Current Issues in Molecular Biology

21 pages, 693 KiB

Open AccessReview

Selected Protective Mechanisms of Human Milk Against Intestinal Protozoal Infections in Infants

by Joanna Wróblewska, Anna Długosz, Marcin Wróblewski, Jarosław Nuszkiewicz, Paweł Sutkowy and Alina Woźniak

Curr. Issues Mol. Biol. 2025, 47(8), 674; https://doi.org/10.3390/cimb47080674 (registering DOI) - 21 Aug 2025

Abstract

Human milk, especially colostrum, is a biologically complex fluid with potent protective properties against gastrointestinal disturbances in infants. Among intestinal protozoa transmitted via the fecal–oral route, this review focuses on Giardia lamblia and Entamoeba histolytica, as the protective role of milk-derived factors [...] Read more.

Human milk, especially colostrum, is a biologically complex fluid with potent protective properties against gastrointestinal disturbances in infants. Among intestinal protozoa transmitted via the fecal–oral route, this review focuses on Giardia lamblia and Entamoeba histolytica, as the protective role of milk-derived factors against these parasites is the most extensively documented. Its protective effects result from a wide range of bioactive components, including mucins, lactoferrin, human milk oligosaccharides, melatonin, and secretory IgA, which support the integrity of the intestinal barrier, regulate immune responses, and inhibit the adhesion and activity of pathogens. The composition of human milk can be influenced by maternal factors such as nutritional status, stress, sleep quality, and physical activity, which may modulate its immunological potential. Dietary intake of micronutrients, fermentable fibers, and fermented foods also appears to play a role in shaping the milk’s protective properties. This review discusses the molecular mechanisms by which selected milk components contribute to the defense against protozoan infections in early life and considers how maternal health and lifestyle may affect the effectiveness of these protective mechanisms. 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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20 pages, 6354 KiB

Open AccessArticle

Cloning and Functional Characterization of a Novel Brevinin-1-Type Peptide from Sylvirana guentheri with Anticancer Activity

by Huyen Thi La, Quynh Bach Thi Nhu, Hai Manh Tran, Huyen Thi Ngo, Phuc Minh Thi Le, Hanh Hong Hoang, Linh Trong Nguyen, Dat Tien Nguyen and Thanh Quang Ta

Curr. Issues Mol. Biol. 2025, 47(8), 673; https://doi.org/10.3390/cimb47080673 - 20 Aug 2025

Abstract

Despite significant medical advancements, two major health challenges persist: antibiotic resistance in microbial pathogens and drug resistance in cancer cells. To address these issues, research has increasingly focused on discovering novel natural compounds with dual antimicrobial and anticancer activities. Among such candidates, antimicrobial [...] Read more.

Despite significant medical advancements, two major health challenges persist: antibiotic resistance in microbial pathogens and drug resistance in cancer cells. To address these issues, research has increasingly focused on discovering novel natural compounds with dual antimicrobial and anticancer activities. Among such candidates, antimicrobial peptides (AMPs) have attracted attention due to their ability to selectively target microbial and cancer cells while exhibiting minimal toxicity toward normal cells. Although Vietnam possesses rich biodiversity, including a wide range of Anura species, studies on AMPs from these organisms remain limited. In this study, a novel AMP, brevinin-1 E8.13, was identified from the skin secretion of Sylvirana guentheri, a frog species native to Vietnam. The brevinin-1 E8.13 peptide was successfully cloned, sequenced, and chemically synthesized. Functional assays revealed that brevinin-1 E8.13 possesses strong antibacterial activity against Staphylococcus aureus and exerts significant antiproliferative effects on various human cancer cell lines, including A549 (lung), AGS (gastric), Jurkat (leukemia), HCT116 (colorectal), HL60 (leukemia), and HepG2 (liver). The peptide demonstrated moderate to potent cytotoxic activity, with IC₅₀ values ranging from 7.5 to 14.8 μM, depending on the cell type. Notably, brevinin-1 E8.13 exhibited low cytotoxicity toward normal human dermal fibroblast (HDF) cells and even promoted cell proliferation at lower concentrations. Furthermore, Chemically Activated Fluorescent Expression (CAFLUX) bioassay results confirmed that the peptide significantly downregulated Cyp1a1 gene expression in HepG2 cells. Collectively, these findings highlight the therapeutic potential of brevinin-1 E8.13 as a dual-function antimicrobial and anticancer agent derived from the skin secretion of Sylvirana guentheri. Full article

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

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21 pages, 1385 KiB

Open AccessReview

Mistletoe in Cancer Cell Biology: Recent Advances

by Chang-Eui Hong and Su-Yun Lyu

Curr. Issues Mol. Biol. 2025, 47(8), 672; https://doi.org/10.3390/cimb47080672 - 20 Aug 2025

Abstract

Mistletoe (Viscum album L.) has been used in complementary cancer therapy for decades, but its mechanisms remained poorly understood until recently. This review synthesizes transformative advances in mistletoe cancer research from 2020 to 2025, focusing on newly discovered molecular mechanisms, immunomodulatory properties, [...] Read more.

