Current Issues in Molecular Biology

22 pages, 8268 KB

Open AccessArticle

Bioinformatics Identification and Experimental Validation of Ferroptosis- and Immune Infiltration-Associated Biomarkers in Ischemic Stroke

by Fan Huang, Mingjing Zhu, Huihui Wang, Zilong Du, Qianqian Wu, Yongjing He, Yilin Liang, Wanxiang Hu and Lu Xie

Curr. Issues Mol. Biol. 2025, 47(12), 1066; https://doi.org/10.3390/cimb47121066 - 18 Dec 2025

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Abstract

Ischemic stroke (IS) continues to pose a significant threat to human health. Few studies have explored the connection between ferroptosis-related genes and immune infiltration in the context of IS. Initially, 303 differentially expressed genes were identified, from which four characteristic genes were distinguished, [...] Read more.

Ischemic stroke (IS) continues to pose a significant threat to human health. Few studies have explored the connection between ferroptosis-related genes and immune infiltration in the context of IS. Initially, 303 differentially expressed genes were identified, from which four characteristic genes were distinguished, all validated for their excellent diagnostic efficacy. Animal experiments confirmed significant brain injury and Ferroptosis post-ischemia–reperfusion in rats, with increased expression of Sdcbp, Ppia, and Sec61g, but no change in Rpl22. Furthermore, these key genes were closely associated with levels of immune infiltration. Notably, Rpl22 and Ppia were regulated by nine common transcription factors. Sdcbp and Rpl22 were most abundantly expressed in Microglia, and Ppia in Oligodendrocytes, while Sec61g exhibited lower overall expression, all showing high activity in immune metabolic pathways. Bioinformatics analysis and experimental verification indicate that Sdcbp, Ppia, and Sec61g are associated with ferroptosis and immune infiltration in IS, and hold promise as therapeutic targets for IS treatment. Full article

(This article belongs to the Section Molecular Medicine)

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22 pages, 880 KB

Open AccessArticle

Chemical Composition and Bioactivity of Nelumbo nucifera Gaertn. Flower Extract Fractions: In Vitro Antioxidant and Anti-Inflammatory Properties

by Jung Ha Choo, So Young Lee, Kyoungin Min and Nae Gyu Kang

Curr. Issues Mol. Biol. 2025, 47(12), 1065; https://doi.org/10.3390/cimb47121065 - 18 Dec 2025

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Abstract

With the aging global population, interest in skin aging and skin health products is increasing. Nelumbo nucifera Gaertn. (lotus) has been widely used for its pharmacological benefits, including antioxidant, anti-inflammatory, skin-whitening, and anti-aging properties. In this study, we aimed to develop a safe [...] Read more.

With the aging global population, interest in skin aging and skin health products is increasing. Nelumbo nucifera Gaertn. (lotus) has been widely used for its pharmacological benefits, including antioxidant, anti-inflammatory, skin-whitening, and anti-aging properties. In this study, we aimed to develop a safe and biologically active extract by extracting lotus flowers with hot water, followed by sequential fractionation using porous resin chromatography with stepwise ethanol elution (100% water and 30%, 70%, and 100% ethanol). The 30% and 70% ethanol fractions showed the highest total polyphenol and flavonoid contents. Liquid chromatography–electrospray ionization–mass spectrometry analysis identified major flavonoids, including myricetin and quercetin derivatives, in these fractions. These fractions were combined to formulate a novel Nelumbo nucifera flower extract (NFE), which exhibited potent antioxidant activity confirmed by 2,2-diphenyl-1-picrylhydrazyl, 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and ferric reducing antioxidant power assays. NFE significantly inhibited nitric oxide and prostaglandin E₂ secretion in lipopolysaccharide-activated murine RAW264.7 macrophages. In human keratinocytes HaCaT cells, NFE reduced tumor necrosis factor-α-induced expression and secretion of the pro-inflammatory cytokines interleukin (IL)-6 and IL-8 without cytotoxicity. These findings demonstrate that NFE has strong in vitro antioxidant and anti-inflammatory activities, supporting its potential as a bioactive ingredient for application in improving skin health preparations. Full article

(This article belongs to the Special Issue Pharmacological Activities and Mechanisms of Action of Natural Products, 2nd Edition)

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5 pages, 183 KB

Open AccessEditorial

Physiology Reimagined: Molecular, Metabolic, and Microenvironmental Forces Driving Epithelial Cancers

by Cristian Scheau and Ana Caruntu

Curr. Issues Mol. Biol. 2025, 47(12), 1064; https://doi.org/10.3390/cimb47121064 - 18 Dec 2025

Cited by 1 | Viewed by 181

Abstract

Epithelial cancers represent a broad spectrum of tumors that develop from epithelia of the skin and glands, as well as the digestive, respiratory, urogenital, and gynecological tracts [...] Full article

(This article belongs to the Special Issue Epithelial Cancers: From Molecular Mechanisms to Therapeutic Innovations)

43 pages, 2793 KB

Open AccessReview

Mechanistic Insights into Antioxidant Interventions Targeting Obesity-Induced Oxidative Stress in the Pathogenesis and Complications of Type 2 Diabetes Mellitus

by Fani-Niki Varra, Panagiotis Theodosis-Nobelos, Viktoria-Konstantina Varra and Michail Varras

Curr. Issues Mol. Biol. 2025, 47(12), 1063; https://doi.org/10.3390/cimb47121063 - 18 Dec 2025

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Abstract

Diabetes mellitus (DM) is a complex, heterogeneous, hyperglycemic chronic metabolic disorder. Type 2 diabetes mellitus (T2DM) is characterized by progressive loss of insulin secretion from pancreatic islet β-cells due to IR (insulin resistance), which is a feature of metabolic syndrome (MetS). Chronic hyperglycemia [...] Read more.

Diabetes mellitus (DM) is a complex, heterogeneous, hyperglycemic chronic metabolic disorder. Type 2 diabetes mellitus (T2DM) is characterized by progressive loss of insulin secretion from pancreatic islet β-cells due to IR (insulin resistance), which is a feature of metabolic syndrome (MetS). Chronic hyperglycemia in patients with T2DM in synergy with other metabolic abnormalities causes complications such as diabetic ketoacidosis, osmotic diuresis and hyperglycemic diabetic coma, as well as chronic microvascular and macrovascular complications such as atherosclerotic cardiovascular disease (ASCVD), peripheral artery disease (PAD) and cerebrovascular events, which implicate the formation of reactive species and the promotion of inflammatory pathways. In these events, natural or synthetic antioxidants and minerals seem to have ameliorative effects and may serve as beneficial co-treatment options. In view of these terms, the aim of this study is to investigate the underlying mechanisms of T2DM, its clinical presentation, and its complications. Additionally, the association of the pathogenesis of T2DM and the occurrence of its complications with obesity, chronic inflammation, oxidative stress (OS), insulin resistance (IR), hepatic steatosis, and dyslipidemia is examined, whilst molecular pathways, such as NF-κB and JAK/STAT, are also summarized, under the scope of the effects of several antioxidant compounds and minerals on their progression. The interrelation of T2DM with these conditions, as well as the effects of antioxidant supplementation, seems to be bidirectional, and it is recommended that obese patients be screened for T2DM and adopt lifestyle changes, including exercise, diet modification, and weight loss, in addition to potentially taking multifunctional supplements that offer antioxidant and anti-inflammatory potential. However, many aspects of the protective mechanisms of such antioxidants remain to be elucidated, with more drawbacks in their pharmacokinetic behavior, such as their poor absorption and solubility, waiting to be resolved. Full article

(This article belongs to the Section Molecular Medicine)

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16 pages, 6166 KB

Open AccessArticle

Potential Use of VYN202, a Novel Small Molecular Bromodomain and Extra-Terminal Inhibitor, in Mitigating Secondhand Smoke (SHS)-Induced Pulmonary Inflammation

by Katelyn A. Sturgis, Benjamin D. Davidson, Andrew W. Richardson, Olivia Hiatt, Blake C. Edwards, Ethan P. Evans, Carrleigh Campbell, Jack H. Radford, Juan A. Arroyo, Benjamin T. Bikman and Paul R. Reynolds

Curr. Issues Mol. Biol. 2025, 47(12), 1062; https://doi.org/10.3390/cimb47121062 - 18 Dec 2025

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Abstract

Inflammation underpins pulmonary disease progression during tobacco smoke exposure, which may culminate in irreversible pulmonary disease. While primary smoke poses a notable risk, nearly half of the US population is also susceptible due to frequent exposure to secondhand smoke (SHS). In the present [...] Read more.

