Current Issues in Molecular Biology

20 pages, 5654 KB

Open AccessArticle

Phage Display Reveals VLRB-Mediated Recognition of Minimal Tumor Glycan Antigen Sialyl-Tn

by Mark Rickard N. Angelia, Abigail Joy D. Rodelas-Angelia, Youngrim Kim, Cheolung Yang, Hyeok Jang, Seungpyo Jeong, Jihyun Mun, Kim D. Thompson and Taesung Jung

Curr. Issues Mol. Biol. 2025, 47(10), 802; https://doi.org/10.3390/cimb47100802 (registering DOI) - 26 Sep 2025

Abstract

Sialyl-Tn (sTn) is a tumor-associated carbohydrate antigen (TACA) abundantly expressed by various types of carcinomas. While conventional antibody-based platforms have traditionally been used for the detection and targeting of sTn, alternative binding scaffolds may offer distinct advantages. Variable lymphocyte receptor B (VLRB), the [...] Read more.

Sialyl-Tn (sTn) is a tumor-associated carbohydrate antigen (TACA) abundantly expressed by various types of carcinomas. While conventional antibody-based platforms have traditionally been used for the detection and targeting of sTn, alternative binding scaffolds may offer distinct advantages. Variable lymphocyte receptor B (VLRB), the immunoglobulin-like molecule of jawless vertebrates, offers a promising alternative for glycan recognition. In this study, a phage-displayed VLRB library was utilized to identify sTn-specific binders. Two candidates, designated as ccombodies A8 and B11, were isolated after four rounds of biopanning. Both were expressed and purified using Ni-affinity and FPLC, yielding proteins with apparent molecular weights of ~27 kDa in SDS-PAGE. Sequence analysis revealed a preference for glycan-binding residues in randomized hypervariable regions, with A8 exhibiting an increased aliphatic content. ELISA confirmed selective binding to sTn and other O-glycans containing the core α-GalNAc, with EC₅₀ values of 18.2 and 14.2 nM for A8 and B11, respectively. Vicia villosa lectin inhibited ccombody binding to sTn, indicating shared epitope recognition. Additionally, both ccombodies bound to sTn-positive glycoproteins and carcinoma cell lines HeLa and LS174T. These findings demonstrate that phage display of VLRBs enables the identification of high-affinity, glycan-specific binders, offering a compelling alternative to immunoglobulin-based platforms for future diagnostic and therapeutic applications targeting tumor-associated glycans. Full article

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

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13 pages, 1803 KB

Open AccessArticle

Effects of High Glucose Concentrations on PC12 Cells: Possible Implications on Neurodegeneration

by Claudia Cannas, Grazia Galleri, Laura Doro, Ilaria Campesi, Alessandra Tiziana Peana and Rossana Migheli

Curr. Issues Mol. Biol. 2025, 47(10), 801; https://doi.org/10.3390/cimb47100801 - 26 Sep 2025

Abstract

Hyperglycemia, which arises in type 1 or 2 diabetes, leads to different complications, such as macrovascular disease, nephropathy, retinopathy, and neuropathy. In addition, different cognitive variations are associated with type 1 diabetes. Long-term changes in glucose metabolism might induce effects on the central [...] Read more.

Hyperglycemia, which arises in type 1 or 2 diabetes, leads to different complications, such as macrovascular disease, nephropathy, retinopathy, and neuropathy. In addition, different cognitive variations are associated with type 1 diabetes. Long-term changes in glucose metabolism might induce effects on the central nervous system (CNS) such as reduced mental performance and loss of consciousness, which could be implicated in neurotoxicity. The direct impact of hyperglycemia and elevated glucose concentrations on neuronal cells remains to be fully elucidated, primarily due to the multifaceted mechanisms underlying glucose neurotoxicity, including apoptosis, oxidative stress, and alterations in signaling cascades. The multifaceted mechanisms further complicate the study of the relationship between diabetes and neurodegeneration. Research in this field is continually advancing, with the aim of investigating these eventual connections and developing more effective preventive and therapeutic strategies. The present study aims to assess the damage induced by different glucose concentrations (from 25 to 150 mM) in a neuronal model, such as PC12 cells, rat pheochromocytoma cells. In glucose-exposed PC12 cells, we have tested oxidative stress, apoptosis, and cell migration by (a) viability screening, (b) intracellular levels of anion superoxide (O₂⁻), (c) extracellular levels of MDA and nitrites, (d) apoptosis, and (e) the wound healing assay. By the cell viability assay, it has emerged that glucose (25–150 mM) showed a stronger effect at the highest concentrations (100 and 150 mM). The increase in MDA and O₂⁻ levels was determined in PC12 cells treated with high glucose concentrations (6.5–8.8 fold for MDA). High concentrations (100 and 150 mM) significantly reduced the expression of full-length caspase-3 (2.8-fold and 4.2-fold decrease at 24 and 72 h) and caspase-9 (3.4-fold and 2.8-fold decrease at 24 h and 5-fold decrease at 72 h) compared with control conditions. Finally, the wound healing assay showed different scenarios during the several time points. Indeed, the wound closure rate was reduced in a dose-dependent manner (24 h: control 18%, G 50 mM 9%, 100 and 150 mM 8%; 48 h: control 26%, G 50 mM 20%, G 100 mM 13%, 150 mM 11%), following the treatment with three concentrations considered (50, 100, 150 mM). The results obtained in these experimental conditions highlight that glucose, at high concentrations, induced cell damage and corroborate the hypothesis that it could be involved in neurodegenerative diseases. Full article

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

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13 pages, 570 KB

Open AccessArticle

TGF-β1 Is Associated with Left Ventricular Dysfunction

by Bartosz Rakoczy, Michal Rac, Andrzej Krzystolik, Violetta Dziedziejko, Krzysztof Safranow, John Omede and Monika Rac

Curr. Issues Mol. Biol. 2025, 47(10), 800; https://doi.org/10.3390/cimb47100800 - 26 Sep 2025

Abstract

There are many contradictory opinions, and the role of TGF-β1 in the vascular effects of atherosclerosis remains unclear. This study aims to verify whether plasma TGF-β1 concentrations are correlated with changes in echocardiographic and vascular parameters in individuals with early coronary artery disease [...] Read more.