Mistletoe (Viscum album L.) has been used in complementary cancer therapy for decades, but its mechanisms remained poorly understood until recently. This review synthesizes transformative advances in mistletoe cancer research from 2020 to 2025, focusing on newly discovered molecular mechanisms, immunomodulatory properties, and clinical applications. We conducted a comprehensive analysis of controlled studies, mechanistic investigations, and real-world evidence published between 2020 and 2025. The discovery of mistletoe-induced immunogenic cell death (ICD) represents a paradigm shift in understanding its anticancer effects. Mistletoe extracts trigger endoplasmic reticulum stress, leading to calreticulin exposure in 18–51% of cancer cells and a 7-fold increase in adenosine triphosphate (ATP) release. Three-dimensional culture models revealed enhanced macrophage reprogramming effects, with a 15.8% increase in pro-inflammatory interleukin (IL)-6 and a 26.4% reduction in immunosuppressive IL-10. Real-world evidence from over 400 non-small-cell lung cancer patients shows that combining mistletoe with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors doubles median overall survival (6.8 to 13.8 months), with biomarker-selected populations experiencing up to a 91.2% reduction in death risk. The Johns Hopkins Phase I trial established intravenous administration safety at 600 mg three times weekly. Advanced analytical approaches including metabolomics, chronobiology, and machine learning are enabling precision medicine applications. These findings position mistletoe as a scientifically validated component of integrative oncology, bridging traditional medicine with evidence-based cancer care. Future research should focus on ferroptosis mechanisms, single-cell immune profiling, and standardized clinical protocols. Full article

(This article belongs to the Special Issue Phytochemicals in Cancer Chemoprevention and Treatment: 2nd Edition)

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16 pages, 14697 KiB

Open AccessArticle

Comparative Study of Reprogramming Efficiency and Regulatory Mechanisms of Placental- and Fibroblast-Derived Induced Pluripotent Stem Cells (iPSCs) in Mules

by Fangyuan Liu, Jia Zhang, Lingyu Kong, Rihan Wu, Qiqi Jiang, Ying Lu and Xihe Li

Curr. Issues Mol. Biol. 2025, 47(8), 671; https://doi.org/10.3390/cimb47080671 - 19 Aug 2025

Abstract

As an interspecies hybrid inheriting genetic material from horse and donkey lineages, mules provide a unique model for studying allele-specific regulatory dynamics. Here, we isolated adult fibroblasts (AFs) and placental fibroblasts (PFs) from mule tissues and reprogrammed them into induced pluripotent stem cells [...] Read more.

As an interspecies hybrid inheriting genetic material from horse and donkey lineages, mules provide a unique model for studying allele-specific regulatory dynamics. Here, we isolated adult fibroblasts (AFs) and placental fibroblasts (PFs) from mule tissues and reprogrammed them into induced pluripotent stem cells (iPSCs). Intriguingly, placental fibroblast-derived iPSCs (mpiPSCs) exhibited reduced reprogramming efficiency compared to adult fibroblast-derived iPSCs (maiPSCs). Through allele-specific expression (ASE) analysis, we systematically dissected transcriptional biases in parental cell types and their reprogrammed counterparts, revealing conserved preferential expression of asinine alleles in core pluripotency regulators (e.g., POU5F1/OCT4, SOX2, NANOG) across both cell lineages. Strikingly, mpiPSCs displayed stronger asinine allele dominance than maiPSCs, suggesting tissue-specific parental genomic imprinting. Mechanistic exploration implicated PI3K-AKT signaling as a potential pathway mediating the reprogramming inefficiency in placental fibroblasts. By integrating transcriptomic profiling with ASE technology, this study uncovers allele selection hierarchies during somatic cell reprogramming in hybrids and establishes a framework for understanding how parental genomic conflicts shape pluripotency establishment. These findings advance interspecies iPSC research by delineating allele-specific regulatory networks and providing insights into the molecular constraints of hybrid cellular reprogramming. Full article

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

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17 pages, 4429 KiB

Open AccessArticle

Bioinformatic Analysis of the Value of Mitophagy and Immune Responses in Corneal Endothelial Dysfunction

by Ruilin Guo, Chenjia Xu, Yi Yu, Minglu Ma, Xiaojuan Dong, Jing Wu, Chen Ouyang, Jie Ling and Ting Huang

Curr. Issues Mol. Biol. 2025, 47(8), 670; https://doi.org/10.3390/cimb47080670 - 19 Aug 2025

Abstract

This study was conducted to elucidate the mitophagy-related differentially expressed genes (MRDEGs) in corneal endothelial dysfunction (CED) and to identify key hub genes that could provide insights into the disease pathogenesis and potential targeted therapies. To achieve this, CED models were established in [...] Read more.

This study was conducted to elucidate the mitophagy-related differentially expressed genes (MRDEGs) in corneal endothelial dysfunction (CED) and to identify key hub genes that could provide insights into the disease pathogenesis and potential targeted therapies. To achieve this, CED models were established in female SD rats, and RNA sequencing of coronal endothelium samples was conducted to generate a self-testing dataset. Comprehensive bioinformatics analyses were executed, which included the identification of differentially expressed genes (DEGs), GO and KEGG enrichment analyses, GSEA, and GSVA. A protein–protein interaction (PPI) network was constructed to identify highly interconnected hub genes, followed by the construction of ROC curves to validate MRDEGs within the dataset, alongside qRT-PCR assays. Our findings revealed a total of 18,511 DEGs, among which 20 genes were characterized as MRDEGs. Enrichment analyses indicated significant associations with monocyte differentiation and lymphocyte proliferation. Importantly, eight hub genes emerged from the PPI network as promising therapeutic targets. In conclusion, this study underscores the important role of MRDEGs and immune infiltration in CED, laying the groundwork for future investigations into targeted therapies for this disease. Full article

(This article belongs to the Section Molecular Medicine)