Inflammation underpins pulmonary disease progression during tobacco smoke exposure, which may culminate in irreversible pulmonary disease. While primary smoke poses a notable risk, nearly half of the US population is also susceptible due to frequent exposure to secondhand smoke (SHS). In the present study, we assessed the potential role of VYN202, a novel small molecular bromodomain and extra-terminal inhibitor, as a possible means of attenuating SHS-mediated inflammation. We exposed wild-type mice to an acute time course of room air (RA), SHS via a nose-only delivery system (Scireq Scientific, Montreal, Canada), or to both SHS and 10 mg/kg VYN202 (efficacious dose from prior inflammatory models) via oral gavage three times a week. Specific smoke exposure delivery to mice involved SHS from two cigarettes over 10 min, equilibration in room air for 10 min, followed by exposure to SHS from one cigarette for an additional 10 min, for a total SHS exposure of 20 min per day, five days a week for 30 days. We evaluated leukocyte abundance and the secretion of inflammatory mediators in bronchoalveolar lavage fluid (BALF). We also assessed general morphology via histology staining and the activation of receptor tyrosine kinase (RTK) family members. While standard hematoxylin and eosin (H&E) staining resulted in unchanged morphology, SHS-mediated increases in BALF protein abundance, total cellularity, and percent PMNs were attenuated with concomitant administration of VYN202. We also discovered SHS-induced activation of RTKs that were pro-inflammatory (JAK1, JAK3, ABL1, and ACK1), as well as RTKs related to endothelial and vascular remodeling (VEGFR3, VEGFR2, EphB4, EphB6, and FAK). Furthermore, inflammatory cytokines including GCSF, IFN-γ, IL-12p70, IL-17A, LIX, and TNF-α were all augmented by SHS exposure. Despite SHS exposure, each of these RTKs and cytokines/chemokines was significantly attenuated by VYN202. In summary, inflammatory responses induced by SHS exposure were mitigated by VYN202. These data reveal fascinating potential for the utility of VYN202 in lessening smoke-induced pulmonary exacerbations. Full article

(This article belongs to the Section Molecular Medicine)

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34 pages, 6958 KB

Open AccessReview

A Novel Integrative Framework for Depression: Combining Network Pharmacology, Artificial Intelligence, and Multi-Omics with a Focus on the Microbiota–Gut–Brain Axis

by Lele Zhang, Kai Chen, Shun Li, Shengjie Liu and Zhenjie Wang

Curr. Issues Mol. Biol. 2025, 47(12), 1061; https://doi.org/10.3390/cimb47121061 - 18 Dec 2025

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Abstract

Major Depressive Disorder (MDD) poses a significant global health burden, characterized by a complex and heterogeneous pathophysiology insufficiently targeted by conventional single-treatment approaches. This review presents an integrative framework incorporating network pharmacology, artificial intelligence (AI), and multi-omics technologies to advance a systems-level understanding [...] Read more.

Major Depressive Disorder (MDD) poses a significant global health burden, characterized by a complex and heterogeneous pathophysiology insufficiently targeted by conventional single-treatment approaches. This review presents an integrative framework incorporating network pharmacology, artificial intelligence (AI), and multi-omics technologies to advance a systems-level understanding and management of MDD. Its central contribution lies in moving beyond reductionist methods by embracing a holistic perspective that accounts for dynamic interactions within biological networks. The primary objective is to demonstrate how AI-powered integration of multi-omics data—spanning genomics, proteomics, and metabolomics—can enable the construction of predictive network models. These models are designed to uncover fundamental disease mechanisms, identify clinically relevant biotypes, and reveal novel therapeutic targets tailored to specific pathological contexts. Methodologically, the review examines the microbiota–gut–brain (MGB) axis as an illustrative case study, detailing its pathogenic roles through neuroimmune alterations, metabolic dysfunction, and disrupted neuro-plasticity. Furthermore, we propose a translational roadmap that includes AI-assisted biomarker discovery, computational drug repurposing, and patient-specific “digital twin” models to advance precision psychiatry. Our analysis confirms that this integrated framework offers a coherent route toward mechanism-based personalized therapies and helps bridge the gap between computational biology and clinical practice. Nevertheless, important challenges remain, particularly pertaining to data heterogeneity, model interpretability, and clinical implementation. In conclusion, we stress that future success will require integrating prospective longitudinal multi-omics cohorts, high-resolution digital phenotyping, and ethically aligned, explainable AI (XAI) systems. These concerted efforts are essential to realize the full potential of precision psychiatry for MDD. Full article

(This article belongs to the Special Issue Unraveling the Role of Epigenetics and Molecular Genetics in Disease Progression via the Gut–Brain Axis)

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17 pages, 2295 KB

Open AccessArticle

The Hippo Pathway in Metaplastic Breast Carcinoma: Prognostic Significance and Therapeutic Implications

by Eleni Papamattheou, Alkistis Papatheodoridi, Ioannis Katsaros, Garyfalia Bletsa, Afroditi Nonni, Constantine Dimitrakakis, Dimitrios Haidopoulos, Angeliki Andrikopoulou, Areti Papakosta, Spyridon Marinopoulos, Aris Giannos, Sofia Koura, Eftychia Papachatzopoulou, Ioannis K. Papapanagiotou, Georgios I. Metaxas, Aikaterini-Gavriela Giannakaki, Meletios-Athanasios Dimopoulos and Flora Zagouri

Curr. Issues Mol. Biol. 2025, 47(12), 1060; https://doi.org/10.3390/cimb47121060 - 18 Dec 2025

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Abstract

Background/objectives: Metaplastic breast carcinoma (MpBC) is a rare, poorly differentiated breast cancer defined by the presence of ductal carcinoma along with areas of matrix-producing, spindle-cell, sarcomatous, or squamous differentiation. It does not express hormone receptors and has a poor overall prognosis. The [...] Read more.

Background/objectives: Metaplastic breast carcinoma (MpBC) is a rare, poorly differentiated breast cancer defined by the presence of ductal carcinoma along with areas of matrix-producing, spindle-cell, sarcomatous, or squamous differentiation. It does not express hormone receptors and has a poor overall prognosis. The Hippo molecular pathway was recently related to cancer progression and adjuvant therapy resistance. The objective of this study was to evaluate the expression of Hippo pathway transducers, YAP/TAZ, CCND1, and CTGF, in MpBC and their relation to the clinicopathological characteristics of the disease. Methods: Specimens from patients with MpBC treated at our department from 2003 to 2021 were analyzed utilizing immunohistochemistry and real-time PCR. Results: Forty-four female patients (62.6 ± 14.7 years old) met inclusion criteria and were included in this study. Strong nuclear YAP/TAZ expression was found in 61.4% of patients, while the expressions of CCND1 and CTGF were 3.9% and 12.5%, respectively. Patients presenting at an advanced stage had a statistically worse prognosis compared to the ones diagnosed with stage IA disease. Adjuvant chemotherapy was associated with better overall survival, while disease recurrence was significantly associated with a worse prognosis. Conclusions: Advanced stage at diagnosis and disease recurrence were significantly associated with worse prognosis in MpBC. However, adjuvant chemotherapy significantly led to better overall survival. The Hippo pathway is frequently deregulated (nuclear YAP/TAZ in 61.4% of patients), suggesting it is a compelling novel therapeutic target for this aggressive disease. Full article

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

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26 pages, 2757 KB

Open AccessArticle

Novel Synthetic Steroid Derivatives: Target Prediction and Biological Evaluation of Antiandrogenic Activity

by David Calderón Guzmán, Norma Osnaya Brizuela, Hugo Juárez Olguín, Maribel Ortiz Herrera, Armando Valenzuela Peraza, Ernestina Hernández Garcia, Alejandra Chávez Riveros, Sarai Calderón Morales, Alberto Rojas Ochoa, Aylin Silva Ortiz, Rebeca Santes Palacios, Víctor Manuel Dorado Gonzalez and Diego García Ortega

Curr. Issues Mol. Biol. 2025, 47(12), 1059; https://doi.org/10.3390/cimb47121059 - 17 Dec 2025

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Abstract

Background: Two natural steroids derived from cholesterol pathways are testosterone and progesterone, androgen and antiandrogen receptor binding. Steroid androgen antagonists can be prescribed to treat an array of diseases and disorders such as gender dysphoria. In men, androgen antagonists are frequently used to [...] Read more.