There are many contradictory opinions, and the role of TGF-β1 in the vascular effects of atherosclerosis remains unclear. This study aims to verify whether plasma TGF-β1 concentrations are correlated with changes in echocardiographic and vascular parameters in individuals with early coronary artery disease (CAD), including those with type 2 diabetes mellitus (T2DM). The study group consisted of 100 patients with early-onset CAD. Patients underwent echocardiography and electrocardiography. The thickness of the internal and middle membrane complex of the carotid and brachial arteries, the ankle-brachial index, and the atherosclerotic plaques present were assessed via Doppler ultrasound. No statistically significant correlation of TGF-β1 with diabetes, hypertension, metabolic syndrome, or myocardial infarction was observed, only weak associations with impaired ventricular function. The positive correlations between right and left ventricular parameters and TGF-β1 level, as well as the negative correlations fractional shortening and deceleration time, were found. The last correlation was strong. There is a strong positive correlation between TGF-β1 and QRS II width and QRS V5 width. The positive correlation was found between TGF-β1 and PLA density and thickness of the intima-media. These associations are very weak. In patients with early-onset CAD, high TGF-β1 concentrations are not associated with heart attacks or the associated risk factors. However, these cases are potentially those with stable plaques. Our study indicates a significant association between TGF-β1 levels and left ventricular diastolic dysfunction and arrhythmia risk in these patients. Full article

(This article belongs to the Special Issue Advances in Molecular Therapies and Disease Associations in Diabetes)

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12 pages, 1331 KB

Open AccessArticle

Obesity Alters the microRNA Expression Profile Related to Metabolic Disorders in Peripheral Blood Mononuclear Cells: Preliminary Results

by Samar Sultan and Marwah Maashi

Curr. Issues Mol. Biol. 2025, 47(10), 799; https://doi.org/10.3390/cimb47100799 - 26 Sep 2025

Abstract

Obesity is a major global health issue associated with an increased risk of early-onset metabolic disorders and chronic inflammation. Identifying the epigenetic mechanisms that contribute to obesity-related metabolic and inflammatory dysregulation is crucial for developing effective prevention and treatment strategies. This pilot study [...] Read more.

Obesity is a major global health issue associated with an increased risk of early-onset metabolic disorders and chronic inflammation. Identifying the epigenetic mechanisms that contribute to obesity-related metabolic and inflammatory dysregulation is crucial for developing effective prevention and treatment strategies. This pilot study aimed to investigate the effects of obesity on the expression of microRNAs (miRNAs) related to metabolic disorders in human peripheral blood mononuclear cells from metabolically healthy obese subjects and non-obese controls. Differentially expressed miRNAs in TaqMan human miRNA arrays were quantified using quantitative PCR. To validate the robustness and generalizability of our findings, we performed cross-validation using the publicly available GSE155096 dataset. The expression of miR-145-5p was significantly increased (4.913-fold change) in obese individuals compared to the non-obese control group. Two miRNAs, miR-27b-3p and miR-17-5p, were downregulated 2.207- and 1.448-fold, respectively, approaching significance. A positive correlation was established between miR-145-5p and free triiodothyronine, eosinophils, and vitamin D. A cross-validation analysis confirmed the direction of change for these key miRNAs. The data suggest that miR-145-5p, miR-27b-3p, and miR-17-5p could be implicated in the progression of obesity in causing metabolic abnormalities, clarifying how molecular factors cause the metabolic deregulation associated with obesity. Full article

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

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23 pages, 4307 KB

Open AccessArticle

Cinnamomum migao H.W. Li Ethanol-Water Extract Suppresses IL-6 Production in Cardiac Fibroblasts: Mechanisms Elucidated via UPLC-Q-TOF-MS, Network Pharmacology, and Experimental Assays

by Yuxin Lu, Yaofeng Li, Can Zhu, Mengyue Guo, Xia Liu and Xiangyun Chen

Curr. Issues Mol. Biol. 2025, 47(10), 798; https://doi.org/10.3390/cimb47100798 - 26 Sep 2025

Abstract

This study aims to elucidate the active components and underlying molecular mechanisms by which the ethanol-water extract of Cinnamomum migao H.W. Li (MG-EWE) inhibits cardiac fibroblast (CF) transdifferentiation and IL-6 production, providing insights into its anti-myocardial fibrosis effects. The chemical composition of MG-EWE [...] Read more.