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2 pages, 436 KiB

Open AccessCorrection

Correction: Kardaş et al. Gallic Acid Protects from Sepsis-Induced Acute Lung Injury. Curr. Issues Mol. Biol. 2024, 46, 1–10

by Süleyman Kardaş, Osman Sezer Çınaroğlu, Ejder Saylav Bora and Oytun Erbaş

Curr. Issues Mol. Biol. 2025, 47(8), 669; https://doi.org/10.3390/cimb47080669 - 19 Aug 2025

Abstract

In the original publication [...] Full article

(This article belongs to the Section Molecular Medicine)

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22 pages, 9229 KiB

Open AccessArticle

Brassinosteroid Coordinates with ROS, Auxin and Gibberellin to Promote Mesocotyl Elongation and Deep-Sowing Tolerance in Maize

by Yahui Wang, Ying Li, Yuze Ma, Xiaolin Wu, Wei Wang, Hui Liu and Xiaoming Li

Curr. Issues Mol. Biol. 2025, 47(8), 668; https://doi.org/10.3390/cimb47080668 - 18 Aug 2025

Abstract

Mesocotyl elongation is the key determinant of deep-sowing tolerance in maize. Sowing at an appropriate depth allows the seedling to exploit water and nutrients stored in deeper soil layers, thereby enhancing its ability to withstand drought and other abiotic stresses. Mesocotyl elongation is [...] Read more.

Mesocotyl elongation is the key determinant of deep-sowing tolerance in maize. Sowing at an appropriate depth allows the seedling to exploit water and nutrients stored in deeper soil layers, thereby enhancing its ability to withstand drought and other abiotic stresses. Mesocotyl elongation is regulated by the phytohormones brassinosteroid (BR), auxin (IAA), gibberellin (GA), and reactive oxygen species (ROS). However, whether and how BR coordinates IAA, GA, and ROS to control mesocotyl elongation in maize remains unclear. Here, we demonstrated that BRs orchestrate ROS, IAA, and GA signaling to remodel cell-wall metabolism in mesocotyl cells, promote cell elongation, and, consequently, strengthen deep-sowing tolerance. BR promoted mesocotyl elongation through multiple routes: (1) decreasing the contents of cell-wall components (hemicellulose, cellulose, and pectin); (2) activating cell-wall-loosening enzymes (cellulase, pectinase, and acidic xylanase); and (3) disturbing ROS homeostasis by elevating superoxide dismutase (SOD) activity. Combined treatments of BR with either IAA or GA further enhanced mesocotyl elongation in a concentration-dependent manner. In deep-sowing trials (15 cm), application of BR alone or in combination with IAA or GA markedly increased mesocotyl length and emergence rate, thereby improving deep-sowing tolerance. Our work indicated that BR integrated ROS, IAA, and GA signals to restructure the cell wall and derived mesocotyl cell elongation, providing both theoretical insights and practical strategies for breeding maize varieties with enhanced deep-sowing tolerance. Full article

(This article belongs to the Special Issue Plant Hormones, Development, and Stress Tolerance)

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23 pages, 3101 KiB

Open AccessReview

Hydroxytyrosol and Brain Tumors: Mechanisms of Action and Therapeutic Potential

by Cristina Cueto-Ureña, María Jesús Ramírez-Expósito, María Pilar Carrera-González and José Manuel Martínez-Martos

Curr. Issues Mol. Biol. 2025, 47(8), 667; https://doi.org/10.3390/cimb47080667 - 18 Aug 2025

Abstract

Central nervous system (CNS) tumors, especially gliomas and IDH-wildtype glioblastoma, present high aggressiveness, low response to current treatments and limited survival. Several biological processes such as oxidative stress, inflammation, apoptosis, and autophagy are involved in their development. Hydroxytyrosol (HTX), a phenolic compound present [...] Read more.

Central nervous system (CNS) tumors, especially gliomas and IDH-wildtype glioblastoma, present high aggressiveness, low response to current treatments and limited survival. Several biological processes such as oxidative stress, inflammation, apoptosis, and autophagy are involved in their development. Hydroxytyrosol (HTX), a phenolic compound present in olives, has shown relevant effects on these processes in experimental models. This review analyzes its chemical characteristics, bioavailability, and ability to cross the blood–brain barrier, as well as its mechanisms of action. Despite its rapid metabolism, HTX can reach the brain in small but functional amounts, and various formulation methods can enhance its delivery to nervous tissue. HTX acts on cellular pathways such as Nrf2, NF-κB, JAK/STAT, PI3K/Akt and SIRT1, regulating redox balance, inflammation, programmed cell death, and autophagy. It can also influence gene expression through epigenetic mechanisms. In cell models, it has shown inhibitory effects on tumor growth and activation of apoptosis, without affecting non-tumor cells. These results support its possible usefulness as an adjunct in the treatment of brain tumors, although further studies in animal and human models are required. Full article

(This article belongs to the Special Issue The Green Revolution in Cancer Research: Bioactive Substances from Plants as Promising Therapeutics)

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23 pages, 32109 KiB

Open AccessArticle

K-562 Extracellular Vesicles Partially Protect Intact Cells from Oxidative Stress and Provide Limited Resistance to Imatinib

by Jiana Sbiet, Einat Beery, Zinab Sarsor, Pia Raanani and Orit Uziel

Curr. Issues Mol. Biol. 2025, 47(8), 666; https://doi.org/10.3390/cimb47080666 - 18 Aug 2025

Abstract

Chronic myeloid leukemia (CML) results from the formation of the BCR-ABL1 chimeric protein which serves as a target for clinically used tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM). Although very efficient, the development of resistance to TKIs remains a critical issue [...] Read more.