Background: Two natural steroids derived from cholesterol pathways are testosterone and progesterone, androgen and antiandrogen receptor binding. Steroid androgen antagonists can be prescribed to treat an array of diseases and disorders such as gender dysphoria. In men, androgen antagonists are frequently used to treat prostate cancer and hyperplasia. Sex hormones regulate the expression of the viral receptors in COVID-19 progression, and these hormones may act as a metabolic signal-mediating response to changes in glucose and Reactive Oxygen Species (ROS). The objective of the present study is to use artificial intelligence (AI) applications in healthcare to predict the targets and to assess biological assays of novel steroid derivatives prepared in house from the commercially available 16-dehydropregnenolone acetate (DPA^®) aimed at achieving the metabolic stability of glucose and steroid brain homeostasis. This suggests the introduction of aromatic or aliphatic structures in the steroid B-ring and D-ring. This is important since the roles of 5α-reductase and ROS in brain control of glucose and novel steroids homeostasis remain unclear. Methods: A tool prediction was used as a tuned algorithm, with the novel steroid derivatives data in web interface to carry out their pharmacological evaluation. The new steroidal derivatives were determined with neuroprotection effect using the select biomarkers of oxidative stress on induced hypoglycemic male rat brain and liver. The enzyme kinetics was established by the inhibition of the 5α-reductase enzyme on the brain myelin. Results: We used novel chemical structures to order the information of a Swiss data bank that allow target predictions. Biological assays suggest that steroid derivatives with an electrophilic center can interact more efficiently with the 5α-reductase enzyme, and by this way, induce neuroprotection in hypoglycemia model. All compounds were synthesized with a yield of 30–80% and evaluated with tool target prediction to understand the molecular mechanisms underlying a given phenotype or bioactivity and to rationalize possible favorable or unfavorable side effects, as well as to predict off-targets of known molecules and to clear the way for drug repurposing. Apart, they turned out to be good inhibitors for the 5α-reductase enzyme. Conclusions: The probed efficacy of these novel steroids with respect to spironolactone control appears to be a promising compound for future hormonal therapy with neuroprotection activity in glucose disorder status. However, further research with clinically meaningful endpoints is needed to optimize the use of androgen antagonists in these hormonal therapies in COVID-19 progression. Full article

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

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17 pages, 604 KB

Open AccessReview

The Promise and Pitfalls of AAV-Mediated Gene Therapy for Duchenne Muscular Dystrophy

by Elizaveta V. Kurshakova, Olga A. Levchenko, Svetlana A. Smirnikhina and Alexander V. Lavrov

Curr. Issues Mol. Biol. 2025, 47(12), 1058; https://doi.org/10.3390/cimb47121058 - 17 Dec 2025

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Abstract

Duchenne muscular dystrophy (DMD) is a severe X-linked hereditary disorder caused by pathogenic variants in the DMD gene encoding the dystrophin protein. The absence of functional dystrophin leads to destabilization of the dystrophin-associated glycoprotein complex (DAPC), sarcolemmal damage, and progressive degeneration of muscle [...] Read more.

Duchenne muscular dystrophy (DMD) is a severe X-linked hereditary disorder caused by pathogenic variants in the DMD gene encoding the dystrophin protein. The absence of functional dystrophin leads to destabilization of the dystrophin-associated glycoprotein complex (DAPC), sarcolemmal damage, and progressive degeneration of muscle fibers. Current therapeutic strategies focus on restoring dystrophin expression using genome editing approaches. Adeno-associated virus (AAV) vectors represent the primary delivery platform due to their strong tropism for muscle tissue, low immunogenicity, and ability to achieve long-term transgene expression. However, the limited packaging capacity of AAV (~4.7 kb) necessitates the use of truncated mini- and micro-dystrophin transgenes as well as compact genome editing systems (SaCas9, NmeCas9, Cas12f, TIGR-Tas, and others). Major challenges include immune responses against the viral capsid and transgene products, as well as the inability to perform repeated administrations. Moreover, the duration of expression is limited by the episomal nature of AAV genomes and their loss during muscle fiber regeneration. Despite substantial progress, unresolved issues concerning safety, immunogenicity, and stability of genetic correction remain, defining the key directions for future research in DMD therapy. Full article

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

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20 pages, 38977 KB

Open AccessArticle

A Trifluoromethyl Quinazoline Compound Regulates the Epithelial–Mesenchymal Transition of Prostatic Hyperplasia Cells by Inhibiting the Secretion of TGF-β1 in Stromal Cells

by Lu Chen, Di Zhang, Gang Yu, Sha Cheng, Bixue Xu, Jia Yu, Jiming Liu and Heng Luo

Curr. Issues Mol. Biol. 2025, 47(12), 1057; https://doi.org/10.3390/cimb47121057 - 17 Dec 2025

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Abstract

Benign prostatic hyperplasia (BPH) is a common disease in elderly men; its occurrence is closely related to the interaction between stromal cells and epithelial cells in the prostate. This article aims to explore the potential therapeutic effect and mechanism of a new trifluoromethyl [...] Read more.

Benign prostatic hyperplasia (BPH) is a common disease in elderly men; its occurrence is closely related to the interaction between stromal cells and epithelial cells in the prostate. This article aims to explore the potential therapeutic effect and mechanism of a new trifluoromethyl quazoline compound (kzl054) on BPH. The results showed that kzl054 had inhibitory activity that limited the growth of prostate hyperplasia cells, BPH-1, and stromal cells, WPMY-1. It could also induce apoptosis of BPH-1 cells and arrest their cell cycle. animal experiment results showed that kzl054 could effectively reduce the volume and prostate index of mouse prostate hyperplasia tissues. Through the establishment of a co-culture system of BPH-1 and WPMY-1 cells, it was found that co-culture could induce EMT in BPH-1 cells. While kzl054 could affect the secretion of TGF-β1 by competitively binding to the colchicine binding site on β-tubulin and inhibiting the expression of β-tubulin, through inhibiting the secretion of TGF-β1 by stromal cells. This study has revealed that compound kzl054 inhibits the secretion of TGF-β1 by targeting the inhibition of microtubule polymerization and regulating the epithelial cell EMT, providing potential candidate molecules and mechanisms for the development of new drugs for the treatment of BPH. Full article

(This article belongs to the Special Issue Molecular Insights: Mechanisms Underlying the Biological Activities of Natural Products—2nd Edition)

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55 pages, 1293 KB

Open AccessReview

Cancer Vaccines: Molecular Mechanisms, Clinical Progress, and Combination Immunotherapies with a Focus on Hepatocellular Carcinoma

by Faris Alrumaihi, Reem A. Alromaihi, Vikalp Kumar and Shehwaz Anwar

Curr. Issues Mol. Biol. 2025, 47(12), 1056; https://doi.org/10.3390/cimb47121056 - 17 Dec 2025

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Abstract

Conventional cancer treatments often fail due to the immunosuppressive tumor microenvironment, immune tolerance, and chronic inflammation. Therefore, new therapeutic approaches are urgently needed. Cancer vaccines can stimulate natural killer cells and cytotoxic T-lymphocytes, and induce long-lasting memory responses that help overcome the immunosuppressive [...] Read more.