This study aims to elucidate the active components and underlying molecular mechanisms by which the ethanol-water extract of Cinnamomum migao H.W. Li (MG-EWE) inhibits cardiac fibroblast (CF) transdifferentiation and IL-6 production, providing insights into its anti-myocardial fibrosis effects. The chemical composition of MG-EWE was characterized using UPLC-Q-TOF-MS. Network pharmacology analysis identified active constituents and their mechanisms in inhibiting IL-6 production in CFs. An isoproterenol (ISO)-induced rat CF model was established to evaluate the effects of MG-EWE and its main monomers, Laurolitsine and Hecogenin, on cell proliferation, migration, collagen metabolism, IL-6 production, and key proteins in the ADRB2/JNK signaling pathway. A total of 173 compounds were identified in MG-EWE, with 14 core constituents regulating IL-6 synthesis via 16 key targets, including ADRB2 and MAPK9. Gene Ontology enrichment indicated that MG-EWE affects phosphorylation and the JNK signaling cascade. Molecular docking showed strong binding affinities between Laurolitsine, Hecogenin, and their targets ADRB2 and JNK. Experimentally, MG-EWE, Laurolitsine, and Hecogenin significantly inhibited ISO-induced CF proliferation, migration, and hydroxyproline synthesis, as well as the expression of p-ADRB2, p-JNK, p-c-Jun, and IL-6. MG-EWE inhibits CF transdifferentiation and IL-6 production via the ADRB2/JNK/c-Jun signaling axis, mediated by its constituents Laurolitsine and Hecogenin, highlighting its potential for drug development targeting myocardial fibrosis. Full article

(This article belongs to the Special Issue Applications of Natural and Pseudo-Natural Products in Drug Discovery and Development 2025)

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16 pages, 3969 KB

Open AccessArticle

Antipsychotic Chlorpromazine Suppresses STAT5 Signaling, Overcomes Resistance Mediated by the Gatekeeper Mutation FLT3-ITD/F691L, and Synergizes with Quizartinib in FLT3-ITD-Positive Cells

by Aki Fujii-Hanamoto, Hirokazu Tanaka, Ko Fujimoto, Takahiro Haeno, Yoshiaki Miyake, Ryosuke Fujiwara, Takahiro Kumode, Kentaro Serizawa, Yasuyoshi Morita, Hitoshi Hanamoto, Shinya Rai and Itaru Matsumura

Curr. Issues Mol. Biol. 2025, 47(10), 797; https://doi.org/10.3390/cimb47100797 - 25 Sep 2025

Abstract

Background: FLT3 mutations, including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) point mutations, represent common genetic alterations in acute myeloid leukemia (AML), with FLT3-ITD associated with poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs), such as quizartinib (Quiz) and gilteritinib, [...] Read more.

Background: FLT3 mutations, including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) point mutations, represent common genetic alterations in acute myeloid leukemia (AML), with FLT3-ITD associated with poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs), such as quizartinib (Quiz) and gilteritinib, have improved clinical outcomes, secondary TKD mutations, particularly the gatekeeper mutation F691L, confer significant resistance. We previously demonstrated that chlorpromazine (CPZ), an antipsychotic drug, inhibits clathrin-mediated endocytosis and selectively suppresses the growth of cancer cells harboring mutant receptor tyrosine kinases. Methods: In this study, we examined the efficacy of CPZ in overcoming TKI resistance using Ba/F3 cells expressing FLT3-ITD or FLT3-ITD/F692L, the murine analog of F691L. Results: Quiz inhibited proliferation of FLT3-ITD cells but was ineffective against FLT3-ITD/F692L cells. CPZ suppressed growth in both cell types. Co-treatment with CPZ and Quiz exhibited synergistic effects in FLT3-ITD cells, but not in FLT3-ITD/F692L cells. CPZ reduced STAT5 phosphorylation and modulated downstream signaling in FLT3-ITD cells, while only partially affecting STAT5 in FLT3-ITD/F692L cells. Expression of constitutively active STAT5 partially rescued CPZ-induced growth inhibition. Conclusions: These findings suggest that STAT5 suppression is a key mechanism of CPZ’s antileukemic activity and support its potential as a therapeutic strategy for FLT3-ITD-positive AML. Full article

(This article belongs to the Section Molecular Pharmacology)

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23 pages, 12833 KB

Open AccessArticle

Enteromorpha prolifera Polysaccharides Alleviate Valproic Acid-Induced Neuronal Apoptosis in a Cellular Model of Autism Spectrum Disorder

by Xulan Zhou, Hui Su, Jiaxuan Chen, Li Liu, Qian Zhou, Xiaochun Xia and Juan Wang

Curr. Issues Mol. Biol. 2025, 47(10), 796; https://doi.org/10.3390/cimb47100796 - 25 Sep 2025

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social/communication deficits and behavioral abnormalities, with neuronal apoptosis and immune-inflammatory dysregulation implicated in its pathogenesis. Marine-derived polysaccharides, particularly those from Enteromorpha prolifera (PEPs), exhibit neuroprotective and anti-inflammatory properties—yet their therapeutic potential for ASD [...] Read more.

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social/communication deficits and behavioral abnormalities, with neuronal apoptosis and immune-inflammatory dysregulation implicated in its pathogenesis. Marine-derived polysaccharides, particularly those from Enteromorpha prolifera (PEPs), exhibit neuroprotective and anti-inflammatory properties—yet their therapeutic potential for ASD remains unexplored. Major monosaccharide components of PEPs were identified as rhamnose, xylose, glucose, glucuronic acid, galactose, and ribose through ion chromatography analysis. Infrared spectroscopy confirmed PEPs as pyranose-type polysaccharides with α-glycosidic bonds and uronic acids, while gel permeation chromatography showed a predominant molecular weight of 3.813 kDa (83.919%). To explore the therapeutic potential of PEPs in ASD, a comprehensive method combining network pharmacology, molecular docking, and in vitro validation was conducted. A total of 235 ASD-related target proteins were predicted, with enrichment analyses indicating significant involvement in pathways such as neuroactive ligand–receptor interaction and the MAPK signaling pathway. In vitro assays using valproic acid (VPA)-induced HT22 neuronal cells showed that PEPs significantly attenuated apoptosis. Western blot analysis further confirmed the downregulation of HSP90AA1, cleaved CASP3/pro-CASP3, p-NF-κB1/NF-κB1, p-AKT1/AKT, and p-mTOR/mTOR, as well as the upregulation of IκBα after PEPs treatment. These findings suggest that PEPs exert neuroprotective effects through the modulation of apoptosis and inflammation-related signaling pathways, supporting their potential as a promising candidate for further study in ASD. Full article

