] Read more.

Cell-free tumor DNA (cftDNA) and cell-free tumor RNA (cftRNA) are emerging as powerful biomarkers for cancer detection, monitoring, and prognosis. These nucleic acids, released into the bloodstream by tumor cells, carry cancer-specific genetic and epigenetic alterations and can be detected non-invasively. Detection before clinical diagnosis offers a unique opportunity for earlier intervention yet requires longitudinal cohort studies to establish pre-diagnostic biomarker profiles. Current technologies enable sensitive quantification of cftDNA and cftRNA, with spike-in controls allowing for absolute quantification of single nucleosome-bound cftDNA, addressing a key limitation in liquid biopsy assays. Advances, such as DNA-PAINT, now permit single-molecule resolution detection of point mutations and methylation patterns characteristic of cancer, while new proteomics methods can identify the tissue of origin of exosome-derived nucleic acid. This review discusses the state-of-the-art detection strategies for cftDNA and cftRNA, highlights the gaps in longitudinal sampling, and outlines future research directions toward integrating multiomic liquid biopsy approaches for improved early diagnosis, monitoring, and relapse detection. Full article

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

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22 pages, 19856 KB

Open AccessArticle

The Complete Chloroplast Genomes of Three Manglietia Species and Phylogenetic Insight into the Genus Manglietia Blume

by Yuan Luo, Wei Luo, Tongxing Zhao, Jing Yang, Lang Yuan, Pinzheng Zhang, Zixin Gong, Haizhu Li, Yongkang Sima and Tao Xu

Curr. Issues Mol. Biol. 2025, 47(9), 737; https://doi.org/10.3390/cimb47090737 - 10 Sep 2025

Abstract

The genus Manglietia Blume is an important group of Magnoliaceae that has high economic and ornamental value. Owing to the small morphological differences among most Manglietia species and the limited sample sizes in previous molecular-level studies, its infrageneric classification remains unclear, and interspecific [...] Read more.

The genus Manglietia Blume is an important group of Magnoliaceae that has high economic and ornamental value. Owing to the small morphological differences among most Manglietia species and the limited sample sizes in previous molecular-level studies, its infrageneric classification remains unclear, and interspecific relationships for some species are still contentious. Clarifying the phylogenetic relationships within the genus Manglietia is crucial for species classification, genetic diversity assessment, and evolutionary developmental studies. This study sequenced, assembled, and annotated the chloroplast (cp) genomes of Manglietia guangnanica, Manglietia hookeri, and Manglietia longirostrata. The results indicated that these cp genomes are canonical quadripartite structures with total lengths of 160,067 bp, 160,067 bp, and 160,076 bp, respectively. All three cp genomes were annotated with 133 genes, comprising 88 protein-coding genes, 37 tRNAs, and 8 rRNAs. A total of 31, 30, and 30 dispersed repeats and 53, 53, and 56 SSRs were detected, respectively. ENC plot, neutrality plot, and PR2 plot analyses indicated that codon usage bias was influenced primarily by natural selection. Nucleotide diversity analysis revealed 8 highly variable regions in the cp genomes, among which petA-psbJ, rpl32-trnL, and ccsA-ndhD are recommended as candidate molecular markers for Manglietia species. Phylogenetic analysis revealed four highly supported clades: Clade I (18 species), Clade II (M. decidua only), Clade III (9 species), and Clade IV (M. caveana only). Among these clades, Clade IV is a newly discovered monotypic clade in this study, which differs from the results of all previous studies. Further investigations of Clades I and III, which include multiple Manglietia species, revealed that the presence or absence of hairs on Twigs, Stipules, and the abaxial surface of the leaf are important morphological characteristics for distinguishing species between these two clades. Furthermore, the results revealed that M. guangnanica and M. calcarea are two distinct species, and the treatment of M. longirostrata as a variety of M. hookeri was not supported by our study. This study enriches the cp genome data of Manglietia, provides new insights into infrageneric classification, and lays a foundation for further phylogenetic and evolutionary studies of Manglietia. Full article

(This article belongs to the Section Molecular Plant Sciences)

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22 pages, 3295 KB

Open AccessArticle

Overexpression of the CAM-Derived NAC Transcription Factor KfNAC83 Enhances Photosynthesis, Water-Deficit Tolerance, and Yield in Arabidopsis

by Kumudu N. Rathnayake, Beate Wone, Madhavi A. Ariyarathne, Won C. Yim and Bernard W. M. Wone

Curr. Issues Mol. Biol. 2025, 47(9), 736; https://doi.org/10.3390/cimb47090736 - 10 Sep 2025

Abstract

Drought stress is a major constraint on plant photosynthesis, growth, and yield, particularly in the context of increasingly frequent and severe extreme weather events driven by global climate change. Enhancing photosynthetic efficiency and abiotic stress tolerance is therefore essential for sustaining crop productivity. [...] Read more.