Conventional cancer treatments often fail due to the immunosuppressive tumor microenvironment, immune tolerance, and chronic inflammation. Therefore, new therapeutic approaches are urgently needed. Cancer vaccines can stimulate natural killer cells and cytotoxic T-lymphocytes, and induce long-lasting memory responses that help overcome the immunosuppressive tumor microenvironment. Recent advances in nucleic acid, peptide, and dendritic cell-based vaccines have improved antigen delivery and immune activation, while combinations with immune checkpoint inhibitors and ablative therapies enhance therapeutic efficacy and durability. Preclinical and clinical studies targeting tumor-associated antigens have shown promising outcomes. With poor survival rates and limited treatment options, hepatocellular carcinoma (HCC) appears to be the most prevalent cause of cancer-related deaths worldwide. Advances in antigen discovery, vaccine delivery systems, and synergistic combination strategies are paving the way for more effective and durable immune responses. By integrating molecular insights with clinical innovation, cancer vaccines hold the potential not only to improve treatment outcomes but also to redefine long-term disease management and survival in HCC. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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17 pages, 672 KB

Open AccessArticle

Genomic Insights into Unspecified Monogenic Forms of Diabetes and Their Associated Comorbidities: Implication for Treatment

by Nadia Kheriji, Hamza Dallali, Mariem Gharbi, Asma Krir, Afef Bahlous, Melika Ben Ahmed, Faten Mahjoub, Abdelmajid Abid, Henda Jamoussi and Rym Kefi

Curr. Issues Mol. Biol. 2025, 47(12), 1055; https://doi.org/10.3390/cimb47121055 - 17 Dec 2025

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Abstract

This study focuses on the genetic and clinical characterization of Monogenic Forms of Diabetes (MFD), which are frequently underdiagnosed or misclassified due to clinical similarities with type 1 and type 2 diabetes. Researchers performed Exome Sequencing on 11 Tunisian patients suspected of having [...] Read more.

This study focuses on the genetic and clinical characterization of Monogenic Forms of Diabetes (MFD), which are frequently underdiagnosed or misclassified due to clinical similarities with type 1 and type 2 diabetes. Researchers performed Exome Sequencing on 11 Tunisian patients suspected of having MFD. The pathogenicity of genetic variants was assessed using filtering and bioinformatics prediction tools. The ORVAL online tool was used to predict the likelihood of combinations of pathogenic variants. Sanger sequencing confirmed likely pathogenic predicted variants in patients and assessed familial segregation. We identified 15 potentially pathogenic variants in 14 genes linked to MFD, including MODY-3, and isolated diabetes with low penetrance for Wolfram syndrome. Additionally, syndromic forms such as partial familial lipodystrophy types 2 and 4, and Wolfram syndrome were detected. Five patients exhibited characteristics of unspecified MFD. This study underscores the importance of genetic screening in individuals with diabetes who have a family history of the disease, particularly those with associated comorbidities. Our findings emphasize the crucial role of genetic testing in refining diabetes classification, leading to more accurate diagnoses. Therefore, integrating genetic research into clinical practice is essential to improving healthcare outcomes for patients with diabetes. Full article

(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases: 3rd Edition)

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19 pages, 4488 KB

Open AccessArticle

Multi-Omics Provides New Insights into the Aroma Regulation of Rhododendron fortunei Lindl Treated with Methyl Jasmonate and Brassinosteroids

by Danyidie Zhang, Yi Qin, Jiayi Wu, Xingyun Zhong, Haichao Hu, Zhihui Chen, Pei Shi and Yueyan Wu

Curr. Issues Mol. Biol. 2025, 47(12), 1054; https://doi.org/10.3390/cimb47121054 - 16 Dec 2025

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Abstract

Rhododendron fortunei Lindl is known for its unique aroma, but the molecular mechanism behind plant hormone-mediated aroma biosynthesis remains unclear. To explore how brassinosteroids (BRs) and methyl jasmonate (MeJA) regulate its aroma, this study analyzed R. fortunei petal samples via physiological assays, volatile [...] Read more.

Rhododendron fortunei Lindl is known for its unique aroma, but the molecular mechanism behind plant hormone-mediated aroma biosynthesis remains unclear. To explore how brassinosteroids (BRs) and methyl jasmonate (MeJA) regulate its aroma, this study analyzed R. fortunei petal samples via physiological assays, volatile metabolome analysis, and transcriptome sequencing. Physiologically, BR/MeJA significantly increased the superoxide dismutase (SOD) and catalase (CAT) activity and decreased the malondialdehyde (MDA) content. Metabolome analysis identified 1268 volatile organic compounds (VOCs), with 265/70 VOCs up-/downregulated in the BR group and 248/181 VOCs up-/downregulated in the MeJA group compared to the controls. Transcriptome sequencing identified 19,333 differentially expressed genes (DEGs), which were enriched in pathways such as terpenoid and polyketide metabolism. Multi-omics screening revealed the candidate gene RfCYP92C6, whose transient overexpression in Nicotiana benthamiana increased the terpenoid content 2.2-fold. These findings clarify the aroma regulation mechanism of BRs/MeJA in R. fortunei and support the improvement of its aroma traits via genetic engineering. Full article

(This article belongs to the Special Issue Molecular Breeding and Genetics Research in Plants—3rd Edition)

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25 pages, 1373 KB

Open AccessArticle

Western Diet Induces Changes in Gene Expression in Multiple Tissues During Early Insulin Resistance and Glucose Intolerance in Male C57BL/6 Mice

by Djordje Radulović, Jurij Dolenšek, Andraž Stožer and Uroš Potočnik

Curr. Issues Mol. Biol. 2025, 47(12), 1053; https://doi.org/10.3390/cimb47121053 - 16 Dec 2025

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Abstract

To better understand the molecular mechanisms by which a Western diet (WD) promotes the development of type 2 diabetes (T2D), we analyzed changes in the expression profiles of multiple glucose-regulatory tissues of male C57BL/6 mice. We fed the mice with either a regular [...] Read more.

To better understand the molecular mechanisms by which a Western diet (WD) promotes the development of type 2 diabetes (T2D), we analyzed changes in the expression profiles of multiple glucose-regulatory tissues of male C57BL/6 mice. We fed the mice with either a regular control diet (CD) or a WD. Standard glucose and insulin tolerance tests were performed, and body weight, plasma glucose, and triglyceride levels were measured to assess the glucose homeostasis in vivo. The WD induced obesity, glucose intolerance, and insulin resistance, with a fasting hyperglycemia. Further, we identified several changes in the gene expression of the analyzed candidate genes in all the examined target tissues, including the downregulation of Tcf7l2 in the liver, pancreas, white and brown adipose tissue (0.72, 0.56, 0.36, and 0.22-fold, respectively), in contrast to a marked upregulation in the intestine (2.57-fold). We also found downregulation of PPARγ in the white and brown adipose tissue (0.55, 0.41-fold, respectively) and upregulation in the pancreas, liver, intestine, and skeletal muscle (1.25, 1.46, 1.97, and 2.59-fold, respectively). Our findings provide important insight into the characteristic pattern of changes in expression of candidate genes during the early stages of insulin resistance and glucose intolerance in this diet-induced mouse model of T2D. Full article

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

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18 pages, 1071 KB

Open AccessReview

The CXCL12/CXCR4 Axis in Sepsis-Induced Acute Lung Injury: Mechanisms and Therapeutic Potential

by Renwei Luo, Qinglu Fan, Qingyun Chen, Zhihao Nie, Lingxuan Dan and Songping Xie

Curr. Issues Mol. Biol. 2025, 47(12), 1052; https://doi.org/10.3390/cimb47121052 - 16 Dec 2025

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Abstract

Sepsis remains a major cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), conditions characterized by high mortality and limited therapeutic options. Among the diverse inflammatory pathways implicated in their pathogenesis, the CXCL12/CXCR4 chemokine axis has gained increasing attention for [...] Read more.