(This article belongs to the Section Molecular Medicine)

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10 pages, 2737 KB

Open AccessArticle

4-Coumarate CoA Ligase Family in Soybean Responds to Heterodera glycines

by Hui Wang, Shumei Liu, Shunbin Zhang, Fengjiao Fan, Chuanwen Yang, Yuxi Duan, Qiumin Chen and Chen Liu

Curr. Issues Mol. Biol. 2025, 47(10), 795; https://doi.org/10.3390/cimb47100795 - 25 Sep 2025

Abstract

Soybean cyst nematode (SCN) development depends on syncytium formation, which requires cell-wall degradation and fusion. Lignin, the main barrier in cell walls, is critical for SCN resistance. 4-Coumarate: CoA ligase (4CL) drives the phenylpropanoid pathway by converting p-coumaric acid to p-coumaroyl-CoA, supplying lignin [...] Read more.

Soybean cyst nematode (SCN) development depends on syncytium formation, which requires cell-wall degradation and fusion. Lignin, the main barrier in cell walls, is critical for SCN resistance. 4-Coumarate: CoA ligase (4CL) drives the phenylpropanoid pathway by converting p-coumaric acid to p-coumaroyl-CoA, supplying lignin precursors. Here, resistant cv. Huipizhiheidou accumulated more lignin than susceptible Williams 82 after SCN inoculation. SCN stress induced distinct Gm4CL-family expression profiles across cultivars; Gm4CL3 and Gm4CL4 were markedly upregulated in Huipizhiheidou. Transient expression of Gm4CL3 in tobacco thickened leaf cell walls, implying enhanced wall reinforcement against SCN. Thus, 4CLs, especially Gm4CL3, may promote lignin deposition and secondary wall thickening to strengthen soybean SCN resistance. Full article

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

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21 pages, 1978 KB

Open AccessArticle

Genotype Combinations and Genetic Risk Score Analyses of MTHFR, MTRR, and MTR Polymorphisms in Hypothyroidism Susceptibility: A Case–Control Study

by Nilgun Tan Tabakoglu, Arzu Ay, Nevra Alkanli and Mehmet Celik

Curr. Issues Mol. Biol. 2025, 47(10), 794; https://doi.org/10.3390/cimb47100794 - 25 Sep 2025

Abstract

Hypothyroidism is a multifactorial endocrine disorder where genetic predisposition plays a significant role. The MTHFR, MTRR, and MTR genes influence thyroid hormone regulation via homocysteine remethylation and DNA methylation. This study examined associations between hypothyroidism and polymorphisms in MTHFR (C677T–rs1801133, A1298C [...] Read more.

Hypothyroidism is a multifactorial endocrine disorder where genetic predisposition plays a significant role. The MTHFR, MTRR, and MTR genes influence thyroid hormone regulation via homocysteine remethylation and DNA methylation. This study examined associations between hypothyroidism and polymorphisms in MTHFR (C677T–rs1801133, A1298C–rs1801131), MTRR (A66G–rs1801394), and MTR (A2756G–rs1805087) genes. Eighty-six patients with hypothyroidism and 87 healthy controls were included. Genotyping was performed using PCR-RFLP. Post hoc analysis confirmed adequate statistical power (95% for MTRR A66G, 84.6% for MTR A2756G). The study adhered to STROBE guidelines. MTHFR polymorphisms showed no significant association when considered individually. However, the MTRR A66G AA genotype was significantly more frequent in patients and conferred a markedly increased disease risk (OR: 4.373; 95% CI: 2.174–8.797; p < 0.001), while the MTR A2756G AG genotype was also more prevalent among patients and associated with higher susceptibility (OR: 2.178; 95% CI: 1.156–4.104; p = 0.008). Genotype combination analysis revealed that CT–AA (OR = 6.898; 95% CI: 1.941–24.516; p = 0.001) and AG–AA (OR = 6.892; 95% CI: 1.494–31.797; p = 0.007) conferred high risk. Certain genotypes correlated with clinical features, including hypercholesterolemia, diabetes, and cardiovascular disease. MTRR A66G and MTR A2756G polymorphisms are associated with hypothyroidism and metabolic comorbidities, both individually and in genotype combinations. These findings underscore the value of multilocus genetic models for understanding thyroid disorders and support the potential role of genetic biomarkers in personalized risk assessment and early diagnosis. GRS analysis demonstrated that each additional risk allele increased hypothyroidism risk (OR = 1.58; 95% CI: 1.18–2.10; p = 0.0018), and the total score showed moderate predictive power (AUC = 0.665; p < 0.001). Full article

(This article belongs to the Section Molecular Medicine)

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17 pages, 7940 KB

Open AccessArticle

Epicatechin Protects Against Post-Cardiac Arrest Brain Injury in Aged Rats via NRG1-Mediated Suppression of Neuroinflammation

by Hui-Hui Wang, Fan Huang, Zi-Long Du and Lu Xie

Curr. Issues Mol. Biol. 2025, 47(10), 793; https://doi.org/10.3390/cimb47100793 - 24 Sep 2025

Abstract

Chronic inflammation conducts an irreplaceable role in the aging process. More importantly, the impact is particularly significant in scenarios involving cardiac arrest and cardiopulmonary resuscitation (CA/CPR), where elderly individuals are inclined to suffer from more severe inflammatory injuries when compared to younger counterparts. [...] Read more.