Drought stress is a major constraint on plant photosynthesis, growth, and yield, particularly in the context of increasingly frequent and severe extreme weather events driven by global climate change. Enhancing photosynthetic efficiency and abiotic stress tolerance is therefore essential for sustaining crop productivity. In this study, we functionally characterized Kalanchoë fedtschenkoi NAC83 (KfNAC83), a transcription factor derived from a heat-tolerant obligate crassulacean acid metabolism (CAM) species, by constitutively overexpressing it in the C₃ model plant Arabidopsis thaliana. Transgenic Arabidopsis lines overexpressing KfNAC83 exhibited significantly enhanced tolerance to water-deficit and NaCl stress, along with improved photosynthetic performance, biomass accumulation, and overall productivity. Transcriptomic analysis revealed that KfNAC83 overexpression increased key components of the jasmonate (JA) signaling pathway in both roots and shoots, suggesting a mechanistic link between KfNAC83 activity and enhanced abiotic stress responses. Additionally, the transgenic lines displayed increased nighttime decarboxylation activity, indicative of partial CAM-like metabolic traits. These findings demonstrate that KfNAC83 functions as a positive regulator of abiotic stress tolerance and growth, likely through modulation of jasmonate-mediated signaling and photosynthetic metabolism. This work highlights the potential of CAM-derived transcription factors for bioengineering abiotic stress-resilient crops in the face of climate change. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Plant Stress Tolerance)

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18 pages, 612 KB

Open AccessReview

Mechanisms of the Effects of Polyphenols on Diabetic Nephropathy

by Masumi Kamiyama, Kotoe Iijima, Rema Okuzawa, Ruka Kawata, Airi Kimura, Yuki Shinohara, Ayana Shimada, Mika Yamanaka, Ayuka Youda and Tamami Iwamoto

Curr. Issues Mol. Biol. 2025, 47(9), 735; https://doi.org/10.3390/cimb47090735 - 10 Sep 2025

Abstract

Diabetic nephropathy is a major challenge in medicine. While a variety of mechanisms underlie the onset and progression of diabetic nephropathy, oxidative stress is critical because it promotes inflammation and creates a vicious cycle that induces podocyte injury, extracellular matrix accumulation, glomerulosclerosis, epithelial–mesenchymal [...] Read more.

Diabetic nephropathy is a major challenge in medicine. While a variety of mechanisms underlie the onset and progression of diabetic nephropathy, oxidative stress is critical because it promotes inflammation and creates a vicious cycle that induces podocyte injury, extracellular matrix accumulation, glomerulosclerosis, epithelial–mesenchymal transition, tubular atrophy, and proteinuria. There are various treatments for diabetic nephropathy, and each has its own limitations. Although the exact mechanisms by which polyphenols suppress diabetic nephropathy have not been elucidated, they may have antioxidant, anti-inflammatory, antifibrotic, and/or anti-apoptotic effects. They may also suppress endoplasmic reticulum stress and ameliorate mitochondrial dysfunction and dyslipidemia. Dietary polyphenols may be able to prevent the onset and slow the progression of diabetic nephropathy; they include resveratrol, quercetin, isoflavones, catechins, and anthocyanidins and have antioxidant, anti-inflammatory, antifibrotic, and anti-apoptotic effects through multiple molecular targets. Furthermore, they have shown few side effects. However, further research is needed to fully elucidate the molecular mechanisms by which polyphenols exert their effects and to clarify their optimal therapeutic use. In this review, we summarize reports published in the past five years regarding their effects on diabetic nephropathy and provide an overview of the potential of polyphenols. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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32 pages, 2372 KB

Open AccessReview

Roxadustat as a Hypoxia-Mimetic Agent: Erythropoietic Mechanisms, Bioanalytical Detection, and Regulatory Considerations in Sports Medicine

by Elena-Christen Creangă, Cristina Ott, Alina-Crenguţa Nicolae, Cristina Manuela Drăgoi and Raluca Stan

Curr. Issues Mol. Biol. 2025, 47(9), 734; https://doi.org/10.3390/cimb47090734 - 9 Sep 2025

Abstract

Roxadustat (ROX) is an orally active inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PHI) that exerts erythropoietic, cardioprotective, and metabolic regulatory effects. Approved for the treatment of anemia associated with chronic kidney disease, ROX promotes endogenous erythropoietin production and improves iron homeostasis, providing a [...] Read more.

Roxadustat (ROX) is an orally active inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PHI) that exerts erythropoietic, cardioprotective, and metabolic regulatory effects. Approved for the treatment of anemia associated with chronic kidney disease, ROX promotes endogenous erythropoietin production and improves iron homeostasis, providing a non-injectable alternative to conventional erythropoiesis-stimulating agents (ESAs). Its ability to enhance oxygen transport and facilitate muscle recovery has, however, led to its misuse in sports, where it is classified as a banned substance by the World Anti-Doping Agency. This review provides a comprehensive overview of the pharmacological properties of ROX, its approved and investigational clinical applications, and its chemical synthesis strategies. Particular emphasis is placed on the analytical methodologies employed for ROX detection in anti-doping settings. Techniques such as liquid chromatography–tandem mass spectrometry (LC–MS/MS), ultraviolet–visible (UV–Vis) spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), and high-performance thin-layer chromatography (HPTLC) are critically assessed for their efficacy in detecting ROX and its metabolites in biological matrices. Given the increasing incidence of ROX misuse among athletes, ongoing optimization of detection protocols and longitudinal monitoring approaches, are essential to uphold both sports integrity and public health. Full article

(This article belongs to the Special Issue Molecular Biology in Drug Design and Precision Therapy)