Sepsis remains a major cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), conditions characterized by high mortality and limited therapeutic options. Among the diverse inflammatory pathways implicated in their pathogenesis, the CXCL12/CXCR4 chemokine axis has gained increasing attention for its dual capacity to drive acute inflammation while also supporting tissue repair. Although numerous studies have investigated this signaling pathway, an integrated framework that reconciles its context-dependent functions, upstream regulatory mechanisms, and translational relevance has been lacking. In this review, we synthesize current evidence on the multifaceted roles of the CXCL12/CXCR4 axis in sepsis-induced ALI, highlighting its cell-type-specific effects in neutrophils, macrophages, alveolar epithelial cells, and endothelial cells through downstream pathways such as NF-κB, MAPK, and PI3K/Akt. We further evaluate emerging therapeutic approaches, including small-molecule antagonists (e.g., AMD3100), natural products, and epigenetic modulators. Newly added sections summarize the upstream regulation of CXCL12 by hypoxia, cytokines, and epigenetic factors, discuss the regulatory influence of the alternative receptor CXCR7/ACKR3, and differentiate preclinical insights from human clinical observations. Finally, we outline key obstacles to clinical translation and propose future directions to develop precision medicine strategies that more effectively target this axis. Collectively, our analysis suggests that although the CXCL12/CXCR4 pathway represents a promising target for ALI/ARDS therapy, its context-dependent and cell-specific actions demand carefully tailored modulation rather than uniform inhibition. Full article

(This article belongs to the Section Molecular Medicine)

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22 pages, 1830 KB

Open AccessEditor’s ChoiceArticle

β-Arrestin 1 Differentially Modulates cAMP and ERK Pathways Downstream of the FSH Receptor

by Sei Hyun Park, Munkhzaya Byambaragchaa, Ye Rin Yu, Jae Won Lee, Min-Jeong Kwak, Seung-Bin Yoon, Ji-Su Kim, Myung-Hwa Kang and Kwan-Sik Min

Curr. Issues Mol. Biol. 2025, 47(12), 1051; https://doi.org/10.3390/cimb47121051 - 16 Dec 2025

Viewed by 232

Abstract

This study compared the gonadotropin gene sequences (LH and FSH subunits) of Cynomolgus and Rhesus monkeys and produced recombinant single-chain LHβ/α and FSHβ/α proteins. The α- and FSHβ-subunit sequences were identical between species, while LHβ showed only minor synonymous differences. The recombinant hormones [...] Read more.

This study compared the gonadotropin gene sequences (LH and FSH subunits) of Cynomolgus and Rhesus monkeys and produced recombinant single-chain LHβ/α and FSHβ/α proteins. The α- and FSHβ-subunit sequences were identical between species, while LHβ showed only minor synonymous differences. The recombinant hormones were successfully expressed and shown to be mainly N-glycosylated. Recombinant monkey FSHβ/α activated cAMP signaling in human FSH receptor-expressing cells, confirming its biological activity. β-arrestin 1 was found to have dual roles: its absence increased cAMP signaling (negative regulation), but it was required for ERK1/2 activation. ERK activation depended mainly on the cAMP/PKA pathway. Human and rat FSH receptors displayed different ERK activation timing, indicating species-specific signaling behavior. Overall, the study establishes a reliable system for producing functional recombinant monkey gonadotropins and clarifies how β-arrestin 1 differentially regulates FSH receptor signaling. Full article

(This article belongs to the Collection Advancements in Molecular Biology and Pharmaceutical Science)

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3 pages, 169 KB

Open AccessEditorial

Unraveling Oxidative Threads: Stress, Pathology, and Resilience in Biochemistry, Molecular, and Cellular Biology (2023–2025)

by Stuart Maudsley

Curr. Issues Mol. Biol. 2025, 47(12), 1050; https://doi.org/10.3390/cimb47121050 - 16 Dec 2025

Cited by 1 | Viewed by 319

Abstract

The years 2023–2025 have generated a profound evolution in biochemistry and molecular and cellular biology, where the threads of oxidative stress weave through aging, environmental insults, and human disease, and—increasingly—therapeutic opportunity [...] Full article

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

47 pages, 1066 KB

Open AccessReview

Cancer Reversion Therapy: Prospects, Progress and Future Directions

by Emmanuel O. Oisakede, David B. Olawade, Oluwakemi Jumoke Bello, Claret Chinenyenwa Analikwu, Eghosasere Egbon, Oluwaseun Fapohunda and Stergios Boussios

Curr. Issues Mol. Biol. 2025, 47(12), 1049; https://doi.org/10.3390/cimb47121049 - 15 Dec 2025

Cited by 1 | Viewed by 558

Abstract

Cancer reversion therapy represents a paradigm shift in oncology, focusing on reprogramming malignant cells to a non-malignant state rather than destroying them. This narrative review synthesizes current evidence, emerging technologies, and future directions in this promising field. Cancer reversion is founded on key [...] Read more.

Cancer reversion therapy represents a paradigm shift in oncology, focusing on reprogramming malignant cells to a non-malignant state rather than destroying them. This narrative review synthesizes current evidence, emerging technologies, and future directions in this promising field. Cancer reversion is founded on key biological observations: somatic cell reprogramming, spontaneous cancer regression, and microenvironmental influences on malignant behavior. Current approaches include epigenetic reprogramming using HDAC inhibitors and DNA methyltransferase inhibitors; microenvironmental modulation through extracellular matrix manipulation and vascular normalization; differentiation therapy exemplified by all-trans retinoic acid in acute promyelocytic leukemia; and targeting oncogene addiction as demonstrated in BCR-ABL-driven leukemias. Emerging technologies accelerating progress include single-cell analyses that reveal cancer heterogeneity and cellular state transitions; CRISPR-based approaches enabling precise genetic and epigenetic manipulation; patient-derived organoids that model tumor complexity; and artificial intelligence applications that identify novel reversion-inducing agents. Critical evaluation reveals that many reported “reversion” phenomena represent stimulus-dependent plasticity or transient growth arrest rather than stable phenotypic normalization. True cancer reversion requires durable, heritable phenotypic changes that persist after treatment withdrawal, with evidence of epigenetic consolidation and functional restoration. Despite promising advances, significant challenges remain: cancer cell plasticity facilitating therapeutic escape, difficulties in establishing stable reversion states, delivery challenges for solid tumors, and the need for combination approaches to address tumor heterogeneity. Future directions include integrated multi-omics analyses to comprehensively map cellular state transitions, studies of natural regression phenomena to identify reversion mechanisms, advanced nanodelivery systems for targeted therapy, and synthetic biology approaches creating intelligent therapeutic systems. By redirecting rather than destroying cancer cells, reversion therapy offers the potential for reduced toxicity and resistance, potentially transforming cancer from a deadly disease to a manageable condition. Full article

(This article belongs to the Section Molecular Medicine)

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15 pages, 1488 KB

Open AccessReview

miRNAs and Alcohol-Related Hepatitis

by Dinuka Bandara, Clara Ashraf Boshra Shaker Romany, Vikash Kumar, Aalam Sohal, Mohanad Al-Qaisi and Nilofar Najafian

Curr. Issues Mol. Biol. 2025, 47(12), 1048; https://doi.org/10.3390/cimb47121048 - 15 Dec 2025

Viewed by 224

Abstract

Alcohol-related hepatitis (AH) is a severe, life-threatening liver inflammation caused by chronic heavy drinking, with high short-term mortality despite abstinence and supportive care. The pathophysiology involves a compromised gut–liver axis, activation of Kupffer cells, stimulation of hepatic stellate cells, and progressive fibrosis. Increasing [...] Read more.

Alcohol-related hepatitis (AH) is a severe, life-threatening liver inflammation caused by chronic heavy drinking, with high short-term mortality despite abstinence and supportive care. The pathophysiology involves a compromised gut–liver axis, activation of Kupffer cells, stimulation of hepatic stellate cells, and progressive fibrosis. Increasing evidence suggests that microRNAs (miRNAs), small non-coding RNAs that regulate gene expression post-transcriptionally, play a role as modulators of these processes. Understanding dysregulated miRNAs in AH may provide insights into novel diagnostic and therapeutic interventions. Several miRNAs have been identified as critical regulators of AH pathogenesis. Upregulated miRNAs, including miRNA-217, miRNA-182, let-7b, miRNA-21, and miRNA-34a, promote inflammation through NF-κB activation, Toll-like receptor (TLR) signaling, cytokine production, and ductular reactions. Conversely, downregulated miRNAs such as miRNA-148a, miRNA-30e, and miRNA-483-3p are associated with impaired hepatocyte differentiation, dysregulated oxidative stress responses, and enhanced Mallory–Denk body formation. Considering that miRNAs are pivotal regulators of AH pathophysiology including immune activation, hepatocyte death, fibrosis, and metabolic dysregulation, their altered expression patterns not only illuminate key pathogenic pathways but also provide promising avenues for biomarker discovery and therapeutic targeting. This review aims to summarize the current literature regarding the miRNA profiles involved in alcohol-related hepatitis, their individual mechanistic roles in pathogenesis of AH, and their potential for biomarkers. Full article

(This article belongs to the Special Issue Molecular Functions of Long Non-Coding RNAs: Implications for Diseases and Therapy)