Chronic inflammation conducts an irreplaceable role in the aging process. More importantly, the impact is particularly significant in scenarios involving cardiac arrest and cardiopulmonary resuscitation (CA/CPR), where elderly individuals are inclined to suffer from more severe inflammatory injuries when compared to younger counterparts. Network pharmacology demonstrated a tight correlation between epicatechin (EC), aging, and the NRG1-NF-κB signaling pathway. With an aim to investigate whether EC suppressing inflammatory aging and alleviating post-CA/CPR brain injury is associated with the inhibition of the NRG1-NF-κB pathway, we established a model of naturally aged 21-month-old rats subjected to CA/CPR. A network pharmacology method was employed to pinpoint possible pathways that connect EC to neuroinflammation associated with aging. Sixty rats were randomly divided into three groups for feeding: a control group (pure water) and EC groups (EC was administered by gavage at doses of 1 mg/kg and 2 mg/kg respectively from the 12th month). Those groups underwent a CA/CPR procedure. At 24-h post-resuscitation, neurological scores, cortical pathology staining and assessments of neural injury were conducted. Expression levels of NRG1-NF-κB pathway-relevant inflammatory factors and proteins underwent systematic investigation by carrying out ELISA, RT-PCR, and Western blotting. In comparison with the 21-month-old groups treated with water, the 21-month-old groups treated with EC at 1 mg/kg and 2 mg/kg demonstrated decreased β-galactosidase staining, aging-correlated proteins and pro-inflammatory factors and NF-κB pathway-relevant proteins, as well as reinforced NRG1-ErbB4 expression. EC lessened inflammatory aging and mitigates post-CA/CPR brain injury in aged rats, associated with the inhibition of the NRG1-NF-κB pathway. Full article

(This article belongs to the Section Molecular Medicine)

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19 pages, 2407 KB

Open AccessArticle

Meta-QTL Analysis and Identification of Candidate Genes Associated with Stalk Lodging in Maize (Zea mays L.)

by Haiyue Fang, Chunxiao Zhang, Wenli Qu, Xiaohui Zhou, Jing Dong, Xueyan Liu, Xiaohui Li and Fengxue Jin

Curr. Issues Mol. Biol. 2025, 47(10), 792; https://doi.org/10.3390/cimb47100792 - 23 Sep 2025

Abstract

Stalk lodging constitutes a primary constraint on achieving consistently high yields in maize. Genetic improvement of lodging resistance requires the identification of stable quantitative trait loci (QTL) to facilitate the application of genomics-assisted breeding for improving selection efficiency in breeding programs. In this [...] Read more.

Stalk lodging constitutes a primary constraint on achieving consistently high yields in maize. Genetic improvement of lodging resistance requires the identification of stable quantitative trait loci (QTL) to facilitate the application of genomics-assisted breeding for improving selection efficiency in breeding programs. In this study, we performed a meta-analysis to identify consensus loci and functionally characterized candidate genes associated with stalk lodging-related traits. Through meta-analysis integrating 889 reported lodging-related QTLs using the IBM2 2008 Neighbors high-density genetic map, we identified 67 meta-QTLs (MQTLs), of which 32 were determined as core MQTLs. Among them, 67% were validated by co-localized marker–trait associations from genome-wide association studies (GWAS). Comparative genomics further revealed 40 evolutionarily conserved orthologs via protein alignment with rice lodging genes, while screening of core MQTL regions detected 802 candidate genes with KEGG enrichment implicating galactose degradation II in cell wall reinforcement, supported by transcriptomic evidence of their roles in lignin biosynthesis pathways modulating mechanical strength. In conclusion, the MQTL identified and validated in our study have significant scope in marker-assisted selection (MAS) breeding and map-based cloning programs for improving maize stalk lodging. Full article

(This article belongs to the Section Molecular Plant Sciences)

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17 pages, 2346 KB

Open AccessArticle

Switching from a High-Fat to a Regular Chow Diet Improves Obesity Progression in Mice

by Yuying Wang, Fenglin Chen, Xiaozhong Wang, Shiwan Wang and Lei Ding

Curr. Issues Mol. Biol. 2025, 47(10), 791; https://doi.org/10.3390/cimb47100791 - 23 Sep 2025

Abstract

The fast-paced lifestyle of modern people has changed their dietary structure and increased the prevalence of obesity, of which a high-fat diet is the main cause. Therefore, this study investigates whether reducing fat intake can improve obesity and physical health. We induced an [...] Read more.

The fast-paced lifestyle of modern people has changed their dietary structure and increased the prevalence of obesity, of which a high-fat diet is the main cause. Therefore, this study investigates whether reducing fat intake can improve obesity and physical health. We induced an obese model with a 60 kcal% fat diet (HFD) for 12 weeks, followed by an intervention with a 4.9 kcal% fat diet (regular chow diet, RD) for 20 weeks. We found that after 20 weeks of RD, various indicators were significantly reduced compared with the HFD group, including dietary intake (3.26 ± 0.38 g, p < 0.01), Lee index (385.24 ± 14.22, p < 0.0001), blood glucose (8.75 ± 2.44 mmol/L, p < 0.01), blood lipids (TC: 2.60 ± 0.63 mmol/L, p < 0.001; TG: 0.72 ± 0.08 mmol/L, p < 0.001; and LDL-C: 0.57 ± 0.30 mmol/L, p < 0.0001), and inflammatory status (IL-6: 32.70 ± 7.55 pg/mL, p < 0.05). In addition, increasing dietary intake also indirectly increased fiber intake, which could promote intestinal microbiota diversity. Changing the diet of obese mice from HFD to RD still maintained the abundance of the probiotics Akkermansia, Parabacteroides, Alloprevotella, and Porphyromonadaceae, among which fiber intake played an important role. Therefore, we found that only reducing dietary fat intake was effective for weight loss, and dietary fiber intake helped maintain a healthy intestinal microbiota balance. Full article