Chronic myeloid leukemia (CML) results from the formation of the BCR-ABL1 chimeric protein which serves as a target for clinically used tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM). Although very efficient, the development of resistance to TKIs remains a critical issue for a subset of patients. In our study we aimed to identify one aspect of IM resistance in K-562 cells, a cell line used as a model for CML. Secreted from all cell types, extracellular vesicles (EVs) are nanoparticles that function as mediators of cell–cell communication. Upon engulfment by other cells they may modulate their phenotype. IM is linked to changes in oxidative metabolism in K-562 cells. Our study explored the putative involvement of EVs secreted from K-562 cells in providing protection from oxidative stress and resistance to IM in these cells. The results of our study showed that the protection from oxidative stress provided by previously exposed K-562 cell, derived EVs is only partial. Similarly, these EVs provided intact K-562 cells with some resistance to IM treatment. These results may suggest that resistance to IM may develop and expand to other cells by EVs that are secreted from already resistant cells, similar to a horizontal transfer of resistance provided by plasmids in bacteria. Full article

(This article belongs to the Special Issue Molecular Insights and Therapeutic Advances in Hematological Disorders)

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9 pages, 1106 KiB

Open AccessCommunication

PRMT5 Inhibition as a Potential Strategy for KRAS Mutant CRC: Downstream Mediators of the PRMT5–KRAS Crosstalk

by Mark Spivak, Moshe Pahmer, Dorna Delrahimnia, Tzuriel Sapir and David Shifteh

Curr. Issues Mol. Biol. 2025, 47(8), 665; https://doi.org/10.3390/cimb47080665 - 18 Aug 2025

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide with KRAS mutations present in nearly 45% of cases. Compared to KRAS wild-type (WT) CRC, KRAS-mutant CRC is associated with poorer prognosis and fewer effective treatment options. Protein Arginine Methyltransferase 5 (PRMT5), [...] Read more.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide with KRAS mutations present in nearly 45% of cases. Compared to KRAS wild-type (WT) CRC, KRAS-mutant CRC is associated with poorer prognosis and fewer effective treatment options. Protein Arginine Methyltransferase 5 (PRMT5), an epigenetic regulator involved in diverse cellular processes, is currently under investigation as a therapeutic target in multiple cancer types. Our previous work demonstrated that PRMT5 inhibition produces stronger therapeutic effects in KRAS-mutant CRC cells than in KRAS WT cells, suggesting potential crosstalk between PRMT5 and KRAS. In this study, we aimed to identify key downstream proteins that may mediate this interaction. Through a literature review, protein–protein interaction analysis (STRING database), gene expression analysis (GEPIA database), and correlation analysis (GEPIA database), we identified MYC, E2F1, and EIF4E as critical candidates. These proteins are shown to interact with both PRMT5 and KRAS in STRING, are overexpressed in CRC tumor samples, and show positive gene expression correlations with PRMT5 and KRAS in patient data. These findings are significant, as they provide new insights into the PRMT5–KRAS crosstalk and suggest potential targets for novel and combination therapies in KRAS-mutant CRC. Further research and biological experiments are needed to verify and outline the exact molecular processes behind MYC, E2F1, and EIF4E’s interactions with both PRMT5 and KRAS. Full article

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

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25 pages, 868 KiB

Open AccessReview

Circadian Rhythm Disruptions and Cardiovascular Disease Risk: The Special Role of Melatonin

by Jarosław Nuszkiewicz, Wojciech Rzepka, Julia Markiel, Marta Porzych, Alina Woźniak and Karolina Szewczyk-Golec

Curr. Issues Mol. Biol. 2025, 47(8), 664; https://doi.org/10.3390/cimb47080664 - 17 Aug 2025

Abstract

Circadian rhythms are endogenous biological cycles that regulate essential cardiovascular functions, including blood pressure, heart rate, vascular tone, and metabolic homeostasis. Disruption of these rhythms due to factors such as shift work, artificial light at night, irregular sleep–wake cycles, or mistimed eating has [...] Read more.

Circadian rhythms are endogenous biological cycles that regulate essential cardiovascular functions, including blood pressure, heart rate, vascular tone, and metabolic homeostasis. Disruption of these rhythms due to factors such as shift work, artificial light at night, irregular sleep–wake cycles, or mistimed eating has been increasingly recognized as an independent risk factor for cardiovascular disease. A growing body of evidence links circadian misalignment to key pathophysiological mechanisms, including endothelial dysfunction, oxidative stress, inflammation, and autonomic imbalance. Melatonin, a hormone produced primarily by the pineal gland, plays a central role in circadian regulation and exhibits potent antioxidant, anti-inflammatory, and cardiometabolic properties. This narrative review synthesizes current findings on the interplay between circadian disruption and cardiovascular risk, with a particular emphasis on the mechanistic and therapeutic role of melatonin. We also highlight the potential of chronotherapeutic strategies, such as timed melatonin supplementation, antihypertensive dosing, and time-restricted eating, to restore circadian alignment and improve cardiovascular outcomes. Despite promising data, translation into clinical practice remains limited. Future research should focus on identifying practical circadian biomarkers, refining chronotherapy protocols, and integrating circadian variables into risk models and clinical workflows. Full article

(This article belongs to the Special Issue Effects of Environmental Factors on Cardiovascular Disease: From Molecular Effects to Possible Future Clinic Application)