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14 pages, 2449 KB

Open AccessArticle

Integrator Complex Subunit 6 Regulates Biological Nature of Hepatocellular Carcinoma by Modulating Epithelial–Mesenchymal Transition

by Sayaka Yonezawa, Keishi Kanno, Minami Shiozaki, Masanori Sugiyama and Masanori Ito

Curr. Issues Mol. Biol. 2025, 47(9), 733; https://doi.org/10.3390/cimb47090733 - 9 Sep 2025

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with limited therapeutic options and frequent resistance to treatment. The integrator complex subunit 6 (INTS6), a regulator of RNA polymerase II transcription, has emerged as a potential tumor suppressor that modulates Wnt/β-catenin [...] Read more.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with limited therapeutic options and frequent resistance to treatment. The integrator complex subunit 6 (INTS6), a regulator of RNA polymerase II transcription, has emerged as a potential tumor suppressor that modulates Wnt/β-catenin signaling and epithelial–mesenchymal transition (EMT). This study aimed to clarify the role of INTS6 in EMT regulation in HCC and to explore the therapeutic potential of small activating RNA (saRNA)-mediated INTS6 induction. The Cancer Genome Atlas (TCGA) dataset was analyzed to assess the clinical relevance of INTS6 in HCC. Functional studies were conducted using a hepatoma cell line to determine the effects of INTS6 modulation on tumor behavior. Data analysis demonstrated that low INTS6 expression was associated with shorter disease-free survival and poorer prognosis in patients receiving conservative treatment. Experimental suppression of INTS6 increased mesenchymal marker expression, whereas saRNA-mediated induction suppressed these markers. Restoring INTS6 expression reduced cell migration, invasion, and proliferation through G1 cell-cycle arrest and enhanced sensitivity to sorafenib. These findings identify INTS6 as a promising therapeutic target in HCC. saRNA-mediated induction of INTS6 may provide a novel strategy, alone or in combination therapy, to overcome drug resistance and improve clinical outcomes. Full article

(This article belongs to the Section Molecular Medicine)

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22 pages, 5512 KB

Open AccessArticle

Sodium Butyrate Ameliorated Bile Acid Metabolism in Diabetes Mellitus by PI3K/AKT Signaling Pathway via the Gut–Liver Axis

by Tingting Zhao, Xi Zhang, Qian Xiang, Yadi Liu, Xuling Li, Junling Gu, Wenqian Zhang, Zhe Wang, Yiran Li, Xiaoshan Lai, Yonghua Zhao and Youhua Xu

Curr. Issues Mol. Biol. 2025, 47(9), 732; https://doi.org/10.3390/cimb47090732 - 9 Sep 2025

Abstract

The liver and gut play a central role in modulating bile acid metabolism. Our recent study found that supplementation with sodium butyrate (NaB) from microbiota might slow diabetes progression and ameliorate liver function in diabetic mice. The role of NaB in the homeostasis [...] Read more.

The liver and gut play a central role in modulating bile acid metabolism. Our recent study found that supplementation with sodium butyrate (NaB) from microbiota might slow diabetes progression and ameliorate liver function in diabetic mice. The role of NaB in the homeostasis of mitochondrial energy metabolism and bile acid metabolism needs to be investigated further, so this study was conducted by us. We used an ELISA kit to detect biochemical indicators related to mice; HE and PAS were used to stain and analyze tissues; CCK8 was used to detect cell viability; and WB was used to detect related indicators. We found here that NaB administration enormously reduced liver hypertrophy and steatosis in diabetic mice, improved liver and gut function and the release of inflammatory factors in diabetic mice, and ameliorated mitochondrial function both in vitro and in vivo. NaB incubation significantly increased bile acid metabolism-related receptors under diabetic conditions; the intracellular content of enzymes related to liver function was elevated within liver cells. Glucose transport proteins GLUT2 and NaB receptor GPR43 were upregulated by NaB on the cell membrane. The actuation of the intracellular signaling proteins PI3K, AKT, and GSK3 was inhibited by NaB under diabetic conditions. The present study proved that the microbiota metabolite NaB has positive effects on bile acid metabolic homeostasis by promoting mitochondrial energy metabolism in enterocytes and the liver, and the GPR43-PI3K-AKT-GSK3 signaling pathway should contribute to this effect. Full article

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

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13 pages, 1097 KB

Open AccessArticle

Astragalus membranaceus Extract Attenuates Inflammatory Cytokines and Matrix-Degrading Enzymes in Human Chondrocytes: A Novel Nutraceutical Strategy for Joint Health

by Alessia Mariano, Rosario Russo, Anna Scotto d’Abusco and Fabiana Superti

Curr. Issues Mol. Biol. 2025, 47(9), 731; https://doi.org/10.3390/cimb47090731 - 9 Sep 2025

Abstract

The dried root extract of Astragalus membranaceus, also known as Astragali radix, is widely used in traditional Chinese medicine for its multiple health benefits and well-established safety profile. Astragalus root extract exhibits several bioactive properties, including anti-inflammatory, antioxidant, antiviral and hepatoprotective [...] Read more.