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

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25 pages, 817 KB

Open AccessReview

Pathogenic and Regulatory Roles of Fibrinolytic Factors in Autoimmune Diseases

by Yosuke Kanno

Curr. Issues Mol. Biol. 2025, 47(10), 790; https://doi.org/10.3390/cimb47100790 - 23 Sep 2025

Abstract

Autoimmune diseases arise from complex interactions of genetic, environmental, and hormonal factors, yet their precise causes remain elusive. Beyond its canonical role in fibrin degradation, the fibrinolytic system is increasingly recognized as both a pathogenic driver and a regulatory modulator in autoimmunity. Key [...] Read more.

Autoimmune diseases arise from complex interactions of genetic, environmental, and hormonal factors, yet their precise causes remain elusive. Beyond its canonical role in fibrin degradation, the fibrinolytic system is increasingly recognized as both a pathogenic driver and a regulatory modulator in autoimmunity. Key factors—plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1)—not only reflect secondary responses to vascular and immune dysregulation but also actively shape innate and adaptive immunity. They influence macrophage activation, dendritic cell maturation, T cell responses, and cytokine production, thereby bridging coagulation, inflammation, and tissue repair. This review integrates current evidence on the dual pathogenic and regulatory roles of fibrinolytic factors, organizing autoimmune diseases into systemic, organ-specific, and secondary syndromes. We further discuss how the imbalance of fibrinolysis can either promote inflammatory persistence or, conversely, facilitate resolution through fibrin clearance and immune homeostasis. By highlighting this bidirectional influence, the review aims to refine our understanding of fibrinolytic components as both contributors to and regulators of autoimmune disease pathogenesis. Full article

(This article belongs to the Section Molecular Medicine)

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17 pages, 1957 KB

Open AccessArticle

In Silico Multitarget Profiling of Non-Selective Beta-Blockers Highlights Their Potential as Key Agents in Breast Cancer Adjuvant Therapy via ADRB2, ERBB2, and NPYR Receptors

by Felipe Muñoz-González, José Correa-Basurto, Iván Ignacio-Mejia and Cindy Bandala

Curr. Issues Mol. Biol. 2025, 47(10), 789; https://doi.org/10.3390/cimb47100789 - 23 Sep 2025

Abstract

Breast cancer (BC) is associated with multiple molecular factors such as overexpression of the beta-2 adrenergic receptor (ADRB2) and the overproduction of its agonists (norepinephrine and epinephrine). The role of adrenergic signaling in BC highlights the therapeutic potential of non-selective beta-blockers (nsBBs) as [...] Read more.

Breast cancer (BC) is associated with multiple molecular factors such as overexpression of the beta-2 adrenergic receptor (ADRB2) and the overproduction of its agonists (norepinephrine and epinephrine). The role of adrenergic signaling in BC highlights the therapeutic potential of non-selective beta-blockers (nsBBs) as inhibitors of well-established protumor signaling pathways related to ADRB2 and their possible affinity for other important protumoral receptors. Our aim was to identify how nsBBs currently prescribed may also interact with receptors other than ADRB2, which are related to the pathophysiology of BC, using bioinformatic intracellular pathway analysis (BIPA). Subsequently, the affinity of nsBBs for both ADRB2 and the targets identified by BIPA was evaluated. We found that, beyond ADRB2, both receptor tyrosine kinase 2 (ERBB2) and neuropeptide Y receptor (NPYR) are promising targets for nsBBs in the adjuvant treatment of BC, according to BIPA. Docking studies showed that the nsBB with the highest binding affinity (ΔG) was carvedilol (−10.5 kcal/mol), followed by propranolol (−8.5 kcal/mol). These in silico findings suggest previously unrecognized pharmacological mechanisms for nsBBs in the possible treatment for BC. Notably, differences in receptor affinity were observed among the nsBBs, with carvedilol exhibiting the strongest binding affinity values on ADRB2, ERBB2, and NPYR as biological targets against BC cells. These promising results require future experimental validation. Full article

(This article belongs to the Topic Antibody-Mediated Therapy and Other Emerging Therapies in Cancer Treatment)

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10 pages, 832 KB

Open AccessArticle

The Time of Blood Collection Does Not Alter the Composition of Leucocyte-Poor Platelet-Rich Plasma: A Quantitative Analysis of Platelets and Key Regenerative Proteins

by Hadrian Platzer, Alena Bork, Malte Wellbrock, Axel Horsch, Ghazal Pourbozorg, Simone Gantz, Reza Sorbi, Sébastien Hagmann, Yannic Bangert and Babak Moradi

Curr. Issues Mol. Biol. 2025, 47(10), 788; https://doi.org/10.3390/cimb47100788 - 23 Sep 2025

Abstract

Platelet-rich plasma (PRP) is increasingly used in orthopedics, with its regenerative potential attributed to platelet-derived cytokines and growth factors. However, variability in PRP composition hampers standardization and reproducibility, contributing to inconsistent outcomes. Since platelet counts in whole blood follow circadian rhythms, we investigated [...] Read more.