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22 pages, 1654 KiB

Open AccessArticle

Astaxanthin Attenuates Chlorpyrifos-Induced Pulmonary Cytotoxicity by Modulating Mitochondrial Redox and Inflammatory Pathways

by Mediha Demet Okudan Altındaş and Adem Güner

Curr. Issues Mol. Biol. 2025, 47(8), 663; https://doi.org/10.3390/cimb47080663 - 17 Aug 2025

Abstract

Chlorpyrifos (CPF), an organophosphate pesticide, is known to induce pulmonary toxicity through oxidative stress, mitochondrial dysfunction, and inflammation. Astaxanthin (ASX), a xanthophyll carotenoid derived primarily from marine microalgae (Haematococcus pluvialis), possesses strong antioxidant properties and has demonstrated cellular protective effects in numerous oxidative [...] Read more.

Chlorpyrifos (CPF), an organophosphate pesticide, is known to induce pulmonary toxicity through oxidative stress, mitochondrial dysfunction, and inflammation. Astaxanthin (ASX), a xanthophyll carotenoid derived primarily from marine microalgae (Haematococcus pluvialis), possesses strong antioxidant properties and has demonstrated cellular protective effects in numerous oxidative stress studies. However, its efficacy against CPF-induced lung cell damage remains uncharacterized. This study revealed the protective role of ASX, as a pretreatment and co-treatment, against CPF-induced cytotoxicity in human A549 lung adenocarcinoma cells by assessing cell viability, intracellular reactive oxygen species (IROS), total oxidative status (TOS), total antioxidant capacity (TAC), mitochondrial membrane potential (MMP), intracellular calcium ions (Ca²⁺), lactate dehydrogenase (LDH) release, malondialdehyde (MDA) levels, glutathione peroxidase (GPx) activity, superoxide dismutase (SOD) activity, DNA fragmentation, and apoptosis/inflammation-associated gene expression. CPF treatment significantly decreased cell viability and TAC, while elevating IROS, TOS, MMP, intracellular Ca²⁺, and LDH release. CPF also increased MDA levels and suppressed GPx and SOD activities. DNA fragmentation and quantitative polymerase chain reaction (qPCR) analysis revealed upregulation of pro-apoptotic and inflammatory markers such as BCL2-associated X protein (BAX), caspase-3 (CASP3), tumor protein p53 (TP53), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), nuclear factor kappa B (NFκB), and voltage-dependent anion-selective channel protein 1 (VDAC1) and suppression of anti-apoptotic B-cell lymphoma 2 (BCL2) and antioxidant defense genes nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). ASX treatment, particularly when administered as a pretreatment, significantly reversed CPF-induced oxidative and inflammatory responses by restoring SOD, GPx, and TAC levels, reducing IROS, TOS, MDA, and LDH release, and downregulating apoptotic and inflammatory gene expressions. ASX pretreatment notably decreased MMP and intracellular Ca²⁺ levels, indicating protection against mitochondrial dysfunction and calcium dysregulation. ASX upregulated Nrf2 and HO-1 expression and restored the BCL2/BAX balance, suggesting inhibition of mitochondrial-mediated apoptosis. Additionally, ASX significantly attenuated CPF-induced anti-angiogenic effects in the in ovo Hen’s Egg Test Chorioallantoic Membrane (HET-CAM) assay. These findings demonstrate, for the first time, that ASX exerts a broad spectrum of protective effects against CPF-induced cytotoxicity in lung cells, mainly through the stabilization of mitochondrial redox status and modulation of apoptosis- and inflammation-related gene pathways, highlighting ASX as a promising candidate for further therapeutic development. Furthermore, the pronounced efficacy observed in the pretreatment regimen suggests that ASX can be evaluated as a potential nutritional preventive strategy in high-risk populations with occupational or environmental CPF exposure. 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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21 pages, 1395 KiB

Open AccessArticle

Unlocking the Anti-Breast Cancer Potential of Aralia chinensis L.

by Juan Xue, Lei Li, Yongjia Shu, Chengshi Xie, Tian Lu and Huifang Chai

Curr. Issues Mol. Biol. 2025, 47(8), 662; https://doi.org/10.3390/cimb47080662 - 16 Aug 2025

Abstract

Aralia chinensis L. has shown potential in breast cancer treatment, yet its pharmacodynamically active components and mechanisms remain undefined. To systematically identify the bioactive constituents absorbed into the bloodstream and elucidate their multi-target mechanisms against breast cancer, we employed ultra-high-performance liquid chromatography in [...] Read more.

Aralia chinensis L. has shown potential in breast cancer treatment, yet its pharmacodynamically active components and mechanisms remain undefined. To systematically identify the bioactive constituents absorbed into the bloodstream and elucidate their multi-target mechanisms against breast cancer, we employed ultra-high-performance liquid chromatography in conjunction with Q Exactive Orbitrap mass spectrometry (UHPLC-Q Exactive Orbitrap-MS) alongside serum pharmacochemistry to analyze the chemical constituents of total saponins derived from A. chinensis (TSAC) and to identify the blood-absorbed prototypes in a rat model. Network pharmacology predicted targets and pathways of serum prototypes, validated by molecular docking and in vitro experiments. We identified 38 triterpenoid saponins, 3 steroidal saponins, and 8 triterpenoids in TSAC, with 22 prototype compounds detected in serum. An integrative analysis encompassing 486 compound targets and 1747 genes associated with breast cancer elucidated critical pathways, notably the PI3K-Akt signaling pathway and resistance mechanisms to EGFR tyrosine kinase inhibitors. Molecular docking confirmed strong binding of araloside A and elatoside L to SRC, PIK3R1, PIK3CA, STAT3, and EGFR. In MCF-7 cells, TSAC suppressed proliferation and migration while downregulating Src, PI3K, and EGFR expression at the gene and protein levels. This study successfully identified TSAC’s serum-absorbed bioactive components and demonstrated their anti-breast cancer effects via multi-target mechanisms involving the Src/PI3K/EGFR axis, providing a crucial pharmacological foundation for developing A. chinensis-derived breast cancer therapies. Full article