The dried root extract of Astragalus membranaceus, also known as Astragali radix, is widely used in traditional Chinese medicine for its multiple health benefits and well-established safety profile. Astragalus root extract exhibits several bioactive properties, including anti-inflammatory, antioxidant, antiviral and hepatoprotective effects. Due to its unique features, it is being investigated in a novel application as a complementary remedy in the management of joint disorders. In this study, we evaluated the effect of Astragalus membranaceus hydroalcoholic root extract (0.01 and 0.1 mg/mL) in vitro on the HTB-94 cell line, a well-known model for studying inflammatory pathways in human chondrocytes. The mRNA modulation levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR), while the protein secretion levels were assessed using an Enzyme-Linked Immunosorbent Assay (ELISA). Results obtained demonstrated that this extract is able to decrease the tumor necrosis factor-α (TNF-α)-induced inflammatory response by downregulating both the mRNA expression and release of the pro-inflammatory mediators Interleukin-6 (IL-6), Interleukin-1β (IL-1β) and Interelukin-8 (IL-8), as well as matrix metalloproteases, including Matrix Metalloprotease-3 (MMP-3), Matrix Metalloprotease-13 (MMP-13) and A disintegrin, and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5). Moreover, the interleukin and matrix metalloprotease production was also assessed in non-TNF-α-stimulated cells, revealing that the extract did not alter the basal levels of these mediators. Finally, our findings highlight the potential benefits of Astragalus membranaceus extract, both in terms of its favorable safety profile and its efficacy mitigating joint inflammatory responses. These results support the potential of this extract as a nutraceutical agent for joint health support. Full article

(This article belongs to the Special Issue Role of Natural Products in Inflammatory Diseases)

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23 pages, 2403 KB

Open AccessReview

Decoding the Tumor Microenvironment: Insights and New Targets from Single-Cell Sequencing and Spatial Transcriptomics

by Shriya Pattabiram, Prakash Gangadaran, Sanjana Dhayalan, Gargii Chatterjee, Danyal Reyaz, Kruthika Prakash, Raksa Arun, Ramya Lakshmi Rajendran, Byeong-Cheol Ahn and Kandasamy Nagarajan Aruljothi

Curr. Issues Mol. Biol. 2025, 47(9), 730; https://doi.org/10.3390/cimb47090730 - 9 Sep 2025

Abstract

The field of oncology has been extensively studied to design more effective and efficient treatments. This review explores the advanced techniques that are transforming our comprehension of cancer and its constituents. Specifically, it highlights the signaling pathways that drive tumor progression, angiogenesis, and [...] Read more.

The field of oncology has been extensively studied to design more effective and efficient treatments. This review explores the advanced techniques that are transforming our comprehension of cancer and its constituents. Specifically, it highlights the signaling pathways that drive tumor progression, angiogenesis, and resistance to therapy, as well as the modern approaches used to identify and characterize these pathways within the tumor microenvironment (TME). Key pathways discussed in this review include vascular endothelial growth factor (VEGF), programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and various extracellular matrix (ECM) pathways. Conventional methods of diagnosis have yielded sufficient knowledge but have failed to reveal the heterogeneity that exists within the TME, resulting in gaps in our understanding of the cellular interaction and spatial dynamics. Single-cell sequencing (SCS) and spatial transcriptomics (ST) are effective tools that can enable the dissection of the TME with the resolution capacity of a single cell. SCS allows the capture of the unique genetic and transcriptomic profiles of individual cells along with rare cell types and new therapeutic targets. ST complements this by providing a spatial map of gene expression, showing the gene expression profiles within the tumor tissue at specific sites with good accuracy. By mapping gene expression patterns at a single cell level and correlating them with the spatial locations, researchers can uncover the intricate networks and microenvironmental influences that contribute to tumor heterogeneity. Full article

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

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13 pages, 1189 KB

Open AccessArticle

Photoinduced Inhibition of Neutrophil Extracellular Traps Formation by Dichromatic Light Irradiation

by Kahramon Mamatkulov, Yersultan Arynbek, Huy Duc Le, Nina Vorobjeva and Grigory Arzumanyan

Curr. Issues Mol. Biol. 2025, 47(9), 729; https://doi.org/10.3390/cimb47090729 - 9 Sep 2025

Abstract

Neutrophils are the first line of defense of the human immune system against pathogens. Photobiomodulation, mediated by mitochondrial photoacceptors such as cytochrome c oxidase, has emerged as a method to modulate neutrophil function through targeted light exposure. Despite the extensive characterization of neutrophil [...] Read more.