Platelet-rich plasma (PRP) is increasingly used in orthopedics, with its regenerative potential attributed to platelet-derived cytokines and growth factors. However, variability in PRP composition hampers standardization and reproducibility, contributing to inconsistent outcomes. Since platelet counts in whole blood follow circadian rhythms, we investigated whether blood collection time affects PRP composition. Venous blood was collected from 25 healthy individuals at 8:00 a.m., 12:00 p.m., and 4:00 p.m. Whole blood was analyzed, and leukocyte-poor PRP (LP-PRP) was prepared for quantification of erythrocytes, leukocytes, and platelets. Platelets were lysed by freeze–thaw cycles, and protein levels of PDGF-BB, IGF1, HGF, IL6, and IL10 were measured via ELISA. Whole blood exhibited diurnal variation in platelet counts. In contrast, LP-PRP was consistently depleted of leukocytes and erythrocytes and showed stable platelet enrichment (PRP/whole blood ratio 2.1 ± 0.3). Protein concentrations in LP-PRP did not differ across collection times. Despite marked interindividual variability, no time-dependent differences were observed in platelet or protein composition. These results demonstrate that LP-PRP is temporally stable, independent of blood sampling time. This robustness supports flexible clinical use and contributes to efforts toward PRP standardization in therapeutic practice. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Medicine 2025)

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39 pages, 497 KB

Open AccessReview

Obesity as a Multifactorial Chronic Disease: Molecular Mechanisms, Systemic Impact, and Emerging Digital Interventions

by Ewelina Młynarska, Kinga Bojdo, Anna Bulicz, Hanna Frankenstein, Magdalena Gąsior, Natalia Kustosik, Jacek Rysz and Beata Franczyk

Curr. Issues Mol. Biol. 2025, 47(10), 787; https://doi.org/10.3390/cimb47100787 - 23 Sep 2025

Abstract

Obesity is a multifactorial chronic disease resulting from complex genetic, molecular, environmental, and behavioral interactions. Its prevalence rises worldwide, affecting cardiovascular, metabolic, oncological, hepatic, respiratory, and skeletal health. Beyond caloric excess, genetic predisposition, epigenetic modifications, gut microbiota dysbiosis, endocrine-disrupting agents, circadian misalignment, and [...] Read more.

Obesity is a multifactorial chronic disease resulting from complex genetic, molecular, environmental, and behavioral interactions. Its prevalence rises worldwide, affecting cardiovascular, metabolic, oncological, hepatic, respiratory, and skeletal health. Beyond caloric excess, genetic predisposition, epigenetic modifications, gut microbiota dysbiosis, endocrine-disrupting agents, circadian misalignment, and intergenerational and prenatal influences are critical determinants of obesity risk. Core pathophysiological mechanisms include insulin resistance, dyslipidemia, chronic low-grade inflammation, and neuroendocrine dysregulation of appetite and energy balance. These processes are linked to comorbidities such as type 2 diabetes, hypertension, atherosclerosis, fatty liver disease, sleep apnea, osteoporosis, and cancer. Advances in molecular profiling, metabolic phenotyping, and body composition analysis are refining obesity classification and enabling precise risk stratification. Current therapeutic strategies include behavioral interventions addressing stress-related mechanisms, pharmacological therapies such as GLP-1 receptor agonists, emerging gene therapy approaches, and bariatric surgery. Gut-derived hormones (leptin, ghrelin, GLP-1, PYY, CCK) are recognized as pivotal regulators of appetite and weight. Preventive strategies increasingly emphasize circadian alignment, while epigenetic inheritance and prenatal exposures such as maternal obesity or smoking highlight early-life programming in future metabolic health. Additionally, artificial intelligence-based platforms and personalized nutrition provide innovative opportunities for individualized prevention and management. This review synthesizes contemporary evidence on the biological basis, systemic consequences, preventive strategies, and evolving therapeutic modalities of obesity, affirming its recognition as a complex chronic disease requiring personalized, multidisciplinary care. Full article

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

17 pages, 3676 KB

Open AccessArticle

Geniposide Inhibits Oral Squamous Cell Carcinoma by Regulating PI3K-Akt Signaling-Mediated Apoptosis: A Multi-Method Validation Study

by Xue Wang, Jianbo Wang, Hua Hua, Ping Wei, Xue Chen, Yusheng Peng, Li Liu, Dongmei Yu, Xiaozhou You and Siye Yang

Curr. Issues Mol. Biol. 2025, 47(9), 786; https://doi.org/10.3390/cimb47090786 - 22 Sep 2025

Abstract

Gardenia jasminoides J.Ellis is an important medicinal and edible resource. The fruit of Gardenia jasminoides J.Ellis contains a natural iridoid called geniposide, which has the ability to dramatically suppress the growth of a number of cancer cell lines. This work examined the impact [...] Read more.