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16 pages, 596 KB

Open AccessReview

Diagnostic Pathways and Molecular Biomarkers in Colorectal Cancer: Current Evidence and Perspectives in Poland

by Bartosz Bichalski, Magda Bichalska-Lach and Dariusz Waniczek

Curr. Issues Mol. Biol. 2025, 47(12), 1047; https://doi.org/10.3390/cimb47121047 - 15 Dec 2025

Viewed by 388

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide and remains a major challenge in contemporary oncology, where early detection is critical for improving treatment outcomes and survival. Despite significant progress in diagnostics and therapy, the epidemiology, risk factors, and molecular [...] Read more.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide and remains a major challenge in contemporary oncology, where early detection is critical for improving treatment outcomes and survival. Despite significant progress in diagnostics and therapy, the epidemiology, risk factors, and molecular mechanisms driving CRC development continue to be intensively investigated. This paper provides an overview of current trends in CRC diagnosis and management, with particular emphasis on advances in molecular medicine and biological sciences. Screening recommendations in Poland are discussed, comparing invasive methods—such as colonoscopy, sigmoidoscopy, and CT colonography—with non-invasive stool-based tests (FOBT, FIT, sDNA-FIT), and evaluating their sensitivity, specificity, and impact on mortality reduction. Key tumor markers with diagnostic, prognostic, and predictive value, including CEA, CA19-9, mSEPT9, ctDNA, TPS, TAG-72, CTCs, and circulating microRNAs, as well as p53 and PTEN proteins, are reviewed in the context of their clinical utility in early detection, disease monitoring, and treatment response assessment. The analysis also highlights the epidemiological situation in Poland and underscores the growing importance of integrating molecular biomarkers with traditional diagnostic methods, which may ultimately support the development of more precise and individualized clinical management strategies in the future. Full article

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

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21 pages, 5220 KB

Open AccessArticle

The Corrective Role of Melatonin in Synergism of Dark Deprivation and CCl₄ Intoxication in the Pathogenesis of Liver Damage a in Rats

by Sevil A. Grabeklis, Liudmila M. Mikhaleva, Alexander M. Dygai, Rositsa A. Vandysheva, Anna I. Anurkina, Maria A. Kozlova and David A. Areshidze

Curr. Issues Mol. Biol. 2025, 47(12), 1046; https://doi.org/10.3390/cimb47121046 - 15 Dec 2025

Viewed by 219

Abstract

Circadian rhythm disruption induced by exposure to light—excessive in duration and intensity (dark deprivation)—and the impact of hepatotoxins are both significant risk factors for liver pathology. The purpose of this research was to evaluate the potentially synergistic effects of continuous lighting and carbon [...] Read more.

Circadian rhythm disruption induced by exposure to light—excessive in duration and intensity (dark deprivation)—and the impact of hepatotoxins are both significant risk factors for liver pathology. The purpose of this research was to evaluate the potentially synergistic effects of continuous lighting and carbon tetrachloride (CCl₄) toxicity on the structural and functional organization and daily (circadian) rhythmicity of the liver in rats, as well as to look at the corrective capability of exogenous melatonin under such influences. The experiment was conducted on 200 outbred 6-month-old Wistar rat males, which were distributed into five groups, including a control (normal light/dark cycle), dark deprivation (constant light), CCl₄ intoxication, and combined exposure to CCl₄ and dark deprivation with or without melatonin administration (0.3 mg/kg). Histological, immunohistochemical (Ki-67, Per2, and Bmal1), biochemical, and ELISA methods were used. Circadian rhythms were analyzed using cosinor. It was shown that dark deprivation and CCl₄ intoxication act synergistically, potentiating liver damage. The most severe necrosis (54.17 ± 9.13%), steatosis (57.85 ± 12.14%), and suppression of regenerative potential (decreased proportion of binucleated hepatocytes to 2.17 ± 0.21%) were observed in the group with combined exposure. This correlated with a substantial decline in melatonin content in blood plasma (7.85 ± 2.1 pg/mL) and a profound disruption in circadian rhythms. Administration of exogenous melatonin exerted pronounced hepatoprotective and chronotropic effects: it significantly reduced pathological changes (necrosis reduced to 16.35 ± 6.17%), stimulated regeneration (binucleated hepatocytes increased to 13.57 ± 0.81%), and restored the circadian rhythms of the studied parameters to levels close to those of the control. The key pathogenetic link in the potentiation of CCl₄ hepatotoxicity under dark deprivation is light-induced deficiency of endogenous melatonin. Exogenous melatonin demonstrated high efficacy in correcting both structural and functional damage and liver desynchronosis, confirming its therapeutic potential under conditions of combined exposure to chronodisruptors and toxins. Full article

(This article belongs to the Special Issue Neuropituitary Hormones in Metabolic Disorders)

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11 pages, 2330 KB

Open AccessArticle

Immunolocalization of p53 and p21 in Kidneys Exposed to T-2 Mycotoxin

by Piret Hussar, Katerina Blagoevska, Monika Dovenska, Lazo Pendovski and Florina Popovska-Percinic

Curr. Issues Mol. Biol. 2025, 47(12), 1045; https://doi.org/10.3390/cimb47121045 - 15 Dec 2025

Viewed by 203

Abstract

T-2 mycotoxins are known to induce toxic effects in animals. The kidneys are particularly vulnerable to oxidative stress induced by toxins, resulting in cellular damage, apoptosis, and disruptions to cell cycle regulation. Cyclin-dependent kinase inhibitor p21 and tumor suppressor protein p53 are key [...] Read more.

T-2 mycotoxins are known to induce toxic effects in animals. The kidneys are particularly vulnerable to oxidative stress induced by toxins, resulting in cellular damage, apoptosis, and disruptions to cell cycle regulation. Cyclin-dependent kinase inhibitor p21 and tumor suppressor protein p53 are key modulators of these pathways. As our knowledge on the immunolocalization of p53 and p21 during T-2 mycotoxicosis in the avian kidney is limited, this study was designed to investigate the immunolocalization of these two critical apoptosis regulatory proteins in the renal tissues of broiler chickens treated with T-2 mycotoxin. In the experiment, ten seven-day-old female Ross chickens (Gallus gallus domesticus) were separated into the control group and T-2 toxin group. T-2 toxin was orally administered to the T-2 toxin group for three days. Then, 24 h after the last dose, chickens were sacrificed and kidney tissues were collected and fixed for immunohistochemical staining. Immunohistochemical analysis using polyclonal primary antibodies against p53 and p21 (Abcam, Cambridge, UK) demonstrated increased expression of p21 and p53 in T-2 toxin-treated chickens’ kidneys compared to healthy chickens in the control group. Both proteins were mainly localized in the epithelial cells of the renal proximal tubules. The enhanced staining intensity of p21 and p53 emphasizes their contribution to T-2-induced renal toxicity and suggests their potential as biomarkers for the early detection of nephrotoxicity. Full article

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

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18 pages, 817 KB

Open AccessReview

Antibody-Mediated Therapy in Gastric Cancer: Past, Present, and Future

by Hong-Beum Kim and Sang-Gon Park

Curr. Issues Mol. Biol. 2025, 47(12), 1044; https://doi.org/10.3390/cimb47121044 - 15 Dec 2025

Viewed by 366

Abstract

The limited efficacy of cytotoxic chemotherapy in the context of gastric cancer treatment is largely driven by profound molecular and biological heterogeneity. In contrast, the development of antibody-mediated therapies has ushered in a new era of precision oncology by enabling selective molecular targeting [...] Read more.