Neutrophils are the first line of defense of the human immune system against pathogens. Photobiomodulation, mediated by mitochondrial photoacceptors such as cytochrome c oxidase, has emerged as a method to modulate neutrophil function through targeted light exposure. Despite the extensive characterization of neutrophil extracellular traps (NETs) formation (NETosis), the wavelength-specific modulation of neutrophil photoactivation and the involvement of redox pathways remain poorly defined. In this study, the effects of monochromatic (365 nm, 415 nm, 437 nm, and 625 nm) and dichromatic LED-light irradiation on NETs formation were systematically examined. The highest netotic responses were elicited by UV-A (365 nm) and violet-blue light (415 nm), whereas 437 nm showed the lowest induction and 625 nm stimulated a moderate netotic response. The pharmacological inhibition of NETosis induced by 365 nm and 415 nm irradiation with specific NADPH oxidase inhibitor, apocynin, and mitochondrial reactive oxygen species (mtROS) scavenger, MitoTEMPO, attenuated NETs formation by engaging both enzymatic and mitochondrial oxidative sources. Notably, mtROS played a dominant role under 415 nm stimulation in contrast to 365 nm-induced NETosis as demonstrated by higher sensitivity to MitoTEMPO. Importantly, combined simultaneous irradiation with 415 nm and 625 nm LEDs resulted in a significant suppression of NETs formation by more than 50%, highlighting a potent inhibitory synergy observed for the first time and suggesting a new approach of wavelength pairing to modulate neutrophil activation. These results were further supported by measurements of ROS production using a luminol-amplified chemiluminescence assay. Collectively, these findings delineate a wavelength- and ROS-dependent framework for light-induced neutrophil activation, with mitochondrial pathways exerting central control particularly under short-wavelength irradiation. Full article

(This article belongs to the Special Issue Molecular Roles of Neutrophil Extracellular Traps in Immune Responses and Disease)

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14 pages, 3075 KB

Open AccessArticle

Macrophage Inhibitory Factor in Myocardial Oxidative Stress and Inflammation During Thioacetamide-Induced Liver Fibrosis: Modulation by Betaine

by Jasmina Djuretić, Jelena Filipovic, Milica Brankovic, Sanja Stankovic, Janko Samardzic, Danijela Vucevic and Tatjana Radosavljevic

Curr. Issues Mol. Biol. 2025, 47(9), 728; https://doi.org/10.3390/cimb47090728 - 9 Sep 2025

Abstract

Chronic liver disease is closely associated with impaired cardiovascular function. Cardiac dysfunction is caused in part by oxidative stress and increased levels of proinflammatory and profibrogenic mediators in myocardial tissue. The present study aims to investigate the role of betaine in the modulation [...] Read more.

Chronic liver disease is closely associated with impaired cardiovascular function. Cardiac dysfunction is caused in part by oxidative stress and increased levels of proinflammatory and profibrogenic mediators in myocardial tissue. The present study aims to investigate the role of betaine in the modulation of MIF-mediated oxidative stress, inflammation, and fibrogenesis in heart during TAA-induced liver fibrosis in mice. The experiment is performed on wild-type and knockout MIF^−/− C57BL/6 mice (MIF^−/− group). They are randomly divided into groups: Control; Bet-group, received betaine (2% wt/v dissolved in drinking water); MIF^−/− mice group; MIF^−/−+Bet; TAA-group, treated with TAA (200 mg/kg b.w.), intraperitoneally, 3×/week/8 weeks); TAA+Bet; MIF^−/−+TAA, and MIF^−/−+TAA+Bet group. After eight weeks of treatment, animals are sacrificed and heart samples are taken to determine oxidative stress parameters, proinflammatory cytokines, profibrogenic factors, and histopathology of myocardial tissue. Our results suggest that MIF contributes significantly to lipid peroxidation of cardiomyocytes, as well as oxidative and nitrosative stress in myocardial tissue in mice with TAA-induced liver fibrosis compared to the control group. In addition, MIF was important for myocardial expression of the proinflammatory cytokines IL-6 and TNF as well as the profibrogenic mediators TGF-β1 and PDGF-BB in TAA-treated mice. Notably, betaine attenuated MIF effects in myocardial tissue reducing levels of MDA, AOPP, TNF, TGF-β1, PDGF-BB and increasing SOD and catalase activity in the coexistence of liver fibrosis. These results emphasize the potential of betaine as a therapeutic agent in mitigating MIF effects and demonstrate the need for further research into its optimal dosage and efficacy in preventing or slowing down cardiac dysfunction in patients with liver cirrhosis. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Antioxidant Activity of Bioorganic Molecules: A Chemical Perspective)

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26 pages, 7167 KB

Open AccessArticle

Transcriptomic Analysis Reveals the Molecular Relationship Between Common Respiratory Infections and Parkinson’s Disease

by Abdulaziz Albeshri, Ahmed Bahieldin and Hani Mohammed Ali

Curr. Issues Mol. Biol. 2025, 47(9), 727; https://doi.org/10.3390/cimb47090727 - 7 Sep 2025

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Abstract

Parkinson’s disease (PD) is one of the most rapidly growing neurological disorders globally. The molecular relationship between common respiratory infections (RIs) and idiopathic Parkinson’s disease (iPD) remains a controversial issue. Multiple studies have linked acute respiratory infections to PD, but the molecular mechanism [...] Read more.