Gardenia jasminoides J.Ellis is an important medicinal and edible resource. The fruit of Gardenia jasminoides J.Ellis contains a natural iridoid called geniposide, which has the ability to dramatically suppress the growth of a number of cancer cell lines. This work examined the impact and potential mechanism of action of geniposide on oral squamous cell carcinoma using network pharmacology, molecular docking, molecular dynamics simulation, and cellular experiments. Based on network pharmacology, 145 potential targets of geniposide in the treatment of OSCC were found. The top five core targets were selected according to the degree values of the nodes, AKT1, EGFR, SRC, HSP90AA1, and PIK3R1, which involved signaling pathways and biological processes, such as the PI3K-Akt signaling pathway, pathways in cancer, phosphorylation, and the regulation of the apoptotic process. Molecular docking showed that geniposide exhibited good binding ability with the core targets AKT1 and EGFR. Molecular dynamics simulations further confirmed the stability of the binding between geniposide and the targets. The results of cell experiments showed that the activity of HSC-3 cells was dose-dependently inhibited by geniposide, and AO/EB staining showed that geniposide was able to induce programmed apoptosis. Meanwhile, it was found that the expressions of p-EGFR, p-AKT, and Bcl-2 were downregulated in HSC-3, and the expressions of PTEN, Bax, and Caspase-3 were upregulated. Geniposide may inhibit OSCC by affecting the PI3K-Akt signaling pathway and apoptotic process by regulating the expressions of p-EGFR, p-AKT, Bcl-2, Bax, Caspase-3, and PTEN. Full article

(This article belongs to the Special Issue Natural Product Drug Activity and Biomedicine Application)

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20 pages, 3442 KB

Open AccessArticle

Synergistic Induction of Apoptosis by Boswellic Acid and Cisplatin in A549 Lung Cancer Cells Through NF-κB Modulation and p53 Pathway Activation

by Mehmet Uğur Karabat and Mehmet Cudi Tuncer

Curr. Issues Mol. Biol. 2025, 47(9), 785; https://doi.org/10.3390/cimb47090785 - 22 Sep 2025

Abstract

The increasing resistance to chemotherapeutic agents in lung cancer significantly contributes to its high mortality. Natural compounds such as acetyl-11-keto-β-boswellic acid (AKBA) have emerged as promising adjuncts to standard therapies. This study investigated the synergistic apoptotic and cytotoxic effects of AKBA in combination [...] Read more.

The increasing resistance to chemotherapeutic agents in lung cancer significantly contributes to its high mortality. Natural compounds such as acetyl-11-keto-β-boswellic acid (AKBA) have emerged as promising adjuncts to standard therapies. This study investigated the synergistic apoptotic and cytotoxic effects of AKBA in combination with cisplatin (Cis) on A549 non-small-cell lung cancer (NSCLC) cells. Cell viability, apoptosis, and gene expression were evaluated using MTS assay, Annexin V-FITC/PI staining, caspase activity, RT-qPCR, and ELISA, complemented by molecular docking (AKBA–p53) and molecular dynamics (AKBA–p53 and Cis–p53) analyses. Combined AKBA + Cis treatment significantly enhanced apoptosis and reduced cell viability compared to monotherapies (p < 0.001), accompanied by upregulation of p53 and caspase-3 and suppression of NF-κB. In silico results further supported direct and stable binding of p53, particularly with AKBA. These findings indicate that AKBA synergizes with Cis to potentiate apoptotic and anti-inflammatory responses in NSCLC and may provide a novel dose-sparing strategy with improved therapeutic efficacy, warranting further in vivo validation. Full article

(This article belongs to the Special Issue Cancer Biomarkers: Discovery and Applications)

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28 pages, 4640 KB

Open AccessArticle

Proteomic Analysis of Low-Temperature Stress Response in Maize (Zea mays L.) at the Seedling Stage

by Tao Yu, Jianguo Zhang, Xuena Ma, Shiliang Cao, Wenyue Li and Gengbin Yang

Curr. Issues Mol. Biol. 2025, 47(9), 784; https://doi.org/10.3390/cimb47090784 - 22 Sep 2025

Abstract

Low temperature severely restricts maize seedling establishment and yield in northern China, but the proteomic basis of low-temperature tolerance in maize remains unclear. This study used TMT-labeled quantitative proteomics combined with data-independent acquisition (DIA) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) to analyze dynamic [...] Read more.

Low temperature severely restricts maize seedling establishment and yield in northern China, but the proteomic basis of low-temperature tolerance in maize remains unclear. This study used TMT-labeled quantitative proteomics combined with data-independent acquisition (DIA) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) to analyze dynamic proteome changes in two maize inbred lines (low-temperature-tolerant B144 and low-temperature-sensitive Q319) at the three-leaf stage under 5 °C treatment. A total of 4367 non-redundant proteins were identified. For differentially expressed proteins (DEPs, fold change >2.0 or <0.5, ANOVA-adjusted p < 0.05, false discovery rate [FDR] < 0.05), B144 showed exclusive upregulation under stress (6 DEPs at 24 h; 16 DEPs at 48 h), while Q319 exhibited mixed regulation (9 DEPs at 24 h: 6 upregulated, 3 downregulated; 21 DEPs at 48 h: 19 upregulated, 2 downregulated). Functional annotation indicated that ribosomal proteins, oxidoreductases, glycerol-3-phosphate permease, and actin were significantly upregulated in both lines. Pathway enrichment analysis revealed associations with carbohydrate metabolism, amino acid biosynthesis, and secondary metabolite synthesis. Weighted gene co-expression network analysis (WGCNA) identified genotype-specific expression patterns: B144 showed differential expression of proteins related to acetyl-CoA synthetase and fatty acid β-oxidation at 24 h and of proteins related to D-3-phosphoglycerate dehydrogenase at 48 h; Q319 showed differential expression of proteasome-related proteins at 24 h and of proteins related to elongation factor 1α (EF-1α) at 48 h. Venn analysis found no shared DEPs between the two lines at 24 h but four overlapping DEPs at 48 h. These results clarify proteomic differences underlying low-temperature tolerance divergence between maize genotypes and provide candidate targets for molecular breeding of low-temperature-tolerant maize. Full article

(This article belongs to the Special Issue Advances in Multi-Omics for Functional Genomics Studies and Molecular Breeding, 2nd Edition)

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