The limited efficacy of cytotoxic chemotherapy in the context of gastric cancer treatment is largely driven by profound molecular and biological heterogeneity. In contrast, the development of antibody-mediated therapies has ushered in a new era of precision oncology by enabling selective molecular targeting and immune modulation. This review includes a comprehensive overview of the evolution of antibody-based therapeutics in gastric cancer, highlighting early breakthroughs, subsequent setbacks, and recent advances that have reshaped the treatment landscape. We summarize the current standard regimens targeting HER2, VEGFR2, PD-1/PD-L1, and CLDN18.2 and examine pivotal clinical trials evaluating monoclonal antibodies directed against these pathways. We also discuss emerging therapeutic modalities, including next-generation antibody–drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies. Trastuzumab first established HER2-targeted therapy in gastric cancer, but the failure of trastuzumab emtansine (T-DM1) led to a decade-long stagnation until the advent of trastuzumab deruxtecan (T-DXd), which demonstrated robust clinical activity and defined a new standard of care. While bevacizumab failed to improve survival, the anti-VEGFR2 antibody ramucirumab emerged as an effective second-line therapy. Immune checkpoint inhibitors, including nivolumab and pembrolizumab, have been incorporated into first-line treatment for PD-L1-positive disease based on landmark trials such as CheckMate 649 and KEYNOTE-811. More recently, the CLDN18.2-targeted antibody zolbetuximab has expanded therapeutic options for biomarker-selected patients. Concurrently, a diverse pipeline of immune-based strategies—such as TROP2-directed ADCs, bispecific antibodies, and CAR-T cell therapies—is undergoing active clinical development. Together, advances in biomarker-driven antibody therapeutics are accelerating personalized cancer care and improving clinical outcomes in patients with gastric cancer. Full article

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

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20 pages, 13476 KB

Open AccessArticle

Role of UGP2 as a Biomarker in Colorectal Cancer: Implications for Tumor Progression, Diagnosis, and Prognosis

by Lijiao Cui, Caiyuan Yu, Shicai Ye, Yuee Yang, Zhiwei Gu, Vincent Kam Wai Wong and Yu Zhou

Curr. Issues Mol. Biol. 2025, 47(12), 1043; https://doi.org/10.3390/cimb47121043 - 15 Dec 2025

Viewed by 248

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for reliable biomarkers and therapeutic targets. To address this need, we focused on UDP-glucose pyrophosphorylase 2 (UGP2). Although UGP2 has been implicated in tumorigenesis across multiple cancers, its [...] Read more.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for reliable biomarkers and therapeutic targets. To address this need, we focused on UDP-glucose pyrophosphorylase 2 (UGP2). Although UGP2 has been implicated in tumorigenesis across multiple cancers, its precise role and clinical significance in CRC remain poorly understood. This study aimed to comprehensively characterize UGP2 in CRC through an integrated approach encompassing proteomic screening, bioinformatics analysis, and experimental validation. We identified UGP2 as a significantly downregulated tumor-suppressive factor in CRC. Specifically, UGP2 expression was significantly downregulated in CRC tissues compared with that in normal controls and exhibited strong correlations with aggressive clinicopathological features, including lymphatic invasion, perineural invasion, and colon polyp history, and patient age. It also demonstrated high diagnostic accuracy in CRC, with an area under the receiver operating characteristic curve (AUC) of 0.990. Reduced UGP2 levels were associated with poorer overall survival and disease-specific survival. Hypermethylation of the UGP2 promoter correlated with a favorable prognosis in patients with CRC. UGP2 expression positively correlated with immune cell infiltration within the tumor microenvironment. Functionally, UGP2 knockdown increased CRC cell proliferation and migration while suppressing apoptosis. Conversely, its overexpression yielded the opposite effects, confirming UGP2’s role in constraining malignant phenotypes. Collectively, these findings establish UGP2 as a key CRC tumor suppressor whose downregulation drives malignant progression and predicts adverse clinical outcomes, suggesting its potential as a dual-purpose diagnostic and prognostic biomarker. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance, 2nd Edition)

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14 pages, 741 KB

Open AccessEditor’s ChoiceReview

Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities

by Mi Eun Kim, Yeeun Lim and Jun Sik Lee

Curr. Issues Mol. Biol. 2025, 47(12), 1042; https://doi.org/10.3390/cimb47121042 - 14 Dec 2025

Viewed by 753

Abstract

Chronic inflammatory diseases are driven by persistent immune activation and metabolic imbalance that disrupt tissue homeostasis. Mitochondrial dysfunction disrupts cellular bioenergetics and immune regulation, driving persistent inflammatory signaling. Mitochondrial dysfunction, characterized by excessive production of ROS, release of mitochondrial DNA, and defective mitophagy, [...] Read more.

Chronic inflammatory diseases are driven by persistent immune activation and metabolic imbalance that disrupt tissue homeostasis. Mitochondrial dysfunction disrupts cellular bioenergetics and immune regulation, driving persistent inflammatory signaling. Mitochondrial dysfunction, characterized by excessive production of ROS, release of mitochondrial DNA, and defective mitophagy, amplifies inflammatory signaling and contributes to disease progression. Meanwhile, metabolic reprogramming in immune and stromal cells establishes distinct bioenergetic profiles. These profiles maintain either pro-inflammatory or anti-inflammatory phenotypes through key signaling regulators such as HIF-1α, AMPK, mTOR, and SIRT3. Crosstalk between mitochondrial and metabolic pathways determines whether inflammation persists or resolves. Recent advances have identified critical molecular regulators, including the NRF2–KEAP1 antioxidant system, the cGAS–STING innate immune pathway, and the PINK1–Parkin mitophagy pathway, as potential therapeutic targets. Pharmacologic modulation of metabolic checkpoints and restoration of mitochondrial homeostasis represent key strategies for re-establishing cellular homeostasis. Developing approaches, including NAD⁺ supplementation, mitochondrial transplantation, and gene-based interventions, also show significant therapeutic potential. This review provides a mechanistic synthesis of how mitochondrial dysfunction and metabolic reprogramming cooperate to maintain chronic inflammation and highlights molecular pathways that represent promising targets for precision therapeutics in inflammatory diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Innovative Therapeutic Approaches in Inflammatory Diseases, Pioneering Precision Medicine Solutions)

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16 pages, 1635 KB

Open AccessReview

Androgen Effects on Amyloid Precursor Protein Processing Pathways in Cancer: A Systematic Review

by Mai Alhadrami, Gideon Stone, Rachel M. Barker, Jennifer C. Palmer, Patrick G. Kehoe and Claire M. Perks

Curr. Issues Mol. Biol. 2025, 47(12), 1041; https://doi.org/10.3390/cimb47121041 - 12 Dec 2025

Viewed by 300

Abstract

Androgens have been shown to be linked to cancer progression, particularly in hormone-dependent cancers such as prostate and breast cancer, but also other cancers. Amyloid precursor protein (APP), which has primarily been studied in Alzheimer’s disease, is gaining recognition for its role in [...] Read more.

Androgens have been shown to be linked to cancer progression, particularly in hormone-dependent cancers such as prostate and breast cancer, but also other cancers. Amyloid precursor protein (APP), which has primarily been studied in Alzheimer’s disease, is gaining recognition for its role in tumor growth and survival. While APP overexpression and androgen receptor (AR) signaling are each associated with cancer progression, the connection between androgens and APP processing in cancer has not been thoroughly investigated. This systematic review was conducted through a comprehensive search of PubMed, Scopus, Web of Science, and EMBASE between 2000 to 2024 for studies examining the effects of androgens on APP and its cleavage enzymes in cancer. Five experimental studies met the inclusion criteria, covering prostate and breast cancer models. Data were extracted and synthesized narratively due to heterogeneity in methods and outcomes. Three studies reported that dihydrotestosterone (DHT) or AR agonists increased the expression and nuclear translocation of ADAM10, a key α-secretase enzyme in the non-amyloidogenic APP processing pathway. Two studies identified APP as an androgen-responsive gene, showing that androgens upregulated APP expression in prostate and breast cancer cells and promoted the proliferation of cancer cells. Inhibition or knockdown of APP and ADAM10 reduced proliferation, supporting their roles in tumor progression. Androgen signaling modulates APP processing in cancer, particularly through the non-amyloidogenic pathway; however, significant knowledge gaps remain. Further studies are needed to explore the interaction between androgens and APP processing in other cancer types, as well as to elucidate downstream signaling pathways regulated at the gene expression level. Full article

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

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24 pages, 5025 KB

Open AccessReview

Plant Growth-Promoting Rhizobacteria and Biochar as Drought Defense Tools: A Comprehensive Review of Mechanisms and Future Directions

by Faezeh Parastesh, Behnam Asgari Lajayer and Bernard Dell

Curr. Issues Mol. Biol. 2025, 47(12), 1040; https://doi.org/10.3390/cimb47121040 - 12 Dec 2025

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Abstract

Drought stress, exacerbated by climate change, is a serious threat to global food security. This review examines the synergistic potential of plant growth-promoting rhizobacteria (PGPR) and biochar as a sustainable strategy for enhancing crop drought resilience. Biochar’s porous structure creates a protective “charosphere” [...] Read more.