Parkinson’s disease (PD) is one of the most rapidly growing neurological disorders globally. The molecular relationship between common respiratory infections (RIs) and idiopathic Parkinson’s disease (iPD) remains a controversial issue. Multiple studies have linked acute respiratory infections to PD, but the molecular mechanism behind this connection is not significantly defined. Therefore, the aim of our study was to investigate potential molecular interactions between RIs and PD. We retrieved eight publicly available RNA-seq datasets from the NCBI Gene Expression Omnibus (NCBI GEO) and performed extensive bioinformatics analysis, including differential gene expression (DGE) analysis, the identification of overlapped differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), pathway and functional enrichment analysis, the construction of protein–protein networks, and the identification of hub genes. Additionally, we applied a machine learning method, a Random Forest model (RF), to external RIs datasets to identify the most important genes. We found that ribosomal subunits, mitochondrial complex proteins, proteasome subunits, and proteins encoding ubiquitin are simultaneously downregulated and co-expressed in RIs and PD. Dysregulation of these proteins may disturb multiple pathways, such as those responsible for ribosome biogenesis, protein synthesis, autophagy, and apoptosis; the ubiquitin–proteasome system (UPS); and the mitochondrial respiratory chain. These processes have been implicated in PD’s pathology, namely in the aggregation of α-synuclein, mitochondrial dysfunction, and the death of dopaminergic neuron cells. Our findings suggest that there are significant similarities in transcriptional responses and dysfunctional molecular mechanisms between RIs, PD, and aging. RIs may modulate PD-relevant pathways in an age- or immune-dependent manner; longitudinal studies are needed to examine the RIs risk factor. Therefore, future studies should experimentally investigate the influence of age, vaccination status, infection type, and severity to clarify the role of RIs in PD’s pathogenesis. Full article

(This article belongs to the Special Issue Omics Analysis for Personalized Medicine)

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21 pages, 1881 KB

Open AccessReview

Tumor Immune Microenvironment and Checkpoint Inhibition in Clear Cell Ovarian Carcinoma: Bridging Tumor Biology and Clinical Application in Immunotherapy

by Fulvio Borella, Giulia Capella, Stefano Cosma, Niccolò Gallio, Federica Gavello, Alberto Revelli, Domenico Ferraioli, Jessica Cusato, Isabella Castellano, Paola Cassoni and Luca Bertero

Curr. Issues Mol. Biol. 2025, 47(9), 726; https://doi.org/10.3390/cimb47090726 - 5 Sep 2025

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Abstract

Clear cell ovarian carcinoma is a rare and aggressive histologic subtype of epithelial ovarian cancer, characterized by a chemoresistant phenotype and distinct immunogenomic features. Despite early-phase trials showing a limited response to immune checkpoint inhibitors (ICIs), emerging evidence reveals a biologically diverse tumor [...] Read more.

Clear cell ovarian carcinoma is a rare and aggressive histologic subtype of epithelial ovarian cancer, characterized by a chemoresistant phenotype and distinct immunogenomic features. Despite early-phase trials showing a limited response to immune checkpoint inhibitors (ICIs), emerging evidence reveals a biologically diverse tumor immune microenvironment, with implications for the efficacy of immunotherapies. Preclinical studies highlight paradoxical associations between immune infiltration and prognosis, as well as genomic drivers—including KRAS, MYC, PI3KCA, TP53, PTEN, and ARID1A—that shape immune evasion and checkpoint ligand expression. Clinically, ICI monotherapy yields modest benefit, while combination regimens—particularly dual checkpoint blockade and targeted co-inhibition—offer improved outcomes. Biomarkers such as PD-L1 CPS ≥ 1%, ARID1A mutations, elevated tumor mutational burden, and PIK3CA alterations emerge as promising predictors of therapeutic response. This review integrates current preclinical and clinical data to propose a precision immunotherapy framework tailored to the immunogenomic landscape of clear cell ovarian carcinoma. Full article

(This article belongs to the Special Issue The Molecular Basis of Immunotherapy in Cancer Treatment)

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20 pages, 1543 KB

Open AccessArticle

The Regulation of Catecholamine Biosynthesis by the Gas Transmitters Carbon Monoxide and Hydrogen Sulfide

by Robert Dingley, Cameron Hourtovenko, James Lee, Sujeenthar Tharmalingam and T. C. Tai

Curr. Issues Mol. Biol. 2025, 47(9), 725; https://doi.org/10.3390/cimb47090725 - 5 Sep 2025

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Abstract

The gas transmitters nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) play important roles in physiological regulation, including adrenal function. Among them, only NO has been directly implicated in controlling catecholamine biosynthesis. This study examined whether CO and H [...] Read more.

The gas transmitters nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) play important roles in physiological regulation, including adrenal function. Among them, only NO has been directly implicated in controlling catecholamine biosynthesis. This study examined whether CO and H₂S exert similar effects by treating PC12 cells with a CO donor (CORM-2) or an H₂S donor (NaHS), with or without glucocorticoid stimulation. Gene expression of tyrosine hydroxylase (Th), dopamine β-hydroxylase (Dbh), and phenylethanolamine N-methyltransferase (Pnmt) was assessed by RT-qPCR, and catecholamine release was measured by ELISA. We found that exogenous CO decreased Th and Dbh expression, attenuated glucocorticoid-induced upregulation of catecholamine biosynthesis genes, and differentially modulated dopamine and norepinephrine release. In contrast, exogenous H₂S treatment had no significant effect. These findings identify CO as a novel regulator of catecholamine biosynthesis and highlight important differences among gas transmitters in stress-related signaling. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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42 pages, 1227 KB

Open AccessReview

Microbial Metabolomes in Alzheimer’s Disease: From Pathogenesis to Therapeutic Potential

by Alejandro Borrego-Ruiz and Juan J. Borrego

Curr. Issues Mol. Biol. 2025, 47(9), 724; https://doi.org/10.3390/cimb47090724 - 5 Sep 2025

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Abstract

Background: Accumulating evidence underscores the potential role of the gut microbiome in the pathogenesis of Alzheimer’s disease, but much remains to be clarified. This review examines current evidence linking gut microbiome dysbiosis to Alzheimer’s disease, focusing on microbial metabolomes and their mechanistic role, [...] Read more.