(This article belongs to the Special Issue Natural Compounds: An Adjuvant Strategy in Cancer Management)

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19 pages, 3962 KiB

Open AccessArticle

Potential of Alkaloids from Zanthoxylum nitidum var. tomentosum in Treating Rat Rheumatoid Arthritis Model and Validation of Molecular Mechanisms

by Yuanle Shen, Linghui Zou, Yinggang Zeng, Ting Xia, Zhenjie Liu, Kaili Hu, Liuping Wang and Jianfang Feng

Curr. Issues Mol. Biol. 2025, 47(8), 661; https://doi.org/10.3390/cimb47080661 - 15 Aug 2025

Abstract

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by synovial hyperplasia and joint destruction. Previous studies have demonstrated that the alkaloids of Rushanhu (ARSHs), the dried root and stem of Zanthoxylum nitidum var. tomentosum, exhibit favorable therapeutic effects on RA, and [...] Read more.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by synovial hyperplasia and joint destruction. Previous studies have demonstrated that the alkaloids of Rushanhu (ARSHs), the dried root and stem of Zanthoxylum nitidum var. tomentosum, exhibit favorable therapeutic effects on RA, and this study aims to investigate the underlying molecular mechanisms involved. Methods: A complete Freund’s adjuvant (CFA)-induced arthritis model in male SD rats (n = 64) was used to evaluate ARSHs. Groups included control, model, methotrexate (MTX), and ARSH-treated. Therapeutic effects were assessed via arthritis index, paw swelling, and serum cytokines (IL-1β, IL-6, IL-17A). Network pharmacology identified bioactive alkaloids and core targets, validated by molecular docking. In vitro mechanisms (proliferation, apoptosis, signaling pathways) were examined in MH7A synovial cells. Results: ARSHs significantly attenuated joint inflammation and damage in CFA rats (* p < 0.01 vs. model), reducing pro-inflammatory cytokines. Fifteen alkaloids (e.g., dihydrochelerythrine, magnoflorine) and 24 targets (e.g., SRC, STAT3, MAPK3) were prioritized. Molecular docking confirmed strong binding (binding energy < −7.0 kcal/mol). In vitro, ARSHs suppressed MH7A proliferation and induced apoptosis via Bcl-2/Bax dysregulation and the inhibition of SRC/STAT3/MAPK3 phosphorylation. Conclusions: ARSHs mitigate RA pathogenesis by targeting the SRC/STAT3/MAPK3 signaling axis in synovial cells. This study provides mechanistic validation of ARSHs as multi-target phytotherapeutic agents against inflammatory arthritis. Full article

(This article belongs to the Special Issue Therapeutic Effects of Natural Bioactive Compounds in the Management of Human Diseases)

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10 pages, 2923 KiB

Open AccessCase Report

Partial Remission Without Recurrence in a 9-Year-Old Golden Retriever with Nasal Carcinoma Treated with Prednisolone/Chlorambucil Metronomic Combination Therapy: A Case Report and Literature Review of Molecular Mechanisms

by Kyuhyung Choi

Curr. Issues Mol. Biol. 2025, 47(8), 660; https://doi.org/10.3390/cimb47080660 - 15 Aug 2025

Abstract

This paper reports the first case in which a hyperlipidemic retriever (due to hypothyroidism) with a nasal tumor was successfully treated—achieving partial remission—and managed using a metronomic combination of chlorambucil (3.74 mg/m², SID) and prednisolone (0.28 mg/kg, SID) orally for 9 [...] Read more.

This paper reports the first case in which a hyperlipidemic retriever (due to hypothyroidism) with a nasal tumor was successfully treated—achieving partial remission—and managed using a metronomic combination of chlorambucil (3.74 mg/m², SID) and prednisolone (0.28 mg/kg, SID) orally for 9 months at a general practice. A 35 kg spayed female golden retriever aged 8 years and 8 months with nosebleeds visited the Bundang New York Animal Hospital in July 2023 after being diagnosed with nasal carcinoma. A protocol of 4 weeks of chemotherapy followed by 1 week of rest was repeated in two cycles and continued metronomically for 9 months without pause after the two cycles. The nasal exudate was significantly reduced. The size of the nasal tumor was monitored using computed tomography (CT) imaging at a referral hospital. Since the first occurrence of epistaxis, 18 months have passed (as of January 2025) and the nasal exudate is barely visible, and the vital signs and weight of the dog remain stable. The size of the nasal tumor significantly decreased after 9 months of chemotherapy completion without moderate side effects, and all the blood work was normalized, including hypercholesteremia. This study demonstrates that, in hyperlipidemic cancer patients, a prednisolone/chlorambucil metronomic combination which is cost-effective can be an alternative to tyrosine kinase inhibitors such as sorafenib, even when excluding the price. Through a literature review, the author also investigates the effect of the hyperlipidemic state on cancer, focusing on carcinoma and vascular endothelial growth factor (VEGF), as well as the RAS-RAF-MEK pathway, which is a target for tyrosine kinase inhibitors, in order to reveal the molecular mechanism of chlorambucil metronomic chemotherapy. Also, the author investigates the molecular pathway of carcinoma development in human hyperlipidemia patients through single-cell RNA sequence analysis using open public data, and discusses the molecular action of chlorambucil. Full article