Drought stress, exacerbated by climate change, is a serious threat to global food security. This review examines the synergistic potential of plant growth-promoting rhizobacteria (PGPR) and biochar as a sustainable strategy for enhancing crop drought resilience. Biochar’s porous structure creates a protective “charosphere” microhabitat, enhancing PGPR colonization and survival. This partnership, in turn, induces multifaceted plant responses through: (1) the modulation of key phytohormones, including abscisic acid (ABA), ethylene (via 1-aminocyclopropane-1-carboxylate (ACC) deaminase activity), and auxins; (2) improved nutrient solubilization and uptake; and (3) the activation of robust antioxidant defense systems. These physiological benefits are orchestrated by a profound reprogramming of the plant transcriptome, which shifts the plant’s expression profile from a stressed to a resilient state by upregulating key genes (e.g., Dehydration-Responsive Element-Binding protein (DREB), Light-Harvesting Chlorophyll B-binding protein (LHCB), Plasma membrane Intrinsic Proteins (PIPs)) and downregulating stress-senescence markers. To realize a climate-resilient farming future, research must be strategically directed toward customizing biochar–PGPR combinations, validating their long-term performance in agronomic environments, and uncovering the molecular bases of their action. Full article

(This article belongs to the Special Issue Biochar as a Soil Amendment: Unraveling Molecular Mechanisms Underpinning Plant Growth Promotion via Gene Expression and Regulatory Networks)

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30 pages, 11628 KB

Open AccessArticle

Advancing Drug Repurposing for Rheumatoid Arthritis: Integrating Protein–Protein Interaction, Molecular Docking, and Dynamics Simulations for Targeted Therapeutic Approaches

by Krishna Swaroop Akey, Bharat Kumar Reddy Sanapalli, Dilep Kumar Sigalapalli, Ramya Tokala and Vidyasrilekha Sanapalli

Curr. Issues Mol. Biol. 2025, 47(12), 1039; https://doi.org/10.3390/cimb47121039 - 12 Dec 2025

Viewed by 437

Abstract

Background: Rheumatoid arthritis (RA) is a systemic chronic inflammatory autoimmune disease causing progressive joint destruction, resulting in significant morbidity and increased mortality. Despite advances in treatment, current pharmacological options, including NSAIDs, DMARDs, and biological agents, have limitations in tissue repair and can [...] Read more.

Background: Rheumatoid arthritis (RA) is a systemic chronic inflammatory autoimmune disease causing progressive joint destruction, resulting in significant morbidity and increased mortality. Despite advances in treatment, current pharmacological options, including NSAIDs, DMARDs, and biological agents, have limitations in tissue repair and can lead to severe side effects. Objectives: This study aims to explore drug repurposing as a viable approach to identify novel therapeutic agents for RA by utilizing existing FDA-approved drugs. Methods: We applied an integrated computational strategy that uniquely combines network pharmacology with molecular docking and dynamics simulations. The process began with the construction of a protein–protein interaction (PPI) network from 2723 RA-associated genes, which identified five central targets: TNF-α, IL-6, IL-1β, STAT3, and AKT1. We then built protein–drug interaction (PDI) networks by screening 2637 FDA-approved drugs against these targets. Critically, the top candidates from this network analysis were not just docked but were further validated using 100 ns molecular dynamics simulations to thoroughly evaluate binding affinity, complex stability, and interaction dynamics. Results: This multi-tiered computational workflow identified Rifampicin, Telmisartan, Danazol, and Pimozide as the most promising repurposing candidates. They demonstrated strong binding affinities and, importantly, formed stable complexes with TNF-α, IL-6, IL-1β, and STAT3, respectively, in dynamic simulations. The key innovation of this study is this sequential funnel approach, which integrates large-scale network data with atomic-level simulation to prioritize high-confidence drug candidates for RA. Conclusions: In conclusion, this study highlights the potential of repurposing FDA-approved drugs to target key proteins involved in RA, offering a cost-effective and time-efficient strategy to discover new therapies. Full article

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

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23 pages, 651 KB

Open AccessReview

Beyond the Exome: The Role of Noncoding and Regulatory Variants in Monogenic Diseases

by Efthalia Moustakli, Nektaria Zagorianakou, Stylianos Makrydimas, Andreas Miltiadous, Alexandros T. Tzallas and George Makrydimas

Curr. Issues Mol. Biol. 2025, 47(12), 1038; https://doi.org/10.3390/cimb47121038 - 12 Dec 2025

Viewed by 498

Abstract

Analysis of coding areas has long been used to study monogenic illnesses, but despite the extensive use of whole-exome sequencing (WES), up to half of suspected cases remain genetically unexplained. Variants outside coding areas can alter splicing, transcript stability, or gene regulation, compromising [...] Read more.

Analysis of coding areas has long been used to study monogenic illnesses, but despite the extensive use of whole-exome sequencing (WES), up to half of suspected cases remain genetically unexplained. Variants outside coding areas can alter splicing, transcript stability, or gene regulation, compromising normal gene activity. These include mutations in noncoding RNAs, promoters, enhancers, deep intronic sequences, and untranslated regions (UTRs). Several well-known disorders have been linked to these mechanisms, including β-thalassemia caused by deep intronic mutations leading to aberrant splicing, familial hypercholesterolemia caused by promoter defects affecting LDLR expression, and inherited retinal diseases driven by noncoding variants influencing retinal gene regulation. These instances show that pathogenic variation is not limited to the exome and can have significant clinical implications. This review summarizes current understanding of noncoding and regulatory variants in monogenic diseases, discusses how they influence diagnosis and therapy, and highlights integrative approaches combining genomic, transcriptomic, and epigenomic data. Multi-layered research has increased diagnostic accuracy and unveiled new therapeutic potentials, although noncoding variations make the connection between genotype and phenotype more complex. Noncoding regions will need to be incorporated into standard diagnostic procedures to convert molecular insights into concrete therapeutic applications in the future. Predictive algorithms, patient-derived model systems, and functional validation testing will all help to simplify this process. Full article

(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases: 3rd Edition)

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20 pages, 3356 KB

Open AccessReview

Neurocardiac Crosstalk: Sympathetic Remodeling and Arrhythmogenesis After Myocardial Infarction

by Tianshui Yu

Curr. Issues Mol. Biol. 2025, 47(12), 1037; https://doi.org/10.3390/cimb47121037 - 12 Dec 2025

Viewed by 398

Abstract

Sympathetic remodeling following myocardial infarction (MI) is a critical mechanism underlying the development of malignant arrhythmias and sudden cardiac death (SCD). The cardiac sympathetic nervous system functions as a multi-level regulatory network, integrating centers from the cerebral cortex (e.g., the insular lobe and [...] Read more.

Sympathetic remodeling following myocardial infarction (MI) is a critical mechanism underlying the development of malignant arrhythmias and sudden cardiac death (SCD). The cardiac sympathetic nervous system functions as a multi-level regulatory network, integrating centers from the cerebral cortex (e.g., the insular lobe and anterior cingulate gyrus), subcortical structures (e.g., the paraventricular nucleus of the hypothalamus), and brainstem nuclei (e.g., the rostral ventrolateral medulla and nucleus of the solitary tract), down to the peripheral ganglia. Post-MI, this entire neural axis undergoes significant remodeling, which manifests as neuroinflammation in the central nervous system, alongside peripheral sympathetic nerve sprouting and heterogeneous hyperinnervation. This article provides a systematic review of the anatomical architecture of the cardiac sympathetic nerve and the regulatory mechanisms of sympathetic remodeling at various levels of the central nervous system after MI. It particularly focuses on key signaling pathways—including the TLR4/MyD88/NF-κB and P2X7R/NLRP3 inflammasome pathways, as well as GABAergic inhibition within the paraventricular nucleus—in addition to the peripheral remodeling mechanisms within the stellate ganglia. By synthesizing insights from these studies, this review offers a novel perspective for understanding the neuroimmune mechanisms of post-MI malignant arrhythmias and provides a theoretical foundation for elucidating the mechanisms of SCD in clinical practice. Full article

(This article belongs to the Special Issue Molecules at Play in Cardiovascular Diseases)

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