Background: Accumulating evidence underscores the potential role of the gut microbiome in the pathogenesis of Alzheimer’s disease, but much remains to be clarified. This review examines current evidence linking gut microbiome dysbiosis to Alzheimer’s disease, focusing on microbial metabolomes and their mechanistic role, as well as on the potential of therapeutic approaches targeting the gut microbiome. Methods: A narrative, non-systematic examination of the literature was conducted to provide a comprehensive overview of the subject under examination. Database searches were performed in PubMed, Scopus, and Web of Science between June and July 2025. Results: Alzheimer’s disease is linked to reduced gut microbial diversity and altered bacterial taxa. Gut microbiome shifts correlate with inflammation and may drive Alzheimer’s disease progression via the microbiota–gut–brain axis. Microbial amyloids and bacterial products can cross both the intestinal and blood–brain barrier, triggering neuroinflammation and promoting amyloid and tau pathologies. Short-chain fatty acids produced by the gut microbiome regulate neuroinflammation, lipid metabolism, and gene expression, impacting Alzheimer’s disease pathology. Therapeutics targeting the gut microbiome, including probiotics, prebiotics, and fecal microbiota transplantation, show promise in modulating neuroinflammation, reducing amyloid and tau pathology, and improving cognitive function in Alzheimer’s disease. Conclusions: The gut microbiome significantly influences Alzheimer’s disease pathogenesis, and its modulation offers potential to slow progression. However, further research is required to validate effective clinical interventions. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Gut Microbiota in Health, Immunity and Disease)

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43 pages, 4194 KB

Open AccessReview

Metabolic Engineering of Terpenoid Biosynthesis in Medicinal Plants: From Genomic Insights to Biotechnological Applications

by Changfeng Guo, Si Xu and Xiaoyun Guo

Curr. Issues Mol. Biol. 2025, 47(9), 723; https://doi.org/10.3390/cimb47090723 - 5 Sep 2025

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Abstract

Terpenoids, which are essential pharmaceutical compounds, encounter significant production challenges due to their low yields in native plants and associated ecological concerns. This review summarizes recent advances in metabolic engineering strategies applied across three complementary platforms: native medicinal plants, microbial systems, and heterologous [...] Read more.

Terpenoids, which are essential pharmaceutical compounds, encounter significant production challenges due to their low yields in native plants and associated ecological concerns. This review summarizes recent advances in metabolic engineering strategies applied across three complementary platforms: native medicinal plants, microbial systems, and heterologous plant hosts. We present how the “Genomic Insights to Biotechnological Applications” paradigm, supported by multi-omics technologies such as genomics, transcriptomics, metabolomics, and related disciplines, contributes to advancing research in this field. These technologies enable the systematic identification of key biosynthetic genes and regulatory networks. CRISPR-based tools, enzyme engineering, and subcellular targeting are presented as pivotal transformative strategies in advancing metabolic engineering approaches. Strategic co-expression and optimization approaches have achieved substantial improvements in product yields, as demonstrated by a 25-fold increase in paclitaxel production and a 38% enhancement in artemisinin yield. Persistent challenges, such as metabolic flux balancing, cytotoxicity, and scale-up economics, are discussed in conjunction with emerging solutions, including machine learning and photoautotrophic chassis systems. We conclude by proposing a strategic roadmap for industrial translation that highlights the essential integration of systems biology and synthetic biology approaches to accelerate the transition of terpenoid biomanufacturing from discovery to commercial-scale application. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2025)

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14 pages, 1378 KB

Open AccessArticle

A Liposomal Formulation Enhances the Anti-Senescence Properties of Nicotinamide Adenine-Dinucleotide (NAD⁺) in Endothelial Cells and Keratinocytes

by Stefano Ministrini, Luca Liberale, Hanns-Eberhard Erle, Giuseppe Percoco, Ali Tfayli, Ali Assi, Ivan Kapitonov, Isabel Greiner and Giovanni Guido Camici

Curr. Issues Mol. Biol. 2025, 47(9), 722; https://doi.org/10.3390/cimb47090722 - 5 Sep 2025

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Abstract

Nicotinamide adenine-dinucleotide (NAD⁺) supplementation is a promising strategy to delay cellular aging in different areas, including cosmetic dermatology. However, low bioavailability and stability of NAD⁺ formulations are the main factors limiting its effectiveness as an anti-aging treatment. In light of [...] Read more.