(This article belongs to the Section Molecular Medicine)

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28 pages, 1195 KiB

Open AccessReview

Targeting Intracellular Pathways in Atopic Dermatitis with Small Molecule Therapeutics

by Georgiana Nitulescu, Octavian Tudorel Olaru, Corina Andrei, George Mihai Nitulescu and Anca Zanfirescu

Curr. Issues Mol. Biol. 2025, 47(8), 659; https://doi.org/10.3390/cimb47080659 - 15 Aug 2025

Abstract

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder characterized by immune dysregulation and epidermal barrier dysfunction. Advances in understanding the interplay of genetic predisposition, cytokine signaling, and environmental triggers have led to the emergence of targeted therapies. Although biologic agents such [...] Read more.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder characterized by immune dysregulation and epidermal barrier dysfunction. Advances in understanding the interplay of genetic predisposition, cytokine signaling, and environmental triggers have led to the emergence of targeted therapies. Although biologic agents such as dupilumab, tralokinumab, and lebrikizumab have revolutionized AD management, their high costs, injectable administration, and limited global accessibility highlight the need for alternative options. Small molecule therapies are gaining momentum as they target intracellular pathways central to AD pathogenesis and offer oral or topical administration routes. This review provides a comprehensive analysis of key agents including Janus kinase (JAK) inhibitors (upadacitinib, abrocitinib, baricitinib, ruxolitinib, delgocitinib), phosphodiesterase 4 (PDE4) inhibitors (crisaborole, difamilast, roflumilast, apremilast), as well as STAT6 degraders (KT621, NX3911), aryl hydrocarbon receptor modulators, histamine H4 receptor antagonists (adriforant, izuforant), and sphingosine-1-phosphate receptor modulators (etrasimod, BMS-986166). We summarize their mechanisms of action, pharmacological profiles, and pivotal clinical trial data, emphasizing their potential to address unmet therapeutic needs. Finally, we discuss safety concerns, long-term tolerability, and future directions for integrating small molecule therapies into precision treatment strategies for moderate-to-severe AD. Full article

(This article belongs to the Special Issue Novel Drugs and Natural Products Discovery)

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26 pages, 5444 KiB

Open AccessArticle

Exploring Novel Inhibitory Compounds Against Phosphatase Gamma 2: A Therapeutic Target for Male Contraceptives

by Hashim M. Aljohani, Bayan T. Bokhari, Alaa M. Saleh, Areej Yahya Alyahyawi, Renad M. Alhamawi, Mariam M. Jaddah, Mohammad A. Alobaidy and Alaa Abdulaziz Eisa

Curr. Issues Mol. Biol. 2025, 47(8), 658; https://doi.org/10.3390/cimb47080658 - 15 Aug 2025

Abstract

Men have limited options for contraception, despite the widely accepted public health benefits of it, placing the contraceptive burden solely on women. The current study focuses on inhibiting the PP1γ2 enzyme, which plays a role in sperm maturation and motility. The study considered [...] Read more.

Men have limited options for contraception, despite the widely accepted public health benefits of it, placing the contraceptive burden solely on women. The current study focuses on inhibiting the PP1γ2 enzyme, which plays a role in sperm maturation and motility. The study considered three top compounds based on the findings of molecular docking. The three compounds exhibited a good interaction profile with a binding affinity score of D751-0223 (−8.7 kcal/mol), D751-014 (−8.1 kcal/mol), and N117-0087 (−8 kcal/mol) measured in kcal/mol. Molecular dynamics simulation (MDS) were performed on the PP1γ2–ligand complexes along with the Apo form. The results suggested that all the complexes were stable with no major deviations observed compared to Apo. The average RMSDs for PP1γ2-D751-0223, D751-014, and Apo were 1.27 Å, 1.73 Å, 1.39 Å, and 1.69 Å, respectively. The PP1γ2–ligand complexes were observed with unique salt bridge interactions such as Glu133-Arg137, Asp4-Lys107, Asp188-Arg116, and Glu120-Arg90. The principal component analysis (PCA) findings indicated that every complex had a distinctive motion state. Furthermore, the net MM/PBSA scores for D751-0223, D751-0143, and N117-0087 were −80.01 kcal/mol, −72.18 kcal/mol, and −64.26 kcal/mol, respectively, while the MM/GBSA and MM/PBSA values were −82, −73.07,−67.26 and −80.01, −72.18, −64.26, measured in kcal/mol, respectively. The WaterSwap energy estimation was performed to validate the former technique, and the findings demonstrated that PP1γ2-D751-0223 is a stable complex, with a value of −51.05 kcal/mol. This work provides a baseline to researchers for the identification of novel therapeutic approaches for non-hormonal male contraceptives. Full article

(This article belongs to the Special Issue Harnessing Genomic Data for Disease Understanding and Drug Discovery)

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19 pages, 1906 KiB

Open AccessReview

The Duodenum-Centered Neurohormonal Hypothesis of Type 2 Diabetes: A Mechanistic Review and Therapeutic Perspective

by Athena N. Kapralou, Christos Yapijakis and George P. Chrousos

Curr. Issues Mol. Biol. 2025, 47(8), 657; https://doi.org/10.3390/cimb47080657 - 14 Aug 2025

Abstract

Type 2 diabetes mellitus (T2DM) is a multifactorial disorder defined by insulin resistance, β-cell dysfunction, and chronic hyperglycemia. Although peripheral mechanisms have been extensively studied, increasing evidence implicates the gastrointestinal tract in disease onset. Insights from bariatric surgery, gut hormone signaling, and incretin-based [...] Read more.