Nicotinamide adenine-dinucleotide (NAD⁺) supplementation is a promising strategy to delay cellular aging in different areas, including cosmetic dermatology. However, low bioavailability and stability of NAD⁺ formulations are the main factors limiting its effectiveness as an anti-aging treatment. In light of the above, a liposomal formulation of NAD⁺ (LF-NAD⁺) was tested in this study and compared to NAD⁺ alone in primary human aortic endothelial cells (HAECs) and primary human epidermal keratinocytes (HEKas). Intracellular NAD⁺ was measured using a colorimetric assay. Cell survival was derived from lactate dehydrogenase release in supernatants. Cell senescence was measured by senescence-associated β-galactosidase staining. Molecular mechanisms underlying the reported effects were analyzed by Western blot. Skin penetration of NAD⁺ was measured ex vivo in skin explants, using infrared spectroscopy. Compared to control NAD⁺ alone, the LF-NAD⁺ formulation increased the intracellular NAD⁺ content and cell survival in HAECs, but not in HEKas. Instead, a significant reduction in the number of senescent cells was observed in both HAECs and HEKas. LF-NAD⁺ treatment was associated with a reduced expression of p16 in both HAECs and HEKas, and to a significant reduction in p21 in HEKas alone. Finally, LF-NAD⁺ increases the skin penetration of the active substance NAD⁺ by 30% compared to the application of NAD⁺ alone. LF-NAD⁺, enhances the anti-aging effects of NAD⁺ on vascular and skin cells. Such in vitro findings might indicate a potential anti-aging role in the microcirculation and in the epidermidis. Full article

(This article belongs to the Special Issue Exploring Molecular Pathways in Skin Health and Diseases)

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14 pages, 491 KB

Open AccessReview

Neurodevelopmental Impact of Maternal Immune Activation and Autoimmune Disorders, Environmental Toxicants and Folate Metabolism on Autism Spectrum Disorder

by George Ayoub

Curr. Issues Mol. Biol. 2025, 47(9), 721; https://doi.org/10.3390/cimb47090721 - 4 Sep 2025

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Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in social communication, repetitive behaviors, and sensory sensitivities. While genetic factors contribute significantly to ASD risk, a growing body of evidence implicates environmental exposures and immune-mediated mechanisms in the etiology and [...] Read more.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in social communication, repetitive behaviors, and sensory sensitivities. While genetic factors contribute significantly to ASD risk, a growing body of evidence implicates environmental exposures and immune-mediated mechanisms in the etiology and severity of ASD. This review synthesizes peer-reviewed findings on (1) maternal immune activation, (2) environmental toxicant co-exposures, (3) maternal autoimmune disease, and (4) cerebral folate deficiency (via folate receptor alpha autoantibodies), detailing their mechanistic contributions to core and associated ASD symptoms. Collectively, these findings illuminate converging neuroimmune and metabolic pathways that, when disrupted in utero, substantially alter the developmental trajectory of the brain and increase the likelihood of ASD. Such interruptions leading to developmental changes can trigger immune activation from environmental sources of infection and pollution, with these triggers compounded in cases of autoimmune disease or cerebral folate deficiency. Understanding these mechanisms provides a foundation for early identification, stratified risk assessment, and the development of targeted prenatal interventions. Thus, a lesson we learn from autism is that neurodevelopmental disorders should be understood as the product of combined genetic vulnerabilities and modifiable prenatal and postnatal influences. Further exploration of this framework will open paths for precision intervention and prevention. Full article

(This article belongs to the Special Issue Mental Disorder: Focus on Pathogenesis to Treatment)

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12 pages, 2789 KB

Open AccessArticle

Mechanistic Insights into Vorinostat as a Repositioned Modulator of TACE-Mediated TNF-α Signaling via MAPK and NFκB Pathways

by Jinyoung Park, Muhammad Yasir, Jongseon Choe, Jin-Hee Han, Eun-Taek Han, Won Sun Park and Wanjoo Chun

Curr. Issues Mol. Biol. 2025, 47(9), 720; https://doi.org/10.3390/cimb47090720 - 4 Sep 2025

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Abstract

Vorinostat, an FDA-approved histone deacetylase inhibitor, was evaluated for its potential anti-inflammatory activity through modulation of TACE (ADAM17)-mediated TNF-α signaling. The study was conducted using LPS-stimulated RAW264.7 macrophages. TACE enzymatic activity was assessed by a fluorogenic assay, TNF-α release was measured by ELISA, [...] Read more.

Vorinostat, an FDA-approved histone deacetylase inhibitor, was evaluated for its potential anti-inflammatory activity through modulation of TACE (ADAM17)-mediated TNF-α signaling. The study was conducted using LPS-stimulated RAW264.7 macrophages. TACE enzymatic activity was assessed by a fluorogenic assay, TNF-α release was measured by ELISA, and phosphorylation of MAPKs and NFκB signaling proteins was examined by a western blot. Molecular docking was performed using GNINA to evaluate binding affinity to ERK. Vorinostat was found to modestly inhibit TACE enzymatic activity in vitro, while significantly suppressing TNF-α secretion in cells, comparable to the selective TACE inhibitor BMS-561392. A concentration-dependent reduction in phosphorylated IκB and NFκB was observed, along with selective inhibition of ERK phosphorylation. Docking studies indicated a stable, albeit weaker, binding of vorinostat to ERK compared to reference ERK inhibitors. These findings suggest that vorinostat suppresses TNF-α production primarily through indirect mechanisms involving ERK and NF-κB signaling pathways, rather than by direct TACE inhibition. The repositioning of vorinostat as a modulator of inflammatory signaling is supported, offering potential therapeutic value in inflammatory disorders. Full article

(This article belongs to the Section Molecular Medicine)

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