Type 2 diabetes mellitus (T2DM) is a multifactorial disorder defined by insulin resistance, β-cell dysfunction, and chronic hyperglycemia. Although peripheral mechanisms have been extensively studied, increasing evidence implicates the gastrointestinal tract in disease onset. Insights from bariatric surgery, gut hormone signaling, and incretin-based therapies suggest that the gut contributes actively beyond nutrient absorption. Yet, a cohesive framework integrating these observations remains absent, leaving a critical gap in our understanding of T2DM’s upstream pathophysiology. This work builds upon the anti-incretin theory, which posits that nutrient-stimulated neurohormonal signals—termed “anti-incretins”—arise from the proximal intestine to counteract incretin effects and regulate glycemic homeostasis. The excess of anti-incretin signals, perhaps stimulated by macronutrient composition or chemical additives of modern diets, disrupts this balance and may cause insulin resistance and β-cell depletion, leading to T2D. We hypothesize that the neuroendocrine signals produced by cholecystokinin (CCK)-I and secretin-S cells, both located in the proximal intestine, function as endogenous anti-incretins. In this context, we hypothesize a novel model centered on the chronic overstimulation of I and S cells by high-fat, high glycemic index modern diets. This drives what we term “amplified digestion”—a state marked by heightened vagal and hormonal stimulation of biliary and pancreatic secretions, increased enzymatic and bile acid activity, and alterations in bile acid composition. This condition leads to an extended breakdown of carbohydrates, lipids, and proteins into absorbable units, thereby promoting excessive nutrient absorption and ultimately contributing to insulin resistance and progressive β-cell failure. Multiple lines of clinical, surgical, and experimental evidence converge to support our model, rooted in the physiology of digestion and absorption. Western dietary patterns appear to induce an over-digestive adaptation—marked by excessive vagal and hormonal stimulation of biliary and pancreatic secretion—which amplifies digestive signaling. This heightened state correlates with increased nutrient absorption, insulin resistance, and β-cell dysfunction. Interventions that disrupt this maladaptive signaling—such as truncal vagotomy combined with duodenal bypass—may offer novel, physiology-based strategies for T2DM treatment. This hypothesis outlines a potential upstream contributor to insulin resistance and T2DM, grounded in digestive tract-derived neurohormonal dysregulation. This gut-centered model may provide insight into early, potentially reversible stages of the disease and identify a conceptual therapeutic target. Nonetheless, both the hypothesis and the accompanying surgical strategy—truncal vagotomy combined with proximal intestinal bypass—remain highly exploratory and require systematic validation through mechanistic and clinical studies. Further investigation is warranted to clarify the molecular regulation of I and S enteroendocrine cells, including the genetic and epigenetic factors that may drive hypersecretion. While speculative, interventions—surgical or pharmacologic—designed to modulate these digestive signals could represent a future avenue for research into T2DM prevention or remission, pending rigorous evidence. Full article

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

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10 pages, 1645 KiB

Open AccessArticle

Molecular Characterization of Citrus Accessions Grown for Pre-Breeding Purposes

by Israel Felipe Gonçalves Soares, Felipe Cruz Paula, Conceição de Maria Batista Oliveira, José Dias de Souza Neto, Talles de Oliveira Santos, Rafael Nunes de Almeida, Ana Paula Candido Gabriel Berilli, Sávio da Silva Berilli, Taís Cristina Bastos Soares, Jardel Oliveira Santos, Alexandre Cristiano Santos Júnior and Monique Moreira Moulin

Curr. Issues Mol. Biol. 2025, 47(8), 656; https://doi.org/10.3390/cimb47080656 - 14 Aug 2025

Abstract

The objective of this work was to analyse the genetic diversity of a population of Citrus spp. in the south of the State of Espírito Santo, Brazil, for pre-breeding studies. For that, a total of sixty genotypes were analysed, including ten citrus varieties [...] Read more.

The objective of this work was to analyse the genetic diversity of a population of Citrus spp. in the south of the State of Espírito Santo, Brazil, for pre-breeding studies. For that, a total of sixty genotypes were analysed, including ten citrus varieties from four species of the Citrus genus. The methodology involved DNA extraction, amplification via polymerase chain reaction, and the use of a set of 16 Simple Sequence Repeat markers. These markers identified 42 alleles, with a variation of one to four alleles per locus, an average heterozygosity value of 0.53, and an average polymorphic information content of up to 0.29 per species. After the analysis, a dissimilarity matrix was generated using Jaccard distance and a dendrogram, revealing the formation of two groups: Group I, comprising Citrus sinensis varieties, and Group II, comprising varieties of Citrus latifolia, Citrus aurantifolia, and Citrus reticulata. Our study demonstrated that the combination of these markers allowed for the differentiation of genotypes within the collection. The results obtained are valuable for the future management of the collection and the efficient use of genetic diversity estimation in Citrus spp. Full article

(This article belongs to the Special Issue Molecular Breeding and Genetics Research in Plants, 2nd Edition)

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